Preface

Day after day, healthcare providers administer powerful drugs with a myriad of side effects. Local anesthetics are, by far, the drugs most used in daily clinical practice with the goal of producing optimal analgesia and anesthesia without patients losing control of their alertness, which is the greatest advantage of local anesthetics. Regional anesthesia has proven to be the technique of choice in patients with alterations of the immune system, for example, cancer patients, favoring a better short- and long-term recovery. These drugs have also been investigated as antimicrobials, anti-asthmatics, anti-inflammatories, anti-neoplastics, and anti-arrhythmics.

This book, *Topics in Local Anesthetics*, reviews and updates some basic and selected clinical applications of anesthetics, as well as examines the prevention and management of complications related to their use. The first three chapters discuss the aspects of pharmacokinetics and pharmacodynamics, especially the pharmacokinetics of bupivacaine in pregnant women. These aspects are essential to decrease the possibilities of systemic toxicity as well as effects on the fetus and the newborn. The use of adjuvant drugs dates back to the beginning of the last century and the advent of novel drugs has resulted in the prolongation of analgesia and regional anesthesia, as well as the reduction of toxic effects as it is possible to decrease the dosage of local anesthetics.

The safe use of these drugs requires knowledge of anatomy and the various techniques used to administer anesthetics, including topical, local, intravenous, endotracheal anesthesia, peripheral nerve blocks, interpleural, intra-articular, epidural, spinal, or a combination of any of these. The book reviews some of these techniques, with special emphasis on dentistry, maxillofacial surgery, and spinal anesthesia in ambulatory surgery. It also provides updated information on the effect of local anesthetics on the wound healing process, and their potential non-anesthetic uses. There is also a chapter dedicated to systemic toxicity.

As the editor, I want to thank my friend and co-editor Enrique Hernández-Cortez for his invaluable support to finish the book. I also wish to thank the authors and friends who contributed to this project.

Finally, it is my pleasure to thank my beloved wife Teresa for her love, patience, and support in the edition of this book, as well as my children and grandchildren, from whom I used much of their family time to finish this project.

**II**

**Chapter 9 151**

**Chapter 10 165**

Complications Associated with Local Anesthesia in Oral

*by Divya Garg, Shikha Soni and Rakesh Karnawat*

and Maxillofacial Surgery *by Basak Keskin Yalcin*

Local Anesthetic Systemic Toxicity

**Victor Whizar-Lugo** Associate Researcher at Institutos Nacionales de Salud, Lotus Medical Group, Tijuana BC, México

> **Enrique Hernández-Cortez** Instituto Mexicano del Seguro Social, León, México

**1**

**Chapter 1**

**Abstract**

Local Anesthetics

described and are briefly reviewed.

subarachnoid, and intravenous anesthesia.

**1. Introduction**

**Keywords:** local anesthetics, pharmacology, toxicity

*Víctor M. Whizar-Lugo, Karen L. Íñiguez-López,* 

*Ana C. Cárdenas-Maytorena and Cristian D. Ramírez-Puerta*

The fascinating history of local anesthetics (LAs) began in South America with the herbal and traditional use of cocaine leaves by the indigenous peoples of Peru and Bolivia, the sacred plant of the Incas *Erythroxylum coca*. The use for anesthetic purposes dates back to 1884. Since then, the evolution of LAs has been closely related to research motivated by its efficacy and safety versus toxicity. According to their chemical structure, these drugs are classified into two main groups: esters and amino amides; however, there are three LAs with different characteristics: articaine, sameridine, and centbucridine. The pharmacological and toxic mode of action is primarily in the voltage-dependent sodium channels located in the cell membrane, which clinically produces analgesia, anesthesia, seizures, arrhythmias, and cardiac arrest. The quality of anesthesia and analgesia depends on the type of LA, dose, and application technique, while the deleterious effects are secondary to its plasma concentration. Nonanesthetic properties of LAs such as their antimicrobial, antineoplastic, antiarrhythmics, antitussive, and antiasthmatics effects have been

Local anesthetics (LAs) are drugs commonly used in medicine and especially in anesthesiology, which when administered in the vicinity of peripheral neural tissue produce changes in the conformation of voltage-dependent sodium channels that depolarize the neural tissue and produce analgesia, anesthesia, and sympathetic and motor block in the dermatomes of the affected nerves without altering consciousness. This inhibitory phenomenon is reversible and transitory and is known as regional anesthesia and is classified into local, peripheral nerves, nervous plexuses, peridural,

LAs are safe and effective drugs, although when wrongly managed, they can reach

high plasma concentrations and produce systemic toxicity (LAST) that manifests primarily in the central nervous system (CNS) and cardiovascular system (CVS), causing side effects that can occasionally lead to death. Local neuro toxicity has also been described when injected in the vicinity of the peripheral nervous system or at

subarachnoid or epidural space. Myotoxic effects have also been described. The main clinical use of LAs is to achieve pain insensitivity, although they have other pharmacological uses such as antiarrhythmic, anti-asthmatic, antiinflammatory, antithrombotic, bacteriostatic, and bactericidal effects that have been demonstrated, as well as antitumoral agent enhancer activity [1–3]. LAs are grouped into two categories: those of the ester type and those of the amino-amide

#### **Chapter 1**

## Local Anesthetics

*Víctor M. Whizar-Lugo, Karen L. Íñiguez-López, Ana C. Cárdenas-Maytorena and Cristian D. Ramírez-Puerta*

#### **Abstract**

The fascinating history of local anesthetics (LAs) began in South America with the herbal and traditional use of cocaine leaves by the indigenous peoples of Peru and Bolivia, the sacred plant of the Incas *Erythroxylum coca*. The use for anesthetic purposes dates back to 1884. Since then, the evolution of LAs has been closely related to research motivated by its efficacy and safety versus toxicity. According to their chemical structure, these drugs are classified into two main groups: esters and amino amides; however, there are three LAs with different characteristics: articaine, sameridine, and centbucridine. The pharmacological and toxic mode of action is primarily in the voltage-dependent sodium channels located in the cell membrane, which clinically produces analgesia, anesthesia, seizures, arrhythmias, and cardiac arrest. The quality of anesthesia and analgesia depends on the type of LA, dose, and application technique, while the deleterious effects are secondary to its plasma concentration. Nonanesthetic properties of LAs such as their antimicrobial, antineoplastic, antiarrhythmics, antitussive, and antiasthmatics effects have been described and are briefly reviewed.

**Keywords:** local anesthetics, pharmacology, toxicity

#### **1. Introduction**

Local anesthetics (LAs) are drugs commonly used in medicine and especially in anesthesiology, which when administered in the vicinity of peripheral neural tissue produce changes in the conformation of voltage-dependent sodium channels that depolarize the neural tissue and produce analgesia, anesthesia, and sympathetic and motor block in the dermatomes of the affected nerves without altering consciousness. This inhibitory phenomenon is reversible and transitory and is known as regional anesthesia and is classified into local, peripheral nerves, nervous plexuses, peridural, subarachnoid, and intravenous anesthesia.

LAs are safe and effective drugs, although when wrongly managed, they can reach high plasma concentrations and produce systemic toxicity (LAST) that manifests primarily in the central nervous system (CNS) and cardiovascular system (CVS), causing side effects that can occasionally lead to death. Local neuro toxicity has also been described when injected in the vicinity of the peripheral nervous system or at subarachnoid or epidural space. Myotoxic effects have also been described.

The main clinical use of LAs is to achieve pain insensitivity, although they have other pharmacological uses such as antiarrhythmic, anti-asthmatic, antiinflammatory, antithrombotic, bacteriostatic, and bactericidal effects that have been demonstrated, as well as antitumoral agent enhancer activity [1–3]. LAs are grouped into two categories: those of the ester type and those of the amino-amide group. They are the only drugs used in regional anesthesia, although it has been described that other drugs with different molecular structure such as amitriptyline, meperidine, eugenols, beta-adrenergic antagonists, alpha2 agonists, spasmolytics, anticonvulsants, and antihistamines have local anesthetic effects [4–6]. There are three LAs that due to their chemical structure differ from the classic LAs: articaine, sameridine, and centbucridine. Articaine is classified into the amide group, it is fat soluble and short acting and has intermediate potency, with rapid metabolism due to an ester group in its structure. Sameridine, on the other hand, has mixed effects as an opioid agonist and LA properties under investigation for intrathecal use [7, 8]. Centbucridine is a nonester, nonamide drug still under clinical investigation [9].

In this introductory chapter, the most important properties of LAs are detailed, emphasizing their pharmacological classification, pharmacokinetic profile, action mechanisms, side effects, and some relevant clinical aspects, as well as their nonanesthetic uses.

#### **2. Brief history of the discovery and evolution of LAs**

In the Andean Mountains, centuries ago, the Incas began using cocaine leaves which they chewed or ingested in the form of potions that provided them with plenty of energy to carry out their religious rituals. In addition, as a powerful stimulant, the coca leaf was chewed to mitigate the effects derived from altitude, hunger or fatigue and as a medicine for gastrointestinal discomfort, colds, or bruises. This sacred plant of the Incas, *Erythroxylum coca*, caught the attention of Europeans who took it to the old continent at the end of the 16th century. It was until 1859 when Paulo Mantegazza, an Italian physiologist, wrote *Sulle virtu igieniche e Medicinale della Coca* (On the hygienic and medicinal properties of coca and on nervine nourishment in general) where he pointed out its healing properties. The German chemist Albert Niemann isolated the active substance from these leaves and called it cocaine, noting its power to anesthetize the tongue. In 1884, Sigmund Freud wrote his famous monograph entitled *Ueber coca.* Like some of his contemporaries, Freud acknowledged that cocaine had local anesthetic effects when applied to the mucous membranes, but it was Karl Köller who used it for the first time for anesthetic purposes when applied in various mucous membranes and in the conjunctiva for surgical purposes. It is Köller to whom it is attributed the beginning of local anesthesia [10–12].

The knowledge of the toxic and additive effects of cocaine became public quickly; it went from being the LA in vogue to a potent CNS stimulant that until today is a social stigma. This fired the investigation toward new LAs, and safer drugs were found. Benzocaine was synthesized in 1890, and in 1904, Alfred Einhorn introduced procaine by degrading cocaine, which was later marketed as novocaine® and was the most widely used LA in the world. Tetracaine was synthesized in 1928 and introduced into clinical anesthesia in 1932. In 1943 Löfgren discovered lidocaine that was introduced for clinical use in 1947 and is currently the most used LA. Mepivacaine appeared in 1956, and in 1963, the clinical use of bupivacaine was introduced, while etidocaine began to be used in 1972. Other LAs appeared during the following years but were withdrawn from the market due to their toxic effects. In 1970, Albrigth [13] mentioned some deaths attributed to bupivacaine and etidocaine. His editorial was enough to start basic and clinical research in search of new drugs with a better safety profile. The result was the introduction of ropivacaine in 1997 and levobupivacaine in 1999, both levoisomeric drugs. It is noteworthy that these two LAs had been discovered in 1957 and 1972, respectively (**Table 1**).

**3**

*Local Anesthetics*

toxicity are obtained.

*Chronological appearance of local anesthetics.*

**3.1 Cellular membrane**

These proteins are called cell receptors.

**3. Basics data**

**Table 1.**

*DOI: http://dx.doi.org/10.5772/intechopen.93643*

The levoisomeric LAs did not replace other LAs but are complementary to the therapeutic armamentarium in regional anesthesia. Both ropivacaine and levobupivacaine have been conquering a special place in regional anesthesia techniques, but their toxicity is still superior to procaine, chloroprocaine, and lidocaine. While these LAs are not comparable in potency and duration, they still have a place in anesthesiology, with the exception of intrathecal lidocaine. The history of these drugs will continue to be written as new results on therapeutic effectiveness and

**Local anesthetics Year of synthesis Introduction in clinic**

Cocaine 1860 1884 Procaine 1904 1905 Dibucaine 1925 1930 Tetracaine 1928 1932 Lidocaine 1943 1947 Chloroprocaine 1950 1952 Mepivacaine 1956 1957 Prilocaine 1959 1960 Bupivacaine 1957 1963 Etidocaine 1971 1972 Ropivacaine 1957 1997 Levobupivacaine 1972 1999

It is necessary to know some elementary aspects of the structure and function of the cell membrane, as well as to understand the role of voltage-dependent sodium channels, which are protein structures that are located in the cell membrane and play a paramount role in cellular electrical activity and impulse transmission.

The cell membrane is a barrier of lipids and proteins, which forms the outer surface of eukaryotic cells. The lipid part of the membrane is formed by a bilayer with a thickness of 60–100 Å, which gives it structure and constitutes a barrier that prevents the passage of water-soluble substances. It has three important types of lipids: phospholipids, glycolipids and cholesterol. The membrane proteins are suspended individually or in groups within the lipid structure and shape the various channels. The selectivity of transmembrane protein channels allows the cell to control the entry and exit of substances, as well as transport between cell compartments. Membrane proteins not only facilitate selective transport, but in addition, they are able to carry out active transport against the concentration gradient with special pumps, such as the sodium-potassium pump. Other functions of the membrane, such as the recognition and binding of certain substances on the cell surface, are also determined by the protein part of the membrane.

#### *Local Anesthetics DOI: http://dx.doi.org/10.5772/intechopen.93643*


#### **Table 1.**

*Topics in Local Anesthetics*

nonanesthetic uses.

local anesthesia [10–12].

respectively (**Table 1**).

group. They are the only drugs used in regional anesthesia, although it has been described that other drugs with different molecular structure such as amitriptyline, meperidine, eugenols, beta-adrenergic antagonists, alpha2 agonists, spasmolytics, anticonvulsants, and antihistamines have local anesthetic effects [4–6]. There are three LAs that due to their chemical structure differ from the classic LAs: articaine, sameridine, and centbucridine. Articaine is classified into the amide group, it is fat soluble and short acting and has intermediate potency, with rapid metabolism due to an ester group in its structure. Sameridine, on the other hand, has mixed effects as an opioid agonist and LA properties under investigation for intrathecal use [7, 8]. Centbucridine is a nonester, nonamide drug still under clinical investigation [9]. In this introductory chapter, the most important properties of LAs are detailed, emphasizing their pharmacological classification, pharmacokinetic profile, action mechanisms, side effects, and some relevant clinical aspects, as well as their

In the Andean Mountains, centuries ago, the Incas began using cocaine leaves which they chewed or ingested in the form of potions that provided them with plenty of energy to carry out their religious rituals. In addition, as a powerful stimulant, the coca leaf was chewed to mitigate the effects derived from altitude, hunger or fatigue and as a medicine for gastrointestinal discomfort, colds, or bruises. This sacred plant of the Incas, *Erythroxylum coca*, caught the attention of Europeans who took it to the old continent at the end of the 16th century. It was until 1859 when Paulo Mantegazza, an Italian physiologist, wrote *Sulle virtu igieniche e Medicinale della Coca* (On the hygienic and medicinal properties of coca and on nervine nourishment in general) where he pointed out its healing properties. The German chemist Albert Niemann isolated the active substance from these leaves and called it cocaine, noting its power to anesthetize the tongue. In 1884, Sigmund Freud wrote his famous monograph entitled *Ueber coca.* Like some of his contemporaries, Freud acknowledged that cocaine had local anesthetic effects when applied to the mucous membranes, but it was Karl Köller who used it for the first time for anesthetic purposes when applied in various mucous membranes and in the conjunctiva for surgical purposes. It is Köller to whom it is attributed the beginning of

The knowledge of the toxic and additive effects of cocaine became public quickly; it went from being the LA in vogue to a potent CNS stimulant that until today is a social stigma. This fired the investigation toward new LAs, and safer drugs were found. Benzocaine was synthesized in 1890, and in 1904, Alfred Einhorn introduced procaine by degrading cocaine, which was later marketed as novocaine® and was the most widely used LA in the world. Tetracaine was synthesized in 1928 and introduced into clinical anesthesia in 1932. In 1943 Löfgren discovered lidocaine that was introduced for clinical use in 1947 and is currently the most used LA. Mepivacaine appeared in 1956, and in 1963, the clinical use of bupivacaine was introduced, while etidocaine began to be used in 1972. Other LAs appeared during the following years but were withdrawn from the market due to their toxic effects. In 1970, Albrigth [13] mentioned some deaths attributed to bupivacaine and etidocaine. His editorial was enough to start basic and clinical research in search of new drugs with a better safety profile. The result was the introduction of ropivacaine in 1997 and levobupivacaine in 1999, both levoisomeric drugs. It is noteworthy that these two LAs had been discovered in 1957 and 1972,

**2. Brief history of the discovery and evolution of LAs**

**2**

*Chronological appearance of local anesthetics.*

The levoisomeric LAs did not replace other LAs but are complementary to the therapeutic armamentarium in regional anesthesia. Both ropivacaine and levobupivacaine have been conquering a special place in regional anesthesia techniques, but their toxicity is still superior to procaine, chloroprocaine, and lidocaine. While these LAs are not comparable in potency and duration, they still have a place in anesthesiology, with the exception of intrathecal lidocaine. The history of these drugs will continue to be written as new results on therapeutic effectiveness and toxicity are obtained.

#### **3. Basics data**

It is necessary to know some elementary aspects of the structure and function of the cell membrane, as well as to understand the role of voltage-dependent sodium channels, which are protein structures that are located in the cell membrane and play a paramount role in cellular electrical activity and impulse transmission.

#### **3.1 Cellular membrane**

The cell membrane is a barrier of lipids and proteins, which forms the outer surface of eukaryotic cells. The lipid part of the membrane is formed by a bilayer with a thickness of 60–100 Å, which gives it structure and constitutes a barrier that prevents the passage of water-soluble substances. It has three important types of lipids: phospholipids, glycolipids and cholesterol. The membrane proteins are suspended individually or in groups within the lipid structure and shape the various channels. The selectivity of transmembrane protein channels allows the cell to control the entry and exit of substances, as well as transport between cell compartments. Membrane proteins not only facilitate selective transport, but in addition, they are able to carry out active transport against the concentration gradient with special pumps, such as the sodium-potassium pump. Other functions of the membrane, such as the recognition and binding of certain substances on the cell surface, are also determined by the protein part of the membrane. These proteins are called cell receptors.

Cellular receptors are connected to internal systems that only act when certain substances bind to the membrane surface. Many of the cell controls act through this mechanism. Some metabolic pathways do not take action unless the "signal" molecule—for example—a hormone, has reached the cell surface. Glycoproteins are located in the membrane that identify other cells as members of an individual or as strangers. The interactions between the cells that make up a tissue are based on membrane proteins. In this manner, the structure of the membranes depends on the lipids, while the functions depend on the proteins.

#### **3.2 Physiology of nerve transmission**

The resting cell membrane maintains a voltage difference of 40–90 mV between the inner and outer layers, the inside being negative and the outside positive. This is the so-called resting potential, which is maintained by an active mechanism of the Na/K pump. The polarized membrane does not allow the passage of sodium ions (Na+) through the voltage-dependent sodium channels that are in resting state. When an electrical stimulus arrives, the membrane depolarization begins by activating the sodium channels that open to give way to the Na+ , which enter the intracellular medium, transforming the negativity of the transmembrane potential. This initiates a cycle of changes of sodium channels in four functional stages: resting, activated, inactivated, and deactivated. In the resting state, the outer gate of the sodium channel is closed, and the internal gate or closing gate is open. When a stimulus reaches the membrane, the sodium channel is activated by opening the external gate and letting Na+ pass. When the membrane potential rises to +20 mV, the closure of the internal gate is triggered, and it enters an inactive state. The channel is deactivated when the membrane potential reaches −60 mV. When the passage of Na+ ceases through the pore of the sodium channel, the potassium channel increases its permeability, allowing this ion to pass inside the cell due to differences in concentration (concentration gradient). Then the initial phase is restored; the Na-K pump mobilizes Na+ outside and K+ inside the cell. Sodium channels pass from the inactive-deactivated state to the initial resting state. All these movements of Na+ and K+ are manifested in changes in the transmembrane electrical potential, generating the action potential that is propagated along the nerve fiber (**Figure 1**) [14]. Because there is a potential difference across the cell membrane, the membrane is said to be polarized. If the membrane potential becomes more positive than it is at the resting potential, the membrane is said to be depolarized. This whole process lasts 1 millisecond; 30% is consumed by the depolarization phase. According to the electrical instant, the sodium channels dependent on voltage exist in four stages; resting (−90 mV), activated (−60 mV), inactivated (+20 mV) and deactivated (−60 mV).

#### **3.3 Voltage-dependent sodium channels**

Hodgkin and Huxley proposed that cell membranes contained channels that facilitated ionic passage through them, which was confirmed when ionic currents that selectively flow through these transmembrane pores were directly measured. In 1972, Singer and Nicolson [15–17] proposed the ¨Fluid Mosaic Model¨ in the structure of the cell membranes were they described the cell membrane as a twodimensional liquid that restricts the lateral diffusion of membrane components and includes the integral proteins inserted in the lipid bilayer, some of which completely cross it and others cross it partially. Of these membrane proteins, three primary groups stand out: the channels, pumps, and receptors that constitute the transport system through cell membranes and regulate the movements of small molecules and ions that cannot pass through the lipid bilayer.

**5**

sodium Na+

**Figure 1.**

*8: 159–162 [14].*

next number indicates the subfamily gene (Na+

the channel pore through which the Na+

the specific isoform of the channel, for example Na+

from each other by a lowercase letter, for example Na<sup>+</sup>

*Local Anesthetics*

*DOI: http://dx.doi.org/10.5772/intechopen.93643*

Sodium channels are protein structures that are integrated into the lipid bilayer of the cell membrane and are responsible for orchestrating the electrical signals that are transmitted by certain tissues, such as nerves and the heart's electrical conduction system. They are tubular-shaped components that resemble pores filled with water and are distributed through the whole cell membrane, primarily at the beginning of axons and in Ranvier nodes. This ion channels are divided into three types; those regulated by voltage, those regulated by extracellular ligand and those regulated by intracellular ligands, although other authors classify them into only two groups; those regulated by voltage and those operated by receptors [18–20]. The family of voltage-regulated sodium channels is composed of nine members that have been described in mammals and a tenth component related to a protein. All of them are members of a super family of ion channels that also includes potassium and calcium channels. Its nomenclature is complex and the chemical symbol of

*Representation of the four structural phases of sodium channels and their relationship with the action potential. Modified from Columb MO, MacLennan K. Local anesthetics agents. Anaesth Intensive Care Med 2007;* 

is used first, followed by V indicating voltage regulated (Na+

assigned in the chronological order in which the genes were discovered. There are variants that come together or splice in each family member, which are told apart

The sodium channels are formed by an alpha subunit, a simple polypeptide with a relative molecular mass of ~260,000 and are responsible for the selectivity and gate voltage. Some sodium channels have beta 1 and 2 subunits. These sodium ionophores are made up of four homologous domains; each of these four domains contains six transmembrane segments known as alpha-helices. This causes each sodium channel to cross the cell membrane 24 times. The center of this structure is

the LAs in their hydrophilic form on their way to be fixed in the internal pore of the

V). The

V1), and the next number identifies

V1.1. This last number was

V1.1. a. [18, 19].

passes into the interior of the cell and also

#### **Figure 1.**

*Topics in Local Anesthetics*

gate and letting Na+

pump mobilizes Na+

Na+

K+

lipids, while the functions depend on the proteins.

the sodium channels that open to give way to the Na+

outside and K+

**3.3 Voltage-dependent sodium channels**

ions that cannot pass through the lipid bilayer.

**3.2 Physiology of nerve transmission**

Cellular receptors are connected to internal systems that only act when certain substances bind to the membrane surface. Many of the cell controls act through this mechanism. Some metabolic pathways do not take action unless the "signal" molecule—for example—a hormone, has reached the cell surface. Glycoproteins are located in the membrane that identify other cells as members of an individual or as strangers. The interactions between the cells that make up a tissue are based on membrane proteins. In this manner, the structure of the membranes depends on the

The resting cell membrane maintains a voltage difference of 40–90 mV between the inner and outer layers, the inside being negative and the outside positive. This is the so-called resting potential, which is maintained by an active mechanism of the Na/K pump. The polarized membrane does not allow the passage of sodium ions (Na+) through the voltage-dependent sodium channels that are in resting state. When an electrical stimulus arrives, the membrane depolarization begins by activating

medium, transforming the negativity of the transmembrane potential. This initiates a cycle of changes of sodium channels in four functional stages: resting, activated, inactivated, and deactivated. In the resting state, the outer gate of the sodium channel is closed, and the internal gate or closing gate is open. When a stimulus reaches the membrane, the sodium channel is activated by opening the external

closure of the internal gate is triggered, and it enters an inactive state. The channel is deactivated when the membrane potential reaches −60 mV. When the passage of

inactive-deactivated state to the initial resting state. All these movements of Na+

 are manifested in changes in the transmembrane electrical potential, generating the action potential that is propagated along the nerve fiber (**Figure 1**) [14]. Because there is a potential difference across the cell membrane, the membrane is said to be polarized. If the membrane potential becomes more positive than it is at the resting potential, the membrane is said to be depolarized. This whole process lasts 1 millisecond; 30% is consumed by the depolarization phase. According to the electrical instant, the sodium channels dependent on voltage exist in four stages; resting (−90 mV), activated (−60 mV), inactivated (+20 mV) and deactivated (−60 mV).

Hodgkin and Huxley proposed that cell membranes contained channels that facilitated ionic passage through them, which was confirmed when ionic currents that selectively flow through these transmembrane pores were directly measured. In 1972, Singer and Nicolson [15–17] proposed the ¨Fluid Mosaic Model¨ in the structure of the cell membranes were they described the cell membrane as a twodimensional liquid that restricts the lateral diffusion of membrane components and includes the integral proteins inserted in the lipid bilayer, some of which completely cross it and others cross it partially. Of these membrane proteins, three primary groups stand out: the channels, pumps, and receptors that constitute the transport system through cell membranes and regulate the movements of small molecules and

 ceases through the pore of the sodium channel, the potassium channel increases its permeability, allowing this ion to pass inside the cell due to differences in concentration (concentration gradient). Then the initial phase is restored; the Na-K

pass. When the membrane potential rises to +20 mV, the

inside the cell. Sodium channels pass from the

, which enter the intracellular

and

**4**

*Representation of the four structural phases of sodium channels and their relationship with the action potential. Modified from Columb MO, MacLennan K. Local anesthetics agents. Anaesth Intensive Care Med 2007; 8: 159–162 [14].*

Sodium channels are protein structures that are integrated into the lipid bilayer of the cell membrane and are responsible for orchestrating the electrical signals that are transmitted by certain tissues, such as nerves and the heart's electrical conduction system. They are tubular-shaped components that resemble pores filled with water and are distributed through the whole cell membrane, primarily at the beginning of axons and in Ranvier nodes. This ion channels are divided into three types; those regulated by voltage, those regulated by extracellular ligand and those regulated by intracellular ligands, although other authors classify them into only two groups; those regulated by voltage and those operated by receptors [18–20]. The family of voltage-regulated sodium channels is composed of nine members that have been described in mammals and a tenth component related to a protein. All of them are members of a super family of ion channels that also includes potassium and calcium channels. Its nomenclature is complex and the chemical symbol of sodium Na+ is used first, followed by V indicating voltage regulated (Na+ V). The next number indicates the subfamily gene (Na+ V1), and the next number identifies the specific isoform of the channel, for example Na+ V1.1. This last number was assigned in the chronological order in which the genes were discovered. There are variants that come together or splice in each family member, which are told apart from each other by a lowercase letter, for example Na<sup>+</sup> V1.1. a. [18, 19].

The sodium channels are formed by an alpha subunit, a simple polypeptide with a relative molecular mass of ~260,000 and are responsible for the selectivity and gate voltage. Some sodium channels have beta 1 and 2 subunits. These sodium ionophores are made up of four homologous domains; each of these four domains contains six transmembrane segments known as alpha-helices. This causes each sodium channel to cross the cell membrane 24 times. The center of this structure is the channel pore through which the Na+ passes into the interior of the cell and also the LAs in their hydrophilic form on their way to be fixed in the internal pore of the sodium channel, where the voltage sensor is located. This voltage sensor is located in the fourth segment of each domain, where the LAs are fixed in the sixth segment of Domains 3 and 4. The voltage sensor has a very high positive charge, and these four domains are connected to each other by segments or hydrophilic bridges formed by amino acids that are located on the extracellular side of the membrane. The bridge that joins segments 5 and 6 of each domain is known as a pore handle and covers the pore of the channel to allow only the passage of Na<sup>+</sup> . This channel structure is responsible for selectivity and is vulnerable to certain toxins that can inactivate the sodium channel, although another description mentions that the selectivity filter is given by a narrowing of the ionic pore located below its gate [19].

The gate of the ionic pore is the initial portion of the sodium channel on the outer side of the cell membrane, is made up of protein "walls" and has an aqueous cavity similar to an irregular cylinder, where the external vestibule is located, which contains the selectivity filter and the voltage sensor. The closure gate is located in the most distal portion of the sodium channel, on the intracellular side of the cell membrane. The sodium channel inlet measures about 1.2 nm and narrows to about 0.3 to 0.5 nm at the site where the selectivity filter is located, which consists of aspartic acid, glycine, lysine, and alanine. The exact mechanism of how these channels discriminate between different cations is not known [19].

**Figure 2** shows a representation of a voltage-dependent sodium channel, which is in the lipid bilayer of the cell membrane. Its four domains (D1, D2, D3, and D4) are each made up of six segments (alpha helices) that cross the entire cell membrane, emphasizing segment 4, colored in black and corresponding to the voltage sensor, which has a positive charge. On the extracellular face of the cell membrane there are two types of structures that connect the six segments, the one marked with T between segments 5 and 6 of each domain represent the site where some toxins act. The FS selectivity filter in the initial portion of the ionic pore is shown. The site where LAs act is marked with an X. This site has been highly

#### **Figure 2.**

*Diagram of the voltage-dependent sodium channel with its 4 domains. Each domain has 6 helices that cross the cell membrane. The black stars located at the junctions of the helices 5 and 6 of each domain (pore handle) are the sites where cellular toxins (TTX) act. The sodium channel inactivation gate (IC) is located on the intracellular face between domain 3 and 4. The effector site of local anesthetics is located on helix 6 (or segment 6) of domains 3 and 4, although some schemes also draw it in domain 1.*

**7**

*Local Anesthetics*

port of Na+

*DOI: http://dx.doi.org/10.5772/intechopen.93643*

place it in segment 6 of Domain 1.

**4. Mechanism of action of LAs**

opens for a millisecond and about 7000 Na+

phase of the action potential [14, 21–23].

and reach their site of action;

sodium channel.

period and repolarization.

segments 6 of Domains 3 and 4.

until the ionophores become impermeable to Na+

controversial and is located in the final portion of the ionic pore near the intracellular surface of the membrane. The available information suggests that domains 3 and 4 appear to contain this point in segment 6, although some references also

Among other tissues, sodium channels are located in excitable membranes such as the CNS membranes, peripheral nervous system, and the conduction system of the heart. During a nervous impulse, the cell goes through three different phases; it first depolarizes as the sodium channels open, then a refractory period follows until the cell finally repolarizes when the sodium channels become impermeable to Na+

The intracytoplasmic junction between Domain III and Domain IV (CI in **Figure 2**)

As mentioned before, LAs inhibit the electrical impulse by selectively interfering with the function of voltage-dependent sodium channels by preventing the trans-

the cells. When an electrical impulse reaches the excitable cell, the sodium channel

izes again and enters a phase of inactivation, which is due to the activation of the intracytoplasmic junction between Domain III and IV. Unlike the tetrodotoxin and saxitoxin that act outside the cell membrane, LAs are temporarily fixed to the alpha helices 6 of Domains 3 and 4, which alters the voltage sensor and closes the inactivation gate, which obstructs the sodium channel and results in blockage of the initial

There are two ways by which LAs reach the internal gate of the sodium channel

where they interact (segment 6 of Domains 3 and 4) in the internal gate of the

through the sodium channels when they are open and reach their site of action by closing the sodium channel [14, 20, 23, 24]. LAs have no effect on the resting phase or on the potential threshold, although they can prolong the refractory

**Figure 3** illustrates these two routes of arrival of LAs to their receptor site in

Another factor that determines the action of LAs is the impulse frequency, the basis of the modulated receptor hypothesis, which suggests that these drugs bind more closely to the receptor within the ionic gate of voltage-dependent sodium channels when these are in an open or inactive state, that is in the depolarization phase, that when they are in a resting state, at which time they are separated from them. LAs that bind and dissociate rapidly such as lidocaine are little affected by this phenomenon, which is not the case with molecules such as bupivacaine,

a.It has been postulated that LAs in their neutral, lipophilic (hydrophobic, B) form easily enter the lipid cell membrane in free form and from there contribute to the closure of sodium channels by the expansion of the cell membrane. From this location, LAs also pass into the cellular interior where they ionize and

transform into their charged form (hydrophilic, BH+

b.LAs in their cationic or hydrophilic form (BH<sup>+</sup>

through the ionic pore of sodium ionophores, from outside to inside of

pass. A refractory period continues

, and the membrane repolar-

), which reaches the site

) enter the cell cytoplasm

is responsible for this inactivation according to the "ball and chain" model.

.

#### *Local Anesthetics DOI: http://dx.doi.org/10.5772/intechopen.93643*

*Topics in Local Anesthetics*

sodium channel, where the voltage sensor is located. This voltage sensor is located in the fourth segment of each domain, where the LAs are fixed in the sixth segment of Domains 3 and 4. The voltage sensor has a very high positive charge, and these four domains are connected to each other by segments or hydrophilic bridges formed by amino acids that are located on the extracellular side of the membrane. The bridge that joins segments 5 and 6 of each domain is known as a pore handle and covers

responsible for selectivity and is vulnerable to certain toxins that can inactivate the sodium channel, although another description mentions that the selectivity filter is

The gate of the ionic pore is the initial portion of the sodium channel on the outer side of the cell membrane, is made up of protein "walls" and has an aqueous cavity similar to an irregular cylinder, where the external vestibule is located, which contains the selectivity filter and the voltage sensor. The closure gate is located in the most distal portion of the sodium channel, on the intracellular side of the cell membrane. The sodium channel inlet measures about 1.2 nm and narrows to about 0.3 to 0.5 nm at the site where the selectivity filter is located, which consists of aspartic acid, glycine, lysine, and alanine. The exact mechanism of how these

**Figure 2** shows a representation of a voltage-dependent sodium channel, which is in the lipid bilayer of the cell membrane. Its four domains (D1, D2, D3, and D4) are each made up of six segments (alpha helices) that cross the entire cell membrane, emphasizing segment 4, colored in black and corresponding to the voltage sensor, which has a positive charge. On the extracellular face of the cell membrane there are two types of structures that connect the six segments, the one marked with T between segments 5 and 6 of each domain represent the site where some toxins act. The FS selectivity filter in the initial portion of the ionic pore is shown. The site where LAs act is marked with an X. This site has been highly

*Diagram of the voltage-dependent sodium channel with its 4 domains. Each domain has 6 helices that cross the cell membrane. The black stars located at the junctions of the helices 5 and 6 of each domain (pore handle) are the sites where cellular toxins (TTX) act. The sodium channel inactivation gate (IC) is located on the intracellular face between domain 3 and 4. The effector site of local anesthetics is located on helix 6 (or segment* 

*6) of domains 3 and 4, although some schemes also draw it in domain 1.*

. This channel structure is

the pore of the channel to allow only the passage of Na<sup>+</sup>

given by a narrowing of the ionic pore located below its gate [19].

channels discriminate between different cations is not known [19].

**6**

**Figure 2.**

controversial and is located in the final portion of the ionic pore near the intracellular surface of the membrane. The available information suggests that domains 3 and 4 appear to contain this point in segment 6, although some references also place it in segment 6 of Domain 1.

Among other tissues, sodium channels are located in excitable membranes such as the CNS membranes, peripheral nervous system, and the conduction system of the heart. During a nervous impulse, the cell goes through three different phases; it first depolarizes as the sodium channels open, then a refractory period follows until the cell finally repolarizes when the sodium channels become impermeable to Na+ . The intracytoplasmic junction between Domain III and Domain IV (CI in **Figure 2**) is responsible for this inactivation according to the "ball and chain" model.

#### **4. Mechanism of action of LAs**

As mentioned before, LAs inhibit the electrical impulse by selectively interfering with the function of voltage-dependent sodium channels by preventing the transport of Na+ through the ionic pore of sodium ionophores, from outside to inside of the cells. When an electrical impulse reaches the excitable cell, the sodium channel opens for a millisecond and about 7000 Na+ pass. A refractory period continues until the ionophores become impermeable to Na+ , and the membrane repolarizes again and enters a phase of inactivation, which is due to the activation of the intracytoplasmic junction between Domain III and IV. Unlike the tetrodotoxin and saxitoxin that act outside the cell membrane, LAs are temporarily fixed to the alpha helices 6 of Domains 3 and 4, which alters the voltage sensor and closes the inactivation gate, which obstructs the sodium channel and results in blockage of the initial phase of the action potential [14, 21–23].

There are two ways by which LAs reach the internal gate of the sodium channel and reach their site of action;


**Figure 3** illustrates these two routes of arrival of LAs to their receptor site in segments 6 of Domains 3 and 4.

Another factor that determines the action of LAs is the impulse frequency, the basis of the modulated receptor hypothesis, which suggests that these drugs bind more closely to the receptor within the ionic gate of voltage-dependent sodium channels when these are in an open or inactive state, that is in the depolarization phase, that when they are in a resting state, at which time they are separated from them. LAs that bind and dissociate rapidly such as lidocaine are little affected by this phenomenon, which is not the case with molecules such as bupivacaine,

#### **Figure 3.**

*Arrival pathways of LAs to the sodium channel. The hydrophobic pathway refers to the passage of LAs in their neutral (lipophilic) form that easily penetrate the cell membrane. Once in the cell membrane, the LA (B) expands it and by mechanical effect closes the sodium channel. This same neutral form of LA penetrates the cell, where it is protonized by incorporating an H+, (BH+ cationic form) that easily reaches the internal gate of the sodium channel and attaches to segment 6 of domains 3 and 4, activating the closure of the sodium channel. The hydrophilic pathway exemplified in the right portion of the scheme illustrates how a cationic LA (BH+) penetrates through and is fixed in the sodium channel.*

ropivacaine, or etidocaine that are benefitted when the stimulation frequency is high, since it does not give time to recover to their resting state. This phenomenon explains the greater toxicity of some LAs [24, 25].

The affinity of LAs for the sodium channel is what determines their pharmacological action and also their toxic effects. The most important clinical outcome of these events at the level of voltage-dependent sodium channels and their interaction with LAs molecules are two results: regional anesthesia-analgesia and/or deleterious toxic effects.

#### **5. Chemical structure of LAs**

LAs are divided into two groups according to their chemical structure: the amino esters (cocaine, procaine, chloroprocaine, and tetracaine) and the amino amides (lidocaine, bupivacaine, mepivacaine, ropivacaine, and prilocaine). The typical molecule of a LA consists of three components: a) an aromatic lipophilic ring, usually benzene, b) an amphipathic intermediate chain of about 6 to 9 Å, and c) a terminal tertiary amine, hydrophilic, which is a base proton acceptor (H+ ). The intermediate chain binds the basic amine with the aromatic ring and has an ester (CO)- or amide (CNH)-type bond. Each of these three parts of the LA formula contributes to different properties. The aromatic ring of the molecule improves the liposolubility of the compound that can be increased by aliphatic substitutions at certain sites (R). When the liposolubility of LAs is increased, its diffusion is increased through nerve structures (nerve sheaths and axonal membranes), which improves their anesthetic and toxic potency since a greater proportion of the drug enters the neural tissue and is fixed there with higher affinity. An example of this phenomenon is bupivacaine which has greater potency than lidocaine; the first

**9**

**Figure 4.**

*Typical structural formula of a local anesthetic.*

*Local Anesthetics*

structure of LAs.

most toxic LA.

*DOI: http://dx.doi.org/10.5772/intechopen.93643*

through the lipid membranes [11, 25].

is prepared at 0.5% (5 mg/mL) and the second at 2% (20 mg/mL). The terminal amine may exist in tertiary form (3 junctions) that is liposoluble and facilitates cell membrane penetration, or as a quaternary form (4 junctions) that is positively charged and makes the molecule water soluble, which makes it difficult to pass

As stated before, the aromatic ring determines the degree of lipoafinity of the LA, and the terminal amine acts as an *on-off switch,* allowing the LA to exist as either lipoafin or water soluble. Both the tertiary and quaternary forms play a very important role in the sequence of events that lead to nerve conduction blockage. The tertiary hydrophilic amine, which is kept charged to the physiological pH and gives it its condition of weak bases with a positive charge, is the part that will be fixed to the receptor in the sodium channel of the cell membrane to exert the pharmacological effect. The presence of an ester or amide group in the intermediate chain provides the basis for their classification and also determines the metabolism of these substances. LAs with ester binding are readily hydrolyzed in the plasma by cholinesterase; instead, those with an amide junction are biotransformed by liver microsomes via the microsomal system. **Figure 4** shows the elementary chemical

If the size of the molecule of a LA is increased, its potency and duration of action increase but also its toxicity. There is a direct correlation between potency, duration of effect, lipophilic character, molecular size and toxicity. Chloroprocaine is the least toxic, followed by procaine, prilocaine, lidocaine, mepivacaine, etidocaine, ropivacaine, bupivacaine, tetracaine and dibucaine, with cocaine being the

Another aspect of capital importance is the stereoisomerism that some LAs have. It refers to the existence of molecules with the same structural and molecular formula, but with different spatial orientation around a particular atom, the chiral center. It is like a reflection in a mirror, like placing one hand next to the other; they are the same but cannot be superimposed, they are mirror images. LAs of the pipecoloxylidide family (mepivacaine, bupivacaine and ropivacaine), as well as etidocaine and prilocaine are chiral compounds, with an asymmetric carbon atom, which can exist in their enantiomeric form, such as mirror images. When the compound deflects the polarized light to the left it is an S-isomer (Sinus) or levo-isomer, if the light is rotated to the right it is an R-isomer (Rectus) or dextro-isomer. Although the S and R isomers have a similar pharmacological activity, the clinical importance of the isomerism is that the same drug can have different biological activity. For example, the S-enantiomers of amino-amide LAs produce greater vasoconstriction and have less systemic toxicity than D-isomer. The typical example of stereoisomerism is

#### *Local Anesthetics DOI: http://dx.doi.org/10.5772/intechopen.93643*

*Topics in Local Anesthetics*

ropivacaine, or etidocaine that are benefitted when the stimulation frequency is high, since it does not give time to recover to their resting state. This phenomenon

*Arrival pathways of LAs to the sodium channel. The hydrophobic pathway refers to the passage of LAs in their neutral (lipophilic) form that easily penetrate the cell membrane. Once in the cell membrane, the LA (B) expands it and by mechanical effect closes the sodium channel. This same neutral form of LA penetrates the cell, where it is protonized by incorporating an H+, (BH+ cationic form) that easily reaches the internal gate of the sodium channel and attaches to segment 6 of domains 3 and 4, activating the closure of the sodium channel. The hydrophilic pathway exemplified in the right portion of the scheme illustrates how a cationic LA (BH+)* 

The affinity of LAs for the sodium channel is what determines their pharmacological action and also their toxic effects. The most important clinical outcome of these events at the level of voltage-dependent sodium channels and their interaction with LAs molecules are two results: regional anesthesia-analgesia and/or deleterious

LAs are divided into two groups according to their chemical structure: the amino esters (cocaine, procaine, chloroprocaine, and tetracaine) and the amino amides (lidocaine, bupivacaine, mepivacaine, ropivacaine, and prilocaine). The typical molecule of a LA consists of three components: a) an aromatic lipophilic ring, usually benzene, b) an amphipathic intermediate chain of about 6 to 9 Å, and c) a terminal tertiary amine, hydrophilic, which is a base proton acceptor (H+

intermediate chain binds the basic amine with the aromatic ring and has an ester (CO)- or amide (CNH)-type bond. Each of these three parts of the LA formula contributes to different properties. The aromatic ring of the molecule improves the liposolubility of the compound that can be increased by aliphatic substitutions at certain sites (R). When the liposolubility of LAs is increased, its diffusion is increased through nerve structures (nerve sheaths and axonal membranes), which improves their anesthetic and toxic potency since a greater proportion of the drug enters the neural tissue and is fixed there with higher affinity. An example of this phenomenon is bupivacaine which has greater potency than lidocaine; the first

). The

explains the greater toxicity of some LAs [24, 25].

*penetrates through and is fixed in the sodium channel.*

**8**

toxic effects.

**Figure 3.**

**5. Chemical structure of LAs**

is prepared at 0.5% (5 mg/mL) and the second at 2% (20 mg/mL). The terminal amine may exist in tertiary form (3 junctions) that is liposoluble and facilitates cell membrane penetration, or as a quaternary form (4 junctions) that is positively charged and makes the molecule water soluble, which makes it difficult to pass through the lipid membranes [11, 25].

As stated before, the aromatic ring determines the degree of lipoafinity of the LA, and the terminal amine acts as an *on-off switch,* allowing the LA to exist as either lipoafin or water soluble. Both the tertiary and quaternary forms play a very important role in the sequence of events that lead to nerve conduction blockage. The tertiary hydrophilic amine, which is kept charged to the physiological pH and gives it its condition of weak bases with a positive charge, is the part that will be fixed to the receptor in the sodium channel of the cell membrane to exert the pharmacological effect. The presence of an ester or amide group in the intermediate chain provides the basis for their classification and also determines the metabolism of these substances. LAs with ester binding are readily hydrolyzed in the plasma by cholinesterase; instead, those with an amide junction are biotransformed by liver microsomes via the microsomal system. **Figure 4** shows the elementary chemical structure of LAs.

If the size of the molecule of a LA is increased, its potency and duration of action increase but also its toxicity. There is a direct correlation between potency, duration of effect, lipophilic character, molecular size and toxicity. Chloroprocaine is the least toxic, followed by procaine, prilocaine, lidocaine, mepivacaine, etidocaine, ropivacaine, bupivacaine, tetracaine and dibucaine, with cocaine being the most toxic LA.

Another aspect of capital importance is the stereoisomerism that some LAs have. It refers to the existence of molecules with the same structural and molecular formula, but with different spatial orientation around a particular atom, the chiral center. It is like a reflection in a mirror, like placing one hand next to the other; they are the same but cannot be superimposed, they are mirror images. LAs of the pipecoloxylidide family (mepivacaine, bupivacaine and ropivacaine), as well as etidocaine and prilocaine are chiral compounds, with an asymmetric carbon atom, which can exist in their enantiomeric form, such as mirror images. When the compound deflects the polarized light to the left it is an S-isomer (Sinus) or levo-isomer, if the light is rotated to the right it is an R-isomer (Rectus) or dextro-isomer. Although the S and R isomers have a similar pharmacological activity, the clinical importance of the isomerism is that the same drug can have different biological activity. For example, the S-enantiomers of amino-amide LAs produce greater vasoconstriction and have less systemic toxicity than D-isomer. The typical example of stereoisomerism is

**Figure 4.** *Typical structural formula of a local anesthetic.*


**Table 2.**

*Chemical classification of local anesthetics.*

bupivacaine, which contains the dextro-isomer and levo-isomer. The mixture of both is known as racemic combination. Ropivacaine only has a L-isomer. Lidocaine and ametocaine are aquirales since they do not have stereoisomers. D-isomers have more affinity for sodium channels than L-isomers, this makes the former more toxic [26, 27]. **Table 2** shows the chemical classification of LAs.

#### **6. Physical properties, activity, and potency**

LAs are small molecules 220–350 Daltons weight, weak bases, poorly soluble and unstable in water, and therefore, they must be combined with a strong acid to obtain a stable salt that is soluble in water at pH 4.7. The solubility in water is directly related to the degree of ionization and inversely related to the fat solubility. In solution, LAs exist in two forms: basic, nonionized (B) and acidic, cationic, ionized (BH+ ). The ratio between these two forms depends on the dissociation constant (Ka) of the conjugated acid and on the local concentration of H+ ions. At a specific pH for each LA, the concentration of B is equal to that of BH+ . This pH is called pKa. The relationship can be expressed like this: pKa = pH-log (B) / (BH+ ). At a pH of 7.40, the percentage of BH+ form will be higher the higher the pKa. Diffusion of a LA is passive. In order to act they must contact the axon and for this they must pass through the epineurium, perineurium and endoneurium of the peripheral nerve, as well as the myelin layer in the myelinated fibers (lipid-rich structures), and finally cross the cell membrane to be in contact with the receptor site on sodium channels. The fat-soluble basic form B diffuses easily through the perineural structures and the axonal membrane; once inside the cell it is protonized and it is this ionized form that occupies the aforementioned receptor site [23, 25].

The minimum inhibitory concentration (MIC) is necessary to block the conduction of a nerve impulse along a nerve fiber within a certain period. The MIC is different for each LA and allows to differentiate them according to their potency. Several factors can determine the Cm: the size of the fibers (higher MIC for the thicker ones), the pH (lower MIC at higher pH), calcium concentration (higher MIC at higher calcium concentration), and frequency of nerve stimulation (smaller MIC at higher frequency).

Due to the characteristics of the nerve fibers, LAs first block the unmyelinated fibers (C fibers, which correspond to the postganglionic neurons of the autonomic nervous system), those of nociceptive conduction (analgesia), proprioceptive, tactile sensitivity, and pressure (anesthesia), and finally, the motor fibers (motor block).

**11**

**Table 3.**

*Local Anesthetics*

of action.

*DOI: http://dx.doi.org/10.5772/intechopen.93643*

The latency period of a nerve block is not linked to the potency of the LA, but seems to depend on its lipid solubility and pKa, that is, on the pH in which 50% of the molecules are in ionized form and 50% in nonionized form. The higher the pKa, the greater the latency time of a LA. On the other hand, the decrease in tissue pH can lengthen the latency time by limiting the formation of free base; instead, carbonation of a LA solution shortens its latency time. Alkalinization has also been shown to produce a better sensory and motor quality nerve block and may increase diffusion of block height. By alkalinizing LAs, their ionization increases and the percentage of fat solubility of the LA increases, facilitating its diffusion through the lipid structures of the nerves, including the axonal membrane. The addition of 1 mL of sodium bicarbonate to 10 mL of lidocaine improves the onset of extradural or peripheral block for 3–5 min, also increasing its duration

With the exception of cocaine and ropivacaine, LAs produce vasodilation. Adding a vasoconstrictor to LAs is an acceptable routine since two basic actions were demonstrated: increased duration of action and decreased absorption. It also increases the intensity of sensory and motor block in neuroaxial anesthesia. Epinephrine was one of the first drugs to be injected into the subarachnoid space: however, its use was not widespread as the initial results were disappointing. The local vasoconstriction produced by adrenaline favors the decrease in the absorption of LAs, which favor a longer interaction, in addition to decreasing blood concentrations levels and thus their potential for systemic toxicity. On the other hand, epinephrine has an effect on alpha2 receptors in the CNS, especially in the spinal cord, which could be another factor for the improvement it has in neuroaxial blocks. Higher concentrations of adrenaline 2: 000,000 (5 μg/mL) do not offer major advantages in terms of prolonging anesthesia or reducing plasma concentrations. Never use solutions with adrenaline to infiltrate areas with terminal arterial circulation such as the fingers, the penis, the nasal tip, or other areas with critical

arterial circulation, since it may promote ischemia and local necrosis.

**% at pH 7.4**

*practice. Editorial Churchill-Livingstone. Philadelphia, USA. 2004 pag 507–537.*

*Physical and chemical characteristics and relative potency of some local anesthetics \**

**Partition coefficient**

• Bupivacaine 8.1 83 3420 95 4 9.6 3.6 • Levobupivacaine 8.1 83 3420 97 4 9.6 3.6 • Etidocaine 7.7 66 7317 94 2 6.7 0.7 • Lidocaine 7.9 76 366 64 1 1 1 • Mepivacaine 7.6 61 130 77 1 1 2.6 • Prilocaine 7.9 76 129 55 1 ¿ 0.8 • Ropivacaine 8.1 83 775 94 4 4.8 3.6 • Chloroprocaine 8.7 95 810 — 0.5 — — • Procaine 8.9 97 100 6 — — — • Tetracaine 8.5 93 5822 94 — — — *\*Modified from Salinas FV, Liu SL, Schlz AM. Analgesics. Ion channel ligands/sodium channels blockers/local anesthetics. Chapter 30. In: Evers AS, Maze M. Editors. Anesthetic pharmacology. Physiologic principles and clinical* 

**Anesthetic pKa Ionized** 

**Physico-chemical characteristics Relative potency in different** 

**% protein binding**

**blocks**

**Epidural Spinal Peripheral** 

**nerve**

#### *Local Anesthetics DOI: http://dx.doi.org/10.5772/intechopen.93643*

*Topics in Local Anesthetics*

bupivacaine, which contains the dextro-isomer and levo-isomer. The mixture of both is known as racemic combination. Ropivacaine only has a L-isomer. Lidocaine and ametocaine are aquirales since they do not have stereoisomers. D-isomers have more affinity for sodium channels than L-isomers, this makes the former more toxic

Etidocaine Ropivacaine Levobupivacaine

LAs are small molecules 220–350 Daltons weight, weak bases, poorly soluble and unstable in water, and therefore, they must be combined with a strong acid to obtain a stable salt that is soluble in water at pH 4.7. The solubility in water is directly related to the degree of ionization and inversely related to the fat solubility. In solution, LAs exist in two forms: basic, nonionized (B) and acidic, cationic, ionized

). The ratio between these two forms depends on the dissociation constant

LA is passive. In order to act they must contact the axon and for this they must pass through the epineurium, perineurium and endoneurium of the peripheral nerve, as well as the myelin layer in the myelinated fibers (lipid-rich structures), and finally cross the cell membrane to be in contact with the receptor site on sodium channels. The fat-soluble basic form B diffuses easily through the perineural structures and the axonal membrane; once inside the cell it is protonized and it is this ionized form

The minimum inhibitory concentration (MIC) is necessary to block the conduction of a nerve impulse along a nerve fiber within a certain period. The MIC is different for each LA and allows to differentiate them according to their potency. Several factors can determine the Cm: the size of the fibers (higher MIC for the thicker ones), the pH (lower MIC at higher pH), calcium concentration (higher MIC at higher calcium concentration), and frequency of nerve stimulation (smaller

Due to the characteristics of the nerve fibers, LAs first block the unmyelinated fibers (C fibers, which correspond to the postganglionic neurons of the autonomic

nervous system), those of nociceptive conduction (analgesia), proprioceptive, tactile sensitivity, and pressure (anesthesia), and finally, the motor fibers

form will be higher the higher the pKa. Diffusion of a

ions. At a specific

. This pH is called pKa.

). At a pH of

[26, 27]. **Table 2** shows the chemical classification of LAs.

**Amino ester Amino amide** Cocaine Dibucaine Benzocaine Lidocaine Procaine Mepivacaine Tetracaine Prilocaine 2-cloroprocaine Bupivacaine

(Ka) of the conjugated acid and on the local concentration of H+

The relationship can be expressed like this: pKa = pH-log (B) / (BH+

pH for each LA, the concentration of B is equal to that of BH+

that occupies the aforementioned receptor site [23, 25].

**6. Physical properties, activity, and potency**

**10**

(motor block).

(BH+

**Table 2.**

*Chemical classification of local anesthetics.*

7.40, the percentage of BH+

MIC at higher frequency).

The latency period of a nerve block is not linked to the potency of the LA, but seems to depend on its lipid solubility and pKa, that is, on the pH in which 50% of the molecules are in ionized form and 50% in nonionized form. The higher the pKa, the greater the latency time of a LA. On the other hand, the decrease in tissue pH can lengthen the latency time by limiting the formation of free base; instead, carbonation of a LA solution shortens its latency time. Alkalinization has also been shown to produce a better sensory and motor quality nerve block and may increase diffusion of block height. By alkalinizing LAs, their ionization increases and the percentage of fat solubility of the LA increases, facilitating its diffusion through the lipid structures of the nerves, including the axonal membrane. The addition of 1 mL of sodium bicarbonate to 10 mL of lidocaine improves the onset of extradural or peripheral block for 3–5 min, also increasing its duration of action.

With the exception of cocaine and ropivacaine, LAs produce vasodilation. Adding a vasoconstrictor to LAs is an acceptable routine since two basic actions were demonstrated: increased duration of action and decreased absorption. It also increases the intensity of sensory and motor block in neuroaxial anesthesia. Epinephrine was one of the first drugs to be injected into the subarachnoid space: however, its use was not widespread as the initial results were disappointing. The local vasoconstriction produced by adrenaline favors the decrease in the absorption of LAs, which favor a longer interaction, in addition to decreasing blood concentrations levels and thus their potential for systemic toxicity. On the other hand, epinephrine has an effect on alpha2 receptors in the CNS, especially in the spinal cord, which could be another factor for the improvement it has in neuroaxial blocks. Higher concentrations of adrenaline 2: 000,000 (5 μg/mL) do not offer major advantages in terms of prolonging anesthesia or reducing plasma concentrations. Never use solutions with adrenaline to infiltrate areas with terminal arterial circulation such as the fingers, the penis, the nasal tip, or other areas with critical arterial circulation, since it may promote ischemia and local necrosis.


*\*Modified from Salinas FV, Liu SL, Schlz AM. Analgesics. Ion channel ligands/sodium channels blockers/local anesthetics. Chapter 30. In: Evers AS, Maze M. Editors. Anesthetic pharmacology. Physiologic principles and clinical practice. Editorial Churchill-Livingstone. Philadelphia, USA. 2004 pag 507–537.*

#### **Table 3.**

*Physical and chemical characteristics and relative potency of some local anesthetics \**

The phenomenon of tachyphylaxis or acute tolerance to LAs is characterized by a decreased effectiveness of a LA with repeated administration of the same dose. Its prevalence and mechanisms have not been well defined. This phenomenon occurs with different anesthetics, with different application techniques, and has been seen to develop more frequently when redosing is administered after the analgesic effect of the previous dose has ended [28, 29]. It has been mentioned that it could be due to a progressive acidification of the injection site that is established more rapidly with weak pKa LAs. A central mechanism through spinal cord sensitization that could be avoided by pretreatment with NMDA or nitric oxide antagonists has also been described [29–31].

The potency of LAs refers to the sensitivity of the neural tissue to the different LAs. This potency increases with increasing affinity for lipids. The binding capacity of LAs to the phospholipid membrane as a result of the physicochemical characteristics and the interaction in vivo is directly related to their potency. Other factors affecting the potency of a LA include: hydrogen ion balance, fiber size, type, and myelination, vasodilator/vasoconstrictive properties (affects vascular absorption rate), frequency of nerve stimulation, tissue pH, and electrolyte concentrations (hypokalemia and hypercalcemia antagonize the block).

**Table 3** shows some physical and chemical characteristics as well as the relative potency of some frequently used LAs.

#### **7. Pharmacokinetics**

The anesthetic and analgesic results of the injection of a LA in the vicinity of the neural tissue depend on the factors that have already been described. Plasma levels are affected by the injection site, the degree of absorption, its tissue distribution, its metabolism, and elimination, among other factors that have already been discussed.

#### **7.1 Absorption**

The quantity of LA that is absorbed from its application site and reaches the bloodstream is an important toxicity and elimination factor. LAs with poor absorption are safer. The absorption depends, on one hand, on the characteristics of the tissue; it increases in very vascularized territories and diminishes in fatty tissue. The plasma concentration depends on the total dose administered rather than the concentration, for most LAs there is a linear relationship between total dose and blood concentration [32]. On the other hand, the physicochemical characteristics also modulate the absorption of the drug, for example, the most lipophilic LAs and with greater affinity for proteins will be absorbed more slowly than those with less affinity for fatty tissue. Remember that the most lipophilic are also the most potent LAs. The decrease in absorption when adrenaline is added is more effective for LAs of short action and lower potency [33, 34]. With this, gradual absorption is achieved, the duration of action is prolonged and plasma levels are decreased as well as hemorrhage in the operative field.

#### **7.2 Distribution**

It depends on the physicochemical characteristics of each LA, its coefficient of solubility and plasma protein binding. A higher coefficient of solubility together with a lower degree of protein binding favors an easier distribution in peripheral tissues and a lower plasma concentration. LAs cross the blood-brain and placental

**13**

maturity.

**8. Clinical aspects**

**8.1 Amino ester LAs**

has no use in regional anesthesia.

*Local Anesthetics*

*DOI: http://dx.doi.org/10.5772/intechopen.93643*

with the longest duration of action.

**7.3 Metabolism and elimination**

esters are eliminated by the kidney.

Prilocaine is metabolized outside the liver.

LAs most commonly used in anesthesiology.

barriers by simple diffusion; this diffusion is greater when the ability to bind to plasma proteins is lower. Variable levels bind to plasma proteins in the bloodstream, particularly alpha-1- glycoprotein acid. This protein-binding property correlates with its affinity for sodium channels and predicts the duration of neural blockage. Bupivacaine has the highest percentage of protein binding and is therefore the LA

LAs differ in their metabolism according to their chemical structure; those with ester-type binding (except cocaine) are rapidly hydrolyzed by plasma esterases, so the duration of their action increases with the deficit of this enzyme or the presence of atypical cholinesterase. Cocaine is hydrolyzed in the liver. The metabolites of the

Amide LAs are metabolized in the liver. This is a slow process, which favors a longer half-life than esters and can accumulate when repeated doses or infusions are administered. Liver function interferes with the elimination of these drugs; extraction, perfusion and hepatic metabolism are definitive factors, as it is the degree of protein binding. The metabolites and the nonmetabolized drug are eliminated by urine and a small amount by feces. Elimination is favored by an acid urinary pH.

The fact that amino ester-type LAs are rapidly metabolized favors that they remain in the blood for a short period of time, including placental blood and the fetus. Those of the amino-amide type pass more easily to the fetus, especially those with lower affinity to plasma proteins such as lidocaine, which can result in fetal toxicity. When the fetus has been compromised by any pathology and is acidotic, more ionization of the LA that has passed into its fetal circulation is favored. In this way the LA will remain longer in the fetus with the possibility of severe toxicity. In the newborn, this toxicity can be accentuated since there is no hepatocellular

LAs are one of the most commonly used drugs in clinical anesthesia; either by the neuroaxial route, in the vicinity of nerves and nerve plexuses, subcutaneous, transcutaneous, trans mucosal, intraarticular, and intravenously. The introduction of levoisomeric LAs, the evolution of regional anesthesia techniques with the recommendations of epidural test dose with a vasoactive marker, fractional peridural doses, low and intrathecal minidose, multiple injections with low volumes for nerve plexuses blocks, the use of nerve stimulator, guides with ultrasound and other imaging techniques, as well as the addition of adjuvant drugs such as opioids, alpha2 agonists, NMDA receptor antagonists, among others have done regional anesthesia safer. **Tables 4** and **5** categorize the most important formulas and characteristics of

The precursor of this group is cocaine. They are characterized by being metabolized by plasmatic esterases, short half-life and being related to allergic reactions. The most commonly used are procaine, chloroprocaine, and tetracaine. Benzocaine

#### *Local Anesthetics DOI: http://dx.doi.org/10.5772/intechopen.93643*

*Topics in Local Anesthetics*

been described [29–31].

**7. Pharmacokinetics**

**7.1 Absorption**

**7.2 Distribution**

The phenomenon of tachyphylaxis or acute tolerance to LAs is characterized by a decreased effectiveness of a LA with repeated administration of the same dose. Its prevalence and mechanisms have not been well defined. This phenomenon occurs with different anesthetics, with different application techniques, and has been seen to develop more frequently when redosing is administered after the analgesic effect of the previous dose has ended [28, 29]. It has been mentioned that it could be due to a progressive acidification of the injection site that is established more rapidly with weak pKa LAs. A central mechanism through spinal cord sensitization that could be avoided by pretreatment with NMDA or nitric oxide antagonists has also

The potency of LAs refers to the sensitivity of the neural tissue to the different LAs. This potency increases with increasing affinity for lipids. The binding capacity of LAs to the phospholipid membrane as a result of the physicochemical characteristics and the interaction in vivo is directly related to their potency. Other factors affecting the potency of a LA include: hydrogen ion balance, fiber size, type, and myelination, vasodilator/vasoconstrictive properties (affects vascular absorption rate), frequency of nerve stimulation, tissue pH, and electrolyte concentrations

**Table 3** shows some physical and chemical characteristics as well as the relative

The anesthetic and analgesic results of the injection of a LA in the vicinity of the neural tissue depend on the factors that have already been described. Plasma levels are affected by the injection site, the degree of absorption, its tissue distribution, its metabolism, and elimination, among other factors that have already been discussed.

The quantity of LA that is absorbed from its application site and reaches the bloodstream is an important toxicity and elimination factor. LAs with poor absorption are safer. The absorption depends, on one hand, on the characteristics of the tissue; it increases in very vascularized territories and diminishes in fatty tissue. The plasma concentration depends on the total dose administered rather than the concentration, for most LAs there is a linear relationship between total dose and blood concentration [32]. On the other hand, the physicochemical characteristics also modulate the absorption of the drug, for example, the most lipophilic LAs and with greater affinity for proteins will be absorbed more slowly than those with less affinity for fatty tissue. Remember that the most lipophilic are also the most potent LAs. The decrease in absorption when adrenaline is added is more effective for LAs of short action and lower potency [33, 34]. With this, gradual absorption is achieved, the duration of action is prolonged and plasma levels are decreased as well

It depends on the physicochemical characteristics of each LA, its coefficient of solubility and plasma protein binding. A higher coefficient of solubility together with a lower degree of protein binding favors an easier distribution in peripheral tissues and a lower plasma concentration. LAs cross the blood-brain and placental

(hypokalemia and hypercalcemia antagonize the block).

potency of some frequently used LAs.

as hemorrhage in the operative field.

**12**

barriers by simple diffusion; this diffusion is greater when the ability to bind to plasma proteins is lower. Variable levels bind to plasma proteins in the bloodstream, particularly alpha-1- glycoprotein acid. This protein-binding property correlates with its affinity for sodium channels and predicts the duration of neural blockage. Bupivacaine has the highest percentage of protein binding and is therefore the LA with the longest duration of action.

#### **7.3 Metabolism and elimination**

LAs differ in their metabolism according to their chemical structure; those with ester-type binding (except cocaine) are rapidly hydrolyzed by plasma esterases, so the duration of their action increases with the deficit of this enzyme or the presence of atypical cholinesterase. Cocaine is hydrolyzed in the liver. The metabolites of the esters are eliminated by the kidney.

Amide LAs are metabolized in the liver. This is a slow process, which favors a longer half-life than esters and can accumulate when repeated doses or infusions are administered. Liver function interferes with the elimination of these drugs; extraction, perfusion and hepatic metabolism are definitive factors, as it is the degree of protein binding. The metabolites and the nonmetabolized drug are eliminated by urine and a small amount by feces. Elimination is favored by an acid urinary pH. Prilocaine is metabolized outside the liver.

The fact that amino ester-type LAs are rapidly metabolized favors that they remain in the blood for a short period of time, including placental blood and the fetus. Those of the amino-amide type pass more easily to the fetus, especially those with lower affinity to plasma proteins such as lidocaine, which can result in fetal toxicity. When the fetus has been compromised by any pathology and is acidotic, more ionization of the LA that has passed into its fetal circulation is favored. In this way the LA will remain longer in the fetus with the possibility of severe toxicity. In the newborn, this toxicity can be accentuated since there is no hepatocellular maturity.

#### **8. Clinical aspects**

LAs are one of the most commonly used drugs in clinical anesthesia; either by the neuroaxial route, in the vicinity of nerves and nerve plexuses, subcutaneous, transcutaneous, trans mucosal, intraarticular, and intravenously. The introduction of levoisomeric LAs, the evolution of regional anesthesia techniques with the recommendations of epidural test dose with a vasoactive marker, fractional peridural doses, low and intrathecal minidose, multiple injections with low volumes for nerve plexuses blocks, the use of nerve stimulator, guides with ultrasound and other imaging techniques, as well as the addition of adjuvant drugs such as opioids, alpha2 agonists, NMDA receptor antagonists, among others have done regional anesthesia safer. **Tables 4** and **5** categorize the most important formulas and characteristics of LAs most commonly used in anesthesiology.

#### **8.1 Amino ester LAs**

The precursor of this group is cocaine. They are characterized by being metabolized by plasmatic esterases, short half-life and being related to allergic reactions. The most commonly used are procaine, chloroprocaine, and tetracaine. Benzocaine has no use in regional anesthesia.

**Table 4.**

*Formulae and characteristics of amino ester local anesthetics.*

#### **8.2 Amino amide LAs**

They are the most used in regional anesthesia. Lidocaine is the typical anesthetic with which almost all new drugs in this group have been compared. Even when they have differences such as latency time, duration, and toxicity they have a mechanism of action common to all LAs. They can be divided into two large groups: those of short duration and those of long duration.

Slow long-release of LAs are recent advances that have improved the management of postoperative pain. Nanostructured carriers, such as liposomes and polymers, facilitate the prolonged release of LAs. Exparel® was the first approved liposomal LA to combine racemic bupivacaine with liposomes. Polymersomes have advances over liposomes with complementary profiles, inspiring the emergence of hybrid carriers [35, 36]. Also, multilamellar vesicles with ropivacaine are being investigated to prolong its analgesic effect [37].

**15**

*Local Anesthetics*

*DOI: http://dx.doi.org/10.5772/intechopen.93643*

**Formulae Most important features**

It is the prototype in this group. After intravenous administration, the apparent volume of distribution is 92 L. Its alpha half-life is 8.3 min, its beta half-life is 108 min, and its plasma clearance 0.77 L/min. Its metabolism is hepatic, with an extraction coefficient of 0.7. The addition of adrenaline decreases its passage to the blood by 30%. It has a duration of action that varies from 2 to 3 hours depending on the site of administration and the addition of adrenaline. The toxic neurological manifestations of lidocaine are directly proportional to plasma levels. If these are low (0.5 to 4 mg / mL); lidocaine is anticonvulsant, at higher levels (8 mg/mL) it can cause seizures. In the heart, lidocaine blocks sodium channels, decreasing contraction (V max), the amplitude and duration of the action potential, and increases the duration of the refractory period. These effects are only observed with elevated plasma levels. The action on the heart can be summarized in: dose automatism: below 5 mg/mL, onset of sinus bradycardia; conduction: no modification (atrioventricular or intraventricular) at usual doses; contractility: decrease, but only at doses that cause frank toxicity. At low plasma levels, lidocaine increases vascular tone; at higher levels vasodilation occurs. Direct intravascular injection does not produce obvious hemodynamic alterations as long as the dose is not greater than 3 mg/kg. From 4 to 8 mg/kg, cardiovascular depression occurs, which is dangerous if the dose is greater than 8 mg/kg. If there is heart failure, the toxicity threshold decreases. Its pharmacokinetic properties are similar to those of lidocaine, although it is less vasodilator. It is used in infiltration for peripheral nerve and in epidural anesthesia. The usual concentrations range between 0.5 and 2%. It is 40 times less toxic than lidocaine. An ideal use is intravenous regional anesthesia. A potential risk is the appearance of methemoglobinemia (total doses greater than 500 to 600 mg), so its use in obstetrics is restricted or contraindicated.

First approved in Germany in 1976, in Canada in 1982 and in 2000 by the FDA. It has a thiophene group, an ester group and also an amide group. It has been classified in the amide group by its intermediate chain and because it is metabolized in the liver. However, its ester portion allows it to be degraded by plasma pseudocholinesterase. The mean maximum plasma drug concentration is about 400 μg/L for articaine with epinephrine 1:200,000 and 580 μg/L without epinephrine. The elimination halftime is approximately 20 min. The rapid breakdown to the inactive metabolite articainic acid is related to a very low systemic toxicity and consequently to the possibility of repeated injections. It has been associated with paresis and long-lasting paraesthesia, which are more frequent than those produced by lidocaine. It is commonly

Its molecular formula is C15H22N2O-HCL, soluble in water and very resistant to acid and alkaline hydrolysis. It is available in concentrations of 1%, 1.5% and 2%. The latency and duration of action are similar to those of prilocaine and its potency resembles lidocaine. Useful concentrations range between 0.5 and 2%. It diffuses well through tissues, which allows favorable blocking despite a less optimal needle placement. It produces an intense motor block. It is used to perform infiltration, peridural and spinal anesthesia (with a lower incidence of neurological alterations than lidocaine). Its use is not advised in obstetrics based on its prolonged metabolism in the fetus and in the newborn. It is recommended for peripheral nerve blocks in certain conditions: patients with cardiac risk or with drugs that potentiate toxicity. Adrenaline decreases the absorption of mepivacaine but does not prolong its duration of

used in dentistry.

action.

#### *Local Anesthetics DOI: http://dx.doi.org/10.5772/intechopen.93643*

*Topics in Local Anesthetics*

**Formulae Important features**

In addition to blocking the impulse of axonal conduction, it has the ability to inhibit neurotransmitter recapture in adrenergic neuronal endings, which means accumulation of norepinephrine in sympathetic synapses inducing vasoconstriction and cardiac stimulation. In the CNS, the accumulation of norepinephrine causes stimulation; however, some adrenergic neurotransmitters in the CNS are inhibited, in particular the dopamine recapture resulting in euphoria and abuse potential. Its clinical utility is limited to topical anesthesia, in solutions 4 and 10%. Due to its vasoconstrictor action, it has been used in anesthesia of the nasal mucosa to

It has been used at 0.5, 1, 2, 5, and 10% for infiltration, peripheral, and spinal blocks. Procaine is of special interest in dentistry in 2% solution with 1:50,000 adrenaline. The allergic capacity of para-aminobenzoic acid (PABA) limits its clinical utility. The maximum doses are 750 mg with adrenaline and 500 mg without vasoconstrictor. It has been used by the subarachnoid route in increasing concentrations to establish the differential

It is used in solutions 1, 2, and 3% for infiltration, peripheral blockages, and epidural anesthesia. Due to its brief time of action, it is very useful in peridural block in cesarean section. The neurotoxicity observed after intrathecal injection, attributed to the sodium bisulfite in the solution, has limited the wide use caused by its low systemic toxicity. The maximum recommended doses are 800 mg with adrenaline and 600 mg without it. There are studies that favor intrathecal injection of chloroprocaine without

Useful in topical anesthesia in the form of ointment, chewable tablets, and gel. It is poorly soluble and remains in the place of its application. It is not

It has pKa of 8.46, plasma protein binding of 75.6% and N-heptane / water partition coefficient of 4.1. Despite its high systemic toxicity, it has been used in subarachnoid anesthesia in hyperbaric solutions 1 and 2% due to its high efficacy. Its latency is not very long, and the duration of the anesthetic effect is 2 to 3 hours, because its plasma hydrolysis is quite slow. Its use has

facilitate nasotracheal intubation.

diagnosis in some painful syndromes.

methylparaben.

used in regional anesthesia.

**14**

**8.2 Amino amide LAs**

**Table 4.**

short duration and those of long duration.

*Formulae and characteristics of amino ester local anesthetics.*

investigated to prolong its analgesic effect [37].

They are the most used in regional anesthesia. Lidocaine is the typical anesthetic with which almost all new drugs in this group have been compared. Even when they have differences such as latency time, duration, and toxicity they have a mechanism of action common to all LAs. They can be divided into two large groups: those of

been replaced by levoisomeric anesthetics.

Slow long-release of LAs are recent advances that have improved the manage-

ment of postoperative pain. Nanostructured carriers, such as liposomes and polymers, facilitate the prolonged release of LAs. Exparel® was the first approved liposomal LA to combine racemic bupivacaine with liposomes. Polymersomes have advances over liposomes with complementary profiles, inspiring the emergence of hybrid carriers [35, 36]. Also, multilamellar vesicles with ropivacaine are being


action.


**Table 5.**

*Formulae and characteristics of local amino-amide type anesthetics.*

#### **8.3 There are 3 LAs: articaine, sameridine, and centbucridine, which due to their special physico-chemical characteristics deserve a brief description**

#### *8.3.1 Articaine*

It is a short-acting LA with intermediate potency. It has been included in the amide group, but it contains an additional ester group that is quickly hydrolyzed by esterases, a chemical characteristic that accelerates its metabolism. The plasma protein binding rate of articaine and articainic acid is 70%. I.V. articaine 80 mg does not produce toxic effects in healthy individuals. It has been used neuraxially, ocularly, intravenously, and in regional blocks. It is suitable and safe for procedures requiring a short duration of action in which a fast onset of anesthesia is desired,

**17**

*Local Anesthetics*

*8.3.2 Sameridine*

postoperative pain.

*8.3.3 Centbucridine*

*DOI: http://dx.doi.org/10.5772/intechopen.93643*

e.g., dental procedures and ambulatory spinal anesthesia. Its most frequent use is in dentistry, where it has demonstrated efficacy and safety. Complete anesthesia is achieved in 90% of cases, using articaine 4% 60–80 mg with epinephrine 1: 200,000. It diffuses well through soft tissue and bone; concentration in the alveolus of a tooth in the upper jaw after extraction was about 100 times higher than that in systemic circulation. In comparative clinical trials, its effects were not generally significantly different from those of other short-acting LAs like lidocaine, prilocaine, and chloroprocaine. There is no conclusive evidence demonstrating above average neurotoxicity, although cases of frequent persistent paresthesia after articaine use have been described [38–41]. Saralaya et al. compared 4% articaine with 1:100,000 epinephrine versus 2% lidocaine with 1: 100,000 epinephrine in 50 patients operated on the third molar. These authors found that the mean onset time for articaine and lidocaine was 3.16 ± 0.55 and 3.2 ± 0.48 min, respectively. Postoperative analgesia was longer in the articaine group and its duration of action was 289.04 ± 40 and 361.88 ± 40 min, respectively, compared to lidocaine, which is 144.2 ± 12 and 197.44 ± 25 min, respectively. These authors recommend articaine since it was more potent and with a longer duration of action with better postoperative analgesia and could be considered as an alternative to lidocaine [42]. Even in the presence of pulpitis, articaine proved to be more effective than lidocaine in patients undergoing root canal treatment [43]. There is no information available on the use

of articaine during lactation, so its use is not entirely recommended yet.

This drug has mixed characteristics: LA and μ-opioid partial agonist. It is structurally similar to meperidine. It is a compound that is still under investigation (N-ethyl-1-hexyl-N-methyl-4-phenyl-4-piperidine carboxyamide hydrochloride) mainly for spinal anesthesia. Liver hydroxylation is the primary metabolic pathway, and no local neurotoxicity has been found in animal studies. Its effect on respiration is directly related to plasma levels. In healthy volunteers [44] 25 mg vs. intrathecal bupivacaine 15 mg has similar effects on resting ventilation. The ventilatory response to hypoxia and hypercarbia were found to be discreetly diminished in the group treated with sameridine. Intravenous doses of 0.73 mg/kg depress the ventilatory response to hypercarbia [45]. The clinical doses of 150 μg/kg have no significant effects on ventilation [46]. Intrathecal doses of 15–25 mg of sameridine are sufficient for inguinal and orthopedic surgery, respectively. Doses of 5–20 mg are comparable with 100 mg of intrathecal lidocaine. The advantage is that sameridine produces residual analgesia and reduces the need for opioids in the first hours of the postoperative period [7, 8], so it could have a role in the management of

It is a nonester, nonamide LA, chemically known as 4-N-butylamino-1,2,3,4 tetrahydroacridine hydrochloride. It is a quinolone derivative drug with LA effects synthesized in 1982 by Patnaik et al. [47–49]. It is 5 to 8 times more potent than lidocaine, while its LD50 is one fourth that of lidocaine. It has vasoconstrictor and antihistamine effects, rapid onset of action (1–3 min), duration of action is prolonged (2.5 hours), and no events of cardiotoxicity or neurotoxicity have been reported. Centbucridine has been investigated for infiltration, conjunctival surface, in peripheral nerves, neuroaxial anesthesia, intravenous regional anesthesia; however, the majority of studies are in dental anesthesia [9, 50–52]. Most studies compare 0.5% centbucridine vs. 2% lidocaine, with similar anesthetic results,

#### *Local Anesthetics DOI: http://dx.doi.org/10.5772/intechopen.93643*

*Topics in Local Anesthetics*

**Formulae Most important features**

of the prolonged action.

widely used in pain clinic.

peripheral nerve blocks.

It is more fat-soluble and has a higher degree of affinity to plasma proteins than lidocaine, has a short latency and longer duration. Epidural route is used at 0.5 to 1%. It produces greater motor blockage than sensitive which makes it useful in abdominal surgery, its use in obstetric analgesia anesthesia is not advised. Its beta halflife is 2.5 hours, and care should be taken in liver disorders because

It is a racemic mixture, long-acting drug that produces a differential sensory-motor block at low concentrations. It has a limited placental transfer, so it is widely used in obstetrics in concentrations of up to 0.5%. Higher concentrations are not recommended in obstetrics. It is the LA with greater cardio and neuro toxicity and greater difficulty in resuscitation since it has a great affinity for voltage-dependent sodium channels. However, after lidocaine, it is the most used. It is

It is bupivacaine levoisomer. It has pharmacological properties similar to bupivacaine but less toxicity. Its toxicity depends on the route of administration and the dose, its pharmacokinetic is similar to bupivacaine and its plasma peak is 30 min after epidural administration, with an alpha-glycoprotein and albumin binding greater than 97% at concentrations of 0.1 at 1 ug/mL. It is metabolized in the liver and the kidney does not seem to intervene in its elimination. Produces differential blockade similar to bupivacaine, which depends on the dose and concentration, which will be less than 0.25% such as 0.0625 and 0.125% for epidural analgesia, and 0.5% to 0.75% for neuroaxial anesthesia and

The first levoisomeric LA for clinical use. The plasma alpha glycoprotein binding is 95%, with a pKa of 8.1 and a partition coefficient of 141. Due to its low absorption, it has a longer elimination half-life and its pharmacokinetic has a linear proportional to the dose, with a volume of distribution of 47 liters. Like bupivacaine, it has a greater effect on C fibers than A, which produces a sensory rather than motor block. The clinical experience is excellent in neuroaxial anesthesia and peripheral nerve blocks. It is of great value by epidural route (obstetrics), and in postoperative analgesia. It is characterized by a block of greater latency and long duration. Less analgesic potency than bupivacaine and levobupivacaine. It is less cardiotoxic and neurotoxic than bupivacaine with a better response to resuscitation. Usefull in pain

**16**

*8.3.1 Articaine*

**Table 5.**

**8.3 There are 3 LAs: articaine, sameridine, and centbucridine, which due to their special physico-chemical characteristics deserve a brief description**

clinic.

*Formulae and characteristics of local amino-amide type anesthetics.*

It is a short-acting LA with intermediate potency. It has been included in the amide group, but it contains an additional ester group that is quickly hydrolyzed by esterases, a chemical characteristic that accelerates its metabolism. The plasma protein binding rate of articaine and articainic acid is 70%. I.V. articaine 80 mg does not produce toxic effects in healthy individuals. It has been used neuraxially, ocularly, intravenously, and in regional blocks. It is suitable and safe for procedures requiring a short duration of action in which a fast onset of anesthesia is desired,

e.g., dental procedures and ambulatory spinal anesthesia. Its most frequent use is in dentistry, where it has demonstrated efficacy and safety. Complete anesthesia is achieved in 90% of cases, using articaine 4% 60–80 mg with epinephrine 1: 200,000. It diffuses well through soft tissue and bone; concentration in the alveolus of a tooth in the upper jaw after extraction was about 100 times higher than that in systemic circulation. In comparative clinical trials, its effects were not generally significantly different from those of other short-acting LAs like lidocaine, prilocaine, and chloroprocaine. There is no conclusive evidence demonstrating above average neurotoxicity, although cases of frequent persistent paresthesia after articaine use have been described [38–41]. Saralaya et al. compared 4% articaine with 1:100,000 epinephrine versus 2% lidocaine with 1: 100,000 epinephrine in 50 patients operated on the third molar. These authors found that the mean onset time for articaine and lidocaine was 3.16 ± 0.55 and 3.2 ± 0.48 min, respectively. Postoperative analgesia was longer in the articaine group and its duration of action was 289.04 ± 40 and 361.88 ± 40 min, respectively, compared to lidocaine, which is 144.2 ± 12 and 197.44 ± 25 min, respectively. These authors recommend articaine since it was more potent and with a longer duration of action with better postoperative analgesia and could be considered as an alternative to lidocaine [42]. Even in the presence of pulpitis, articaine proved to be more effective than lidocaine in patients undergoing root canal treatment [43]. There is no information available on the use of articaine during lactation, so its use is not entirely recommended yet.

#### *8.3.2 Sameridine*

This drug has mixed characteristics: LA and μ-opioid partial agonist. It is structurally similar to meperidine. It is a compound that is still under investigation (N-ethyl-1-hexyl-N-methyl-4-phenyl-4-piperidine carboxyamide hydrochloride) mainly for spinal anesthesia. Liver hydroxylation is the primary metabolic pathway, and no local neurotoxicity has been found in animal studies. Its effect on respiration is directly related to plasma levels. In healthy volunteers [44] 25 mg vs. intrathecal bupivacaine 15 mg has similar effects on resting ventilation. The ventilatory response to hypoxia and hypercarbia were found to be discreetly diminished in the group treated with sameridine. Intravenous doses of 0.73 mg/kg depress the ventilatory response to hypercarbia [45]. The clinical doses of 150 μg/kg have no significant effects on ventilation [46]. Intrathecal doses of 15–25 mg of sameridine are sufficient for inguinal and orthopedic surgery, respectively. Doses of 5–20 mg are comparable with 100 mg of intrathecal lidocaine. The advantage is that sameridine produces residual analgesia and reduces the need for opioids in the first hours of the postoperative period [7, 8], so it could have a role in the management of postoperative pain.

#### *8.3.3 Centbucridine*

It is a nonester, nonamide LA, chemically known as 4-N-butylamino-1,2,3,4 tetrahydroacridine hydrochloride. It is a quinolone derivative drug with LA effects synthesized in 1982 by Patnaik et al. [47–49]. It is 5 to 8 times more potent than lidocaine, while its LD50 is one fourth that of lidocaine. It has vasoconstrictor and antihistamine effects, rapid onset of action (1–3 min), duration of action is prolonged (2.5 hours), and no events of cardiotoxicity or neurotoxicity have been reported. Centbucridine has been investigated for infiltration, conjunctival surface, in peripheral nerves, neuroaxial anesthesia, intravenous regional anesthesia; however, the majority of studies are in dental anesthesia [9, 50–52]. Most studies compare 0.5% centbucridine vs. 2% lidocaine, with similar anesthetic results,

although some have found longer anesthetic duration in patients who were treated with centbucridine [51, 53]. Centbucridine can be used with confidence in dental patients who cannot tolerate other LAs or when epinephrine is contraindicated.

#### **8.4 Maximum dose of LAs**

Another clinical aspect of capital interest is the maximum doses of each LA. The maximum recommended doses have been established arbitrarily by the pharmaceutical industry [54] and vary according to the route of administration, the type of anesthetic, with or without vasoconstrictors, as well as the type of patient and surgery. **Table 6** shows the maximum recommended doses for the most commonly used LAs, without these doses having been established by studies conducted specifically to determine the safest and most effective amounts of each. Note the variants, sometimes with important ranges; 200 mg of lidocaine is recommended in Europe, while in the United States this dose reaches 300 mg when epinephrine is not used. Notwithstanding these differences, it is advisable to stay below the maximum recommended dosage range to avoid undesirable toxic effects.

#### **8.5 Adequate anesthetic technique**

Regional anesthesia techniques are important not only in the expected results, but to reduce undesirable side effects of LAs. It is known that spinal anesthesia produces lower plasma concentrations of LAs, unlike interpleural injection that in theory results in higher concentrations, and therefore, could be the procedure that produces more toxic events. However, this situation is hypothetical, since toxic events occur more frequently in peripheral blockages and peridural injections. For different types of nerve blocks, the same total injected dose produces different blood concentrations for mepivacaine, lidocaine, prilocaine and etidocaine, with the intercostal block being the one that produces the highest blood absorption, followed by injections in the peridural space. Plexus nerve blocks and subcutaneous injection are those that have a lower degree of absorption of LAs.

#### **8.6 Undesirable side effects**

The anesthetic and analgesic effects of LAs and their toxicity originate in the same mechanism of action; its interaction in the sodium channels. The therapeutic efficacy and safety of LAs has been proven from the moment of their discovery and it was precisely the deleterious effects that prompted the search for safer agents.


**19**

*Local Anesthetics*

*8.6.1 Toxicity*

*DOI: http://dx.doi.org/10.5772/intechopen.93643*

read chapter 10 of this book.

1.Toxic reactions to:

2.Allergic reactions

sodium channels.

a.To the LA

a.Systemic and local

b.Not related to the LAs

b.To conservatives or antioxidants

possibility of cardio and neuro toxicity.

doses of LAs and have been linked to toxic events.

In 1905 Braun mentioned the characteristics that a new LA should have: *In addition to producing local anesthesia, any new drug in this abundant group should have the following properties: be less toxic than the standard available, it should not irritate or damage tissues, it must be soluble in water, and stable in solution, it must be able to mix with adrenaline, and must be rapidly absorbed into the cell membrane* [55]. More than a century of these recommendations have passed, and we still use LAs that do not meet these characteristics. LAs are used with an acceptable safety margin, without being the ideal drug. The following paragraphs briefly describe the most interesting side effects due to their magnitude and frequency. For more information on toxicity

The history of LAs toxicity began at the end of the 19th century, when clinicians

Events due to toxicity still occur in expert hands and are more related to the type

• Potency of the LA. The greater the fat solubility, the greater potency and more

• Isomerism. LAs that contain a dextroisomer are more toxic than levoisomers. The former have been shown to have a higher affinity for the effector site of

• Total administered dose (plasma concentration). Toxicity is related to plasmatic concentration of AL, and this depends directly on the total administered dose. Epidural blocks and tumescent subcutaneous infiltrations use the highest

of block and the dose injected. Various factors have been described:

of that time realized the deleterious effects of cocaine and began the search for better drugs. Albright's editorial in 1979 [13] commented on six deaths due to cardiovascular collapse after the administration of bupivacaine or etidocaine whipped up this investigation in such a rapid way that currently there are safer drugs. The most important systemic toxic reactions are on CNS and the cardiovascular system. The CNS is affected with lower plasma concentrations than those that cause cardiovascular toxicity and is manifested by alterations in cognition, seizures, and coma. Arrhythmias with or without cardiovascular collapse of difficult management and death occur in the cardiovascular system. The incidence of systemic toxicity has been reduced to 0.01%, with regional blockages being the most associated with these events (7.5/10,000). The current use of ultrasound-guided nerve blocks is likely to reduce these statistics. Toxic effects can be grouped into two large groups:

#### **Table 6.** *Maximum dose of LAs [54].*

#### *Local Anesthetics DOI: http://dx.doi.org/10.5772/intechopen.93643*

In 1905 Braun mentioned the characteristics that a new LA should have: *In addition to producing local anesthesia, any new drug in this abundant group should have the following properties: be less toxic than the standard available, it should not irritate or damage tissues, it must be soluble in water, and stable in solution, it must be able to mix with adrenaline, and must be rapidly absorbed into the cell membrane* [55]. More than a century of these recommendations have passed, and we still use LAs that do not meet these characteristics. LAs are used with an acceptable safety margin, without being the ideal drug. The following paragraphs briefly describe the most interesting side effects due to their magnitude and frequency. For more information on toxicity read chapter 10 of this book.

#### *8.6.1 Toxicity*

*Topics in Local Anesthetics*

**8.4 Maximum dose of LAs**

**8.5 Adequate anesthetic technique**

**8.6 Undesirable side effects**

Maximum dose of lidocaine: Without epinephrine

200 mg (in Europe), 300 mg (in USA) With epinephrine (5 μg/mL) 500 mg in both regions

Maximum dose of PPX anesthetics: Bupivacaine 150–175 mg Levobupivacaine 150 mg Ropivacaine 200–300 mg

brachial by 20–30%

*Maximum dose of LAs [54].*

although some have found longer anesthetic duration in patients who were treated with centbucridine [51, 53]. Centbucridine can be used with confidence in dental patients who cannot tolerate other LAs or when epinephrine is contraindicated.

Another clinical aspect of capital interest is the maximum doses of each LA. The maximum recommended doses have been established arbitrarily by the pharmaceutical industry [54] and vary according to the route of administration, the type of anesthetic, with or without vasoconstrictors, as well as the type of patient and surgery. **Table 6** shows the maximum recommended doses for the most commonly used LAs, without these doses having been established by studies conducted specifically to determine the safest and most effective amounts of each. Note the variants, sometimes with important ranges; 200 mg of lidocaine is recommended in Europe, while in the United States this dose reaches 300 mg when epinephrine is not used. Notwithstanding these differences, it is advisable to stay below the maximum

Regional anesthesia techniques are important not only in the expected results, but to reduce undesirable side effects of LAs. It is known that spinal anesthesia produces lower plasma concentrations of LAs, unlike interpleural injection that in theory results in higher concentrations, and therefore, could be the procedure that produces more toxic events. However, this situation is hypothetical, since toxic events occur more frequently in peripheral blockages and peridural injections. For different types of nerve blocks, the same total injected dose produces different blood concentrations for mepivacaine, lidocaine, prilocaine and etidocaine, with the intercostal block being the one that produces the highest blood absorption, followed by injections in the peridural space. Plexus nerve blocks and subcutaneous

The anesthetic and analgesic effects of LAs and their toxicity originate in the same mechanism of action; its interaction in the sodium channels. The therapeutic efficacy and safety of LAs has been proven from the moment of their discovery and it was precisely the deleterious effects that prompted the search for safer agents.

Epinephrine 1: 200,000 reduces absorption of subcutaneous lidocaine by 50%, intercostal, epidural and

recommended dosage range to avoid undesirable toxic effects.

injection are those that have a lower degree of absorption of LAs.

**18**

**Table 6.**

The history of LAs toxicity began at the end of the 19th century, when clinicians of that time realized the deleterious effects of cocaine and began the search for better drugs. Albright's editorial in 1979 [13] commented on six deaths due to cardiovascular collapse after the administration of bupivacaine or etidocaine whipped up this investigation in such a rapid way that currently there are safer drugs. The most important systemic toxic reactions are on CNS and the cardiovascular system. The CNS is affected with lower plasma concentrations than those that cause cardiovascular toxicity and is manifested by alterations in cognition, seizures, and coma. Arrhythmias with or without cardiovascular collapse of difficult management and death occur in the cardiovascular system. The incidence of systemic toxicity has been reduced to 0.01%, with regional blockages being the most associated with these events (7.5/10,000). The current use of ultrasound-guided nerve blocks is likely to reduce these statistics. Toxic effects can be grouped into two large groups:

#### 1.Toxic reactions to:

a.Systemic and local

b.Not related to the LAs

2.Allergic reactions

a.To the LA

b.To conservatives or antioxidants

Events due to toxicity still occur in expert hands and are more related to the type of block and the dose injected. Various factors have been described:


In the ester group, cocaine remains the most toxic LA, and procaine and chloroprocaine are the least potent and least toxic potency, not only in the ester group, but among all known LAs. In the amino-amide group racemic bupivacaine, etidocaine, and mepivacaine are more toxic than levobupivacaine and ropivacaine. Lidocaine and prilocaine are the least toxic in this group.

Cardiotoxicity. The toxic effects of LAs on the cardiovascular system are divided into two groups; the physiological changes that are generated with some regional anesthesia techniques and the effects that derive from the actions of these drugs on sodium, potassium, calcium channels, and beta myocardial receptors. These side effects on the cardiovascular system can be explained by the following four mechanisms:


#### *8.6.2 Neurotoxicity*

The toxicity of LAs on the nervous system manifests itself in two areas; those that are triggered by high blood concentrations and are due to their action on sodium channels in the CNS, and those that are caused by the direct application of the anesthetic on or in the vicinity of neural structures, especially the injection of lidocaine in the subarachnoid space.

#### *8.6.3 Myotoxicity*

It is well known that continuous perineural injection and direct intramuscular injection of LAs have toxic effects on the striated muscle causing inflammatory

**21**

*Local Anesthetics*

*8.6.4 Allergies*

*DOI: http://dx.doi.org/10.5772/intechopen.93643*

and tetracaine are the ones that produce minor alterations.

True allergies to LAs are rare and generally occur more with ester-type, although allergies have been reported with amino-amide LAs, including new levoisomeric anesthetics [62]. These allergies have a highly variable frequency that ranges from 1: 350 to 1:20,000 and fortunately most are trivial, although occasionally they are factors of significant morbidity and mortality. The incidence of true IgE-mediated LA allergy remains unclear and is presumed to be as low as 0.7–1%. On some occasions these reactions have been attributed to preservatives (methylparaben) or antioxidants (bisulfites) that are contained in some commercial presentations [63, 64]. When someone is reactive to a LA, they will be allergic to it for the rest of their life due to the response of mast cells that release chemical mediators that are responsible for the clinical responses in each patient. These mediators include histamine, leukotrienes, chemotactic substances, lysosomal enzymes, prostaglandins, kinins, and platelet activating factors that facilitate capillary permeation with plasma leakage in the surrounding area. The manifestations of true allergy range from mild to severe and sometimes are deadly. The faster the clinical manifestations occur, the more severe the reaction. The most frequent expression is contact dermatitis, but they can also manifest as urticaria, rash, rhinitis, bronchial spasm, angioneurotic edema, tachycardia, and hypotension and lead to anaphylactic shock. Immunoglobulin E-mediated anaphylaxis can induce respiratory failure and cardiopulmonary collapse. The treatment of true allergies to LAs depends on their severity; mild or moderate reactions disappear spontaneously. In severe reactions it

changes. These drugs act on external cell membranes and on the membranes of intracytoplasmic organelles, especially on the double mitochondrial membrane. Bupivacaine produces alterations in active intracellular oxidative metabolism by depolarizing the mitochondrial membrane and oxidation of the pyridine nucleotide. This results in the opening of permeability transition pore (PTP), a type of channel located in intracellular membranes that plays an important role in various forms of cell death. Injury mechanisms involved early and late abnormalities to cytoplasmic calcium (Ca2+) homeostasis by the sarcoplasmic reticulum Ca2+ ATPase and cytochrome C release. All of these alterations were dependent on bupivacaine concentration and were only found in voluntary striated muscle mitochondria, while mitochondria from esophageal muscle were resistant to bupivacaine [57]. In rabbits, continuous axillary block with placebo vs. 0.25% bupivacaine, at 24 hours neutrophilic infiltration was found in the placebo group, while the group receiving bupivacaine had a large amount of eosinophils. One week later, lymphocytes, plasma cells, macrophages and fibroblasts were found with data of muscle regeneration [58]. Zink et al. [59] compared bupivacaine vs. ropivacaine and demonstrated that the former induced necrosis and apoptosis of muscle fibers, while the latter produced less severe changes in porcine skeletal muscle. These same researchers [60] confirmed their initial results that bupivacaine 0.5% is more myotoxic than ropivacaine 0.75%, by inducing irreversible myonecrosis with calcium deposits, scar formation, and muscle regeneration. The incidence of myotoxicity in ophthalmic studies was 0.77%. Inflammatory changes within a few days after exposure marked the onset of myotoxicity, and muscle degeneration continued within the first week after exposure. Recovery time in human muscles ranged from 4 days to 1 year. None partial and complete recovery was observed in 61% and 38% of patients, respectively [61]. All LAs that have been studied have a similar myotoxic potential in terms of the tissue alterations produced, but they differ in the intensity of these lesions. Bupivacaine and chloroprocaine are the most toxic and procaine

#### *Local Anesthetics DOI: http://dx.doi.org/10.5772/intechopen.93643*

*Topics in Local Anesthetics*

seizures and coma [56].

mechanisms:

and prilocaine are the least toxic in this group.

• Injection site. In general terms, the blood absorption of LAs varies according to the injection site, although it is modified by factors such as the type of anesthetic injected, the addition of vasoconstrictors, and the speed and frequency of injection. The interpleural route favors high absorptions due to the large injection surface and its vascularity. However, this route has not been more frequently related to systemic toxicity, perhaps due to the lung capacity to fix and eliminate the concentration of LA up to ~40%. Spinal administration does not produce systemic toxicity from small doses and decreased vascularity. Injections close to the brain (facial, nasal, oral, neck) have larger possibility of neurological systemic toxicity, either by direct intra-arterial injection or by retrograde flow that transports small doses of the LA directly to the brain tissue than induces

• Patient's health/ASA. Factors such as age, liver and kidney dysfunction, hypoxemia, acidosis, pregnancy, and pharmacological interactions (cytochrome P450 inhibitors) modify the possibility of systemic toxicity.

In the ester group, cocaine remains the most toxic LA, and procaine and chloroprocaine are the least potent and least toxic potency, not only in the ester group, but among all known LAs. In the amino-amide group racemic bupivacaine, etidocaine, and mepivacaine are more toxic than levobupivacaine and ropivacaine. Lidocaine

Cardiotoxicity. The toxic effects of LAs on the cardiovascular system are divided into two groups; the physiological changes that are generated with some regional anesthesia techniques and the effects that derive from the actions of these drugs on sodium, potassium, calcium channels, and beta myocardial receptors. These side effects on the cardiovascular system can be explained by the following four

1.Regional effect due to the blockage of sympathetic preganglionic fibers

2.A direct cardio depressant/arrhythmogenic effect due to sudden and elevated plasma concentrations of local anesthetic by intravascular injection or exag-

4.Systemic absorption of toxic dose can cause spinal depression and secondary

The toxicity of LAs on the nervous system manifests itself in two areas; those that are triggered by high blood concentrations and are due to their action on sodium channels in the CNS, and those that are caused by the direct application of the anesthetic on or in the vicinity of neural structures, especially the injection of

It is well known that continuous perineural injection and direct intramuscular injection of LAs have toxic effects on the striated muscle causing inflammatory

secondary to the neuroaxial injection of the LA.

3.Cardio depressant effect mediated through the CNS.

gerated absorption from the injection site.

circulatory collapse.

lidocaine in the subarachnoid space.

*8.6.2 Neurotoxicity*

*8.6.3 Myotoxicity*

**20**

changes. These drugs act on external cell membranes and on the membranes of intracytoplasmic organelles, especially on the double mitochondrial membrane. Bupivacaine produces alterations in active intracellular oxidative metabolism by depolarizing the mitochondrial membrane and oxidation of the pyridine nucleotide. This results in the opening of permeability transition pore (PTP), a type of channel located in intracellular membranes that plays an important role in various forms of cell death. Injury mechanisms involved early and late abnormalities to cytoplasmic calcium (Ca2+) homeostasis by the sarcoplasmic reticulum Ca2+ ATPase and cytochrome C release. All of these alterations were dependent on bupivacaine concentration and were only found in voluntary striated muscle mitochondria, while mitochondria from esophageal muscle were resistant to bupivacaine [57]. In rabbits, continuous axillary block with placebo vs. 0.25% bupivacaine, at 24 hours neutrophilic infiltration was found in the placebo group, while the group receiving bupivacaine had a large amount of eosinophils. One week later, lymphocytes, plasma cells, macrophages and fibroblasts were found with data of muscle regeneration [58]. Zink et al. [59] compared bupivacaine vs. ropivacaine and demonstrated that the former induced necrosis and apoptosis of muscle fibers, while the latter produced less severe changes in porcine skeletal muscle. These same researchers [60] confirmed their initial results that bupivacaine 0.5% is more myotoxic than ropivacaine 0.75%, by inducing irreversible myonecrosis with calcium deposits, scar formation, and muscle regeneration. The incidence of myotoxicity in ophthalmic studies was 0.77%. Inflammatory changes within a few days after exposure marked the onset of myotoxicity, and muscle degeneration continued within the first week after exposure. Recovery time in human muscles ranged from 4 days to 1 year. None partial and complete recovery was observed in 61% and 38% of patients, respectively [61]. All LAs that have been studied have a similar myotoxic potential in terms of the tissue alterations produced, but they differ in the intensity of these lesions. Bupivacaine and chloroprocaine are the most toxic and procaine and tetracaine are the ones that produce minor alterations.

#### *8.6.4 Allergies*

True allergies to LAs are rare and generally occur more with ester-type, although allergies have been reported with amino-amide LAs, including new levoisomeric anesthetics [62]. These allergies have a highly variable frequency that ranges from 1: 350 to 1:20,000 and fortunately most are trivial, although occasionally they are factors of significant morbidity and mortality. The incidence of true IgE-mediated LA allergy remains unclear and is presumed to be as low as 0.7–1%. On some occasions these reactions have been attributed to preservatives (methylparaben) or antioxidants (bisulfites) that are contained in some commercial presentations [63, 64]. When someone is reactive to a LA, they will be allergic to it for the rest of their life due to the response of mast cells that release chemical mediators that are responsible for the clinical responses in each patient. These mediators include histamine, leukotrienes, chemotactic substances, lysosomal enzymes, prostaglandins, kinins, and platelet activating factors that facilitate capillary permeation with plasma leakage in the surrounding area. The manifestations of true allergy range from mild to severe and sometimes are deadly. The faster the clinical manifestations occur, the more severe the reaction. The most frequent expression is contact dermatitis, but they can also manifest as urticaria, rash, rhinitis, bronchial spasm, angioneurotic edema, tachycardia, and hypotension and lead to anaphylactic shock. Immunoglobulin E-mediated anaphylaxis can induce respiratory failure and cardiopulmonary collapse. The treatment of true allergies to LAs depends on their severity; mild or moderate reactions disappear spontaneously. In severe reactions it

is recommended to use steroids, H1 blockers, antihistamines, or epinephrine. When there is a probable or proven history of allergy to LAs, caution should be exercised: if allergy to an ester compound is found, it should be switched to an amino-amide anesthetic, preferably one without methyl paraben or metabisulfite. When the allergy is to an amino-amide anesthetic, it is advisable to change to another anesthetic from the same group.

#### *8.6.5 Methemoglobinemia*

Prilocaine is metabolized to O-toluidine which can cause methemoglobinemia in susceptible individuals, especially when more than 500 mg is used. In pregnant women, this problem is even more critical since fetal blood poorly reduces methemoglobin. Management is with 1–5 mg of methylene blue.

#### *8.6.6 Rebound pain*

When the analgesic effect of a peripheral nerve block performed with LAs, a state of hyperalgesia known as rebound pain may occur 12–24 hours postoperatively, with intensity disproportionate for the type of the performed surgery. It has been classified as a complication of peripheral nerve blocks, the etiology of which is unknown. Several factors have been considered, including neurotoxicity of LAs, its effects on nociceptors, direct neurotrauma, the possibility of hyperalgesia induced by systemic opioids before or during the block. Its frequency is unknown, although it seems to be increasing, especially in outpatient surgery where it has been reported in up to 40%. It is a relevant complication since it hinders the postoperative evolution, disturbing sleep, increasing the opioid requirement and delaying hospital discharge. Preventive analgesia before the blockage subsides, intra-articular or intravenous anti-inflammatory drugs, and the use of adjuvants added to nerveblock or systemic solutions can reduce rebound pain [65–67].

#### **9. Nonanesthetic uses of LAs**

Some nonanesthetic (off-label) uses of LAs have been described. Although these investigations have not been precisely determined, this topic deserves a brief description.

#### **9.1 Cough, laryngospasm, and asthma**

Lidocaine has been used successfully to prevent or treat cough and laryngospasm induced during tracheal extubation, as well as in patients with asthma and chronic cough difficult to treat [68–70]. The meta-analysis of Yang et al. found that iv lidocaine decreases postoperative airway complications [71]. Nebulized lidocaine has been used with encouraging results in patients with asthma, chronic cough, and laryngospasm; doses ranging from 10 to 400 mg are a therapeutic alternative in asthma and cough that is difficult to manage [72]. Its mechanism of action has been related to the decrease in airway inflammation via downregulation of TLR2 [73].

#### **9.2 Effects of LAs on cancer**

Regional anesthesia is preferably used in oncological surgery since it does not interfere with the immune system, and the postoperative outcome of these patients is better. On the other hand, there is evidence that LAs could have direct

**23**

*Local Anesthetics*

**9.3 Antibiotics**

**10. Conclusions**

medical and dental practice.

*DOI: http://dx.doi.org/10.5772/intechopen.93643*

bial application of lidocaine [2, 78–80].

antineoplastic effects [74, 75]**.** Some malignancies have increased voltage-dependent sodium channel activity. Blocking these channels with LAs may help inhibit tumor progression [76]. Zheng et al. found an anti-melanoma activity of ropivacaine and lidocaine but not bupivacaine, via targeting small GTPases [77].

Besides pain insensitivity, it has been shown that the in vitro and in vivo use of LAs have bacteriostatic, bactericidal, fungistatic, and fungicidal properties against a wide spectrum of microorganisms, this action being attributed to the interruption of the membrane permeability of microbial cells, leading to leakage of cellular components and subsequent cell lysis. Different LAs showed varying degrees of antimicrobial capacity; bupivacaine and lidocaine, for example, inhibit growth to a significantly greater extent than ropivacaine. Higher concentrations, prolonged exposure, and higher temperature correlate with a proportional increase in inhibition of microbial growth. Reducing the incidence of endophthalmitis after intravitreal injection, prophylaxis for surgical wound infections, preventing the incidence of catheter-associated infections, reducing oral biofilms in the oral mucosa, and preventing infection-causing bacteria nosocomial are some examples of antimicro-

The first LA anesthetic was derived from the plant *Erythroxylum coca*, and regional anesthesia began in 1884 when Karl Köller anesthetized the cornea of his patients for surgical purposes. Since then, a host of events, drugs, discoveries, and various anesthesia techniques have culminated in safer and more effective regional anesthesia. LAs have an impressive history of efficacy and safety in medical and dental practice, but still have deleterious effects that can—on rare occasions—cause the death of our patients. Knowing the basics of the substrates where LAs work makes it easier to understand the action mechanisms that these drugs have on voltage-dependent sodium channels. The sequence of events that occur from the choice of the patient, the preparation and injection of LAs to the production of regional anesthesia-analgesia and/or its toxic effects are complex. These physiological and pathophysiological events depend on features as varied as the structural and physico-chemical characteristics, total injected dose, injection site, adjuvant drugs, physical condition of the patient, among others. The safe practice of regional anesthesia definitely reduces catastrophes, but these disasters can appear at any time. LAs have an impressive history of efficacy and safety in

antineoplastic effects [74, 75]**.** Some malignancies have increased voltage-dependent sodium channel activity. Blocking these channels with LAs may help inhibit tumor progression [76]. Zheng et al. found an anti-melanoma activity of ropivacaine and lidocaine but not bupivacaine, via targeting small GTPases [77].

#### **9.3 Antibiotics**

*Topics in Local Anesthetics*

thetic from the same group.

*8.6.5 Methemoglobinemia*

*8.6.6 Rebound pain*

is recommended to use steroids, H1 blockers, antihistamines, or epinephrine. When there is a probable or proven history of allergy to LAs, caution should be exercised: if allergy to an ester compound is found, it should be switched to an amino-amide anesthetic, preferably one without methyl paraben or metabisulfite. When the allergy is to an amino-amide anesthetic, it is advisable to change to another anes-

Prilocaine is metabolized to O-toluidine which can cause methemoglobinemia in susceptible individuals, especially when more than 500 mg is used. In pregnant women, this problem is even more critical since fetal blood poorly reduces methe-

When the analgesic effect of a peripheral nerve block performed with LAs, a state of hyperalgesia known as rebound pain may occur 12–24 hours postoperatively, with intensity disproportionate for the type of the performed surgery. It has been classified as a complication of peripheral nerve blocks, the etiology of which is unknown. Several factors have been considered, including neurotoxicity of LAs, its effects on nociceptors, direct neurotrauma, the possibility of hyperalgesia induced by systemic opioids before or during the block. Its frequency is unknown, although it seems to be increasing, especially in outpatient surgery where it has been reported in up to 40%. It is a relevant complication since it hinders the postoperative evolution, disturbing sleep, increasing the opioid requirement and delaying hospital discharge. Preventive analgesia before the blockage subsides, intra-articular or intravenous anti-inflammatory drugs, and the use of adjuvants added to nerve-

Some nonanesthetic (off-label) uses of LAs have been described. Although these investigations have not been precisely determined, this topic deserves a brief

Lidocaine has been used successfully to prevent or treat cough and laryngospasm induced during tracheal extubation, as well as in patients with asthma and chronic cough difficult to treat [68–70]. The meta-analysis of Yang et al. found that iv lidocaine decreases postoperative airway complications [71]. Nebulized lidocaine has been used with encouraging results in patients with asthma, chronic cough, and laryngospasm; doses ranging from 10 to 400 mg are a therapeutic alternative in asthma and cough that is difficult to manage [72]. Its mechanism of action has been related to the decrease in airway inflammation via downregulation of TLR2 [73].

Regional anesthesia is preferably used in oncological surgery since it does not interfere with the immune system, and the postoperative outcome of these patients is better. On the other hand, there is evidence that LAs could have direct

moglobin. Management is with 1–5 mg of methylene blue.

block or systemic solutions can reduce rebound pain [65–67].

**9. Nonanesthetic uses of LAs**

**9.2 Effects of LAs on cancer**

**9.1 Cough, laryngospasm, and asthma**

description.

**22**

Besides pain insensitivity, it has been shown that the in vitro and in vivo use of LAs have bacteriostatic, bactericidal, fungistatic, and fungicidal properties against a wide spectrum of microorganisms, this action being attributed to the interruption of the membrane permeability of microbial cells, leading to leakage of cellular components and subsequent cell lysis. Different LAs showed varying degrees of antimicrobial capacity; bupivacaine and lidocaine, for example, inhibit growth to a significantly greater extent than ropivacaine. Higher concentrations, prolonged exposure, and higher temperature correlate with a proportional increase in inhibition of microbial growth. Reducing the incidence of endophthalmitis after intravitreal injection, prophylaxis for surgical wound infections, preventing the incidence of catheter-associated infections, reducing oral biofilms in the oral mucosa, and preventing infection-causing bacteria nosocomial are some examples of antimicrobial application of lidocaine [2, 78–80].

#### **10. Conclusions**

The first LA anesthetic was derived from the plant *Erythroxylum coca*, and regional anesthesia began in 1884 when Karl Köller anesthetized the cornea of his patients for surgical purposes. Since then, a host of events, drugs, discoveries, and various anesthesia techniques have culminated in safer and more effective regional anesthesia. LAs have an impressive history of efficacy and safety in medical and dental practice, but still have deleterious effects that can—on rare occasions—cause the death of our patients. Knowing the basics of the substrates where LAs work makes it easier to understand the action mechanisms that these drugs have on voltage-dependent sodium channels. The sequence of events that occur from the choice of the patient, the preparation and injection of LAs to the production of regional anesthesia-analgesia and/or its toxic effects are complex. These physiological and pathophysiological events depend on features as varied as the structural and physico-chemical characteristics, total injected dose, injection site, adjuvant drugs, physical condition of the patient, among others. The safe practice of regional anesthesia definitely reduces catastrophes, but these disasters can appear at any time. LAs have an impressive history of efficacy and safety in medical and dental practice.

*Topics in Local Anesthetics*

#### **Author details**

Víctor M. Whizar-Lugo1 \*, Karen L. Íñiguez-López<sup>2</sup> , Ana C. Cárdenas-Maytorena3 and Cristian D. Ramírez-Puerta4

1 Institutos Nacionales de Salud, Lotus Medical Group, Tijuana BC, México

2 Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, México City, México

3 Lotus Med Group, Tijuana BC, México

4 School of Medicine, Campus Tijuana, Universidad Autónoma de Baja California, Tijuana BC, México

\*Address all correspondence to: vwhizar@anestesia-dolor.org

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**25**

*Local Anesthetics*

**References**

*DOI: http://dx.doi.org/10.5772/intechopen.93643*

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[9] Samsi AB, Bhalerao RA, Shah SC, Mody BB, Paul T, Satoskar RS. Evaluation of centbucridine as a local anesthetic. Anesthesia and Analgesia.

[10] Hugin W. La planta divina de los incas; estimulante, curativa, encantadora. La anestesia local. En Hugin W. Anestesia. Descubrimientos, avances, hitos históricos. Bazilea, Suiza. Ediciones Roche. 1989. Pag 75-96

[11] Fink RB. Leaves and needles: The introduction of surgical local anesthesia.

[12] Whizar LV, Carrada PS. Anestesia subaracnoidea. Cien años después. Revista Mexicana de Anestesiología.

[14] Columb MO, MacLennan K. Local anaesthetics agents. Anaesthesia and Intensive Care Medicine.

[15] Singer SJ, Nicolson GL. The fluid mosaic model of the structure of cell membranes. Science. 1972;**175**:720-731. DOI: 10.1126/science.175.4023.720

[16] Nicolson GL. The fluid-mosaic model of membrane structure: Still relevant to understanding the structure, function and dynamics of biological membranes after more than 40 years. Biochimica et Biophysica Acta. 2014;**1838**(6):1451-1466. DOI: 10.1016/j.

Anesthesiology. 1985;**63**:77-83

[13] Albrigth GA. Cardiac arrest following regional anesthesia with etidocaine or bupivacaine. Anesthesiology. 1979;**51**:285-287

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[1] Hollmann MW, Durieux ME, Graf BM. Novel local anaesthetics and novel indications for local anaesthetics. Current Opinion in Anaesthesiology. 2001;**14**:741-749. DOI: 10.1097/00001503-200112000-00023

[2] Razavi BM, Fazly Bazzaz BS. A review and new insights to antimicrobial action of local anesthetics. European Journal of Clinical Microbiology & Infectious Diseases. 2019;**38**:991-1002. DOI: 10.1007/s10096-018-03460-4

[3] Lagadinou M, Onisor MO, Rigas A, Musetescu DV, Gkentzi D et al. Antimicrobial properties on nonantibiotic drugs in the era of increased bacterial resistance. Antibiotics (Basel). 2020;**9**(3). pii: E107. DOIi: 10.3390/

[4] Norris MC, Honet JE, Leighton BL,

[5] Patel D, Janardhan Y, Merai B, et al. Comparison of intrathecal meperidine and lidocaine in endoscopic urological procedures. Canadian Journal of Anaesthesia. 1990;**37**:567-570

[6] Sangarlangkarn S, Klaewtanong V, Jonglerttrakool P, Khankaew V.

Meperidine as a spinal anesthetic agent:

[7] Westman L, Valentin A, Eriksson E, Ekblom A. Intrathecal administration of sameridine to patients subjected to arthroscopic joint surgery. Acta Anaesthesiologica Scandinavica.

A comparison with lidocaineglucose. Anesthesia and Analgesia.

[8] Mulroy MF, Greengrass R,

Ganapathy S, et al. Sameridine is safe

1987;**66**:235-240

1998;**42**:691-697

Arkoosh VA. A comparison of meperidine and lidocaine for -spinal anesthesia for postpartum tubal ligation. Regional Anesthesia.

antibiotics9030107

1996;**21**:84-88

### **References**

*Topics in Local Anesthetics*

**24**

**Author details**

Víctor M. Whizar-Lugo1

México City, México

Tijuana BC, México

and Cristian D. Ramírez-Puerta4

3 Lotus Med Group, Tijuana BC, México

provided the original work is properly cited.

\*, Karen L. Íñiguez-López<sup>2</sup>

1 Institutos Nacionales de Salud, Lotus Medical Group, Tijuana BC, México

2 Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social,

\*Address all correspondence to: vwhizar@anestesia-dolor.org

4 School of Medicine, Campus Tijuana, Universidad Autónoma de Baja California,

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

, Ana C. Cárdenas-Maytorena3

[1] Hollmann MW, Durieux ME, Graf BM. Novel local anaesthetics and novel indications for local anaesthetics. Current Opinion in Anaesthesiology. 2001;**14**:741-749. DOI: 10.1097/00001503-200112000-00023

[2] Razavi BM, Fazly Bazzaz BS. A review and new insights to antimicrobial action of local anesthetics. European Journal of Clinical Microbiology & Infectious Diseases. 2019;**38**:991-1002. DOI: 10.1007/s10096-018-03460-4

[3] Lagadinou M, Onisor MO, Rigas A, Musetescu DV, Gkentzi D et al. Antimicrobial properties on nonantibiotic drugs in the era of increased bacterial resistance. Antibiotics (Basel). 2020;**9**(3). pii: E107. DOIi: 10.3390/ antibiotics9030107

[4] Norris MC, Honet JE, Leighton BL, Arkoosh VA. A comparison of meperidine and lidocaine for -spinal anesthesia for postpartum tubal ligation. Regional Anesthesia. 1996;**21**:84-88

[5] Patel D, Janardhan Y, Merai B, et al. Comparison of intrathecal meperidine and lidocaine in endoscopic urological procedures. Canadian Journal of Anaesthesia. 1990;**37**:567-570

[6] Sangarlangkarn S, Klaewtanong V, Jonglerttrakool P, Khankaew V. Meperidine as a spinal anesthetic agent: A comparison with lidocaineglucose. Anesthesia and Analgesia. 1987;**66**:235-240

[7] Westman L, Valentin A, Eriksson E, Ekblom A. Intrathecal administration of sameridine to patients subjected to arthroscopic joint surgery. Acta Anaesthesiologica Scandinavica. 1998;**42**:691-697

[8] Mulroy MF, Greengrass R, Ganapathy S, et al. Sameridine is safe and effective for spinal anesthesia: A comparative dose-ranging study with lidocaine for inguinal hernia repair. Anesthesia and Analgesia. 1999;**88**:815-821

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[18] Denac H, Mevissen M, Scholtysik G. Structure, function and pharmacology of volatage-gated sodium channels. Naunyn-Schmiedeberg's Archives of Pharmacology. 2000;**362**:453-479

[19] Catterall WA, Goldin AL, Waxman SG. International union of pharmacology. XLVII. Nomenclature and structure-function relationships of voltaged-gated sodium channels. Pharmacological Reviews. 2005;**57**: 397-409. DOI: 10.1124/pr.57.4.4

[20] Catterall WA, Swanson TM. Structural basis for pharmacology of voltage-gated sodium and calcium channels. Molecular Pharmacology. 2015;**88**(1):141-150. DOI: 10.1124/ mol.114.097659

[21] Wang SY, Nau C, Wang GK. Residues in Na+ channel D3-S6 segment modulate both batrachotoxin and local anesthetic affinities. Biophysical Journal. 2000;**79**:1379-1387

[22] Yarov-Yarovoy V, Brown J, Sharp EM, et al. Molecular determinants of voltaged-dependent gating and binding of pore-blocking drugs in transmembrane segment IIIS6 of the Na<sup>+</sup> channel alpha subunit. The Journal of Biological Chemistry. 2001;**276**:20-27

[23] Scholz A. Mechanisms of local anaesthetics on voltaged-gated sodium and others ion channels. British Journal of Anaesthesia. 2002;**89**:52-61

[24] Butterworth JF, Strichartz GR. Molecular mechanisms of local anesthesia: A review. Anesthesiology. 1990;**72**:711-734

[25] Strichartz GR. Neural physiology and local anesthetic action. In: Cousins MJ, Bridenbaugh PO (Editors). Neural Blockade in Clinical Anesthesia and Management of Pain. Philadelphia, Lippincott-Raven; 1998. p. 42

[26] Burke D, Henderson DJ. Chirality: A blueprint for the future. British Journal of Anaesthesia. 2002;**88**:563-576

[27] Harrison NL. Optical isomers open a new window on anesthetic mechanism. Anesthesiology. 1998;**88**:566-568

[28] Kongsgaard UE, Werner MU. Tachyphylaxis to local anaesthetics. What is the clinical evidence? A systematic review. Acta Anaesthesiologica Scandinavica. 2016;**60**(1):6-14. DOI: 10.1111/ aas.12631

[29] Lee KC, Wilder RT, Smith RL, Berde CB. Thermal hyperalgesia accelerates and MK-801 prevents the development of tachyphylaxis to rat sciatic nerve blockade. Anesthesiology. 1994;**81**(5):1284-1293. DOI: 10.1097/00000542-199411000-00024

[30] Wilder RT, Sholas MG, Berde CB. NG-nitro-L-arginine methyl ester (L-NAME) prevents tachyphylaxis to local anesthetics in a dose-dependent manner. Anesthesia and Analgesia. 1996;**83**(6):1251-1255

[31] Morrison LM, Emanuelsson BM, McClure JH, Pollok AJ, McKeown DW, Brockway M, et al. Efficacy and kinetics of extradural ropivacaine: Comparison with bupivacaine. British Journal of Anaesthesia. 1994;**72**(2):164-169. DOI: 10.1093/bja/72.2.164

[32] Miller RJ, Cameron AJ, Dimech J, Orec RJ, Lightfoot NJ. Plasma ropivacaine concentrations following local infiltration analgesia in total knee arthroplasty: A pharmacokinetic study to determine safety following fixed-dose administration. Regional Anesthesia and Pain Medicine. 2018;**43**(4):347-351. DOI: 10.1097/ AAP.0000000000000727

**27**

*Local Anesthetics*

pag 507-537

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review. British Dental Journal. 2017 Nov;**223**(7):501-506. DOI: 10.1038/

[42] Saralaya S, Adirajaiah SB, Anehosur V. 4% articaine and 2% lignocaine for surgical removal of third molar by mandibular nerve block: A randomized clinical trial for efficacy and safety. Journal of Oral and Maxillofacial Surgery. 2019;**18**(3):405- 411. DOI: 10.1007/s12663-018-1109-0

[43] Nagendrababu V, Duncan HF, Whitworth J, Nekoofar MH, Pulikkotil SJ, et al. Is articaine more effective than lidocaine in patients with irreversible pulpitis? An umbrella review. International Endodontic Journal. 2020;**53**(2):200-213. DOI:

[44] Modalen AO, Westman L, Arlander E, Eriksson LI, Lindahl SG. Hypercarbic and hypoxic ventilatory

administration of bupivacaine and sameridine. Anesthesia and Analgesia.

[45] Osterlund Modalen A, Arlander E, Eriksson LI, Lindahl SG. The effects on hypercarbic ventilatory response of sameridine compared to morphine and placebo. Anesthesia and Analgesia.

responses after intrathecal

sj.bdj.2017.782

10.1111/iej.13215

2003;**96**:570-575

2001;**92**:529-534

1999;**88**:160-165

[46] Osterlund A, Arlander E, Eriksson LI, Lindhal SG. The effects on resting ventilation of intravenous infusions of morphine or sameridine, a novel molecule with both local anesthetic and opioid properties. Anesthesia and Analgesia.

[47] Patnaik GK, Rastogi SN, Anand N, Dhawan BN. Evaluation of local anaesthetic activity of 4-N-butylamino-1,2,3,4 tetrahydroacridine hydrochloride (Centbucridine)--a 4-substituted polymethylenequinoline. Indian

[33] Lagan G, McClure HA. Review of local anaesthetics agents. Anaesthesia &

Critical Care. 2004;**15**:247-254

[34] Salinas FV, Liu SL, Schlz AM. Analgesics. Ion channel ligands/sodium channels blockers/local anesthetics. Chapter 30. En: Evers AS, Maze M. Editores. Anesthetic Pharmacology. Physiologic Principles and Clinical Practice. Editorial Churchill-

Livingstone. Philadelphia, USA. 2004

[35] He Y, Qin L, Huang Y, Ma C. Advances of nano-structured extendedrelease local anesthetics. Nanoscale Research Letters. 2020;**15**(1):13. DOI:

10.1186/s11671-019-3241-2

[36] Malik O, Kaye AD, Kaye A, Belani K, Urman RD. Emerging roles of liposomal bupivacaine in anesthesia practice. Journal of Anaesthesiology Clinical Pharmacology. 2017;**33**(2):151- 156. DOI: 10.4103/joacp.JOACP\_375\_15

[37] Kao HW, Lin YY, Gwathney WJ, Hong K. Formulation and evaluation of multilamellar vesicles ropivacaine in pain management. International Journal of Nanomedicine. 2019;**14**:7891-7901.

[38] Snoeck M. Articaine: A review of its use for local and regional anesthesia.

2012;**5**:23-33. DOI: 10.2147/LRA.S16682

[39] Kakroudi SH, Mehta S, Millar BJ. Articaine hydrochloride: Is it the solution? Dental Update. 2015;**42**(1)

Local and Regional Anesthesia.

88-90, 92-3. DOI: 10.12968/

Clinical Pharmacokinetics. 1997;**33**(6):417-425. DOI:

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Articaine and neurotoxicity - a

Clinical pharmacokinetics of articaine.

10.2165/00003088-199733060-00002

[41] Hopman AJG, Baart JA, Brand HS.

denu.2015.42.1.88

DOI: 10.2147/IJN.S215952

#### *Local Anesthetics DOI: http://dx.doi.org/10.5772/intechopen.93643*

*Topics in Local Anesthetics*

[17] Lombard J. Once upon a time the cell membranes: 175 years of cell boundary research. Biology Direct. 2014;**9**:32. DOI: 10.1186/s13062-014-0032-7

Neural Blockade in Clinical Anesthesia and Management of Pain. Philadelphia,

[26] Burke D, Henderson DJ. Chirality: A blueprint for the future. British Journal of Anaesthesia. 2002;**88**:563-576

[27] Harrison NL. Optical isomers open a new window on anesthetic mechanism. Anesthesiology. 1998;**88**:566-568

[28] Kongsgaard UE, Werner MU. Tachyphylaxis to local anaesthetics. What is the clinical evidence? A systematic review. Acta Anaesthesiologica Scandinavica. 2016;**60**(1):6-14. DOI: 10.1111/

[29] Lee KC, Wilder RT, Smith RL, Berde CB. Thermal hyperalgesia accelerates and MK-801 prevents the development of tachyphylaxis to rat sciatic nerve blockade. Anesthesiology.

10.1097/00000542-199411000-00024

[30] Wilder RT, Sholas MG, Berde CB. NG-nitro-L-arginine methyl ester (L-NAME) prevents tachyphylaxis to local anesthetics in a dose-dependent manner. Anesthesia and Analgesia.

[31] Morrison LM, Emanuelsson BM, McClure JH, Pollok AJ, McKeown DW, Brockway M, et al. Efficacy and kinetics of extradural ropivacaine: Comparison with bupivacaine. British Journal of Anaesthesia. 1994;**72**(2):164-169. DOI:

[32] Miller RJ, Cameron AJ, Dimech J,

ropivacaine concentrations following local infiltration analgesia in total knee arthroplasty: A pharmacokinetic study to determine safety following fixed-dose administration. Regional Anesthesia and Pain Medicine. 2018;**43**(4):347-351. DOI: 10.1097/

Orec RJ, Lightfoot NJ. Plasma

AAP.0000000000000727

1994;**81**(5):1284-1293. DOI:

1996;**83**(6):1251-1255

10.1093/bja/72.2.164

aas.12631

Lippincott-Raven; 1998. p. 42

[18] Denac H, Mevissen M, Scholtysik G. Structure, function and pharmacology of volatage-gated sodium channels. Naunyn-Schmiedeberg's Archives of Pharmacology. 2000;**362**:453-479

[19] Catterall WA, Goldin AL, Waxman SG. International union of pharmacology. XLVII. Nomenclature and structure-function relationships of voltaged-gated sodium channels. Pharmacological Reviews. 2005;**57**: 397-409. DOI: 10.1124/pr.57.4.4

[20] Catterall WA, Swanson TM. Structural basis for pharmacology of voltage-gated sodium and calcium channels. Molecular Pharmacology. 2015;**88**(1):141-150. DOI: 10.1124/

[21] Wang SY, Nau C, Wang GK.

modulate both batrachotoxin and local anesthetic affinities. Biophysical

Journal. 2000;**79**:1379-1387

[22] Yarov-Yarovoy V, Brown J,

Sharp EM, et al. Molecular determinants of voltaged-dependent gating and binding of pore-blocking drugs in transmembrane segment IIIS6 of the

 channel alpha subunit. The Journal of Biological Chemistry. 2001;**276**:20-27

[23] Scholz A. Mechanisms of local anaesthetics on voltaged-gated sodium and others ion channels. British Journal

[24] Butterworth JF, Strichartz GR. Molecular mechanisms of local anesthesia: A review. Anesthesiology.

[25] Strichartz GR. Neural physiology and local anesthetic action. In:

Cousins MJ, Bridenbaugh PO (Editors).

of Anaesthesia. 2002;**89**:52-61

1990;**72**:711-734

channel D3-S6 segment

mol.114.097659

Residues in Na+

**26**

Na<sup>+</sup>

[33] Lagan G, McClure HA. Review of local anaesthetics agents. Anaesthesia & Critical Care. 2004;**15**:247-254

[34] Salinas FV, Liu SL, Schlz AM. Analgesics. Ion channel ligands/sodium channels blockers/local anesthetics. Chapter 30. En: Evers AS, Maze M. Editores. Anesthetic Pharmacology. Physiologic Principles and Clinical Practice. Editorial Churchill-Livingstone. Philadelphia, USA. 2004 pag 507-537

[35] He Y, Qin L, Huang Y, Ma C. Advances of nano-structured extendedrelease local anesthetics. Nanoscale Research Letters. 2020;**15**(1):13. DOI: 10.1186/s11671-019-3241-2

[36] Malik O, Kaye AD, Kaye A, Belani K, Urman RD. Emerging roles of liposomal bupivacaine in anesthesia practice. Journal of Anaesthesiology Clinical Pharmacology. 2017;**33**(2):151- 156. DOI: 10.4103/joacp.JOACP\_375\_15

[37] Kao HW, Lin YY, Gwathney WJ, Hong K. Formulation and evaluation of multilamellar vesicles ropivacaine in pain management. International Journal of Nanomedicine. 2019;**14**:7891-7901. DOI: 10.2147/IJN.S215952

[38] Snoeck M. Articaine: A review of its use for local and regional anesthesia. Local and Regional Anesthesia. 2012;**5**:23-33. DOI: 10.2147/LRA.S16682

[39] Kakroudi SH, Mehta S, Millar BJ. Articaine hydrochloride: Is it the solution? Dental Update. 2015;**42**(1) 88-90, 92-3. DOI: 10.12968/ denu.2015.42.1.88

[40] Oertel R, Rahn R, Kirch W. Clinical pharmacokinetics of articaine. Clinical Pharmacokinetics. 1997;**33**(6):417-425. DOI: 10.2165/00003088-199733060-00002

[41] Hopman AJG, Baart JA, Brand HS. Articaine and neurotoxicity - a

review. British Dental Journal. 2017 Nov;**223**(7):501-506. DOI: 10.1038/ sj.bdj.2017.782

[42] Saralaya S, Adirajaiah SB, Anehosur V. 4% articaine and 2% lignocaine for surgical removal of third molar by mandibular nerve block: A randomized clinical trial for efficacy and safety. Journal of Oral and Maxillofacial Surgery. 2019;**18**(3):405- 411. DOI: 10.1007/s12663-018-1109-0

[43] Nagendrababu V, Duncan HF, Whitworth J, Nekoofar MH, Pulikkotil SJ, et al. Is articaine more effective than lidocaine in patients with irreversible pulpitis? An umbrella review. International Endodontic Journal. 2020;**53**(2):200-213. DOI: 10.1111/iej.13215

[44] Modalen AO, Westman L, Arlander E, Eriksson LI, Lindahl SG. Hypercarbic and hypoxic ventilatory responses after intrathecal administration of bupivacaine and sameridine. Anesthesia and Analgesia. 2003;**96**:570-575

[45] Osterlund Modalen A, Arlander E, Eriksson LI, Lindahl SG. The effects on hypercarbic ventilatory response of sameridine compared to morphine and placebo. Anesthesia and Analgesia. 2001;**92**:529-534

[46] Osterlund A, Arlander E, Eriksson LI, Lindhal SG. The effects on resting ventilation of intravenous infusions of morphine or sameridine, a novel molecule with both local anesthetic and opioid properties. Anesthesia and Analgesia. 1999;**88**:160-165

[47] Patnaik GK, Rastogi SN, Anand N, Dhawan BN. Evaluation of local anaesthetic activity of 4-N-butylamino-1,2,3,4 tetrahydroacridine hydrochloride (Centbucridine)--a 4-substituted polymethylenequinoline. Indian

Journal of Experimental Biology. 1982;**20**(4):327-329

[48] Gupta PP, Nityanand S, Shipstone AC, Dhawan BN. Experimental evaluation of potential neurotoxicity of 4-N-butylamino 1,2,3,4-tetrahydroacridine hydrochloride (Centbucridine)--a new local anaesthetic agent. Indian Journal of Experimental Biology. 1982;**20**(4):339-443

[49] Gupta PP, Tangri AN, Saxena RC, Dhawan BN. Clinical pharmacology studies on 4-N-butylamino-1,2,3,4-tetrahydroacridine hydrochloride (Centbucridine)--a new local anaesthetic agent. Indian Journal of Experimental Biology. 1982;**20**(4):344-346

[50] Goyal A, Jain G, Jain A, Ansari T, Bumb S. A new era of local anaesththetic agent: Centbucridine. Archives of CraniOroFacial Sciences. 2013;**1**(3):40-43

[51] Gune NS, Katre AN. Comparison of 0.5% centbucridine and 2% lignocaine as local anesthetic agents for dental procedures in children: A randomised controlled trial. Indian Journal of Pediatrics. 2020;**87**(4):268-274. DOI: 10.1007/s12098-019-03161-6

[52] Suri YV, Patnaik GK, Nayak BC, Gupta PP, Singh D, Dhawan BN. Evaluation of centbucridine for intravenous regional anaesthesia. Indian Journal of Medical Research. 1983;**77**:722-727

[53] Mansuri S, Bhayat A, Omar E, Jarab F, Ahmed MS. A randomized controlled trail comparing the efficacy of 0.5% centbucridine to 2% lignocaine as local anesthetics in dental extractions. International Journal of Dentistry. 2011;**2011**:795047. DOI: 10.1155/2011/795047

[54] Per H, Rosenberg PH, Veering BT, Urmey WF. Maximum recommended

doses of local anesthetics: A multifactorial concept. Regional Anesthesia and Pain Medicine. 2004;**29**:564-575

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[58] Pere P, Watanabe H, Pitkanen M, Wahlstrom T, Rosenberg PH. Local myotoxicity of bupivacaine in rabbits after continuous supraclavicular brachial plexus block. Regional Anesthesia. 1993;**18**:304-307

[59] Zink W, Seif C, Bohl JR, et al. The acute myotoxic effects of bupivacaine and ropivacaine after continuous peripheral nerve blockades. Anesthesia and Analgesia. 2003;**97**:1173-1179

[60] Zink W, Bohl J, Hacke N, Sinner B, Martin E, Graf BM. Long term myotoxic effects of bupivacaine and ropivacaine after continuous peripheral nerve blocks. Anesthesia and Analgesia. 2005;**101**:548-554

[61] Hussain N, McCartney CJL, Neal JM, Chippor J, Banfield L, Abdallah FW. Local anaesthetic-induced myotoxicity in regional anaesthesia: A systematic review and empirical analysis. British Journal of Anaesthesia. 2018;**121**(4):822-841. DOI: 10.1016/j. bja.2018.05.076

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a ropivacaína peridural. Anestesia en

Mexico. 2004;**16**:180-183

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a2016.0017

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a ropivacaína peridural. Anestesia en Mexico. 2004;**16**:180-183

*Topics in Local Anesthetics*

1982;**20**(4):327-329

1982;**20**(4):339-443

1982;**20**(4):344-346

2013;**1**(3):40-43

1983;**77**:722-727

10.1155/2011/795047

studies on 4-N-butylamino-1,2,3,4-tetrahydroacridine

[50] Goyal A, Jain G, Jain A,

10.1007/s12098-019-03161-6

[52] Suri YV, Patnaik GK, Nayak BC, Gupta PP, Singh D, Dhawan BN. Evaluation of centbucridine for intravenous regional anaesthesia. Indian Journal of Medical Research.

[53] Mansuri S, Bhayat A, Omar E, Jarab F, Ahmed MS. A randomized controlled trail comparing the efficacy of 0.5% centbucridine to 2% lignocaine as local anesthetics in dental extractions. International Journal of Dentistry. 2011;**2011**:795047. DOI:

[54] Per H, Rosenberg PH, Veering BT, Urmey WF. Maximum recommended

Journal of Experimental Biology.

doses of local anesthetics: A multifactorial concept. Regional Anesthesia and Pain Medicine.

[55] Braun H. Ubre einiger neue

Analgesia. 1978;**57**:428-443

ortliche anaesthetica (Stovain, Alypin, Novocain). Dtsch KimWochenschr.

[56] Aldrete JA, Romo-Salas F, Arora S, et al. Reverse arterial blood flow as a pathway for central nervous systemic toxic response following injection of local anesthtetics. Anesthesia and

[57] Irwin W, Fontaine E, Agnolucci L, et al. Bupivacaine myotoxicity is mediated by mitochondria. The Journal of Biological

[58] Pere P, Watanabe H, Pitkanen M, Wahlstrom T, Rosenberg PH. Local myotoxicity of bupivacaine in rabbits after continuous supraclavicular brachial plexus block. Regional Anesthesia. 1993;**18**:304-307

[59] Zink W, Seif C, Bohl JR, et al. The acute myotoxic effects of bupivacaine and ropivacaine after continuous peripheral nerve blockades. Anesthesia and Analgesia. 2003;**97**:1173-1179

[60] Zink W, Bohl J, Hacke N, Sinner B, Martin E, Graf BM. Long term myotoxic effects of bupivacaine and ropivacaine after continuous peripheral nerve blocks. Anesthesia and Analgesia.

[61] Hussain N, McCartney CJL, Neal JM, Chippor J, Banfield L,

[62] Whizar-Lugo VM, Ontiveros-Morales P, Garfias-Flores M. Alergia

Abdallah FW. Local anaesthetic-induced myotoxicity in regional anaesthesia: A systematic review and empirical analysis. British Journal of Anaesthesia. 2018;**121**(4):822-841. DOI: 10.1016/j.

2005;**101**:548-554

bja.2018.05.076

Chemistry. 2002;**277**:12221-12227

2004;**29**:564-575

1905;**31**:1667-1671

Experimental evaluation of potential neurotoxicity of 4-N-butylamino 1,2,3,4-tetrahydroacridine

hydrochloride (Centbucridine)--a new local anaesthetic agent. Indian Journal of Experimental Biology.

[49] Gupta PP, Tangri AN, Saxena RC, Dhawan BN. Clinical pharmacology

hydrochloride (Centbucridine)--a new local anaesthetic agent. Indian Journal of Experimental Biology.

Ansari T, Bumb S. A new era of local anaesththetic agent: Centbucridine. Archives of CraniOroFacial Sciences.

[51] Gune NS, Katre AN. Comparison of 0.5% centbucridine and 2% lignocaine as local anesthetic agents for dental procedures in children: A randomised controlled trial. Indian Journal of Pediatrics. 2020;**87**(4):268-274. DOI:

[48] Gupta PP, Nityanand S, Shipstone AC, Dhawan BN.

**28**

[63] Bhole MV, Manson AL, Seneviratne SL, Misbah SA. IgEmediated allergy to local anaesthetics: Separating fact from perception: A UK perspective. British Journal of Anaesthesia. 2012;**108**(6):903-911. DOI: 10.1093/bja/aes162

[64] Grzanka A, Wasilewska I, Śliwczyńska M, Misiołek H. Hypersensitivity lo local anesthetics. Anaesthesiology Intensive Therapy. 2016;**48**(2):128-134. DOI: 10.5603/AIT. a2016.0017

[65] Nobre LV, Cunha GP, Sousa PCCB, Takeda A, Cunha Ferraro LH. Peripheral nerve block and rebound pain: Literature review. Revista Brasileira de Anestesiologia. 2019;**69**(6):587-593. DOI: 10.1016/j.bjan.2019.05.001

[66] Dada O, Gonzalez Zacarias A, Ongaigui C, Echeverria-Villalobos M, Kushelev M, et al. Does rebound pain after peripheral nerve block for orthopedic surgery impact postoperative analgesia and opioid consumption? A narrative review. International Journal of Environmental Research and Public Health. 2019;16(18). pii: E3257. DOI: 10.3390/ijerph16183257.

[67] An K, Elkassabany NM, Liu J. Dexamethasone as adjuvant to bupivacaine prolongs the duration of thermal antinociception and prevents bupivacaine-induced rebound hyperalgesia via regional mechanism in a mouse sciatic nerve block model. PLoS One. 2015;**10**(4):e0123459. DOI: 10.1371/journal.pone.0123459

[68] Lim KG, Rank MA, Hahn PY, Keogh KA, Morgenthaler TI, Olson EJ. Long-term safety of nebulized lidocaine for adults with difficult-to-control chronic cough: A case series. Chest. 2013;**143**(4):1060-1065. DOI: 10.1378/ chest.12-1533

[69] Truesdale K, Jurdi A. Nebulized lidocaine in the treatment of intractable cough. The American Journal of Hospice & Palliative Care. 2013;**30**(6):587-589. DOI: 10.1177/1049909112458577

[70] Oon Z, Ha CB, Sicinski M. Nebulized lidocaine in the treatment of refractory postoperative laryngospasm: A case report. A&A Practice. 2019;**13**(1):20-22. DOI: 10.1213/ XAA.0000000000000974

[71] Yang SS, Wang NN, Postonogova T, Yang GJ, McGillion M, Beique F, et al. Intravenous lidocaine to prevent postoperative airway complications in adults: A systematic review and metaanalysis. British Journal of Anaesthesia. 2020;**124**(3):314-323. DOI: 10.1016/j. bja.2019.11.033

[72] Slaton RM, Thomas RH, Mbathi JW. Evidence for therapeutic uses of nebulized lidocaine in the treatment of intractable cough and asthma. The Annals of Pharmacotherapy. 2013;**47**(4):578-585. DOI: 10.1345/aph.1R573

[73] Wang L, Wang M, Li S, Wu H, Shen Q, Zhang S, et al. Nebulized lidocaine ameliorates allergic airway inflammation via downregulation of TLR2. Molecular Immunology. 2018;**97**:94-100. DOI: 10.1016/j. molimm.2018.03.010

[74] Liu H, Dilger JP, Lin J. Effects of local anesthetics on cancer cells. Pharmacology & Therapeutics. 2020;**107558**. DOI: 10.1016/j. pharmthera.2020.107558

[75] Chamaraux-Tran TN, Piegeler T. The amide local anesthetic lidocaine in cancer surgery-potential antimetastatic effects and preservation of immune cell function? A narrative review. Frontiers in Medicine (Lausanne). 2017;**4**:235. DOI: 10.3389/fmed.2017.00235

[76] Mao L, Lin S, Lin J. The effects of anesthetics on tumor progression. International Journal of Physiology, Pathophysiology and Pharmacology. 2013;**5**(1):1-10

**Chapter 2**

**Abstract**

conduction

**31**

**1. Introduction**

paralysis in the innervated region.

normally applied by local injection [2].

nerve function [1] (**Figure 1**).

Anesthetics

*Javier Marcos Michel-Levy*

Pharmacokinetics and

Pharmacodynamics of Local

pharmacokinetics and pharmacodynamics of local anesthetics.

**Keywords:** esters, amides, pKa, Na<sup>+</sup> channel, pH, nerve fibers kinetics, block

When applied locally to nerve tissues in appropriate concentrations, local anesthetics (LAs) reversibly block the action potentials responsible for nerve conduction. They act anywhere in the nervous system and in any type of nerve fiber. Therefore, a LA in contact with a nerve trunk can produce both sensory and motor

The practical advantage of LAs is that their action is reversible in concentrations of clinical importance; their administration is followed by complete recovery of

LAs are drugs primarily utilized in clinical settings to induce local anesthesia. The term local anesthesia, unlike general anesthesia, is defined as loss of sensation within a confined region without loss of the patient's consciousness. LAs are purposely used to relieve pain and induce numbness during surgical procedures and are

Local anesthetics are basically weak bases whose structure consists of an aromatic half connected to a substituted amine through an ester amide linkage. The pKa values of local anesthetics are close to physiological pH, both protonated and unprotonated forms are present. The individual structures confer different physiochemical and clinical characteristics. Potency is correlated to lipid solubility in vitro, but less so in vivo. The duration of action is associated with the extent of protein binding. The onset of action is related to pKa. The intrinsic vasodilator activity varies between drugs and influences potency and duration of action. Local anesthetics block nerve conduction and interact directly with specific receptor on the Na<sup>+</sup> channel, inhibiting Na<sup>+</sup> ion influx and impairing Propagation of the action potential in axons. There are some characteristics in the blocking of nerve conduction and are related to size and function of the peripheral nerves, and to the fact that a specific concentration of local anesthetics may produce a different intensity of block. Some pathological states like decreased cardiac output, severe hepatic disease, renal disease, cholinesterase activity, fetal acidosis, sepsis, etc. altered the

[77] Zheng Q, Peng X, Zhang Y. Cytotoxicity of amide-linked local anesthetics on melanoma cells via inhibition of Ras and RhoA signaling independent of sodium channel blockade. BMC Anesthesiology. 2020;**20**(1):43. DOI: 10.1186/ s12871-020-00957-4

[78] Kaewjiaranai T, Srisatjaluk RL, Sakdajeyont W, Pairuchvej V, Wongsirichat N. The efficiency of topical anesthetics as antimicrobial agents: A review of use in dentistry. Journal of Dental Anesthesia and Pain Medicine. 2018;**18**(4):223-233. DOI: 10.17245/jdapm.2018.18.4.223

[79] Johnson SM, Saint John BE, Dine AP. Local anesthetics as antimicrobial agents: A review. Surgical Infections. 2008;**9**(2):205-213. DOI: 10.1089/ sur.2007.036

[80] Pelz K, Wiedmann-Al-Ahmad M, Bogdan C, Otten JE. Analysis of the antimicrobial activity of local anaesthetics used for dental analgesia. Journal of Medical Microbiology. 2008;**57**:88-94

#### **Chapter 2**

*Topics in Local Anesthetics*

2013;**5**(1):1-10

s12871-020-00957-4

sur.2007.036

2008;**57**:88-94

International Journal of Physiology, Pathophysiology and Pharmacology.

[77] Zheng Q, Peng X, Zhang Y. Cytotoxicity of amide-linked local anesthetics on melanoma cells via inhibition of Ras and RhoA signaling independent of sodium channel blockade. BMC Anesthesiology. 2020;**20**(1):43. DOI: 10.1186/

[78] Kaewjiaranai T, Srisatjaluk RL, Sakdajeyont W, Pairuchvej V, Wongsirichat N. The efficiency of topical anesthetics as antimicrobial agents: A review of use in dentistry. Journal of Dental Anesthesia and Pain Medicine. 2018;**18**(4):223-233. DOI: 10.17245/jdapm.2018.18.4.223

[79] Johnson SM, Saint John BE, Dine AP. Local anesthetics as antimicrobial agents: A review. Surgical Infections. 2008;**9**(2):205-213. DOI: 10.1089/

[80] Pelz K, Wiedmann-Al-Ahmad M, Bogdan C, Otten JE. Analysis of the antimicrobial activity of local anaesthetics used for dental analgesia. Journal of Medical Microbiology.

**30**

## Pharmacokinetics and Pharmacodynamics of Local Anesthetics

*Javier Marcos Michel-Levy*

#### **Abstract**

Local anesthetics are basically weak bases whose structure consists of an aromatic half connected to a substituted amine through an ester amide linkage. The pKa values of local anesthetics are close to physiological pH, both protonated and unprotonated forms are present. The individual structures confer different physiochemical and clinical characteristics. Potency is correlated to lipid solubility in vitro, but less so in vivo. The duration of action is associated with the extent of protein binding. The onset of action is related to pKa. The intrinsic vasodilator activity varies between drugs and influences potency and duration of action. Local anesthetics block nerve conduction and interact directly with specific receptor on the Na<sup>+</sup> channel, inhibiting Na<sup>+</sup> ion influx and impairing Propagation of the action potential in axons. There are some characteristics in the blocking of nerve conduction and are related to size and function of the peripheral nerves, and to the fact that a specific concentration of local anesthetics may produce a different intensity of block. Some pathological states like decreased cardiac output, severe hepatic disease, renal disease, cholinesterase activity, fetal acidosis, sepsis, etc. altered the pharmacokinetics and pharmacodynamics of local anesthetics.

**Keywords:** esters, amides, pKa, Na<sup>+</sup> channel, pH, nerve fibers kinetics, block conduction

#### **1. Introduction**

When applied locally to nerve tissues in appropriate concentrations, local anesthetics (LAs) reversibly block the action potentials responsible for nerve conduction. They act anywhere in the nervous system and in any type of nerve fiber. Therefore, a LA in contact with a nerve trunk can produce both sensory and motor paralysis in the innervated region.

The practical advantage of LAs is that their action is reversible in concentrations of clinical importance; their administration is followed by complete recovery of nerve function [1] (**Figure 1**).

LAs are drugs primarily utilized in clinical settings to induce local anesthesia. The term local anesthesia, unlike general anesthesia, is defined as loss of sensation within a confined region without loss of the patient's consciousness. LAs are purposely used to relieve pain and induce numbness during surgical procedures and are normally applied by local injection [2].

which consist of the plasma membranes of Schawnn cells that wrap themselves

Myelin considerably increases the speed of nerve conduction as it achieves that action current generated by an action potential travels through the axoplasm to the nodes of Ranvier, these are periodic interruptions of the myelin sheath, where

In the nodes of Ranvier of the myelinated fibers, there is a high concentration of

During the transmission of an impulse, the intra and extracellular ratios of Na<sup>+</sup>


In a depolarization stream, Na<sup>+</sup> channels they are activated, admitting extracellular Na<sup>+</sup> ions influx into the cell. After that (ms), Na+ channels inactivate. The channels get back to the initial repolarization state. The course that involves sodium channels passing from an open or closed state is called a "gate." Gate is the result of the change of polarities after a potential. It is about explaining the mode of action of

ion perviousness increases, leaving Na<sup>+</sup> ions to move inside the cell and the resting membrane potential be moved. An action potential is released when depolarization enough for the membrane potential to come a threshold value, it is concerning +15 mV. During repolarization, the electrical status of the cell is restored by K+ diffusing out of the cell, and at the end the resting membrane potential has been

, which serve to propagate the impulses, although they are also


. However, when

around the axon during growth.

*DOI: http://dx.doi.org/10.5772/intechopen.91700*

action potentials are regenerated.

and K+ ions are inverted. Na<sup>+</sup>

observed along the axons of unmyelinated fibers.

*Pharmacokinetics and Pharmacodynamics of Local Anesthetics*

/K<sup>+</sup>

restored; but the cell has effectively gained Na<sup>+</sup> and lost K<sup>+</sup>

sodium channels Na<sup>+</sup>

K<sup>+</sup> ions are restored.

Na<sup>+</sup> /K+

**Figure 2.**

**33**

*Universo-review.ca free Google.*

#### **2. Anatomy of the peripheral nerve**

All peripheral nerves are similar in structure; neuron is the basic functional neuronal unit responsible for the conduction of nerve impulses. A typical neuron consists of a cell body (soma) that contains a large nucleus; the soma is attached to several branching processes called dendrites and a single axon. Axons vary in length and there is one only per neuron, they are a long and slender, and are also called nerve fibers; while dendrites receive incoming information and axons conduct outgoing information. Individual nerve fibers bind together, like wires in an electrical cable, and each axon is enveloped by the endoneurium (delicate layer of loose connective tissue around each axon). Groups of axons are closely associated within a bundle called a fascicle that is surrounded by perineurium (imparts mechanical strength and also acts as a diffusion barrier). Epineurium is a denser collagenous tissue that surrounds the entire nerve and holds it loosely to the connective tissue through which it travels. The paraneurium consists of loose connective tissue that keeps a stable relationship between adjacent structures filling the spaces in between them; this tissue promotes functional mobility of nerves during joint and muscular motion.

Nerves take in blood from the contiguous blood vessels along their course. These vessels that nourish larger nerves are macroscopic in bore and irregularly settled, conceive anastomoses to put on longitudinally common vessels that provision the nerve and emit subsidiary embranchments [3].

Each peripheral axon has its own cell membrane called axolemma, nonmyelinated nerves such as nociceptive afferent type C fibers, and autonomous postganglionic efferent fibers contain axons coated by only one layer of cells. All large-caliber sensory and motor fibers are lined with multiple layers of myelin,

#### *Pharmacokinetics and Pharmacodynamics of Local Anesthetics DOI: http://dx.doi.org/10.5772/intechopen.91700*

which consist of the plasma membranes of Schawnn cells that wrap themselves around the axon during growth.

Myelin considerably increases the speed of nerve conduction as it achieves that action current generated by an action potential travels through the axoplasm to the nodes of Ranvier, these are periodic interruptions of the myelin sheath, where action potentials are regenerated.

In the nodes of Ranvier of the myelinated fibers, there is a high concentration of sodium channels Na<sup>+</sup> , which serve to propagate the impulses, although they are also observed along the axons of unmyelinated fibers.

During the transmission of an impulse, the intra and extracellular ratios of Na<sup>+</sup> and K+ ions are inverted. Na<sup>+</sup> /K<sup>+</sup> -ATPase is stopped during depolarization and Na<sup>+</sup> ion perviousness increases, leaving Na<sup>+</sup> ions to move inside the cell and the resting membrane potential be moved. An action potential is released when depolarization enough for the membrane potential to come a threshold value, it is concerning +15 mV. During repolarization, the electrical status of the cell is restored by K+ diffusing out of the cell, and at the end the resting membrane potential has been restored; but the cell has effectively gained Na<sup>+</sup> and lost K<sup>+</sup> . However, when Na<sup>+</sup> /K+ -ATPase is reactivated, the normal intra and extracellular ratios of Na<sup>+</sup> and K<sup>+</sup> ions are restored.

In a depolarization stream, Na<sup>+</sup> channels they are activated, admitting extracellular Na<sup>+</sup> ions influx into the cell. After that (ms), Na+ channels inactivate. The channels get back to the initial repolarization state. The course that involves sodium channels passing from an open or closed state is called a "gate." Gate is the result of the change of polarities after a potential. It is about explaining the mode of action of

**Figure 2.** *Universo-review.ca free Google.*

**2. Anatomy of the peripheral nerve**

**Figure 1.** *Notes cards google.*

*Topics in Local Anesthetics*

joint and muscular motion.

**32**

nerve and emit subsidiary embranchments [3].

All peripheral nerves are similar in structure; neuron is the basic functional neuronal unit responsible for the conduction of nerve impulses. A typical neuron consists of a cell body (soma) that contains a large nucleus; the soma is attached to several branching processes called dendrites and a single axon. Axons vary in length and there is one only per neuron, they are a long and slender, and are also called nerve fibers; while dendrites receive incoming information and axons conduct outgoing information. Individual nerve fibers bind together, like wires in an electrical cable, and each axon is enveloped by the endoneurium (delicate layer of loose connective tissue around each axon). Groups of axons are closely associated within a bundle called a fascicle that is surrounded by perineurium (imparts mechanical strength and also acts as a diffusion barrier). Epineurium is a denser collagenous tissue that surrounds the entire nerve and holds it loosely to the connective tissue through which it travels. The paraneurium consists of loose connective tissue that keeps a stable relationship between adjacent structures filling the spaces in between them; this tissue promotes functional mobility of nerves during

Nerves take in blood from the contiguous blood vessels along their course. These vessels that nourish larger nerves are macroscopic in bore and irregularly settled, conceive anastomoses to put on longitudinally common vessels that provision the

Each peripheral axon has its own cell membrane called axolemma, nonmyelinated nerves such as nociceptive afferent type C fibers, and autonomous postganglionic efferent fibers contain axons coated by only one layer of cells. All large-caliber sensory and motor fibers are lined with multiple layers of myelin,


In this way, local anesthetics can be classified into two groups: aminoesters and aminoamides. The aromatic ring provides a lipophilic character to the portion of the molecule in which it is found, while the tertiary amine end is hydrophilic, because it is protonated and has a positive charge in the physiological pH range [6] (**Figure 3**). The ester-type LAs include benzocaine, procaine, cocaine, and tetracaine. The amide-type LAs include mepivacaine, lidocaine, ropivacaine, bupivacaine, and etidocaine. Lidocaine and bupivacaine are the most commonly used LAs, both are amide-type compounds, which are much more resistant than ester-type compounds

In addition to the intrinsic binding affinities of LA drugs to the Na<sup>+</sup> channel, other variables also strongly influence the relative duration of local anesthesia; these include the volume, concentration, lipophilicity, pKa, pH, repeated injections, the

LAs in solution maintain a rapid chemical equilibrium between the basic

is given by the Henderson-Hasselbach equation (it was originally derived to describe the pH changes resulting from the addition of H<sup>+</sup> or OH ions to any buffer system). At a certain concentration of hydrogen ion (log10ˉ<sup>1</sup> [-pH]) specified for each drug, the concentration of LA in its basic form in a solution is equal to the

**Structural groups of some commonly used local anesthetics (duration of action)**

), the ratio of the two states

presence of vasoconstrictors, and the precision of drug injection.

uncharged form (B) and the charged cationic form (BH<sup>+</sup>

*Pharmacokinetics and Pharmacodynamics of Local Anesthetics*

*DOI: http://dx.doi.org/10.5772/intechopen.91700*

to hydrolysis (**Table 2**).

**Amides**

Cocaine

Proxymetacaine

Benzocaine Chloroprocaine Oxybuprocaine Procaine (30–45 min)

Propoxycaine Tetracaine

**Table 2.** *Groups of LA.*

**35**

**Esters of meta-aminobenzoic acid**

**Esters of para-aminobenzoic acid**

Bupivacaine (2–8 h) Cinchocaine (2–3 h) Etidocaine (2–6 h) Levobupivacaine (2–8 h) Lidocaine (1–2 h) Mepivacaine (1.5–3 h) Prilocaine (1–2 h) Ropivacaine (4–6 h) **Ester of benzoic acid**

**3.1 Hydrogen ion concentration**

#### **Table 1.**

*Fiber type.*

these channels, with the presence of voltage-dependent doors in the light of the same (**Figure 2**).

The currents of depolarization and repolarization move longitudinally along the nerve membrane and result in conduction of the nerve impulse. In unmyelinated nerves, the impulses spread at speeds of about 2 m/s. In myelinated nerves, the depolarization current jumps from node to node; this phenomenon, known as saltatory conduction, increases conduction velocity to around 120 m/s and is highly energy-efficient [4].

Neurons can usefully be classified according their diameter and speed of conduction (**Table 1**).

#### **3. Local anesthetic molecule**

The local anesthetic molecule consists of three components: (a) lipophilic aromatic ring, (b) intermediate ester or amide chain, and (c) terminal amine. Each of these contributes distinct properties to the molecule [5].

**Figure 3.** *Saltatory conduction. Wikiwand free Google.*

*Pharmacokinetics and Pharmacodynamics of Local Anesthetics DOI: http://dx.doi.org/10.5772/intechopen.91700*

In this way, local anesthetics can be classified into two groups: aminoesters and aminoamides. The aromatic ring provides a lipophilic character to the portion of the molecule in which it is found, while the tertiary amine end is hydrophilic, because it is protonated and has a positive charge in the physiological pH range [6] (**Figure 3**).

The ester-type LAs include benzocaine, procaine, cocaine, and tetracaine. The amide-type LAs include mepivacaine, lidocaine, ropivacaine, bupivacaine, and etidocaine. Lidocaine and bupivacaine are the most commonly used LAs, both are amide-type compounds, which are much more resistant than ester-type compounds to hydrolysis (**Table 2**).

In addition to the intrinsic binding affinities of LA drugs to the Na<sup>+</sup> channel, other variables also strongly influence the relative duration of local anesthesia; these include the volume, concentration, lipophilicity, pKa, pH, repeated injections, the presence of vasoconstrictors, and the precision of drug injection.

#### **3.1 Hydrogen ion concentration**

these channels, with the presence of voltage-dependent doors in the light of the

B Preganglionic autonomic Yes <3 3–15 1.2 C Postganglionic sympathetic No 0.3–1.3 0.7–2.3 2

**Function Myelinated Diameter**

Aα Proprioception, somatic motor Yes 12–20 70–120 0.4–0.5 Aβ Touch, pressure Yes 5–12 30–70 0.4–0.5 Aγ Motor to muscle spindle Yes 3–6 15–30 0.4–0.5 Aδ Pain, cold, touch Yes 2–5 12–30 0.4–0.5

**(mm)**

**Conduction velocity (m/s)**

No 0.4–1.2 0.5–2 2

**Spike duration (ms)**

The currents of depolarization and repolarization move longitudinally along the nerve membrane and result in conduction of the nerve impulse. In unmyelinated nerves, the impulses spread at speeds of about 2 m/s. In myelinated nerves, the depolarization current jumps from node to node; this phenomenon, known as saltatory conduction, increases conduction velocity to around 120 m/s and is highly

Neurons can usefully be classified according their diameter and speed of con-

The local anesthetic molecule consists of three components: (a) lipophilic aromatic ring, (b) intermediate ester or amide chain, and (c) terminal amine. Each of

same (**Figure 2**).

**Table 1.** *Fiber type.*

**Fiber type**

*Topics in Local Anesthetics*

energy-efficient [4].

duction (**Table 1**).

**Figure 3.**

**34**

*Saltatory conduction. Wikiwand free Google.*

**3. Local anesthetic molecule**

C Pain, temperature (dr)

mechanoreception, reflex responses

these contributes distinct properties to the molecule [5].

LAs in solution maintain a rapid chemical equilibrium between the basic uncharged form (B) and the charged cationic form (BH<sup>+</sup> ), the ratio of the two states is given by the Henderson-Hasselbach equation (it was originally derived to describe the pH changes resulting from the addition of H<sup>+</sup> or OH ions to any buffer system). At a certain concentration of hydrogen ion (log10ˉ<sup>1</sup> [-pH]) specified for each drug, the concentration of LA in its basic form in a solution is equal to the


**Table 2.** *Groups of LA.*

concentration of loaded cation. The logarithm of this concentration of hydrogen ion is called pKa.

convention is that which assigns a sequence of priority to the four atoms or group attached to the chiral center. The molecule is described as though it were being viewed from the front with the smallest group extending away from the viewer. If the arrangement of the largest to the smallest groups is clockwise, the enantiomer is designated "R" for rectus. If the arrangement is anticlockwise it is designated "S" for sinister. The optical direction is the added to complete the description. Most synthetic chiral drugs are racemic mixtures, less potent because the D-forms are much less active. The clinical behavior of the enantiomers, and in particular their

toxicity, is related to the chiral form [10] (**Figure 5** and **Table 3**).

*Pharmacokinetics and Pharmacodynamics of Local Anesthetics*

*DOI: http://dx.doi.org/10.5772/intechopen.91700*

**Figure 4.**

**Figure 5.**

**37**

*LA molecule free Google.*

*Na receptor. Memorang.*

$$\text{pH} = \text{pKa} + \log\left[\text{HCO}\_3^-\right] / \left[\text{H}\_2\text{CO}\_3\right]$$

$$\text{pKa} = \text{pH} - \log\left[\text{base}\right] / \left[\text{conjugate acid}\right]$$

$$\left[\text{base}\right] / \left[\text{conjugate acid}\right] = 1.0$$

The dissociation constant of LA (pKa value) is the highly significant fact affecting the quickness of their beginning of action. The pKa values rule the ratio of the LA that is present in nonprotonated pattern at physiological pH values and hence disposable to spread through tissue walls to its spot of action.

Lower pKa values are conjoint with a prompt beginning of blockade, then more of the drug is present as the unprotonated base at pH 7.4. In contradistinction, bigger values are conjointed with a slower beginning, since fewer of the drug is present as the nonprotonated base at pH 7.4. For instance, lidocaine has a pKa value roughly 7.7. At pH 7.4, around one-third of these drugs is present in solution as the nonprotonated base B and is disposable to spread through the nerve scabbard. In contradistinction, bupivacaine and ropivacaine have a pKa value of 8.1, and at a pH 7.4 only 17% is present in solution as nonprotonated, diffusible base. These discrepancies are responsible for the more prompt beginning of action of lidocaine and slower beginning of action of ropivacaine and bupivacaine.

#### **3.2 Alkalization of local anesthetics**

Factors that increase the conversion of the free LA base (B) to the active form (BH<sup>+</sup> ) in the neuroplasm increase the diffusion gradient and the concentration of BH+ in the Na<sup>+</sup> channel. This technique is of clinical interest because it is used to shorten the latency of onset of effective anesthesia, particularly useful in the context of extending an epidural block for urgent operative delivery.

The addition of bicarbonate will raise the pH of the weakly acidic solution nearer the pKa. Example: addition of 1.0 mL NaHCO3 8.4% to 10.0 mL of lidocaine 2% will raise its pH from 6.5 to 7.2; this means more drug will exist in the non-ionized form, so penetration will be more rapid [7].

Carbonation is a variation on alkalization, and is based on a similar principle but with a different site of action; when carbon dioxide diffuses across the neurilemma, it is rapidly buffered by intracellular proteins, so that changes in pH are minimal. Carbonated solutions are unstable, the LA may be precipitated and any added vasoconstrictor is more easily hydrolyzed [8].

#### **3.3 Chirality**

Chirality is derived from Greek, and means "having handedness," and is defined a particular type of stereoisomerism. Right and left hands are mirror images of each other but cannot be superimposed when the palms are facing in the same direction (**Figure 4**) [9]. These particular isomers are known as enantiomers and this form of stereoisomerism is dependent on the presence of one or more chiral centers, which typically comprise a carbon atom with four groups attached. These enantiomers have the capacity to rotate polarized light, and, so, are also known as optical isomers.

Enantiomers that rotate polarized light to the right are described as (+), and are the same as dextro or D isomers. Enantiomers that rotate polarized light to the left are described as (�), and are the same as levo or L isomers. The currently accepted *Pharmacokinetics and Pharmacodynamics of Local Anesthetics DOI: http://dx.doi.org/10.5772/intechopen.91700*

convention is that which assigns a sequence of priority to the four atoms or group attached to the chiral center. The molecule is described as though it were being viewed from the front with the smallest group extending away from the viewer. If the arrangement of the largest to the smallest groups is clockwise, the enantiomer is designated "R" for rectus. If the arrangement is anticlockwise it is designated "S" for sinister. The optical direction is the added to complete the description. Most synthetic chiral drugs are racemic mixtures, less potent because the D-forms are much less active. The clinical behavior of the enantiomers, and in particular their toxicity, is related to the chiral form [10] (**Figure 5** and **Table 3**).

**Figure 4.**

concentration of loaded cation. The logarithm of this concentration of hydrogen ion

pKa ¼ pH � log base ½ �*=*½ � conjugate acid ½ � base *=*½conjugate acid� ¼ 1*:*0

The dissociation constant of LA (pKa value) is the highly significant fact affecting the quickness of their beginning of action. The pKa values rule the ratio of the LA that is present in nonprotonated pattern at physiological pH values and hence

Lower pKa values are conjoint with a prompt beginning of blockade, then more

Factors that increase the conversion of the free LA base (B) to the active form

) in the neuroplasm increase the diffusion gradient and the concentration of BH+ in the Na<sup>+</sup> channel. This technique is of clinical interest because it is used to shorten the latency of onset of effective anesthesia, particularly useful in the con-

The addition of bicarbonate will raise the pH of the weakly acidic solution nearer the pKa. Example: addition of 1.0 mL NaHCO3 8.4% to 10.0 mL of lidocaine 2% will raise its pH from 6.5 to 7.2; this means more drug will exist in the non-ionized form,

Carbonation is a variation on alkalization, and is based on a similar principle but with a different site of action; when carbon dioxide diffuses across the neurilemma, it is rapidly buffered by intracellular proteins, so that changes in pH are minimal. Carbonated solutions are unstable, the LA may be precipitated and any added

Chirality is derived from Greek, and means "having handedness," and is defined a particular type of stereoisomerism. Right and left hands are mirror images of each other but cannot be superimposed when the palms are facing in the same direction (**Figure 4**) [9]. These particular isomers are known as enantiomers and this form of stereoisomerism is dependent on the presence of one or more chiral centers, which typically comprise a carbon atom with four groups attached. These enantiomers have the capacity to rotate polarized light, and, so, are also known as optical

Enantiomers that rotate polarized light to the right are described as (+), and are the same as dextro or D isomers. Enantiomers that rotate polarized light to the left are described as (�), and are the same as levo or L isomers. The currently accepted

of the drug is present as the unprotonated base at pH 7.4. In contradistinction, bigger values are conjointed with a slower beginning, since fewer of the drug is present as the nonprotonated base at pH 7.4. For instance, lidocaine has a pKa value roughly 7.7. At pH 7.4, around one-third of these drugs is present in solution as the nonprotonated base B and is disposable to spread through the nerve scabbard. In contradistinction, bupivacaine and ropivacaine have a pKa value of 8.1, and at a pH 7.4 only 17% is present in solution as nonprotonated, diffusible base. These discrepancies are responsible for the more prompt beginning of action of lidocaine

� ½ �*=*½ � H2CO3

pH ¼ pKa þ log HCO3

disposable to spread through tissue walls to its spot of action.

and slower beginning of action of ropivacaine and bupivacaine.

text of extending an epidural block for urgent operative delivery.

**3.2 Alkalization of local anesthetics**

so penetration will be more rapid [7].

vasoconstrictor is more easily hydrolyzed [8].

(BH<sup>+</sup>

**3.3 Chirality**

isomers.

**36**

is called pKa.

*Topics in Local Anesthetics*

*Na receptor. Memorang.*

	-

**Figure 5.** *LA molecule free Google.* **Bupivacaine:** S(�) enantiomer has less affinity for, and dissociates quicker from myocardial Na<sup>+</sup> channels. The cardio and central nervous system toxicity is reduced. S(�) exerts some vasoconstrictor activity.

**Ropivacaine:** S(�) enantiomer is a safer cardiovascular profile.

**Prilocaine:** S(+) enantiomer is a stronger vasoconstrictor, metabolized slowly than the R(�) form which therefore produces higher concentrations of 0-toluidine and a greater risk of methaemoglobinaemia.

**Lidocaine:** Achiral.

**Table 3.** *Quimical structure.*

#### **4. Pharmacodynamics**

Most LA drugs are tertiary amine bases (B), which are dispensed as hydrochloride salts (B.HCL). In this way, their easily disband to pattern acidic solutions:

B*:*HCL< >BH<sup>þ</sup> þ CL�

Japan. TTX has been an invaluable tool for the identification of various neuronal

tion and the plasma concentration resulting from the LA injected [14, 15].

**4.1 Mode and site of action of local anesthetics in Na<sup>+</sup> channels**

*Pharmacokinetics and Pharmacodynamics of Local Anesthetics*

*DOI: http://dx.doi.org/10.5772/intechopen.91700*

The concentration of LA in blood is determined by the amount injected, the rate of absorption from the injection site, the rate of distribution by tissues, the rate of biotransformation and drug elimination [14]. The patient's factors, such as age, cardiovascular situation, and hepatic function, influence the physiological disposi-

Mammalian voltage-gated Na<sup>+</sup> channels are normally activated at a threshold of around 50 mV, and the probability of channels being open is maximal around +20 mV. At a single-channel level, the time course of Na+ channel activation is strongly voltage dependent. The probability of being open during depolarization rises slowly at the threshold and becomes rather fast at the more positive potentials. In contrast, the open Na<sup>+</sup> channels inactivate rapidly, with a dwell time that is generally 1 ms or less. Unlike the activation process, the time course of inactivation of the open Na<sup>+</sup> channel is not voltage dependent [16]. At the level of macroscopic currents, Na<sup>+</sup> currents rise (activate) and decay (inactivate) with overlapping time course, as would be expected from an ensemble of currents from

Detailed kinetic analyses of macroscopic Na<sup>+</sup> currents in the presence of various LAs reveal complicated pharmacological profiles under voltage-clamp conditions. Voltage-sensitive Na<sup>+</sup> channels are integral proteins that cross neuronal membranes and surround an aqueous pore. Most Na<sup>+</sup> channels consist of three subunits (α1, β1, and β2), the largest subunit being α1, the site of ion conduction and LAs binding; the external surface of the α-subunit is heavily glycosylated, which serves to orient the channel properly within the plasma membrane. The α1 unit bears a molecular weight up of 260 kDa, and consists of an unique long peptide chain holding four hydrophobic regions (domains I–IV), which go across the membrane and symmetrically encircle the pore. The four domains are joined

Every domain includes six membrane-spanning somites (S1–S6). The S4 somite

is a potential sensor, and the brief curl among S5 and S6 forms portion of the sheathing of the external pore of the gutter. The intracellular bridgework among

Na<sup>+</sup> channel isoforms [11–13].

**Figure 6.**

*Amino-base free Google.*

single channels [17, 18].

**39**

to each other by intracellular bridgeworks.

After infiltrating the tissues, a ratio of the protonated basic pattern (BH<sup>+</sup> ) is turned to the unprotonated basic pattern (B) at the pH of the extracellular fluid:

$$\rm{BH}^+ + \rm{HCO\_3}^- << \rm{B} + \rm{H\_2O} + \rm{CO\_2}$$

Solely the unprotonated pattern B penetrates through the neurilemmal membrane, captures H+ in the neuroplasm, and raises approach to its spot of action in the open Na<sup>+</sup> channel, inducing its blockade. The unprotonated pattern B may further straight permeate to the Na<sup>+</sup> channel across the neurilemma, and recruits H+ into the Na<sup>+</sup> channel.

It is able to induce blockade by membrane expansion (ME), bring about puffiness of the lipoprotein matrix of the Na<sup>+</sup> channel (e.g., benzocaine). Tetrodotoxin and saxitoxin directly block the Na<sup>+</sup> channel from the exterior of the membrane, close to the external pore [11–13] (**Figure 6**).

The primary target of LAs is the voltage-gated Na<sup>+</sup> channel, which is responsible for the generation of action potentials in excitable membranes, there is an inverse relationship between action potentials and local anesthesia [13]. LAs also interact with many other types of ion channels, particularly K<sup>+</sup> and Ca2+ channels, notwithstanding they have a limited relationship at these sites. They do not mostly alter the neuronal resting potential, save in exceedingly raised concentrations. In the same way, they do not change the sill potential needed for impulse spread, even if the gear of depolarization and repolarization is diminished, and conduction velocity is reduced and may cause undesirable side effects, usually considered that the toxic effects of bupivacaine on the heart are partially related to its effects on K<sup>+</sup> and Ca2+ channels.

Mammalian voltage-gated Na<sup>+</sup> channels exist in different isoforms in various excitable tissues such as skeletal muscles, cardiac tissues, central nervous system (CNS), and peripheral nervous system (PNS) [14]. In addition, multiple major isoforms are present in CNS and PNS, some of these neuronal Na<sup>+</sup> channels are sensitive to tetrodotoxin (TTX) and some are resistant. Tetrodotoxin (TTX) is a potent naturally occurring neurotoxin isolated from puffer fish; it has been responsible for human intoxications and fatalities. Its usual route of toxicity is via the ingestion of contaminated puffer fish, which are a culinary delicacy, especially in

*Pharmacokinetics and Pharmacodynamics of Local Anesthetics DOI: http://dx.doi.org/10.5772/intechopen.91700*

**Figure 6.** *Amino-base free Google.*

**4. Pharmacodynamics**

methaemoglobinaemia. **Lidocaine:** Achiral.

*Topics in Local Anesthetics*

activity.

**Table 3.** *Quimical structure.*

the Na<sup>+</sup> channel.

channels.

**38**

Most LA drugs are tertiary amine bases (B), which are dispensed as hydrochloride salts (B.HCL). In this way, their easily disband to pattern acidic solutions:

B*:*HCL< >BH<sup>þ</sup> þ CL�

) is

After infiltrating the tissues, a ratio of the protonated basic pattern (BH<sup>+</sup>

**Bupivacaine:** S(�) enantiomer has less affinity for, and dissociates quicker from myocardial Na<sup>+</sup> channels. The cardio and central nervous system toxicity is reduced. S(�) exerts some vasoconstrictor

**Prilocaine:** S(+) enantiomer is a stronger vasoconstrictor, metabolized slowly than the R(�) form

which therefore produces higher concentrations of 0-toluidine and a greater risk of

**Ropivacaine:** S(�) enantiomer is a safer cardiovascular profile.

turned to the unprotonated basic pattern (B) at the pH of the extracellular fluid:

Solely the unprotonated pattern B penetrates through the neurilemmal membrane, captures H+ in the neuroplasm, and raises approach to its spot of action in the open Na<sup>+</sup> channel, inducing its blockade. The unprotonated pattern B may further straight permeate to the Na<sup>+</sup> channel across the neurilemma, and recruits H+ into

It is able to induce blockade by membrane expansion (ME), bring about puffiness of the lipoprotein matrix of the Na<sup>+</sup> channel (e.g., benzocaine). Tetrodotoxin and saxitoxin directly block the Na<sup>+</sup> channel from the exterior of the membrane,

The primary target of LAs is the voltage-gated Na<sup>+</sup> channel, which is responsible for the generation of action potentials in excitable membranes, there is an inverse relationship between action potentials and local anesthesia [13]. LAs also interact with many other types of ion channels, particularly K<sup>+</sup> and Ca2+ channels, notwithstanding they have a limited relationship at these sites. They do not mostly alter the neuronal resting potential, save in exceedingly raised concentrations. In the same way, they do not change the sill potential needed for impulse spread, even if the gear of depolarization and repolarization is diminished, and conduction velocity is reduced and may cause undesirable side effects, usually considered that the toxic effects of bupivacaine on the heart are partially related to its effects on K<sup>+</sup> and Ca2+

Mammalian voltage-gated Na<sup>+</sup> channels exist in different isoforms in various excitable tissues such as skeletal muscles, cardiac tissues, central nervous system (CNS), and peripheral nervous system (PNS) [14]. In addition, multiple major isoforms are present in CNS and PNS, some of these neuronal Na<sup>+</sup> channels are sensitive to tetrodotoxin (TTX) and some are resistant. Tetrodotoxin (TTX) is a potent naturally occurring neurotoxin isolated from puffer fish; it has been responsible for human intoxications and fatalities. Its usual route of toxicity is via the ingestion of contaminated puffer fish, which are a culinary delicacy, especially in

� < >B þ H2O þ CO2

BH<sup>þ</sup> þ HCO3

close to the external pore [11–13] (**Figure 6**).

Japan. TTX has been an invaluable tool for the identification of various neuronal Na<sup>+</sup> channel isoforms [11–13].

The concentration of LA in blood is determined by the amount injected, the rate of absorption from the injection site, the rate of distribution by tissues, the rate of biotransformation and drug elimination [14]. The patient's factors, such as age, cardiovascular situation, and hepatic function, influence the physiological disposition and the plasma concentration resulting from the LA injected [14, 15].

#### **4.1 Mode and site of action of local anesthetics in Na<sup>+</sup> channels**

Mammalian voltage-gated Na<sup>+</sup> channels are normally activated at a threshold of around 50 mV, and the probability of channels being open is maximal around +20 mV. At a single-channel level, the time course of Na+ channel activation is strongly voltage dependent. The probability of being open during depolarization rises slowly at the threshold and becomes rather fast at the more positive potentials. In contrast, the open Na<sup>+</sup> channels inactivate rapidly, with a dwell time that is generally 1 ms or less. Unlike the activation process, the time course of inactivation of the open Na<sup>+</sup> channel is not voltage dependent [16]. At the level of macroscopic currents, Na<sup>+</sup> currents rise (activate) and decay (inactivate) with overlapping time course, as would be expected from an ensemble of currents from single channels [17, 18].

Detailed kinetic analyses of macroscopic Na<sup>+</sup> currents in the presence of various LAs reveal complicated pharmacological profiles under voltage-clamp conditions. Voltage-sensitive Na<sup>+</sup> channels are integral proteins that cross neuronal membranes and surround an aqueous pore. Most Na<sup>+</sup> channels consist of three subunits (α1, β1, and β2), the largest subunit being α1, the site of ion conduction and LAs binding; the external surface of the α-subunit is heavily glycosylated, which serves to orient the channel properly within the plasma membrane. The α1 unit bears a molecular weight up of 260 kDa, and consists of an unique long peptide chain holding four hydrophobic regions (domains I–IV), which go across the membrane and symmetrically encircle the pore. The four domains are joined to each other by intracellular bridgeworks.

Every domain includes six membrane-spanning somites (S1–S6). The S4 somite is a potential sensor, and the brief curl among S5 and S6 forms portion of the sheathing of the external pore of the gutter. The intracellular bridgework among

two of the domains (III and IV) is the speedy inactivation gateway. This gateway is liable for the speedy inactivation of Na<sup>+</sup> channels.

LAs reduce peak Na<sup>+</sup> currents during the test potential a few minutes after external perfusion of the drug solution at the holding potential (<�100 mV). This reduction in peak current is dose dependent, and the potency ranking of various LAs derived from their dose-response curves correlates well with the relative duration of local anesthesia they elicit in vivo. This LA block of the Na<sup>+</sup> channel at resting potential is termed "tonic block."

Most LAs are found to shift the apparent steady-state inactivation curve to the hyperpolarizing direction. Steady-state inactivation measures the availability of resting Na<sup>+</sup> channels at various prepulse voltages at which Na<sup>+</sup> channels normally do not open [7]. This closed-channel inactivation is strongly voltage dependent, unlike the open channel inactivation. A shift of the steady-state inactivation curve by LA toward the hyperpolarizing direction has significant physiological consequences. To begin with, if the steady-state inactivation curve is indeed shifted by LAs upon binding, a large fraction of Na<sup>+</sup> channels with LAs bound will be in their inactivated state at the resting potential and therefore will be unavailable to carry currents for the generation of action potentials. Another implication is that the inactivated state of the Na<sup>+</sup> channel binds more strongly than other channel states (generalized modulated receptor hypothesis envisioned by Hondeghem and Katzung [19]). They proposed that different states of Na<sup>+</sup> channels (open, resting, and inactivated) have different binding affinities for LAs, and that the affinity of the inactivated state is the highest.

Repetitive pulses produce an additional block of Na<sup>+</sup> currents in the presence of LA. This additional block of Na+ currents is termed "use-dependent block" or "frequency-dependent block," with the two terms used interchangeably. The usedependent block by LAs may be physiologically important for pain therapy, as many afferent fibers fire action potentials at a high frequency, particularly in the pathological states. In theory, LAs with a potent use-dependent attribute will be more effective than LAs without this attribute in blocking the high-frequency abnormal firings of sensory afferent fibers.

#### **4.2 Potency of local anesthetic**

The potency of a LA is regulated mainly by lipid solubility, the time of onset by the pKa of the substance, and the duration of action by protein binding. The more lipophilic the LA, the more potent it is [20, 21]. Nerve-blocking potency of LAs increases also with increasing molecular weight [22].

The peripheral vascular effects of the local anesthetic have significant effects; many anesthetics have a biphasic effect on vascular smooth muscle, at low concentrations they produce vasoconstriction and at higher concentrations they produce vasodilation. However, the vasodilator effect differs between the different drugs, the effects on vascular blood flow and its tone are complex, and vary among other factors, depending on the concentration, time, and vascular bed near the point of

**Local anesthetic Partition coefficient**

**Short effect** Procaine

**Moderate effect** Lidocaine

**Long effect** Tetracaine

Cloroprocaine

Mepivacaine Prilocaine

Bupivacaine Ropivacaine Etidocaine

Benzocaine 1.44 Procaine 2.51 Mepivacaine 2.69 Prilocaine 2.73 Lidocaine 3.40 Bupivacaine 4.05 Etidocaine 4.19 Tetracaine 4.32 Oxybuprocaine 4.38

*Partition coefficients (n-octanol/water) of some local anesthetics.*

*Pharmacokinetics and Pharmacodynamics of Local Anesthetics*

*DOI: http://dx.doi.org/10.5772/intechopen.91700*

Pharmacokinetics was originally described as the quantitative studio and mathematical review of drug and it's metabolite in the organism. The concept has been mostly obsequious to the prosecution of drug absorption, distribution, metabolism and excretion, and to their explanation in numerical terminus. Pharmacokinetics is once in a while portrayed as "what the body does to drugs." The two highly large

application.

**Table 5.**

*Onset and duration.*

**Table 4.**

**5. Pharmacokinetics**

pharmacokinetic uniforms are:

• Clearance (CL)

**41**

• Volume of distribution (V)

LA appears to have a ceiling effect. Above a partition coefficient of 4 there is no observed increase in potency [23]. Unfortunately, greater lipid solubility also increases toxicity, decreasing the therapeutic index for more hydrophobic drugs. Larger more lipophilic LAs permeate nerve membrane more readily and bind Na<sup>+</sup> channels with greater affinity (**Table 4**).

More lipid-soluble LAs are relatively water insoluble, high protein bound in blood, and less readily removed by bloodstream from nerve membranes, and this affinity of the drug to lipid membranes and therefore greater proximity to its site of action in the Na<sup>+</sup> channel.

#### **4.3 Onset and duration of action of local anesthetics**

The onset of nerve conduction blockade depends on the physicochemical properties of each LA. The latency also depends on the dose or concentration of the drug used. The duration of the effect of local anesthetics is very variable (**Table 5**).

#### *Pharmacokinetics and Pharmacodynamics of Local Anesthetics DOI: http://dx.doi.org/10.5772/intechopen.91700*


#### **Table 4.**

two of the domains (III and IV) is the speedy inactivation gateway. This gateway is

LAs reduce peak Na<sup>+</sup> currents during the test potential a few minutes after external perfusion of the drug solution at the holding potential (<�100 mV). This reduction in peak current is dose dependent, and the potency ranking of various LAs derived from their dose-response curves correlates well with the relative duration of local anesthesia they elicit in vivo. This LA block of the Na<sup>+</sup> channel at

Most LAs are found to shift the apparent steady-state inactivation curve to the hyperpolarizing direction. Steady-state inactivation measures the availability of resting Na<sup>+</sup> channels at various prepulse voltages at which Na<sup>+</sup> channels normally do not open [7]. This closed-channel inactivation is strongly voltage dependent, unlike the open channel inactivation. A shift of the steady-state inactivation curve by LA toward the hyperpolarizing direction has significant physiological consequences. To begin with, if the steady-state inactivation curve is indeed shifted by LAs upon binding, a large fraction of Na<sup>+</sup> channels with LAs bound will be in their inactivated state at the resting potential and therefore will be unavailable to carry currents for the generation of action potentials. Another implication is that the inactivated state of the Na<sup>+</sup> channel binds more strongly than other channel states (generalized modulated receptor hypothesis envisioned by Hondeghem and Katzung [19]). They proposed that different states of Na<sup>+</sup> channels (open, resting, and inactivated) have different binding affinities for LAs, and that the affinity of

Repetitive pulses produce an additional block of Na<sup>+</sup> currents in the presence of

The potency of a LA is regulated mainly by lipid solubility, the time of onset by the pKa of the substance, and the duration of action by protein binding. The more lipophilic the LA, the more potent it is [20, 21]. Nerve-blocking potency of LAs

LA appears to have a ceiling effect. Above a partition coefficient of 4 there is no

observed increase in potency [23]. Unfortunately, greater lipid solubility also increases toxicity, decreasing the therapeutic index for more hydrophobic drugs. Larger more lipophilic LAs permeate nerve membrane more readily and bind Na<sup>+</sup>

More lipid-soluble LAs are relatively water insoluble, high protein bound in blood, and less readily removed by bloodstream from nerve membranes, and this affinity of the drug to lipid membranes and therefore greater proximity to its site of

The onset of nerve conduction blockade depends on the physicochemical properties of each LA. The latency also depends on the dose or concentration of the drug used. The duration of the effect of local anesthetics is very variable (**Table 5**).

LA. This additional block of Na+ currents is termed "use-dependent block" or "frequency-dependent block," with the two terms used interchangeably. The usedependent block by LAs may be physiologically important for pain therapy, as many afferent fibers fire action potentials at a high frequency, particularly in the pathological states. In theory, LAs with a potent use-dependent attribute will be more effective than LAs without this attribute in blocking the high-frequency

liable for the speedy inactivation of Na<sup>+</sup> channels.

resting potential is termed "tonic block."

*Topics in Local Anesthetics*

the inactivated state is the highest.

abnormal firings of sensory afferent fibers.

channels with greater affinity (**Table 4**).

action in the Na<sup>+</sup> channel.

**40**

increases also with increasing molecular weight [22].

**4.3 Onset and duration of action of local anesthetics**

**4.2 Potency of local anesthetic**

*Partition coefficients (n-octanol/water) of some local anesthetics.*


### **Table 5.**

*Onset and duration.*

The peripheral vascular effects of the local anesthetic have significant effects; many anesthetics have a biphasic effect on vascular smooth muscle, at low concentrations they produce vasoconstriction and at higher concentrations they produce vasodilation. However, the vasodilator effect differs between the different drugs, the effects on vascular blood flow and its tone are complex, and vary among other factors, depending on the concentration, time, and vascular bed near the point of application.

### **5. Pharmacokinetics**

Pharmacokinetics was originally described as the quantitative studio and mathematical review of drug and it's metabolite in the organism. The concept has been mostly obsequious to the prosecution of drug absorption, distribution, metabolism and excretion, and to their explanation in numerical terminus. Pharmacokinetics is once in a while portrayed as "what the body does to drugs." The two highly large pharmacokinetic uniforms are:


The volume of distribution depicts the seeming volume disposable in the organism for the allocation of the drug, whereas the clearance shows capacity of the organism to eliminate the drug. These two uniforms are kindred to the terminal or elimination half-life of the drug. In other words, after one half-life, the concentration of the drug in the body will be half of the starting dose. Half-life is defined as the time required for the plasma concentration to decrease by 50% during the terminal phase of decline, by the following expression:

$$\mathbf{t}\% = \mathbf{0}.693 \times \mathbf{Vd}/\mathbf{CL}.$$

Accordingly, the terminal half-life is regularly heterogeneous, which depends on the early pharmacokinetics constant volume (V) and clearance (CL). A prolonged terminal half-life can throw back an enhanced volume of distribution, a narrow clearance, or together these changes, while a brief terminal half-life can reflect a decreased volume of distribution, an enhanced clearance or both together [8] (**Table 6**).

Clearance depicts the quantity of blood or plasma since that a drug would need to be thoroughly eliminated in unit time in order to guarantee its put-out from the body. It is a theoretic thought, inasmuch as in practice drugs are incompletely withdrawn from a nay larger quantity of plasma. Clearance values are generally expressed as a quantity cleared in unit time and are generally measured in mL min�<sup>1</sup> or L h�<sup>1</sup> .

Also, clearance can be determined as the timing of drug elimination (mg min�<sup>1</sup> ) per unit of blood or plasma concentration (mg mL�<sup>1</sup> ).

$$\text{plasma clearance} \,\left(\text{mL }\,\text{min}^{-1}\right) = \frac{\text{timing of drug removal } \left(\text{mg }\,\text{min}^{-1}\right)}{\text{plasma centralization } \left(\text{mg }\,\text{mL}^{-1}\right)}$$

Plasma clearance is as a rule steadfast; the cadence of drug removal is right away proportional to plasma concentration. Total body clearance is the addition of various ways of drug elimination that are carried out by various organs in the body:

$$\mathbf{CL} = \mathbf{CL\_{R}} + \mathbf{CL\_{H}} + \mathbf{CL\_{X}}$$

where CL is total clearance, CLR is renal clearance, CLH is hepatic clearance and CLX is clearance by other routes (**Table 7**).

After absorption from the site of injection, the plasma concentration of LAs depends on their rate of distribution in tissues and their elimination from the body. Subsequent to an intravenous injection, the plasma concentration of all LAs in general falls in a biexponential ways. There is an incipient quick allocation time (half-life 1–3 min), conjoint with their rapid inlet by greatly perfused organs (e.g., lung, liver, kidney). Afterward, there is a slower reduction in plasma centralization, which depicts the put-out of LAs by metabolism and excretion. The final half-life of most ester anesthetics is comparatively brief (10 min) owing to their prompt

hydrolysis by plasma cholinesterase, in hallmark, the terminal half-life of the amides oscillates from 100 min (lidocaine) to 200 min (bupivacaine).

plasma clearance is usually less than liver blood flow (**Table 8**).

*Pharmacokinetics and metabolism of local anesthetics.*

**Drug Hepatic clearance (mL min**�**<sup>1</sup> kg**�**<sup>1</sup>**

*DOI: http://dx.doi.org/10.5772/intechopen.91700*

*Pharmacokinetics and Pharmacodynamics of Local Anesthetics*

**Terminal halflife (min)**

**Table 7.** *Hepatic clearance.*

Lidocaine 17.0 (12.6–21.4) 1190 (882–1498)

**Clearance (mL min**�**<sup>1</sup> kg**�**<sup>1</sup>**

Cocaine 48 31 2.0 Norcocaine

Procaine 8 60 0.7 Diethylaminoethanol

Tetracaine 15 47 1.0 Butyl-aminobenzoate

Lidocaine 100 15 1.3 Monoethylglycine-

Prilocaine 100 34 2.7 N-propylamine

Bupivacaine 200 9 1.1 Pipecolic acid

Levobupivacaine 200 9 1.1 Pipecolic acid

Ropivacaine 110 7 0.7 3-Hydroxy-ropivacain

**)**

**Apparent volume of distribution**

**) Hepatic clearance (mL min**�**<sup>1</sup> 70 kg**�**<sup>1</sup>**

**)**

**)**

**Metabolites (L kg**�**<sup>1</sup>**

Ecgonine Benzoylated

p-aminobenzoate

Dimethyl-aminoethanol

xylidide Ethylglycine 2,6-xylidine 4-hydroxy-2,6-xylidine

o-toluidine

Pipecolyl-xylidide

Pipecolyl-xylidide

4-Hydroxy-ropivacain

sustained.

**43**

**Table 8.**

**6. Conclusions**

Their volume of distribution is rather greater than total body water, while their

LAs are drugs widely used in medicine and dentistry. These medications cause reversible neural block by their action in the sodium channels (**Figure 7**) located in

Some clinical conditions can modify the pharmacokinetics of LAs, specially cardiovascular disorders and chronic hepatic diseases like cirrhosis can decline the clearance and volume of distribution of LAs, with changeable impact on the terminal half-life. In neonates, the clearance of LAs is diminished and their half-life is


**Table 6.** *Volume of distribution.*


#### **Table 7.**

The volume of distribution depicts the seeming volume disposable in the organ-

t½ ¼ 0*:*693 � Vd*=*CL*:*

Accordingly, the terminal half-life is regularly heterogeneous, which depends on the early pharmacokinetics constant volume (V) and clearance (CL). A prolonged terminal half-life can throw back an enhanced volume of distribution, a narrow clearance, or together these changes, while a brief terminal half-life can reflect a decreased volume of distribution, an enhanced clearance or both together [8]

Clearance depicts the quantity of blood or plasma since that a drug would need to be thoroughly eliminated in unit time in order to guarantee its put-out from the body. It is a theoretic thought, inasmuch as in practice drugs are incompletely withdrawn from a nay larger quantity of plasma. Clearance values are generally expressed as a quantity cleared in unit time and are generally measured in

Also, clearance can be determined as the timing of drug elimination (mg min�<sup>1</sup>

plasma clearance mL min �<sup>1</sup> <sup>¼</sup> timing of drug removal mg min �<sup>1</sup>

CL ¼ CLR þ CLH þ CLX

After absorption from the site of injection, the plasma concentration of LAs depends on their rate of distribution in tissues and their elimination from the body. Subsequent to an intravenous injection, the plasma concentration of all LAs in general falls in a biexponential ways. There is an incipient quick allocation time (half-life 1–3 min), conjoint with their rapid inlet by greatly perfused organs (e.g., lung, liver, kidney). Afterward, there is a slower reduction in plasma centralization, which depicts the put-out of LAs by metabolism and excretion. The final half-life of most ester anesthetics is comparatively brief (10 min) owing to their prompt

**Drug Volume of distribution (ml/kg) Volume of distribution (L 70 kg)**

Lidocaine 900 (500�1300) 63 (35�91) Bupivacaine 1050 (650�1450) 74 (46�104) Prilocaine 2700 (2100�3300) 189 (147�241)

where CL is total clearance, CLR is renal clearance, CLH is hepatic clearance and

Plasma clearance is as a rule steadfast; the cadence of drug removal is right away proportional to plasma concentration. Total body clearance is the addition of various ways of drug elimination that are carried out by various organs in the body:

).

plasma centralization mg mL�<sup>1</sup>

)

ism for the allocation of the drug, whereas the clearance shows capacity of the organism to eliminate the drug. These two uniforms are kindred to the terminal or elimination half-life of the drug. In other words, after one half-life, the concentration of the drug in the body will be half of the starting dose. Half-life is defined as the time required for the plasma concentration to decrease by 50% during the

terminal phase of decline, by the following expression:

(**Table 6**).

**Table 6.**

**42**

*Volume of distribution.*

mL min�<sup>1</sup> or L h�<sup>1</sup>

*Topics in Local Anesthetics*

.

CLX is clearance by other routes (**Table 7**).

per unit of blood or plasma concentration (mg mL�<sup>1</sup>

*Hepatic clearance.*


#### **Table 8.**

*Pharmacokinetics and metabolism of local anesthetics.*

hydrolysis by plasma cholinesterase, in hallmark, the terminal half-life of the amides oscillates from 100 min (lidocaine) to 200 min (bupivacaine).

Their volume of distribution is rather greater than total body water, while their plasma clearance is usually less than liver blood flow (**Table 8**).

Some clinical conditions can modify the pharmacokinetics of LAs, specially cardiovascular disorders and chronic hepatic diseases like cirrhosis can decline the clearance and volume of distribution of LAs, with changeable impact on the terminal half-life. In neonates, the clearance of LAs is diminished and their half-life is sustained.

#### **6. Conclusions**

LAs are drugs widely used in medicine and dentistry. These medications cause reversible neural block by their action in the sodium channels (**Figure 7**) located in

**References**

McGraw Hill; 2011

[1] Brunton L, editor. Goodman and Gilman. The Pharmacological Bases of Therapeutics. 12th ed. New York:

*DOI: http://dx.doi.org/10.5772/intechopen.91700*

*Pharmacokinetics and Pharmacodynamics of Local Anesthetics*

Biology. 2016;**26**(19):R870-R872. DOI:

[13] Thottumkara AP, Parsons WH, Du Bois J. Saxitoxin. Angewandte Chemie (International Ed. in English). 2014; **53**(23):5760-5784. DOI: 10.1002/

[14] Tucker GT. Pharmacokinetics of local anaesthetics. British Journal of Anaesthesia. 1986;**58**(7):717-731. DOI:

[15] Rosenberg PH, Veering BT, Urmey WF. Maximum recommended

[16] Skou JC. Local anaesthetics. VI. Relation between blocking potency and penetration of a monomolecular layer of

[17] Aldrich RW, Corey DP, Stevens CF. A reinterpretation of mammalian sodium channel gating based on single channel recording. Nature. 1983; **306**(5942):436-441. DOI: 10.1038/

[18] Hille B. Gating mechanisms. In: Ionic Channels of Excitable Membranes. Sunderland, Massachusetts: Sinauer;

[19] Hondeghem LM, Katzung BG. Time- and voltage-dependent

doses of local anesthetics: A multifactorial concept. Regional Anesthesia and Pain Medicine. 2004; **29**(6):564-575. DOI: 10.1016/j.

[12] Bane V, Lehane M, Dikshit M, O'Riordan A, Furey A. Tetrodotoxin: Chemistry, toxicity, source, distribution and detection. Toxins (Basel). 2014; **6**(2):693-755. DOI: 10.3390/toxins

10.1016/j.cub.2016.05.067

6020693

anie.201308235

10.1093/bja/58.7.717

rapm.2004.08.003

306436a0

1992. pp. 472-503

lipoids from nerves. Acta Pharmacologica et Toxicologica (Copenh). 1954;**10**(4):325-337. DOI: 10.1111/j.1600-0773.1954.tb01349.x

[2] Goldin AL, Barchi RL, Caldwell JH, Hofmann F, Howe JR, Hunter JC, et al. Nomenclature of voltage-gated sodium channels. Neuron. 2000;**28**(2):365-368. DOI: 10.1016/s0896-6273(00)00116-1

[3] Hadzic A. Hadzic's Textbook of Regional Anesthesia and Acute Pain Management. The New York School of Regional Anesthesia. 2nd ed. NY: McGraw-Hill Education; 2017

[4] Bovill J, Fee H. Physiology for Anaesthesiologists. UK: Taylor and

[5] Becker DE, Reed KL. Essentials of local anesthetic pharmacology.

[6] Gropper MA, editor. Miller's Anesthesia. 9th ed. US: Elsevier; 2019

[7] Hodgkin AL, Huxley AF. A

current and its application to conduction and excitation in nerve. 1952. Bulletin of Mathematical Biology. 1990;**52**(1–2):25-71. DOI: 10.1007/

Practice of Pharmacology for Anaesthetists. 5th ed. New Jersey: Wiley, John & Sons, Inc.; 2008

en México. 2006;**18**(2):181-182

Drug chirality in anesthesia. Anesthesiology. 2002;**97**:497-502

Lötters S. Tetrodotoxin. Current

quantitative description of membrane

[8] Calvey N, Williams N. Principles and

[9] Carrada PS. Carta al editor. Anestesia

[10] Weiskopf R, Nau C, Strichartz G.

[11] Lorentz MN, Stokes AN, Rößler DC,

Anesthesia Progress. 2006;**53**(3):98-109. DOI: 10.2344/0003-3006(2006)53[98,

Francis Group; 2004

EOLAP]2.0.CO;2

bf02459568

**45**

**Figure 7.** *Sodium channel. Wikipedia.*

the nerve membranes. The unprotonated molecule configuration of the LA is introduced through the membrane from the outside and the protonated molecule acts with the sodium channel from the inside. The potency of a LA is given by liposolubility, the onset time by dissociation constant (pKa), and the duration of action by protein binding. Local anesthetics are weak bases whose structure consists of an aromatic moiety connected to a substituted amine through an ester or amide linkage. Consequently, LAs are classified as aminoester or aminoamide compounds. Amino acids are hydrolyzed by plasma cholinesterase, while aminoamides are metabolized in the liver. Aminoamides cause less allergic reactions.

### **Conflict of interest**

The author declares no conflict of interests.

#### **Author details**

Javier Marcos Michel-Levy Hospital Obrero N°8, Caja Nacional de Salud, Trinidad-Beni, Bolivia

\*Address all correspondence to: jmichel\_levy@hotmail.com

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Pharmacokinetics and Pharmacodynamics of Local Anesthetics DOI: http://dx.doi.org/10.5772/intechopen.91700*

#### **References**

the nerve membranes. The unprotonated molecule configuration of the LA is introduced through the membrane from the outside and the protonated molecule acts with the sodium channel from the inside. The potency of a LA is given by liposolubility, the onset time by dissociation constant (pKa), and the duration of action by protein binding. Local anesthetics are weak bases whose structure consists of an aromatic moiety connected to a substituted amine through an ester or amide linkage. Consequently, LAs are classified as aminoester or aminoamide compounds. Amino acids are hydrolyzed by plasma cholinesterase, while aminoamides are

metabolized in the liver. Aminoamides cause less allergic reactions.

Hospital Obrero N°8, Caja Nacional de Salud, Trinidad-Beni, Bolivia

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

\*Address all correspondence to: jmichel\_levy@hotmail.com

The author declares no conflict of interests.

**Conflict of interest**

**Figure 7.**

*Sodium channel. Wikipedia.*

*Topics in Local Anesthetics*

**Author details**

**44**

Javier Marcos Michel-Levy

provided the original work is properly cited.

[1] Brunton L, editor. Goodman and Gilman. The Pharmacological Bases of Therapeutics. 12th ed. New York: McGraw Hill; 2011

[2] Goldin AL, Barchi RL, Caldwell JH, Hofmann F, Howe JR, Hunter JC, et al. Nomenclature of voltage-gated sodium channels. Neuron. 2000;**28**(2):365-368. DOI: 10.1016/s0896-6273(00)00116-1

[3] Hadzic A. Hadzic's Textbook of Regional Anesthesia and Acute Pain Management. The New York School of Regional Anesthesia. 2nd ed. NY: McGraw-Hill Education; 2017

[4] Bovill J, Fee H. Physiology for Anaesthesiologists. UK: Taylor and Francis Group; 2004

[5] Becker DE, Reed KL. Essentials of local anesthetic pharmacology. Anesthesia Progress. 2006;**53**(3):98-109. DOI: 10.2344/0003-3006(2006)53[98, EOLAP]2.0.CO;2

[6] Gropper MA, editor. Miller's Anesthesia. 9th ed. US: Elsevier; 2019

[7] Hodgkin AL, Huxley AF. A quantitative description of membrane current and its application to conduction and excitation in nerve. 1952. Bulletin of Mathematical Biology. 1990;**52**(1–2):25-71. DOI: 10.1007/ bf02459568

[8] Calvey N, Williams N. Principles and Practice of Pharmacology for Anaesthetists. 5th ed. New Jersey: Wiley, John & Sons, Inc.; 2008

[9] Carrada PS. Carta al editor. Anestesia en México. 2006;**18**(2):181-182

[10] Weiskopf R, Nau C, Strichartz G. Drug chirality in anesthesia. Anesthesiology. 2002;**97**:497-502

[11] Lorentz MN, Stokes AN, Rößler DC, Lötters S. Tetrodotoxin. Current

Biology. 2016;**26**(19):R870-R872. DOI: 10.1016/j.cub.2016.05.067

[12] Bane V, Lehane M, Dikshit M, O'Riordan A, Furey A. Tetrodotoxin: Chemistry, toxicity, source, distribution and detection. Toxins (Basel). 2014; **6**(2):693-755. DOI: 10.3390/toxins 6020693

[13] Thottumkara AP, Parsons WH, Du Bois J. Saxitoxin. Angewandte Chemie (International Ed. in English). 2014; **53**(23):5760-5784. DOI: 10.1002/ anie.201308235

[14] Tucker GT. Pharmacokinetics of local anaesthetics. British Journal of Anaesthesia. 1986;**58**(7):717-731. DOI: 10.1093/bja/58.7.717

[15] Rosenberg PH, Veering BT, Urmey WF. Maximum recommended doses of local anesthetics: A multifactorial concept. Regional Anesthesia and Pain Medicine. 2004; **29**(6):564-575. DOI: 10.1016/j. rapm.2004.08.003

[16] Skou JC. Local anaesthetics. VI. Relation between blocking potency and penetration of a monomolecular layer of lipoids from nerves. Acta Pharmacologica et Toxicologica (Copenh). 1954;**10**(4):325-337. DOI: 10.1111/j.1600-0773.1954.tb01349.x

[17] Aldrich RW, Corey DP, Stevens CF. A reinterpretation of mammalian sodium channel gating based on single channel recording. Nature. 1983; **306**(5942):436-441. DOI: 10.1038/ 306436a0

[18] Hille B. Gating mechanisms. In: Ionic Channels of Excitable Membranes. Sunderland, Massachusetts: Sinauer; 1992. pp. 472-503

[19] Hondeghem LM, Katzung BG. Time- and voltage-dependent

interactions of antiarrhythmic drugs with cardiac sodium channels. Biochimica et Biophysica Acta. 1977;**472** (3–4):373-398. DOI: 10.1016/0304-4157 (77)90003-x

[20] Grouls RJ, Ackerman EW, Korsten HH, Hellebrekers LJ, Breimer DD. Partition coefficients (n-octanol/water) of N-butyl-paminobenzoate and other local anesthetics measured by reversed-phase high-performance liquid chromatography. Journal of Chromatography. B, Biomedical Sciences and Applications. 1997;**694**(2): 421-425. DOI: 10.1016/s0378-4347(97) 00207-7

[21] Dullenkopf A, Borgeat A. Local anesthetics. Differences and similarities in the "-cains". Anaesthesist. 2003; **52**(4):329-340. DOI: 10.1007/ s00101-003-0463-5

[22] Sanchez V, Arthur GR, Strichartz GR. Fundamental properties of local anesthetics. I. The dependence of lidocaine's ionization and octanol: buffer partitioning on solvent and temperature. Anesthesia and Analgesia. 1987;**66**(2):159-165

[23] Bricker S. The Anaesthesia Science Viva Book. 3rd ed. New York, NY: Cambridge University Press; 2017

**47**

**Chapter 3**

**Abstract**

deeper understanding.

**1. Introduction**

**Keywords:** pharmacokinetics, pregnant, bupivacaine

**2. Cardiovascular changes of pregnancy**

Pregnant Women

*Yazmín Guillén-Dolores*

Bupivacaine Pharmacokinetics in

Pregnancy, labor, and delivery are accompanied by physiological changes that impact on the use of the drugs to which they are exposed. The anesthesiologist needs to understand the principal differences in management of this particular population. The study of the main pharmacokinetic changes associated with pregnancy is relevant for the proper management of drugs to avoid adverse effects. The objective of this chapter is to review the physiological changes that impact on the pharmacokinetics of the pregnant woman with a focus on local anesthetics of the amide type, specifically bupivacaine, and the main studies that have led to a

Pregnancy and labor are accompanied by important physiological and anatomical changes. There is a modification in the metabolism of drugs and changes in their pharmacokinetics as well as their interaction with organs and systems. Anesthesia in the obstetric patient is influenced by physiological changes, concomitant diseases, and preferences for a specific drug. Local anesthetics are a special topic due to the frequent use of them during labor, the performance of cesarean section, or another non-obstetric procedure in the pregnant patient. It is necessary to know the pharmacokinetics of the local anesthetic most frequently used in our practice, bupivacaine, plain or hyperbaric, or one of its enantiomers. The objective of this review is to know the main studies that have evaluated pharmacokinetics and their

During pregnancy many hemodynamic and hormonal changes occur like cardiovascular adaptations such as increased heart rate, plasmatic volume, cardiac output and sympathetic tone, or a reduction in peripheral resistances. The heart moves to the left and up during pregnancy, since the diaphragm progressively rises through the gravid uterus. These changes may be more important in post-term periods that are defined as pregnancies greater than 294 days (≥42 weeks of gestation periods) [1]. The increase in cardiac output and blood volume may increase the distribution of some drugs; the water-soluble ones will increase in their absorption as well as the liposoluble by the augmentation of the maternal fat, and there is an increase of the

interaction with systems and organs in the mother and placental passage.

#### **Chapter 3**

interactions of antiarrhythmic drugs with cardiac sodium channels.

*Topics in Local Anesthetics*

[20] Grouls RJ, Ackerman EW, Korsten HH, Hellebrekers LJ, Breimer DD. Partition coefficients (n-octanol/water) of N-butyl-paminobenzoate and other local

high-performance liquid chromatography. Journal of Chromatography. B, Biomedical

s00101-003-0463-5

1987;**66**(2):159-165

**46**

[22] Sanchez V, Arthur GR,

(77)90003-x

00207-7

Biochimica et Biophysica Acta. 1977;**472** (3–4):373-398. DOI: 10.1016/0304-4157

anesthetics measured by reversed-phase

Sciences and Applications. 1997;**694**(2): 421-425. DOI: 10.1016/s0378-4347(97)

[21] Dullenkopf A, Borgeat A. Local anesthetics. Differences and similarities in the "-cains". Anaesthesist. 2003; **52**(4):329-340. DOI: 10.1007/

Strichartz GR. Fundamental properties of local anesthetics. I. The dependence of lidocaine's ionization and octanol: buffer partitioning on solvent and temperature. Anesthesia and Analgesia.

[23] Bricker S. The Anaesthesia Science Viva Book. 3rd ed. New York, NY: Cambridge University Press; 2017

## Bupivacaine Pharmacokinetics in Pregnant Women

*Yazmín Guillén-Dolores*

#### **Abstract**

Pregnancy, labor, and delivery are accompanied by physiological changes that impact on the use of the drugs to which they are exposed. The anesthesiologist needs to understand the principal differences in management of this particular population. The study of the main pharmacokinetic changes associated with pregnancy is relevant for the proper management of drugs to avoid adverse effects. The objective of this chapter is to review the physiological changes that impact on the pharmacokinetics of the pregnant woman with a focus on local anesthetics of the amide type, specifically bupivacaine, and the main studies that have led to a deeper understanding.

**Keywords:** pharmacokinetics, pregnant, bupivacaine

#### **1. Introduction**

Pregnancy and labor are accompanied by important physiological and anatomical changes. There is a modification in the metabolism of drugs and changes in their pharmacokinetics as well as their interaction with organs and systems. Anesthesia in the obstetric patient is influenced by physiological changes, concomitant diseases, and preferences for a specific drug. Local anesthetics are a special topic due to the frequent use of them during labor, the performance of cesarean section, or another non-obstetric procedure in the pregnant patient. It is necessary to know the pharmacokinetics of the local anesthetic most frequently used in our practice, bupivacaine, plain or hyperbaric, or one of its enantiomers. The objective of this review is to know the main studies that have evaluated pharmacokinetics and their interaction with systems and organs in the mother and placental passage.

#### **2. Cardiovascular changes of pregnancy**

During pregnancy many hemodynamic and hormonal changes occur like cardiovascular adaptations such as increased heart rate, plasmatic volume, cardiac output and sympathetic tone, or a reduction in peripheral resistances. The heart moves to the left and up during pregnancy, since the diaphragm progressively rises through the gravid uterus. These changes may be more important in post-term periods that are defined as pregnancies greater than 294 days (≥42 weeks of gestation periods) [1]. The increase in cardiac output and blood volume may increase the distribution of some drugs; the water-soluble ones will increase in their absorption as well as the liposoluble by the augmentation of the maternal fat, and there is an increase of the

glomerular filtration and the renal sanguineous irrigation, which will produce an increase in the clearance of the drug [2].

The blood volume increases by 30–50%, and this rise begins in the first trimester and continues rising until week 30 of gestation and returns to its normal volume after pregnancy. A phenomenon is a dilutional anemia since the proportion of plasma volumes in relation to blood volume increases proportionally greater than red cells, and the hemoglobin concentrations will vary between 11 and 12 g/100 mL at the end of pregnancy. The increase in plasma volume is related to the size of the fetus; one theory is that the adrenal glands of the fetus can initiate an increase in blood volume by providing dehydroepiandrosterone (precursor of estrogen) to the placenta, stimulating the liver to produce angiotensin, which increases aldosterone production and fluid retention [3].

Increased blood volume and increased cardiac output may respond to an initial vasodilation caused by a vasodilating substance that may be prostacyclin or the endothelial-derived relaxing factor. This increase in blood volume is necessary to meet the needs of the fetus and compensate for the loss of maternal blood at delivery; the mother can lose up to 20% of their blood volume without a significant change in his hematocrit [3]. Cardiac output increases to 30–50% during pregnancy, peaks at weeks 28–32, and then decreases a little during the last weeks. The values increase to 4.5–6.5 L/min and decrease as the term of pregnancy approaches but are considerably lower in the lateral position than in the supine position. The supine position during labor is associated with an 8% incidence of hypotension, and 15–20% of patients will have aortoiliac and vena cava compression. The reduced cardiac output lowers uterine blood flow, and this adversely affects the fetus. The cardiac return is diverted from the vena cava through the vertebral and azygos systems to the superior vena cava, and this enlarges the epidural veins and provides an explanation for the reduced amount of local anesthetic needed for spinal or epidural analgesia in pregnancy, and there is an increase in sympathetic activity that results in vasoconstriction that reduced the degree of hypotension observed [4].

Uterine blood flow increases to 200 mL/min by week 28 and 500 mL/min by the end of pregnancy, the uterine musculature receives approximately 20% of the total uterine blood flow, while the area of the placenta receives 80% by what to the placenta, that is to say, 400 mL of blood per minute or approximately 80 mL of blood per 100 g of tissue per minute [4].

#### **3. Pharmacokinetics of bupivacaine and main studies**

Bupivacaine is a local anesthetic amide type, synthesized in 1957 by Ekenstam in Switzerland, and has a mechanism of action through the obstruction of sodium channels to the nerve membrane, preventing the generation of an action potential. It is used for intraoperative local anesthesia, postoperative analgesia, and chronic pain treatment. It is widely used in pregnant patients and provides excellent sensory anesthesia with reported concentrations at 0.5% [5].

The effectiveness of bupivacaine was evaluated by the toxicity, the latency, and the degree of motor block, the sympathetic block, and the sensory block, as well as the elimination time. The absorption and distribution are influenced by the vascularity of the injection site, the mode of injection, and the degree of ionization of the drug. After IV administration, its half-life is 45 min corresponding to redistribution and 2.5 h due to elimination. It is metabolized by the liver by N-dealkylation and glucuronide conjugation. Elimination is urinary. Although some metabolites are eliminated via the pulmonary and bile fluid, the portion bound to proteins is the active part, and the unbound is responsible for the toxic effects [5].

**49**

*Bupivacaine Pharmacokinetics in Pregnant Women DOI: http://dx.doi.org/10.5772/intechopen.87184*

eral hairy surface increases from 3.7 m2

a decrease in density of the microvilli [6].

\_\_\_

function [7].

distribution [7].

to proteins [10].

arrhythmias in patients [1].

retaining large quantities for its release back to the fetus [6].

is regulated by variations in pH and protein binding [6].

diameter and has a duration of analgesia of up to 72 h [9].

**4. Studies of bupivacaine in QT interval**

tion of time are studied, according to the following formula [7]:

The pharmacokinetics in the mother-fetus binomial changes, the fetus and the placenta function as deposits, the placenta has the capacity to metabolize drugs, and it is possible to modulate the elimination of the drug by producing metabolites and

in week 25 to 11 m2

*dt* <sup>=</sup> <sup>−</sup>*kCn* (1)

during the last month of

due to

The apparent volume of distribution increases during pregnancy with the increase in plasma volume, approximately 40–50% from the beginning of pregnancy to a maximum of 32 weeks. During the placental growth phase, the periph-

gestation, and the fetal-mother exchange surface decreases from 92 to 767 m2

Since the drugs that cross the placenta reach the fetus via the umbilical venous blood and 50% of it enters the liver circulation and the rest goes through the venous duct, then half of the transported drug is susceptible to hepatic metabolism and the other half enters the fetal circulation directly. The distribution of a drug in the fetus

The drugs once inside the organism move between the compartments, and to analyze it the changes in the concentration of the drug in a compartment as a func-

where dC/dt equals the change in concentration in relation to time and −kCn refers to the decrease in the concentration of a drug which is an exponential type

When the rate of change is independent of the concentration of the drug, it is called a zero-order process, and when the process and the rate of change are proportional to the concentration of the drug, it is called a first-order process, the mother-fetus, which behaves like a model of two compartments with bidirectional

Bupivacaine has an asymmetric carbon atom and can take the form of two enantiomers (R + dextrobupivacaine and S-levobupivacaine), form different threedimensional relationships in the asymmetric medium of receptors and enzymes, and result in differences in toxicity, distribution, cardiotoxicity, and neurotoxicity [8]. Levobupivacaine is soluble in water with a molecular weight of 325, a partition coefficient of 1624, and a pKa of 8.09. Both the partition coefficient and the pKa are very similar to those of bupivacaine. Its pH is 4.0–6.5. Its maximum plasma concentration reaches 30 min, and its volume of distribution is 67 L [8]. Liposomal bupivacaine is composed of multivesicular liposomes with 10–30 micrometers in

Bupivacaine has a pKa of 8.1, ionized fraction of 15% at a pH of 7.4, fat/buffer coefficient of 115, protein binding 95%, molecular weight of 288 Daltons, and an effective anesthetic concentration in the rat sciatic nerve of 0.25. The main determinant of adverse systemic effects is the free fraction, which is not bound

Spinal anesthesia involves changes in the mother's hemodynamic, including decreased venous return, decreased systemic vascular resistance, and a compensatory increase in cardiac output. These changes increase the risk of intraoperative

*dC*

*Bupivacaine Pharmacokinetics in Pregnant Women DOI: http://dx.doi.org/10.5772/intechopen.87184*

*Topics in Local Anesthetics*

increase in the clearance of the drug [2].

production and fluid retention [3].

blood per 100 g of tissue per minute [4].

**3. Pharmacokinetics of bupivacaine and main studies**

anesthesia with reported concentrations at 0.5% [5].

Bupivacaine is a local anesthetic amide type, synthesized in 1957 by Ekenstam in Switzerland, and has a mechanism of action through the obstruction of sodium channels to the nerve membrane, preventing the generation of an action potential. It is used for intraoperative local anesthesia, postoperative analgesia, and chronic pain treatment. It is widely used in pregnant patients and provides excellent sensory

The effectiveness of bupivacaine was evaluated by the toxicity, the latency, and the degree of motor block, the sympathetic block, and the sensory block, as well as the elimination time. The absorption and distribution are influenced by the vascularity of the injection site, the mode of injection, and the degree of ionization of the drug. After IV administration, its half-life is 45 min corresponding to redistribution and 2.5 h due to elimination. It is metabolized by the liver by N-dealkylation and glucuronide conjugation. Elimination is urinary. Although some metabolites are eliminated via the pulmonary and bile fluid, the portion bound to proteins is the active part, and the unbound is responsible for the toxic effects [5].

glomerular filtration and the renal sanguineous irrigation, which will produce an

The blood volume increases by 30–50%, and this rise begins in the first trimester and continues rising until week 30 of gestation and returns to its normal volume after pregnancy. A phenomenon is a dilutional anemia since the proportion of plasma volumes in relation to blood volume increases proportionally greater than red cells, and the hemoglobin concentrations will vary between 11 and 12 g/100 mL at the end of pregnancy. The increase in plasma volume is related to the size of the fetus; one theory is that the adrenal glands of the fetus can initiate an increase in blood volume by providing dehydroepiandrosterone (precursor of estrogen) to the placenta, stimulating the liver to produce angiotensin, which increases aldosterone

Increased blood volume and increased cardiac output may respond to an initial vasodilation caused by a vasodilating substance that may be prostacyclin or the endothelial-derived relaxing factor. This increase in blood volume is necessary to meet the needs of the fetus and compensate for the loss of maternal blood at delivery; the mother can lose up to 20% of their blood volume without a significant change in his hematocrit [3]. Cardiac output increases to 30–50% during pregnancy, peaks at weeks 28–32, and then decreases a little during the last weeks. The values increase to 4.5–6.5 L/min and decrease as the term of pregnancy approaches but are considerably lower in the lateral position than in the supine position. The supine position during labor is associated with an 8% incidence of hypotension, and 15–20% of patients will have aortoiliac and vena cava compression. The reduced cardiac output lowers uterine blood flow, and this adversely affects the fetus. The cardiac return is diverted from the vena cava through the vertebral and azygos systems to the superior vena cava, and this enlarges the epidural veins and provides an explanation for the reduced amount of local anesthetic needed for spinal or epidural analgesia in pregnancy, and there is an increase in sympathetic activity that results in vasoconstriction that reduced the degree of hypotension observed [4]. Uterine blood flow increases to 200 mL/min by week 28 and 500 mL/min by the end of pregnancy, the uterine musculature receives approximately 20% of the total uterine blood flow, while the area of the placenta receives 80% by what to the placenta, that is to say, 400 mL of blood per minute or approximately 80 mL of

**48**

The pharmacokinetics in the mother-fetus binomial changes, the fetus and the placenta function as deposits, the placenta has the capacity to metabolize drugs, and it is possible to modulate the elimination of the drug by producing metabolites and retaining large quantities for its release back to the fetus [6].

The apparent volume of distribution increases during pregnancy with the increase in plasma volume, approximately 40–50% from the beginning of pregnancy to a maximum of 32 weeks. During the placental growth phase, the peripheral hairy surface increases from 3.7 m2 in week 25 to 11 m2 during the last month of gestation, and the fetal-mother exchange surface decreases from 92 to 767 m2 due to a decrease in density of the microvilli [6].

Since the drugs that cross the placenta reach the fetus via the umbilical venous blood and 50% of it enters the liver circulation and the rest goes through the venous duct, then half of the transported drug is susceptible to hepatic metabolism and the other half enters the fetal circulation directly. The distribution of a drug in the fetus is regulated by variations in pH and protein binding [6].

The drugs once inside the organism move between the compartments, and to analyze it the changes in the concentration of the drug in a compartment as a function of time are studied, according to the following formula [7]:

$$\frac{dC}{dt} = -kCn\tag{1}$$

where dC/dt equals the change in concentration in relation to time and −kCn refers to the decrease in the concentration of a drug which is an exponential type function [7].

When the rate of change is independent of the concentration of the drug, it is called a zero-order process, and when the process and the rate of change are proportional to the concentration of the drug, it is called a first-order process, the mother-fetus, which behaves like a model of two compartments with bidirectional distribution [7].

Bupivacaine has an asymmetric carbon atom and can take the form of two enantiomers (R + dextrobupivacaine and S-levobupivacaine), form different threedimensional relationships in the asymmetric medium of receptors and enzymes, and result in differences in toxicity, distribution, cardiotoxicity, and neurotoxicity [8]. Levobupivacaine is soluble in water with a molecular weight of 325, a partition coefficient of 1624, and a pKa of 8.09. Both the partition coefficient and the pKa are very similar to those of bupivacaine. Its pH is 4.0–6.5. Its maximum plasma concentration reaches 30 min, and its volume of distribution is 67 L [8]. Liposomal bupivacaine is composed of multivesicular liposomes with 10–30 micrometers in diameter and has a duration of analgesia of up to 72 h [9].

Bupivacaine has a pKa of 8.1, ionized fraction of 15% at a pH of 7.4, fat/buffer coefficient of 115, protein binding 95%, molecular weight of 288 Daltons, and an effective anesthetic concentration in the rat sciatic nerve of 0.25. The main determinant of adverse systemic effects is the free fraction, which is not bound to proteins [10].

#### **4. Studies of bupivacaine in QT interval**

Spinal anesthesia involves changes in the mother's hemodynamic, including decreased venous return, decreased systemic vascular resistance, and a compensatory increase in cardiac output. These changes increase the risk of intraoperative arrhythmias in patients [1].

Local anesthetics routinely used include bupivacaine and its enantiomer levobupivacaine, the latter having a clinical profile close to bupivacaine, but it is less toxic to both the nervous system and the cardiovascular system, which makes it useful in obstetric anesthesia, where large volumes of local anesthetics may be required. It has been reported that bupivacaine and levobupivacaine cause a concentration-dependent inhibition of the amplitude of gravid myometrial contractions in rats [11].

Local anesthetics are amphiphilic and can enter a variety of cellular compartments and potentially interact with many different cell membranes, organelles (including the inhibition of mitochondrial adenosine production), and a variety of membrane junctions and charged cytosol molecules. Other mechanisms, which can contribute to myometrial inhibition, include the blocking of ionotropic signaling pathways (sodium, potassium, or calcium) and interference with protein modulation of calcium and potassium channels [11].

The practice of using low concentrations (0.125–0.25%) makes it less likely that the inhibitory concentrations in the plasma reach the clinical practice [11]. The toxic effect of local anesthetics on myocardial contractility and cardiac conduction is due to the alteration of the calcium channel [12]. In a study by Mahmut et al., 40 healthy pregnant patients were included; they evaluated QT interval, which increased significantly in the post-term group, which makes them susceptible to the development of arrhythmias; and they concluded that care must be taken during the induction of spinal anesthesia in term pregnancies as well as cardiovascular monitoring should be prolonged in this type of patients [13].

The Dogan et al. study used 12 mg of 0.5% hyperbaric bupivacaine or 0.5% of levobupivacaine for the spinal levobupivacaine group and calculated the QTc with the Bazzett formula and the QT dispersion (difference between the maximum and minimum QTc). They studied 60 patients. The mean maximum QTc was longer in levobupivacaine, and the minimum mean QTc was also longer. In the bupivacaine group, the maximum QTc was longer than levobupivacaine [14].

#### **5. Pharmacokinetic studies in rats**

It is known that the placenta does not limit the fetal transfer of local anesthetics administered to the mother; using a human placental model in rats, it is suggested that bupivacaine accumulates in the placenta [15]. The study of Morishima et al., a study in the University of Columbia with a model of rats, administered 1 mg/kg of bupivacaine followed by an infusion of 0.33 mg/kg/min, over a total period of 15 min. The maximum dose of bupivacaine was 1200–1400 ng/mL, which is similar to the concentration of plasma bupivacaine in pregnant women under cesarean section with epidural anesthesia [1].

The pharmacokinetic analysis of bupivacaine was assumed as an open twocompartment model. A transient reduction in heart rate occurred during the infusion of bupivacaine [1].

#### **5.1 Pharmacokinetic parameters**

The mean peak concentration of bupivacaine in maternal plasma was 3123 ± 370 ng/mL, the concentration decreased to 26 ± 12 ng/mL at 180 min, and after 240 min, it became undetectable. In plasma 4′-hydroxybupivacaine and 2,6-pipecoloxylidine were not detected. The half-life of distribution was 37.7 ± 2.4 min, the volume of distribution in stable state 3.86 ± 0.29 l/kg, and the total clearance 93.3 ± 8.6 mL/min<sup>−</sup><sup>1</sup> .kg<sup>−</sup><sup>1</sup> ; other parameters were K12 0.462 ± 0.066; K21 0.081 ± 0.008 and K10 0.166 ± 0.021. In fetal plasma, a bupivacaine peak of

**51**

rine 5 μg/ml<sup>−</sup><sup>1</sup>

higher than in healthy volunteers [16].

*Bupivacaine Pharmacokinetics in Pregnant Women DOI: http://dx.doi.org/10.5772/intechopen.87184*

sion was the highest sample of those obtained at any time [1].

The largest metabolite detected in rats was 3-hydroxybupivacaine [1].

**6. Studies about bupivacaine in multimodal analgesia**

**6.1 Blockage of the transverse abdominal muscle**

320 ± 38 ng/mL was detected rapidly, and the drug became undetectable at 4 h. A bupivacaine concentration of 4817 ± 976 ng/g in the amnion at the end of the infu-

While the dose of bupivacaine decreases, 3-hydroxybupivacaine remains virtually constant in the amnion and myometrium, and the 3-hydroxybupivacaine also kept increasing. Despite a high concentration of 3-hydroxybupivacaine in these tissues, the amniotic fluid concentration was not as high as expected. The 4-hydroxybupivacaine and the 2.6 pipecoloxylidide were only detected in traces in samples obtained in 2 h.

In the fetus, the 3-hydroxybupivacaine remains detectable in the liver up to 4 h, while it virtually disappears from other tissues, because most of the umbilical venous blood perfused in fetal liver, and bupivacaine transmitted to the fetus, can directly enter the fetal liver; this may suggest that the fetal liver is capable of metabolizing bupivacaine. However, because polar metabolites do not cross the placental membrane bidirectionally, 3-hydroxybupivacaine probably accumulates in the fetus [1].

In the study by Eslamian et al., a randomized, double-blind, placebo-controlled study of 50 pregnant women under elective cesarean section, transverse abdominis plane (TAP) block was used. The preparation was performed with 40 mL of 0.25% hyperbaric bupivacaine plus 2 mL of normal saline for the placebo group of 400 mL of 0.25% hyperbaric bupivacaine plus 2 mL of sufentanil for the study group. The block was guided with ultrasound; the patients who received 40 mL of hyperbaric bupivacaine 0.25% plus 10 μg of sufentanil consumed less morphine during 24 h after surgery compared to the control group (p = 0.002); the mean difference in morphine consumption was 15.6 mg in the first 24 h of the postoperative period. There were no

differences in the EVA scale between one group and another with>0.05 [15].

between 10 and 90 min and a second delayed peak of 90 min [10].

, venous concentrations were 2.62 mg/L<sup>−</sup><sup>1</sup>

In the Trabelsi et al. study, a group of 17 pregnant patients were administered with spinal anesthesia with hyperbaric bupivacaine with 5 μg of sufentanil, and abdominal ultrasound-guided TAP block was placed with 20 mL 0.25% bupivacaine bilaterally. They found an accumulated average of bupivacaine of 1.4 ± 0.2 mg/kg (range of 1.05–1.79 mg/kg); the CMAX was 802.36 ng/mL (231.8–3504.5 ng/mL) and was reached at 30 min (TMAX). The mean area under the curve (AUC) (0–24 h) was 4505.4 ng/mL, and the elimination half-life was 8.75 h for bupivacaine, demonstrating that bilateral blockade increases the total concentration of bupivacaine in the plasma after administering spinal anesthesia with bupivacaine. Plasma concentrations occurred at 30 min after injection, all peak concentrations were reached

In the Lacassie study, in 12 pregnant women and 11 healthy volunteers, the transverse muscle was blocked with levobupivacaine 0.25%, 20 mL with epineph-

volume of distribution of levobupivacaine was 172 L (70 kg) (IC 95% 137–207)

**6.2 Use of patient-controlled analgesia (PCA pumps) in different combinations**

The Stourac study worked with pregnant women under epidural analgesia; they used 12.5 mg of bupivacaine and 5 μg of sufentanil in 10 mL of normal saline, and boluses of half the dose every 60–90 min were administered. Another group using

, below the level toxic, the

*Bupivacaine Pharmacokinetics in Pregnant Women DOI: http://dx.doi.org/10.5772/intechopen.87184*

*Topics in Local Anesthetics*

Local anesthetics routinely used include bupivacaine and its enantiomer levobupivacaine, the latter having a clinical profile close to bupivacaine, but it is less toxic to both the nervous system and the cardiovascular system, which makes it useful in obstetric anesthesia, where large volumes of local anesthetics may be required. It has been reported that bupivacaine and levobupivacaine cause a concentration-dependent

Local anesthetics are amphiphilic and can enter a variety of cellular compartments and potentially interact with many different cell membranes, organelles (including the inhibition of mitochondrial adenosine production), and a variety of membrane junctions and charged cytosol molecules. Other mechanisms, which can contribute to myometrial inhibition, include the blocking of ionotropic signaling pathways (sodium, potassium, or calcium) and interference with protein modula-

The practice of using low concentrations (0.125–0.25%) makes it less likely that the inhibitory concentrations in the plasma reach the clinical practice [11]. The toxic effect of local anesthetics on myocardial contractility and cardiac conduction is due to the alteration of the calcium channel [12]. In a study by Mahmut et al., 40 healthy pregnant patients were included; they evaluated QT interval, which increased significantly in the post-term group, which makes them susceptible to the development of arrhythmias; and they concluded that care must be taken during the induction of spinal anesthesia in term pregnancies as well as cardiovascular

The Dogan et al. study used 12 mg of 0.5% hyperbaric bupivacaine or 0.5% of levobupivacaine for the spinal levobupivacaine group and calculated the QTc with the Bazzett formula and the QT dispersion (difference between the maximum and minimum QTc). They studied 60 patients. The mean maximum QTc was longer in levobupivacaine, and the minimum mean QTc was also longer. In the bupivacaine

It is known that the placenta does not limit the fetal transfer of local anesthetics administered to the mother; using a human placental model in rats, it is suggested that bupivacaine accumulates in the placenta [15]. The study of Morishima et al., a study in the University of Columbia with a model of rats, administered 1 mg/kg of bupivacaine followed by an infusion of 0.33 mg/kg/min, over a total period of 15 min. The maximum dose of bupivacaine was 1200–1400 ng/mL, which is similar to the concentration of plasma bupivacaine in pregnant women under cesarean

The pharmacokinetic analysis of bupivacaine was assumed as an open twocompartment model. A transient reduction in heart rate occurred during the

The mean peak concentration of bupivacaine in maternal plasma was 3123 ± 370 ng/mL, the concentration decreased to 26 ± 12 ng/mL at 180 min, and after 240 min, it became undetectable. In plasma 4′-hydroxybupivacaine and 2,6-pipecoloxylidine were not detected. The half-life of distribution was 37.7 ± 2.4 min, the volume of distribution in stable state 3.86 ± 0.29 l/kg, and the

.kg<sup>−</sup><sup>1</sup>

K21 0.081 ± 0.008 and K10 0.166 ± 0.021. In fetal plasma, a bupivacaine peak of

; other parameters were K12 0.462 ± 0.066;

inhibition of the amplitude of gravid myometrial contractions in rats [11].

tion of calcium and potassium channels [11].

**5. Pharmacokinetic studies in rats**

section with epidural anesthesia [1].

**5.1 Pharmacokinetic parameters**

total clearance 93.3 ± 8.6 mL/min<sup>−</sup><sup>1</sup>

infusion of bupivacaine [1].

monitoring should be prolonged in this type of patients [13].

group, the maximum QTc was longer than levobupivacaine [14].

**50**

320 ± 38 ng/mL was detected rapidly, and the drug became undetectable at 4 h. A bupivacaine concentration of 4817 ± 976 ng/g in the amnion at the end of the infusion was the highest sample of those obtained at any time [1].

While the dose of bupivacaine decreases, 3-hydroxybupivacaine remains virtually constant in the amnion and myometrium, and the 3-hydroxybupivacaine also kept increasing. Despite a high concentration of 3-hydroxybupivacaine in these tissues, the amniotic fluid concentration was not as high as expected. The 4-hydroxybupivacaine and the 2.6 pipecoloxylidide were only detected in traces in samples obtained in 2 h. The largest metabolite detected in rats was 3-hydroxybupivacaine [1].

In the fetus, the 3-hydroxybupivacaine remains detectable in the liver up to 4 h, while it virtually disappears from other tissues, because most of the umbilical venous blood perfused in fetal liver, and bupivacaine transmitted to the fetus, can directly enter the fetal liver; this may suggest that the fetal liver is capable of metabolizing bupivacaine. However, because polar metabolites do not cross the placental membrane bidirectionally, 3-hydroxybupivacaine probably accumulates in the fetus [1].

#### **6. Studies about bupivacaine in multimodal analgesia**

#### **6.1 Blockage of the transverse abdominal muscle**

In the study by Eslamian et al., a randomized, double-blind, placebo-controlled study of 50 pregnant women under elective cesarean section, transverse abdominis plane (TAP) block was used. The preparation was performed with 40 mL of 0.25% hyperbaric bupivacaine plus 2 mL of normal saline for the placebo group of 400 mL of 0.25% hyperbaric bupivacaine plus 2 mL of sufentanil for the study group. The block was guided with ultrasound; the patients who received 40 mL of hyperbaric bupivacaine 0.25% plus 10 μg of sufentanil consumed less morphine during 24 h after surgery compared to the control group (p = 0.002); the mean difference in morphine consumption was 15.6 mg in the first 24 h of the postoperative period. There were no differences in the EVA scale between one group and another with>0.05 [15].

In the Trabelsi et al. study, a group of 17 pregnant patients were administered with spinal anesthesia with hyperbaric bupivacaine with 5 μg of sufentanil, and abdominal ultrasound-guided TAP block was placed with 20 mL 0.25% bupivacaine bilaterally. They found an accumulated average of bupivacaine of 1.4 ± 0.2 mg/kg (range of 1.05–1.79 mg/kg); the CMAX was 802.36 ng/mL (231.8–3504.5 ng/mL) and was reached at 30 min (TMAX). The mean area under the curve (AUC) (0–24 h) was 4505.4 ng/mL, and the elimination half-life was 8.75 h for bupivacaine, demonstrating that bilateral blockade increases the total concentration of bupivacaine in the plasma after administering spinal anesthesia with bupivacaine. Plasma concentrations occurred at 30 min after injection, all peak concentrations were reached between 10 and 90 min and a second delayed peak of 90 min [10].

In the Lacassie study, in 12 pregnant women and 11 healthy volunteers, the transverse muscle was blocked with levobupivacaine 0.25%, 20 mL with epinephrine 5 μg/ml<sup>−</sup><sup>1</sup> , venous concentrations were 2.62 mg/L<sup>−</sup><sup>1</sup> , below the level toxic, the volume of distribution of levobupivacaine was 172 L (70 kg) (IC 95% 137–207) higher than in healthy volunteers [16].

#### **6.2 Use of patient-controlled analgesia (PCA pumps) in different combinations**

The Stourac study worked with pregnant women under epidural analgesia; they used 12.5 mg of bupivacaine and 5 μg of sufentanil in 10 mL of normal saline, and boluses of half the dose every 60–90 min were administered. Another group using

PCA pumps with remifentanil connecting a 50 mL syringe with remifentanil at a concentration of 20 μg/mL studied a total of 24 patients, and there was no significant difference between the groups. The level of satisfaction of the patients was 88% with epidural analgesia and 85% with PCA pump. Among the complications, only one had hypotension, with remifentanil, and experienced drowsiness and dizziness as well as temporary anxiolysis [8].

In the Chen et al. study, they determined the lowest effective concentration of levobupivacaine and levobupivacaine with fentanyl, and one group received 1.2 mg/mL of levobupivacaine and 2 μg/mL of fentanyl. They determined that the concentrations of 0.6 mg/mL of levobupivacaine plus 2 μg/mL of fentanyl and 1 mg/mL of levobupivacaine were the lowest concentrations of the drugs required for effective analgesia, and they analyzed a total of 83 pregnant women and showed that levobupivacaine alone produces a comparable analgesia with levobupivacaine with narcotic; in addition, those who received narcotics had more adverse effects [17].

#### **6.3 Studies in the capacity of blocking muscle fibers**

In the Fanning et al. study, pregnant patients received spinal anesthesia with 10–12 mg at 0.5% hyperbaric bupivacaine with 20–25 μg of intrathecal fentanyl and 100–150 μg of intrathecal morphine. After the placental extraction, a small segment of the myometrium was removed from the incisional surface of the lower uterine segment. Each sample was dissected in four longitudinal muscles. The muscle was exposed to bupivacaine or levobupivacaine and chemical contractions were induced. Eight muscle samples were included. Bupivacaine and levobupivacaine caused a concentration-dependent decrease in the amplitude of the contractions reaching a statistical significance of p = 0.002 for bupivacaine and p = 0.001 for levobupivacaine compared to the control period before the administration of any drug [18]. There was no significant difference between bupivacaine and levobupivacaine in its effects on contraction of the myometrium, in the amplitude of the contractions, and in the interval between contractions for bupivacaine and levobupivacaine; there was no difference between the EC50 (effective concentration 50) and the effect of both drugs in contractility which was reversible. No increase in contractile amplitude was observed. The maximum concentrations in plasma were 1053 μg/mL (3.24 × 10–6 m) for bupivacaine and 1017 μg/mL (3.13 × 10–6 m) for levobupivacaine. They concluded that bupivacaine and its enantiomer levobupivacaine cause a similar decrease in concentration-dependent contractions. The concentrations required for their inhibitory effect on the amplitude of the contractions were much higher (33 times) than the clinically relevant plasma concentrations of these drugs after epidural administration and are unlikely to be significant in the low epidural dose scenario to analgesia in labor periods [18].

The combination with clonidine, a partial agonist of alpha 2 adrenergic receptors, interacts with the local anesthetic in the neural axis. The analgesic effect is due to its action in spinal and supraspinal α-adrenergic receptors, including the activation of postsynaptic α-2 receptors, since the noradrenergic descending pathways of cholinergic neurons and the release of nitric oxide and substances such as enkephalin reduce the absorption of local anesthetics by a vasoconstrictor effect, improving quality and increasing the duration of anesthetic blockade. It is recommended at doses of 1 μg/kg combined with bupivacaine [12]. In a Brazilian study, 66 pregnant patients were divided into two groups: a group with 8 mg of bupivacaine +75 μg of clonidine and 100 μg of morphine +0.9% saline and another group with 10 mg of bupivacaine +75 μg of clonidine +100 μg of morphine + saline 0.9%; the total volume administered was 4 ml in both groups, and there was no difference in hemodynamic parameters, adverse effects, and level of consciousness, only the

**53**

*Bupivacaine Pharmacokinetics in Pregnant Women DOI: http://dx.doi.org/10.5772/intechopen.87184*

**7. Bupivacaine and placental transfer to fetus**

spinal fluid cerebral [19].

in various fetal tissues [20].

and the umbilical artery, respectively [11].

regression time of the motor block, in group 1, of 198.48 ± 47.63 min, and in group 2 of 232.84 ± 63.66 min; p = 0.00073. They concluded that morphine and clonidine at low doses produce adequate postoperative analgesia in pregnant patients [12].

In the study Zhan et al., 70 pregnant or obstetric patients were studied; 0.5% spinal isobaric bupivacaine was 4 mg; the ED50 of intrathecal bupivacaine for motor block was 3.96 mg (IC 95% 3.83–4.98) for pregnant women versus 4.51 mg (95% CI 4.27–4.76) for nonpregnant women. The potency of bupivacaine for motor block in pregnant versus non-pregnant women was 1.14 times higher (95% CI 1.05–1.24). This is because the supine position can increase the dissemination of the injected drugs due to the increase in intra-abdominal pressure, in addition to the increase in blood flow in the vasculature in the epidural veins, which distends and compresses the intraspinal space decreasing the volume of the

The analysis of the placental intervillous space shows to be an appropriate place of investigation because this space is initially filled with blood coming from the maternal spiral arteries that interchange with the fetal venous blood, when the blood of the mother flows toward the branched villi. Although it is an important interchange interface, the intervillous space has been studied as the transport of substances between the mother, the placenta, and the fetus; obtaining blood from this compartment has provided a unique opportunity to study the maternal-fetal physiological relationship in a more physiological way [20]. The importance of this is that the reduced ability of the fetus to eliminate drugs can cause prolonged effects on the fetus, since half of the fetal circulation reaches the umbilical vein and directly reaches the fetal heart and brain by passing to the fetus. Liver immaturity contributes to the presentation of adverse effects, the fetus eliminates the drug by diffusion into the maternal compartment, although the majority of the metabolites are more polar and it is unlikely that the placental membrane crosses the placental membrane back to the compartment maternal, possibly resulting in the accumulation of metabolites

In the study by Barros et al., a Brazilian study, the concentrations of bupivacaine

The R-bupivacaine concentrations were 2.9 times higher in the placental intervillous space than the fetal umbilical vein concentrations and 3.16 times higher than the concentrations in the fetal umbilical artery. There were no cardiocirculatory changes, neonatal repercussions in the APGAR, or respiratory depression. There was no significant difference in the ratio of enantiomer concentrations between the

and lidocaine as well as its metabolite (MEGX) and its placental transfer were analyzed in 10 healthy pregnant patients, under elective cesarean and epidural anesthesia. The administration of the medication was epidural of 0.1 mg of fentanyl citrate, 112.5 mg of 0.5% bupivacaine with 2:200000 epinephrine, and 200 mg of lidocaine 2% without vasoconstrictor injected into the epidural space [11]. The concentrations of bupivacaine enantiomers were high in the maternal plasma and placental intervillous space than in the umbilical vein and the umbilical artery. The concentrations of S-bupivacaine in the maternal plasma were higher than the R-bupivacaine concentrations, and the values were 195.2 and 186.0 ng/mL. There were no significant differences (P < 0.05) between their concentrations in umbilical fetal vessels [11]. The placental transfer was 33% for R-bupivacaine and 31% for the S-bupivacaine. The concentrations of the enantiomer S-bupivacaine were 3.5 and 3.82 times higher in the placental intervillous space than that of the umbilical vein

*Bupivacaine Pharmacokinetics in Pregnant Women DOI: http://dx.doi.org/10.5772/intechopen.87184*

*Topics in Local Anesthetics*

dizziness as well as temporary anxiolysis [8].

who received narcotics had more adverse effects [17].

**6.3 Studies in the capacity of blocking muscle fibers**

low epidural dose scenario to analgesia in labor periods [18].

The combination with clonidine, a partial agonist of alpha 2 adrenergic receptors, interacts with the local anesthetic in the neural axis. The analgesic effect is due to its action in spinal and supraspinal α-adrenergic receptors, including the activation of postsynaptic α-2 receptors, since the noradrenergic descending pathways of cholinergic neurons and the release of nitric oxide and substances such as enkephalin reduce the absorption of local anesthetics by a vasoconstrictor effect, improving quality and increasing the duration of anesthetic blockade. It is recommended at doses of 1 μg/kg combined with bupivacaine [12]. In a Brazilian study, 66 pregnant patients were divided into two groups: a group with 8 mg of bupivacaine +75 μg of clonidine and 100 μg of morphine +0.9% saline and another group with 10 mg of bupivacaine +75 μg of clonidine +100 μg of morphine + saline 0.9%; the total volume administered was 4 ml in both groups, and there was no difference in hemodynamic parameters, adverse effects, and level of consciousness, only the

PCA pumps with remifentanil connecting a 50 mL syringe with remifentanil at a concentration of 20 μg/mL studied a total of 24 patients, and there was no significant difference between the groups. The level of satisfaction of the patients was 88% with epidural analgesia and 85% with PCA pump. Among the complications, only one had hypotension, with remifentanil, and experienced drowsiness and

In the Chen et al. study, they determined the lowest effective concentration of levobupivacaine and levobupivacaine with fentanyl, and one group received 1.2 mg/mL of levobupivacaine and 2 μg/mL of fentanyl. They determined that the concentrations of 0.6 mg/mL of levobupivacaine plus 2 μg/mL of fentanyl and 1 mg/mL of levobupivacaine were the lowest concentrations of the drugs required for effective analgesia, and they analyzed a total of 83 pregnant women and showed that levobupivacaine alone produces a comparable analgesia with levobupivacaine with narcotic; in addition, those

In the Fanning et al. study, pregnant patients received spinal anesthesia with 10–12 mg at 0.5% hyperbaric bupivacaine with 20–25 μg of intrathecal fentanyl and 100–150 μg of intrathecal morphine. After the placental extraction, a small segment of the myometrium was removed from the incisional surface of the lower uterine segment. Each sample was dissected in four longitudinal muscles. The muscle was exposed to bupivacaine or levobupivacaine and chemical contractions were induced. Eight muscle samples were included. Bupivacaine and levobupivacaine caused a concentration-dependent decrease in the amplitude of the contractions reaching a statistical significance of p = 0.002 for bupivacaine and p = 0.001 for levobupivacaine compared to the control period before the administration of any drug [18]. There was no significant difference between bupivacaine and levobupivacaine in its effects on contraction of the myometrium, in the amplitude of the contractions, and in the interval between contractions for bupivacaine and levobupivacaine; there was no difference between the EC50 (effective concentration 50) and the effect of both drugs in contractility which was reversible. No increase in contractile amplitude was observed. The maximum concentrations in plasma were 1053 μg/mL (3.24 × 10–6 m) for bupivacaine and 1017 μg/mL (3.13 × 10–6 m) for levobupivacaine. They concluded that bupivacaine and its enantiomer levobupivacaine cause a similar decrease in concentration-dependent contractions. The concentrations required for their inhibitory effect on the amplitude of the contractions were much higher (33 times) than the clinically relevant plasma concentrations of these drugs after epidural administration and are unlikely to be significant in the

**52**

regression time of the motor block, in group 1, of 198.48 ± 47.63 min, and in group 2 of 232.84 ± 63.66 min; p = 0.00073. They concluded that morphine and clonidine at low doses produce adequate postoperative analgesia in pregnant patients [12].

In the study Zhan et al., 70 pregnant or obstetric patients were studied; 0.5% spinal isobaric bupivacaine was 4 mg; the ED50 of intrathecal bupivacaine for motor block was 3.96 mg (IC 95% 3.83–4.98) for pregnant women versus 4.51 mg (95% CI 4.27–4.76) for nonpregnant women. The potency of bupivacaine for motor block in pregnant versus non-pregnant women was 1.14 times higher (95% CI 1.05–1.24). This is because the supine position can increase the dissemination of the injected drugs due to the increase in intra-abdominal pressure, in addition to the increase in blood flow in the vasculature in the epidural veins, which distends and compresses the intraspinal space decreasing the volume of the spinal fluid cerebral [19].

#### **7. Bupivacaine and placental transfer to fetus**

The analysis of the placental intervillous space shows to be an appropriate place of investigation because this space is initially filled with blood coming from the maternal spiral arteries that interchange with the fetal venous blood, when the blood of the mother flows toward the branched villi. Although it is an important interchange interface, the intervillous space has been studied as the transport of substances between the mother, the placenta, and the fetus; obtaining blood from this compartment has provided a unique opportunity to study the maternal-fetal physiological relationship in a more physiological way [20]. The importance of this is that the reduced ability of the fetus to eliminate drugs can cause prolonged effects on the fetus, since half of the fetal circulation reaches the umbilical vein and directly reaches the fetal heart and brain by passing to the fetus. Liver immaturity contributes to the presentation of adverse effects, the fetus eliminates the drug by diffusion into the maternal compartment, although the majority of the metabolites are more polar and it is unlikely that the placental membrane crosses the placental membrane back to the compartment maternal, possibly resulting in the accumulation of metabolites in various fetal tissues [20].

In the study by Barros et al., a Brazilian study, the concentrations of bupivacaine and lidocaine as well as its metabolite (MEGX) and its placental transfer were analyzed in 10 healthy pregnant patients, under elective cesarean and epidural anesthesia. The administration of the medication was epidural of 0.1 mg of fentanyl citrate, 112.5 mg of 0.5% bupivacaine with 2:200000 epinephrine, and 200 mg of lidocaine 2% without vasoconstrictor injected into the epidural space [11]. The concentrations of bupivacaine enantiomers were high in the maternal plasma and placental intervillous space than in the umbilical vein and the umbilical artery. The concentrations of S-bupivacaine in the maternal plasma were higher than the R-bupivacaine concentrations, and the values were 195.2 and 186.0 ng/mL. There were no significant differences (P < 0.05) between their concentrations in umbilical fetal vessels [11]. The placental transfer was 33% for R-bupivacaine and 31% for the S-bupivacaine. The concentrations of the enantiomer S-bupivacaine were 3.5 and 3.82 times higher in the placental intervillous space than that of the umbilical vein and the umbilical artery, respectively [11].

The R-bupivacaine concentrations were 2.9 times higher in the placental intervillous space than the fetal umbilical vein concentrations and 3.16 times higher than the concentrations in the fetal umbilical artery. There were no cardiocirculatory changes, neonatal repercussions in the APGAR, or respiratory depression. There was no significant difference in the ratio of enantiomer concentrations between the

different compartments, maternal or fetal. This study showed that the intervillous space acts as a drug reservoir [11].

### **8. Conclusion**

In conclusion, local anesthetics, including bupivacaine, are among the drugs most commonly used in clinical practice for the management of pregnant patients for obstetric or non-obstetric procedures. It is essential to know the pharmacokinetics of the drug in order to understand the concentrations of the drugs which we can obtain adequate analgesic and anesthetic effects, trying to diminish the toxic effects.

### **Acknowledgements**

I thank the Instituto Nacional de Cardiología Ignacio Chávez for allowing me to carry out my work, promoting research and dissemination of knowledge.

### **Conflict of interest**

I declared that I do not have any conflict of interests.

#### **Author details**

Yazmín Guillén-Dolores Instituto Nacional de Cardiología Ignacio Chávez, México City, México

\*Address all correspondence to: gudyyazy@hotmail.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**55**

bp.2012.073

*Bupivacaine Pharmacokinetics in Pregnant Women DOI: http://dx.doi.org/10.5772/intechopen.87184*

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[6] Briggs GG, Freeman RK, Yaffe SS. Drugs in Pregnancy and Lactation. 4th ed. Baltimore: Williams and

[7] Foster RH, Markham A. Levobupivacaine: A review of its pharmacology and use as a local anaesthetic. Drugs. 2000;**59**(3):551-579

[8] Stourac P, Suchomelova H, Stodulkova M, Huser M, Krikava I, Janku P, et al. Comparison of parturient - controlled remifentanil with epidural bupivacain and sufentanil for labour analgesia: Randomised controlled trial. Biomedical Papers of the Medical Faculty of the University Palacky, Olomouc, Czech Republic. 2014;**158**(2):227-232. DOI: 10.5507/

1978;**25**(3):87-91

pp. 1843-1844

2006;**53**:1474-1495

Wilkins; 1994

**References**

*Bupivacaine Pharmacokinetics in Pregnant Women DOI: http://dx.doi.org/10.5772/intechopen.87184*

#### **References**

*Topics in Local Anesthetics*

**8. Conclusion**

**Acknowledgements**

**Conflict of interest**

**Author details**

Yazmín Guillén-Dolores

effects.

space acts as a drug reservoir [11].

different compartments, maternal or fetal. This study showed that the intervillous

In conclusion, local anesthetics, including bupivacaine, are among the drugs most commonly used in clinical practice for the management of pregnant patients for obstetric or non-obstetric procedures. It is essential to know the pharmacokinetics of the drug in order to understand the concentrations of the drugs which we can obtain adequate analgesic and anesthetic effects, trying to diminish the toxic

I thank the Instituto Nacional de Cardiología Ignacio Chávez for allowing me to

carry out my work, promoting research and dissemination of knowledge.

Instituto Nacional de Cardiología Ignacio Chávez, México City, México

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

\*Address all correspondence to: gudyyazy@hotmail.com

provided the original work is properly cited.

I declared that I do not have any conflict of interests.

**54**

[1] Morishima HO, Ishizaki A, Zhang Y, Whittington RA, Suckow RF, Cooper TB. Disposition of bupivacaine and its metabolites in the maternal, placental, and fetal compartments in rats. Anesthesiology. 2000;**93**(4):1069-1074

[2] Babst CR, Gilling BN. Bupivacaine: A review. Anesthesia Progress. 1978;**25**(3):87-91

[3] Elkayam U. Pregnancy and cardiovascular disease. In: Braunwald E, editor. Heart Disease. A Textbook of Cardiovascular Medicine. 8th ed. Philadelphia: WB Saunders; 2007. pp. 1843-1844

[4] González I, Armada E, Díaz J, Gallego P, García-Moll M, González A, et al. Guías de práctica clínica de la Sociedad Española de Cardiología en la gestante con cardiopatía. Revista Española de Cardiología. 2006;**53**:1474-1495

[5] Rudolph AM. Pharmacodynamics in the maternal-fetal-placental unit. NIDA Research Monograph. 1995;**154**:163-174

[6] Briggs GG, Freeman RK, Yaffe SS. Drugs in Pregnancy and Lactation. 4th ed. Baltimore: Williams and Wilkins; 1994

[7] Foster RH, Markham A. Levobupivacaine: A review of its pharmacology and use as a local anaesthetic. Drugs. 2000;**59**(3):551-579

[8] Stourac P, Suchomelova H, Stodulkova M, Huser M, Krikava I, Janku P, et al. Comparison of parturient - controlled remifentanil with epidural bupivacain and sufentanil for labour analgesia: Randomised controlled trial. Biomedical Papers of the Medical Faculty of the University Palacky, Olomouc, Czech Republic. 2014;**158**(2):227-232. DOI: 10.5507/ bp.2012.073

[9] Lirk P, Picardi S, Hollmann MW. Local anaesthetics: 10 essentials. European Journal of Anaesthesiology. 2014;**31**(11):575-585. DOI: 10.1097/ EJA.0000000000000137

[10] Trabelsi B, Charfi R, Bennasr L, Marzouk SB, Eljebari H, Jebabli N, et al. Pharmacokinetics of bupivacaine after bilateral ultrasound-guided transversus abdominis planeblock following cesarean delivery under spinal anesthesia. International Journal of Obstetric Anesthesia. 2017;**32**:17-20. DOI: 10.1016/j.ijoa.2017.04.007

[11] de Barros Duarte L, Dantas Móises EC, Cavalli RC, Lanchote VL, Duarte G, da Cunha SP. Distribution of bupivacaine enantiomers and lidocaine and its metabolite in the placental intervillous space and in the different maternal and fetal compartments in term pregnant women. Journal of Clinical Pharmacology. 2011;**51**(2):212-217. DOI: 10.1177/0091270010365551

[12] Braga Ade F, Frias JA, Braga FS, Pereira RI, Titotto SM. Spinal anesthesia for elective ceasarean section: Use of different doses of hyperbaric bupivacaine associated with morphine and clonidine. Acta Cirúrgica Brasileira. 2013;**28**(1):26-32

[13] Mahmut Alp K, Adnan I, Evren B, Nuray A, Orhan B, Besli F. Effect of spinal anesthesia on the QT interval in term and post-term pregnancies scheduled for elective cesarean section, a prospective study. The Journal of Maternal Fetal and Neonatal Medicine. 27 Jan 2019:1-5. DOI: 10.1080/14767058.2019.1569620. [Epub ahead of print]

[14] Dogan Z, Yildiz H, Akcay A, Coskuner I, Arikan DC, Silay E, et al. The effect of intraspinal bupivacaine versus levobupivacaine on the QTc intervals during caesarean section:

A randomized, double-blind, prospective study. Basic and Clinical Pharmacology and Toxicology. 2014;**114**(3):248-253. DOI: 10.1111/bcpt.12146

[15] Eslamian L, Kabiri-Nasab M, Agha-Husseini M, Azimaraghi O, Barzin G, Movafegh A. Adding sufentanil to TAP block hyperbaric bupivacaine decreases post-cesarean delivery morphine consumption. Acta Medica Iranica. 2016;**54**(3):185-190

[16] Lacassie HJ, Rolle A, Cortínez LI, Solari S, Corvetto MA, Altermatt FR. Pharmacokinetics of levobupivacaine with epinephrine in transversus abdominis plane block for postoperative analgesia after caesarean section. British Journal of Anaesthesia. 2018;**121**(2): 469-475. DOI: 10.1016/j.bja.2018.02.070

[17] Chen SY, Liu FL, Cherng YG, Fan SZ, Leighton BL, Chang HC, et al. Patient-controlled epidural levobupivacaine with or without fentanyl for post-cesarean section pain relief. BioMed Research International. 2014;**2014**:965152. DOI: 10.1155/2014/965152

[18] Fanning RA, Campion DP, Collins CB, Keely S, Briggs LP, O'Connor JJ, et al. A comparison of the inhibitory effects of bupivacaine and levobupivacaine on isolated human pregnant myometrium contractility. Anesthesia and Analgesia. 2008;**107**(4):1303-1307. DOI: 10.1213/ ane.0b013e3181804245

[19] Zhan Q, Huang S, Geng G, Xie Y. Comparison of relative potency of intrathecal bupivacaine for motor block in pregnant versus non-pregnant women. International Journal of Obstetric Anesthesia. 2011;**20**(3): 219-223. DOI: 10.1016/j.ijoa.2011.01.001

[20] Pacifici GM, Nottoli R. Placental transfer of drugs administered to the mother. Clinical Pharmacokinetics. 1995;**28**(3):235-269. DOI: 10.2165/00003088-199528030-00005

**57**

**Chapter 4**

**Abstract**

opioids, neurotoxicity

**1. Introduction**

Anesthetics

Adjuvant Drugs to Local

*Nandita Mehta and Sayyidah Aasima tu Nisa Qazi*

lipophilic (fentanyl and sufentanil) and hydrophilic (morphine).

Local anesthetics have a potential to be used in a wide variety of situations including central neuraxial blocks, peripheral nerve blocks, intravenous, and local infiltration both for surgeries and acute and chronic pain management. Their use can be limited by their duration of action and the dose-dependent adverse effects on the cardiac and central nervous system. Adjuvants are drugs which, when coadministered along with local anesthetic agents, improve the latency of onset and duration of analgesia and counteract disadvantageous effects of local anesthetics. There is a wide armamentarium of adjuvant drugs to choose to be added in neuraxial and peripheral nerve blocks. They can be broadly divided into non-opioids and opioids, with non-opioids being vasoconstrictors, α2-adrenoceptor agonists, anti-inflammatory agents, acetylcholine esterase inhibitors (neostigmine), adenosine, ketorolac, midazolam, magnesium, and sodium bicarbonate and opioids being

**Keywords:** local anesthetics, adjuvants, neuraxial blocks, peripheral nerve blocks,

Local anesthetics (LA) are widely used in clinical practice for regional anesthesia or analgesia in various locations like central neuraxial blockade, peripheral nerve block, intravenously, and local infiltration. Infiltration with LA around the nerve produces analgesia by interrupting pain signals to the brain. The analgesic effect of a nerve block with LAs lasts only a few hours. Therefore, after surgery patients may suffer from moderate to severe acute pain. The duration of the action of LA can be prolonged by either increasing the dose or administering a continuous infusion of the drug, which can lead to dose-dependent side effects on the cardiovascular system and/or central nervous system (CNS) [1, 2]. The popularity of peripheral nerve blocks for surgical anesthesia as well as for postoperative analgesia has increased significantly due to anesthetists becoming more familiar with ultrasound-guided techniques. While the use of catheters for continuous infusions allows for sustained pain relief during the perioperative period, they can increase the challenges related to patient management, catheter displacement, and the potential for increased infection risk. In the case a long-acting LA or continuous block is used, sensory block is also associated with prolonged motor block in the postoperative period. Prolonged motor blockade in the postoperative period is undesirable as it leads to delayed mobilization of the patient and hence increased risk of complications.

#### **Chapter 4**

*Topics in Local Anesthetics*

DOI: 10.1111/bcpt.12146

2016;**54**(3):185-190

A randomized, double-blind, prospective study. Basic and Clinical Pharmacology and Toxicology. 2014;**114**(3):248-253.

[15] Eslamian L, Kabiri-Nasab M, Agha-Husseini M, Azimaraghi O, Barzin G, Movafegh A. Adding sufentanil to TAP block hyperbaric bupivacaine decreases post-cesarean delivery morphine consumption. Acta Medica Iranica.

[16] Lacassie HJ, Rolle A, Cortínez LI, Solari S, Corvetto MA, Altermatt FR. Pharmacokinetics of levobupivacaine with epinephrine in transversus

abdominis plane block for postoperative analgesia after caesarean section. British Journal of Anaesthesia. 2018;**121**(2): 469-475. DOI: 10.1016/j.bja.2018.02.070

[17] Chen SY, Liu FL, Cherng YG, Fan SZ, Leighton BL, Chang HC, et al. Patient-controlled epidural levobupivacaine with or without fentanyl for post-cesarean section pain relief. BioMed Research International. 2014;**2014**:965152. DOI: 10.1155/2014/965152

[18] Fanning RA, Campion DP, Collins CB, Keely S, Briggs LP, O'Connor JJ, et al. A comparison of the inhibitory effects of bupivacaine and levobupivacaine on isolated human pregnant myometrium

ane.0b013e3181804245

contractility. Anesthesia and Analgesia. 2008;**107**(4):1303-1307. DOI: 10.1213/

[19] Zhan Q, Huang S, Geng G, Xie Y. Comparison of relative potency of intrathecal bupivacaine for motor block in pregnant versus non-pregnant women. International Journal of Obstetric Anesthesia. 2011;**20**(3): 219-223. DOI: 10.1016/j.ijoa.2011.01.001

[20] Pacifici GM, Nottoli R. Placental transfer of drugs administered to the mother. Clinical Pharmacokinetics.

10.2165/00003088-199528030-00005

1995;**28**(3):235-269. DOI:

**56**

## Adjuvant Drugs to Local Anesthetics

*Nandita Mehta and Sayyidah Aasima tu Nisa Qazi*

#### **Abstract**

Local anesthetics have a potential to be used in a wide variety of situations including central neuraxial blocks, peripheral nerve blocks, intravenous, and local infiltration both for surgeries and acute and chronic pain management. Their use can be limited by their duration of action and the dose-dependent adverse effects on the cardiac and central nervous system. Adjuvants are drugs which, when coadministered along with local anesthetic agents, improve the latency of onset and duration of analgesia and counteract disadvantageous effects of local anesthetics. There is a wide armamentarium of adjuvant drugs to choose to be added in neuraxial and peripheral nerve blocks. They can be broadly divided into non-opioids and opioids, with non-opioids being vasoconstrictors, α2-adrenoceptor agonists, anti-inflammatory agents, acetylcholine esterase inhibitors (neostigmine), adenosine, ketorolac, midazolam, magnesium, and sodium bicarbonate and opioids being lipophilic (fentanyl and sufentanil) and hydrophilic (morphine).

**Keywords:** local anesthetics, adjuvants, neuraxial blocks, peripheral nerve blocks, opioids, neurotoxicity

#### **1. Introduction**

Local anesthetics (LA) are widely used in clinical practice for regional anesthesia or analgesia in various locations like central neuraxial blockade, peripheral nerve block, intravenously, and local infiltration. Infiltration with LA around the nerve produces analgesia by interrupting pain signals to the brain. The analgesic effect of a nerve block with LAs lasts only a few hours. Therefore, after surgery patients may suffer from moderate to severe acute pain. The duration of the action of LA can be prolonged by either increasing the dose or administering a continuous infusion of the drug, which can lead to dose-dependent side effects on the cardiovascular system and/or central nervous system (CNS) [1, 2]. The popularity of peripheral nerve blocks for surgical anesthesia as well as for postoperative analgesia has increased significantly due to anesthetists becoming more familiar with ultrasound-guided techniques. While the use of catheters for continuous infusions allows for sustained pain relief during the perioperative period, they can increase the challenges related to patient management, catheter displacement, and the potential for increased infection risk. In the case a long-acting LA or continuous block is used, sensory block is also associated with prolonged motor block in the postoperative period. Prolonged motor blockade in the postoperative period is undesirable as it leads to delayed mobilization of the patient and hence increased risk of complications.

The adjuvant drugs of regional LAs improve the quality and duration of anesthesia and analgesia and patient safety, thus increasing patient satisfaction and comfort [3, 4]. The aim of this chapter is to discuss the past, present, and future trends in the use of adjuvants, as well as their benefits and side effects.

#### **2. Adjuvants drugs**

Adjuvants are drugs which, when administered along with LA agents, may improve the latency of onset and duration of analgesia and counteract the undesirable effects associated with large doses of LAs. The use of adjuvant drugs has the potential to improve the efficacy of peripheral and central neuraxial blocks and decrease LA systemic toxicity by chiefly prolonging the duration of sensory block,


**59**

**3.1 Morphine**

*Adjuvant Drugs to Local Anesthetics*

these adjuvants.

**3. Opioids**

*DOI: http://dx.doi.org/10.5772/intechopen.91980*

sedation, and minimum adverse effects.

enhancing motor blockade, and limiting the overall dose requirement of LAs. An ideal adjuvant should not only shorten the speed of onset of action of the LA drug but also reduce its dosage along with providing hemodynamic stability, optimal

A wide variety of adjuvant drugs have been used for both neuraxial and peripheral nerve blocks (**Table 1**). They can be broadly divided into non-opioids and opioids. Current research is directed toward a search for agents and techniques which would prolong LA action while limiting its side effects and giving the patient its maximum benefit. These include techniques like the use of charged molecules to produce LA action (tonicaine and n-butyl tetracaine), newer delivery mechanisms for prolonged bioavailability (liposomal, cyclodextrin, and microsphere systems), and the use of other drugs (dextrans, adenosine, neuromuscular blockers) [3, 4]. While the use of LA adjuvants in regional anesthesia [5, 6] is in widespread clinical off-label use and has been subject to multiple clinical trials, we would like to emphasize on the fact that only a few adjuvants have been approved by the Food and Drug Administration (FDA), so absolute caution must be exercised while using

Opioids are the most common and the earliest used LA adjuvants. Their use in neuraxial and peripheral nerve blocks has evolved greatly over the last 30 years. It is advisable to use specific opioids, at appropriate doses and routes of administration that result in a primarily spinal site of action rather than a systemic opioid [7]. Afferent noxious stimuli from peripheral tissues converge in the dorsal horn of the spinal cord, where the primary nociceptive neuron synapses with the interneurons and the second-order nociceptive neuron in the spinothalamic tract. Blockade of these opioid receptors by agonists helps to suppress afferent nociceptive input from pain sites by modulating the release of pain-pathway associated peptides [8]. Opioids produce analgesia by mimicking the actions at specific receptors of endogenous opioid peptides. These peptides are beta-endorphin, met-enkephalin, and dynorphin. The three main types of opiate receptors, each with its own subtypes, are mu (μ), delta (δ), and kappa (*ĸ*) [9]. The most important target for opioids is the μ-receptor (endorphin), and intrathecal opioids appear to selectively modulate C- and A-fibers with minimal impact on dorsal root axons. The enkephalins are the primary endogenous ligands of the delta receptor and are involved with spinal analgesia. Dynorphin is the ligand for the kappa receptor. Activation of the kappa receptor results in segmental spinal analgesia and sedation. Most of the mixed agonist–antagonist opioids like butorphanol bind to the kappa receptor.

The exact mechanism of action of opioids at peripheral nerve is still uncertain. Evidences have begun to support the presence of peripheral opioid receptors [10]. The possible mechanism of prolonged analgesia by peripheral opioid administration could be through direct binding at opioid receptors of dorsal nerve root aided by axonal flow, diffusion through brachial plexus sheath to extradural or subarachnoid space to dorsal horn, and central action after peripheral systemic uptake [11].

The first opioid to be used intrathecally was morphine with the initial clinical study published in 1979 [12]. Morphine being relatively less hydrophobic than other opioids remains in the CSF for a longer time and therefore occupies the rostral receptor sites for a longer duration than other opioids [13]. Consequently, morphine

#### *Adjuvant Drugs to Local Anesthetics DOI: http://dx.doi.org/10.5772/intechopen.91980*

enhancing motor blockade, and limiting the overall dose requirement of LAs. An ideal adjuvant should not only shorten the speed of onset of action of the LA drug but also reduce its dosage along with providing hemodynamic stability, optimal sedation, and minimum adverse effects.

A wide variety of adjuvant drugs have been used for both neuraxial and peripheral nerve blocks (**Table 1**). They can be broadly divided into non-opioids and opioids.

Current research is directed toward a search for agents and techniques which would prolong LA action while limiting its side effects and giving the patient its maximum benefit. These include techniques like the use of charged molecules to produce LA action (tonicaine and n-butyl tetracaine), newer delivery mechanisms for prolonged bioavailability (liposomal, cyclodextrin, and microsphere systems), and the use of other drugs (dextrans, adenosine, neuromuscular blockers) [3, 4].

While the use of LA adjuvants in regional anesthesia [5, 6] is in widespread clinical off-label use and has been subject to multiple clinical trials, we would like to emphasize on the fact that only a few adjuvants have been approved by the Food and Drug Administration (FDA), so absolute caution must be exercised while using these adjuvants.

#### **3. Opioids**

*Topics in Local Anesthetics*

**2. Adjuvants drugs**

Opioids • Morphine • Pethidine • Fentanyl • Sufentanil • Hydromorphone • Buprenorphine • Diamorphine • Tramadol Vasoactive agents • Epinephrine • Phenylephrine

Alpha-2 adrenergic agonists

Nonsteroidal anti-inflammatory drugs

• Clonidine • Dexmedetomidine

Steroids • Dexamethasone

• Parecoxib • Lornoxicam Other agents • Ketamine • Midazolam • Neostigmine • Droperidol • Magnesium sulfate • Sodium bicarbonate • Potassium chloride • Adenosine • Dextran

The adjuvant drugs of regional LAs improve the quality and duration of anesthesia and analgesia and patient safety, thus increasing patient satisfaction and comfort [3, 4]. The aim of this chapter is to discuss the past, present, and future trends in

Adjuvants are drugs which, when administered along with LA agents, may improve the latency of onset and duration of analgesia and counteract the undesirable effects associated with large doses of LAs. The use of adjuvant drugs has the potential to improve the efficacy of peripheral and central neuraxial blocks and decrease LA systemic toxicity by chiefly prolonging the duration of sensory block,

the use of adjuvants, as well as their benefits and side effects.

**58**

**Table 1.**

*Classification of adjuvant drugs.*

Opioids are the most common and the earliest used LA adjuvants. Their use in neuraxial and peripheral nerve blocks has evolved greatly over the last 30 years. It is advisable to use specific opioids, at appropriate doses and routes of administration that result in a primarily spinal site of action rather than a systemic opioid [7]. Afferent noxious stimuli from peripheral tissues converge in the dorsal horn of the spinal cord, where the primary nociceptive neuron synapses with the interneurons and the second-order nociceptive neuron in the spinothalamic tract. Blockade of these opioid receptors by agonists helps to suppress afferent nociceptive input from pain sites by modulating the release of pain-pathway associated peptides [8]. Opioids produce analgesia by mimicking the actions at specific receptors of endogenous opioid peptides. These peptides are beta-endorphin, met-enkephalin, and dynorphin. The three main types of opiate receptors, each with its own subtypes, are mu (μ), delta (δ), and kappa (*ĸ*) [9]. The most important target for opioids is the μ-receptor (endorphin), and intrathecal opioids appear to selectively modulate C- and A-fibers with minimal impact on dorsal root axons. The enkephalins are the primary endogenous ligands of the delta receptor and are involved with spinal analgesia. Dynorphin is the ligand for the kappa receptor. Activation of the kappa receptor results in segmental spinal analgesia and sedation. Most of the mixed agonist–antagonist opioids like butorphanol bind to the kappa receptor.

The exact mechanism of action of opioids at peripheral nerve is still uncertain. Evidences have begun to support the presence of peripheral opioid receptors [10]. The possible mechanism of prolonged analgesia by peripheral opioid administration could be through direct binding at opioid receptors of dorsal nerve root aided by axonal flow, diffusion through brachial plexus sheath to extradural or subarachnoid space to dorsal horn, and central action after peripheral systemic uptake [11].

#### **3.1 Morphine**

The first opioid to be used intrathecally was morphine with the initial clinical study published in 1979 [12]. Morphine being relatively less hydrophobic than other opioids remains in the CSF for a longer time and therefore occupies the rostral receptor sites for a longer duration than other opioids [13]. Consequently, morphine produces a long-lasting and adequate analgesia with intrathecal use [14]. However, this huge advantage is offset by the increased risk of adverse effects, especially postoperative respiratory depression [15], which remains a particular concern among anesthetists. Intrathecal and epidural morphine are associated with a high incidence of side effects like nausea, vomiting, pruritus, urinary retention, sedation, and delayed respiratory depression [13, 16]. The recommended dose for intrathecal administration is 50–300 μg, while as 2–5 mg of epidural loading dose is considered adequate. The risk of side effects increases exponentially with the increase in the dose [16, 17].

#### **3.2 Pethidine**

Pethidine (meperidine) is a lipophilic phenylpiperidine derivate that is 30 times more lipid soluble and 10 times less potent than morphine, leading to a faster onset and a shorter duration of action than morphine. Pethidine possesses some local anesthetic properties (motor and sensory fiber block) which lets it stand out from the rest of the opioid agents. Pethidine is a popular choice for obstetric analgesia used mainly in epidural analgesia during labor. Intrathecal use of pethidine is not recommended. The incidence of nausea, vomiting, and hypotension is more with pethidine than with morphine. Pethidine can be injected as a loading dose of 25–50 mg in the epidural space.

#### **3.3 Fentanyl**

In addition to acting on the spinal cord receptors and peripheral receptors, fentanyl is also reported to have a local anesthetic like action, but this requires a very high concentration (50 g/mL) which is not clinically feasible [18]. Fentanyl as an adjuvant to LA causes significant prolongation of duration of analgesia but delays the onset of both sensory and motor blockade compared to LAs alone [19]. The change in pH of the anesthetic solution resulting in slower penetration of nerve membrane by LA is considered to be responsible for this effect [20]. The recommended intrathecal dose is 10–25 μg, and the epidural loading dose is 50–100 μg. Fentanyl as adjuvant does not prolong motor block, so it allows early ambulation, thereby reducing the morbidity. The duration of action is 2–4 h, and the risk of respiratory depression is very low and of short duration [17].

#### **3.4 Sufentanil**

A potent agonistic opioid was synthesized in the mid-1970s. A piperidine derivative is 6–10 times more potent than fentanyl, depending on the route of administration; it has been registered for intravenous, epidural, and subarachnoid administration. It is considered to be more lipid soluble than its counterparts, a better μ receptor ligand. It is an extremely potent opioid with a faster onset of action than its counterparts. Its use in clinical practice is limited by its short duration of action and high side effect profile. The recommended intrathecal dose is 2.5–10 μg, and epidural loading dose is 10–50 μg [17].

#### **3.5 Hydromorphone**

This opioid has intermediate lipid solubility. Due to its hydrophilicity, epidural hydromorphone can cross the blood-brain barrier faster and provide fast onset and modest duration of action.

**61**

*Adjuvant Drugs to Local Anesthetics*

**3.6 Buprenorphine**

**3.7 Diamorphine**

**3.8 Tramadol**

to have Na+

and K+

**4. Vasoactive agents**

vasopressor used.

**4.1 Epinephrine**

*DOI: http://dx.doi.org/10.5772/intechopen.91980*

Buprenorphine is a highly lipophilic partial opioid receptor agonist. It is also considered to have local-anesthetic-like capacity by blocking voltage-gated sodium channels. Buprenorphine and its metabolite nor-buprenorphine have been shown to act on κ and δ opioid receptors in addition to μ receptors which account for its antihyperalgesic effects. The risk of side effects like postoperative nausea and vomiting

It is a diacetylated analogue of morphine with a potency of approximately 1.5–2 times that of morphine. This leads to a faster onset and slightly shorter duration of action than morphine. It is a lipophilic semi-synthetic opioid and is a prodrug that is converted to its active metabolites (morphine and 6-monoacetyl morphine) by deacetylation in the liver and neural tissues. The recommended intrathecal dose is

Tramadol is a weak centrally acting opioid. A potency ratio of oral morphine to oral tramadol has been reported to be between 1:4 and 1:10. It has been shown

tive signals similar to that of LAs. The central and peripheral analgesic effects of tramadol have not been fully explained, but it is a selective agonist of μ-receptors. Tramadol also prevents reuptake of noradrenaline and enhances both serotonin and noradrenaline release. The monoaminergic activity of tramadol increases the inhibitory activity of the descending pain pathways, resulting in a suppression of

Vasoactive drugs are the oldest adjuvants that have been used, although at the beginning their action was attributed more to the fact that their vasoconstrictor effect prolonged the anesthetic and analgesic results of LAs by decreasing the blood flow of the site where they were injected. Adrenaline was the first

Epinephrine has been used along with LA in neuraxial and peripheral nerve blocks since Heinrich Braun first experimented with its use as a "chemical tourniquet" in the early 1900s [24]. Epinephrine potentiates the LA action. The substantia gelatinosa of the dorsal horn of the spinal cord houses alpha-2 adrenoreceptors wherein the epinephrine by its direct action mediates its antinociceptive properties resulting in presynaptic inhibition of transmitter release from Aδ and C fibers. Also its vasoconstrictive properties limit the systemic absorption of LA leading to prolonged duration of action. There are concerns about epinephrine being a potent vasoconstrictive agent can place the blood supply of the spinal cord at risk and may lead to ischemia of the spinal cord leading to permanent damage. Epinephrine is

channel blocking properties and can block motor and nocicep-

(PONV) is more with the use of perineural buprenorphine [21].

300–400 μg, and epidural loading dose is 2–5 mg [17, 22].

nociceptive transmission at the spinal level [23].

typically administered in doses of 0.2–0.3 mg [25].

#### **3.6 Buprenorphine**

*Topics in Local Anesthetics*

dose [16, 17].

**3.2 Pethidine**

**3.3 Fentanyl**

**3.4 Sufentanil**

**3.5 Hydromorphone**

modest duration of action.

25–50 mg in the epidural space.

produces a long-lasting and adequate analgesia with intrathecal use [14]. However, this huge advantage is offset by the increased risk of adverse effects, especially postoperative respiratory depression [15], which remains a particular concern among anesthetists. Intrathecal and epidural morphine are associated with a high incidence of side effects like nausea, vomiting, pruritus, urinary retention, sedation, and delayed respiratory depression [13, 16]. The recommended dose for intrathecal administration is 50–300 μg, while as 2–5 mg of epidural loading dose is considered adequate. The risk of side effects increases exponentially with the increase in the

Pethidine (meperidine) is a lipophilic phenylpiperidine derivate that is 30 times more lipid soluble and 10 times less potent than morphine, leading to a faster onset and a shorter duration of action than morphine. Pethidine possesses some local anesthetic properties (motor and sensory fiber block) which lets it stand out from the rest of the opioid agents. Pethidine is a popular choice for obstetric analgesia used mainly in epidural analgesia during labor. Intrathecal use of pethidine is not recommended. The incidence of nausea, vomiting, and hypotension is more with pethidine than with morphine. Pethidine can be injected as a loading dose of

In addition to acting on the spinal cord receptors and peripheral receptors, fentanyl is also reported to have a local anesthetic like action, but this requires a very high concentration (50 g/mL) which is not clinically feasible [18]. Fentanyl as an adjuvant to LA causes significant prolongation of duration of analgesia but delays the onset of both sensory and motor blockade compared to LAs alone [19]. The change in pH of the anesthetic solution resulting in slower penetration of nerve membrane by LA is considered to be responsible for this effect [20]. The recommended intrathecal dose is 10–25 μg, and the epidural loading dose is 50–100 μg. Fentanyl as adjuvant does not prolong motor block, so it allows early ambulation, thereby reducing the morbidity. The duration of action is 2–4 h, and the risk of

A potent agonistic opioid was synthesized in the mid-1970s. A piperidine derivative is 6–10 times more potent than fentanyl, depending on the route of administration; it has been registered for intravenous, epidural, and subarachnoid administration. It is considered to be more lipid soluble than its counterparts, a better μ receptor ligand. It is an extremely potent opioid with a faster onset of action than its counterparts. Its use in clinical practice is limited by its short duration of action and high side effect profile. The recommended intrathecal dose is 2.5–10 μg,

This opioid has intermediate lipid solubility. Due to its hydrophilicity, epidural hydromorphone can cross the blood-brain barrier faster and provide fast onset and

respiratory depression is very low and of short duration [17].

and epidural loading dose is 10–50 μg [17].

**60**

Buprenorphine is a highly lipophilic partial opioid receptor agonist. It is also considered to have local-anesthetic-like capacity by blocking voltage-gated sodium channels. Buprenorphine and its metabolite nor-buprenorphine have been shown to act on κ and δ opioid receptors in addition to μ receptors which account for its antihyperalgesic effects. The risk of side effects like postoperative nausea and vomiting (PONV) is more with the use of perineural buprenorphine [21].

#### **3.7 Diamorphine**

It is a diacetylated analogue of morphine with a potency of approximately 1.5–2 times that of morphine. This leads to a faster onset and slightly shorter duration of action than morphine. It is a lipophilic semi-synthetic opioid and is a prodrug that is converted to its active metabolites (morphine and 6-monoacetyl morphine) by deacetylation in the liver and neural tissues. The recommended intrathecal dose is 300–400 μg, and epidural loading dose is 2–5 mg [17, 22].

#### **3.8 Tramadol**

Tramadol is a weak centrally acting opioid. A potency ratio of oral morphine to oral tramadol has been reported to be between 1:4 and 1:10. It has been shown to have Na+ and K+ channel blocking properties and can block motor and nociceptive signals similar to that of LAs. The central and peripheral analgesic effects of tramadol have not been fully explained, but it is a selective agonist of μ-receptors. Tramadol also prevents reuptake of noradrenaline and enhances both serotonin and noradrenaline release. The monoaminergic activity of tramadol increases the inhibitory activity of the descending pain pathways, resulting in a suppression of nociceptive transmission at the spinal level [23].

#### **4. Vasoactive agents**

Vasoactive drugs are the oldest adjuvants that have been used, although at the beginning their action was attributed more to the fact that their vasoconstrictor effect prolonged the anesthetic and analgesic results of LAs by decreasing the blood flow of the site where they were injected. Adrenaline was the first vasopressor used.

#### **4.1 Epinephrine**

Epinephrine has been used along with LA in neuraxial and peripheral nerve blocks since Heinrich Braun first experimented with its use as a "chemical tourniquet" in the early 1900s [24]. Epinephrine potentiates the LA action. The substantia gelatinosa of the dorsal horn of the spinal cord houses alpha-2 adrenoreceptors wherein the epinephrine by its direct action mediates its antinociceptive properties resulting in presynaptic inhibition of transmitter release from Aδ and C fibers. Also its vasoconstrictive properties limit the systemic absorption of LA leading to prolonged duration of action. There are concerns about epinephrine being a potent vasoconstrictive agent can place the blood supply of the spinal cord at risk and may lead to ischemia of the spinal cord leading to permanent damage. Epinephrine is typically administered in doses of 0.2–0.3 mg [25].

#### **4.2 Phenylephrine**

Phenylephrine has a mechanism of action similar to that of epinephrine. It has vasoconstrictive abilities, thus limiting the uptake of LA and prolonging their duration of action. Phenylephrine in the dose of 2–5 mg prolongs both lidocaine and tetracaine spinal anesthesia to a similar extent as epinephrine. The use of phenylephrine has declined in popularity because of its association with transient neurologic symptoms (TNS) [26].

#### **5. Alpha-2 adrenergic agonists**

Alpha-2 adrenergic receptor agonists have recently been the focus of interest for their sedative, analgesic, perioperative sympatholytic, anesthetic sparing, and hemodynamic stabilizing properties. The central α-2-AR agonists inhibit nociceptive impulses by activating post-junctional α-2-adrenoceptors in the dorsal horn of the spinal cord. These receptors are located on primary afferent terminals (both at peripheral and at spinal endings), on neurons in the superficial lamina of the spinal cord, and within several brainstem nuclei responsible for analgesia. They block the conduction of C- and A-delta fibers and increase potassium conductance, thus intensifying conduction block. They also cause local vasoconstriction, thereby reducing vascular uptake of the LA from around the neural structures and in turn prolonging the duration of action [27–29].

#### **5.1 Clonidine**

Clonidine is an imidazole derivative with selective partial agonist properties which inhibit the nociceptive impulses by acting on the post-junctional alpha-2 adrenoreceptors in the dorsal horn of the spinal cord. In neuraxial blocks, it has a local effect leading to decreased sympathetic outflow, while in peripheral nerve blocks it prolongs the duration of analgesia by hyperpolarization of cyclic nucleotide-gated cation channels. Clonidine enhances and prolongs sensory and enhances motor blockade when used along with LA for epidural or peripheral nerve blocks [30]. The alpha-2 adrenergic agonists also enhance analgesia from intraspinal opioids by interactions with both pre- and post-synaptic receptors within the spinal cord.

Although there is no agreement on the doses of intrathecal clonidine [31], the most commonly used doses vary widely. The most recommended dose for intrathecal use is 15–150 μg, with the incidence of adverse effects (bradycardia, sedation, hypotension) increasing with doses above 150 μg. Clonidine can be used via epidural route with a bolus dose of 75–150 μg. In pediatric anesthesia, the use of clonidine (1 μg/kg) as an adjuvant along with LA for caudal blocks doubles the duration of analgesia when compared to LA alone but causes marked sedation [17].

Clonidine has been found to prolong the action of local anesthetics in peripheral blocks in the postoperative period. This effect of clonidine is dose-related. After brachial plexus block with mepivacaine, the minimum doses which significantly prolong analgesia and anesthesia are 0.1 and 0.5 μg/kg, respectively [32].

#### **5.2 Dexmedetomidine**

Dexmedetomidine is seven times more selective agonist to alpha-2 receptor than clonidine (seven times more specific for alpha-2 than alpha-1) but has a similar mechanism of blocking hyperpolarization-activated cation channels. When used as an adjuvant to LA for neuraxial block, dexmedetomidine leads to reduced onset

**63**

*Adjuvant Drugs to Local Anesthetics*

**6. Steroids: dexamethasone**

effects [34].

LA [35–40].

*DOI: http://dx.doi.org/10.5772/intechopen.91980*

needed; although rare, even cardiac arrest can occur.

removed, suggesting a direct action in the membrane.

time of sensory and motor block, increased duration of sensory block, and delayed recovery from motor blockade. It leads to prolongation of postoperative analgesia, decreased requirement of additional analgesics, delayed first rescue analgesic, and decreased postoperative shivering. Dose in spinal anesthesia varies from 3 to 15 μg as an adjuvant to LA [33]. For caudal epidural block, 1–2 μg/kg of dexmedetomidine along with bupivacaine can lead to prolonged analgesia without significant side

The most common reported adverse effects are bradycardia and hypotension. Bradycardia due to dexmedetomidine is resistant to atropine, and higher doses are

It has been shown that clonidine and dexmedetomidine administered orally, intramuscularly, and intravenously also prolong the anesthetic effect of intrathecal

Acute inflammation from tissue injury has an important role in surgical pain, and glucocorticoids may be useful for its anti-inflammatory effect. Johansson et al. [41] investigated the corticosteroid effect on the plantar nerve of rats finding that methylprednisolone suppresses transmission in thin unmyelinated C fibers but not in myelinated A-beta fibers. The effect was reversed when the corticosteroid was

Dexamethasone-induced prolongation of peripheral nerve blockade following LA injection is commonly attributed to its anti-inflammatory action. It also improves the quality and duration of analgesia over LAs alone. This is thought to be mediated by its capacity to alter the release of inflammatory mediators, reduce ectopic neuronal discharge, and inhibit potassium channel-mediated discharge of nociceptive C fibers [41]. Its action on glucocorticoid receptor is considered to alter the functioning of ion channels and produce acidosis around the nerve cell, thereby reducing the concentration of LA required to produce blockade of signal transmission or trapping the highly ionized bupivacaine molecule into the neuronal cell. Studies using dexamethasone for postoperative pain relief have produced positive results mainly in surgery involving large amounts of tissue trauma. A systematic review and meta-analysis included 1695 patients distributed in 29 controlled clinical trials where dexamethasone 4 and 8 mg perineural was used as adjuvant to LA. These authors found that dexamethasone increased the mean (95% CI) duration of analgesia by 233 (172–295) min when injected with short- or mediumterm action LA and by 488 (419–557) min when injected with long-term action LA, p < 0.00001 for both. However, these results should be taken with caution due to the great heterogeneity of results, with I2 exceeding 90% for both analysis. Meta-regression did not show an interaction between dose of perineural dexamethasone (4–10 mg) and duration of analgesia (r2 = 0.02, p = 0.54). There were no differences between 4 and 8 mg dexamethasone on subgroup analysis [42]. After reviewing the current literature, Wiesmann et al. [43] prefer a systemic application mode (intravenously) over a perineural route of dexamethasone administration as a complement to peripheral nerve blocks. A single dose of dexamethasone could be a useful complement to prolong peripheral nerve blocks. In a randomized controlled triple-blind crossover study in 24 male volunteers, the authors used ultrasoundguided ulnar nerve blocks (ropivacaine 0.75% wt/vol, 3 ml, with saline 1 ml with or without dexamethasone 4 mg) which were performed on three occasions in each volunteer along with an IV injection of saline 1 ml with or without dexamethasone 4 mg. The median [inter-quartile range (IQR)] duration of sensory block was 6.87

#### *Adjuvant Drugs to Local Anesthetics DOI: http://dx.doi.org/10.5772/intechopen.91980*

*Topics in Local Anesthetics*

**4.2 Phenylephrine**

neurologic symptoms (TNS) [26].

**5. Alpha-2 adrenergic agonists**

prolonging the duration of action [27–29].

**5.1 Clonidine**

Phenylephrine has a mechanism of action similar to that of epinephrine. It has vasoconstrictive abilities, thus limiting the uptake of LA and prolonging their duration of action. Phenylephrine in the dose of 2–5 mg prolongs both lidocaine and tetracaine spinal anesthesia to a similar extent as epinephrine. The use of phenylephrine has declined in popularity because of its association with transient

Alpha-2 adrenergic receptor agonists have recently been the focus of interest for their sedative, analgesic, perioperative sympatholytic, anesthetic sparing, and hemodynamic stabilizing properties. The central α-2-AR agonists inhibit nociceptive impulses by activating post-junctional α-2-adrenoceptors in the dorsal horn of the spinal cord. These receptors are located on primary afferent terminals (both at peripheral and at spinal endings), on neurons in the superficial lamina of the spinal cord, and within several brainstem nuclei responsible for analgesia. They block the conduction of C- and A-delta fibers and increase potassium conductance, thus intensifying conduction block. They also cause local vasoconstriction, thereby reducing vascular uptake of the LA from around the neural structures and in turn

Clonidine is an imidazole derivative with selective partial agonist properties which inhibit the nociceptive impulses by acting on the post-junctional alpha-2 adrenoreceptors in the dorsal horn of the spinal cord. In neuraxial blocks, it has a local effect leading to decreased sympathetic outflow, while in peripheral nerve blocks it prolongs the duration of analgesia by hyperpolarization of cyclic nucleotide-gated cation channels. Clonidine enhances and prolongs sensory and enhances motor blockade when used along with LA for epidural or peripheral nerve blocks [30]. The alpha-2 adrenergic agonists also enhance analgesia from intraspinal opioids by interactions with both pre- and post-synaptic receptors within the spinal cord. Although there is no agreement on the doses of intrathecal clonidine [31], the most commonly used doses vary widely. The most recommended dose for intrathecal use is 15–150 μg, with the incidence of adverse effects (bradycardia, sedation, hypotension) increasing with doses above 150 μg. Clonidine can be used via epidural route with a bolus dose of 75–150 μg. In pediatric anesthesia, the use of clonidine (1 μg/kg) as an adjuvant along with LA for caudal blocks doubles the duration of analgesia when compared to LA alone but causes marked sedation [17]. Clonidine has been found to prolong the action of local anesthetics in peripheral blocks in the postoperative period. This effect of clonidine is dose-related. After brachial plexus block with mepivacaine, the minimum doses which significantly

prolong analgesia and anesthesia are 0.1 and 0.5 μg/kg, respectively [32].

Dexmedetomidine is seven times more selective agonist to alpha-2 receptor than

clonidine (seven times more specific for alpha-2 than alpha-1) but has a similar mechanism of blocking hyperpolarization-activated cation channels. When used as an adjuvant to LA for neuraxial block, dexmedetomidine leads to reduced onset

**62**

**5.2 Dexmedetomidine**

time of sensory and motor block, increased duration of sensory block, and delayed recovery from motor blockade. It leads to prolongation of postoperative analgesia, decreased requirement of additional analgesics, delayed first rescue analgesic, and decreased postoperative shivering. Dose in spinal anesthesia varies from 3 to 15 μg as an adjuvant to LA [33]. For caudal epidural block, 1–2 μg/kg of dexmedetomidine along with bupivacaine can lead to prolonged analgesia without significant side effects [34].

The most common reported adverse effects are bradycardia and hypotension. Bradycardia due to dexmedetomidine is resistant to atropine, and higher doses are needed; although rare, even cardiac arrest can occur.

It has been shown that clonidine and dexmedetomidine administered orally, intramuscularly, and intravenously also prolong the anesthetic effect of intrathecal LA [35–40].

#### **6. Steroids: dexamethasone**

Acute inflammation from tissue injury has an important role in surgical pain, and glucocorticoids may be useful for its anti-inflammatory effect. Johansson et al. [41] investigated the corticosteroid effect on the plantar nerve of rats finding that methylprednisolone suppresses transmission in thin unmyelinated C fibers but not in myelinated A-beta fibers. The effect was reversed when the corticosteroid was removed, suggesting a direct action in the membrane.

Dexamethasone-induced prolongation of peripheral nerve blockade following LA injection is commonly attributed to its anti-inflammatory action. It also improves the quality and duration of analgesia over LAs alone. This is thought to be mediated by its capacity to alter the release of inflammatory mediators, reduce ectopic neuronal discharge, and inhibit potassium channel-mediated discharge of nociceptive C fibers [41]. Its action on glucocorticoid receptor is considered to alter the functioning of ion channels and produce acidosis around the nerve cell, thereby reducing the concentration of LA required to produce blockade of signal transmission or trapping the highly ionized bupivacaine molecule into the neuronal cell. Studies using dexamethasone for postoperative pain relief have produced positive results mainly in surgery involving large amounts of tissue trauma. A systematic review and meta-analysis included 1695 patients distributed in 29 controlled clinical trials where dexamethasone 4 and 8 mg perineural was used as adjuvant to LA. These authors found that dexamethasone increased the mean (95% CI) duration of analgesia by 233 (172–295) min when injected with short- or mediumterm action LA and by 488 (419–557) min when injected with long-term action LA, p < 0.00001 for both. However, these results should be taken with caution due to the great heterogeneity of results, with I2 exceeding 90% for both analysis. Meta-regression did not show an interaction between dose of perineural dexamethasone (4–10 mg) and duration of analgesia (r2 = 0.02, p = 0.54). There were no differences between 4 and 8 mg dexamethasone on subgroup analysis [42]. After reviewing the current literature, Wiesmann et al. [43] prefer a systemic application mode (intravenously) over a perineural route of dexamethasone administration as a complement to peripheral nerve blocks. A single dose of dexamethasone could be a useful complement to prolong peripheral nerve blocks. In a randomized controlled triple-blind crossover study in 24 male volunteers, the authors used ultrasoundguided ulnar nerve blocks (ropivacaine 0.75% wt/vol, 3 ml, with saline 1 ml with or without dexamethasone 4 mg) which were performed on three occasions in each volunteer along with an IV injection of saline 1 ml with or without dexamethasone 4 mg. The median [inter-quartile range (IQR)] duration of sensory block was 6.87

(5.85–7.62) h in the control group, 7.37 (5.78–7.93) h in the perineural group, and 7.37 (6.10–7.97) h in the IV group (P = 0.61). There was also no significant difference in block onset time between the three groups. Dexamethasone 4 mg had no clinically significant effect on the duration of sensory block provided by ropivacaine applied to the ulnar nerve [44]. The role of dexamethasone as an adjunct in peripheral nerve blockades is still unclear.

#### **7. Nonsteroidal anti-inflammatory drugs (NSAIDs)**

Several studies have demonstrated that the presence of COX-2 receptors in the dorsal horn of the spinal cord could regulate spinal nociceptive transmission [45]. Some studies suggest that administering a COX-2 antagonist directly on the central or peripheral nerve might have a better analgesic profile than intravenous administration of the same drug [46]. Basically COX-2 inhibitors reduce inflammation and pain sensation by inhibiting prostaglandin production. However, the role of COX-2 in the central nervous system is of more importance. Inflammation can induce COX-2 production and will lead to the release of prostanoids that sensitize the peripheral nociceptor terminals and produce localized hyperalgesia. It is hence thought that the administration of COX-2 antagonist on spinal or peripheral nerves may be a more effective mode of pain relief than the intravenous or intramuscular route. There are very less studies on this subject. Further research and studies need to be conducted to verify the use of NSAIDs as adjuvants.

#### **8. Miscellaneous agents**

#### **8.1 Ketamine**

Ketamine is a noncompetitive antagonist of NMDA receptor that has been shown to have local anesthetic properties. Ketamine acts on more than one region. It has actions at monoaminergic receptors, opioid receptors, voltage-sensitive calcium channels, and muscarinic receptors, in addition to local anesthetic actions through sodium channel blockade. Systemic ketamine causes central summation in the second-order pain neuron and decreases severe pain [3, 47, 48]. Epidural administration of ketamine at 0.5–1 mg/kg has been shown to reduce intraoperative and postoperative analgesic requirements without increased side effects [25]. Preservative-free S(+)-ketamine administered during caudal block for children at a dose of 0.5 mg/kg has been shown to extend analgesia time by several hours [17]. Intrathecal administration of ketamine is not recommended.

The risk of psychomimetic adverse effects such as hallucinations is a worrying factor for most anesthetists, limiting its use, but it can be easily overcome by using intravenous benzodiazepines as premedication prior to the block.

#### **8.2 Midazolam**

Midazolam, a water-soluble benzodiazepine, an indirect agonist of the gammaaminobutyric acid (GABA) receptor, has been studied primarily as an adjuvant for neuraxial anesthesia. Addition of preservative-free midazolam to 0.5% hyperbaric bupivacaine for subarachnoid block in infraumbilical surgery has been found to prolong the duration of effective analgesia as compared to the same concentration of bupivacaine alone and delays the need for postoperative rescue analgesics

**65**

*Adjuvant Drugs to Local Anesthetics*

12 h is considered safe.

**8.4 Magnesium sulfate**

**8.5 Sodium bicarbonate**

**8.3 Neostigmine**

*DOI: http://dx.doi.org/10.5772/intechopen.91980*

the side effects increasing as the dose rises.

raise the excitation threshold of A-beta fibers.

without having any reported significant side effects or hemodynamic instability. The use of intrathecal midazolam also decreases the incidence of postoperative nausea and vomiting. A small diluted intrathecal dose (1–2.5 mg) of preservative-free midazolam is reported to have few systemic side effects and is free of short-term neurotoxicity [49]. An infusion of epidural midazolam at 10–20 μg/kg/h for up to

Neostigmine is an acetylcholinesterase inhibitor that can enhance analgesia by acting on muscarinic receptors and increasing endogenous acetylcholine at the nerve terminal. It produces spinal analgesia in the preclinical models. Intrathecal neostigmine produces analgesia by the inhibition of (endogenous spinal neurotransmitter) acetylcholine destruction via muscarinic and cholinergic receptors located at dorsal horn of spinal cord, substantia gelatinosa, and in lesser amounts at laminae III and V [50]. There is a high incidence of nausea and vomiting and prolongation of recovery from spinal anesthesia following intrathecal administration of neostigmine, implying that it may not be a useful additive for ambulatory spinal anesthesia. The dose of intrathecal neostigmine ranges from 10 to 50 μg with

Magnesium is an N-methyl-D-aspartate (NMDA) antagonist that plays a role in moderating calcium influx into neurons. Research has demonstrated that magnesium decreases peripheral nerve excitability and enhances the ability of lidocaine to

Intrathecal and epidural use of magnesium has shown variable results. It may prolong LA/opioid block in women in labor at a dose of 50 mg, but a very high dose of magnesium has been reported to produce transient neurological toxicity [17]. Farzanegan et al. compared the combination of bupivacaine 12.5 mg and morphine 2 mg versus bupivacaine 12.5 mg and morphine 2 mg and magnesium 50 mg versus placebo epidurally for postoperative analgesia after thoracotomy. These authors achieved better analgesia and lower consumption of postoperative morphine significantly in the magnesium group [51]. In preeclamptic parturients doses of 50 mg of intrathecal magnesium with epidural ropivacaine significantly prolonged postoperative analgesia compared with 1 mg intrathecal midazolam without any complications [52]. In a recent meta-analysis, 11 studies showed that the use of epidural magnesium as an adjuvant to bupivacaine is still controversial. Although epidural magnesium prolonged the time of the first rescue analgesic and reduced the number of patients who required rescue analgesics, as well as the requirement of

these analgesics, further studies are needed to assess their usefulness [53].

Local anesthetic agents are usually packed at low pH to enhance their shelf life. In anesthetic practice, there has been considerable interest in studying the effect of pH on the onset, duration, and potency of blockade of LAs. It is proven that alkalinization of the LA improves the quality of block by influencing the portioning coefficient of anesthetic between aqueous solution and biological membranes [20]. Adding sodium bicarbonate to lidocaine decreases the latency of onset and enhances the depth of epidural blockade by increasing the concentration

#### *Adjuvant Drugs to Local Anesthetics DOI: http://dx.doi.org/10.5772/intechopen.91980*

without having any reported significant side effects or hemodynamic instability. The use of intrathecal midazolam also decreases the incidence of postoperative nausea and vomiting. A small diluted intrathecal dose (1–2.5 mg) of preservative-free midazolam is reported to have few systemic side effects and is free of short-term neurotoxicity [49]. An infusion of epidural midazolam at 10–20 μg/kg/h for up to 12 h is considered safe.

#### **8.3 Neostigmine**

*Topics in Local Anesthetics*

blockades is still unclear.

**8. Miscellaneous agents**

**8.1 Ketamine**

**8.2 Midazolam**

(5.85–7.62) h in the control group, 7.37 (5.78–7.93) h in the perineural group, and 7.37 (6.10–7.97) h in the IV group (P = 0.61). There was also no significant difference in block onset time between the three groups. Dexamethasone 4 mg had no clinically significant effect on the duration of sensory block provided by ropivacaine applied to the ulnar nerve [44]. The role of dexamethasone as an adjunct in peripheral nerve

Several studies have demonstrated that the presence of COX-2 receptors in the dorsal horn of the spinal cord could regulate spinal nociceptive transmission [45]. Some studies suggest that administering a COX-2 antagonist directly on the central or peripheral nerve might have a better analgesic profile than intravenous administration of the same drug [46]. Basically COX-2 inhibitors reduce inflammation and pain sensation by inhibiting prostaglandin production. However, the role of COX-2 in the central nervous system is of more importance. Inflammation can induce COX-2 production and will lead to the release of prostanoids that sensitize the peripheral nociceptor terminals and produce localized hyperalgesia. It is hence thought that the administration of COX-2 antagonist on spinal or peripheral nerves may be a more effective mode of pain relief than the intravenous or intramuscular route. There are very less studies on this subject. Further research and studies need

Ketamine is a noncompetitive antagonist of NMDA receptor that has been shown to have local anesthetic properties. Ketamine acts on more than one region. It has actions at monoaminergic receptors, opioid receptors, voltage-sensitive calcium channels, and muscarinic receptors, in addition to local anesthetic actions through sodium channel blockade. Systemic ketamine causes central summation in the second-order pain neuron and decreases severe pain [3, 47, 48]. Epidural administration of ketamine at 0.5–1 mg/kg has been shown to reduce intraoperative and postoperative analgesic requirements without increased side effects [25]. Preservative-free S(+)-ketamine administered during caudal block for children at a dose of 0.5 mg/kg has been shown to extend analgesia time by several hours [17].

The risk of psychomimetic adverse effects such as hallucinations is a worrying factor for most anesthetists, limiting its use, but it can be easily overcome by using

Midazolam, a water-soluble benzodiazepine, an indirect agonist of the gammaaminobutyric acid (GABA) receptor, has been studied primarily as an adjuvant for neuraxial anesthesia. Addition of preservative-free midazolam to 0.5% hyperbaric bupivacaine for subarachnoid block in infraumbilical surgery has been found to prolong the duration of effective analgesia as compared to the same concentration of bupivacaine alone and delays the need for postoperative rescue analgesics

**7. Nonsteroidal anti-inflammatory drugs (NSAIDs)**

to be conducted to verify the use of NSAIDs as adjuvants.

Intrathecal administration of ketamine is not recommended.

intravenous benzodiazepines as premedication prior to the block.

**64**

Neostigmine is an acetylcholinesterase inhibitor that can enhance analgesia by acting on muscarinic receptors and increasing endogenous acetylcholine at the nerve terminal. It produces spinal analgesia in the preclinical models. Intrathecal neostigmine produces analgesia by the inhibition of (endogenous spinal neurotransmitter) acetylcholine destruction via muscarinic and cholinergic receptors located at dorsal horn of spinal cord, substantia gelatinosa, and in lesser amounts at laminae III and V [50]. There is a high incidence of nausea and vomiting and prolongation of recovery from spinal anesthesia following intrathecal administration of neostigmine, implying that it may not be a useful additive for ambulatory spinal anesthesia. The dose of intrathecal neostigmine ranges from 10 to 50 μg with the side effects increasing as the dose rises.

#### **8.4 Magnesium sulfate**

Magnesium is an N-methyl-D-aspartate (NMDA) antagonist that plays a role in moderating calcium influx into neurons. Research has demonstrated that magnesium decreases peripheral nerve excitability and enhances the ability of lidocaine to raise the excitation threshold of A-beta fibers.

Intrathecal and epidural use of magnesium has shown variable results. It may prolong LA/opioid block in women in labor at a dose of 50 mg, but a very high dose of magnesium has been reported to produce transient neurological toxicity [17]. Farzanegan et al. compared the combination of bupivacaine 12.5 mg and morphine 2 mg versus bupivacaine 12.5 mg and morphine 2 mg and magnesium 50 mg versus placebo epidurally for postoperative analgesia after thoracotomy. These authors achieved better analgesia and lower consumption of postoperative morphine significantly in the magnesium group [51]. In preeclamptic parturients doses of 50 mg of intrathecal magnesium with epidural ropivacaine significantly prolonged postoperative analgesia compared with 1 mg intrathecal midazolam without any complications [52]. In a recent meta-analysis, 11 studies showed that the use of epidural magnesium as an adjuvant to bupivacaine is still controversial. Although epidural magnesium prolonged the time of the first rescue analgesic and reduced the number of patients who required rescue analgesics, as well as the requirement of these analgesics, further studies are needed to assess their usefulness [53].

#### **8.5 Sodium bicarbonate**

Local anesthetic agents are usually packed at low pH to enhance their shelf life. In anesthetic practice, there has been considerable interest in studying the effect of pH on the onset, duration, and potency of blockade of LAs. It is proven that alkalinization of the LA improves the quality of block by influencing the portioning coefficient of anesthetic between aqueous solution and biological membranes [20]. Adding sodium bicarbonate to lidocaine decreases the latency of onset and enhances the depth of epidural blockade by increasing the concentration of non-ionized drug. The alkaline pH increases the extraneural amount of nonionized LA, which is the form that diffuses through the lipid phase of the neural membrane leading to more rapid diffusion across perineural tissue barriers [54]. CO2 produced by the addition of bicarbonate and bicarbonate per se reduces the margin of conduction safety of the neural membrane. Moreover, CO2 penetrates into the nerve, where it may determine trapping of the active cationic form of LA by acidifying the axoplasm [55].

*Adjuvant Drugs to Local Anesthetics*

**9. Conclusion**

opioid analgesics.

**Conflict of interests**

**67**

**Author details**

provided the original work is properly cited.

Nandita Mehta\* and Sayyidah Aasima tu Nisa Qazi

\*Address all correspondence to: drnanditamehta@gmail.com

tions that may limit their use and require further investigation.

The authors declare no conflict of interest.

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

Department of Anaesthesia and Critical Care, ASCOMS Jammu, J&K, India

*DOI: http://dx.doi.org/10.5772/intechopen.91980*

Locoregional anesthesia is increasingly used as it has demonstrated efficacy, safety, and low costs. Patients and surgeons have realized its enormous advantages. Although the use of LA in the management of locoregional anesthesia, postoperative pain, and chronic pain is limited by its duration of action and dose-dependent adverse effects that mainly affect the cardiovascular and CNS systems, this has been improved with the use of various LA adjuvant drugs. Adjuvants are medications that work synergistically with LAs to improve the onset, duration, and quality of anesthesia-analgesia in regional techniques, as well as greatly reducing the use of

The arsenal of adjuvants has developed from adrenaline, opioids, to a large group of non-opioid medications with various mechanisms of action. Opioids are the most commonly used adjuvants and range from morphine, fentanyl, and sufentanil to hydromorphone, buprenorphine, and tramadol with very different results. Its use has been limited by its adverse effects such as respiratory depression, nausea, vomiting, and pruritus, especially with its neuraxial use. Other adjuvants include alpha-2 agonists such as clonidine and dexmedetomidine, midazolam, NMDA antagonists including ketamine and magnesium, neostigmine, sodium bicarbonate, and nonsteroidal anti-inflammatory drugs. Concern regarding the safety profile of these adjuvants is due to their potential neurotoxicity and neurological complica-

#### **8.6 Potassium chloride**

Movements of ions through the nerve membrane are considered one of the main steps in the process of excitation and propagation of nerve stimuli. A nerve impulse can be effectively blocked by accumulation of potassium ions outside the neuron [56]. Thus, administration of exogenous potassium chloride will reinforce and prolong the blockade produced by LA. The addition of potassium chloride to LA increases the extracellular concentration and depolarizes the nerve membrane and thus blocks the conduction of nerve impulses. Potassium chloride up to 4 mmol/l to isotonic solutions of lidocaine enhances the clinical effectiveness of the combination [57]. The addition of physiological amounts of potassium chloride shortens the latency period and prolongs the duration of the blockade.

#### **8.7 Adenosine**

Adenosine receptors are expressed on the surface of most cells. Five classes of adenosine receptors have been identified. The A1 and A2 receptors are present centrally and peripherally, with agonism of the A1 receptor leading to antinociceptive response and that of the A2 receptor being algogenic (i.e., activation results in pain). The diagnostic and therapeutic role for intrathecal adenosine in acute and chronic pain states is under investigation by several research groups. Intrathecal adenosine decreases the spontaneous and evoked pain intensity in patients with neuropathic pain involving hyperalgesia/dysesthesia/allodynia [58]. Its interaction along with spinal LA is just beginning to be studied.

#### **8.8 Dextran**

Low molecular weight dextran (LMWD) was used as an adjuvant with LA as early as in the 1970s, but the efficacy of dextrans including LMWD remained controversial, as several studies reported an absence of any substantial difference in analgesic duration with their addition. That might have been due to poor techniques of regional anesthesia. The use of USG regional blocks has rekindled the use of LMWD as adjuvant. The addition of LMWD to a LA and epinephrine mixture when used as an infiltration anesthesia [59], or to a LA alone when performing a regional block [33], safely prolongs the effective action by reducing systemic absorption. More studies need to be conducted to elicit the exact mechanism and dosing ranges.

A word of caution regarding the use of additives in LAs is that only preparations without preservatives should be used, since these can be neurotoxic. Also, only adjuvants in clinically safe doses should be used in order to avoid getting the side effects due to excessive dosages.

Hence further research is required to find the exact mechanism of action and the safe dose of various adjuvants in order to avoid cardiovascular and neurological complications. The practice of making off-label use of drugs without getting FDA approval should be discouraged.

### **9. Conclusion**

*Topics in Local Anesthetics*

acidifying the axoplasm [55].

**8.6 Potassium chloride**

**8.7 Adenosine**

**8.8 Dextran**

dosing ranges.

effects due to excessive dosages.

approval should be discouraged.

of non-ionized drug. The alkaline pH increases the extraneural amount of nonionized LA, which is the form that diffuses through the lipid phase of the neural membrane leading to more rapid diffusion across perineural tissue barriers [54]. CO2 produced by the addition of bicarbonate and bicarbonate per se reduces the margin of conduction safety of the neural membrane. Moreover, CO2 penetrates into the nerve, where it may determine trapping of the active cationic form of LA by

Movements of ions through the nerve membrane are considered one of the main steps in the process of excitation and propagation of nerve stimuli. A nerve impulse can be effectively blocked by accumulation of potassium ions outside the neuron [56]. Thus, administration of exogenous potassium chloride will reinforce and prolong the blockade produced by LA. The addition of potassium chloride to LA increases the extracellular concentration and depolarizes the nerve membrane and thus blocks the conduction of nerve impulses. Potassium chloride up to 4 mmol/l to isotonic solutions of lidocaine enhances the clinical effectiveness of the combination [57]. The addition of physiological amounts of potassium chloride shortens the

Adenosine receptors are expressed on the surface of most cells. Five classes of adenosine receptors have been identified. The A1 and A2 receptors are present centrally and peripherally, with agonism of the A1 receptor leading to antinociceptive response and that of the A2 receptor being algogenic (i.e., activation results in pain). The diagnostic and therapeutic role for intrathecal adenosine in acute and chronic pain states is under investigation by several research groups. Intrathecal adenosine decreases the spontaneous and evoked pain intensity in patients with neuropathic pain involving hyperalgesia/dysesthesia/allodynia [58]. Its interaction

Low molecular weight dextran (LMWD) was used as an adjuvant with LA as early as in the 1970s, but the efficacy of dextrans including LMWD remained controversial, as several studies reported an absence of any substantial difference in analgesic duration with their addition. That might have been due to poor techniques of regional anesthesia. The use of USG regional blocks has rekindled the use of LMWD as adjuvant. The addition of LMWD to a LA and epinephrine mixture when used as an infiltration anesthesia [59], or to a LA alone when performing a regional block [33], safely prolongs the effective action by reducing systemic absorption. More studies need to be conducted to elicit the exact mechanism and

A word of caution regarding the use of additives in LAs is that only preparations

Hence further research is required to find the exact mechanism of action and the safe dose of various adjuvants in order to avoid cardiovascular and neurological complications. The practice of making off-label use of drugs without getting FDA

without preservatives should be used, since these can be neurotoxic. Also, only adjuvants in clinically safe doses should be used in order to avoid getting the side

latency period and prolongs the duration of the blockade.

along with spinal LA is just beginning to be studied.

**66**

Locoregional anesthesia is increasingly used as it has demonstrated efficacy, safety, and low costs. Patients and surgeons have realized its enormous advantages. Although the use of LA in the management of locoregional anesthesia, postoperative pain, and chronic pain is limited by its duration of action and dose-dependent adverse effects that mainly affect the cardiovascular and CNS systems, this has been improved with the use of various LA adjuvant drugs. Adjuvants are medications that work synergistically with LAs to improve the onset, duration, and quality of anesthesia-analgesia in regional techniques, as well as greatly reducing the use of opioid analgesics.

The arsenal of adjuvants has developed from adrenaline, opioids, to a large group of non-opioid medications with various mechanisms of action. Opioids are the most commonly used adjuvants and range from morphine, fentanyl, and sufentanil to hydromorphone, buprenorphine, and tramadol with very different results. Its use has been limited by its adverse effects such as respiratory depression, nausea, vomiting, and pruritus, especially with its neuraxial use. Other adjuvants include alpha-2 agonists such as clonidine and dexmedetomidine, midazolam, NMDA antagonists including ketamine and magnesium, neostigmine, sodium bicarbonate, and nonsteroidal anti-inflammatory drugs. Concern regarding the safety profile of these adjuvants is due to their potential neurotoxicity and neurological complications that may limit their use and require further investigation.

#### **Conflict of interests**

The authors declare no conflict of interest.

### **Author details**

Nandita Mehta\* and Sayyidah Aasima tu Nisa Qazi Department of Anaesthesia and Critical Care, ASCOMS Jammu, J&K, India

\*Address all correspondence to: drnanditamehta@gmail.com

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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dexmedetomidine with buprenorphine as adjuvant to bupivacaine in spinal anaesthesia. Journal of Clinical and Diagnostic Research. 2014;**8**(2):114-117. DOI: 10.7860/JCDR/2014/7883.4023

[34] El-Hennawy AM, Abd-Elwahab AM, Abd-Elmaksoud AM, El-Ozairy HS, Boulis SR. Addition of clonidine or dexmedetomidine to bupivacaine prolongs caudal analgesia in children. British Journal of Anaesthesia.

2009;**103**(2):268-274. DOI: 10.1093/bja/

intramuscular clonidine. Wiadomości

[36] Rhee K, Kang K, Kim J, Jeon Y. Intravenous clonidine prolongs bupivacaine spinal anesthesia. Acta Anaesthesiologica Scandinavica. 2003;**47**:1001-1005. DOI:

10.1034/j.1399-6576.2003.00158.x

[38] Reddy VS, Shaik NA, Donthu B, Reddy Sannala VK, Jangam V.

Intravenous dexmedetomidine versus

clonidine for prolongation of bupivacaine spinal anesthesia and analgesia: A randomized double-blind study. Journal of Anaesthesiology

[37] Whizar-Lugo V, Gómez-Ramírez IA, Cisneros-Corral R, Martínez-Gallegos N. Intravenous dexmedetomidine vs. intravenous clonidine to prolong bupivacaine spinal anesthesia. A double blind study. Anest

Mex. 2007;**19**:143-146

[35] Dziubdziela W, Jałowiecki P, Kawecki P. Prolongation of bupivacaine

spinal anaesthesia by oral and

Lekarskie. 2003;**56**:520-526

1996;**83**:1046-1050

aep159

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acute spinal cord injury. Journal of Neurotrauma. 1998;**15**(12):1005-1013

[46] Liu X, Zhao X, Lou J, Wang Y, Shen X. Parecoxib added to ropivacaine prolongs duration of axillary brachial plexus blockade and relieves postoperative pain. Clinical Orthopaedics and Related Research. 2013;**471**(2):562-568

[47] Reboso Morales JA, González MF. Ketamina. Revista Española de Anestesiología y Reanimación. 1999;**46**(3):111-122

[48] Tawfic QA. A review of the use of ketamine in pain management. Journal of Opioid Management. 2013;**9**(5): 379-388. DOI: 10.5055/jom.2013.0180

[49] Shadangi BK, Garg R, Pandey R, Das T. Effects of intrathecal midazolam in spinal anaesthesia: A prospective randomised case control study. Singapore Medical Journal. 2011;**52**(6):432

[50] Lauretti GR, Lima IC. The effects of intrathecal neostigmine on somatic and visceral pain: İmprovement by association with a peripheral anticholinergic. Anesthesia and Analgesia. 1996;**82**(3):617-620

[51] Farzanegan B, Zangi M, Saeedi K, Khalili A, Rajabi M, et al. Effect of adding magnesium sulphate to epidural bupivacaine and morphine on postthoracotomy pain management: A randomized, double-blind, clinical trial. Basic & Clinical Pharmacology & Toxicology. 2018;**123**(5):602-606. DOI: 10.1111/bcpt.13047

[52] Paleti S, Prasad PK, Lakshmi BS. A randomized clinical trial of intrathecal magnesium sulfate versus midazolam with epidural administration of 0.75% ropivacaine for patients with preeclampsia scheduled for elective cesarean section. Journal of Anaesthesiology Clinical Pharmacology. 2018;**34**(1):23-28. DOI: 10.4103/joacp. JOACP\_74\_17

[53] Li LQ, Fang MD, Wang C, Lu HL, Wang LX, Xu HY, et al. Comparative evaluation of epidural bupivacaine alone and bupivacaine combined with magnesium sulfate in providing postoperative analgesia: A meta-analysis of randomized controlled trials. BMC Anesthesiology. 2020;**20**(1):39. DOI: 10.1186/s12871-020-0947-8

[54] Strobel GE, Bianchi CB. The effects of pH gradients on the action of procaine and lidocaine in intact and desheathed sciatic nerves. The Journal of Pharmacology and Experimental Therapeutics. 1970;**172**:1-17

[55] Wong K, Strichartz GR, Raymond SA. On the mechanisms of potentiation of local anesthetics by bicarbonate buffer: Drug structureactivity studies on isolated peripheral nerve. Anesthesia and Analgesia. 1993;**76**:131-143

[56] Aldrete JA, Barnes DR, Sidon MA, et al. Studies on effects of potassium chloride to lidocaine. Anesthesia & Analgesia. 1969;**48**(2):269-276

[57] Kircha S, Barsa J, Fink BR. Potentiation of nerve block in vivo by physiological adjuvants in the solution. British Journal of Anaesthesia. 1983;**55**(6):549-553

[58] Belfrage M, Segerdahl M, Arner S, Sollevi A. The safety and efficacy of intrathecal adenosine in patients with chronic neuropathic pain. Anesthesia and Analgesia. 1999;**89**:136-142

[59] Ueda W, Hirakawa M, Mori K. Inhibition of epinephrine absorption by dextran. Anesthesiology. 1985;**62**:72-75

**73**

**1. Introduction**

**Chapter 5**

**Abstract**

Anesthesia

Current Local Anesthetic

Applications in Regional

Complete anesthesia is often described using terminology that pertains to the pharmacodynamic effects of the medications administered. This vocabulary often includes akinesia, analgesia, amnesia and hypnosis. Local anesthesia is more specific and represents the administration of an amide or ester local anesthetic, to affect analgesia, at or around the site of administration. Anesthesiologists employ a breadth of different clinical techniques that utilize local anesthetic medications. These techniques include topical, mucosal, endotracheal, intravenous, peripheral nerve block, epidural, and intrathecal (spinal) administration. Unique to the fields of anesthesiology and pain medicine, however, is the administration of epidural and intrathecal local anesthetic. Together, these routes are jointly referred to as neuraxial anesthesia and are often utilized to facilitate surgical intervention, labor analgesia, or pain therapy. The history of neuraxial local anesthetic administration is rich and intriguing. The anatomy of the spinal cord and surrounding structures is complex and pertinent to the pharmacologic discussion of neuraxial local anesthetic administration. The pharmacodynamic and pharmacokinetic interactions of local anesthetics, when administered via the neuraxial route, are unique and worthy of continued investigation. Much has been studied, but there is still more to be discovered.

*Jeffrey M. Carness and Mark J. Lenart*

These topics will be the focus of our discussion.

**Keywords:** anesthetics, local, anesthesia, conduction, pharmacology,

anesthesia, epidural, ropivacaine, bupivacaine, lidocaine, chloroprocaine

administration and dosage pharmacokinetics, drug-related side effects and adverse reactions, injections, spinal, injections, epidural, epidural space, analgesia, epidural,

Anesthesia is often described using terminology that references the pharmacodynamic effects of a medication. This terminology often includes akinesia (loss or impairment of voluntary movement), analgesia (insensibility to pain), amnesia (loss of memory) and hypnosis (any of various conditions that resemble sleep). Local anesthesia is more specific and represents the administration of a medication, typically an amide or ester local anesthetic, to affect analgesia, and possibly akinesia, at or around the site of administration. Anesthesiologists employ a breadth of different clinical techniques that utilize local anesthetic medications. These techniques include topical, mucosal, endotracheal, intravenous, peripheral

#### **Chapter 5**

## Current Local Anesthetic Applications in Regional Anesthesia

*Jeffrey M. Carness and Mark J. Lenart*

#### **Abstract**

Complete anesthesia is often described using terminology that pertains to the pharmacodynamic effects of the medications administered. This vocabulary often includes akinesia, analgesia, amnesia and hypnosis. Local anesthesia is more specific and represents the administration of an amide or ester local anesthetic, to affect analgesia, at or around the site of administration. Anesthesiologists employ a breadth of different clinical techniques that utilize local anesthetic medications. These techniques include topical, mucosal, endotracheal, intravenous, peripheral nerve block, epidural, and intrathecal (spinal) administration. Unique to the fields of anesthesiology and pain medicine, however, is the administration of epidural and intrathecal local anesthetic. Together, these routes are jointly referred to as neuraxial anesthesia and are often utilized to facilitate surgical intervention, labor analgesia, or pain therapy. The history of neuraxial local anesthetic administration is rich and intriguing. The anatomy of the spinal cord and surrounding structures is complex and pertinent to the pharmacologic discussion of neuraxial local anesthetic administration. The pharmacodynamic and pharmacokinetic interactions of local anesthetics, when administered via the neuraxial route, are unique and worthy of continued investigation. Much has been studied, but there is still more to be discovered. These topics will be the focus of our discussion.

**Keywords:** anesthetics, local, anesthesia, conduction, pharmacology, administration and dosage pharmacokinetics, drug-related side effects and adverse reactions, injections, spinal, injections, epidural, epidural space, analgesia, epidural, anesthesia, epidural, ropivacaine, bupivacaine, lidocaine, chloroprocaine

#### **1. Introduction**

Anesthesia is often described using terminology that references the pharmacodynamic effects of a medication. This terminology often includes akinesia (loss or impairment of voluntary movement), analgesia (insensibility to pain), amnesia (loss of memory) and hypnosis (any of various conditions that resemble sleep). Local anesthesia is more specific and represents the administration of a medication, typically an amide or ester local anesthetic, to affect analgesia, and possibly akinesia, at or around the site of administration. Anesthesiologists employ a breadth of different clinical techniques that utilize local anesthetic medications. These techniques include topical, mucosal, endotracheal, intravenous, peripheral

nerve block, epidural, and intrathecal (spinal) administration. Unique to the fields of anesthesiology and pain medicine, however, is the administration of local anesthetics via the epidural and intrathecal routes. Together, these routes are jointly referred to as neuraxial anesthesia and are often utilized to facilitate surgical intervention, labor analgesia, or pain therapy. Much has been studied, but there is still more to be discovered. These topics will be the focus of our discussion.

### **2. Neuraxial anesthesia**

#### **2.1 Basic anatomy**

To understand the pharmacokinetic, pharmacodynamic, and pharmacotherapeutic activity of local anesthetics in this region, one needs a thorough understanding of neuraxial anatomy. The term neuraxis refers to the axial unpaired portion of the central nervous system. Of great importance to the discussion of neuraxial anesthesia is the spinal cord, nerve roots, and the meninges and vertebral bodies that house and protect them.

#### *2.1.1 Membranes*

The spinal cord is surrounded by three protective membranes which delineate potential and actual neuraxial spaces. Listed from outermost to innermost, these membranes are termed meninges and refer to the dura mater, the arachnoid mater and the pia mater. The pia mater directly envelops the spinal cord (**Figure 1**). Epidural refers to the potential space between the ligamentum flavum and the outer surface of the dura mater. Subdural refers to a potential space between the dura mater and the arachnoid mater. The term intrathecal refers to the thecal sac or the dura mater enclosure of the cerebrospinal fluid-filled sub-arachnoid (i.e., subarachnoid mater) space. This space remains outside of the pia mater. These spaces are surrounded by the bony architecture created by the vertebrae.

**75**

**Figure 2.**

*Current Local Anesthetic Applications in Regional Anesthesia*

The vertebral column protects the spinal cord and provides support for standing and walking. The vertebral column is easily recognized by its three curvatures (cervical lordosis, thoracic kyphosis, and lumbar lordosis) and five sections, to include the cervical, thoracic, lumbar, sacral and coccygeal regions. Each region consists of seven, twelve, five, five, and four vertebrae respectively for a total of 33. Each vertebra consists of two components: a vertebral body and the remaining vertebral arch. The vertebral arch is composed of several components to include laminae, pedicles, spinous, and transverse processes (**Figure 2**). Access to the epidural and intrathecal space for neuraxial local anesthetic administration is obtained via the spaces between each vertebra. Variation in bony structure between lumbar, thoracic, and cervical vertebrae will dictate the approach to these specific regions (e.g., the greater downward angle of the thoracic spinous processes necessitates a steeper midline approach). Between each of the vertebra are several ligaments that are also typically traversed when administering neuraxial local anesthetics. From superficial to deep are the supraspinous ligament, interspinous ligament, and the ligamentum flavum (named for its yellow pigmentation). The interspinous ligament is affixed to the inferior and superior aspect of the spinous processes. The supraspinous ligament attaches to the tips of the vertebral spinous processes (**Figure 3**) and runs

The epidural space contains several anatomic structures and tissues to include vasculature, nerve roots, and adipose tissue. The internal vertebral venous plexus, also known as the epidural venous plexus, assists with vertebral venous drainage and serves as an alternate conduit for venous return in the setting of compromised caval blood flow. The plexus consists of two larger anterior longitudinal veins, located in the anterior aspect of the spinal canal, and two smaller posterior longitudinal veins. These veins are connected by transverse veins, completing the plexus. The longitudinal veins are located more posteriorly at the level of the cervical and lumbar vertebrae, and more posterolaterally at the level of the thorax [1]. The plexus is surrounded by epidural adipose tissue. Combined with reported

*Human vertebral column and vertebrae. The human vertebral column consists of 33 vertebrae.*

*DOI: http://dx.doi.org/10.5772/intechopen.88528*

from the level of C7 to the sacrum.

*2.1.3 Vasculature/adipose tissue*

*2.1.2 Bones and ligaments*

**Figure 1.** *Meninges—protective membranes of the spinal cord.*

#### *2.1.2 Bones and ligaments*

*Topics in Local Anesthetics*

**2. Neuraxial anesthesia**

that house and protect them.

**2.1 Basic anatomy**

*2.1.1 Membranes*

discussion.

nerve block, epidural, and intrathecal (spinal) administration. Unique to the fields of anesthesiology and pain medicine, however, is the administration of local anesthetics via the epidural and intrathecal routes. Together, these routes are jointly referred to as neuraxial anesthesia and are often utilized to facilitate surgical intervention, labor analgesia, or pain therapy. Much has been studied, but there is still more to be discovered. These topics will be the focus of our

To understand the pharmacokinetic, pharmacodynamic, and pharmacotherapeutic activity of local anesthetics in this region, one needs a thorough understanding of neuraxial anatomy. The term neuraxis refers to the axial unpaired portion of the central nervous system. Of great importance to the discussion of neuraxial anesthesia is the spinal cord, nerve roots, and the meninges and vertebral bodies

The spinal cord is surrounded by three protective membranes which delineate potential and actual neuraxial spaces. Listed from outermost to innermost, these membranes are termed meninges and refer to the dura mater, the arachnoid mater and the pia mater. The pia mater directly envelops the spinal cord (**Figure 1**). Epidural refers to the potential space between the ligamentum flavum and the outer surface of the dura mater. Subdural refers to a potential space between the dura mater and the arachnoid mater. The term intrathecal refers to the thecal sac or the dura mater enclosure of the cerebrospinal fluid-filled sub-arachnoid (i.e., subarachnoid mater) space. This space remains outside of the pia mater. These spaces

are surrounded by the bony architecture created by the vertebrae.

**74**

**Figure 1.**

*Meninges—protective membranes of the spinal cord.*

The vertebral column protects the spinal cord and provides support for standing and walking. The vertebral column is easily recognized by its three curvatures (cervical lordosis, thoracic kyphosis, and lumbar lordosis) and five sections, to include the cervical, thoracic, lumbar, sacral and coccygeal regions. Each region consists of seven, twelve, five, five, and four vertebrae respectively for a total of 33. Each vertebra consists of two components: a vertebral body and the remaining vertebral arch. The vertebral arch is composed of several components to include laminae, pedicles, spinous, and transverse processes (**Figure 2**). Access to the epidural and intrathecal space for neuraxial local anesthetic administration is obtained via the spaces between each vertebra. Variation in bony structure between lumbar, thoracic, and cervical vertebrae will dictate the approach to these specific regions (e.g., the greater downward angle of the thoracic spinous processes necessitates a steeper midline approach). Between each of the vertebra are several ligaments that are also typically traversed when administering neuraxial local anesthetics. From superficial to deep are the supraspinous ligament, interspinous ligament, and the ligamentum flavum (named for its yellow pigmentation). The interspinous ligament is affixed to the inferior and superior aspect of the spinous processes. The supraspinous ligament attaches to the tips of the vertebral spinous processes (**Figure 3**) and runs from the level of C7 to the sacrum.

#### *2.1.3 Vasculature/adipose tissue*

The epidural space contains several anatomic structures and tissues to include vasculature, nerve roots, and adipose tissue. The internal vertebral venous plexus, also known as the epidural venous plexus, assists with vertebral venous drainage and serves as an alternate conduit for venous return in the setting of compromised caval blood flow. The plexus consists of two larger anterior longitudinal veins, located in the anterior aspect of the spinal canal, and two smaller posterior longitudinal veins. These veins are connected by transverse veins, completing the plexus. The longitudinal veins are located more posteriorly at the level of the cervical and lumbar vertebrae, and more posterolaterally at the level of the thorax [1]. The plexus is surrounded by epidural adipose tissue. Combined with reported

#### **Figure 3.**

*Spinal ligaments—this file is licensed under the Creative Commons Public Domain Mark 1.0—https:// commons.wikimedia.org/wiki/File:Gray301.png.*

disruptions in the posterior fusions of the left and right ligamentum flavum, the adipose tissue and vasculature serve to provide variation in the construct of this potential space when expanded by local anesthetic.

#### **2.2 Intrathecal administration**

#### *2.2.1 History of spinal anesthesia*

Various local anesthetics have been investigated for surgical anesthesia (**Table 1**). These are divided into two primary categories of local anesthetics (i.e., esters and amides). Initial studies began with the investigation of the spinal effects of esters such as cocaine. This was followed by investigation of amylocaine (no longer utilized in clinical practice), procaine (also known as Novocain), dibucaine and tetracaine. Of note, amylocaine was first synthesized circa 1903 and is referenced as the first synthetic local anesthetic to be utilized in spinal anesthesia [2]. This was followed by the synthesis of procaine (circa 1904) with subsequent early twentieth-century investigation into its intrathecal administration. Procaine likely found greater clinical application as a result of the presumed systemic effects (to include physical dependence) and presumed neurotoxic effects of spinal cocaine administration [3]. Of note, however, is the side effect profile of procaine, which commonly includes nausea, vasomotor paralysis, and a greater risk for anaphylaxis associated with its metabolite para-aminobenzoic acid (PABA) [3, 4]. The period of 1930 through the early 1940s saw the discovery and intrathecal employment of longer acting local anesthetics (i.e., dibucaine and tetracaine). In 1930, Jones described his experiences with the administration of dibucaine (also known as cinchocaine or nupercaine) [5, 6]. With a shorter duration of action compared to dibucaine, a more favorable ratio of sensory to motor fiber blockade, less sympathetic blockade than procaine, and less perceived toxicity, initial studies into the administration of tetracaine showed significant promise [7, 8]. In 1945, lidocaine (originally called Xylocaine as it is a xylidine derivative) was initially administered as a spinal anesthetic. As a

**77**

**Table 1.**

*Local anesthetics for spinal anesthesia.*

tion of both levobupivacaine and ropivacaine continue.

*Current Local Anesthetic Applications in Regional Anesthesia*

short-acting amide local anesthetic, its pharmacologic profile was deemed ideal for short to moderate duration operative procedures [9]. Subsequently, in 1946, procaine was used to synthesize chloroprocaine. Initial reports for the use of chloroprocaine for spinal anesthesia were positive [10], and chloroprocaine was approved for spinal anesthesia by the United States Food and Drug Administration in 1955. With rapid ester hydrolysis neutralizing the effects of chloroprocaine, it became the local anesthetic of choice for the fastest onset and fastest resolution of spinal blockade. The rapid ester hydrolysis also created an environment in which almost twice the amount of chloroprocaine could be administered, compared to procaine, without toxicity. The improved safety profile also likely contributed to the popularity of this medication [10]. Despite investigations into other spinally administered local anesthetics, these three local anesthetics (i.e., chloroprocaine, lidocaine, and tetracaine) would find widespread use for short duration, moderate duration, and long duration operative procedures for the next half of a century. Shortly after the approval of chloroprocaine, mepivacaine (1956) [11] and prilocaine (1965) [12] would see their first usage in spinal anesthesia. These two medications, both xylidine derivatives as well, demonstrate similar potency when compared to lidocaine [9]. With subsequent studies demonstrating a risk for the development of transient neurologic symptoms associated with intrathecal lidocaine administration, it would seem that mepivacaine and prilocaine are currently undergoing further investigation and may serve as alternatives to lidocaine for ambulatory or surgical procedures of short to moderate duration [13–15]. The mid-1960s discovery, synthesis, and spinal administration of bupivacaine, an intermediate to long-acting amide local anesthetic, resulted in widespread popular clinical application [16, 17]. When evidence surfaced regarding the potential for racemic bupivacaine toxicity, two (S)-enantiomers of bupivacaine were researched and scrutinized for spinal anesthesia administration. Initial studies utilizing spinal ropivacaine (S-enantiomer of bupivacaine) were conducted in the early 1990s [18–20]. Additional studies regarding the other pure (S)-enantiomer of bupivacaine, levobupivacaine, were initiated in 1999 [21–23]. Intrathecal administra-

*DOI: http://dx.doi.org/10.5772/intechopen.88528*

*Current Local Anesthetic Applications in Regional Anesthesia DOI: http://dx.doi.org/10.5772/intechopen.88528*


#### **Table 1.**

*Topics in Local Anesthetics*

disruptions in the posterior fusions of the left and right ligamentum flavum, the adipose tissue and vasculature serve to provide variation in the construct of this

*Spinal ligaments—this file is licensed under the Creative Commons Public Domain Mark 1.0—https://*

Various local anesthetics have been investigated for surgical anesthesia (**Table 1**). These are divided into two primary categories of local anesthetics (i.e., esters and amides). Initial studies began with the investigation of the spinal effects of esters such as cocaine. This was followed by investigation of amylocaine (no longer utilized in clinical practice), procaine (also known as Novocain), dibucaine and tetracaine. Of note, amylocaine was first synthesized circa 1903 and is referenced as the first synthetic local anesthetic to be utilized in spinal anesthesia [2]. This was followed by the synthesis of procaine (circa 1904) with subsequent early twentieth-century investigation into its intrathecal administration. Procaine likely found greater clinical application as a result of the presumed systemic effects (to include physical dependence) and presumed neurotoxic effects of spinal cocaine administration [3]. Of note, however, is the side effect profile of procaine, which commonly includes nausea, vasomotor paralysis, and a greater risk for anaphylaxis associated with its metabolite para-aminobenzoic acid (PABA) [3, 4]. The period of 1930 through the early 1940s saw the discovery and intrathecal employment of longer acting local anesthetics (i.e., dibucaine and tetracaine). In 1930, Jones described his experiences with the administration of dibucaine (also known as cinchocaine or nupercaine) [5, 6]. With a shorter duration of action compared to dibucaine, a more favorable ratio of sensory to motor fiber blockade, less sympathetic blockade than procaine, and less perceived toxicity, initial studies into the administration of tetracaine showed significant promise [7, 8]. In 1945, lidocaine (originally called Xylocaine as it is a xylidine derivative) was initially administered as a spinal anesthetic. As a

potential space when expanded by local anesthetic.

**2.2 Intrathecal administration**

*commons.wikimedia.org/wiki/File:Gray301.png.*

**Figure 3.**

*2.2.1 History of spinal anesthesia*

**76**

*Local anesthetics for spinal anesthesia.*

short-acting amide local anesthetic, its pharmacologic profile was deemed ideal for short to moderate duration operative procedures [9]. Subsequently, in 1946, procaine was used to synthesize chloroprocaine. Initial reports for the use of chloroprocaine for spinal anesthesia were positive [10], and chloroprocaine was approved for spinal anesthesia by the United States Food and Drug Administration in 1955. With rapid ester hydrolysis neutralizing the effects of chloroprocaine, it became the local anesthetic of choice for the fastest onset and fastest resolution of spinal blockade. The rapid ester hydrolysis also created an environment in which almost twice the amount of chloroprocaine could be administered, compared to procaine, without toxicity. The improved safety profile also likely contributed to the popularity of this medication [10]. Despite investigations into other spinally administered local anesthetics, these three local anesthetics (i.e., chloroprocaine, lidocaine, and tetracaine) would find widespread use for short duration, moderate duration, and long duration operative procedures for the next half of a century. Shortly after the approval of chloroprocaine, mepivacaine (1956) [11] and prilocaine (1965) [12] would see their first usage in spinal anesthesia. These two medications, both xylidine derivatives as well, demonstrate similar potency when compared to lidocaine [9]. With subsequent studies demonstrating a risk for the development of transient neurologic symptoms associated with intrathecal lidocaine administration, it would seem that mepivacaine and prilocaine are currently undergoing further investigation and may serve as alternatives to lidocaine for ambulatory or surgical procedures of short to moderate duration [13–15]. The mid-1960s discovery, synthesis, and spinal administration of bupivacaine, an intermediate to long-acting amide local anesthetic, resulted in widespread popular clinical application [16, 17]. When evidence surfaced regarding the potential for racemic bupivacaine toxicity, two (S)-enantiomers of bupivacaine were researched and scrutinized for spinal anesthesia administration. Initial studies utilizing spinal ropivacaine (S-enantiomer of bupivacaine) were conducted in the early 1990s [18–20]. Additional studies regarding the other pure (S)-enantiomer of bupivacaine, levobupivacaine, were initiated in 1999 [21–23]. Intrathecal administration of both levobupivacaine and ropivacaine continue.

#### *2.2.2 Pharmacokinetics of intrathecal local anesthetic administration*

The exact mechanism and site of action of local anesthetics in the intrathecal space are not clear. Some evidence suggest that local anesthetics work to directly inhibit Na+ and K+ ion channel conduction at the peripheral dorsal nerve root and the spinal cord within the thecal sac [9, 24]. For this to occur, the local anesthetic must be absorbed by the neuron and bind to an intracellular site on the Na+ /K+ ion channels. This may only occur when the channels are seen in a conformation associated with depolarization. Thus, the activity of local anesthetics is referred to as "use-dependent" activity [25, 26]. Understandably, there are a minimum number of axonal Na+ /K+ channels which must depolarize to continue the propagation of the neuronal impulse. The term "conduction safety" has been utilized to refer to the overabundance of summation action potential necessary at the axonal regional level to facilitate continued propagation of this impulse. Due to the decreased conduction safety at the telodendron of the axon, as compared to the trunk, it is believed that the local anesthetic blockade has a greater effect in this region [27]. Recognizing the complexity of the neurophysiology of pain, this view of an isolated Na+ /K+ channel mechanism may be too simplistic [24]. Primary, secondary, and tertiary synaptic activity occurs as sensory input is transmitted from the peripheral nervous system to the central nervous system and ultimately to the primary sensory cortex of the brain. It is widely recognized that neuronal transmission relies on both excitatory and inhibitory post-synaptic potentials for inter-neuronal transmission. Liu et al. summarized the current understanding of the research, which considers a multitude of potential sites for the activity of spinally administered local anesthetics, to include neuronal transmission at the level of the dorsal and anterior horn of the spinal cord [9]. It has been postulated that there may be a role for calcium ion channel manipulation (low voltage and high voltage L-type calcium channels) in this region [28]. Furthermore, it has been proposed that local anesthetics administered in the intrathecal space may contribute to the inhibition of substance P activity at the level of the dorsal root ganglion and the dorsal horn of the spinal cord [29]. Local anesthetics may also contribute to γ-aminobutyric acid inhibitory potentiation resulting in the inhibition of sensory transmission [30].

Even more fascinating is the discussion and research regarding alteration in electrical "coding" by disruption or alteration in "after-potentials" or "after-oscillations." This begins with interruption in neuronal transmission by an incomplete local anesthetic neuronal blockade due to sub-blocking concentrations of local anesthetic. Inhibition of sequential firing, or the depolarization of specific neurons, or disruption of weighted telodendron discharge patterns on a single neuron may contribute to changes in temporal excitability patterns sufficient to disrupt sensory input [27].

The extent of clinical activity depends upon several pharmacokinetic factors which can modify the overall visible clinical effects of the local anesthetic. By report, there are over 25 different factors, some theoretical, which can affect the spread and distribution of local anesthetics within the neuraxis [31]. Patient characteristics include age, height, intra-abdominal pressure, patient position, CSF currents, and CSF volume. Local anesthetic characteristics include potency, dosage, baricity, lipid solubility, degree of protein binding, and the log of the acid dissociation constant (i.e., the pKa). These local anesthetic characteristics further determine the amount of local anesthetic absorption (neuronal, myelin, adipose, or vasculature) and will ultimately contribute to the observed clinical effect.

#### *2.2.2.1 Cerebrospinal fluid*

The intrathecal route of local anesthetic administration is unique in that it bypasses first pass metabolism by the liver and mechanically penetrates the blood-brain

**79**

*Current Local Anesthetic Applications in Regional Anesthesia*

barrier. This deposition into the cerebrospinal fluid generates unique pharmacokinetic considerations. As Greene et al. states, "Uptake of local anesthetic injected into the CSF determines which neuronal functions are affected, elimination from the CSF determines the duration, and distribution within the CSF determines the extent of

Cerebrospinal fluid is maintained within the ventricular system of the brain, to include the cisterns and the intracranial subarachnoid space, as well as the spinal subarachnoid space (i.e., the thecal sac). There is approximately 150 ml of cerebrospinal fluid in the healthy, adult patient. CSF is continuously produced by the choroid plexus, and absorbed via arachnoid villi, at a rate of ~20 ml/h with 400–600 ml of CSF generated daily [32]. Decreased CSF volume at the time of injection increases the concentration of local anesthetic in the administered region and influences the clinical effect. Conditions which increase intra-abdominal pressure, and redistribute CSF, will mimic CSF volume depletion (i.e., obesity, pregnancy, etc.), amplify CSF oscillation, and potentially modify the effects of the local anesthetic as well [33].

altered neuronal function" [31]. A discussion of CSF is therefore critical.

*2.2.2.2 Absorption, mechanism, onset and duration of action of spinal local* 

concentration gradient is established between the spinal cord, intrathecal

and lidocaine have been shown to increase spinal blood flow [35, 36].

hydrogen ion dissociation at equilibrium by the following equation:

Ka values are typically very small (i.e., 1 × 10<sup>−</sup><sup>3</sup>

Ka = \_ [B][H+]

manipulation more challenging. However, the inverse logarithmic value of the Ka can be utilized to express pKa. These pKa values represent the log of the Ka

BH+ (1)

), making comparison and

The uptake or absorption of local anesthetic into the vasculature also limits the distribution and clinical effects of spinal anesthesia. As vascular absorption is greatest in the epidural space, and the meninges are permeable to local anesthetic, a

space, and the epidural space [34]. While there is little intrathecal vascular absorption, some local anesthetic may penetrate the pia mater and be absorbed by vasculature in the spinal cord directly. It is also believed that a more efficient mechanism is vascular absorption via the increased surface area in the perivascular space (where blood vessels perforate the pia mater) [24, 34]. Of additional interest is consideration of the effects that local anesthetics have on spinal vasculature. Bupivacaine and ropivacaine have been shown to decrease spinal blood flow, whereas tetracaine

With regard to absorption, local anesthetic must be in an electrically neutral configuration (i.e., as an uncharged hydrophobic form of the medication) to penetrate neuronal tissue. This concept necessitates further discussion of acid dissociation. Becker and Reed provide a summary for reference [37]. In order to maintain stability in solution, local anesthetics are formulated as a hydrochloride salt creating a quaternary amine formulation that is electrically charged to enable water solubility (hydrophilic). The local anesthetic must, therefore, revert to the uncharged lipophilic (hydrophobic) tertiary amine form for neuronal penetration (i.e., the electrically neutral form). The more a local anesthetic dissociates and releases hydrogen ions at the body's physiologically neutral pH of 7.4, the more local anesthetic will remain in the tertiary form and the greater the neuronal absorption (**Figure 4**). Understanding the resting pH of the medication is useful, as is understanding hydrogen ion dissociation. The dissociation equilibrium between hydrogen ions and the deprotonated local anesthetic constitutes the equilibrium that determines the Ka (acid dissociation constant) of the drug. It is expressed as a ratio of

*DOI: http://dx.doi.org/10.5772/intechopen.88528*

*anesthetics*

#### *Current Local Anesthetic Applications in Regional Anesthesia DOI: http://dx.doi.org/10.5772/intechopen.88528*

*Topics in Local Anesthetics*

and K+

inhibit Na+

*2.2.2 Pharmacokinetics of intrathecal local anesthetic administration*

absorbed by the neuron and bind to an intracellular site on the Na+

physiology of pain, this view of an isolated Na+

The exact mechanism and site of action of local anesthetics in the intrathecal space are not clear. Some evidence suggest that local anesthetics work to directly

spinal cord within the thecal sac [9, 24]. For this to occur, the local anesthetic must be

channels which must depolarize to continue the propagation of the neuronal impulse. The term "conduction safety" has been utilized to refer to the overabundance of summation action potential necessary at the axonal regional level to facilitate continued propagation of this impulse. Due to the decreased conduction safety at the telodendron of the axon, as compared to the trunk, it is believed that the local anesthetic blockade has a greater effect in this region [27]. Recognizing the complexity of the neuro-

simplistic [24]. Primary, secondary, and tertiary synaptic activity occurs as sensory input is transmitted from the peripheral nervous system to the central nervous system and ultimately to the primary sensory cortex of the brain. It is widely recognized that neuronal transmission relies on both excitatory and inhibitory post-synaptic potentials for inter-neuronal transmission. Liu et al. summarized the current understanding of the research, which considers a multitude of potential sites for the activity of spinally administered local anesthetics, to include neuronal transmission at the level of the dorsal and anterior horn of the spinal cord [9]. It has been postulated that there may be a role for calcium ion channel manipulation (low voltage and high voltage L-type calcium channels) in this region [28]. Furthermore, it has been proposed that local anesthetics administered in the intrathecal space may contribute to the inhibition of substance P activity at the level of the dorsal root ganglion and the dorsal horn of the spinal cord [29]. Local anesthetics may also contribute to γ-aminobutyric acid inhibi-

tory potentiation resulting in the inhibition of sensory transmission [30].

vasculature) and will ultimately contribute to the observed clinical effect.

first pass metabolism by the liver and mechanically penetrates the blood-brain

The intrathecal route of local anesthetic administration is unique in that it bypasses

Even more fascinating is the discussion and research regarding alteration in electrical "coding" by disruption or alteration in "after-potentials" or "after-oscillations." This begins with interruption in neuronal transmission by an incomplete local anesthetic neuronal blockade due to sub-blocking concentrations of local anesthetic. Inhibition of sequential firing, or the depolarization of specific neurons, or disruption of weighted telodendron discharge patterns on a single neuron may contribute to changes in temporal excitability patterns sufficient to disrupt sensory input [27]. The extent of clinical activity depends upon several pharmacokinetic factors which can modify the overall visible clinical effects of the local anesthetic. By report, there are over 25 different factors, some theoretical, which can affect the spread and distribution of local anesthetics within the neuraxis [31]. Patient characteristics include age, height, intra-abdominal pressure, patient position, CSF currents, and CSF volume. Local anesthetic characteristics include potency, dosage, baricity, lipid solubility, degree of protein binding, and the log of the acid dissociation constant (i.e., the pKa). These local anesthetic characteristics further determine the amount of local anesthetic absorption (neuronal, myelin, adipose, or

/K+

This may only occur when the channels are seen in a conformation associated with depolarization. Thus, the activity of local anesthetics is referred to as "use-dependent"

activity [25, 26]. Understandably, there are a minimum number of axonal Na+

ion channel conduction at the peripheral dorsal nerve root and the

/K+

channel mechanism may be too

ion channels.

/K+

**78**

*2.2.2.1 Cerebrospinal fluid*

barrier. This deposition into the cerebrospinal fluid generates unique pharmacokinetic considerations. As Greene et al. states, "Uptake of local anesthetic injected into the CSF determines which neuronal functions are affected, elimination from the CSF determines the duration, and distribution within the CSF determines the extent of altered neuronal function" [31]. A discussion of CSF is therefore critical.

Cerebrospinal fluid is maintained within the ventricular system of the brain, to include the cisterns and the intracranial subarachnoid space, as well as the spinal subarachnoid space (i.e., the thecal sac). There is approximately 150 ml of cerebrospinal fluid in the healthy, adult patient. CSF is continuously produced by the choroid plexus, and absorbed via arachnoid villi, at a rate of ~20 ml/h with 400–600 ml of CSF generated daily [32]. Decreased CSF volume at the time of injection increases the concentration of local anesthetic in the administered region and influences the clinical effect. Conditions which increase intra-abdominal pressure, and redistribute CSF, will mimic CSF volume depletion (i.e., obesity, pregnancy, etc.), amplify CSF oscillation, and potentially modify the effects of the local anesthetic as well [33].

#### *2.2.2.2 Absorption, mechanism, onset and duration of action of spinal local anesthetics*

The uptake or absorption of local anesthetic into the vasculature also limits the distribution and clinical effects of spinal anesthesia. As vascular absorption is greatest in the epidural space, and the meninges are permeable to local anesthetic, a concentration gradient is established between the spinal cord, intrathecal space, and the epidural space [34]. While there is little intrathecal vascular absorption, some local anesthetic may penetrate the pia mater and be absorbed by vasculature in the spinal cord directly. It is also believed that a more efficient mechanism is vascular absorption via the increased surface area in the perivascular space (where blood vessels perforate the pia mater) [24, 34]. Of additional interest is consideration of the effects that local anesthetics have on spinal vasculature. Bupivacaine and ropivacaine have been shown to decrease spinal blood flow, whereas tetracaine and lidocaine have been shown to increase spinal blood flow [35, 36].

With regard to absorption, local anesthetic must be in an electrically neutral configuration (i.e., as an uncharged hydrophobic form of the medication) to penetrate neuronal tissue. This concept necessitates further discussion of acid dissociation. Becker and Reed provide a summary for reference [37]. In order to maintain stability in solution, local anesthetics are formulated as a hydrochloride salt creating a quaternary amine formulation that is electrically charged to enable water solubility (hydrophilic). The local anesthetic must, therefore, revert to the uncharged lipophilic (hydrophobic) tertiary amine form for neuronal penetration (i.e., the electrically neutral form). The more a local anesthetic dissociates and releases hydrogen ions at the body's physiologically neutral pH of 7.4, the more local anesthetic will remain in the tertiary form and the greater the neuronal absorption (**Figure 4**). Understanding the resting pH of the medication is useful, as is understanding hydrogen ion dissociation. The dissociation equilibrium between hydrogen ions and the deprotonated local anesthetic constitutes the equilibrium that determines the Ka (acid dissociation constant) of the drug. It is expressed as a ratio of hydrogen ion dissociation at equilibrium by the following equation: Ka = \_

$$\mathbf{K\_a = \frac{\{\mathbf{B\}}{\cdot}\{\mathbf{H}\mathbf{+}\}}{\mathbf{B\mathbf{H}}\mathbf{+}}} \tag{1}$$

Ka values are typically very small (i.e., 1 × 10<sup>−</sup><sup>3</sup> ), making comparison and manipulation more challenging. However, the inverse logarithmic value of the Ka can be utilized to express pKa. These pKa values represent the log of the Ka

#### **Figure 4.**

*Mechanism of action of local anesthetics—this file is licensed under the Creative Commons Attribution-Share Alike 3.0 Unported license. https://commons.wikimedia.org/wiki/File:LA\_andNaV.svg.*

(acid dissociation constant), or the pH at which 50% of the drug is in the protonated electrically charged hydrophilic quaternary amine form, and 50% is in the uncharged, lipophilic tertiary amine form. Values range from 7.6 ➔ ~9.0, meaning that no local anesthetics reach complete equilibrium within the body's normal pH range of 7.35–7.45. The pKa values for mepivacaine (~7.6), prilocaine (~7.9) and lidocaine (~7.9) most closely approximate physiologic pH, suggesting that their neuronal absorption occurs more quickly, leading to faster onset of clinical symptoms. The pKa values of bupivacaine (~8.1) and ropivacaine (~8.1) have a somewhat slower onset of clinical effect [37].

In addition to neuronal and vascular absorption, the lipid absorption of a local anesthetic also plays a role in the time of onset—the greater the lipid solubility, the faster the myelin/neuronal penetration. As reported by Becker and Reed, however, this appears only to be true in vitro. They hypothesize that the higher lipid solubility "may impede dispersion throughout tissue fluids." When applied in vivo, the lipid solubility appears to promote adipose tissue absorption over neuronal absorption leading to a delayed onset of clinical effect [37]. This helps to explain the clinically observed pharmacologic effects of long-acting local anesthetics (i.e., bupivacaine/ ropivacaine/tetracaine) versus shorter-acting local anesthetics such as lidocaine and mepivacaine. Lidocaine and mepivacaine have a much faster onset of action compared to bupivacaine and ropivacaine when administered intrathecally (despite the increased lipid solubility of bupivacaine/ropivacaine).

The pharmacokinetic variable that appears to have the greatest influence on the duration of action is the degree of intrathecal protein binding. Clement et al. demonstrated that the non-protein bound or unbound fraction of intrathecal bupivacaine is lower than lidocaine. Because bupivacaine has a higher degree of protein binding, it has a longer observed clinical effect [38].

#### *2.2.3 Pharmacodynamics of intrathecal local anesthetic administration*

The nature of the surgical procedure, or site of pain origination, will dictate pursuit of a specific distribution of anesthesia. The distributed effect of intrathecal local anesthetic administration is often measured via perceived differences in sensation of temperature or sharp tactile stimulation. Each spinal nerve provides a specific anatomic distribution of sensation, or dermatome, which may be measured. In addition to the desired clinical sensory blockade, pharmacodynamic effects may be seen throughout several organ systems to include the cardiovascular, respiratory, gastrointestinal, renal, and immune systems.

**81**

*Current Local Anesthetic Applications in Regional Anesthesia*

Undoubtedly, the spinal administration of local anesthesia can result in hypotension. This is largely believed to be secondary to a sympathetic nervous system blockade in the region of the pre-ganglionic neuron prior to its synapse on the sympathetic chain ganglion. This blockade results in vascular dilation, which produces a decrease in systemic vascular resistance (SVR) (venous > arterial). This decrease in SVR, and the associated decrease in preload, may stimulate a reflexive baroreceptor response increasing the heart rate to maintain cardiac output. However, it has been well reported that patients may also experience a different type of cardiac reflex known as the Reverse Bainbridge (atrial), or Bezold-Jarisch reflex (ventricular). These reflexes stem from the recognition of a decreased preload to either the atria or ventricle, which results in reflexive bradycardia to slow the heart and allow for

Additionally, the distribution of local anesthetic can block cardiac accelerator fibers which stem from thoracic sympathetic ganglia T1-T4, further preventing the reflexive cardiac baroreceptor response. Due to the complexity of these interacting variables, changes to cardiac output with spinal anesthesia are also variable. Ultimately, spinal anesthesia often results in a decrease in mean arterial pressure (MAP), though this is not necessarily true for pre-eclamptic patients with non-sympathetically mediated elevations in blood pressure. When untreated, depressed cardiovascular effects may result in decreased cerebral perfusion, nausea/vomiting, and cardiovascular collapse.

In 1991, Steinbrook et al. investigated the effects of spinal lidocaine and bupivacaine on resting pulmonary function in eleven volunteers. They identified a slight decrease in end-tidal CO2 (34 mmHg ➔ 31 mmHg) with an inverse age correlation (i.e., younger patients had a greater drop in end-tidal CO2). They reported the absence of significant change in tidal volume, respiratory rate, and minute ventilation, hypothesizing instead an increase in dead space ventilation associated with spinal administration. They further comment on the paralysis of abdominal musculature leading to an increase in chest wall compliance and a decrease in mechanical work of breathing. It is interesting to note their comments regarding increased chest wall compliance and increased respiratory frequency variation [39]. Of note, they also allude to spinal level deafferentation of the chest wall receptors, but make no specific reference to intercostal involvement.

It is well recognized that the kidney receives direct sympathetic innervation from renal sympathetic nerve fibers derived from the sympathetic chain ganglia. In addition, the kidney auto-regulates its blood flow utilizing humoral/endocrine factors released as a result of changes sensed in the macula densa. It is believed that this mechanism functions both interdependently and independently from sympathetic function, enabling the preservation of renal blood flow in the absence of sympathetic directive. As described by Smith et al. [40], "It is possible to assume that the renal vascular bed acquires autonomy de novo only as a consequence of denervation, but in view of the rapidity and smoothness of anesthetic denervation any such assumption seems quite superfluous." It is now understood that there is little effect on overall renal function as a result of spinal or epidural sympathetic blockade from local anesthetic administration. Glomerular filtration and renal blood flow are recognized to only decrease slightly in direct relation to decreases in mean arterial

pressure associated with the sympathetic blockade [40–42].

increased filling time. This ultimately results in a lower cardiac output.

*DOI: http://dx.doi.org/10.5772/intechopen.88528*

*2.2.3.1 Cardiovascular*

*2.2.3.2 Respiratory*

*2.2.3.3 Renal*

#### *2.2.3.1 Cardiovascular*

*Topics in Local Anesthetics*

**Figure 4.**

slower onset of clinical effect [37].

the increased lipid solubility of bupivacaine/ropivacaine).

*2.2.3 Pharmacodynamics of intrathecal local anesthetic administration*

binding, it has a longer observed clinical effect [38].

gastrointestinal, renal, and immune systems.

(acid dissociation constant), or the pH at which 50% of the drug is in the protonated electrically charged hydrophilic quaternary amine form, and 50% is in the uncharged, lipophilic tertiary amine form. Values range from 7.6 ➔ ~9.0, meaning that no local anesthetics reach complete equilibrium within the body's normal pH range of 7.35–7.45. The pKa values for mepivacaine (~7.6), prilocaine (~7.9) and lidocaine (~7.9) most closely approximate physiologic pH, suggesting that their neuronal absorption occurs more quickly, leading to faster onset of clinical symptoms. The pKa values of bupivacaine (~8.1) and ropivacaine (~8.1) have a somewhat

*Alike 3.0 Unported license. https://commons.wikimedia.org/wiki/File:LA\_andNaV.svg.*

*Mechanism of action of local anesthetics—this file is licensed under the Creative Commons Attribution-Share* 

In addition to neuronal and vascular absorption, the lipid absorption of a local anesthetic also plays a role in the time of onset—the greater the lipid solubility, the faster the myelin/neuronal penetration. As reported by Becker and Reed, however, this appears only to be true in vitro. They hypothesize that the higher lipid solubility "may impede dispersion throughout tissue fluids." When applied in vivo, the lipid solubility appears to promote adipose tissue absorption over neuronal absorption leading to a delayed onset of clinical effect [37]. This helps to explain the clinically observed pharmacologic effects of long-acting local anesthetics (i.e., bupivacaine/ ropivacaine/tetracaine) versus shorter-acting local anesthetics such as lidocaine and mepivacaine. Lidocaine and mepivacaine have a much faster onset of action compared to bupivacaine and ropivacaine when administered intrathecally (despite

The pharmacokinetic variable that appears to have the greatest influence on the duration of action is the degree of intrathecal protein binding. Clement et al. demonstrated that the non-protein bound or unbound fraction of intrathecal bupivacaine is lower than lidocaine. Because bupivacaine has a higher degree of protein

The nature of the surgical procedure, or site of pain origination, will dictate pursuit of a specific distribution of anesthesia. The distributed effect of intrathecal local anesthetic administration is often measured via perceived differences in sensation of temperature or sharp tactile stimulation. Each spinal nerve provides a specific anatomic distribution of sensation, or dermatome, which may be measured. In addition to the desired clinical sensory blockade, pharmacodynamic effects may be seen throughout several organ systems to include the cardiovascular, respiratory,

**80**

Undoubtedly, the spinal administration of local anesthesia can result in hypotension. This is largely believed to be secondary to a sympathetic nervous system blockade in the region of the pre-ganglionic neuron prior to its synapse on the sympathetic chain ganglion. This blockade results in vascular dilation, which produces a decrease in systemic vascular resistance (SVR) (venous > arterial). This decrease in SVR, and the associated decrease in preload, may stimulate a reflexive baroreceptor response increasing the heart rate to maintain cardiac output. However, it has been well reported that patients may also experience a different type of cardiac reflex known as the Reverse Bainbridge (atrial), or Bezold-Jarisch reflex (ventricular). These reflexes stem from the recognition of a decreased preload to either the atria or ventricle, which results in reflexive bradycardia to slow the heart and allow for increased filling time. This ultimately results in a lower cardiac output.

Additionally, the distribution of local anesthetic can block cardiac accelerator fibers which stem from thoracic sympathetic ganglia T1-T4, further preventing the reflexive cardiac baroreceptor response. Due to the complexity of these interacting variables, changes to cardiac output with spinal anesthesia are also variable. Ultimately, spinal anesthesia often results in a decrease in mean arterial pressure (MAP), though this is not necessarily true for pre-eclamptic patients with non-sympathetically mediated elevations in blood pressure. When untreated, depressed cardiovascular effects may result in decreased cerebral perfusion, nausea/vomiting, and cardiovascular collapse.

#### *2.2.3.2 Respiratory*

In 1991, Steinbrook et al. investigated the effects of spinal lidocaine and bupivacaine on resting pulmonary function in eleven volunteers. They identified a slight decrease in end-tidal CO2 (34 mmHg ➔ 31 mmHg) with an inverse age correlation (i.e., younger patients had a greater drop in end-tidal CO2). They reported the absence of significant change in tidal volume, respiratory rate, and minute ventilation, hypothesizing instead an increase in dead space ventilation associated with spinal administration. They further comment on the paralysis of abdominal musculature leading to an increase in chest wall compliance and a decrease in mechanical work of breathing. It is interesting to note their comments regarding increased chest wall compliance and increased respiratory frequency variation [39]. Of note, they also allude to spinal level deafferentation of the chest wall receptors, but make no specific reference to intercostal involvement.

#### *2.2.3.3 Renal*

It is well recognized that the kidney receives direct sympathetic innervation from renal sympathetic nerve fibers derived from the sympathetic chain ganglia. In addition, the kidney auto-regulates its blood flow utilizing humoral/endocrine factors released as a result of changes sensed in the macula densa. It is believed that this mechanism functions both interdependently and independently from sympathetic function, enabling the preservation of renal blood flow in the absence of sympathetic directive. As described by Smith et al. [40], "It is possible to assume that the renal vascular bed acquires autonomy de novo only as a consequence of denervation, but in view of the rapidity and smoothness of anesthetic denervation any such assumption seems quite superfluous." It is now understood that there is little effect on overall renal function as a result of spinal or epidural sympathetic blockade from local anesthetic administration. Glomerular filtration and renal blood flow are recognized to only decrease slightly in direct relation to decreases in mean arterial pressure associated with the sympathetic blockade [40–42].

#### *2.2.3.4 Digestive*

Sympathetic nervous system blockade as a consequence of spinal local anesthetic administration leads to unimpeded parasympathetic nervous system activity and gastrointestinal hyperactivity. Hypotension encountered as a result of spinal local anesthesia may lead to gastrointestinal ischemia and the release of emetogenic substances such as serotonin. Furthermore, hypotension may lead to hypoperfusion of the area postrema of the medulla (brain stem—known chemoreceptor trigger zone for vomiting) resulting in increased serotonin release. The combination of these factors may contribute to intraoperative/postoperative nausea and vomiting. It is also important to recognize that hypotension associated with spinal local anesthetic administration may result in hypoperfusion of the liver. Because hepatic blood flow is not auto-regulated, this low perfusion pressure may result in impairment of metabolic functions to include subsequent drug metabolism [43].

#### *2.2.3.5 Immune*

Regarding the anti-inflammatory and immunomodulatory effects of local anesthetics, Cassuto et al. wrote that it is well recognized that the innate and adaptive immune systems contribute to the destruction of foreign substances and tissue repair following injury. The immune cells involved in these processes include neutrophils, macrophages, monocytes, mast cells, T-cells, and B-cells. These cells must undergo chemotactic targeting to the area of injury, adhere to blood vessel walls, traverse the blood vessel wall into the tissue, engulf the offending agent, and destroy it. Local anesthetics have been thought to interfere with every step of this process. They inhibit leukocyte adherence to the vascular endothelium by possibly interrupting interactions between leukocyte cell membrane integrins and their receptors (cellular adhesion molecules—CAMs) expressed on the vascular endothelium. Similarly, they inhibit the trans-endothelial migration and motility of leukocytes and may interfere with the "priming" of leukocytes, preventing their full pathogen-destroying capability by decreasing their free radical production. It has been suggested that local anesthetics further interrupt the normal cellular actomyosin filament activity resulting in disruption of the ability of the leukocyte to modulate the cell membrane to engulf the offending agent for lysosomal destruction. Furthermore, local anesthetics are responsible for a dose-dependent decrease in the release of lysosomal enzymes [44, 45].

Of additional interest are the anti-inflammatory properties of local anesthetics that are believed to stem from their inhibition of arachidonic acid derivative synthesis, their release of histamine, and their attenuation of cytokine release (i.e., IL-1, IL-6, IL-8, TNF-alpha, etc.). Inhibition of phospholipase A2 synthesis prevents arachidonic acid cleavage; inhibition of prostaglandin E1/E2 synthesis has been attributed to a potential reduction in inflammatory pain; inhibition of thromboxane A2 synthesis results in decreased platelet aggregation; and inhibition of leukotriene B4 synthesis has been implicated in the reduction of capillary hyper-permeability, resulting in decreased edema formation due to inflammatory plasma extravasation. Based on this aggregate model of cell membrane interference (i.e., ion channel inhibition, cell membrane protein cleavage, cell membrane receptor binding and inhibition, cell membrane actomyosin function disruption, etc.) researchers have targeted investigation of specific local anesthetics for their antibacterial and antiviral effects [44, 46].

#### *2.2.3.6 Factors which effect intrathecal spread*

Several factors are considered relevant to the intrathecal spread of local anesthetic. These factors may be divided into three categories: factors specific to the

**83**

clearance decreased with advancing age [49–52].

Finally, procedural components may have an impact on the distribution of local anesthetic. It is known that the initial pressure generated by the injection of local anesthetic creates waves within the CSF. It was previously believed that generation of additional fluid waves, via a technique known as barbotage, would facilitate greater spread. Several investigations have demonstrated that barbotage does not affect the

*Current Local Anesthetic Applications in Regional Anesthesia*

local anesthetic solution, factors specific to the patient, and factors specific to the procedure itself. All of these have been described in an article by Hocking and

With regard to the local anesthetic solution, the degree of intrathecal spread is related to the baricity, temperature, viscosity, and dosage of local anesthetic administered. Baricity is the ratio of substance density to CSF density. As such, there are hyperbaric, hypobaric or isobaric (i.e., denser than cerebrospinal fluid, less dense than cerebrospinal fluid, or similar density to cerebrospinal fluid) formulations of local anesthetic solution. Upon injection, baricity affects the caudal versus cephalad spread of solution within the CSF. Baricity, in combination with patient positioning, will ultimately determine the spread and distribution of local anesthetic within the thecal sac. Temperature also affects the density of a local anesthetic solution such that a refrigerated or warmed solution may possess a baricity different from its manufactured specification. Investigations evaluating the additional effect of local anesthetic solution viscosity on intrathecal spread suggest that increased viscosity is associated with increased local anesthetic distribution within the intrathecal space [48]. Finally, there is a relationship between dosage, volume, and concentration. Recognizably, changes in any of these variables influence the others as they pertain to the specific mixture of a local anesthetic solution prepared for administration. Though several studies have been performed to evaluate these factors, dosage seems to have the most significant impact on the intrathecal spread of local anesthetic. In discussing patient factors, patient height, position, and age all contribute to the spread of intrathecal local anesthetic. Though it may affect spread, gross height is not a reliable characteristic for determination of local anesthetic dosing. Hartwell et al. demonstrated a correlation between vertebral column length and the level of local anesthetic sensory blockade. As a surrogate for height, the authors suggest the use of vertebral column length instead. This recommendation is based on the recognition that there may be patient height differences attributed to differences in extremity length, which have no reference value with regard to thecal sac dimensions or cerebrospinal fluid volume. Regarding thecal sac characteristics, it is recognized that the vertebral column curvatures (and thus variations in thecal sac positioning) influence the intrathecal spread of local anesthetic. The interplay between lumbar lordosis, thoracic kyphosis, and baricity helps to explain the largely "dependent" thoracic distribution of hyperbaric local anesthetic solutions after intrathecal injection and positioning of a patient in the supine position. With regard to baricity, it was demonstrated that the density of CSF varies between patients. CSF in women is less dense than in men. It is less dense in pregnant women than in non-pregnant women and is less dense in pre-menopausal women than in post-menopausal women. This fact has unique importance in that a significant portion of surgeries performed under spinal anesthesia are cesarean sections in premenopausal, pregnant women who can be expected to have decreased CSF density. It has been further demonstrated that extremes of age can impact the spread of intrathecal local anesthetic. Veering et al. reported on the increasing length of time required for the maximum upper level of analgesia to be seen with advancing age. This was associated with an inverse onset of motor blockade relationship such that a faster onset of motor blockade was seen with advancing age. Furthermore, the time to peak plasma concentration of local anesthetic was increased, and the total plasma

Wildsmith which may be referenced for additional information [47].

*DOI: http://dx.doi.org/10.5772/intechopen.88528*

#### *Current Local Anesthetic Applications in Regional Anesthesia DOI: http://dx.doi.org/10.5772/intechopen.88528*

*Topics in Local Anesthetics*

Sympathetic nervous system blockade as a consequence of spinal local anesthetic administration leads to unimpeded parasympathetic nervous system activity and gastrointestinal hyperactivity. Hypotension encountered as a result of spinal local anesthesia may lead to gastrointestinal ischemia and the release of emetogenic substances such as serotonin. Furthermore, hypotension may lead to hypoperfusion of the area postrema of the medulla (brain stem—known chemoreceptor trigger zone for vomiting) resulting in increased serotonin release. The combination of these factors may contribute to intraoperative/postoperative nausea and vomiting. It is also important to recognize that hypotension associated with spinal local anesthetic administration may result in hypoperfusion of the liver. Because hepatic blood flow is not auto-regulated, this low perfusion pressure may result in impairment of

Regarding the anti-inflammatory and immunomodulatory effects of local anesthetics, Cassuto et al. wrote that it is well recognized that the innate and adaptive immune systems contribute to the destruction of foreign substances and tissue repair following injury. The immune cells involved in these processes include neutrophils, macrophages, monocytes, mast cells, T-cells, and B-cells. These cells must undergo chemotactic targeting to the area of injury, adhere to blood vessel walls, traverse the blood vessel wall into the tissue, engulf the offending agent, and destroy it. Local anesthetics have been thought to interfere with every step of this process. They inhibit leukocyte adherence to the vascular endothelium by possibly interrupting interactions between leukocyte cell membrane integrins and their receptors (cellular adhesion molecules—CAMs) expressed on the vascular endothelium. Similarly, they inhibit the trans-endothelial migration and motility of leukocytes and may interfere with the "priming" of leukocytes, preventing their full pathogen-destroying capability by decreasing their free radical production. It has been suggested that local anesthetics further interrupt the normal cellular actomyosin filament activity resulting in disruption of the ability of the leukocyte to modulate the cell membrane to engulf the offending agent for lysosomal destruction. Furthermore, local anesthetics are responsible for

metabolic functions to include subsequent drug metabolism [43].

a dose-dependent decrease in the release of lysosomal enzymes [44, 45].

*2.2.3.6 Factors which effect intrathecal spread*

Of additional interest are the anti-inflammatory properties of local anesthetics that are believed to stem from their inhibition of arachidonic acid derivative synthesis, their release of histamine, and their attenuation of cytokine release (i.e., IL-1, IL-6, IL-8, TNF-alpha, etc.). Inhibition of phospholipase A2 synthesis prevents arachidonic acid cleavage; inhibition of prostaglandin E1/E2 synthesis has been attributed to a potential reduction in inflammatory pain; inhibition of thromboxane A2 synthesis results in decreased platelet aggregation; and inhibition of leukotriene B4 synthesis has been implicated in the reduction of capillary hyper-permeability, resulting in decreased edema formation due to inflammatory plasma extravasation. Based on this aggregate model of cell membrane interference (i.e., ion channel inhibition, cell membrane protein cleavage, cell membrane receptor binding and inhibition, cell membrane actomyosin function disruption, etc.) researchers have targeted investigation of specific local anesthetics for their antibacterial and antiviral effects [44, 46].

Several factors are considered relevant to the intrathecal spread of local anesthetic. These factors may be divided into three categories: factors specific to the

*2.2.3.4 Digestive*

*2.2.3.5 Immune*

**82**

local anesthetic solution, factors specific to the patient, and factors specific to the procedure itself. All of these have been described in an article by Hocking and Wildsmith which may be referenced for additional information [47].

With regard to the local anesthetic solution, the degree of intrathecal spread is related to the baricity, temperature, viscosity, and dosage of local anesthetic administered. Baricity is the ratio of substance density to CSF density. As such, there are hyperbaric, hypobaric or isobaric (i.e., denser than cerebrospinal fluid, less dense than cerebrospinal fluid, or similar density to cerebrospinal fluid) formulations of local anesthetic solution. Upon injection, baricity affects the caudal versus cephalad spread of solution within the CSF. Baricity, in combination with patient positioning, will ultimately determine the spread and distribution of local anesthetic within the thecal sac. Temperature also affects the density of a local anesthetic solution such that a refrigerated or warmed solution may possess a baricity different from its manufactured specification. Investigations evaluating the additional effect of local anesthetic solution viscosity on intrathecal spread suggest that increased viscosity is associated with increased local anesthetic distribution within the intrathecal space [48]. Finally, there is a relationship between dosage, volume, and concentration. Recognizably, changes in any of these variables influence the others as they pertain to the specific mixture of a local anesthetic solution prepared for administration. Though several studies have been performed to evaluate these factors, dosage seems to have the most significant impact on the intrathecal spread of local anesthetic.

In discussing patient factors, patient height, position, and age all contribute to the spread of intrathecal local anesthetic. Though it may affect spread, gross height is not a reliable characteristic for determination of local anesthetic dosing. Hartwell et al. demonstrated a correlation between vertebral column length and the level of local anesthetic sensory blockade. As a surrogate for height, the authors suggest the use of vertebral column length instead. This recommendation is based on the recognition that there may be patient height differences attributed to differences in extremity length, which have no reference value with regard to thecal sac dimensions or cerebrospinal fluid volume. Regarding thecal sac characteristics, it is recognized that the vertebral column curvatures (and thus variations in thecal sac positioning) influence the intrathecal spread of local anesthetic. The interplay between lumbar lordosis, thoracic kyphosis, and baricity helps to explain the largely "dependent" thoracic distribution of hyperbaric local anesthetic solutions after intrathecal injection and positioning of a patient in the supine position. With regard to baricity, it was demonstrated that the density of CSF varies between patients. CSF in women is less dense than in men. It is less dense in pregnant women than in non-pregnant women and is less dense in pre-menopausal women than in post-menopausal women. This fact has unique importance in that a significant portion of surgeries performed under spinal anesthesia are cesarean sections in premenopausal, pregnant women who can be expected to have decreased CSF density. It has been further demonstrated that extremes of age can impact the spread of intrathecal local anesthetic. Veering et al. reported on the increasing length of time required for the maximum upper level of analgesia to be seen with advancing age. This was associated with an inverse onset of motor blockade relationship such that a faster onset of motor blockade was seen with advancing age. Furthermore, the time to peak plasma concentration of local anesthetic was increased, and the total plasma clearance decreased with advancing age [49–52].

Finally, procedural components may have an impact on the distribution of local anesthetic. It is known that the initial pressure generated by the injection of local anesthetic creates waves within the CSF. It was previously believed that generation of additional fluid waves, via a technique known as barbotage, would facilitate greater spread. Several investigations have demonstrated that barbotage does not affect the

ultimate height of the sensory blockade. It may, however, slightly decrease the time to achieve maximum sensory and motor blockade, though this may be of limited clinical value [53–55]. Regarding injection speed and pressure itself, studies have been mixed. It would seem that utilizing increasing speed, and pressure of injection potentially facilitates a greater spread of isobaric local anesthetic with diminishing effects seen with hyperbaric local anesthetic [47, 56]. Lastly, the needle orientation and approach (midline versus paramedian) to the neuraxis may alter local anesthetic distribution. James et al. demonstrated a faster onset of T4 block when the Sprotte needle was inserted with the side eye facing cephalad [57]. Urmey et al., similar to Neigh et al., also reported a higher dermatomal distribution when the side aperture of the needle was oriented in a cephalad manner [58, 59]. To the contrary, Masse et al. reported that the orientation of the aperture of the Whitacre needle did not influence the cephalad spread of hyperbaric bupivacaine in parturients [60]. Stienstra et al. demonstrated that a paramedian approach with steep angle (70–100 degrees from level) was also associated with a greater cephalad sensory blockade [61].

#### *2.2.4 Adverse effects*

#### *2.2.4.1 Local anesthetic systemic toxicity*

Each local anesthetic has a unique pharmacokinetic profile. This profile dictates the potential for adverse events that may be seen with local anesthetic administration. One of the most concerning adverse effects is local anesthetic systemic toxicity (LAST). Inadvertent vascular administration or changes in vascular absorption may result in a constellation of symptoms, dependent upon the rate of increase in serum concentration and the injection location. Symptoms are typically classified into two groups: central nervous system or cardiovascular. Central nervous system (CNS) symptoms may include dizziness, perioral numbness, tinnitus, metallic taste, agitation, seizures, and coma. Cardiovascular (CV) symptoms, usually seen with increasing serum concentrations, may include dysrhythmias (i.e., tachycardia, bradycardia, and ventricular ectopy), myocardial depression, hypotension, and asystole. It is important to note, however, that CNS symptoms may not be noted prior to the onset of cardiovascular collapse. The potential for local anesthetic toxicity may be conceptualized using a metric estimation of the ratio of CV toxic dose: CNS toxic dose. This ratio is lower (i.e., more potential for cardiac toxicity) for amide anesthetics such as ropivacaine and bupivacaine (with bupivacaine having the lowest ratio and greatest potential for toxicity). This is due in part to its lipid solubility, greater protein binding, and hepatic metabolism [62, 63]. An exact mechanism for LAST has yet to be fully elucidated, but it has been suggested that the ultimate cause is likely a combination of Na<sup>+</sup> /K+ /Ca2+ ion channel blockade (resulting in myocardial depression) in conjunction with metabotropic intracellular effects. These intracellular effects include a potential mitochondrial translocase inhibition, which may prevent the movement of the acyl portion of fats and ketones into the inner mitochondria for energy processing. This substrate reduction may create a synergistic depression of cardiac function as a consequence of the myocardial reliance on mitochondrial oxidation of fatty acids and ketones for energy [63].

It is important to recognize that certain pathophysiologic states will also affect the toxicity of local anesthetics. These include renal dysfunction, cardiac dysfunction, and hepatic dysfunction. In patients with renal dysfunction, a greater volume of distribution and greater alpha-1 glycoprotein binding would portend a lower free fraction serum concentration. However, there is often a hyperdynamic circulation associated with diminished elimination of the agent leading to a variable serum concentration and recommendations for reduced dosages [63]. Patients with severe heart failure

**85**

*Current Local Anesthetic Applications in Regional Anesthesia*

experience a decreased intravascular uptake portending a lower serum concentration. However, they often experience diminished renal and hepatic perfusion leading to a decreased rate of metabolism and elimination necessitating recommendations for reduced dosages as well. Finally, severe hepatic disease, with its associated decreased hepatic metabolism, necessitates decreased local anesthetic administration to offset the delayed metabolism and elimination of the local anesthetic from the body [63]. Regardless of the manifestation, the key to successful treatment is early consideration of the diagnosis. The development and widespread distribution of lipid emulsion has improved the survival of such cases via a mechanism that includes a combination of reduced tissue binding and improved energetic-metabolic effects. Since the first report of a patient saved by lipid rescue in 2006 [64] case reports and clinical experi-

ence have continued to add to the body of evidence suggesting its efficacy.

bupivacaine, mepivacaine, etc., have been investigated as well.

*2.2.4.2.1 Reported incidence of neurotoxicity*

*2.2.4.2.2 Neurotoxicity mechanism*

Initial concerns regarding the administration of lidocaine for spinal anesthesia surfaced in the early 1990s. At that time, microcatheters were being employed for the continuous intrathecal administration of lidocaine. A case report in 1991 brought to light the potential for cauda equina syndrome associated with intrathecal lidocaine administration. This was believed to be a result of pooling of high concentration (5%) lidocaine inside the caudal dural sac [65]. Ongoing surveillance and reporting, however, indicated a continuum of symptoms. This was described at the time as Transient Radicular Irritation (TRI) associated with intrathecal bolus lidocaine administration for spinal anesthesia. These symptoms were later reclassified and have come to be better known as Transient Neurologic Symptoms (i.e., the occurrence of sensory radicular neuropathic pain in the absence of motor dysfunction that resolves within 72 h) [66]. Additional studies were performed to evaluate for contributing causes to include concentration, baricity, dosage, and adjuncts (i.e., epinephrine, dextrose, etc.). Furthermore, the occurrence of TNS with alternative local anesthetics, such as

According to data presented by Brull et al., the incidence of radiculopathy or neuropathy following contemporary spinal local anesthetic administration is believed to occur in 3.78 out of 10,000 spinal esthetics. They further report that the risk of cauda equina syndrome with spinal anesthesia is less frequent, occurring in ~0.11/10,000, and the risk of permanent neurologic injury is reportedly exceedingly rare [67].

The exact mechanism for the occurrence of neurologic injury or production of transient neurologic symptoms is unknown. Recognizably, each local anesthetic has a different pharmacodynamic profile resulting in greater frequency (i.e., lidocaine) versus lesser frequency (i.e., bupivacaine) of neurologic symptoms believed to be secondary to neuronal insult. There has been a suggestion that neurologic symptoms following spinal local anesthetic administration may stem from the local vasoconstrictive properties of the local anesthetic [68]. It is understood that different local anesthetics have different vasoconstrictive effects and that these effects are also dose-dependent. High concentrations of local anesthetic result in vasodilation, whereas low concentrations have a more vasoconstrictive effect [68]. This vasoconstrictive effect at low dose may result in neuronal ischemia. Certainly, there is always the potential for mechanical trauma from the needle or intrafascicular

*DOI: http://dx.doi.org/10.5772/intechopen.88528*

*2.2.4.2 Neurotoxicity*

#### *Current Local Anesthetic Applications in Regional Anesthesia DOI: http://dx.doi.org/10.5772/intechopen.88528*

experience a decreased intravascular uptake portending a lower serum concentration. However, they often experience diminished renal and hepatic perfusion leading to a decreased rate of metabolism and elimination necessitating recommendations for reduced dosages as well. Finally, severe hepatic disease, with its associated decreased hepatic metabolism, necessitates decreased local anesthetic administration to offset the delayed metabolism and elimination of the local anesthetic from the body [63].

Regardless of the manifestation, the key to successful treatment is early consideration of the diagnosis. The development and widespread distribution of lipid emulsion has improved the survival of such cases via a mechanism that includes a combination of reduced tissue binding and improved energetic-metabolic effects. Since the first report of a patient saved by lipid rescue in 2006 [64] case reports and clinical experience have continued to add to the body of evidence suggesting its efficacy.

#### *2.2.4.2 Neurotoxicity*

*Topics in Local Anesthetics*

*2.2.4 Adverse effects*

*2.2.4.1 Local anesthetic systemic toxicity*

ultimate height of the sensory blockade. It may, however, slightly decrease the time to achieve maximum sensory and motor blockade, though this may be of limited clinical value [53–55]. Regarding injection speed and pressure itself, studies have been mixed. It would seem that utilizing increasing speed, and pressure of injection potentially facilitates a greater spread of isobaric local anesthetic with diminishing effects seen with hyperbaric local anesthetic [47, 56]. Lastly, the needle orientation and approach (midline versus paramedian) to the neuraxis may alter local anesthetic distribution. James et al. demonstrated a faster onset of T4 block when the Sprotte needle was inserted with the side eye facing cephalad [57]. Urmey et al., similar to Neigh et al., also reported a higher dermatomal distribution when the side aperture of the needle was oriented in a cephalad manner [58, 59]. To the contrary, Masse et al. reported that the orientation of the aperture of the Whitacre needle did not influence the cephalad spread of hyperbaric bupivacaine in parturients [60]. Stienstra et al. demonstrated that a paramedian approach with steep angle (70–100 degrees from level) was also

Each local anesthetic has a unique pharmacokinetic profile. This profile dictates the potential for adverse events that may be seen with local anesthetic administration. One of the most concerning adverse effects is local anesthetic systemic toxicity (LAST). Inadvertent vascular administration or changes in vascular absorption may result in a constellation of symptoms, dependent upon the rate of increase in serum concentration and the injection location. Symptoms are typically classified into two groups: central nervous system or cardiovascular. Central nervous system (CNS) symptoms may include dizziness, perioral numbness, tinnitus, metallic taste, agitation, seizures, and coma. Cardiovascular (CV) symptoms, usually seen with increasing serum concentrations, may include dysrhythmias (i.e., tachycardia, bradycardia, and ventricular ectopy), myocardial depression, hypotension, and asystole. It is important to note, however, that CNS symptoms may not be noted prior to the onset of cardiovascular collapse. The potential for local anesthetic toxicity may be conceptualized using a metric estimation of the ratio of CV toxic dose: CNS toxic dose. This ratio is lower (i.e., more potential for cardiac toxicity) for amide anesthetics such as ropivacaine and bupivacaine (with bupivacaine having the lowest ratio and greatest potential for toxicity). This is due in part to its lipid solubility, greater protein binding, and hepatic metabolism [62, 63]. An exact mechanism for LAST has yet to be fully elucidated, but it has been suggested

(resulting in myocardial depression) in conjunction with metabotropic intracellular effects. These intracellular effects include a potential mitochondrial translocase inhibition, which may prevent the movement of the acyl portion of fats and ketones into the inner mitochondria for energy processing. This substrate reduction may create a synergistic depression of cardiac function as a consequence of the myocardial reliance on mitochondrial oxidation of fatty acids and ketones for energy [63]. It is important to recognize that certain pathophysiologic states will also affect the toxicity of local anesthetics. These include renal dysfunction, cardiac dysfunction, and hepatic dysfunction. In patients with renal dysfunction, a greater volume of distribution and greater alpha-1 glycoprotein binding would portend a lower free fraction serum concentration. However, there is often a hyperdynamic circulation associated with diminished elimination of the agent leading to a variable serum concentration and recommendations for reduced dosages [63]. Patients with severe heart failure

/K+

/Ca2+ ion channel blockade

associated with a greater cephalad sensory blockade [61].

that the ultimate cause is likely a combination of Na<sup>+</sup>

**84**

Initial concerns regarding the administration of lidocaine for spinal anesthesia surfaced in the early 1990s. At that time, microcatheters were being employed for the continuous intrathecal administration of lidocaine. A case report in 1991 brought to light the potential for cauda equina syndrome associated with intrathecal lidocaine administration. This was believed to be a result of pooling of high concentration (5%) lidocaine inside the caudal dural sac [65]. Ongoing surveillance and reporting, however, indicated a continuum of symptoms. This was described at the time as Transient Radicular Irritation (TRI) associated with intrathecal bolus lidocaine administration for spinal anesthesia. These symptoms were later reclassified and have come to be better known as Transient Neurologic Symptoms (i.e., the occurrence of sensory radicular neuropathic pain in the absence of motor dysfunction that resolves within 72 h) [66]. Additional studies were performed to evaluate for contributing causes to include concentration, baricity, dosage, and adjuncts (i.e., epinephrine, dextrose, etc.). Furthermore, the occurrence of TNS with alternative local anesthetics, such as bupivacaine, mepivacaine, etc., have been investigated as well.

#### *2.2.4.2.1 Reported incidence of neurotoxicity*

According to data presented by Brull et al., the incidence of radiculopathy or neuropathy following contemporary spinal local anesthetic administration is believed to occur in 3.78 out of 10,000 spinal esthetics. They further report that the risk of cauda equina syndrome with spinal anesthesia is less frequent, occurring in ~0.11/10,000, and the risk of permanent neurologic injury is reportedly exceedingly rare [67].

#### *2.2.4.2.2 Neurotoxicity mechanism*

The exact mechanism for the occurrence of neurologic injury or production of transient neurologic symptoms is unknown. Recognizably, each local anesthetic has a different pharmacodynamic profile resulting in greater frequency (i.e., lidocaine) versus lesser frequency (i.e., bupivacaine) of neurologic symptoms believed to be secondary to neuronal insult. There has been a suggestion that neurologic symptoms following spinal local anesthetic administration may stem from the local vasoconstrictive properties of the local anesthetic [68]. It is understood that different local anesthetics have different vasoconstrictive effects and that these effects are also dose-dependent. High concentrations of local anesthetic result in vasodilation, whereas low concentrations have a more vasoconstrictive effect [68]. This vasoconstrictive effect at low dose may result in neuronal ischemia. Certainly, there is always the potential for mechanical trauma from the needle or intrafascicular

injection with increased intrafascicular administration pressures leading to neuronal ischemia and injury [65]. This, however, is rare. There is research that suggests the effects of local anesthetics are the result of their impact on intracellular metabolism, such as on the mitogen-activated protein kinase (MAPK) and caspase pathways. It is interesting to note the activation of different MAPK pathways with specific local anesthetics (i.e., tetracaine activates the c-Jun N-terminal kinase pathway versus lidocaine activation of the p38 MAPK pathway) [69]. Furthermore, use of lipoxygenase inhibitors seems to diminish the degree of neuronal apoptosis in response to lidocaine administration suggesting a potential role for inflammatory mediators in the generation of neurotoxicity [69]. Kan et al. further investigated an inflammatory component by demonstrating the ability to regulate levels of caspase-9 and matrix-metalloprotease-3 expression via preemptive incubation with subsequent inflammatory signaling pathway modification. This resulted in decreased apoptosis in response to in vitro neuronal lidocaine administration [70].

#### *2.2.4.3 Other adverse effects*

#### *2.2.4.3.1 Hypotension*

Hypotension after spinal local anesthetic administration is a well-known direct effect of sympathetic nervous system blockade with venous pooling of blood in the lower extremities. Defining hypotension is as challenging as determining treatment since the literature utilizes different definitions (i.e. <100 mmHg, <90 mmHg, <80% of baseline, etc.) [71]. Numerous studies have evaluated different methodologies for treating this hypotension. Definition and treatment are beyond the scope of this chapter.

#### *2.2.4.3.2 Infectious complications*

Historically, and anecdotally, spinal local anesthetic administration has a low reported incidence of infectious complications, and include, but are not limited to paraspinal abscesses, spinal/epidural abscesses, meningitis, arachnoiditis, and systemic inflammation with sepsis. In reviewing the literature for infectious complications, a very low correlating incidence was discovered. Moore and Bridenbaugh, after reviewing 52,112 spinal anesthetics, reported the occurrence of three central nervous system infections (i.e., 0.06 cases per 1000) [72]. In a more recent review, Horlocker et al. reported on the occurrence of two infectious complications out of 4767 consecutive spinal anesthetics which were reviewed (i.e., 0.4 cases per 1000). One case was a disc abscess and the other a paraspinal abscess. Both patients remained neurologically intact after appropriate treatment. Infections associated with spinal local anesthetic injection are infrequent and, as discussed previously, may be due in part to the concentration-dependent antibacterial effects of local anesthetic administration [73].

#### *2.2.4.3.3 Vertebral canal hematoma*

The etiology of vertebral canal hematoma after neuraxial local anesthetic administration appears multifactorial with patient-related (i.e., demographics, comorbidities, etc.), medication-related and procedural contributions [74]. Historical demographic data portrays a potential predisposition based upon age and gender [75]. The retrospectively reported incidence of vertebral canal hematoma varies widely and ranges from 1:3600 (seen in patients receiving a spinal local anesthetic for total knee arthroplasty), to 1:200,000 (as seen in obstetric patients receiving an epidural local anesthetic for labor analgesia) [74, 76, 77]. The report on the Third National Audit Project of the Royal College of Anesthetists further suggests a prospective

**87**

*2.2.4.3.6 Hearing loss*

*Current Local Anesthetic Applications in Regional Anesthesia*

incidence of 8 vertebral canal hematomas in 707,425 (~ 1:88,000). Interestingly, 46% of these neuraxial blocks were spinals, and there were zero vertebral canal hematomas associated with spinal instrumentation. Recognizably, this complication portends a notably poor prognosis associated with persistent neurologic deficit [78].

Administration of spinal anesthesia is associated with a disruption in thermoregulation. The threshold for vasoconstriction and shivering in response to hypothermia becomes dysregulated. According to Kurz et al., the threshold for triggering a thermoregulatory response to hypothermia is decreased by ~0.5°C. Temperature is lost more quickly during the initial 30 min after spinal anesthesia (as a result of core-to-peripheral redistribution of heat) when compared to epidural local anesthetic administration. This is believed to be secondary to a lesser degree of autonomic thermal dysregulation in the lower extremities with epidural local anesthesia administration (i.e., failure to obtain a complete blockade with epidural versus spinal local anesthesia administration). This clinical effect garners greater importance when considering the detrimental effects of hypothermia (i.e., wound infection, coagulopathy, delayed arousal from anesthesia, etc.). Though beyond the scope of this chapter, yet still of clinical importance, is the potential additive effect of intrathecal opioid administration on the disruptive thermoregulatory effect of

The term post-dural puncture headache often refers to a clinical constellation of symptoms seen after penetration of the dura mater. Symptoms include the presence of a transient, self-limited, positional, frontal-occipital headache traditionally believed to occur within 72 h of dural penetration. In addition, patients may complain of nausea (+/− vomiting), dizziness, tinnitus, neck stiffness, or photophobia. Studies indicate a significant association with specific types of needles used for spinal local anesthetic administration. Smaller gauge, pencil point needles (i.e., spinal needles) are less often associated with post-dural puncture headaches, as compared to larger gauge cutting needles (i.e., epidural needles). For this reason, post-dural puncture headache is less often associated with spinal local anesthetic administration, as compared to inadvertent puncture with epidural catheter placement. Historically, treatments focused on bed rest, hydration, caffeine, and analgesics to include acetaminophen and NSAIDs. These conservative treatments are not currently supported by evidence of efficacy. The sterile epidural injection of blood (i.e., an epidural blood patch), is recognized as traditional therapy and is effective in providing adequate pain relief in ~65–70% of patients. Optimally, in light of the challenges with treating post-dural puncture headaches, it is best to avoid inadvertent dural puncture. If inadvertent dural puncture occurs, techniques to minimize

the likelihood of post-dural puncture headache should be considered [82].

Hearing loss after neuraxial local anesthetic administration deserves special consideration. Some providers remain unaware of the potential for this type of transient, self-limited low-frequency sensorineural hearing loss. This type of hearing loss may be as prevalent as 10–50% of all spinal local anesthetic administrations (with such variable reported prevalence due to the limited degree of patient/ clinician awareness). Interestingly, it seems the same risk factors for a post-dural

*DOI: http://dx.doi.org/10.5772/intechopen.88528*

*2.2.4.3.4 Thermoregulatory disruption*

spinal local anesthetic administration [79–81].

*2.2.4.3.5 Post-dural puncture headache*

incidence of 8 vertebral canal hematomas in 707,425 (~ 1:88,000). Interestingly, 46% of these neuraxial blocks were spinals, and there were zero vertebral canal hematomas associated with spinal instrumentation. Recognizably, this complication portends a notably poor prognosis associated with persistent neurologic deficit [78].

#### *2.2.4.3.4 Thermoregulatory disruption*

*Topics in Local Anesthetics*

*2.2.4.3 Other adverse effects*

*2.2.4.3.2 Infectious complications*

*2.2.4.3.3 Vertebral canal hematoma*

*2.2.4.3.1 Hypotension*

injection with increased intrafascicular administration pressures leading to neuronal ischemia and injury [65]. This, however, is rare. There is research that suggests the effects of local anesthetics are the result of their impact on intracellular metabolism, such as on the mitogen-activated protein kinase (MAPK) and caspase pathways. It is interesting to note the activation of different MAPK pathways with specific local anesthetics (i.e., tetracaine activates the c-Jun N-terminal kinase pathway versus lidocaine activation of the p38 MAPK pathway) [69]. Furthermore, use of lipoxygenase inhibitors seems to diminish the degree of neuronal apoptosis in response to lidocaine administration suggesting a potential role for inflammatory mediators in the generation of neurotoxicity [69]. Kan et al. further investigated an inflammatory component by demonstrating the ability to regulate levels of caspase-9 and matrix-metalloprotease-3 expression via preemptive incubation with subsequent inflammatory signaling pathway modification. This resulted in decreased apoptosis in response to in vitro neuronal lidocaine administration [70].

Hypotension after spinal local anesthetic administration is a well-known direct effect of sympathetic nervous system blockade with venous pooling of blood in the lower extremities. Defining hypotension is as challenging as determining treatment since the literature utilizes different definitions (i.e. <100 mmHg, <90 mmHg, <80% of baseline, etc.) [71]. Numerous studies have evaluated different methodologies for treating this hypotension. Definition and treatment are beyond the scope of this chapter.

Historically, and anecdotally, spinal local anesthetic administration has a low reported incidence of infectious complications, and include, but are not limited to paraspinal abscesses, spinal/epidural abscesses, meningitis, arachnoiditis, and systemic inflammation with sepsis. In reviewing the literature for infectious complications, a very low correlating incidence was discovered. Moore and Bridenbaugh, after reviewing 52,112 spinal anesthetics, reported the occurrence of three central nervous system infections (i.e., 0.06 cases per 1000) [72]. In a more recent review, Horlocker et al. reported on the occurrence of two infectious complications out of 4767 consecutive spinal anesthetics which were reviewed (i.e., 0.4 cases per 1000). One case was a disc abscess and the other a paraspinal abscess. Both patients remained neurologically intact after appropriate treatment. Infections associated with spinal local anesthetic injection are infrequent and, as discussed previously, may be due in part to the concentration-dependent antibacterial effects of local anesthetic administration [73].

The etiology of vertebral canal hematoma after neuraxial local anesthetic administration appears multifactorial with patient-related (i.e., demographics, comorbidities, etc.), medication-related and procedural contributions [74]. Historical demographic data portrays a potential predisposition based upon age and gender [75]. The retrospectively reported incidence of vertebral canal hematoma varies widely and ranges from 1:3600 (seen in patients receiving a spinal local anesthetic for total knee arthroplasty), to 1:200,000 (as seen in obstetric patients receiving an epidural local anesthetic for labor analgesia) [74, 76, 77]. The report on the Third National Audit Project of the Royal College of Anesthetists further suggests a prospective

**86**

Administration of spinal anesthesia is associated with a disruption in thermoregulation. The threshold for vasoconstriction and shivering in response to hypothermia becomes dysregulated. According to Kurz et al., the threshold for triggering a thermoregulatory response to hypothermia is decreased by ~0.5°C. Temperature is lost more quickly during the initial 30 min after spinal anesthesia (as a result of core-to-peripheral redistribution of heat) when compared to epidural local anesthetic administration. This is believed to be secondary to a lesser degree of autonomic thermal dysregulation in the lower extremities with epidural local anesthesia administration (i.e., failure to obtain a complete blockade with epidural versus spinal local anesthesia administration). This clinical effect garners greater importance when considering the detrimental effects of hypothermia (i.e., wound infection, coagulopathy, delayed arousal from anesthesia, etc.). Though beyond the scope of this chapter, yet still of clinical importance, is the potential additive effect of intrathecal opioid administration on the disruptive thermoregulatory effect of spinal local anesthetic administration [79–81].

#### *2.2.4.3.5 Post-dural puncture headache*

The term post-dural puncture headache often refers to a clinical constellation of symptoms seen after penetration of the dura mater. Symptoms include the presence of a transient, self-limited, positional, frontal-occipital headache traditionally believed to occur within 72 h of dural penetration. In addition, patients may complain of nausea (+/− vomiting), dizziness, tinnitus, neck stiffness, or photophobia. Studies indicate a significant association with specific types of needles used for spinal local anesthetic administration. Smaller gauge, pencil point needles (i.e., spinal needles) are less often associated with post-dural puncture headaches, as compared to larger gauge cutting needles (i.e., epidural needles). For this reason, post-dural puncture headache is less often associated with spinal local anesthetic administration, as compared to inadvertent puncture with epidural catheter placement. Historically, treatments focused on bed rest, hydration, caffeine, and analgesics to include acetaminophen and NSAIDs. These conservative treatments are not currently supported by evidence of efficacy. The sterile epidural injection of blood (i.e., an epidural blood patch), is recognized as traditional therapy and is effective in providing adequate pain relief in ~65–70% of patients. Optimally, in light of the challenges with treating post-dural puncture headaches, it is best to avoid inadvertent dural puncture. If inadvertent dural puncture occurs, techniques to minimize the likelihood of post-dural puncture headache should be considered [82].

#### *2.2.4.3.6 Hearing loss*

Hearing loss after neuraxial local anesthetic administration deserves special consideration. Some providers remain unaware of the potential for this type of transient, self-limited low-frequency sensorineural hearing loss. This type of hearing loss may be as prevalent as 10–50% of all spinal local anesthetic administrations (with such variable reported prevalence due to the limited degree of patient/ clinician awareness). Interestingly, it seems the same risk factors for a post-dural

puncture headache apply in the setting of post-spinal local anesthesia hearing loss. According to Sprung et al., the subarachnoid space is contiguous with a small canal in the ear (i.e., the cochlear aqueduct) that transmits cerebrospinal fluid pressure to the inner ear. Sound waves are theorized to be transmitted through the fluid in the middle ear onto the basilar membrane. Changes in transmitted pressure to the middle ear are hypothesized to distort the interpretation of these sound waves through the basilar membrane. Decreases in cerebrospinal fluid pressure, as transmitted through the cochlear canal and into the fluid of the inner ear, is believed to be the mechanism by which patients suffer a loss of low-frequency sensorineural hearing after spinal anesthesia administration [83].

#### **2.3 Epidural administration**

#### *2.3.1 Contents and structure of the epidural space*

Transitioning to a discussion of epidural local anesthetic administration generates an opportunity for a brief discussion of the epidural anatomy to supplement the anatomy discussed at the beginning of the chapter.

#### *2.3.1.1 Definition/surrounding bony construct*

The epidural space is widest posteriorly in the midline and averages about 5 mm between the ligamentum flavum and the dura in the lumbar region. The boundaries of the epidural space are:

Above: the foramen magnum where the periosteal and spinal layers of the dura fuse

Below: the sacrococcygeal membrane

Anteriorly: the posterior longitudinal ligament covering the posterior aspect of the vertebral bodies and the intervertebral discs

Posteriorly: the anterior surfaces of the vertebral lamina and the ligamentum flavum Laterally: the pedicles of the vertebrae and the intervertebral foramina [1, 84]

Interestingly, spinal nerve root cuffs are identified along the lateral aspect of the epidural space. These have previously been defined as "prolongations of the dura and arachnoid lamina" and are believed to enclose spinal nerve roots within this space. Previously referred to as "dural cuffs," it is now believed that the cuffs include not only the dura mater but the arachnoid mater as well, thus making this previous term inaccurate [85]. This construct may influence the spread of local anesthetic when administered via the epidural route.

#### *2.3.1.2 Adipose tissue*

The contents of the spinal canal are cushioned in a packing of fat, through which injected solutions track while spreading to target receptors. This adipose tissue is richly vascularized [86, 87] yet lies mostly unattached in the spinal canal. In the region of nerve roots, collagen concentration increases and coalesces with the fat in the intervertebral foramina. Adipose tissue "competes" for its share of the drug, along with nervous tissue and vasculature, and is an important pharmacologic space and repository. Medications with high lipid solubility and/or lipoprotein binding tend to enter and remain in this tissue, depending on local blood flow, and can impact drug behavior in the epidural space profoundly. This competition with extraneural tissue then generates, when compared to spinal doses, a higher epidural medication dosage requirement [88].

**89**

*Current Local Anesthetic Applications in Regional Anesthesia*

noid space, draining to the regional lymph nodes.

*2.3.2 Pharmacokinetics of epidural local anesthetic administration*

*2.3.2.1 Factors which affect epidural spread*

*2.3.2.2 Absorption, potency, duration, onset*

ent segmental analgesia.

Spinal arteries, epidural veins, and lymphatics are all co-inhabitors of this space. Spinal arteries derive from the vertebral, ascending cervical, deep cervical, intercostal, lumbar, and iliolumbar arteries. They lie chiefly in the lateral epidural space. Epidural veins arise from the internal vertebral venous plexus and drain both the spinal cord and the spinal canal. Lying mainly anterolaterally, they pass through the intervertebral foramina on their journey toward the vertebral, posterior intercostal, lumbar and lateral sacral veins. It is through this network that increased pressures (intra-abdominal and intrathoracic) are transmitted to the epidural space [84]. The lack of valves in this system results in the distention of these vessels and a consequent reduction in epidural space volume. The lymphatic network is located anteriorly to the intervertebral foramen and aid in the cleansing of the subarach-

The interrelationship between the factors that influence epidural blockade and the clinical effect is surprisingly complex. Epidural analgesia is not a simple matter of spinal root or ganglion blockade, but rather is the end state of action at various sites after passage through multiple sites. Unique to epidural local anesthetic administration is the concept of rivulets. Hogan reported the spread of injected ink as "rivulets" through numerous small channels rather than as a unified advancing front [89]. Injection results in circumferential spread anteriorly and posteriorly around the thecal sac. Laterally, epidural solution extrudes beyond the intervertebral foramen following a parallel path along the paraspinous musculature fascial plane [89]. Hogan et al. also noted that the lateral spread of epidural solution sporadically encompassed the more proximal dorsal nerve root prior to the dorsal root ganglion in the "axilla" of the nerve root. This non-uniform distribution of solution, within the epidural space, may then correlate with clinical data suggesting that slow, not fast, injection rates (0.3–0.75 ml/s) result in the most effective spread of analgesia [89]. Undoubtedly, this variation in epidural space content combined with varying spread contributes to the somewhat unpredictable clinical effects seen with epidural local anesthetic administration.

As mentioned above, and contrary to the effects of intrathecal local anesthetic, the complex nature of epidural analgesia is suggested by the lack of relevance of physical factors affecting anatomical spread when compared to the clinically pres-

Local anesthetics stabilize excitable cell membranes and block sodium and potassium flux through the axonal membrane ion pores. The anesthetic profile and clinical characteristics of a local anesthetic depends on its lipid solubility, protein binding, and dissociation constant (pKa). Lipid solubility is generally agreed to be the primary determinant of intrinsic anesthetic potency. Protein binding is the characteristic associated with duration of action of the agent since those that attach to protein components of nerve membranes are less likely to diffuse from the site of action to enter the systemic circulation. The pKa of a compound, as discussed earlier

*DOI: http://dx.doi.org/10.5772/intechopen.88528*

*2.3.1.3 Vasculature*

*2.3.1.4 Rivulets*

#### *2.3.1.3 Vasculature*

*Topics in Local Anesthetics*

**2.3 Epidural administration**

of the epidural space are:

dura fuse

puncture headache apply in the setting of post-spinal local anesthesia hearing loss. According to Sprung et al., the subarachnoid space is contiguous with a small canal in the ear (i.e., the cochlear aqueduct) that transmits cerebrospinal fluid pressure to the inner ear. Sound waves are theorized to be transmitted through the fluid in the middle ear onto the basilar membrane. Changes in transmitted pressure to the middle ear are hypothesized to distort the interpretation of these sound waves through the basilar membrane. Decreases in cerebrospinal fluid pressure, as transmitted through the cochlear canal and into the fluid of the inner ear, is believed to be the mechanism by which patients suffer a loss of low-frequency sensorineural

Transitioning to a discussion of epidural local anesthetic administration generates an opportunity for a brief discussion of the epidural anatomy to supplement

The epidural space is widest posteriorly in the midline and averages about 5 mm between the ligamentum flavum and the dura in the lumbar region. The boundaries

Above: the foramen magnum where the periosteal and spinal layers of the

Anteriorly: the posterior longitudinal ligament covering the posterior aspect of

Posteriorly: the anterior surfaces of the vertebral lamina and the ligamentum flavum Laterally: the pedicles of the vertebrae and the intervertebral foramina [1, 84]

Interestingly, spinal nerve root cuffs are identified along the lateral aspect of the epidural space. These have previously been defined as "prolongations of the dura and arachnoid lamina" and are believed to enclose spinal nerve roots within this space. Previously referred to as "dural cuffs," it is now believed that the cuffs include not only the dura mater but the arachnoid mater as well, thus making this previous term inaccurate [85]. This construct may influence the spread of local anesthetic

The contents of the spinal canal are cushioned in a packing of fat, through which injected solutions track while spreading to target receptors. This adipose tissue is richly vascularized [86, 87] yet lies mostly unattached in the spinal canal. In the region of nerve roots, collagen concentration increases and coalesces with the fat in the intervertebral foramina. Adipose tissue "competes" for its share of the drug, along with nervous tissue and vasculature, and is an important pharmacologic space and repository. Medications with high lipid solubility and/or lipoprotein binding tend to enter and remain in this tissue, depending on local blood flow, and can impact drug behavior in the epidural space profoundly. This competition with extraneural tissue then generates, when compared to spinal doses, a higher epidural medication dosage requirement [88].

hearing after spinal anesthesia administration [83].

*2.3.1 Contents and structure of the epidural space*

*2.3.1.1 Definition/surrounding bony construct*

Below: the sacrococcygeal membrane

when administered via the epidural route.

*2.3.1.2 Adipose tissue*

the vertebral bodies and the intervertebral discs

the anatomy discussed at the beginning of the chapter.

**88**

Spinal arteries, epidural veins, and lymphatics are all co-inhabitors of this space. Spinal arteries derive from the vertebral, ascending cervical, deep cervical, intercostal, lumbar, and iliolumbar arteries. They lie chiefly in the lateral epidural space. Epidural veins arise from the internal vertebral venous plexus and drain both the spinal cord and the spinal canal. Lying mainly anterolaterally, they pass through the intervertebral foramina on their journey toward the vertebral, posterior intercostal, lumbar and lateral sacral veins. It is through this network that increased pressures (intra-abdominal and intrathoracic) are transmitted to the epidural space [84]. The lack of valves in this system results in the distention of these vessels and a consequent reduction in epidural space volume. The lymphatic network is located anteriorly to the intervertebral foramen and aid in the cleansing of the subarachnoid space, draining to the regional lymph nodes.

#### *2.3.1.4 Rivulets*

The interrelationship between the factors that influence epidural blockade and the clinical effect is surprisingly complex. Epidural analgesia is not a simple matter of spinal root or ganglion blockade, but rather is the end state of action at various sites after passage through multiple sites. Unique to epidural local anesthetic administration is the concept of rivulets. Hogan reported the spread of injected ink as "rivulets" through numerous small channels rather than as a unified advancing front [89]. Injection results in circumferential spread anteriorly and posteriorly around the thecal sac. Laterally, epidural solution extrudes beyond the intervertebral foramen following a parallel path along the paraspinous musculature fascial plane [89]. Hogan et al. also noted that the lateral spread of epidural solution sporadically encompassed the more proximal dorsal nerve root prior to the dorsal root ganglion in the "axilla" of the nerve root. This non-uniform distribution of solution, within the epidural space, may then correlate with clinical data suggesting that slow, not fast, injection rates (0.3–0.75 ml/s) result in the most effective spread of analgesia [89]. Undoubtedly, this variation in epidural space content combined with varying spread contributes to the somewhat unpredictable clinical effects seen with epidural local anesthetic administration.

#### *2.3.2 Pharmacokinetics of epidural local anesthetic administration*

#### *2.3.2.1 Factors which affect epidural spread*

As mentioned above, and contrary to the effects of intrathecal local anesthetic, the complex nature of epidural analgesia is suggested by the lack of relevance of physical factors affecting anatomical spread when compared to the clinically present segmental analgesia.

#### *2.3.2.2 Absorption, potency, duration, onset*

Local anesthetics stabilize excitable cell membranes and block sodium and potassium flux through the axonal membrane ion pores. The anesthetic profile and clinical characteristics of a local anesthetic depends on its lipid solubility, protein binding, and dissociation constant (pKa). Lipid solubility is generally agreed to be the primary determinant of intrinsic anesthetic potency. Protein binding is the characteristic associated with duration of action of the agent since those that attach to protein components of nerve membranes are less likely to diffuse from the site of action to enter the systemic circulation. The pKa of a compound, as discussed earlier in detail and defined as the pH at which there is equilibrium between the ionized and unionized states of the molecule, impacts the rate of onset of clinical effect. This value is important for effective anesthesia because the uncharged form of the molecule is essential for epineural diffusion across lipid nerve sheaths and cell membranes. Conversely, only the charged form can dissociate in water and diffuse through cellular fluid and intracellular metabolism [90, 91].

#### *2.3.2.3 Metabolism*

The metabolic mechanism of local anesthetics depends on their chemical classification. Amide-type local anesthetics, including ropivacaine, are primarily metabolized by the hepatic esterase activity seen in the P450 system in the liver [92, 93]. Ester-type local anesthetics (procaine, benzocaine, tetracaine) are predominantly hydrolyzed by plasma pseudocholinesterase.

#### *2.3.3 Pharmacodynamics of epidural local anesthetic administration*

#### *2.3.3.1 Measuring effects*

A discussion of clinical effect should include a comment on the differential blockade. Independent of differences in nerve fiber size and resistance to blockade, local anesthetics have varied differential blockade characteristics. Even within a single agent, the differential blockade can vary. As an example, bupivacaine, one of the best agents at producing effective analgesia while sparing motor loss, loses its motor-sparing characteristics as the bupivacaine concentration is increased from 0.5 to 0.75%.

The mode of action of epidural analgesia is far from clear. Proposed sites of action have included: (1) mixed spinal nerves in the paravertebral space, (2) dorsal root ganglia, (3) spinal roots, and (4) the periphery of the spinal cord. Regardless, blockade of a nerve fiber varies based on the duration of exposure, the exposed length of the axon, the type and site of the axon, and the concentration of local anesthetic at the axonal membrane.

Tachyphylaxis describes the condition of acute tolerance to local anesthetic drugs, though its mechanism is not well understood. The relationship between the change of response and interval between injections is complicated. However, it is likely the interval between the disappearance of analgesia and the subsequently repeated injection of local anesthetic is primary. When it occurs, decreasing analgesic effectiveness is noted, including a decrease in the number of dermatomes blocked as well as a decrease in motor block, showing that all measurable components of anesthesia are affected. Simply, with repeated doses, fewer segments are anesthetized, the duration of action is decreased, and both motor and sensory blockade are less intense [94].

The response to epidural blockade includes both autonomic blockade as a result of sympathetic interruption and somatic pain blockade (similar to intrathecal injection of local anesthetic, but with a greater duration of time to achieve clinical effect). The sympathetic blockade has consequent effects on vascular beds, cardiac functioning, and other visceral structures as discussed previously. Somatic pain blockade provides for the potential of anatomic functional restoration secondary to pain responses. Both results can occur as a consequence of epidural blockade and may be utilized in the operating room, in the labor suite or the pain clinic.

#### **3. Conclusions**

In conclusion, the administration of local anesthetic via the intrathecal or epidural route possesses unique pharmacokinetic and pharmacodynamic properties. These

**91**

provided the original work is properly cited.

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

*Current Local Anesthetic Applications in Regional Anesthesia*

properties are influenced by the complex anatomy of bones, ligaments, membranes, vasculature, and adipose tissue. Understandably, the mechanism of action of local anes-

ment of Ca2+ ion channels, γ-aminobutyric acid, and substance P have been proposed. Pharmacokinetic variables affecting the clinical picture associated with local anesthetic administration include the protein binding, lipid solubility, and pKa. Spinal local anesthetic pharmacodynamic effects are variable and influenced by factors that are unique to the local anesthetic solution, factors that are unique to the patient, and factors that are associated with the method of local anesthetic administration. Epidural pharmacodynamic effects are characterized by a lack of relevance of physical factors affecting anatomical spread when compared to the clinically present segmental analgesia. Both spinal and epidural local anesthetic administration are associated with clinical effects that involve the cardiovascular, pulmonary, digestive, renal, and immune systems to varying degrees of significance. Local anesthetic toxicity affects the nervous system and cardiovascular system to varying degrees based on the properties of the individual local anesthetic (i.e., lipid solubility, CV: CNS toxicity ratio, etc.) and the toxic dosage administered. Regardless of the manifestations of toxicity, the key to successful treatment is early consideration of the diagnosis. The development and widespread distribution of lipid emulsion has improved survival and should be considered in all cases where local anesthetic toxicity is a concern.

The views expressed in the manuscript are those of the authors and do not reflect the official policy or position of the Department of the Navy, Department of

The authors have no conflict of interest or financial disclosure to report.

\* and Mark J. Lenart<sup>2</sup>

2 Naval Medical Center, Portsmouth, Virginia, USA

1 United States Naval Hospital, Bremerton, Washington, USA

\*Address all correspondence to: jeffrey.m.carness.mil@mail.mil

We are military service members. This work was prepared as part of our official duties. Title 17 U.S.C. 105 provides that "Copyright protection under this title is not available for any work of the United States Government." Title 17 U.S.C. 101 defines a United States Government work as a work prepared by a military service member

ion channel activity. Additional involve-

and K+

*DOI: http://dx.doi.org/10.5772/intechopen.88528*

thetics is complex with primary Na+

**Conflict of interest**

**Author details**

Jeffrey M. Carness1

Defense, or the U.S. Government.

as part of that person's official duties.

*Current Local Anesthetic Applications in Regional Anesthesia DOI: http://dx.doi.org/10.5772/intechopen.88528*

properties are influenced by the complex anatomy of bones, ligaments, membranes, vasculature, and adipose tissue. Understandably, the mechanism of action of local anesthetics is complex with primary Na+ and K+ ion channel activity. Additional involvement of Ca2+ ion channels, γ-aminobutyric acid, and substance P have been proposed.

Pharmacokinetic variables affecting the clinical picture associated with local anesthetic administration include the protein binding, lipid solubility, and pKa. Spinal local anesthetic pharmacodynamic effects are variable and influenced by factors that are unique to the local anesthetic solution, factors that are unique to the patient, and factors that are associated with the method of local anesthetic administration. Epidural pharmacodynamic effects are characterized by a lack of relevance of physical factors affecting anatomical spread when compared to the clinically present segmental analgesia. Both spinal and epidural local anesthetic administration are associated with clinical effects that involve the cardiovascular, pulmonary, digestive, renal, and immune systems to varying degrees of significance. Local anesthetic toxicity affects the nervous system and cardiovascular system to varying degrees based on the properties of the individual local anesthetic (i.e., lipid solubility, CV: CNS toxicity ratio, etc.) and the toxic dosage administered. Regardless of the manifestations of toxicity, the key to successful treatment is early consideration of the diagnosis. The development and widespread distribution of lipid emulsion has improved survival and should be considered in all cases where local anesthetic toxicity is a concern.

#### **Conflict of interest**

*Topics in Local Anesthetics*

*2.3.2.3 Metabolism*

*2.3.3.1 Measuring effects*

in detail and defined as the pH at which there is equilibrium between the ionized and unionized states of the molecule, impacts the rate of onset of clinical effect. This value is important for effective anesthesia because the uncharged form of the molecule is essential for epineural diffusion across lipid nerve sheaths and cell membranes. Conversely, only the charged form can dissociate in water and diffuse

The metabolic mechanism of local anesthetics depends on their chemical classification. Amide-type local anesthetics, including ropivacaine, are primarily metabolized by the hepatic esterase activity seen in the P450 system in the liver [92, 93]. Ester-type local anesthetics (procaine, benzocaine, tetracaine) are predomi-

A discussion of clinical effect should include a comment on the differential blockade. Independent of differences in nerve fiber size and resistance to blockade, local anesthetics have varied differential blockade characteristics. Even within a single agent, the differential blockade can vary. As an example, bupivacaine, one of the best agents at producing effective analgesia while sparing motor loss, loses its motor-sparing characteristics as the bupivacaine concentration is increased from 0.5 to 0.75%. The mode of action of epidural analgesia is far from clear. Proposed sites of action have included: (1) mixed spinal nerves in the paravertebral space, (2) dorsal root ganglia, (3) spinal roots, and (4) the periphery of the spinal cord. Regardless, blockade of a nerve fiber varies based on the duration of exposure, the exposed length of the axon, the type and site of the axon, and the concentration of local anesthetic at the axonal membrane. Tachyphylaxis describes the condition of acute tolerance to local anesthetic drugs, though its mechanism is not well understood. The relationship between the change of response and interval between injections is complicated. However, it is likely the interval between the disappearance of analgesia and the subsequently repeated injection of local anesthetic is primary. When it occurs, decreasing analgesic effectiveness is noted, including a decrease in the number of dermatomes blocked as well as a decrease in motor block, showing that all measurable components of anesthesia are affected. Simply, with repeated doses, fewer segments are anesthetized, the duration of action is decreased, and both motor and sensory blockade are less intense [94]. The response to epidural blockade includes both autonomic blockade as a result

of sympathetic interruption and somatic pain blockade (similar to intrathecal injection of local anesthetic, but with a greater duration of time to achieve clinical effect). The sympathetic blockade has consequent effects on vascular beds, cardiac functioning, and other visceral structures as discussed previously. Somatic pain blockade provides for the potential of anatomic functional restoration secondary to pain responses. Both results can occur as a consequence of epidural blockade and

may be utilized in the operating room, in the labor suite or the pain clinic.

In conclusion, the administration of local anesthetic via the intrathecal or epidural route possesses unique pharmacokinetic and pharmacodynamic properties. These

through cellular fluid and intracellular metabolism [90, 91].

*2.3.3 Pharmacodynamics of epidural local anesthetic administration*

nantly hydrolyzed by plasma pseudocholinesterase.

**90**

**3. Conclusions**

The views expressed in the manuscript are those of the authors and do not reflect the official policy or position of the Department of the Navy, Department of Defense, or the U.S. Government.

We are military service members. This work was prepared as part of our official duties. Title 17 U.S.C. 105 provides that "Copyright protection under this title is not available for any work of the United States Government." Title 17 U.S.C. 101 defines a United States Government work as a work prepared by a military service member as part of that person's official duties.

The authors have no conflict of interest or financial disclosure to report.

#### **Author details**

Jeffrey M. Carness1 \* and Mark J. Lenart<sup>2</sup>

1 United States Naval Hospital, Bremerton, Washington, USA

2 Naval Medical Center, Portsmouth, Virginia, USA

\*Address all correspondence to: jeffrey.m.carness.mil@mail.mil

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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[2] Barker AE. A report on clinical experiences with spinal analgesia in 100 cases, and some reflections on the procedure. British Medical Journal. 1907;**1**(2412):665-674

[3] Axelrod EH, Alexander GD, Brown M, Schork MA. Procaine spinal anesthesia: A pilot study of the incidence of transient neurologic symptoms. Journal of Clinical Anesthesia. 1998;**10**(5):404-409

[4] Johnson S. Cocaine to procaine: An unexpected history of local anaesthesia. Biomedical Journal of Scientific & Technical Research. 2018;**7**(2):1-4. DOI: 10.26717/ BJSTR.2018.07.001467

[5] Jones WH. Percaine: A new regional and spinal analgesic, with special reference to high thoracic nerve root block and a new technique. Proceedings of the Royal Society of Medicine. 1930;**23**(7):919-928

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[14] Hampl KF, Heinzmann-Wiedmer S, Luginbuehl I, Harms C, Seeberger M, Schneider MC, et al. Transient neurologic symptoms after spinal anesthesia: A lower incidence with prilocaine and bupivacaine than with lidocaine. Anesthesiology. 1998;**88**(3):629-633

[15] Manassero A, Fanelli A. Prilocaine hydrochloride 2% hyperbaric solution for intrathecal injection: A clinical review. Local and Regional Anesthesia. 2017;**10**:15-24. DOI: 10.2147/LRA. S112756

[16] Ekblom L, Widman B. LAC-43 and tetracaine in spinal anaesthesia. A controlled clinical study. Acta Anaesthesiologica Scandinavica. Supplementum. 1966;**23**:419-425

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European Journal of Anaesthesiology. 2014;**31**(11):575-585. DOI: 10.1097/

Waxman SG. Modulation of impulse conduction along the axonal tree. Annual Review of Biophysics and Bioengineering. 1980;**9**:143-179

EJA.0000000000000137

[26] Swadlow HA, Kocsis JD,

[27] Raymond SA. Subblocking concentrations of local anesthetics: Effects on impulse generation and conduction in single myelinated sciatic nerve axons in frog. Anesthesia and Analgesia. 1992;**75**(6):906-921. DOI: 10.1213/00000539-199212000-00008

[28] Sugiyama K, Muteki T. Local anesthetics depress the calcium current of rat sensory neurons in culture. Anesthesiology. 1994;**80**(6):1369-1378. DOI:

10.1097/00000542-199406000-00025

Strichartz GR, et al. Local anesthetics inhibit substance P binding and evoked increases in intracellular Ca2+.

[29] Li YM, Wingrove DE, Too HP, Marnerakis M, Stimson ER,

[30] Nordmark J, Rydqvist B. Local anaesthetics potentiate GABA-mediated Cl- currents by inhibiting GABA uptake.

Neuroreport. 1997;**8**(2):465-468

[31] Greene NM. Distribution of local anesthetic solutions within the subarachnoid space. Anesthesia and Analgesia. 1985;**64**(7):715-730

[32] Sakka L, Coll G, Chazal J. Anatomy and physiology of cerebrospinal fluid. European Annals of

Otorhinolaryngology, Head and Neck Diseases. 2011;**128**(6):309-316. DOI:

[33] Higuchi H, Hirata J, Adachi Y, Kazama T. Influence of lumbosacral

10.1016/j.anorl.2011.03.002

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199501000-00021

*DOI: http://dx.doi.org/10.5772/intechopen.88528*

[18] van Kleef JW, Veering BT, Burm AG. Spinal anesthesia with ropivacaine: A double-blind study on the efficacy and safety of 0.5% and 0.75% solutions in patients undergoing minor lower limb surgery. Anesthesia and Analgesia. 1994;**78**(6):1125-1130

[19] Wahedi W, Nolte H, Klein P. Ropivacaine for spinal anesthesia. A dose-finding study. Der Anaesthesist.

10.1097/00000542-199801000-00025

10.1097/00000542-199911000-00013

[21] Burlacu CL, Buggy DJ. Update on local anesthetics: Focus on levobupivacaine. Therapeutics and Clinical Risk Management. 2008;**4**(2):381-392. DOI: 10.2147/tcrm.

McDonald SB, Liu SS. Hyperbaric spinal levobupivacaine: A comparison to racemic bupivacaine in volunteers.

[23] Glaser C, Marhofer P, Zimpfer G, Heinz MT, Sitzwohl C, Kapral S, et al. Levobupivacaine versus racemic bupivacaine for spinal anesthesia.

[24] Olschewski A, Hempelmann G, Vogel W, Safronov BV. Blockade of Na+ and K+ currents by local anesthetics in the dorsal horn neurons of the spinal cord. Anesthesiology.

10.1097/00000542-199801000-00025

[25] Lirk P, Picardi S, Hollmann MW. Local anaesthetics: 10 essentials.

1996;**45**(8):737-744. DOI:

[20] Gautier PE, De Kock M, Van Steenberge A, Poth N, Lahaye-Goffart B, Fanard L, et al. Intrathecal ropivacaine for ambulatory

surgery. Anesthesiology. 1999;**91**(5):1239-1245. DOI:

[22] Alley EA, Kopacz DJ,

Anesthesia and Analgesia. 2002;**94**(1):188-193

Anesthesia and Analgesia. 2002;**94**(1):194-198

1998;**88**(1):172-179. DOI:

s1433

*Current Local Anesthetic Applications in Regional Anesthesia DOI: http://dx.doi.org/10.5772/intechopen.88528*

[18] van Kleef JW, Veering BT, Burm AG. Spinal anesthesia with ropivacaine: A double-blind study on the efficacy and safety of 0.5% and 0.75% solutions in patients undergoing minor lower limb surgery. Anesthesia and Analgesia. 1994;**78**(6):1125-1130

[19] Wahedi W, Nolte H, Klein P. Ropivacaine for spinal anesthesia. A dose-finding study. Der Anaesthesist. 1996;**45**(8):737-744. DOI: 10.1097/00000542-199801000-00025

[20] Gautier PE, De Kock M, Van Steenberge A, Poth N, Lahaye-Goffart B, Fanard L, et al. Intrathecal ropivacaine for ambulatory surgery. Anesthesiology. 1999;**91**(5):1239-1245. DOI: 10.1097/00000542-199911000-00013

[21] Burlacu CL, Buggy DJ. Update on local anesthetics: Focus on levobupivacaine. Therapeutics and Clinical Risk Management. 2008;**4**(2):381-392. DOI: 10.2147/tcrm. s1433

[22] Alley EA, Kopacz DJ, McDonald SB, Liu SS. Hyperbaric spinal levobupivacaine: A comparison to racemic bupivacaine in volunteers. Anesthesia and Analgesia. 2002;**94**(1):188-193

[23] Glaser C, Marhofer P, Zimpfer G, Heinz MT, Sitzwohl C, Kapral S, et al. Levobupivacaine versus racemic bupivacaine for spinal anesthesia. Anesthesia and Analgesia. 2002;**94**(1):194-198

[24] Olschewski A, Hempelmann G, Vogel W, Safronov BV. Blockade of Na+ and K+ currents by local anesthetics in the dorsal horn neurons of the spinal cord. Anesthesiology. 1998;**88**(1):172-179. DOI: 10.1097/00000542-199801000-00025

[25] Lirk P, Picardi S, Hollmann MW. Local anaesthetics: 10 essentials.

European Journal of Anaesthesiology. 2014;**31**(11):575-585. DOI: 10.1097/ EJA.0000000000000137

[26] Swadlow HA, Kocsis JD, Waxman SG. Modulation of impulse conduction along the axonal tree. Annual Review of Biophysics and Bioengineering. 1980;**9**:143-179

[27] Raymond SA. Subblocking concentrations of local anesthetics: Effects on impulse generation and conduction in single myelinated sciatic nerve axons in frog. Anesthesia and Analgesia. 1992;**75**(6):906-921. DOI: 10.1213/00000539-199212000-00008

[28] Sugiyama K, Muteki T. Local anesthetics depress the calcium current of rat sensory neurons in culture. Anesthesiology. 1994;**80**(6):1369-1378. DOI: 10.1097/00000542-199406000-00025

[29] Li YM, Wingrove DE, Too HP, Marnerakis M, Stimson ER, Strichartz GR, et al. Local anesthetics inhibit substance P binding and evoked increases in intracellular Ca2+. Anesthesiology. 1995;**82**(1): 166-173. DOI: 10.1097/00000542- 199501000-00021

[30] Nordmark J, Rydqvist B. Local anaesthetics potentiate GABA-mediated Cl- currents by inhibiting GABA uptake. Neuroreport. 1997;**8**(2):465-468

[31] Greene NM. Distribution of local anesthetic solutions within the subarachnoid space. Anesthesia and Analgesia. 1985;**64**(7):715-730

[32] Sakka L, Coll G, Chazal J. Anatomy and physiology of cerebrospinal fluid. European Annals of Otorhinolaryngology, Head and Neck Diseases. 2011;**128**(6):309-316. DOI: 10.1016/j.anorl.2011.03.002

[33] Higuchi H, Hirata J, Adachi Y, Kazama T. Influence of lumbosacral

**92**

*Topics in Local Anesthetics*

& Pain. 2005;**5**(3):98-100

1907;**1**(2412):665-674

[1] Richardson J, Groen GJ. Applied epidural anatomy. Continuing

[2] Barker AE. A report on clinical experiences with spinal analgesia in 100 cases, and some reflections on the procedure. British Medical Journal.

[3] Axelrod EH, Alexander GD, Brown M, Schork MA. Procaine spinal

anesthesia: A pilot study of the incidence of transient neurologic symptoms. Journal of Clinical Anesthesia. 1998;**10**(5):404-409

[4] Johnson S. Cocaine to procaine: An unexpected history of local anaesthesia. Biomedical Journal of Scientific & Technical Research. 2018;**7**(2):1-4. DOI: 10.26717/ BJSTR.2018.07.001467

[5] Jones WH. Percaine: A new regional and spinal analgesic, with special reference to high thoracic nerve root block and a new technique. Proceedings of the Royal Society of Medicine.

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[79] Kurz A, Sessler DI, Schroeder M, Kurz M. Thermoregulatory response thresholds during spinal anesthesia. Anesthesia and Analgesia. 1993;**77**(4):721-726

[80] Joris J, Ozaki M, Sessler DI, Hardy AF, Lamy M, McGuire J, et al. Epidural anesthesia impairs both central and peripheral thermoregulatory control during general anesthesia. Anesthesiology. 1994;**80**(2):268-277. DOI: 10.1097/00000542-199402000-00006

[81] Saito T, Sessler DI, Fujita K, Ooi Y, Jeffrey R. Thermoregulatory effects of spinal and epidural anesthesia during cesarean delivery. Regional Anesthesia and Pain Medicine. 1998;**23**(4):418-423

[82] Kwak KH. Postdural puncture headache. Korean Journal of Anesthesiology. 2017;**70**(2):136-143. DOI: 10.4097/kjae.2017.70.2.136

[83] Sprung J, Bourke DL, Contreras MG, Warner ME, Findlay J. Perioperative hearing impairment. Anesthesiology. 2003;**98**(1):241-257

[84] Bromage PR. Epidural Analgesia. Philadelphia: Saunders; 1978

[85] Reina MA, Villanueva MC, Maches F, Carrera A, Lopez A, De Andres JA. The ultrastructure of the human spinal nerve root cuff in the lumbar spine. Anesthesia and Analgesia. 2008;**106**(1):339-344. DOI: 10.1213/01. ane.0000295803.31074.dc

[86] Tretjakoff D. Das epidurales Fettgewebe. Zeitschrift fur Anatomie und Entwicklungsgeschichte. 1926;**79**(1):101-111

[87] Ramsey HJ. Fat in the epidural space in young and adult cats. The American Journal of Anatomy. 1959;**104**:345-379

[88] Burm AG. Clinical pharmacokinetics of epidural and spinal anaesthesia. Clinical Pharmacokinetics. 1989;**16**(5): 283-311

[89] Hogan Q. Distribution of solution in the epidural space: Examination by cryomicrotome section. Regional Anesthesia and Pain Medicine. 2002;**27**(2):150-156

[90] Erdemir HA, Soper LE, Sweet RB. Studies of factors affecting peridural anesthesia. Anesthesia and Analgesia. 1965;**44**(4):400-404

[91] Moore PA, Hersh EV. Local anesthetics: Pharmacology and toxicity. Dental Clinics of North America. 2010;**54**(4):587-599. DOI: 10.1016/j. cden.2010.06.015

[92] Covino BG. The pharmacology of local anesthetic agents. In: Stanley TH, Petty WC, editors. Anesthesiology, Developments in Critical Care Medicine and Anesthesiology. Vol. 11. Dordrecht: Springer; 1986

[93] Oda Y, Furuichi K, Tanaka K, Hiroi T, Imaoka S, Asada A, et al. Metabolism of a new local anesthetic, ropivacaine, by human hepatic cytochrome P450. Anesthesiology.

*Topics in Local Anesthetics*

1995;**82**(1):214-220. DOI: 10.1097/00000542-199501000-00026

[94] Bromage PR, Pettigrew RT, Crowell DE. Tachyphylaxis in epidural analgesia: I. Augmentation and decay of local anesthesia. The Journal of Clinical Pharmacology and the Journal of New Drugs. 1969;**9**(1):30-38

**99**

**Chapter 6**

**Abstract**

function.

prilocaine, chloroprocaine

**1. Introduction**

Local Anaesthetics for Spinal

*Margaretha Barbara Breebaart*

Anaesthesia in Day-Case Surgery

Day-case procedures require a high turnover, high quality and low costs. Lidocaine has long been the gold standard for ambulatory spinal anaesthesia. However, the risk of transient neurological symptoms (TNS) limits its use. The perfect local anaesthetic for spinal anaesthesia in day-case surgery should have fast recovery, fast voiding time and a low risk on TNS and urinary retention. Urinary retention is a result of prolonged sensory blockade of the pelvic nerves and is local anaesthetic dose and potency dependent. As a substitute for lidocaine, several local anaesthetics have been suggested in various doses or combinations with or without additives. However, not all are registered for spinal use or have a shortacting profile. The use of additives has been subject of debate because of possible delay in the recovery of bladder. Recently, the old local anaesthetics chloroprocaine and prilocaine were reintroduced in the market. They provide rapid recovery after spinal anaesthesia in day-case surgery. This chapter gives an overview of the local anaesthetics suitable for spinal anaesthesia in day-case surgery, the advantages and disadvantages and the influence on discharge time and recovery of bladder

**Keywords:** spinal anaesthesia, ambulatory surgery, local anaesthetics, urinary retention, transient neurological symptoms, lidocaine, bupivacaine, mepivacaine,

temporary, they affect the quality of care to a great extent.

significantly higher than with other local anaesthetics [2].

hospitals: faster spontaneous voiding results in faster discharge.

Day-case surgical procedures require an anaesthetic technique with the possibility of a high turnover, a high quality of care and low costs [1]. Spinal anaesthesia is an easy and cheap technique, has a fast onset and causes minimal side effects. Urinary retention and transient neurological symptom (TNS) are side effects of spinal anaesthesia and reason for some anaesthetists only to provide general anaesthesia in day-case surgery. Despite the fact that these side effects are mostly

Lidocaine is a short-acting local anaesthetic and was frequently used for spinal anaesthesia in day-case surgery until it became clear that the incidence of TNS is

The ideal spinal anaesthesia for day-case surgery provides a rapid onset and a short duration of action, allowing a fast turnover of patients for a double-bed planning. Spontaneous voiding is still a discharge criterion in our and many other

#### **Chapter 6**

*Topics in Local Anesthetics*

1969;**9**(1):30-38

1995;**82**(1):214-220. DOI:

10.1097/00000542-199501000-00026

Crowell DE. Tachyphylaxis in epidural

[94] Bromage PR, Pettigrew RT,

analgesia: I. Augmentation and decay of local anesthesia. The Journal of Clinical Pharmacology and the Journal of New Drugs.

**98**

## Local Anaesthetics for Spinal Anaesthesia in Day-Case Surgery

*Margaretha Barbara Breebaart*

#### **Abstract**

Day-case procedures require a high turnover, high quality and low costs. Lidocaine has long been the gold standard for ambulatory spinal anaesthesia. However, the risk of transient neurological symptoms (TNS) limits its use. The perfect local anaesthetic for spinal anaesthesia in day-case surgery should have fast recovery, fast voiding time and a low risk on TNS and urinary retention. Urinary retention is a result of prolonged sensory blockade of the pelvic nerves and is local anaesthetic dose and potency dependent. As a substitute for lidocaine, several local anaesthetics have been suggested in various doses or combinations with or without additives. However, not all are registered for spinal use or have a shortacting profile. The use of additives has been subject of debate because of possible delay in the recovery of bladder. Recently, the old local anaesthetics chloroprocaine and prilocaine were reintroduced in the market. They provide rapid recovery after spinal anaesthesia in day-case surgery. This chapter gives an overview of the local anaesthetics suitable for spinal anaesthesia in day-case surgery, the advantages and disadvantages and the influence on discharge time and recovery of bladder function.

**Keywords:** spinal anaesthesia, ambulatory surgery, local anaesthetics, urinary retention, transient neurological symptoms, lidocaine, bupivacaine, mepivacaine, prilocaine, chloroprocaine

#### **1. Introduction**

Day-case surgical procedures require an anaesthetic technique with the possibility of a high turnover, a high quality of care and low costs [1]. Spinal anaesthesia is an easy and cheap technique, has a fast onset and causes minimal side effects. Urinary retention and transient neurological symptom (TNS) are side effects of spinal anaesthesia and reason for some anaesthetists only to provide general anaesthesia in day-case surgery. Despite the fact that these side effects are mostly temporary, they affect the quality of care to a great extent.

Lidocaine is a short-acting local anaesthetic and was frequently used for spinal anaesthesia in day-case surgery until it became clear that the incidence of TNS is significantly higher than with other local anaesthetics [2].

The ideal spinal anaesthesia for day-case surgery provides a rapid onset and a short duration of action, allowing a fast turnover of patients for a double-bed planning. Spontaneous voiding is still a discharge criterion in our and many other hospitals: faster spontaneous voiding results in faster discharge.

Urinary retention after spinal anaesthesia is most often a result of a prolonged sensory blockade of the pelvic nerves. The duration of a spinal block is local anaesthetic dose and potency dependent [3]. The dose of a local anaesthetic to provide adequate surgical anaesthesia can be lowered by using spinal additive drugs [4]. Opioids and clonidine prolong the duration and increase the quality of the sensory nerve block in spinal anaesthesia. By adding spinal clonidine, the local anaesthetic dose can be reduced without increasing the risk of block failure [5]. The question rises if the benefit of lowering local anaesthetic dose outweighs the side effects of the additive administered.

The incidence of urinary retention after spinal anaesthesia has been reported with a high variability. There is neither uniformity nor consensus when to catheterise [6]. Fluid policy has also been a subject of debate. A restrictive fluid policy is a way of preventing bladder filling, but a more liberal schedule could speed up the time to void and fasten discharge time. Furthermore, there is an enormous interpatient variability in bladder capacity and in the definition of urinary retention.

Different techniques exist to perform spinal anaesthesia, producing selective spinal anaesthesia by changing baricity, dose and position, like a saddle block or unilateral anaesthesia. Little is known about the effects of these techniques on the restoration of bladder function.

#### **2. Spinal anaesthesia in day-case surgery**

#### **2.1 History of local anaesthetics for day-case surgery**

In 1954, lidocaine was introduced and became very popular for spinal anaesthesia because of its favourable profile for day-case surgery [7]. In 1993, TNS were described after its use [8]. Subsequently, additional case reports and prospective trials were published about the appearance of TNS with lidocaine [9–11]. In 2005, a meta-analysis from Zaric et al. clearly demonstrated an increased risk when lidocaine was used for spinal anaesthesia. However, many physicians were not really concerned by these symptoms because they were transient and lidocaine remained very popular. Even up to now, some clinicians still prefer lidocaine.

The appearance of TNS did initiate a quest for the replacement of lidocaine to provide cost-effective, short-acting spinal anaesthesia with a low incidence of side effects. It should also be noted that with the progression of modern medicine, patient satisfaction became more important as an indicator of the quality of care. Temporary side effects that were not considered very important previously now became clinically relevant.

#### **2.2 Spinal anaesthesia: advantages and disadvantages**

Spinal anaesthesia is an easy technique that has proven its benefit for many years [12]. After injection of the local anaesthetic solution in the CSF, it provides good surgical anaesthesia for procedures below the umbilicus. The incidence of PONV is low and allows eating and drinking immediately after the procedure.

Although the incidence is low, spinal anaesthesia can fail by producing an insufficient block height or a patchy block [13]. The duration of spinal anaesthesia cannot be extended when the duration of surgery outlasts surgical anaesthesia. When this happens a conversion to general anaesthesia must be made.

Several side effects can occur after injection of the local anaesthetic. Sympathetic block, hypotension and cardiovascular depression can occur, especially when block height exceeds the fifth thoracic dermatome or when patients are of older age [12].

**101**

anaesthesia [32].

of POCD than general anaesthesia [34].

*Local Anaesthetics for Spinal Anaesthesia in Day-Case Surgery*

and PDPH. Bleeding or abscess formation are rare but can occur.

Late side effects from spinal anaesthesia are urinary retention, TNS, backache

TNS are described as a dull bouncing pain or dysesthesia at the gluteal region or lower limbs after spinal anaesthesia. The symptoms mostly occur within 24 h after block regression, and there is an interval of 2–5 h between mobilisation and onset of the symptoms [16]. The pain mostly disappears within 5 days, but a duration of 3 weeks has been described [17]. The aetiology of these symptoms is not well understood. A neurotoxic mechanism is suspected although no neurologic disorders are observed. Lidocaine and mepivacaine show the highest incidence of TNS, but they are described for other local anaesthetics as well [18]. Lidocaine concentration and osmolarity, early ambulation, age, needle size and level of puncture all have been suggested as contributing factors, but the evidence in literature is weak and controversial. Ambulatory anaesthesia, the lithotomy position and knee arthroscopy are

Spinal and general anaesthesia have frequently been compared in literature. In 2005, a meta-analysis compared different locoregional techniques with general anaesthesia for ambulatory surgery [23]. After including 23 trials with more than 1000 patients, it was concluded that general anaesthesia had a faster onset and a 40 min faster discharge time than spinal anaesthesia. However postoperative pain scores and the incidence of PONV were higher for general anaesthesia. Patients were equally satisfied with all techniques. Comparison of costs was not part of the analysis. After this meta-analysis, more recent studies confirmed the delay in discharge but also showed an increase in urinary retention for spinal anaesthesia. Less PONV and lower pain scores after spinal anaesthesia were consistent findings [24–28].

Spinal anaesthesia displays a clear advantage concerning PONV and postoperative pain scores. It is clear that we should improve recovery time and lower the incidence of urinary retention and TNS when spinal anaesthesia has to compete with general anaesthesia. It is important to realise that the choice of drugs and equipment only has a minor contribution in anaesthesia expenses compared to personnel costs. Reducing turnover times and fasten recovery and discharge have an economical benefit because of saving manpower. Unanticipated admissions and the

A limitation in many studies has been the use of long-acting local anaesthetics,

When it comes to difference on the longer-term outcome, there is not much evidence of superiority of spinal or general anaesthesia. One prospective randomised trial with 200 patients suggests that success rate with in vitro fertilisation might be improved from 15 to 27% when spinal anaesthesia is used instead of general

Postoperative cognitive dysfunction (POCD) is a decline in mental status after surgery. The mechanism is not understood. In 2007, a review by Newman showed that there is no difference in the incidence of POCD after general or spinal anaesthesia [33]. However, the author points out that many studies were underpowered and differences in surgery and testing provided difficulties in methodology. For elderly patients undergoing hip replacement, neuraxial anaesthesia lowers the risk

while short-acting local anaesthetics might provide a faster recovery [31].

To prevent PDPH, smaller and non-cutting needles were developed with a pencil-point-shaped tip. This atraumatic needle tip separates the dural fibres rather than cutting them, with a lower risk of CSF leakage after puncture. After introduc-

tion of these needles, the incidence of PDPH dropped to 0.6–3% [14, 15].

*DOI: http://dx.doi.org/10.5772/intechopen.89018*

known to be risk factors [10, 11, 19–22].

**2.3 Comparison with other anaesthetic techniques**

occurrence of side effects are cost-increasing factors [29, 30].

#### *Local Anaesthetics for Spinal Anaesthesia in Day-Case Surgery DOI: http://dx.doi.org/10.5772/intechopen.89018*

*Topics in Local Anesthetics*

restoration of bladder function.

became clinically relevant.

**2. Spinal anaesthesia in day-case surgery**

**2.1 History of local anaesthetics for day-case surgery**

very popular. Even up to now, some clinicians still prefer lidocaine.

low and allows eating and drinking immediately after the procedure.

When this happens a conversion to general anaesthesia must be made. Several side effects can occur after injection of the local anaesthetic.

**2.2 Spinal anaesthesia: advantages and disadvantages**

Urinary retention after spinal anaesthesia is most often a result of a prolonged sensory blockade of the pelvic nerves. The duration of a spinal block is local anaesthetic dose and potency dependent [3]. The dose of a local anaesthetic to provide adequate surgical anaesthesia can be lowered by using spinal additive drugs [4]. Opioids and clonidine prolong the duration and increase the quality of the sensory nerve block in spinal anaesthesia. By adding spinal clonidine, the local anaesthetic dose can be reduced without increasing the risk of block failure [5]. The question rises if the benefit of lowering local anaesthetic dose outweighs the side effects of the additive administered. The incidence of urinary retention after spinal anaesthesia has been reported with a high variability. There is neither uniformity nor consensus when to catheterise [6]. Fluid policy has also been a subject of debate. A restrictive fluid policy is a way of preventing bladder filling, but a more liberal schedule could speed up the time to void and fasten discharge time. Furthermore, there is an enormous interpatient variability in bladder capacity and in the definition of urinary retention. Different techniques exist to perform spinal anaesthesia, producing selective spinal anaesthesia by changing baricity, dose and position, like a saddle block or unilateral anaesthesia. Little is known about the effects of these techniques on the

In 1954, lidocaine was introduced and became very popular for spinal anaesthesia because of its favourable profile for day-case surgery [7]. In 1993, TNS were described after its use [8]. Subsequently, additional case reports and prospective trials were published about the appearance of TNS with lidocaine [9–11]. In 2005, a meta-analysis from Zaric et al. clearly demonstrated an increased risk when lidocaine was used for spinal anaesthesia. However, many physicians were not really concerned by these symptoms because they were transient and lidocaine remained

The appearance of TNS did initiate a quest for the replacement of lidocaine to provide cost-effective, short-acting spinal anaesthesia with a low incidence of side effects. It should also be noted that with the progression of modern medicine, patient satisfaction became more important as an indicator of the quality of care. Temporary side effects that were not considered very important previously now

Spinal anaesthesia is an easy technique that has proven its benefit for many years [12]. After injection of the local anaesthetic solution in the CSF, it provides good surgical anaesthesia for procedures below the umbilicus. The incidence of PONV is

Although the incidence is low, spinal anaesthesia can fail by producing an insufficient block height or a patchy block [13]. The duration of spinal anaesthesia cannot be extended when the duration of surgery outlasts surgical anaesthesia.

Sympathetic block, hypotension and cardiovascular depression can occur, especially when block height exceeds the fifth thoracic dermatome or when patients are of

**100**

older age [12].

Late side effects from spinal anaesthesia are urinary retention, TNS, backache and PDPH. Bleeding or abscess formation are rare but can occur.

To prevent PDPH, smaller and non-cutting needles were developed with a pencil-point-shaped tip. This atraumatic needle tip separates the dural fibres rather than cutting them, with a lower risk of CSF leakage after puncture. After introduction of these needles, the incidence of PDPH dropped to 0.6–3% [14, 15].

TNS are described as a dull bouncing pain or dysesthesia at the gluteal region or lower limbs after spinal anaesthesia. The symptoms mostly occur within 24 h after block regression, and there is an interval of 2–5 h between mobilisation and onset of the symptoms [16]. The pain mostly disappears within 5 days, but a duration of 3 weeks has been described [17]. The aetiology of these symptoms is not well understood. A neurotoxic mechanism is suspected although no neurologic disorders are observed. Lidocaine and mepivacaine show the highest incidence of TNS, but they are described for other local anaesthetics as well [18]. Lidocaine concentration and osmolarity, early ambulation, age, needle size and level of puncture all have been suggested as contributing factors, but the evidence in literature is weak and controversial. Ambulatory anaesthesia, the lithotomy position and knee arthroscopy are known to be risk factors [10, 11, 19–22].

#### **2.3 Comparison with other anaesthetic techniques**

Spinal and general anaesthesia have frequently been compared in literature. In 2005, a meta-analysis compared different locoregional techniques with general anaesthesia for ambulatory surgery [23]. After including 23 trials with more than 1000 patients, it was concluded that general anaesthesia had a faster onset and a 40 min faster discharge time than spinal anaesthesia. However postoperative pain scores and the incidence of PONV were higher for general anaesthesia. Patients were equally satisfied with all techniques. Comparison of costs was not part of the analysis. After this meta-analysis, more recent studies confirmed the delay in discharge but also showed an increase in urinary retention for spinal anaesthesia. Less PONV and lower pain scores after spinal anaesthesia were consistent findings [24–28].

Spinal anaesthesia displays a clear advantage concerning PONV and postoperative pain scores. It is clear that we should improve recovery time and lower the incidence of urinary retention and TNS when spinal anaesthesia has to compete with general anaesthesia. It is important to realise that the choice of drugs and equipment only has a minor contribution in anaesthesia expenses compared to personnel costs. Reducing turnover times and fasten recovery and discharge have an economical benefit because of saving manpower. Unanticipated admissions and the occurrence of side effects are cost-increasing factors [29, 30].

A limitation in many studies has been the use of long-acting local anaesthetics, while short-acting local anaesthetics might provide a faster recovery [31].

When it comes to difference on the longer-term outcome, there is not much evidence of superiority of spinal or general anaesthesia. One prospective randomised trial with 200 patients suggests that success rate with in vitro fertilisation might be improved from 15 to 27% when spinal anaesthesia is used instead of general anaesthesia [32].

Postoperative cognitive dysfunction (POCD) is a decline in mental status after surgery. The mechanism is not understood. In 2007, a review by Newman showed that there is no difference in the incidence of POCD after general or spinal anaesthesia [33]. However, the author points out that many studies were underpowered and differences in surgery and testing provided difficulties in methodology. For elderly patients undergoing hip replacement, neuraxial anaesthesia lowers the risk of POCD than general anaesthesia [34].

#### **2.4 Spinal anaesthesia and bladder function**

Neuraxial anaesthesia increases the risk of urinary retention since the neurophysiology of the bladder is temporarily disturbed. The duration is dependent on the local anaesthetic used [3, 35, 36]. The temporary malfunction of the detrusor muscle and the lack of urge sensation during spinal anaesthesia increase the risk of bladder distension.

The time for the bladder function to restore relates to the duration of the block, which is determined by local anaesthetic potency and dose. When long-acting local anaesthetics are used, more time is required before bladder function is restored than short-acting substances. When local anaesthetic dose is increased, the time to void is prolonged as well. This causes variable times to void after spinal anaesthesia, ranging from 103 (chloroprocaine) to 462 min (bupivacaine) [3, 37]. To prevent bladder retention in an outpatient setting, the use of short-acting local anaesthetics and voiding before surgery is recommended [38].

In a day-case setting, the incidence of urinary retention after spinal anaesthesia varies between 0 and 30%, although there is consensus that the mean incidence is around 2% [3]. This variability can be explained by the difference in definition, catheterisation protocol and surgical procedure between the reported trials. There are a lot of studies concerning spinal anaesthesia in day-case surgery where urinary retention is not even mentioned. It is remarkable though that when trials were designed to study bladder function, high incidences like 23–30% are found [39, 40]. This may be explained by the closer monitoring of bladder volume.

#### **2.5 Modifying spinal anaesthesia**

Different aspects of spinal anaesthesia can be modified (**Figure 1**). Changing the solution for spinal injection, the anaesthetic technique or fluid policy can influence the duration of the sensory and motor block, the risk of certain side effects or discharge time. Modifying certain discharge criteria, like the necessity to void, can influence discharge time as well.

**103**

**Figure 2.**

*Different local anaesthetics and year of production.*

*Local Anaesthetics for Spinal Anaesthesia in Day-Case Surgery*

more local anaesthetics have been produced (**Figure 2**).

When a local anaesthetic substance is injected into the CSF, it diffuses through the lipophilic nerve membrane and reaches the sodium channel [41]. As a consequence, the sodium channel is blocked and impulses cannot be conducted along the different nerve fibres. This results in a sensory, motor and sympathetic block. After a certain period, the local anaesthetic molecules dissociate from the sodium channel and are absorbed in the blood stream to be degraded. Local anaesthetics are divided in two groups: amides and esters. Amides are degraded by the liver, and esters are rapidly hydrolysed by pseudocholinesterases in the blood stream. Every local anaesthetic has its own pharmacologic properties (pKa, liposolubility, protein binding), which not only determine the potency but also the onset and duration of the spinal block [42]. Since the first spinal anaesthesia was performed with cocaine,

The duration of the sensory and motor block is dose dependent in neuraxial anaesthesia. Increasing local anaesthetic dose prolongs motor and sensory block. Winnie stated that locoregional anaesthesia always works provided you put the right dose of the right drug in the right place. This is also true for spinal anaesthesia. Unfortunately for spinal anaesthesia in day-case surgery, a working spinal

*DOI: http://dx.doi.org/10.5772/intechopen.89018*

*2.5.1 Local anaesthetics*

**Figure 1.** *Variables in spinal anaesthesia for day-case surgery.*

#### *2.5.1 Local anaesthetics*

*Topics in Local Anesthetics*

bladder distension.

**2.4 Spinal anaesthesia and bladder function**

and voiding before surgery is recommended [38].

**2.5 Modifying spinal anaesthesia**

influence discharge time as well.

*Variables in spinal anaesthesia for day-case surgery.*

This may be explained by the closer monitoring of bladder volume.

Neuraxial anaesthesia increases the risk of urinary retention since the neurophysiology of the bladder is temporarily disturbed. The duration is dependent on the local anaesthetic used [3, 35, 36]. The temporary malfunction of the detrusor muscle and the lack of urge sensation during spinal anaesthesia increase the risk of

The time for the bladder function to restore relates to the duration of the block, which is determined by local anaesthetic potency and dose. When long-acting local anaesthetics are used, more time is required before bladder function is restored than short-acting substances. When local anaesthetic dose is increased, the time to void is prolonged as well. This causes variable times to void after spinal anaesthesia, ranging from 103 (chloroprocaine) to 462 min (bupivacaine) [3, 37]. To prevent bladder retention in an outpatient setting, the use of short-acting local anaesthetics

In a day-case setting, the incidence of urinary retention after spinal anaesthesia varies between 0 and 30%, although there is consensus that the mean incidence is around 2% [3]. This variability can be explained by the difference in definition, catheterisation protocol and surgical procedure between the reported trials. There are a lot of studies concerning spinal anaesthesia in day-case surgery where urinary retention is not even mentioned. It is remarkable though that when trials were designed to study bladder function, high incidences like 23–30% are found [39, 40].

Different aspects of spinal anaesthesia can be modified (**Figure 1**). Changing the

solution for spinal injection, the anaesthetic technique or fluid policy can influence the duration of the sensory and motor block, the risk of certain side effects or discharge time. Modifying certain discharge criteria, like the necessity to void, can

**102**

**Figure 1.**

When a local anaesthetic substance is injected into the CSF, it diffuses through the lipophilic nerve membrane and reaches the sodium channel [41]. As a consequence, the sodium channel is blocked and impulses cannot be conducted along the different nerve fibres. This results in a sensory, motor and sympathetic block. After a certain period, the local anaesthetic molecules dissociate from the sodium channel and are absorbed in the blood stream to be degraded. Local anaesthetics are divided in two groups: amides and esters. Amides are degraded by the liver, and esters are rapidly hydrolysed by pseudocholinesterases in the blood stream. Every local anaesthetic has its own pharmacologic properties (pKa, liposolubility, protein binding), which not only determine the potency but also the onset and duration of the spinal block [42]. Since the first spinal anaesthesia was performed with cocaine, more local anaesthetics have been produced (**Figure 2**).

The duration of the sensory and motor block is dose dependent in neuraxial anaesthesia. Increasing local anaesthetic dose prolongs motor and sensory block. Winnie stated that locoregional anaesthesia always works provided you put the right dose of the right drug in the right place. This is also true for spinal anaesthesia. Unfortunately for spinal anaesthesia in day-case surgery, a working spinal

**Figure 2.** *Different local anaesthetics and year of production.*

anaesthesia is not enough. The duration of the spinal block should be short but long enough to do provide surgical anaesthesia with a minimal risk of insufficient block height and with minimal side effects.

Lidocaine has always been a popular drug for spinal anaesthesia. It can provide 60 min of anaesthesia below the umbilicus with minimal time to achieve discharge criteria [43, 44]. The question arises if lidocaine should still be used in the twentyfirst century because of its side effects, and many studies have compared it to its alternatives [45, 46].

Bupivacaine is a long-acting local anaesthetic from the amide group and has a low incidence of TNS. It has been the most common alternative for lidocaine for years. Because of its pharmacological profile, the recovery of motor and sensory block is delayed compared to short-acting local anaesthetics. The incidence of postoperative urinary retention with long-acting local anaesthetics like bupivacaine and tetracaine is higher than with short-acting local anaesthetics [3, 47]. Successful spinal anaesthesia with low doses of bupivacaine between 5 and 10 mg without additives has been described for outpatients. The incidence of urinary retention was still 3.7–16% [48, 49]. Furthermore, with these low doses, block height becomes unpredictable and the risk of block failure is high [48, 50, 51]. A meta-analysis of 17 trials looked at the use of bupivacaine for ambulatory knee arthroscopy. This paper warned for an increased risk of a failed block with doses below 7.5 mg, unless a unilateral spinal technique was used or additives were administered to the solution [52].

Other local anaesthetics like procaine and mepivacaine also have a considerable risk of TNS or have an unfavourable profile regarding block resolution and discharge times [53, 54].

Levobupivacaine and ropivacaine are both amide local anaesthetics that have similar properties to bupivacaine. Ropivacaine also is a pure enantiomer, is less potent and produces less motor block than bupivacaine. Both products are not officially registered for spinal use but used "off-label" frequently. The recovery and discharge for ambulatory surgery is not as fast as lidocaine, and micturition problems are comparable [55]. There is controversy about the suggested faster recovery of ropivacaine compared to bupivacaine [56].

Although there is enough literature to support the use of these two products for spinal anaesthesia for ambulatory surgery, reintroduction of chloroprocaine and prilocaine, which are in many countries registered for spinal use, seems to have more advantages [57–59].

Chloroprocaine is a local anaesthetic from the ester group. It has a fast- and short-acting profile. It became unpopular in the 1950s after the publication of toxic neurologic symptoms, which were probably caused by the additives in the solution. The additive-free form is now approved an available for spinal use in Europe and is considered safe [60–62]. It has been shown to be suitable for spinal anaesthesia in day-case surgery and has a faster regression than long-acting local anaesthetics and available short-acting local anaesthetics [60]. The recommended dose varies between 40 and 60 mg for ambulatory surgery. Discharge times between 178 and 277 min are found. Up to date only one patient has been reported with TNS after spinal anaesthesia with chloroprocaine, demonstrating the low incidence of TNS and suitability for day-case surgery [63]. Furthermore the frequency of bladder retention is very low, even when a fluid preload is administered [64].

A meta-analyses of the advantage of the pharmacokinetic profile proofed to translate in a clinical advantage such as faster block regression, ambulation and discharge as well [65].

Prilocaine is an amide local anaesthetic with an intermediate duration of action after spinal administration. It never gained much attention because of the popularity of lidocaine. It is available in the hyperbaric form and provides anaesthesia for

**105**

*2.5.3 Additives*

*Local Anaesthetics for Spinal Anaesthesia in Day-Case Surgery*

75–90 min after spinal administration. The duration of the spinal block is prolonged compared to an equal dose of lidocaine, but combined with fentanyl it is a better alternative than bupivacaine for ambulatory knee arthroscopy [66]. Doses between 20 and 70 mg are described in literature, but 50 mg hyperbaric prilocaine seems sufficient for day-case arthroscopies, although rescue analgesia was necessary in 11 and 7.5% of the patients [67, 68]. The ED90 was 38 mg for bilateral spinal anaesthe-

The incidence of urinary retention after 60 mg prilocaine in a day-case setting was described as high as 23% [40]. Articaine is an amide local anaesthetic with intermediate potency and a short duration of action. It is an amide but differs slightly because it also contains an ester group and can be hydrolysed. Further metabolism and excretion is primarily in the kidneys [70]. Articaine provides faster motor and sensory block regression and earlier spontaneous voiding than prilocaine; low-dose bupivacaine and lidocaine A comparison of equal doses of spinal articaine and chloroprocaine showed faster block regression for chloroprocaine [71]. Unfortunately, articaine is not available everywhere and its use is off-label.

The baricity of a local anaesthetic is defined as its density compared to the density of the CSF**.** Baricity partly determines the spread of the molecules in the CSF after injection. The molecules sink or float in the CSF depending on their relative gravity. Most local anaesthetics are isobaric or slightly hypobaric. It must be remembered that an increase in temperature of the solution can change baricity, making isobaric substances slightly hypobaric once injected [72]. Hyperbaric

When hyperbaric or hypobaric substances are used for spinal anaesthesia, the spread of the local anaesthetic can be influenced by changing the position of the patient. Hyperbaric substances might have a more favourable profile because of faster block regression. Hyperbaric lidocaine, ropivacaine and bupivacaine showed faster recovery than the plain solutions and with higher or comparable cephalad spread [73–76]. No differences were found between hyperbaric and plain chloroprocaine [77]. It is believed that hyperbaric substances produce a more cephalad block spread because the molecules are dragged down over the lumbar curve to the lowest level of the thoracic kyphosis when the patient is allowed to resume the supine position. This more cephalad spread of local anaesthetic might result in a dilution of molecules in the CSF and thus a lower "mg per segment" concentration. The time necessary to absorb the local anaesthetic molecules is shorter because of a lower concentration which might explain faster block regression of a hyperbaric

Local anaesthetics can be combined with other drugs to prolong the duration of sensory or motor block or increase the level or intensity of sensory analgesia. It also allows local anaesthetic dose reduction without shortening the duration of the block but with a more favourable recovery profile. For day-case surgery, several additives

Intrathecal opioids have a direct analgesic effect after binding on the opioids receptors that are present at the spinal cord level. This is mainly through their effect on the C and A-delta fibres. The mechanism by which opioids and local anaesthetics interact is not fully understood but results in an increased somatic analgesia without influencing motor or sympathetic blockade. Intrathecal lipophilic opioids, like

were studied to reduce local anaesthetic dose in a day-case setting.

substances are also available. These solutions contain glucose.

substance than a plain local anaesthetic [78].

*DOI: http://dx.doi.org/10.5772/intechopen.89018*

sia for knee arthroscopies [69].

*2.5.2 Baricity*

#### *Local Anaesthetics for Spinal Anaesthesia in Day-Case Surgery DOI: http://dx.doi.org/10.5772/intechopen.89018*

75–90 min after spinal administration. The duration of the spinal block is prolonged compared to an equal dose of lidocaine, but combined with fentanyl it is a better alternative than bupivacaine for ambulatory knee arthroscopy [66]. Doses between 20 and 70 mg are described in literature, but 50 mg hyperbaric prilocaine seems sufficient for day-case arthroscopies, although rescue analgesia was necessary in 11 and 7.5% of the patients [67, 68]. The ED90 was 38 mg for bilateral spinal anaesthesia for knee arthroscopies [69].

The incidence of urinary retention after 60 mg prilocaine in a day-case setting was described as high as 23% [40]. Articaine is an amide local anaesthetic with intermediate potency and a short duration of action. It is an amide but differs slightly because it also contains an ester group and can be hydrolysed. Further metabolism and excretion is primarily in the kidneys [70]. Articaine provides faster motor and sensory block regression and earlier spontaneous voiding than prilocaine; low-dose bupivacaine and lidocaine A comparison of equal doses of spinal articaine and chloroprocaine showed faster block regression for chloroprocaine [71]. Unfortunately, articaine is not available everywhere and its use is off-label.

#### *2.5.2 Baricity*

*Topics in Local Anesthetics*

alternatives [45, 46].

charge times [53, 54].

more advantages [57–59].

discharge as well [65].

of ropivacaine compared to bupivacaine [56].

height and with minimal side effects.

anaesthesia is not enough. The duration of the spinal block should be short but long enough to do provide surgical anaesthesia with a minimal risk of insufficient block

Lidocaine has always been a popular drug for spinal anaesthesia. It can provide 60 min of anaesthesia below the umbilicus with minimal time to achieve discharge criteria [43, 44]. The question arises if lidocaine should still be used in the twentyfirst century because of its side effects, and many studies have compared it to its

Bupivacaine is a long-acting local anaesthetic from the amide group and has a low incidence of TNS. It has been the most common alternative for lidocaine for years. Because of its pharmacological profile, the recovery of motor and sensory block is delayed compared to short-acting local anaesthetics. The incidence of postoperative urinary retention with long-acting local anaesthetics like bupivacaine and tetracaine is higher than with short-acting local anaesthetics [3, 47]. Successful spinal anaesthesia with low doses of bupivacaine between 5 and 10 mg without additives has been described for outpatients. The incidence of urinary retention was still 3.7–16% [48, 49]. Furthermore, with these low doses, block height becomes unpredictable and the risk of block failure is high [48, 50, 51]. A meta-analysis of 17 trials looked at the use of bupivacaine for ambulatory knee arthroscopy. This paper warned for an increased risk of a failed block with doses below 7.5 mg, unless a unilateral spinal

Other local anaesthetics like procaine and mepivacaine also have a considerable

Levobupivacaine and ropivacaine are both amide local anaesthetics that have similar properties to bupivacaine. Ropivacaine also is a pure enantiomer, is less potent and produces less motor block than bupivacaine. Both products are not officially registered for spinal use but used "off-label" frequently. The recovery and discharge for ambulatory surgery is not as fast as lidocaine, and micturition problems are comparable [55]. There is controversy about the suggested faster recovery

Although there is enough literature to support the use of these two products for spinal anaesthesia for ambulatory surgery, reintroduction of chloroprocaine and prilocaine, which are in many countries registered for spinal use, seems to have

Chloroprocaine is a local anaesthetic from the ester group. It has a fast- and short-acting profile. It became unpopular in the 1950s after the publication of toxic neurologic symptoms, which were probably caused by the additives in the solution. The additive-free form is now approved an available for spinal use in Europe and is considered safe [60–62]. It has been shown to be suitable for spinal anaesthesia in day-case surgery and has a faster regression than long-acting local anaesthetics and available short-acting local anaesthetics [60]. The recommended dose varies between 40 and 60 mg for ambulatory surgery. Discharge times between 178 and 277 min are found. Up to date only one patient has been reported with TNS after spinal anaesthesia with chloroprocaine, demonstrating the low incidence of TNS and suitability for day-case surgery [63]. Furthermore the frequency of bladder

A meta-analyses of the advantage of the pharmacokinetic profile proofed to translate in a clinical advantage such as faster block regression, ambulation and

Prilocaine is an amide local anaesthetic with an intermediate duration of action after spinal administration. It never gained much attention because of the popularity of lidocaine. It is available in the hyperbaric form and provides anaesthesia for

retention is very low, even when a fluid preload is administered [64].

risk of TNS or have an unfavourable profile regarding block resolution and dis-

technique was used or additives were administered to the solution [52].

**104**

The baricity of a local anaesthetic is defined as its density compared to the density of the CSF**.** Baricity partly determines the spread of the molecules in the CSF after injection. The molecules sink or float in the CSF depending on their relative gravity. Most local anaesthetics are isobaric or slightly hypobaric. It must be remembered that an increase in temperature of the solution can change baricity, making isobaric substances slightly hypobaric once injected [72]. Hyperbaric substances are also available. These solutions contain glucose.

When hyperbaric or hypobaric substances are used for spinal anaesthesia, the spread of the local anaesthetic can be influenced by changing the position of the patient. Hyperbaric substances might have a more favourable profile because of faster block regression. Hyperbaric lidocaine, ropivacaine and bupivacaine showed faster recovery than the plain solutions and with higher or comparable cephalad spread [73–76]. No differences were found between hyperbaric and plain chloroprocaine [77]. It is believed that hyperbaric substances produce a more cephalad block spread because the molecules are dragged down over the lumbar curve to the lowest level of the thoracic kyphosis when the patient is allowed to resume the supine position. This more cephalad spread of local anaesthetic might result in a dilution of molecules in the CSF and thus a lower "mg per segment" concentration. The time necessary to absorb the local anaesthetic molecules is shorter because of a lower concentration which might explain faster block regression of a hyperbaric substance than a plain local anaesthetic [78].

#### *2.5.3 Additives*

Local anaesthetics can be combined with other drugs to prolong the duration of sensory or motor block or increase the level or intensity of sensory analgesia. It also allows local anaesthetic dose reduction without shortening the duration of the block but with a more favourable recovery profile. For day-case surgery, several additives were studied to reduce local anaesthetic dose in a day-case setting.

Intrathecal opioids have a direct analgesic effect after binding on the opioids receptors that are present at the spinal cord level. This is mainly through their effect on the C and A-delta fibres. The mechanism by which opioids and local anaesthetics interact is not fully understood but results in an increased somatic analgesia without influencing motor or sympathetic blockade. Intrathecal lipophilic opioids, like

fentanyl and sufentanil, increase the quality and prolong the duration of sensory analgesia after spinal anaesthesia [4, 79].

For day-case surgery, the combination of a local anaesthetic with an opioid could provide fast-onset and sufficient analgesia without prolonged motor block. Side effects like respiratory depression, which can occur after spinal hydrophilic opioids, are not clinically relevant with low doses of lipophilic opioids [80].

However the incidence of pruritus after intrathecal opioids varies but can be severe [81]. A meta-analysis in 2011 evaluated the effect of intrathecal opioids. The analysis concluded that morphine provided longer postoperative analgesia up to 12 h but also increased the risk of respiratory depression and PONV. The addition of fentanyl increased the risk of pruritus but had no effect on respiration [82]. Extremely small doses such as 3 mg of bupivacaine or 20 mg of lidocaine in combination with an opioid have been described [83–85]. However as described above, opioids will also decrease the sensation of bladder fullness and weaken the detrusor contraction. This might delay voiding [86, 87]. This possible delay in voiding time could not be confirmed by all studies, but it is clear that it is dose dependent [6, 88, 89].

Clonidine binds alpha-2 receptors on the presynaptic C fibres and the A-delta fibres. It intensifies sensory and motor block, but the exact working mechanism is not known [90]. Clonidine allows local anaesthetic dose reduction. The advantage of clonidine compared to opioids is the lack of respiratory depression and pruritus as a side effect. However, marked haemodynamic changes and sedation can occur [5].

Vasoconstrictors decrease local anaesthetic uptake by reducing spinal cord blood flow. Epinephrine prolongs the duration and improves the quality of a spinal block in a dose-dependent fashion. It allows local anaesthetic dose reduction in a daycase setting but has a variable prolongation. Addition of epinephrine to lidocaine, procaine or bupivacaine caused a delay in discharge in a day-case setting [91, 92]. In combination with chloroprocaine in volunteers, it provided unexplained flu-like symptoms [93].

Several other additives, like neostigmine and magnesium, have been studied, but were not suitable because of side effects or prolonged time to ambulation [94–96].

#### *2.5.4 Spinal anaesthetic technique*

Several techniques are available to perform spinal anaesthesia. When isobaric solutions are injected, drug spread is affected by many factors, which mostly are patient dependent and can therefore not be influenced [78]. Urmey et al. showed that pointing the aperture of the spinal needle cephalad resulted in a more cephalad spread and faster block regression after 60 mg lidocaine in a day-case setting [97].

The availability of hyperbaric substances allows us to control intrathecal drug spread, by which a restriction of the sensory block to the surgical site can be obtained, like a saddle block or a unilateral block. Low doses of hyperbaric prilocaine or bupivacaine produce adequate analgesia limited to the sacral region for perianal surgery [98–101]. However a sitting position has to be obtained for at least 10 min or even more to prevent secondary spread of the local anaesthetic after repositioning the patient, what may result in an insufficient block [78].

Unilateral spinal blocks with a reduced local anaesthetic dose were compared to bilateral spinal anaesthesia in a day-case setting. Unilateral blocks resulted in faster recovery of sensory and motor block and more haemodynamic stability [102–105]. In a meta-analysis, Nair et al. concluded that a unilateral technique with small doses of bupivacaine (4–6 mg) is suitable for unilateral anaesthesia [52].

The duration of lateral decubitus, the amount of hip flexion and the position during injection were studied to improve the unilaterality and the success rate of the block [106, 107]. However, the idea that a spinal block is fixed after 15–30 min

**107**

*Local Anaesthetics for Spinal Anaesthesia in Day-Case Surgery*

is not correct, since redistribution can be seen up to 1.5 h after injection [78]. Unilateral spinal anaesthesia has been thought to reduce bladder disturbances, as only one side of bladder innervation would be impaired. Because the physiologic function of the detrusor reflex is complex, there is still controversy whether this is

Should patients receive a 'normal' or 'restricted' amount of intravenous and oral fluids? Restricting fluid can delay bladder filling and prevent urinary retention, but it can also delay voiding and discharge, when required [110–112]. Restriction of fluids might cause minor discomfort in outpatients. A fluid load can even reduce PONV after general anaesthesia [113–115]. However, if IV fluid is not restricted, the bladder may fill too early during anaesthesia, risking overdistension [35, 116, 117]. Different amounts of fluid between 750 and 1200 ml have been suggested as a maximum in order to prevent bladder retention. However in these papers, different local anaesthetics were used, fluid loads up to 4000 ml were administered, bladder volumes were not always measured, and most procedures were considered as high risk for urinary retention, such as inguinal hernia repair and urological procedures

There even is controversy weather fluid load always correlates with bladder filling in such a short period. When 800–1200 ml IV fluid was administered, neither correlation with bladder filling was found nor could a difference in voiding interval or urinary retention be detected compared to a restrictive regimen [37, 113, 119, 120]. One study found a correlation between bladder volume and IV fluid when more than 900 ml was administered [121]. It may be concluded that excessive volumes should be avoided, but a restrictive policy may not be necessary to prevent

Moreover, with the common policy to freely allow patients to drink clear fluids up to 2 h before surgery, the bladder may fill intraoperatively regardless of

Discharge time is an indicator of efficiency of an ambulatory surgery unit. For safe and good clinical practice, guidelines and criteria are useful. Depending on the healthcare system, discharge criteria can vary in different countries or regions. There are several scores that can be used to test home readiness for ambulatory surgery. The modified Aldrete score [122] and the PADSS score [123] are two of them. Voiding and oral intake are parts of the PADSS and the modified Aldrete score as discharge criteria. In both scores, readiness for discharge can be achieved without

Waiting for oral intake and voiding can delay discharge for both general and spinal anaesthesia. A large trial of 1184 patients showed that spinal anaesthesia was responsible for a 44 min delay in discharge for women [49, 124, 125]. There is agreement in literature that after general anaesthesia and absence of patient or surgery-

However, guidelines available are not clear weather voiding should be required after spinal anaesthesia. In the day-case and short-stay surgery guidelines from the British association of day surgery, the following guideline can be found: "Voiding is also not always required, although it is important to identify and retain patients who are at particular risk of developing later problems, such as those who have experienced prolonged instrumentation or manipulation of the bladder" [127]*.*

*DOI: http://dx.doi.org/10.5772/intechopen.89018*

really true [39, 108, 109].

*2.5.5 Fluid policy*

[118, 123].

urinary retention.

*2.5.6 Discharge criteria*

restricted intravenous fluid administration.

voiding or oral intake, when all other variables are optimal.

related risk factors, patients can be discharged without voiding [126].

is not correct, since redistribution can be seen up to 1.5 h after injection [78]. Unilateral spinal anaesthesia has been thought to reduce bladder disturbances, as only one side of bladder innervation would be impaired. Because the physiologic function of the detrusor reflex is complex, there is still controversy whether this is really true [39, 108, 109].

#### *2.5.5 Fluid policy*

*Topics in Local Anesthetics*

symptoms [93].

*2.5.4 Spinal anaesthetic technique*

analgesia after spinal anaesthesia [4, 79].

fentanyl and sufentanil, increase the quality and prolong the duration of sensory

provide fast-onset and sufficient analgesia without prolonged motor block. Side effects like respiratory depression, which can occur after spinal hydrophilic opioids,

However the incidence of pruritus after intrathecal opioids varies but can be severe [81]. A meta-analysis in 2011 evaluated the effect of intrathecal opioids. The analysis concluded that morphine provided longer postoperative analgesia up to 12 h but also increased the risk of respiratory depression and PONV. The addition of fentanyl increased the risk of pruritus but had no effect on respiration [82]. Extremely small doses such as 3 mg of bupivacaine or 20 mg of lidocaine in combination with an opioid have been described [83–85]. However as described above, opioids will also decrease the sensation of bladder fullness and weaken the detrusor contraction. This might delay voiding [86, 87]. This possible delay in voiding time could not be

are not clinically relevant with low doses of lipophilic opioids [80].

confirmed by all studies, but it is clear that it is dose dependent [6, 88, 89].

Clonidine binds alpha-2 receptors on the presynaptic C fibres and the A-delta fibres. It intensifies sensory and motor block, but the exact working mechanism is not known [90]. Clonidine allows local anaesthetic dose reduction. The advantage of clonidine compared to opioids is the lack of respiratory depression and pruritus as a side effect. However, marked haemodynamic changes and sedation can occur [5]. Vasoconstrictors decrease local anaesthetic uptake by reducing spinal cord blood flow. Epinephrine prolongs the duration and improves the quality of a spinal block in a dose-dependent fashion. It allows local anaesthetic dose reduction in a daycase setting but has a variable prolongation. Addition of epinephrine to lidocaine, procaine or bupivacaine caused a delay in discharge in a day-case setting [91, 92]. In combination with chloroprocaine in volunteers, it provided unexplained flu-like

Several other additives, like neostigmine and magnesium, have been studied, but were not suitable because of side effects or prolonged time to ambulation [94–96].

Several techniques are available to perform spinal anaesthesia. When isobaric solutions are injected, drug spread is affected by many factors, which mostly are patient dependent and can therefore not be influenced [78]. Urmey et al. showed that pointing the aperture of the spinal needle cephalad resulted in a more cephalad spread and faster block regression after 60 mg lidocaine in a day-case setting [97]. The availability of hyperbaric substances allows us to control intrathecal drug spread, by which a restriction of the sensory block to the surgical site can be obtained, like a saddle block or a unilateral block. Low doses of hyperbaric prilocaine or bupivacaine produce adequate analgesia limited to the sacral region for perianal surgery [98–101]. However a sitting position has to be obtained for at least 10 min or even more to prevent secondary spread of the local anaesthetic after

Unilateral spinal blocks with a reduced local anaesthetic dose were compared to bilateral spinal anaesthesia in a day-case setting. Unilateral blocks resulted in faster recovery of sensory and motor block and more haemodynamic stability [102–105]. In a meta-analysis, Nair et al. concluded that a unilateral technique with small doses

The duration of lateral decubitus, the amount of hip flexion and the position during injection were studied to improve the unilaterality and the success rate of the block [106, 107]. However, the idea that a spinal block is fixed after 15–30 min

repositioning the patient, what may result in an insufficient block [78].

of bupivacaine (4–6 mg) is suitable for unilateral anaesthesia [52].

For day-case surgery, the combination of a local anaesthetic with an opioid could

**106**

Should patients receive a 'normal' or 'restricted' amount of intravenous and oral fluids? Restricting fluid can delay bladder filling and prevent urinary retention, but it can also delay voiding and discharge, when required [110–112]. Restriction of fluids might cause minor discomfort in outpatients. A fluid load can even reduce PONV after general anaesthesia [113–115]. However, if IV fluid is not restricted, the bladder may fill too early during anaesthesia, risking overdistension [35, 116, 117].

Different amounts of fluid between 750 and 1200 ml have been suggested as a maximum in order to prevent bladder retention. However in these papers, different local anaesthetics were used, fluid loads up to 4000 ml were administered, bladder volumes were not always measured, and most procedures were considered as high risk for urinary retention, such as inguinal hernia repair and urological procedures [118, 123].

There even is controversy weather fluid load always correlates with bladder filling in such a short period. When 800–1200 ml IV fluid was administered, neither correlation with bladder filling was found nor could a difference in voiding interval or urinary retention be detected compared to a restrictive regimen [37, 113, 119, 120]. One study found a correlation between bladder volume and IV fluid when more than 900 ml was administered [121]. It may be concluded that excessive volumes should be avoided, but a restrictive policy may not be necessary to prevent urinary retention.

Moreover, with the common policy to freely allow patients to drink clear fluids up to 2 h before surgery, the bladder may fill intraoperatively regardless of restricted intravenous fluid administration.

#### *2.5.6 Discharge criteria*

Discharge time is an indicator of efficiency of an ambulatory surgery unit. For safe and good clinical practice, guidelines and criteria are useful. Depending on the healthcare system, discharge criteria can vary in different countries or regions. There are several scores that can be used to test home readiness for ambulatory surgery. The modified Aldrete score [122] and the PADSS score [123] are two of them. Voiding and oral intake are parts of the PADSS and the modified Aldrete score as discharge criteria. In both scores, readiness for discharge can be achieved without voiding or oral intake, when all other variables are optimal.

Waiting for oral intake and voiding can delay discharge for both general and spinal anaesthesia. A large trial of 1184 patients showed that spinal anaesthesia was responsible for a 44 min delay in discharge for women [49, 124, 125]. There is agreement in literature that after general anaesthesia and absence of patient or surgeryrelated risk factors, patients can be discharged without voiding [126].

However, guidelines available are not clear weather voiding should be required after spinal anaesthesia. In the day-case and short-stay surgery guidelines from the British association of day surgery, the following guideline can be found: "Voiding is also not always required, although it is important to identify and retain patients who are at particular risk of developing later problems, such as those who have experienced prolonged instrumentation or manipulation of the bladder" [127]*.*

The American Society of Anesthesiologists (ASA) guidelines recommend voiding before discharge only when risk factors are present as well [128]. Since spinal anaesthesia is regarded as a risk factor on its own, the guidelines are subject to different interpretation [121]. Patients operated for urogenital surgery, hernia repair, those who had experienced bladder problems in the past, patients with prostate disease and aged persons should void before discharge [35, 37, 129, 130], regardless of anaesthetic technique.

*Local Anaesthetics for Spinal Anaesthesia in Day-Case Surgery*

*DOI: http://dx.doi.org/10.5772/intechopen.89018*

**109**

**Author details**

Margaretha Barbara Breebaart

provided the original work is properly cited.

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium

\*Address all correspondence to: margaretha.breebaart@uza.be

An often-quoted abstract concludes that even high-risk patients can be discharged without voiding. Although 1719 patients were included in the study, only 30 patients were identified as high risk. Those patients could not void and were discharged and followed by a home nurse. Three patients had to be catheterised at home. No bladder volumes were measured [131]. Mulroy et al. compared an accelerated protocol where low-risk patients could be discharged after neuraxial anaesthesia when measured bladder volume was below 400 ml. He concluded, after examining 46 patients who went home without voiding, that discharge after spinal anaesthesia with short-acting local anaesthetics is safe without voiding when bladder volume is below 400 ml [110].

Other authors agree that short-acting local anaesthetics should be used and bladder volumes should be monitored when patients are discharged without voiding. Some advice patients to return to the hospital when no voiding took place within 8 h of interval after discharge or until the evening of the day of surgery [3, 35, 38, 132]. After anaesthesia, overdistension of the bladder is not always clear for the patient [121]. Instructions when to return to the hospital based on measured bladder volumes seem a better option [38].

#### **3. Conclusions**

Effective anaesthesia, fast block regression and fast voiding are of uppermost importance in creating a good flow for spinal anaesthesia in day-case surgery. For this, we need a local anaesthetic with a favourable pharmacokinetic profile.

For years, lidocaine has been the drug of choice for spinal use in day-case surgery. The importance of quality of care and the demand for a fast turnover in our modern ambulatory practice has increased. Therefore, nowadays, the intrathecal use of lidocaine is criticised because of its high incidence of TNS.

Different aspects of spinal anaesthesia were studied in order to minimise side effects and to obtain short discharge times. Discharge time is mainly affected by the time to void and the occurrence of micturition problems.

Not only the local anaesthetic choice but also dose contributes to the optimal flow in a day-case setting. Other factors are also important, such as spinal anaesthetic technique, fluid policy and discharge criteria.

*Local Anaesthetics for Spinal Anaesthesia in Day-Case Surgery DOI: http://dx.doi.org/10.5772/intechopen.89018*

*Topics in Local Anesthetics*

of anaesthetic technique.

der volume is below 400 ml [110].

**3. Conclusions**

bladder volumes seem a better option [38].

The American Society of Anesthesiologists (ASA) guidelines recommend voiding before discharge only when risk factors are present as well [128]. Since spinal anaesthesia is regarded as a risk factor on its own, the guidelines are subject to different interpretation [121]. Patients operated for urogenital surgery, hernia repair, those who had experienced bladder problems in the past, patients with prostate disease and aged persons should void before discharge [35, 37, 129, 130], regardless

An often-quoted abstract concludes that even high-risk patients can be discharged without voiding. Although 1719 patients were included in the study, only 30 patients were identified as high risk. Those patients could not void and were discharged and followed by a home nurse. Three patients had to be catheterised at home. No bladder volumes were measured [131]. Mulroy et al. compared an accelerated protocol where low-risk patients could be discharged after neuraxial anaesthesia when measured bladder volume was below 400 ml. He concluded, after examining 46 patients who went home without voiding, that discharge after spinal anaesthesia with short-acting local anaesthetics is safe without voiding when blad-

Other authors agree that short-acting local anaesthetics should be used and bladder volumes should be monitored when patients are discharged without voiding. Some advice patients to return to the hospital when no voiding took place within 8 h of interval after discharge or until the evening of the day of surgery [3, 35, 38, 132]. After anaesthesia, overdistension of the bladder is not always clear for the patient [121]. Instructions when to return to the hospital based on measured

Effective anaesthesia, fast block regression and fast voiding are of uppermost importance in creating a good flow for spinal anaesthesia in day-case surgery. For this, we need a local anaesthetic with a favourable pharmacokinetic profile. For years, lidocaine has been the drug of choice for spinal use in day-case surgery. The importance of quality of care and the demand for a fast turnover in our modern ambulatory practice has increased. Therefore, nowadays, the intrathecal

Different aspects of spinal anaesthesia were studied in order to minimise side effects and to obtain short discharge times. Discharge time is mainly affected by the

Not only the local anaesthetic choice but also dose contributes to the optimal flow in a day-case setting. Other factors are also important, such as spinal anaes-

use of lidocaine is criticised because of its high incidence of TNS.

time to void and the occurrence of micturition problems.

thetic technique, fluid policy and discharge criteria.

**108**

#### **Author details**

Margaretha Barbara Breebaart Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium

\*Address all correspondence to: margaretha.breebaart@uza.be

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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[82] Popping DM et al. Opioids added to local anesthetics for single-shot intrathecal anesthesia in patients undergoing minor surgery: A metaanalysis of randomized trials. Pain.

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[92] Chiu AA et al. The effects of epinephrine on lidocaine spinal anesthesia: A cross-over study. Anesthesia and Analgesia.

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in humans. Anesthesiology.

1995;**82**(2):331-343

s00540-008-0677-4

1997;**84**(2):337-341

McDonald SB. Spinal 2-chloroprocaine: A dose-ranging study and the effect of added epinephrine. Anesthesia and

Tuttle R. Phase I safety assessment of intrathecal neostigmine methylsulfate

[95] Albrecht E et al. The analgesic efficacy and safety of neuraxial magnesium sulphate: A quantitative review. Anaesthesia. 2012;**68**:190-202. DOI: 10.1111/j.1365-2044.2012.07337.x

[96] Dayioglu H et al. Effects of adding magnesium to bupivacaine and fentanyl for spinal anesthesia in knee arthroscopy. Journal of Anesthesia. 2009;**23**(1):19-25. DOI: 10.1007/

[97] Urmey WF et al. The direction of the Whitacre needle aperture affects the extent and duration of isobaric spinal anesthesia. Anesthesia and Analgesia.

[98] Schmittner MD et al. Randomized clinical trial of perianal surgery performed under spinal saddle block versus total intravenous anaesthesia. The British Journal of Surgery.

2010;**97**(1):12-20. DOI: 10.1002/bjs.6792

[99] Schmittner MD et al. Practicability and patients' subjective experiences of low-dose spinal anaesthesia using

*DOI: http://dx.doi.org/10.5772/intechopen.89018*

2012;**153**(4):784-793. DOI: 10.1016/j.

[83] Ben-David B et al. A comparison of minidose lidocaine-fentanyl and conventional-dose lidocaine spinal anesthesia. Anesthesia and Analgesia.

[84] Korhonen AM et al. Intrathecal hyperbaric bupivacaine 3 mg + fentanyl 10 microg for outpatient knee arthroscopy with tourniquet. Acta Anaesthesiologica Scandinavica.

[85] Ben-David B et al. Intrathecal fentanyl with small-dose dilute

[86] Kuipers PW et al. Intrathecal opioids and lower urinary tract function: A urodynamic evaluation. Anesthesiology. 2004;**100**(6):1497-1503

[87] Kamphuis ET et al. The effects of spinal anesthesia with lidocaine and sufentanil on lower urinary tract functions. Anesthesia and Analgesia. 2008;**107**(6):2073-2078. DOI: 10.1213/

[88] Kairaluoma P et al. Hyperbaric articaine with or without fentanyl in spinal anaesthesia: Patient and observer blinded comparison. Acta Anaesthesiologica Scandinavica.

ane.0b013e318187bc0e

2013;**57**(1):118-125. DOI:

[89] Goel S, Bhardwaj N,

2003;**20**(4):294-297

[90] Eisenach JC, De Kock M, Klimscha W. Alpha(2)-adrenergic agonists for regional anesthesia. A clinical review of clonidine (1984-1995). Anesthesiology. 1996;**85**(3):655-674

10.1111/j.1399-6576.2012.02794.x

Grover VK. Intrathecal fentanyl added to intrathecal bupivacaine for day case surgery: A randomized study. European Journal of Anaesthesiology.

bupivacaine: Better anesthesia without prolonging recovery. Anesthesia and Analgesia. 1997;**85**(3):560-565

pain.2011.11.028

2000;**91**(4):865-870

2003;**47**(3):342-346

*Local Anaesthetics for Spinal Anaesthesia in Day-Case Surgery DOI: http://dx.doi.org/10.5772/intechopen.89018*

2012;**153**(4):784-793. DOI: 10.1016/j. pain.2011.11.028

*Topics in Local Anesthetics*

ANE.0b013e3181e30bb8

DOI: 10.1093/bja/aen357

s12630-014-0189-7

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[80] Varrassi G et al. Ventilatory effects of subarachnoid fentanyl in the elderly. Anaesthesia. 1992;**47**(7):558-562

[82] Popping DM et al. Opioids added to local anesthetics for single-shot intrathecal anesthesia in patients undergoing minor surgery: A metaanalysis of randomized trials. Pain.

[81] Chaney MA. Side effects of intrathecal and epidural opioids. Canadian Journal of Anaesthesia. 1995;**42**(10):891-903. DOI: 10.1007/

Anaesthesia. 2004;**93**(4):568-578. DOI:

1995;**81**(4):697-702

10.1093/bja/aei008

1995;**39**(7):881-884

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10.1093/bja/aeh204

BF03011037

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**114**

aas.12107

[83] Ben-David B et al. A comparison of minidose lidocaine-fentanyl and conventional-dose lidocaine spinal anesthesia. Anesthesia and Analgesia. 2000;**91**(4):865-870

[84] Korhonen AM et al. Intrathecal hyperbaric bupivacaine 3 mg + fentanyl 10 microg for outpatient knee arthroscopy with tourniquet. Acta Anaesthesiologica Scandinavica. 2003;**47**(3):342-346

[85] Ben-David B et al. Intrathecal fentanyl with small-dose dilute bupivacaine: Better anesthesia without prolonging recovery. Anesthesia and Analgesia. 1997;**85**(3):560-565

[86] Kuipers PW et al. Intrathecal opioids and lower urinary tract function: A urodynamic evaluation. Anesthesiology. 2004;**100**(6):1497-1503

[87] Kamphuis ET et al. The effects of spinal anesthesia with lidocaine and sufentanil on lower urinary tract functions. Anesthesia and Analgesia. 2008;**107**(6):2073-2078. DOI: 10.1213/ ane.0b013e318187bc0e

[88] Kairaluoma P et al. Hyperbaric articaine with or without fentanyl in spinal anaesthesia: Patient and observer blinded comparison. Acta Anaesthesiologica Scandinavica. 2013;**57**(1):118-125. DOI: 10.1111/j.1399-6576.2012.02794.x

[89] Goel S, Bhardwaj N, Grover VK. Intrathecal fentanyl added to intrathecal bupivacaine for day case surgery: A randomized study. European Journal of Anaesthesiology. 2003;**20**(4):294-297

[90] Eisenach JC, De Kock M, Klimscha W. Alpha(2)-adrenergic agonists for regional anesthesia. A clinical review of clonidine (1984-1995). Anesthesiology. 1996;**85**(3):655-674

[91] Moore JM et al. The effect of epinephrine on small-dose hyperbaric bupivacaine spinal anesthesia: Clinical implications for ambulatory surgery. Anesthesia and Analgesia. 1998;**86**(5):973-977

[92] Chiu AA et al. The effects of epinephrine on lidocaine spinal anesthesia: A cross-over study. Anesthesia and Analgesia. 1995;**80**(4):735-739

[93] Smith KN, Kopacz DJ, McDonald SB. Spinal 2-chloroprocaine: A dose-ranging study and the effect of added epinephrine. Anesthesia and Analgesia. 2004;**98**(1):81-88

[94] Hood DD, Eisenach JC, Tuttle R. Phase I safety assessment of intrathecal neostigmine methylsulfate in humans. Anesthesiology. 1995;**82**(2):331-343

[95] Albrecht E et al. The analgesic efficacy and safety of neuraxial magnesium sulphate: A quantitative review. Anaesthesia. 2012;**68**:190-202. DOI: 10.1111/j.1365-2044.2012.07337.x

[96] Dayioglu H et al. Effects of adding magnesium to bupivacaine and fentanyl for spinal anesthesia in knee arthroscopy. Journal of Anesthesia. 2009;**23**(1):19-25. DOI: 10.1007/ s00540-008-0677-4

[97] Urmey WF et al. The direction of the Whitacre needle aperture affects the extent and duration of isobaric spinal anesthesia. Anesthesia and Analgesia. 1997;**84**(2):337-341

[98] Schmittner MD et al. Randomized clinical trial of perianal surgery performed under spinal saddle block versus total intravenous anaesthesia. The British Journal of Surgery. 2010;**97**(1):12-20. DOI: 10.1002/bjs.6792

[99] Schmittner MD et al. Practicability and patients' subjective experiences of low-dose spinal anaesthesia using

hyperbaric bupivacaine for transanal surgery. International Journal of Colorectal Disease. 2009;**24**(7):827-836. DOI: 10.1007/s00384-009-0681-7

[100] Gudaityte J et al. Low-dose spinal hyperbaric bupivacaine for adult anorectal surgery: A double-blinded, randomized, controlled study. Journal of Clinical Anesthesia. 2009;**21**(7):474- 481. DOI: 10.1016/j.jclinane.2008.11.014

[101] Gebhardt V et al. Dosage finding for low-dose spinal anaesthesia using hyperbaric prilocaine in patients undergoing perianal outpatient surgery. Acta Anaesthesiologica Scandinavica. 2013;**57**(2):249-256. DOI: 10.1111/ aas.12031

[102] Akhtar MN et al. Comparison of haemodynamic changes in patients undergoing unilateral and bilateral spinal anaesthesia. Journal of the College of Physicians and Surgeons– Pakistan. 2012;**22**(12):747-750. DOI: 12.2012/JCPSP.747750

[103] Casati A, Fanelli G. Unilateral spinal anesthesia. State of the art. Minerva Anestesiologica. 2001;**67**(12):855-862

[104] Borghi B et al. Unilateral spinal block for outpatient knee arthroscopy: A dose-finding study. Journal of Clinical Anesthesia. 2003;**15**(5):351-356

[105] Imbelloni LE, Beato L, Gouveia MA. Low isobaric 0.5% bupivacaine doses for unilateral spinal anesthesia. Revista Brasileira de Anestesiologia. 2004;**54**(3):423-430

[106] Kim JT et al. The influence of spinal flexion in the lateral decubitus position on the unilaterality of spinal anesthesia. Anesthesia and Analgesia. 2013;**117**(4):1017-1021. DOI: 10.1213/ ANE.0b013e3182a1ee53

[107] Al Malyan M et al. Role of patient posture during puncture on successful unilateral spinal anaesthesia in outpatient lower abdominal surgery. European Journal of Anaesthesiology. 2006;**23**(6):491-495. DOI: 10.1017/ s0265021506000020

[108] Esmaoglu A et al. Bilateral vs. unilateral spinal anesthesia for outpatient knee arthroscopies. Knee Surgery, Sports Traumatology, Arthroscopy. 2004;**12**(2):155-158. DOI: 10.1007/s00167-003-0350-2

[109] Fry CH, Meng E, Young JS. The physiological function of lower urinary tract smooth muscle. Autonomic Neuroscience. 2010;**154**(1-2):3-13. DOI: 10.1016/j.autneu.2009.10.006

[110] Mulroy MF et al. Ambulatory surgery patients may be discharged before voiding after short-acting spinal and epidural anesthesia. Anesthesiology. 2002;**97**(2):315-319

[111] Bailey HR, Ferguson JA. Prevention of urinary retention by fluid restriction following anorectal operations. Diseases of the Colon and Rectum. 1976;**19**(3):250-252

[112] Orbey BC et al. Do we still need to restrict preoperative fluid administration in ambulatory anorectal surgery under spinal anaesthesia? Techniques in Coloproctology. 2009;**13**(1):35-40. DOI: 10.1007/ s10151-009-0456-8

[113] Yogendran S et al. A prospective randomized double-blinded study of the effect of intravenous fluid therapy on adverse outcomes on outpatient surgery. Anesthesia and Analgesia. 1995;**80**(4):682-686

[114] Ali SZ et al. Effect of supplemental pre-operative fluid on postoperative

**117**

*Local Anaesthetics for Spinal Anaesthesia in Day-Case Surgery*

[122] Aldrete JA. Modifications to the postanesthesia score for use in ambulatory surgery. Journal of Perianesthesia Nursing.

[123] Chung F, Chan VW, Ong D. A postanesthetic discharge scoring system for home readiness after ambulatory surgery. Journal of Clinical Anesthesia.

[124] Junger A et al. Factors determining length of stay of surgical day-case patients. European Journal of Anaesthesiology. 2001;**18**(5):314-321

[125] Gebhardt V, Weiss M, Schmittner C, Schmittner MD. Discharge times for knee arthroscopy in spinal vs. general anesthesia. Central European Journal of

1998;**13**(3):148-155

1995;**7**(6):500-506

Medicine. 2014;**9**(3):446

of bladder function after

1999;**91**(1):42-50

[126] Pavlin DJ et al. Management

outpatient surgery. Anesthesiology.

[127] Association of Anaesthetists of Great, B., Ireland, S. British Association of Day. Day case and short stay surgery: 2. Anaesthesia. 2011;**66**(5):417-434. DOI: 10.1111/j.1365-2044.2011.06651.x

[128] Apfelbaum JL et al. Practice guidelines for postanesthetic care: An updated report by the American Society of Anesthesiologists Task Force on Postanesthetic care. Anesthesiology. 2013;**118**(2):291-307. DOI: 10.1097/

[129] Pertek JP, Haberer JP. Effects of anesthesia on postoperative micturition and urinary retention. Annales Françaises d'Anesthèsie et de Rèanimation. 1995;**14**(4):340-351

[130] Petros JG et al. Factors influencing postoperative urinary retention in patients undergoing elective inguinal

ALN.0b013e31827773e9

*DOI: http://dx.doi.org/10.5772/intechopen.89018*

nausea and vomiting. Anaesthesia.

Wilkinson DJ. An open randomized study of the effects of intravenous fluid replacement during day case anaesthesia. Ambulatory Surgery. 1994;**2**:49-51

[116] Toyonaga T et al. Postoperative urinary retention after surgery for benign anorectal disease: Potential risk factors and strategy for prevention. International Journal of Colorectal Disease. 2006;**21**(7):676-682. DOI: 10.1007/s00384-005-0077-2

[117] Tammela T. Postoperative urinary retention--why the patient cannot void. Scandinavian Journal of Urology and Nephrology. Supplementum.

2003;**58**(8):780-784

1995;**175**:75-77

DOI: 10.1213/01.

s00402-007-0481-x

[118] Keita H et al. Predictive factors of early postoperative urinary retention in the

ANE.0000159165.90094.40

postanesthesia care unit. Anesthesia and Analgesia. 2005;**101**(2):592-596.

[119] Zaheer S et al. Urinary retention after operations for benign anorectal diseases. Diseases of the Colon and Rectum. 1998;**41**(6):696-704

[120] Luger TJ et al. Management of temporary urinary retention after arthroscopic knee surgery in lowdose spinal anesthesia: Development of a simple algorithm. Archives of Orthopaedic and Trauma Surgery. 2008;**128**(6):607-612. DOI: 10.1007/

[121] Pavlin DJ et al. Voiding in patients managed with or without ultrasound monitoring of bladder volume after outpatient surgery. Anesthesia and Analgesia. 1999;**89**(1):90-97

[115] Bakhshi KN, Igbal S,

*Local Anaesthetics for Spinal Anaesthesia in Day-Case Surgery DOI: http://dx.doi.org/10.5772/intechopen.89018*

nausea and vomiting. Anaesthesia. 2003;**58**(8):780-784

*Topics in Local Anesthetics*

hyperbaric bupivacaine for transanal surgery. International Journal of

Colorectal Disease. 2009;**24**(7):827-836. DOI: 10.1007/s00384-009-0681-7

[107] Al Malyan M et al. Role of patient posture during puncture on successful

unilateral spinal anaesthesia in outpatient lower abdominal surgery. European Journal of Anaesthesiology. 2006;**23**(6):491-495. DOI: 10.1017/

[108] Esmaoglu A et al. Bilateral vs. unilateral spinal anesthesia for outpatient knee arthroscopies. Knee Surgery, Sports Traumatology,

10.1007/s00167-003-0350-2

10.1016/j.autneu.2009.10.006

[110] Mulroy MF et al. Ambulatory surgery patients may be discharged before voiding after short-acting spinal and epidural anesthesia. Anesthesiology. 2002;**97**(2):315-319

[111] Bailey HR, Ferguson JA. Prevention of urinary retention by fluid restriction

following anorectal operations. Diseases of the Colon and Rectum.

[112] Orbey BC et al. Do we still need to restrict preoperative fluid administration in ambulatory anorectal surgery under spinal anaesthesia? Techniques in Coloproctology. 2009;**13**(1):35-40. DOI: 10.1007/

[113] Yogendran S et al. A prospective randomized double-blinded study of the effect of intravenous fluid therapy on adverse outcomes on outpatient surgery. Anesthesia and Analgesia.

[114] Ali SZ et al. Effect of supplemental pre-operative fluid on postoperative

1976;**19**(3):250-252

s10151-009-0456-8

1995;**80**(4):682-686

Arthroscopy. 2004;**12**(2):155-158. DOI:

[109] Fry CH, Meng E, Young JS. The physiological function of lower urinary tract smooth muscle. Autonomic Neuroscience. 2010;**154**(1-2):3-13. DOI:

s0265021506000020

[100] Gudaityte J et al. Low-dose spinal hyperbaric bupivacaine for adult anorectal surgery: A double-blinded, randomized, controlled study. Journal of Clinical Anesthesia. 2009;**21**(7):474- 481. DOI: 10.1016/j.jclinane.2008.11.014

[101] Gebhardt V et al. Dosage finding for low-dose spinal anaesthesia using hyperbaric prilocaine in patients undergoing perianal outpatient surgery. Acta Anaesthesiologica Scandinavica. 2013;**57**(2):249-256. DOI: 10.1111/

[102] Akhtar MN et al. Comparison of haemodynamic changes in patients undergoing unilateral and bilateral spinal anaesthesia. Journal of the College of Physicians and Surgeons– Pakistan. 2012;**22**(12):747-750. DOI:

[103] Casati A, Fanelli G. Unilateral spinal anesthesia. State of the art. Minerva Anestesiologica.

[104] Borghi B et al. Unilateral spinal block for outpatient knee arthroscopy: A dose-finding study. Journal of Clinical

Anesthesia. 2003;**15**(5):351-356

[106] Kim JT et al. The influence of spinal flexion in the lateral decubitus position on the unilaterality of spinal anesthesia. Anesthesia and Analgesia. 2013;**117**(4):1017-1021. DOI: 10.1213/

ANE.0b013e3182a1ee53

[105] Imbelloni LE, Beato L, Gouveia MA. Low isobaric 0.5% bupivacaine doses for unilateral spinal anesthesia. Revista Brasileira de Anestesiologia. 2004;**54**(3):423-430

aas.12031

12.2012/JCPSP.747750

2001;**67**(12):855-862

**116**

[115] Bakhshi KN, Igbal S, Wilkinson DJ. An open randomized study of the effects of intravenous fluid replacement during day case anaesthesia. Ambulatory Surgery. 1994;**2**:49-51

[116] Toyonaga T et al. Postoperative urinary retention after surgery for benign anorectal disease: Potential risk factors and strategy for prevention. International Journal of Colorectal Disease. 2006;**21**(7):676-682. DOI: 10.1007/s00384-005-0077-2

[117] Tammela T. Postoperative urinary retention--why the patient cannot void. Scandinavian Journal of Urology and Nephrology. Supplementum. 1995;**175**:75-77

[118] Keita H et al. Predictive factors of early postoperative urinary retention in the postanesthesia care unit. Anesthesia and Analgesia. 2005;**101**(2):592-596. DOI: 10.1213/01. ANE.0000159165.90094.40

[119] Zaheer S et al. Urinary retention after operations for benign anorectal diseases. Diseases of the Colon and Rectum. 1998;**41**(6):696-704

[120] Luger TJ et al. Management of temporary urinary retention after arthroscopic knee surgery in lowdose spinal anesthesia: Development of a simple algorithm. Archives of Orthopaedic and Trauma Surgery. 2008;**128**(6):607-612. DOI: 10.1007/ s00402-007-0481-x

[121] Pavlin DJ et al. Voiding in patients managed with or without ultrasound monitoring of bladder volume after outpatient surgery. Anesthesia and Analgesia. 1999;**89**(1):90-97

[122] Aldrete JA. Modifications to the postanesthesia score for use in ambulatory surgery. Journal of Perianesthesia Nursing. 1998;**13**(3):148-155

[123] Chung F, Chan VW, Ong D. A postanesthetic discharge scoring system for home readiness after ambulatory surgery. Journal of Clinical Anesthesia. 1995;**7**(6):500-506

[124] Junger A et al. Factors determining length of stay of surgical day-case patients. European Journal of Anaesthesiology. 2001;**18**(5):314-321

[125] Gebhardt V, Weiss M, Schmittner C, Schmittner MD. Discharge times for knee arthroscopy in spinal vs. general anesthesia. Central European Journal of Medicine. 2014;**9**(3):446

[126] Pavlin DJ et al. Management of bladder function after outpatient surgery. Anesthesiology. 1999;**91**(1):42-50

[127] Association of Anaesthetists of Great, B., Ireland, S. British Association of Day. Day case and short stay surgery: 2. Anaesthesia. 2011;**66**(5):417-434. DOI: 10.1111/j.1365-2044.2011.06651.x

[128] Apfelbaum JL et al. Practice guidelines for postanesthetic care: An updated report by the American Society of Anesthesiologists Task Force on Postanesthetic care. Anesthesiology. 2013;**118**(2):291-307. DOI: 10.1097/ ALN.0b013e31827773e9

[129] Pertek JP, Haberer JP. Effects of anesthesia on postoperative micturition and urinary retention. Annales Françaises d'Anesthèsie et de Rèanimation. 1995;**14**(4):340-351

[130] Petros JG et al. Factors influencing postoperative urinary retention in patients undergoing elective inguinal

herniorrhaphy. American Journal of Surgery. 1991;**161**(4):431-433

[131] Fritz WT, George L, Krulll N, Krug J. Utilisation of a home nursing protocol allows ambulatory surgery patients to be discharged prior to voiding. Anesthesia and Analgesia. 1998;**84**(2S):S6

[132] Mulroy MF. Outpatients do not need to void after short neuraxial blocks. Anesthesiology. 2009;**111**(6):1388. DOI: 10.1097/ ALN.0b013e3181bfa8d3

**119**

**Chapter 7**

**Abstract**

to traction.

strength, wound healing, drug effects

**regarding structure and duration)**

Pharmacologically, there is a selective blockade of Na+

of some intracellular signaling pathways [3, 4].

nism of action of LA is not related only to binding to the Na<sup>+</sup>

Local Anesthetics Infiltration and

It is a good practice, nowadays, to infiltrate local anesthetics along the incision

to prevent postoperative pain. This can reduce the use of opioids and the side effects they cause. It is known clearly that the surgical trauma causes inflammatory reaction, and this can be the beginning of a bad cicatrization or even a scar. The use of local anesthetics preventing the acute pain is a very simple technique and has proved to be useful. Nevertheless, the reaction that various anesthetics have over the tissues and the cicatrization process is yet controversial and deserves to be investigated deeply. The use of different formulations of these drugs has been stimulated. The duration and secureness have been the goals of many researches. Levobupivacaine, ropivacaine, and bupivacaine for their long action; lidocaine for less toxicity; and liposomal formulation for the longest duration ever seen, all of them have been indicated in the postoperative pain management. The aim of this chapter is to evaluate the role of long duration local anesthetics on the inflammatory reaction and consequently the collagen production and resistance of the tissue

**Keywords:** local anesthetics, pharmacology, ropivacaine, bupivacaine, tensile

**1. Introduction (local anesthetics, general comments, classification** 

important role in other targets (channels and receptors); for example, in K<sup>+</sup>

Ca++ channels, they have an anti-inflammatory effect by bounding to G protein (inhibiting the adhesion of polymorphonuclear leukocytes, macrophages, and monocytes), increase the release of glutamate, as well as interfering in the activity

There are at least five applications for the use of LA in anesthesiology: local infiltration, regional intravenous anesthesia (Bier block), peripheral nerve block, central nervous system (CNS) blockade (spinal anesthesia, epidural, and caudal), and topical deposit (EMLA, eye drops in ophthalmology) [3]. In this

Local anesthetics (LA) are widely used in clinical practice in anesthesiology. They possess the common property of transient interruption in the neural conduction, and in the fibers C and Aδ, they cause interruption of pain transmission.

channels [1, 2]. The mecha-

channels. LA have an

and

*João Abrão, Marcelo Antunes and Luis Vicente Garcia*

Wound Healing Process

#### **Chapter 7**

*Topics in Local Anesthetics*

1998;**84**(2S):S6

herniorrhaphy. American Journal of Surgery. 1991;**161**(4):431-433

[131] Fritz WT, George L, Krulll N, Krug J. Utilisation of a home nursing protocol allows ambulatory surgery patients to be discharged prior to voiding. Anesthesia and Analgesia.

[132] Mulroy MF. Outpatients do not need to void after short neuraxial blocks. Anesthesiology. 2009;**111**(6):1388. DOI: 10.1097/

ALN.0b013e3181bfa8d3

**118**

## Local Anesthetics Infiltration and Wound Healing Process

*João Abrão, Marcelo Antunes and Luis Vicente Garcia*

#### **Abstract**

It is a good practice, nowadays, to infiltrate local anesthetics along the incision to prevent postoperative pain. This can reduce the use of opioids and the side effects they cause. It is known clearly that the surgical trauma causes inflammatory reaction, and this can be the beginning of a bad cicatrization or even a scar. The use of local anesthetics preventing the acute pain is a very simple technique and has proved to be useful. Nevertheless, the reaction that various anesthetics have over the tissues and the cicatrization process is yet controversial and deserves to be investigated deeply. The use of different formulations of these drugs has been stimulated. The duration and secureness have been the goals of many researches. Levobupivacaine, ropivacaine, and bupivacaine for their long action; lidocaine for less toxicity; and liposomal formulation for the longest duration ever seen, all of them have been indicated in the postoperative pain management. The aim of this chapter is to evaluate the role of long duration local anesthetics on the inflammatory reaction and consequently the collagen production and resistance of the tissue to traction.

**Keywords:** local anesthetics, pharmacology, ropivacaine, bupivacaine, tensile strength, wound healing, drug effects

#### **1. Introduction (local anesthetics, general comments, classification regarding structure and duration)**

Local anesthetics (LA) are widely used in clinical practice in anesthesiology. They possess the common property of transient interruption in the neural conduction, and in the fibers C and Aδ, they cause interruption of pain transmission. Pharmacologically, there is a selective blockade of Na+ channels [1, 2]. The mechanism of action of LA is not related only to binding to the Na<sup>+</sup> channels. LA have an important role in other targets (channels and receptors); for example, in K<sup>+</sup> and Ca++ channels, they have an anti-inflammatory effect by bounding to G protein (inhibiting the adhesion of polymorphonuclear leukocytes, macrophages, and monocytes), increase the release of glutamate, as well as interfering in the activity of some intracellular signaling pathways [3, 4].

There are at least five applications for the use of LA in anesthesiology: local infiltration, regional intravenous anesthesia (Bier block), peripheral nerve block, central nervous system (CNS) blockade (spinal anesthesia, epidural, and caudal), and topical deposit (EMLA, eye drops in ophthalmology) [3]. In this

chapter, we will discuss its application in the infiltration of the operative wound and its effects in the inflammatory process, after a brief discussion about the pharmacological structure of LA.

#### **2. Na+ channel structure: the main target of conventional LA**

The Na+ channel is composed of one alpha subunit and one or two beta subunits, which can be present in three different states: resting, open, and inactivated (**Figure 1**). The AL binds to the Na+ channel after crossing the plasma membrane, that is, they bind to an internal portion of the alpha subunit preventing its activation and consequent depolarization of the membrane (**Figure 2**). Thus, the impulse is not propagated through the neurons, which prevents the perception of nociceptive pain [5, 6].

**Figure 1.** *Na+ channels—it opens with the voltage changes (depolarization) propagated by the electrical impulse.*

**Figure 2.**

*The electric stimuli are not able to open the Na+ channel because it is blocked by the LA.*

#### **3. Classification of AL (esters and amides and justify the use of each)**

In its chemical structure, the LA are weak bases that possess in its molecule a lipophilic portion (aromatic ring) and another hydrophilic (tertiary amine) separated by an intermediate chain (hydrocarbon chain containing an ester or an amide group) (**Figure 3**) [7, 8].

The latter allows the classification of LA in amino-esters or amino-amides. These two groups differ in relation to its biotransformation site (the ester forms are metabolized by plasmatic esterases, while amide forms are degraded by hepatic enzymes) [9, 10].

**121**

**Table 1.**

[14–16].

*Local Anesthetics Infiltration and Wound Healing Process*

Regarding the allergenic potential—the para amino benzoic acid (PABA) is an allergenic metabolite of the amino esters. Caution must be observed with some LA formulations, because methylparaben and metabisulfite are allergenic used as a

The size of the alkyl chain, in the amino group or aromatic ring, confers the LA molecule its hydrophobic character and its permeability in the lipid bilayer. So, the larger the nitrogenated radicals will be their potency and duration of LA blockades [12].

Followed by the application of AL in the patient, a fraction will be absorbed by the bloodstream (plasma). Depending on the dose administered, the LA may reach higher or lesser degree the noble organs (e.g., brain and heart) producing physiological alterations in these tissues as well. The total dose used should comply with a maximum limit to try to avoid these undesirable effects, known as systemic LA toxicity [13]. Usually, in clinical practice, we must respect the maximum dose of each LA. Note that the CNS effects of lidocaine vary according to its plasma concentration (**Table 1**)—the higher the plasma concentration, the greater the risk to the patient, even develop a cardio-respiratory arrest. Thus, it is mandatory to observe

LA may also induce cardiac toxicity depending on the dose employed, acting directly in the heart (specialized conduction tissues) and decreasing the contractility of ventricular myocytes. Bupivacaine is more cardio depressor than lidocaine

*DOI: http://dx.doi.org/10.5772/intechopen.89278*

preservative [11].

*LA generic structural formula.*

**Figure 3.**

**4. LA toxicity**

the maximum allowable doses for each LA.

**Plasma concentration (mcg/mL) Effect** 1–5 Analgesia

10–15 Seizures

*CNS toxicity—lidocaine plasma concentrations and its effects [17].*

>25 CV depression

5–10 Numbness of tongue, tinnitus

15–25 Coma, respiratory failure

*Local Anesthetics Infiltration and Wound Healing Process DOI: http://dx.doi.org/10.5772/intechopen.89278*

**Figure 3.** *LA generic structural formula.*

*Topics in Local Anesthetics*

**2. Na+**

The Na+

The AL binds to the Na+

pharmacological structure of LA.

chapter, we will discuss its application in the infiltration of the operative wound and its effects in the inflammatory process, after a brief discussion about the

 **channel structure: the main target of conventional LA**

channel is composed of one alpha subunit and one or two beta subunits,

channel after crossing the plasma membrane, that is, they

which can be present in three different states: resting, open, and inactivated (**Figure 1**).

bind to an internal portion of the alpha subunit preventing its activation and consequent depolarization of the membrane (**Figure 2**). Thus, the impulse is not propagated

**3. Classification of AL (esters and amides and justify the use of each)**

 *channels—it opens with the voltage changes (depolarization) propagated by the electrical impulse.*

In its chemical structure, the LA are weak bases that possess in its molecule a lipophilic portion (aromatic ring) and another hydrophilic (tertiary amine) separated by an intermediate chain (hydrocarbon chain containing an ester or an amide

 *channel because it is blocked by the LA.*

The latter allows the classification of LA in amino-esters or amino-amides. These two groups differ in relation to its biotransformation site (the ester forms are metabolized by plasmatic esterases, while amide forms are degraded by hepatic

through the neurons, which prevents the perception of nociceptive pain [5, 6].

**120**

**Figure 2.**

**Figure 1.** *Na+*

group) (**Figure 3**) [7, 8].

*The electric stimuli are not able to open the Na+*

enzymes) [9, 10].

Regarding the allergenic potential—the para amino benzoic acid (PABA) is an allergenic metabolite of the amino esters. Caution must be observed with some LA formulations, because methylparaben and metabisulfite are allergenic used as a preservative [11].

The size of the alkyl chain, in the amino group or aromatic ring, confers the LA molecule its hydrophobic character and its permeability in the lipid bilayer. So, the larger the nitrogenated radicals will be their potency and duration of LA blockades [12].

#### **4. LA toxicity**

Followed by the application of AL in the patient, a fraction will be absorbed by the bloodstream (plasma). Depending on the dose administered, the LA may reach higher or lesser degree the noble organs (e.g., brain and heart) producing physiological alterations in these tissues as well. The total dose used should comply with a maximum limit to try to avoid these undesirable effects, known as systemic LA toxicity [13]. Usually, in clinical practice, we must respect the maximum dose of each LA. Note that the CNS effects of lidocaine vary according to its plasma concentration (**Table 1**)—the higher the plasma concentration, the greater the risk to the patient, even develop a cardio-respiratory arrest. Thus, it is mandatory to observe the maximum allowable doses for each LA.

LA may also induce cardiac toxicity depending on the dose employed, acting directly in the heart (specialized conduction tissues) and decreasing the contractility of ventricular myocytes. Bupivacaine is more cardio depressor than lidocaine [14–16].


**Table 1.** *CNS toxicity—lidocaine plasma concentrations and its effects [17].*

#### **5. Long-term local anesthetics: ropivacaine, bupivacaine, and levobupivacaine. (Pharmacological characteristics: concentration used in practice, toxic dose and care). Liposome formulations**

The duration of action of LA is influenced by its effect on the vascular smooth muscle tone (vasoconstriction/vasodilatation) adjacent to the place where it is deposited. Other factors that determine its duration include the volume and concentration used, the approach itself (infiltrative versus regional peripheral nerve versus CNS blocks), the target tissue (fiber's diameter and myelin sheath), and the plasma protein binding (drug-specific affinity).

Long-term LA are the most used in clinical practice in anesthesiology at the following maximal allowed doses—bupivacaine (2 mg/kg), levobupivacaine (2 mg/kg), and ropivacaine (3 mg/kg).

#### **5.1 Bupivacaine**

Bupivacaine is presented as a racemic mixture of enantiomers R+ and S<sup>−</sup>. The optical isometry due to the presence of a chiral carbon (asymmetric) confers several possibilities in the formulation of the LA.

Bupivacaine promotes differential conduction blockade. As it produces more sensory than motor blockade, it plays an important role in the postoperative pain control. The use of epinephrine (5 μg/mL) gives a small increase in its duration of action (as opposed to lidocaine, which takes great advantage over this association). The use of large volumes for infiltration should be taken with cautious and done gradually and intermittently (3–5 mL at 5 min intervals). The patient should always be monitored to detect any unintentional intravascular injection of LA. Bupivacaine presents a higher risk of cardiac toxicity, when compared to levobupivacaine and ropivacaine. Every injection of this anesthetic should be done with the utmost care, always checking the positioning of the needle (by aspirating the syringe ensuring that the needle bevel is not intravascular).

#### **5.2 Levobupivacaine**

This anesthetic is the S-isomer of the bupivacaine, having the advantage of less neuro-cardio-toxicity due to lower affinity for these tissues. From a cardiac point of view, it causes a shorter prolongation of the QT interval and lower negative inotropism than racemic or R+ bupivacaine [18]. Its analgesic profile is similar to bupivacaine, because its duration of action is also long-lasting. Like ropivacaine, it has an intrinsic vasoconstrictor effect.

#### **5.3 Ropivacaine**

It is an anesthetic formulated by the pure enantiomer S of 1-propyl 2′-6′ pipecoloxylide [19]. As levobupivacaine, it has a safer profile than bupivacaine, because it has a lower toxicity in the CNS and heart. Its duration of action is long-lasting, like that of bupivacaine and levobupivacaine. It is widely used in infiltrative anesthesia and peripheral nerve blocks in anesthesiology. The same precautions should be taken with the use (intermittent and monitored injections). It is worth remembering that ropivacaine possesses intrinsic vasoconstrictor effect, which confers lower vascular absorption and increases its duration of action (levobupivacaine also owns this property).

**123**

**8.1 Magnesium**

*Local Anesthetics Infiltration and Wound Healing Process*

New methods of releasing the LA have been used in order to prolong the analgesia conferred by these anesthetic drugs. One of them is to produce liposomes spheres loaded with LA. This system allows LA deposit in the center of the liposomes, being involved by a double lipid layer. This setting allows a slower, controlled, and gradual release of LA, (72–96 h), consequently providing extended analgesic duration [20–23]. Liposomal bupivacaine (LB) has a decreased spread when compared with conventional bupivacaine. Therefore, several injections are needed and next to each other to obtain better results. In the infiltrative technique, it should be injected continuously from the fascia to the dermis. Unlike conventional formulations, which use bupivacaine HCl, the LB is produced only with its unprotonated basic form.

**7. Infiltrative or transdermal techniques: practical recommendations**

When the LA is used to infiltrate the operative wound, the anesthesiologist should seek a balance between the dose employed considering the size of the area to be anesthetized. In other words, it is sought to dilute the total dose used to cover most of the tissues operated. Thus, the same amount of LA used for infiltration on one side (e.g., right breast) needs to be diluted (doubling the volume) and to be employed bilaterally (e.g., right and left breast), always keep in mind that we must

This approach allows an alternative to single dose injection of LA, namely the implantation of catheters for complementary use of the medication (continuous and/or in bolus, known as Patient Controlled Analgesia PCA) in order to prolong its therapeutic effect. In clinical practice, these resources increase costs because they need to be supervised, in addition to the increased risk of infection at the catheter implant site. New approaches are being investigated to optimize postoperative analgesia—use of newer drugs, innovative delivery systems (liposomal bupivacaine

**(magnesium, epinephrine, clonidine, morphine, dexmedetomidine,** 

With the advent of several approaches in the treatment of postoperative pain, the anesthesiologist can associate the use of various drugs and techniques aiming at greater efficacy in their control. The simultaneous use of several drugs (with pharmacological synergism) allows the anesthesiologist to decrease the total dose employed, when compared to the isolated use of each of them. This is one of the reasons for the use of adjuvants with the LA [24–26]. Another reason is to reduce opioid consumption in the post-operative period and associated collateral effects. Usually, there is a consensus about the use of adjuvants in anesthesia, that is, the anesthesiologist must balance risks versus benefits and mainly the common sense. It

Magnesium sulfate antagonizes ionotropic N-methyl-D-aspartate (NMDA) glutamatergic receptor interfering in calcium homeostasis (membrane potential).

*DOI: http://dx.doi.org/10.5772/intechopen.89278*

**6. Liposomal formulations**

respect the maximum safety doses.

**and steroids). Is it worth?**

and ropivacaine), and the use of adjuvants along with LA.

is his/her responsibility to do the best choice in each case.

**8. Non-anesthetic drugs (adjuvants) injected together with LA** 

#### **6. Liposomal formulations**

*Topics in Local Anesthetics*

and ropivacaine (3 mg/kg).

**5.1 Bupivacaine**

**5. Long-term local anesthetics: ropivacaine, bupivacaine, and** 

Bupivacaine is presented as a racemic mixture of enantiomers R+

plasma protein binding (drug-specific affinity).

possibilities in the formulation of the LA.

that the needle bevel is not intravascular).

has an intrinsic vasoconstrictor effect.

**5.2 Levobupivacaine**

**5.3 Ropivacaine**

this property).

**levobupivacaine. (Pharmacological characteristics: concentration used in practice, toxic dose and care). Liposome formulations**

The duration of action of LA is influenced by its effect on the vascular smooth muscle tone (vasoconstriction/vasodilatation) adjacent to the place where it is deposited. Other factors that determine its duration include the volume and concentration used, the approach itself (infiltrative versus regional peripheral nerve versus CNS blocks), the target tissue (fiber's diameter and myelin sheath), and the

Long-term LA are the most used in clinical practice in anesthesiology at the following maximal allowed doses—bupivacaine (2 mg/kg), levobupivacaine (2 mg/kg),

optical isometry due to the presence of a chiral carbon (asymmetric) confers several

Bupivacaine promotes differential conduction blockade. As it produces more sensory than motor blockade, it plays an important role in the postoperative pain control. The use of epinephrine (5 μg/mL) gives a small increase in its duration of action (as opposed to lidocaine, which takes great advantage over this association). The use of large volumes for infiltration should be taken with cautious and done gradually and intermittently (3–5 mL at 5 min intervals). The patient should always be monitored to detect any unintentional intravascular injection of LA. Bupivacaine presents a higher risk of cardiac toxicity, when compared to levobupivacaine and ropivacaine. Every injection of this anesthetic should be done with the utmost care, always checking the positioning of the needle (by aspirating the syringe ensuring

This anesthetic is the S-isomer of the bupivacaine, having the advantage of less neuro-cardio-toxicity due to lower affinity for these tissues. From a cardiac point of view, it causes a shorter prolongation of the QT interval and lower negative inotropism than racemic or R+ bupivacaine [18]. Its analgesic profile is similar to bupivacaine, because its duration of action is also long-lasting. Like ropivacaine, it

It is an anesthetic formulated by the pure enantiomer S of 1-propyl 2′-6′ pipecoloxylide [19]. As levobupivacaine, it has a safer profile than bupivacaine, because it has a lower toxicity in the CNS and heart. Its duration of action is long-lasting, like that of bupivacaine and levobupivacaine. It is widely used in infiltrative anesthesia and peripheral nerve blocks in anesthesiology. The same precautions should be taken with the use (intermittent and monitored injections). It is worth remembering that ropivacaine possesses intrinsic vasoconstrictor effect, which confers lower vascular absorption and increases its duration of action (levobupivacaine also owns

and S<sup>−</sup>. The

**122**

New methods of releasing the LA have been used in order to prolong the analgesia conferred by these anesthetic drugs. One of them is to produce liposomes spheres loaded with LA. This system allows LA deposit in the center of the liposomes, being involved by a double lipid layer. This setting allows a slower, controlled, and gradual release of LA, (72–96 h), consequently providing extended analgesic duration [20–23]. Liposomal bupivacaine (LB) has a decreased spread when compared with conventional bupivacaine. Therefore, several injections are needed and next to each other to obtain better results. In the infiltrative technique, it should be injected continuously from the fascia to the dermis. Unlike conventional formulations, which use bupivacaine HCl, the LB is produced only with its unprotonated basic form.

#### **7. Infiltrative or transdermal techniques: practical recommendations**

When the LA is used to infiltrate the operative wound, the anesthesiologist should seek a balance between the dose employed considering the size of the area to be anesthetized. In other words, it is sought to dilute the total dose used to cover most of the tissues operated. Thus, the same amount of LA used for infiltration on one side (e.g., right breast) needs to be diluted (doubling the volume) and to be employed bilaterally (e.g., right and left breast), always keep in mind that we must respect the maximum safety doses.

This approach allows an alternative to single dose injection of LA, namely the implantation of catheters for complementary use of the medication (continuous and/or in bolus, known as Patient Controlled Analgesia PCA) in order to prolong its therapeutic effect. In clinical practice, these resources increase costs because they need to be supervised, in addition to the increased risk of infection at the catheter implant site. New approaches are being investigated to optimize postoperative analgesia—use of newer drugs, innovative delivery systems (liposomal bupivacaine and ropivacaine), and the use of adjuvants along with LA.

#### **8. Non-anesthetic drugs (adjuvants) injected together with LA (magnesium, epinephrine, clonidine, morphine, dexmedetomidine, and steroids). Is it worth?**

With the advent of several approaches in the treatment of postoperative pain, the anesthesiologist can associate the use of various drugs and techniques aiming at greater efficacy in their control. The simultaneous use of several drugs (with pharmacological synergism) allows the anesthesiologist to decrease the total dose employed, when compared to the isolated use of each of them. This is one of the reasons for the use of adjuvants with the LA [24–26]. Another reason is to reduce opioid consumption in the post-operative period and associated collateral effects.

Usually, there is a consensus about the use of adjuvants in anesthesia, that is, the anesthesiologist must balance risks versus benefits and mainly the common sense. It is his/her responsibility to do the best choice in each case.

#### **8.1 Magnesium**

Magnesium sulfate antagonizes ionotropic N-methyl-D-aspartate (NMDA) glutamatergic receptor interfering in calcium homeostasis (membrane potential). When injected together with LA in regional anesthesia, some evidence suggest that its use is beneficial [27]. Conversely, the use of magnesium sulfate intravenously is controversial [28, 29].

#### **8.2 Dexmedetomidine**

Dexmedetomidine (DMD) is a strong and highly selective α2-adrenoceptor agonist. When added to local anesthetics can enhance the analgesic efficacy of the peripheral regional nerve block [30]. DMD is eight times more selective than clonidine. It has analgesic, sedative, and antihypertensive effects, when used in systemic route. This substance has been associated with bupivacaine and lidocaine aiming prolonging the analgesic effect [31].

#### **8.3 Epinephrine**

Epinephrine has been used mixed to local anesthetics since a long time ago, and its recommended concentration is 5–10 μg/mL. It has, besides vasoconstrictive action that prolongates the local anesthesia, an analgesic effect mediated by alpha-2 adrenoceptor activation [32]. The vasoconstrictor effect of epinephrine can prevent inadvertent intravascular administration of local anesthetic solutions. Nowadays, the use of ultrasonography made such use largely redundant [33].

The onset time of local anesthesia after single injection was considered clinically significantly reduced when epinephrine was added to lidocaine or bupivacaine, when performing peripheral nerve blocks [34]. Current recommendations, however, allow the use of epinephrine in peripheral blocks only when ultrasonography is not available [35].

#### **8.4 Clonidine**

Clonidine applied at perineural sites, in doses up to 1.5 mcg/kg, acts as an adjuvant to local anesthetics prolonging analgesia and sensory/motor blocks [36]. It has intrinsic analgesic properties, inhibiting action potentials of C and Aδ fibers, as well as modulates the redistribution of local anesthetics through alpha1-receptors activation [37].

Side effects of this drug are dose dependent and include sedation, by decreasing sympathetic outflow (suppressing the release of norepinephrine in locus ceruleus (CNS) and substantia gelatinosa), hypotension, bradycardia, dry mouth, constipation, dizziness, and drowsiness [38].

Clonidine represents a good addition for the armamentarium of anesthesiologists because it prolongs the duration of analgesia, provides a faster onset of action, and improves the quality of nerve blocks (decreasing opioid consumption) [39, 40].

#### **8.5 Morphine**

Morphine is used by several routes and dosages (intrathecal: 100–200 mcg, epidural: 1–5 mg, peripheral nerve block: 75–100 mcg/kg, intravenous and intramuscular) [41]. Despite its use to prolong the analgesia, it is important to the anesthesiologist to pay attention at recommended doses to avoid the undesirable side effects (pruritus, nausea, vomiting, urinary retention, and respiratory failure). Always double check the vials before the administration of this medication because there are several vials currently in use (2, 4, 5, 8, and 10 mg/ml). All vital signals must be monitored at post-anesthetic care unit after the morphine use to early detect any cardiovascular or respiratory complications: bradycardia, hypotension, hypoxemia, and respiratory failure [42].

**125**

*Local Anesthetics Infiltration and Wound Healing Process*

Dexamethasone, a potent anti-inflammatory agent, has been investigated for its role as an adjuvant to local anesthetics in neuraxial as well as peripheral nerve blocks. This steroid has been used in intrathecal anesthesia (8 mg preservative free), in epidural analgesia (4–8 mg) and as an adjuvant in a variety of peripheral blocks, like brachial plexus, ankle block, and TAP block. A meta-analysis has found it to significantly prolong the duration of brachial plexus block when using conventional local anesthetics solutions [43]. Besides all the researches about the role of dexamethasone in neural block, one question has not been answered yet: is the

better and prolonged analgesia caused by systemic effects of the steroid?

The wound healing is a continuous process, but for didactic understanding, it can be divided into four phases [44, 45]. The first phase occurs just after the incision or lesion of the skin, as soon as the blood leaks out of the body. There is a vasoconstriction, and the platelets stick together to initiate the coagulation. This phase is called the hemostasis phase. The platelet plug is reinforced by threads of fibrin. The hemostasis phase occurs very rapidly, in a question of seconds. As the fibrin mesh is formed, the blood is transformed from liquid to a gel state, that is, the pro-coagulant effect of prothrombin. This clot keeps the platelets and blood cells trapped in the wound area. Just after the injury of the skin, the epidermal tissue and the keratinocytes release the interleukin-1 (IL-1) pre-stored in these sites. The coagulation process activates the clotting cascade which is responsible to give the matrix for the influx of inflammatory cells. The degranulation of the platelets releases alpha granules, which secrete growth factors, like epidermal growth factor (EGF), platelet derived growth factor (PDGF), and transforming growth factor-beta (TGFβ). The PDGF and the IL-1 are responsible for attracting neutrophils to the wound site to remove bacteria [44]. The monocytes cells are converted to macrophages by influence of TGF-β, what has an important role in the initiation of the granulation tissue and a many proinflammatory cytokines (IL-1 and IL-6), besides other growth factors, like fibroblast growth factor (FGF), EGF, TGF-β, and PDGF. All these growth factors and the added endothelial cell proliferation ensues the angiogenesis beginning. During this hemostasis phase, the injured blood vessels leak transudate causing localized swelling and cell migrations to the site of wound. The damaged cells, pathogens, and bacteria are removed. White cells, growth factors, nutrients, and enzymes create the swelling, heat, pain, and redness, normally seen in the wound healing. This phase where all these signs appear is called the inflammatory phase. This phase is not a problem unless it is prolonged and excessive. After all the bacteria and debris are removed, the wound is rebuilt with a new tissue made up of collagen and extracellular matrix. This is the proliferative phase. In this phase, new blood vessels are formed, so that the granulation tissue can receive enough oxygen and nutrients. The myofibroblasts are responsible for the contraction of the wound, making the granulation tissue to take the ideal dimensions to the lesion. The granulation in this phase is pink or red. If there is a dark color is a sign of infection, ischemia or poor perfusion. At the end of this process the epitelial cells resurface the wound extension, what is called the maturation or remodelling phase. In this stage, it is wise to maintain the wound moist and hydrated to optimize the epithelialization [46]. Some authors consider that the wound healing has only three phases, and this is comprehensible as long as the hemostasis phase and the inflammatory phase are so concomitant, dynamic, and interactive, that they consider it just as an

*DOI: http://dx.doi.org/10.5772/intechopen.89278*

**9. The four stages of wound healing**

**8.6 Steroids**

#### **8.6 Steroids**

*Topics in Local Anesthetics*

controversial [28, 29].

**8.2 Dexmedetomidine**

**8.3 Epinephrine**

is not available [35].

**8.4 Clonidine**

**8.5 Morphine**

prolonging the analgesic effect [31].

tion, dizziness, and drowsiness [38].

hypoxemia, and respiratory failure [42].

When injected together with LA in regional anesthesia, some evidence suggest that its use is beneficial [27]. Conversely, the use of magnesium sulfate intravenously is

Dexmedetomidine (DMD) is a strong and highly selective α2-adrenoceptor agonist. When added to local anesthetics can enhance the analgesic efficacy of the peripheral regional nerve block [30]. DMD is eight times more selective than clonidine. It has analgesic, sedative, and antihypertensive effects, when used in systemic route. This substance has been associated with bupivacaine and lidocaine aiming

Epinephrine has been used mixed to local anesthetics since a long time ago, and its recommended concentration is 5–10 μg/mL. It has, besides vasoconstrictive action that prolongates the local anesthesia, an analgesic effect mediated by alpha-2 adrenoceptor activation [32]. The vasoconstrictor effect of epinephrine can prevent inadvertent intravascular administration of local anesthetic solutions. Nowadays,

The onset time of local anesthesia after single injection was considered clinically

Clonidine applied at perineural sites, in doses up to 1.5 mcg/kg, acts as an adjuvant to local anesthetics prolonging analgesia and sensory/motor blocks [36]. It has intrinsic analgesic properties, inhibiting action potentials of C and Aδ fibers, as well as modulates the redistribution of local anesthetics through alpha1-receptors activation [37]. Side effects of this drug are dose dependent and include sedation, by decreasing sympathetic outflow (suppressing the release of norepinephrine in locus ceruleus (CNS) and substantia gelatinosa), hypotension, bradycardia, dry mouth, constipa-

Clonidine represents a good addition for the armamentarium of anesthesiologists because it prolongs the duration of analgesia, provides a faster onset of action, and improves the quality of nerve blocks (decreasing opioid consumption) [39, 40].

Morphine is used by several routes and dosages (intrathecal: 100–200 mcg, epidural: 1–5 mg, peripheral nerve block: 75–100 mcg/kg, intravenous and intramuscular) [41]. Despite its use to prolong the analgesia, it is important to the anesthesiologist to pay attention at recommended doses to avoid the undesirable side effects (pruritus, nausea, vomiting, urinary retention, and respiratory failure). Always double check the vials before the administration of this medication because there are several vials currently in use (2, 4, 5, 8, and 10 mg/ml). All vital signals must be monitored at post-anesthetic care unit after the morphine use to early detect any cardiovascular or respiratory complications: bradycardia, hypotension,

significantly reduced when epinephrine was added to lidocaine or bupivacaine, when performing peripheral nerve blocks [34]. Current recommendations, however, allow the use of epinephrine in peripheral blocks only when ultrasonography

the use of ultrasonography made such use largely redundant [33].

**124**

Dexamethasone, a potent anti-inflammatory agent, has been investigated for its role as an adjuvant to local anesthetics in neuraxial as well as peripheral nerve blocks. This steroid has been used in intrathecal anesthesia (8 mg preservative free), in epidural analgesia (4–8 mg) and as an adjuvant in a variety of peripheral blocks, like brachial plexus, ankle block, and TAP block. A meta-analysis has found it to significantly prolong the duration of brachial plexus block when using conventional local anesthetics solutions [43]. Besides all the researches about the role of dexamethasone in neural block, one question has not been answered yet: is the better and prolonged analgesia caused by systemic effects of the steroid?

#### **9. The four stages of wound healing**

The wound healing is a continuous process, but for didactic understanding, it can be divided into four phases [44, 45]. The first phase occurs just after the incision or lesion of the skin, as soon as the blood leaks out of the body. There is a vasoconstriction, and the platelets stick together to initiate the coagulation. This phase is called the hemostasis phase. The platelet plug is reinforced by threads of fibrin. The hemostasis phase occurs very rapidly, in a question of seconds. As the fibrin mesh is formed, the blood is transformed from liquid to a gel state, that is, the pro-coagulant effect of prothrombin. This clot keeps the platelets and blood cells trapped in the wound area. Just after the injury of the skin, the epidermal tissue and the keratinocytes release the interleukin-1 (IL-1) pre-stored in these sites. The coagulation process activates the clotting cascade which is responsible to give the matrix for the influx of inflammatory cells. The degranulation of the platelets releases alpha granules, which secrete growth factors, like epidermal growth factor (EGF), platelet derived growth factor (PDGF), and transforming growth factor-beta (TGFβ). The PDGF and the IL-1 are responsible for attracting neutrophils to the wound site to remove bacteria [44]. The monocytes cells are converted to macrophages by influence of TGF-β, what has an important role in the initiation of the granulation tissue and a many proinflammatory cytokines (IL-1 and IL-6), besides other growth factors, like fibroblast growth factor (FGF), EGF, TGF-β, and PDGF. All these growth factors and the added endothelial cell proliferation ensues the angiogenesis beginning. During this hemostasis phase, the injured blood vessels leak transudate causing localized swelling and cell migrations to the site of wound. The damaged cells, pathogens, and bacteria are removed. White cells, growth factors, nutrients, and enzymes create the swelling, heat, pain, and redness, normally seen in the wound healing. This phase where all these signs appear is called the inflammatory phase. This phase is not a problem unless it is prolonged and excessive. After all the bacteria and debris are removed, the wound is rebuilt with a new tissue made up of collagen and extracellular matrix. This is the proliferative phase. In this phase, new blood vessels are formed, so that the granulation tissue can receive enough oxygen and nutrients. The myofibroblasts are responsible for the contraction of the wound, making the granulation tissue to take the ideal dimensions to the lesion. The granulation in this phase is pink or red. If there is a dark color is a sign of infection, ischemia or poor perfusion. At the end of this process the epitelial cells resurface the wound extension, what is called the maturation or remodelling phase. In this stage, it is wise to maintain the wound moist and hydrated to optimize the epithelialization [46]. Some authors consider that the wound healing has only three phases, and this is comprehensible as long as the hemostasis phase and the inflammatory phase are so concomitant, dynamic, and interactive, that they consider it just as an

inflammation phase. In fact, the phases do not have a predetermined duration, as Witte and Barbul showed in their article (**Figures 4** and **5**), the migration of cells to the wound site and the matrix formation [47].

**Figure 4.**

*The time course of different cells during healing process. Macrophages and neutrophils are predominant in inflammation phase, whereas lymphocytes peak somewhat later. In the proliferative phase, fibroblasts are more frequent [47].*

**Figure 5.** *Deposition of wound matrix components over time [47].*

#### **10. Local anesthetics can influence the process of wound healing?**

When there is a rupture of vessels, there is an exposure of the subendothelial collagen to the platelets. This contact results in the aggregation and activation of the intrinsic factor of coagulation cascade. In the presence of thrombin, fibronectin, and their fragments, there is the release of cytokines and growth factors from platelets

**127**

**Table 2.**

*Local Anesthetics Infiltration and Wound Healing Process*

(PDGF), transforming growth factor-β (TGF-β), platelet-activating factor (PAF), fibronectin, and serotonin. All this form the local fibrin clot that is the scaffolding for invading cells such as neutrophils, monocytes, fibroblasts, and endothelial cells. The neutrophils are the first cells to invade the wound, increasing the vascular permeability due to inflammation and release of prostaglandins. In the same time, chemotactic substances like complement factors, interleukin, tumor necrosis factor-α (TNF-α), TGF-β, platelet factor 4, and stimulate neutrophil migration [47–49]. The factors associated with wound healing can be seen in **Table 2**.

When analyzing the possible action of the LAs in the wound healing process,

many aspects can take role. Injecting any substance in the surgery site, it is expected that it can have at least a pH influence, as the anesthetic has a pH different of the physiologic one. Many times, epinephrine is used to prolong the duration and lower the toxicity of the drug used [50, 51]. The influence of pain in the wound healing has been studied too [52–54]. The wound healing in the fetus has also been the object of research [55, 56]. And last, the LA probably can have a direct action in the eicosanoids or in the fibroblast formation and so in the

These all are hypothesis that are discussed deeply, and many researches in human have to be done, unfortunately the majority of the manuscripts are in rats

The tissue injury caused by surgery produces directly and indirectly activation of nociceptors and higher expression of proinflammatory cytokines and cyclooxygenase-2 (COX-2), leading to peripheral and central sensitization with subsequent hyperalgesia. The pain and inflammation are maintained by abundant eicosanoids, like prostaglandin E2, released after surgical trauma. The long-acting local anesthetics such as bupivacaine and ropivacaine are used to provide prolonged perioperative pain relief and to diminish the occurrence of postoperative sensitization that manifests with hyperalgesia after the anesthetic effect has dissipated. The occurrence of hyperalgesia is very common when high doses of anesthetic are used [57, 58]. The routine of infiltrating the surgical site reduces the postoperative pain

and they have a different immunologic system than humans.

**Function**

Structure for cell migration

Cytokines, growth factors Regulation of chemo attraction, mitogenesis, fibroplasia

Platelet aggregation

Platelet factor IV Chemotactic for fibroblasts and monocytes, neutralizes activity of heparin, inhibits collagenase Serotonin Induces vascular permeability, chemoattractant for neutrophils Adenosine dinucleotide Stimulates cell proliferation and migration, induces platelet aggregation

Chemo attraction and adhesion

Modulation of chemo attraction, mitogenesis, fibroplasia

Vasoconstriction, platelet aggregation, chemotaxis

Fibrin, plasma fibronectin Coagulation, chemo attraction

Complement Antimicrobial activity, chemo attraction

Fibronectin Early matrix, ligand for platelet aggregation

*Hemostatic and platelet-derived factors associated with wound healing [47].*

*DOI: http://dx.doi.org/10.5772/intechopen.89278*

cicatricial process [56].

**Hemostatic factors**

factor)

Factor XIII (fibrin-stabilizing

Circulatory growth factors

**Platelet-derived factors**

Thromboxane A2

Platelet-activating factor (PAF)

#### *Local Anesthetics Infiltration and Wound Healing Process DOI: http://dx.doi.org/10.5772/intechopen.89278*

*Topics in Local Anesthetics*

the wound site and the matrix formation [47].

inflammation phase. In fact, the phases do not have a predetermined duration, as Witte and Barbul showed in their article (**Figures 4** and **5**), the migration of cells to

*The time course of different cells during healing process. Macrophages and neutrophils are predominant in inflammation phase, whereas lymphocytes peak somewhat later. In the proliferative phase, fibroblasts are more* 

**10. Local anesthetics can influence the process of wound healing?**

*Deposition of wound matrix components over time [47].*

When there is a rupture of vessels, there is an exposure of the subendothelial collagen to the platelets. This contact results in the aggregation and activation of the intrinsic factor of coagulation cascade. In the presence of thrombin, fibronectin, and their fragments, there is the release of cytokines and growth factors from platelets

**126**

**Figure 5.**

**Figure 4.**

*frequent [47].*

(PDGF), transforming growth factor-β (TGF-β), platelet-activating factor (PAF), fibronectin, and serotonin. All this form the local fibrin clot that is the scaffolding for invading cells such as neutrophils, monocytes, fibroblasts, and endothelial cells. The neutrophils are the first cells to invade the wound, increasing the vascular permeability due to inflammation and release of prostaglandins. In the same time, chemotactic substances like complement factors, interleukin, tumor necrosis factor-α (TNF-α), TGF-β, platelet factor 4, and stimulate neutrophil migration [47–49]. The factors associated with wound healing can be seen in **Table 2**.

When analyzing the possible action of the LAs in the wound healing process, many aspects can take role. Injecting any substance in the surgery site, it is expected that it can have at least a pH influence, as the anesthetic has a pH different of the physiologic one. Many times, epinephrine is used to prolong the duration and lower the toxicity of the drug used [50, 51]. The influence of pain in the wound healing has been studied too [52–54]. The wound healing in the fetus has also been the object of research [55, 56]. And last, the LA probably can have a direct action in the eicosanoids or in the fibroblast formation and so in the cicatricial process [56].

These all are hypothesis that are discussed deeply, and many researches in human have to be done, unfortunately the majority of the manuscripts are in rats and they have a different immunologic system than humans.

The tissue injury caused by surgery produces directly and indirectly activation of nociceptors and higher expression of proinflammatory cytokines and cyclooxygenase-2 (COX-2), leading to peripheral and central sensitization with subsequent hyperalgesia. The pain and inflammation are maintained by abundant eicosanoids, like prostaglandin E2, released after surgical trauma. The long-acting local anesthetics such as bupivacaine and ropivacaine are used to provide prolonged perioperative pain relief and to diminish the occurrence of postoperative sensitization that manifests with hyperalgesia after the anesthetic effect has dissipated. The occurrence of hyperalgesia is very common when high doses of anesthetic are used [57, 58]. The routine of infiltrating the surgical site reduces the postoperative pain


#### **Table 2.**

*Hemostatic and platelet-derived factors associated with wound healing [47].*

and morbidity and accelerates the recovery. This can be explained by reducing the production of cytokines. Although LA action is to block the nerve conduction, they have other cellular targets that modulate the inflammation, suggesting that the LAs have an anti-inflammatory effect [59, 60]. Several studies have shown that LA dose-dependently inhibits leukocyte adhesion to synthetic material and to blood vessel walls. LA can induce the release of prostacyclin, and this causes the release of leukocytes previously firmly adherent to vascular endothelium. It is shown that the LA can in low concentration stimulate the phospholipase A2 (PLA2) while in higher concentrations inhibited this enzyme [61].

*Local Anesthetics Infiltration and Wound Healing Process*

We declare that we do not have any conflict of interest.

harm to the tissue cicatrization, and has the property of sparing opioid use, this technique is an important tool in the control of the postoperative pain and must be

*DOI: http://dx.doi.org/10.5772/intechopen.89278*

recommended.

**Conflict of interest**

**129**

**Author details**

João Abrão1

Brazil

provided the original work is properly cited.

\*, Marcelo Antunes2

\*Address all correspondence to: joaoabrao@fmrp.usp.br

Paulo, Ribeirão Preto, SP, Brazil

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

and Luis Vicente Garcia1

1 Medical School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP,

2 Educational Hospital of the Medical School of Ribeirão Preto, University of São

All these considerations are important, but what is important in clinical aspects are the fibroblast formation and the quality of the wound healing. The first question the patient formulates is when he will return to normal life activity. To answer this question, it is important to have not only histological analyzes of the wound but also mechanical testing to be sure that the tissue is ready to normal work. Vasseur and cols in 1984 studied the effects of local anesthetics on abdominal wounds of rabbits [62]; using mechanical testing device, they could demonstrate that the breaking strength in the groups infiltrated with lidocaine or bupivacaine, do not vary consistently from the tissues infiltrated with saline solution, and so they conclude that the local infiltration with lidocaine and bupivacaine does not alter substantially the healing of midline abdominal incisions in rabbits. Abrão and cols in 2014 made a similar work using rats and long-lasting anesthetics, bupivacaine, and ropivacaine [63]. They used a computerized universal testing machine, and they concluded that there were no significant differences among the groups with respect to tensile strength after 14 days. These results, however, are not the same than Hanci and cols in 2012, who found that lidocaine and bupivacaine reduce the collagen production and the wound breaking strength in Wistar rats [64]. To further augment the argument, Kesici and cols in 2018 studied the effect of bupivacaine, levobupivacaine, and procaine in the Sprague Dawley rats [65]. They found that bupivacaine and levobupivacaine affect negatively the wound healing, especially at the late period (21 days). The differences in these studies increase the uncertainty and discussion regarding the effects of local anesthetics. Many aspects must be considered like the animal gender, the use of other analgesic like paracetamol, the infiltration method, and the time of evaluation. Interestingly, there is no work done on humans, who certainly have a different response to pain. Probably, the reason is the difficulty to use the same methodology. All the researches in humans have only clinic evaluation, it is almost impossible to make mechanical tests. Uncertainties in this field only will be clarified with new studies. The clinical studies in human beings have a very subjective way to follow the wound healing. They constitute another subject that must be studied separately. The analogic scale of pain as the consume of opioids has been used as parameters to analyze the efficacy of the method. These studies conclude that ropivacaine (0.3%) can be used alone or with the addition of DMD (1 μg/kg), and there is no effect on wound healing [31, 66]. We must bear in mind that some authors only used a clinic evaluation, what can vary a lot from one researcher to another.

#### **11. Conclusion**

Nowadays, all the anesthesiologists are engaged in avoiding the excessive use of opioids for their side effects in the postoperative pain treatment. In fact, the μ-opioid receptors are impaired by the unrestricted use of morphine like drugs, besides there is an inhibition of the beta-endorphin release. Considering that the infiltration of LA in the surgical site does not produce, clinically any significant

harm to the tissue cicatrization, and has the property of sparing opioid use, this technique is an important tool in the control of the postoperative pain and must be recommended.

### **Conflict of interest**

*Topics in Local Anesthetics*

concentrations inhibited this enzyme [61].

and morbidity and accelerates the recovery. This can be explained by reducing the production of cytokines. Although LA action is to block the nerve conduction, they have other cellular targets that modulate the inflammation, suggesting that the LAs have an anti-inflammatory effect [59, 60]. Several studies have shown that LA dose-dependently inhibits leukocyte adhesion to synthetic material and to blood vessel walls. LA can induce the release of prostacyclin, and this causes the release of leukocytes previously firmly adherent to vascular endothelium. It is shown that the LA can in low concentration stimulate the phospholipase A2 (PLA2) while in higher

All these considerations are important, but what is important in clinical aspects are the fibroblast formation and the quality of the wound healing. The first question the patient formulates is when he will return to normal life activity. To answer this question, it is important to have not only histological analyzes of the wound but also mechanical testing to be sure that the tissue is ready to normal work. Vasseur and cols in 1984 studied the effects of local anesthetics on abdominal wounds of rabbits [62]; using mechanical testing device, they could demonstrate that the breaking strength in the groups infiltrated with lidocaine or bupivacaine, do not vary consistently from the tissues infiltrated with saline solution, and so they conclude that the local infiltration with lidocaine and bupivacaine does not alter substantially the healing of midline abdominal incisions in rabbits. Abrão and cols in 2014 made a similar work using rats and long-lasting anesthetics, bupivacaine, and ropivacaine [63]. They used a computerized universal testing machine, and they concluded that there were no significant differences among the groups with respect to tensile strength after 14 days. These results, however, are not the same than Hanci and cols in 2012, who found that lidocaine and bupivacaine reduce the collagen production and the wound breaking strength in Wistar rats [64]. To further augment the argument, Kesici and cols in 2018 studied the effect of bupivacaine, levobupivacaine, and procaine in the Sprague Dawley rats [65]. They found that bupivacaine and levobupivacaine affect negatively the wound healing, especially at the late period (21 days). The differences in these studies increase the uncertainty and discussion regarding the effects of local anesthetics. Many aspects must be considered like the animal gender, the use of other analgesic like paracetamol, the infiltration method, and the time of evaluation. Interestingly, there is no work done on humans, who certainly have a different response to pain. Probably, the reason is the difficulty to use the same methodology. All the researches in humans have only clinic evaluation, it is almost impossible to make mechanical tests. Uncertainties in this field only will be clarified with new studies. The clinical studies in human beings have a very subjective way to follow the wound healing. They constitute another subject that must be studied separately. The analogic scale of pain as the consume of opioids has been used as parameters to analyze the efficacy of the method. These studies conclude that ropivacaine (0.3%) can be used alone or with the addition of DMD (1 μg/kg), and there is no effect on wound healing [31, 66]. We must bear in mind that some authors only used a clinic evaluation, what can vary a lot from one researcher to

Nowadays, all the anesthesiologists are engaged in avoiding the excessive use of opioids for their side effects in the postoperative pain treatment. In fact, the μ-opioid receptors are impaired by the unrestricted use of morphine like drugs, besides there is an inhibition of the beta-endorphin release. Considering that the infiltration of LA in the surgical site does not produce, clinically any significant

**128**

another.

**11. Conclusion**

We declare that we do not have any conflict of interest.

### **Author details**

João Abrão1 \*, Marcelo Antunes2 and Luis Vicente Garcia1

1 Medical School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil

2 Educational Hospital of the Medical School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil

\*Address all correspondence to: joaoabrao@fmrp.usp.br

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

#### **References**

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[7] Suzuki S, Koköfer A, Gerner P. Local anesthetics. In: Hemmings HC Jr, Egan TD, editors. Pharmacology and Physiology for Anesthesia— Foundations and Clinical Application. 1st ed. Philadelphia: Elsevier Saunders; 2013. pp. 291-308

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[13] Groban L. Central nervous system and cardiac effects from long-acting amide local anesthetic toxicity in the intact animal model. Regional Anesthesia and Pain Medicine. 2003;**28**:3-11. DOI: 10.1053/ rapm.2003.50014

[14] Chamberlain BK, Volpe P, Fleischer S. Inhibition of calciuminduced calcium release from purified cardiac sarcoplasmic reticulum vesicles. The Journal of Biological Chemistry. 1984;**259**:7547-7553

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peripheral nerve block for the management of postoperative pain. Cochrane Database of Systematic Reviews. 2016;**8**:CD011476. DOI: 10.1002/14651858.CD011476.pub2

[24] Bailard NS, Ortiz J, Flores RA. Additives to local anesthetics for peripheral nerve blocks: Evidence, limitations, and recommendations. American Journal of Health-System Pharmacy. 2014;**71**:373-385. DOI:

[25] Emelife PI, Eng MR, Menard BL, Myers AS, Cornett EM, Urman RD, et al. Adjunct medications for peripheral and neuraxial anesthesia. Best Practice & Research. Clinical Anaesthesiology.

2018;**32**:83-99. DOI: 10.1016/j.

[26] Thornton PC, Grant SA,

in peripheral nerve blockade.

AIA.0b013e3181f89af1

Breslin DS. Adjuncts to local anesthetics

International Anesthesiology Clinics. 2010;**48**(4):59-70. DOI: 10.1097/

[27] Koinig H, Wallner T, Marhofer P, Andel H, Hörauf K, Mayer N. Magnesium sulfate reduces intra and postoperative analgesic requirements. Anesthesia and Analgesia. 1998;**87**:206-210. DOI: 10.1097/00000539-199807000-00042

[28] Kara H, Sahin N, Ulusan V,

Anaesthesiology. 2002;**19**:52-56

does not reduce postoperative analgesic requirements.

[30] Mandal D, Das A, Chhaule S, Halder PS, Joydip Paul J, Roy Basunia S, et al. The effect of dexmedetomidine added to preemptive (2% lignocaine with epinephrine) infiltration on

Aydogdu T. Magnesium infusion reduces perioperative pain. European Journal of

[29] Ko SH, Lim HR, Kim DC, Han YJ, Choe H, Song HS. Magnesium sulfate

Anesthesiology. 2001;**95**:640-646. DOI: 10.1097/00000542-200109000-00016.

10.2146/ajhp130336

bpa.2018.06.011

*DOI: http://dx.doi.org/10.5772/intechopen.89278*

channels during the action potential with slow recovery from block during diastole.

[16] Heavner JH. Cardiac toxicity of local anesthetics in the intact isolated heart model: A review. Regional Anesthesia and Pain Medicine. 2002;**27**:545-555

Rathmell JP, Sahfer S, editors. Stoelting's

anaesthetic. Drugs. 2000;**59**:551-579. DOI: 10.2165/00003495-200059030-00013

[19] McClure JH. Ropivacaine. British Journal of Anaesthesia. 1996;**76**:300- 307. DOI: 10.1093/bja/76.2.300

Urman RD. Liposomal bupivacaine and clinical outcomes. Best Practice & Research. Clinical Anaesthesiology.

[21] Mantripragada S. A lipid based depot (DepoFoam® technology) for sustained release drug delivery. Progress in Lipid Research. 2002;**41**:392-406

[22] Kirkness CS, Asche CV, Ren J, Gordon K, Maurer P, Maurer B, et al. Assessment of liposome bupivacaine infiltration versus continuous femoral nerve block for postsurgical analgesia following total knee arthroplasty: A retrospective cohort study. Current Medical Research and Opinion. 2016;**32**:1727-1733. DOI: 10.1080/03007995.2016.1205007

[23] Hamilton TW, Athanassoglou V, Trivella M, Strickland LH, Mellon S, Murray D, et al. Liposomal bupivacaine

2014;**28**:15-27. DOI: 10.1016/j.

Anesthesiology. 1985;**62**:396-405

[17] Maheshwari K, Naguib MA. Local anesthetics. In: Flood P,

Pharmacology & Physiology in Anesthetic Practice. 5th ed. Philadelphia: Lippincott-Williams &

Wilkins; 2015. pp. 282-313

[18] Foster RH, Markham A. Levobupivacaine: A review of its pharmacology and use as a local

[20] Tong YC, Kaye AD,

bpa.2014.02.001

*Local Anesthetics Infiltration and Wound Healing Process DOI: http://dx.doi.org/10.5772/intechopen.89278*

channels during the action potential with slow recovery from block during diastole. Anesthesiology. 1985;**62**:396-405

[16] Heavner JH. Cardiac toxicity of local anesthetics in the intact isolated heart model: A review. Regional Anesthesia and Pain Medicine. 2002;**27**:545-555

[17] Maheshwari K, Naguib MA. Local anesthetics. In: Flood P, Rathmell JP, Sahfer S, editors. Stoelting's Pharmacology & Physiology in Anesthetic Practice. 5th ed. Philadelphia: Lippincott-Williams & Wilkins; 2015. pp. 282-313

[18] Foster RH, Markham A. Levobupivacaine: A review of its pharmacology and use as a local anaesthetic. Drugs. 2000;**59**:551-579. DOI: 10.2165/00003495-200059030-00013

[19] McClure JH. Ropivacaine. British Journal of Anaesthesia. 1996;**76**:300- 307. DOI: 10.1093/bja/76.2.300

[20] Tong YC, Kaye AD, Urman RD. Liposomal bupivacaine and clinical outcomes. Best Practice & Research. Clinical Anaesthesiology. 2014;**28**:15-27. DOI: 10.1016/j. bpa.2014.02.001

[21] Mantripragada S. A lipid based depot (DepoFoam® technology) for sustained release drug delivery. Progress in Lipid Research. 2002;**41**:392-406

[22] Kirkness CS, Asche CV, Ren J, Gordon K, Maurer P, Maurer B, et al. Assessment of liposome bupivacaine infiltration versus continuous femoral nerve block for postsurgical analgesia following total knee arthroplasty: A retrospective cohort study. Current Medical Research and Opinion. 2016;**32**:1727-1733. DOI: 10.1080/03007995.2016.1205007

[23] Hamilton TW, Athanassoglou V, Trivella M, Strickland LH, Mellon S, Murray D, et al. Liposomal bupivacaine peripheral nerve block for the management of postoperative pain. Cochrane Database of Systematic Reviews. 2016;**8**:CD011476. DOI: 10.1002/14651858.CD011476.pub2

[24] Bailard NS, Ortiz J, Flores RA. Additives to local anesthetics for peripheral nerve blocks: Evidence, limitations, and recommendations. American Journal of Health-System Pharmacy. 2014;**71**:373-385. DOI: 10.2146/ajhp130336

[25] Emelife PI, Eng MR, Menard BL, Myers AS, Cornett EM, Urman RD, et al. Adjunct medications for peripheral and neuraxial anesthesia. Best Practice & Research. Clinical Anaesthesiology. 2018;**32**:83-99. DOI: 10.1016/j. bpa.2018.06.011

[26] Thornton PC, Grant SA, Breslin DS. Adjuncts to local anesthetics in peripheral nerve blockade. International Anesthesiology Clinics. 2010;**48**(4):59-70. DOI: 10.1097/ AIA.0b013e3181f89af1

[27] Koinig H, Wallner T, Marhofer P, Andel H, Hörauf K, Mayer N. Magnesium sulfate reduces intra and postoperative analgesic requirements. Anesthesia and Analgesia. 1998;**87**:206-210. DOI: 10.1097/00000539-199807000-00042

[28] Kara H, Sahin N, Ulusan V, Aydogdu T. Magnesium infusion reduces perioperative pain. European Journal of Anaesthesiology. 2002;**19**:52-56

[29] Ko SH, Lim HR, Kim DC, Han YJ, Choe H, Song HS. Magnesium sulfate does not reduce postoperative analgesic requirements. Anesthesiology. 2001;**95**:640-646. DOI: 10.1097/00000542-200109000-00016.

[30] Mandal D, Das A, Chhaule S, Halder PS, Joydip Paul J, Roy Basunia S, et al. The effect of dexmedetomidine added to preemptive (2% lignocaine with epinephrine) infiltration on

**130**

2013. pp. 291-308

*Topics in Local Anesthetics*

pp. 565-582

**References**

[1] Catterall WA, Mackie K. Local anesthetics. In: Brunton L, Chabner B, Knollman B, editors. Goodman & Gilman's the Pharmacological Basis of Therapeutics. 12th ed. New York: The McGraw Hill Companies; 2011.

Cahalan MK, Stock MC, Ortega R, et al. editors. Clinical Anesthesia. 8th ed. Philadelphia: Lippincott-Williams &

[9] Kuhnert BR, Kuhnert RM, Philipson EH, Syracuse CD, Kaine CJ, Yun CH. The half-life of 2-chloroprocaine. Anesthesia and Analgesia. 1986;**65**:

[10] Scott DB, Jebson PJR, Boyes RN. Pharmacokinetic study of the local anaesthetics bupivacaine (Marcaine) and etidocaine (Duranest) in man. British Journal of Anaesthesia.

[11] Boren E, Teuber SS, Naguwa SM, Gershwin ME. A critical review of local anesthetic sensitivity. Clinical Reviews in Allergy and Immunology.

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[31] Vallapu S, Panda NB, Samagh N, Bharti N. Efficacy of dexmedetomidine as an adjuvant to local anesthetic agent in scalp block and scalp infiltration to control postcraniotomy pain: A double-blind randomized trial. Journal of Neurosciences in Rural Practice. 2018;**9**:73-79. DOI: 10.4103/jnrp. jnrp\_310\_17

[32] Collins JG, Kitahata LM, Matsumoto M, Homma E, Suzukawa M. Spinally administered epinephrine suppresses noxiously evoke activity of WDR neurons in the dorsal horn of the spinal cord. Anesthesiology. 1984;**60**:269-275. DOI: 10.1097/00000542-198404000-00001

[33] Swain A, Nag DS, Sahu S, Samaddar DP. Adjuvants to local anesthetics: Current understanding and future trends. World Journal of Clinical Cases. 2017;**5**(8):307-323. DOI: 10.12998/wjcc.v5.i8.307

[34] Córdoba-Fernández A, González-Benítez J, Lobo-Martín A. Onset time of local anesthesia after single injection in toe nerve blocks: A randomized double-blind trial. Journal of Perianesthesia Nursing. 2019;**34**(4):820-828. DOI: 10.1016/j. jopan.2018.09.014

[35] Brummett CM, Williams BA. Additives to local anesthetics for peripheral nerve blockade. International Anesthesiology Clinics. 2011;**49**(4):104-116. DOI: 10.1097/ AIA.0b013e31820e4a49.

[36] Murphy DB, McCartney CJ, Chan VW. Novel analgesic adjuncts for brachial plexus block: A

systematic review. Anesthesia and Analgesia. 2000;**90**:1122-1128. DOI: 10.1097/00000539-200005000-00023

[37] Butterworth JF 5th, Strichartz GR. The alpha 2-adrenergic agonists clonidine and guanfacine produce tonic and phasic block of conduction in rat sciatic nerve fibers. Anesthesia and Analgesia. 1993;**76**:295-301

[38] Kaye AD, Cornett EM, Helander E, Menard B, Hsu E, Hart B, et al. An update on nonopioids: Intravenous or oral analgesics for perioperative pain management. Anesthesiology Clinics. 2017;**35**(2):e55-e71. DOI: 10.1016/j. anclin.2017.01.006

[39] Jellinge ME, Petersen RH. Clonidine can reduce opioid medication during post-operative pain. Ugeskrift for Laeger. 2015;**177**(49):V05150415

[40] Blaudszun G, Lysakowski C, Elia N, Tramèr MR. Effect of perioperative systemic α2 agonists on postoperative morphine consumption and pain intensity: Systematic review and metaanalysis of randomized controlled trials. Anesthesiology. 2012;**116**(6):1312-1322. DOI: 10.1097/ALN.0b013e31825681cb

[41] Cummings K III, Naguib MA. Opioid agonists and antagonists. In: Flood P, Rathmell JP, Shafer S, editors. Stoelting's Pharmacology & Physiology in Anesthetic Practice. 5th ed. Philadelphia: Lippincott-Williams & Wilkins; 2015. pp. 217-256

[42] Dahan A, Niesters M, Smith T, Overdyk F. Opioids. In: Barash PG, Cullen BF, Stoelting RK, Cahalan MK, Stock MC, Ortega R, Sharar SR, Holt NF, editors. Clinical Anesthesia. 8th ed. Philadelphia: Lippincott-Williams & Wilkins; 2017. pp. 505-526

[43] Choi S, Rodseth R, McCartney CJ. Effects of dexamethasone as a local anaesthetic adjuvant for brachial plexus block: A systematic review and

**133**

*Local Anesthetics Infiltration and Wound Healing Process*

patients. Annals of Behavioral Medicine. 2006;**31**(2):165-172. DOI: 10.1207/

[53] Kasaj A, Heib A, Willershausen B.

Effectiveness of a topical salve (Dynexan) on pain sensitivity and early wound healing following nonsurgical periodontal therapy. European Journal of Medical Research.

[54] Gao Z, Cui F, Cao X, Wang D, Li X, Li T. Local infiltration of the surgical wounds with levobupivacaine, dexibuprofen, and norepinephrine to reduce postoperative pain: A randomized, vehicle-controlled, and preclinical study. Biomedicine & Pharmacotherapy. 2017;**92**:459-467. DOI: 10.1016/j.biopha.2017.05.038

[55] Cowin AJ, Brosnan MP,

1998;**212**(3):385-393

10.1038/35068566

Holmes TM, Ferguson MW. Endogenous inflammatory response to dermal wound healing in the fetal and adult mouse. Developmental Dynamics.

[56] Samad TA, Moore KA, Saierstein A, et al. Interleukin-1b-mediated induction of cox-2 in the CNS contributes to inflammatory pain hypersensitivity. Nature. 2001;**410**:471-475. DOI:

[57] Hay JL, White JM, Bochner F, Somogyi AA, Semple TJ, Rounsefell B. Hyperalgesia in opioid-managed chronic pain and opioid-dependent patients. Pain. 2009;**10**(3):316-322. DOI: 10.1016/j.jpain.2008.10.003

Sullivan T, Gentgall M, White J, Rolan P. Comparison of pain models to detect opioid-induced hyperalgesia. Journal of Pain Research. 2012;**5**:99-106. DOI:

Wang XM, et al. The differential effects

[58] Krishnan S, Salter A,

[59] Gordon SM, Chuang BP,

of bupivacaine and lidocaine

10.2147/JPR.S27738

s15324796abm3102\_8

2007;**12**(5):196-199

*DOI: http://dx.doi.org/10.5772/intechopen.89278*

meta-analysis of randomized trials. British Journal of Anaesthesia. 2014;**112**(3):427-

[44] Hantash BM, Zhao L, Knowles JA, Lorenz HP. Adult and fetal wound healing. Frontiers in Bioscience.

[45] Gilmore MA. Phases of wound healing. Dimensions in Oncology

[46] Wound Healing Phases [Internet]. 2019. Available from: https://www. ncbi.nlm.nih.gov/books/NBK470443/

Nursing. 1991;**5**(3):32-34

[Accessed on: 24 June 2019]

1997;**77**(3):509-528

34S. DOI: 10.1097/01. prs.0000225430.42531.c2

[49] Pakyari M, Farrokhi A,

[50] Robson MC, Steed DL,

10.1067/msg.2001.111167

10.1177/147323000903700531

Maharlooei MK, Ghahary A. Critical role of transforming growth factor beta in different phases of wound healing. Advances in Wound Care. 2013;**2**(5):215- 224. DOI: 10.1089/wound.2012.0406

Franz MG. Wound healing: Biologic features and approaches to maximize healing trajectories. Current Problems in Surgery. 2001;**38**(2):72-140. DOI:

[51] Velnar T, Bailey T, Smrkolj V. The wound healing process: An overview of the cellular and molecular mechanisms. Journal of International Medical Research. 2009;**37**(5):1528-1542. DOI:

[52] McGuire L, Heffner K, Glaser R, et al. Pain and wound healing in surgical

[47] Witte MB, Barbul A. General principles of wound healing. Surgical Clinics of North America.

[48] Broughton G 2nd, Janis JE,

Attinger CE. The basic science of wound healing. Plastic and Reconstructive Surgery. 2006;**117**(7 Suppl):12S-

439. DOI: 10.1093/bja/aet417

2008;**13**:51-61

*Local Anesthetics Infiltration and Wound Healing Process DOI: http://dx.doi.org/10.5772/intechopen.89278*

meta-analysis of randomized trials. British Journal of Anaesthesia. 2014;**112**(3):427- 439. DOI: 10.1093/bja/aet417

*Topics in Local Anesthetics*

10.4103/0259-1162.167837

[32] Collins JG, Kitahata LM,

[33] Swain A, Nag DS, Sahu S, Samaddar DP. Adjuvants to local anesthetics: Current understanding and future trends. World Journal of Clinical Cases. 2017;**5**(8):307-323. DOI:

10.12998/wjcc.v5.i8.307

jopan.2018.09.014

Anesthesiology Clinics.

AIA.0b013e31820e4a49.

[34] Córdoba-Fernández A,

[35] Brummett CM, Williams BA. Additives to local anesthetics for

2011;**49**(4):104-116. DOI: 10.1097/

[36] Murphy DB, McCartney CJ, Chan VW. Novel analgesic adjuncts

for brachial plexus block: A

peripheral nerve blockade. International

Matsumoto M, Homma E, Suzukawa M. Spinally administered epinephrine suppresses noxiously evoke activity of WDR neurons in the dorsal horn of the spinal cord.

Anesthesiology. 1984;**60**:269-275. DOI: 10.1097/00000542-198404000-00001

González-Benítez J, Lobo-Martín A. Onset time of local anesthesia after single injection in toe nerve blocks: A randomized double-blind trial. Journal of Perianesthesia Nursing. 2019;**34**(4):820-828. DOI: 10.1016/j.

jnrp\_310\_17

intraoperative hemodynamics and postoperative pain after ambulatory maxillofacial surgeries under general anesthesia. Anesthesia, Essays and Researches. 2016;**10**:324-331. DOI:

systematic review. Anesthesia and Analgesia. 2000;**90**:1122-1128. DOI: 10.1097/00000539-200005000-00023

[37] Butterworth JF 5th, Strichartz GR. The alpha 2-adrenergic agonists

clonidine and guanfacine produce tonic and phasic block of conduction in rat sciatic nerve fibers. Anesthesia and

[38] Kaye AD, Cornett EM, Helander E, Menard B, Hsu E, Hart B, et al. An update on nonopioids: Intravenous or oral analgesics for perioperative pain management. Anesthesiology Clinics. 2017;**35**(2):e55-e71. DOI: 10.1016/j.

[39] Jellinge ME, Petersen RH. Clonidine can reduce opioid medication during post-operative pain. Ugeskrift for Laeger. 2015;**177**(49):V05150415

[40] Blaudszun G, Lysakowski C, Elia N, Tramèr MR. Effect of perioperative systemic α2 agonists on postoperative morphine consumption and pain intensity: Systematic review and metaanalysis of randomized controlled trials. Anesthesiology. 2012;**116**(6):1312-1322. DOI: 10.1097/ALN.0b013e31825681cb

[41] Cummings K III, Naguib MA. Opioid agonists and antagonists. In: Flood P, Rathmell JP, Shafer S, editors. Stoelting's Pharmacology & Physiology in Anesthetic Practice. 5th ed. Philadelphia: Lippincott-Williams &

[42] Dahan A, Niesters M, Smith T, Overdyk F. Opioids. In: Barash PG, Cullen BF, Stoelting RK, Cahalan MK, Stock MC, Ortega R, Sharar SR, Holt NF, editors. Clinical Anesthesia. 8th ed. Philadelphia: Lippincott-Williams & Wilkins; 2017. pp. 505-526

[43] Choi S, Rodseth R, McCartney CJ. Effects of dexamethasone as a local anaesthetic adjuvant for brachial plexus

block: A systematic review and

Wilkins; 2015. pp. 217-256

Analgesia. 1993;**76**:295-301

anclin.2017.01.006

[31] Vallapu S, Panda NB, Samagh N, Bharti N. Efficacy of dexmedetomidine as an adjuvant to local anesthetic agent in scalp block and scalp infiltration to control postcraniotomy pain: A double-blind randomized trial. Journal of Neurosciences in Rural Practice. 2018;**9**:73-79. DOI: 10.4103/jnrp.

**132**

[44] Hantash BM, Zhao L, Knowles JA, Lorenz HP. Adult and fetal wound healing. Frontiers in Bioscience. 2008;**13**:51-61

[45] Gilmore MA. Phases of wound healing. Dimensions in Oncology Nursing. 1991;**5**(3):32-34

[46] Wound Healing Phases [Internet]. 2019. Available from: https://www. ncbi.nlm.nih.gov/books/NBK470443/ [Accessed on: 24 June 2019]

[47] Witte MB, Barbul A. General principles of wound healing. Surgical Clinics of North America. 1997;**77**(3):509-528

[48] Broughton G 2nd, Janis JE, Attinger CE. The basic science of wound healing. Plastic and Reconstructive Surgery. 2006;**117**(7 Suppl):12S-34S. DOI: 10.1097/01. prs.0000225430.42531.c2

[49] Pakyari M, Farrokhi A, Maharlooei MK, Ghahary A. Critical role of transforming growth factor beta in different phases of wound healing. Advances in Wound Care. 2013;**2**(5):215- 224. DOI: 10.1089/wound.2012.0406

[50] Robson MC, Steed DL, Franz MG. Wound healing: Biologic features and approaches to maximize healing trajectories. Current Problems in Surgery. 2001;**38**(2):72-140. DOI: 10.1067/msg.2001.111167

[51] Velnar T, Bailey T, Smrkolj V. The wound healing process: An overview of the cellular and molecular mechanisms. Journal of International Medical Research. 2009;**37**(5):1528-1542. DOI: 10.1177/147323000903700531

[52] McGuire L, Heffner K, Glaser R, et al. Pain and wound healing in surgical patients. Annals of Behavioral Medicine. 2006;**31**(2):165-172. DOI: 10.1207/ s15324796abm3102\_8

[53] Kasaj A, Heib A, Willershausen B. Effectiveness of a topical salve (Dynexan) on pain sensitivity and early wound healing following nonsurgical periodontal therapy. European Journal of Medical Research. 2007;**12**(5):196-199

[54] Gao Z, Cui F, Cao X, Wang D, Li X, Li T. Local infiltration of the surgical wounds with levobupivacaine, dexibuprofen, and norepinephrine to reduce postoperative pain: A randomized, vehicle-controlled, and preclinical study. Biomedicine & Pharmacotherapy. 2017;**92**:459-467. DOI: 10.1016/j.biopha.2017.05.038

[55] Cowin AJ, Brosnan MP, Holmes TM, Ferguson MW. Endogenous inflammatory response to dermal wound healing in the fetal and adult mouse. Developmental Dynamics. 1998;**212**(3):385-393

[56] Samad TA, Moore KA, Saierstein A, et al. Interleukin-1b-mediated induction of cox-2 in the CNS contributes to inflammatory pain hypersensitivity. Nature. 2001;**410**:471-475. DOI: 10.1038/35068566

[57] Hay JL, White JM, Bochner F, Somogyi AA, Semple TJ, Rounsefell B. Hyperalgesia in opioid-managed chronic pain and opioid-dependent patients. Pain. 2009;**10**(3):316-322. DOI: 10.1016/j.jpain.2008.10.003

[58] Krishnan S, Salter A, Sullivan T, Gentgall M, White J, Rolan P. Comparison of pain models to detect opioid-induced hyperalgesia. Journal of Pain Research. 2012;**5**:99-106. DOI: 10.2147/JPR.S27738

[59] Gordon SM, Chuang BP, Wang XM, et al. The differential effects of bupivacaine and lidocaine

on prostaglandin E2 release, cyclooxygenase gene expression and pain in a clinical pain model. Anesthesia and Analgesia. 2008;**106**(1):321-327. DOI: 10.1213/01. ane.0000296474.79437.23

[60] Cassuto J, Sinclair R, Bonderovic M. Anti-inflammatory properties of local anesthetics and their present and potential clinical implications. Acta Anaesthesiologica Scandinavica. 2006;**50**(3):265-282. DOI: 10.1111/j.1399-6576.2006.00936.x

[61] Kunze H, Nahas N, Traynor JR, Wurl M. Effects of local anaesthetics on phospholipases. Biochimica et Biophysica Acta. 1976;**441**(1):93-102

[62] Vasseur PB, Paul HA, Dybdal N, Crumley L. Effects of local anesthetics on healing of abdominal wounds in rabbits. American Journal of Veterinary Research. 1984;**45**(11):2385-2388

[63] Abrão J, Fernandes CR, White PF, et al. Effect of local anaesthetic infiltration with bupivacaine and ropivacaine on wound healing: A placebo-controlled study. International Wound Journal. 2014;**11**(4):379-385. DOI: 10.1111/j.1742-481X.2012.01101

[64] Hancı V, Hakimoğlu S, Özaçmak H, et al. Comparison of the effects of bupivacaine, lidocaine, and tramadol infiltration on wound healing in rats. Revista Brasileira de Anestesiologia. 2012;**62**(6):799-810. DOI: 10.1016/ S0034-7094(12)70180-0

[65] Kesici S, Kesici U, Ulusoy H, Erturkuner P, Turkmen A, Arda O. Effects of local anesthetics on wound healing. Revista Brasileira de Anestesiologia. 2018;**68**(4):375-382. DOI: 10.1016/j.bjan.2018.01.016

[66] Luan H, Zhu P, Zhang X, et al. Effect of dexmedetomidine as an adjuvant to ropivacaine for wound infiltration in patients undergoing

open gastrectomy: A prospective randomized controlled trial. Medicine. 2017;**96**(38):e7950. DOI: 10.1097/ MD.0000000000007950

**135**

**Chapter 8**

**Abstract**

Local Anesthetics in Odontology

Pain has been a faithful companion of human beings and is a result of most of the dental procedures and illness; therefore a good control of dental pain is inevitable and feasible. The administration of local anesthetics has come to be the standard of care of dental profession. All local anesthetics are effective and high safety margin in all patients including childhood. The choice of using a local anesthetic depends on time of the surgical procedure, patient's medical history, and the interaction between local anesthetics and patient usual medications. The use of vasoconstrictors is priority in surgical/dental bleeding, but it must be used with caution in patients with cardiovascular disease to avoid a dental catastrophe. Dentists should be experts in dental-anesthetic techniques and in pharmacology of local anesthetics, since they are the most used medications in odontology. The accidental injection or a high absorption of local anesthetics in blood results in systemic toxicity. In such situation sedation, stunning, diplopia, sensory disturbances, disorientation, muscles spasm, respiratory depression, seizures, or cardiac arrest may be present; the dentist must immediately recognize this clinical complication

**Keywords:** local anesthetics, dental, local anesthesia, local analgesia, complications

Local anesthetics (LAs) are the most used drugs by dentists. Actually, they are safer drugs. More than 40% or urgent dental procedures cause pain that needs and injection of LA. Therefore, dentists should be experts in dental-anesthetic techniques and in pharmacology of LA drugs. The safe administration of LA is the

Pain has been a companion of human beings since their appearance on earth. Before local anesthetics, natural medicine was first used to relieve dental pain. Such medicine has evolved since ancient Egypt and Greek culture until the nineteenth century when LA developed. Actually, LAs are the most secure and effective drugs in medicine for pain prevention and treatment. There are no drugs more effective than LAs to avoid pain; no other drug prevents a nociceptive impulse from reaching the patient's brain, to finally be interpreted as pain. Whenever local anesthetics are administered near a sensitive nerve, it produces an adequate control pain for a limited time with the aids of been a reversible and temporary effect without harm

*Enrique Hernández-Cortez, Cecilia G. Sandoval Larios* 

*and Juan Carlos Flores-Carrillo*

to stablish an early treatment.

standard of care of dentists.

of the anesthetized nervous structure.

**1. Introduction**

#### **Chapter 8**

*Topics in Local Anesthetics*

on prostaglandin E2 release, cyclooxygenase gene expression and pain in a clinical pain model. Anesthesia and Analgesia.

ane.0000296474.79437.23

2006;**50**(3):265-282. DOI: 10.1111/j.1399-6576.2006.00936.x

[61] Kunze H, Nahas N, Traynor JR, Wurl M. Effects of local anaesthetics on phospholipases. Biochimica et Biophysica Acta. 1976;**441**(1):93-102

[62] Vasseur PB, Paul HA, Dybdal N, Crumley L. Effects of local anesthetics on healing of abdominal wounds in rabbits. American Journal of Veterinary Research. 1984;**45**(11):2385-2388

anaesthetic infiltration with bupivacaine and ropivacaine on wound healing: A placebo-controlled study. International Wound Journal. 2014;**11**(4):379-385. DOI: 10.1111/j.1742-481X.2012.01101

[64] Hancı V, Hakimoğlu S, Özaçmak H, et al. Comparison of the effects of bupivacaine, lidocaine, and tramadol infiltration on wound healing in rats. Revista Brasileira de Anestesiologia. 2012;**62**(6):799-810. DOI: 10.1016/

[63] Abrão J, Fernandes CR, White PF, et al. Effect of local

S0034-7094(12)70180-0

[65] Kesici S, Kesici U, Ulusoy H, Erturkuner P, Turkmen A, Arda O. Effects of local anesthetics on wound

[66] Luan H, Zhu P, Zhang X, et al. Effect of dexmedetomidine as an adjuvant to ropivacaine for wound infiltration in patients undergoing

healing. Revista Brasileira de Anestesiologia. 2018;**68**(4):375-382. DOI: 10.1016/j.bjan.2018.01.016

2008;**106**(1):321-327. DOI: 10.1213/01.

open gastrectomy: A prospective randomized controlled trial. Medicine. 2017;**96**(38):e7950. DOI: 10.1097/

MD.0000000000007950

[60] Cassuto J, Sinclair R, Bonderovic M. Anti-inflammatory properties of local anesthetics and their present and potential clinical implications. Acta Anaesthesiologica Scandinavica.

**134**

## Local Anesthetics in Odontology

*Enrique Hernández-Cortez, Cecilia G. Sandoval Larios and Juan Carlos Flores-Carrillo*

#### **Abstract**

Pain has been a faithful companion of human beings and is a result of most of the dental procedures and illness; therefore a good control of dental pain is inevitable and feasible. The administration of local anesthetics has come to be the standard of care of dental profession. All local anesthetics are effective and high safety margin in all patients including childhood. The choice of using a local anesthetic depends on time of the surgical procedure, patient's medical history, and the interaction between local anesthetics and patient usual medications. The use of vasoconstrictors is priority in surgical/dental bleeding, but it must be used with caution in patients with cardiovascular disease to avoid a dental catastrophe. Dentists should be experts in dental-anesthetic techniques and in pharmacology of local anesthetics, since they are the most used medications in odontology. The accidental injection or a high absorption of local anesthetics in blood results in systemic toxicity. In such situation sedation, stunning, diplopia, sensory disturbances, disorientation, muscles spasm, respiratory depression, seizures, or cardiac arrest may be present; the dentist must immediately recognize this clinical complication to stablish an early treatment.

**Keywords:** local anesthetics, dental, local anesthesia, local analgesia, complications

#### **1. Introduction**

Local anesthetics (LAs) are the most used drugs by dentists. Actually, they are safer drugs. More than 40% or urgent dental procedures cause pain that needs and injection of LA. Therefore, dentists should be experts in dental-anesthetic techniques and in pharmacology of LA drugs. The safe administration of LA is the standard of care of dentists.

Pain has been a companion of human beings since their appearance on earth. Before local anesthetics, natural medicine was first used to relieve dental pain. Such medicine has evolved since ancient Egypt and Greek culture until the nineteenth century when LA developed. Actually, LAs are the most secure and effective drugs in medicine for pain prevention and treatment. There are no drugs more effective than LAs to avoid pain; no other drug prevents a nociceptive impulse from reaching the patient's brain, to finally be interpreted as pain. Whenever local anesthetics are administered near a sensitive nerve, it produces an adequate control pain for a limited time with the aids of been a reversible and temporary effect without harm of the anesthetized nervous structure.

The first registered dental anesthesia in history was in 1885 of the alveolar inferior nervous, applied by the medical surgeon William Stewart Halsted. The injected drug was a combination of cocaine and epinephrine [1]. In 1905, 2% procaine with epinephrine 1:50,000 was introduced, giving a quick access to dentists worldwide. Procaine, propoxycaine, and tetracaine were the most used LAs until the middle 1940s. Lidocaine was synthetized in Sweden in 1948 [2]. Articaine was synthetized in 1973 and introduced in dental clinic in 1976 and approved in Canada in 1984 and in the USA until 2000. Articaine has special characteristics of both amino amide and amino ester anesthetics. Its popularity has increased rapidly and is currently displacing the use of lidocaine in dental anesthesia [3].

Annually, a dentist in Canada applies 1800 LA cartridges, while in the USA, more than 300 million of cartridges are administered each year. Therefore, dentists should be experts in pharmacology, complications, and secondary effects of LA. In daily practice there are few complications related to LA, owing its security and the relative low doses that are applied. Nonetheless, it is necessary to consider possible complications, to detect it as soon as possible.

#### **2. Pharmacology of LA**

The synthetic LA has a common chemical structure, constituted by an aromatic ring, a hydrocarbon channel, and an amino group; the hydrocarbon channel and aromatic ring are joined by an ester or amide bond. Most of LAs are tertiary amines. The lipophilic portion is the biggest of the molecule. The aromatic portion proceeds from benzoic acid, aniline, or thiophene (articaine) and is the lipophilic portion. This portion is responsible for the affinity of nerve cells. The hydrophilic portion is an amino ethanol or acetic acid derivative and is responsible of water solubility and diffusion across tissues. LAs are amphipathic; that is, they have lipophilic and hydrophilic characteristics at their opposite ends of their molecules (**Figure 1**) [4]. Amides are the most common molecules; procaine is the prototype of this group and benzocaine for topic application. The minimal concentration of LA to block the conduction of a nociceptive impulse is named potency. The therapeutic value of the drug in terms of efficacy and tolerability is called toxicity. The ability of the drug to reach tissues far from the site of administration of LA is called diffusion. Time between the action of LA and the metabolism of its compounds is named time of action [5].

**Figure 1.** *Local anesthetic molecule.*

#### **3. Mechanism of action of LA**

The type of nervous blockade produced by LA is named non-depolarizing nervous block. Local anesthetics block sodium channels permeability, they selectively

**137**

**Table 1.**

liver [10].

*Local Anesthetics in Odontology*

*DOI: http://dx.doi.org/10.5772/intechopen.91738*

proposed for LA is described in **Table 1**.

of the diffusion across the nerve sheath.

2. Binding of the LA molecule to the receptor

5. Depressed velocity of electric depolarization 6. Failed to teach the value of umbral potential 7. Absence of propagated action potentials

*Sequence of mechanisms of LA to produce conduction block.*

3. Block of the sodium channel 4. Decreased sodium conduction

8. Conduction block

1. Displacement of sodium ions from the sodium channel receptor

inhibit the maximum permeability to sodium, whose values usually are five to six times greater than the necessary minimum to conduct the impulse, when this value fail, and the nerve block occurs. In other words, local anesthesia is induced when the spread of action potential is inhibited, so a painful sensation cannot be transmitted from the site of origin to the brain. Or, LA alter the mechanism to sodium ions to gain access to the axoplasm nerve. The nerve membrane stays in a polarized state due to the impossibility of ionic movement responsible of action potential. LA blocks the entrance of sodium ions into their channels in the nerve cellular membrane. The permeability to sodium is necessary to generate a new action potential to transmit nerve impulses to the brain [6]. The sequence of action mechanism

LAs are classified into two large groups depending on its chemical bond: amides or ester; the latter are almost disappearing in dentistry. The ester LAs are easily hydrolyzed in aqueous solution, while amide bond LAs are relatively resistant to hydrolysis. The most important factors that affect onset and duration of action of LA are tissue pH, drug pKa, diffusion time from the tip of the needle to nerve, nerve morphology, drug concentration, and drug solubility in lipids [7]. The most important of the abovementioned factors are tissue pH and drug pKa. The pH may be reduced in infection sites, so the result would be a delay in the LA onset. In clinics, the amides pK is similar, with the exception of bupivacaine that has a slightly greater pK and an onset time more prolonged. The proximity of the anesthetic to the nerve is another factor that influences the action time of LA; a very clear example is the Gow-Gates blockade, very slow in its installation. The nerve morphology is also an important factor, which thin fibers are quickly anesthetized compared to thicker ones. The duration of action depends on the depth at which the drug may be blocking the sodium channels in the nerve membrane. If the LA causes vasodilatation, it allows a more or less rapid diffusion in the site of action and therefore a short duration of action, especially if the drug is administered alone. This diffusion may be reduced with the aid of vasoconstrictors like epinephrine, although bupivacaine is the only LA that has a prolonged action duration [8]. The two most important factors involved in the action of LA are the drug diffusion across the nerve sheath and the bind to the receptor in the ionic channel; a lipid-soluble free base and without electric charge is responsible

The biotransformation of amides occurs mainly in the liver, although prilocaine is metabolized in plasma and eliminated in the kidney. One of its metabolites could be the origin of methemoglobinemia [9]. The ester LAs are biotransformed in plasma by enzymes called cholinesterase or pseudocholinesterase produced in the

#### *Local Anesthetics in Odontology DOI: http://dx.doi.org/10.5772/intechopen.91738*

*Topics in Local Anesthetics*

The first registered dental anesthesia in history was in 1885 of the alveolar inferior nervous, applied by the medical surgeon William Stewart Halsted. The injected drug was a combination of cocaine and epinephrine [1]. In 1905, 2% procaine with epinephrine 1:50,000 was introduced, giving a quick access to dentists worldwide. Procaine, propoxycaine, and tetracaine were the most used LAs until the middle 1940s. Lidocaine was synthetized in Sweden in 1948 [2]. Articaine was synthetized in 1973 and introduced in dental clinic in 1976 and approved in Canada in 1984 and in the USA until 2000. Articaine has special characteristics of both amino amide and amino ester anesthetics. Its popularity has increased rapidly and is currently

Annually, a dentist in Canada applies 1800 LA cartridges, while in the USA, more than 300 million of cartridges are administered each year. Therefore, dentists should be experts in pharmacology, complications, and secondary effects of LA. In daily practice there are few complications related to LA, owing its security and the relative low doses that are applied. Nonetheless, it is necessary to consider possible

The synthetic LA has a common chemical structure, constituted by an aromatic

The type of nervous blockade produced by LA is named non-depolarizing nervous block. Local anesthetics block sodium channels permeability, they selectively

ring, a hydrocarbon channel, and an amino group; the hydrocarbon channel and aromatic ring are joined by an ester or amide bond. Most of LAs are tertiary amines. The lipophilic portion is the biggest of the molecule. The aromatic portion proceeds from benzoic acid, aniline, or thiophene (articaine) and is the lipophilic portion. This portion is responsible for the affinity of nerve cells. The hydrophilic portion is an amino ethanol or acetic acid derivative and is responsible of water solubility and diffusion across tissues. LAs are amphipathic; that is, they have lipophilic and hydrophilic characteristics at their opposite ends of their molecules (**Figure 1**) [4]. Amides are the most common molecules; procaine is the prototype of this group and benzocaine for topic application. The minimal concentration of LA to block the conduction of a nociceptive impulse is named potency. The therapeutic value of the drug in terms of efficacy and tolerability is called toxicity. The ability of the drug to reach tissues far from the site of administration of LA is called diffusion. Time between the action of LA and the metabolism of its compounds is

displacing the use of lidocaine in dental anesthesia [3].

complications, to detect it as soon as possible.

**2. Pharmacology of LA**

named time of action [5].

**3. Mechanism of action of LA**

**136**

**Figure 1.**

*Local anesthetic molecule.*

inhibit the maximum permeability to sodium, whose values usually are five to six times greater than the necessary minimum to conduct the impulse, when this value fail, and the nerve block occurs. In other words, local anesthesia is induced when the spread of action potential is inhibited, so a painful sensation cannot be transmitted from the site of origin to the brain. Or, LA alter the mechanism to sodium ions to gain access to the axoplasm nerve. The nerve membrane stays in a polarized state due to the impossibility of ionic movement responsible of action potential. LA blocks the entrance of sodium ions into their channels in the nerve cellular membrane. The permeability to sodium is necessary to generate a new action potential to transmit nerve impulses to the brain [6]. The sequence of action mechanism proposed for LA is described in **Table 1**.

LAs are classified into two large groups depending on its chemical bond: amides or ester; the latter are almost disappearing in dentistry. The ester LAs are easily hydrolyzed in aqueous solution, while amide bond LAs are relatively resistant to hydrolysis. The most important factors that affect onset and duration of action of LA are tissue pH, drug pKa, diffusion time from the tip of the needle to nerve, nerve morphology, drug concentration, and drug solubility in lipids [7]. The most important of the abovementioned factors are tissue pH and drug pKa. The pH may be reduced in infection sites, so the result would be a delay in the LA onset. In clinics, the amides pK is similar, with the exception of bupivacaine that has a slightly greater pK and an onset time more prolonged. The proximity of the anesthetic to the nerve is another factor that influences the action time of LA; a very clear example is the Gow-Gates blockade, very slow in its installation. The nerve morphology is also an important factor, which thin fibers are quickly anesthetized compared to thicker ones. The duration of action depends on the depth at which the drug may be blocking the sodium channels in the nerve membrane. If the LA causes vasodilatation, it allows a more or less rapid diffusion in the site of action and therefore a short duration of action, especially if the drug is administered alone. This diffusion may be reduced with the aid of vasoconstrictors like epinephrine, although bupivacaine is the only LA that has a prolonged action duration [8]. The two most important factors involved in the action of LA are the drug diffusion across the nerve sheath and the bind to the receptor in the ionic channel; a lipid-soluble free base and without electric charge is responsible of the diffusion across the nerve sheath.

The biotransformation of amides occurs mainly in the liver, although prilocaine is metabolized in plasma and eliminated in the kidney. One of its metabolites could be the origin of methemoglobinemia [9]. The ester LAs are biotransformed in plasma by enzymes called cholinesterase or pseudocholinesterase produced in the liver [10].


#### **Table 1.**

*Sequence of mechanisms of LA to produce conduction block.*


#### **Table 2.**

*Important properties of LA.*

Despite the great advances in the field or anesthetics in dentistry, the ideal agent do not exist; however, new ALs are increasingly safer. Some of its most important properties are listed in **Table 2**.

#### **4. Most commonly used LA in dentistry**

#### **4.1 Lidocaine**

This is the most common used LA in dentistry since its introduction in 1948 and now considered the gold standard for clinical use. It was the drug that displaced older anesthetics like procaine (Novocain). It has fast onset between 2 and 3 minutes with a longer and profound anesthesia. It is available in various concentrations; the most used are 1 and 2% cartridges with 1:100,000 and 1:50,000 epinephrine. Using lidocaine without a vasoconstrictor is rare in dentistry because of rapid vasodilation and high plasma concentrations as well as higher adverse reaction. For patients who are sensitive to epinephrine, they should limit the amount to a maximum of two cartridges per procedure. Thus, it is true for hypertensive patients, patients with coronary heart disease, and the elderly. Lidocaine combined with 1:50,000 epinephrine is commonly used in active dental bleeding because of diminishing up to 50%. It gives a pulpal anesthesia for up to 90 minutes and sometimes may be comparable to articaine (3–5 hours). Today, lidocaine is referred to local anesthetics toxicity. The maximum recommended dose in combination with epinephrine is 7 mg/kg for an adult or children over 15 kg, not exceeding 500 mg. Lidocaine alone is limited to 4.4 mg/kg, not exceeding 300 mg [11].

#### **4.2 Mepivacaine**

This is an amide type LA, available only in cartridge formed at concentration of 2 and 3%. Mepivacaine combined with a vasoconstrictor in 2% concentration. It is ideal for patients with an absolute contraindication to receive vasoconstrictor.

**139**

*Local Anesthetics in Odontology*

**4.3 Articaine**

**4.4 Bupivacaine**

easily uncoupled from the receptor.

approved by the FDA in children [16].

*DOI: http://dx.doi.org/10.5772/intechopen.91738*

A maximum recommended dose in adult or children is 4.4 mg/kg without exceeding 300 mg a day. Simple mepivacaine at 3% gives anesthesia for about 20–40 minutes in gums, 40 minutes in nerve blocks, and a maximum of 3 hours in soft tissue. It is the most commonly used LA in pediatric patients because of its rapid onset and short dental procedures. It is available in 1:20,000 combination with levonordefrin which is a different profile compared to epinephrine. Their affinity to alpha and beta receptors is 75:25, a low effect on beta receptors. Levonordefrin is one-sixth of the potency of epinephrine. It has the lowest pKa of all LA used in dentistry, which explains the rapid onset [11]. Compared with lidocaine it has a potency of 2 and is metabolized thru oxidase in the liver, and renal elimination in 16% is unchanged.

It is most recently introduced to dental practice. It is an amide type but possesses an ester group, making it the only hybrid LA, thus metabolizing in plasma as well as by the liver in which most of the process takes place, giving a result an inactive metabolite named articainic acid. It is equivalent to lidocaine in its vasodilation effect. It has a fast elimination time of approximately 27 minutes, compared to 40 minutes in amide anesthetics. It offers 90 minutes of pulpal anesthesia and 3 hours in soft tissue, being a reasonable choice in most dental procedures. This is available in dental cartridges at 4%, with epinephrine in 1:100,000 and 1:200,000 concentrations. The maximum dose is 7 mg/kg (72 mg per cartridge) for adults and 5 mg/kg for children under 15 kg [12]. It is the LA with higher risk of postoperative paresthesia in the jaw while rarely happening in other non-dental specialties such as orthopedic, spinal, or eye [13, 14].

It is a long-acting amide LA. Intrapulpal anesthesia as long as offers 6 hours and solf tissue up to 12 hours. It is also the most toxic drug, characterized by cardiovascular affection, inducing sudden collapse. In the same way it can induce longer duration of seizures which may be explained by its slower elimination (0.58 L/minute clearance) and a long half-life. It is four times more potent than lidocaine [15]. Although related to mepivacaine because of their molecular composition they differ chemically, it is 35 times more liposoluble, easily crossing the membrane in nerve cells, binding strongly at receptor sites with greater inactivation of sodium channels which make slow recovery, hence the saying that it is not

Nancarrow et al. studied fatal doses in several LA: for lidocaine 30.8 ± 5.8 mg/ kg/h, ropivacaine 7.3 ± 1.0 mg/kg, and bupivacaine 3.7 ± 1.1 mg/kg. Due to this finding, the toxicity threshold of bupivacaine in dental procedures is low and, an unnoticed injection during infiltration is dangerous and not recommended or

Bupivacaine is available in dental cartridges in 0.5% with 1:200,000. Ropivacaine has demonstrated a 75% safer profile than bupivacaine. It is a longacting LA with the highest pKa (8.1) and binding to plasmatic proteins in 95% compared to the rest of the drugs used in dentistry, which gives a slowest onset, although in dental procedures this is usually not an issue. With a fast onset of 4-8 minutes after injection, 99% of patients reported low sensitivity in the lips vs. 100% reported with lidocaine [17]. The majority of reports of bupivacaine used in third molar extractions and root canal has confirmed its efficiency and security. It is four times more toxic than lidocaine, so the use in dentistry is in lower doses than other areas in anesthesiology. A low incidence in paresthesia near 0.5% with this LA in combination with epinephrine at 1:200000 in an inferior alveolar nerve

#### *Local Anesthetics in Odontology DOI: http://dx.doi.org/10.5772/intechopen.91738*

A maximum recommended dose in adult or children is 4.4 mg/kg without exceeding 300 mg a day. Simple mepivacaine at 3% gives anesthesia for about 20–40 minutes in gums, 40 minutes in nerve blocks, and a maximum of 3 hours in soft tissue. It is the most commonly used LA in pediatric patients because of its rapid onset and short dental procedures. It is available in 1:20,000 combination with levonordefrin which is a different profile compared to epinephrine. Their affinity to alpha and beta receptors is 75:25, a low effect on beta receptors. Levonordefrin is one-sixth of the potency of epinephrine. It has the lowest pKa of all LA used in dentistry, which explains the rapid onset [11]. Compared with lidocaine it has a potency of 2 and is metabolized thru oxidase in the liver, and renal elimination in 16% is unchanged.

#### **4.3 Articaine**

*Topics in Local Anesthetics*

Active, injected, or topically administered

No systemic toxicity when properly used

Sterilizable without losing its properties

Specific action Reversible action Quickly onset action Adequate duration of action

Non-irritating Non-permanent harm

High therapeutic ratio Chemically stable Long half-life

Slight allergenic

*Important properties of LA.*

**Table 2.**

properties are listed in **Table 2**.

**4.1 Lidocaine**

**4. Most commonly used LA in dentistry**

Ability to combine with other agents without losing their properties

Despite the great advances in the field or anesthetics in dentistry, the ideal agent do not exist; however, new ALs are increasingly safer. Some of its most important

This is the most common used LA in dentistry since its introduction in 1948 and now considered the gold standard for clinical use. It was the drug that displaced older anesthetics like procaine (Novocain). It has fast onset between 2 and 3 minutes with a longer and profound anesthesia. It is available in various concentrations; the most used are 1 and 2% cartridges with 1:100,000 and 1:50,000 epinephrine. Using lidocaine without a vasoconstrictor is rare in dentistry because of rapid vasodilation and high plasma concentrations as well as higher adverse reaction. For patients who are sensitive to epinephrine, they should limit the amount to a maximum of two cartridges per procedure. Thus, it is true for hypertensive patients, patients with coronary heart disease, and the elderly. Lidocaine combined with 1:50,000 epinephrine is commonly used in active dental bleeding because of diminishing up to 50%. It gives a pulpal anesthesia for up to 90 minutes and sometimes may be comparable to articaine (3–5 hours). Today, lidocaine is referred to local anesthetics toxicity. The maximum recommended dose in combination with epinephrine is 7 mg/kg for an adult or children over 15 kg, not exceeding 500 mg.

Lidocaine alone is limited to 4.4 mg/kg, not exceeding 300 mg [11].

This is an amide type LA, available only in cartridge formed at concentration of 2 and 3%. Mepivacaine combined with a vasoconstrictor in 2% concentration. It is ideal for patients with an absolute contraindication to receive vasoconstrictor.

**138**

**4.2 Mepivacaine**

It is most recently introduced to dental practice. It is an amide type but possesses an ester group, making it the only hybrid LA, thus metabolizing in plasma as well as by the liver in which most of the process takes place, giving a result an inactive metabolite named articainic acid. It is equivalent to lidocaine in its vasodilation effect. It has a fast elimination time of approximately 27 minutes, compared to 40 minutes in amide anesthetics. It offers 90 minutes of pulpal anesthesia and 3 hours in soft tissue, being a reasonable choice in most dental procedures. This is available in dental cartridges at 4%, with epinephrine in 1:100,000 and 1:200,000 concentrations. The maximum dose is 7 mg/kg (72 mg per cartridge) for adults and 5 mg/kg for children under 15 kg [12]. It is the LA with higher risk of postoperative paresthesia in the jaw while rarely happening in other non-dental specialties such as orthopedic, spinal, or eye [13, 14].

#### **4.4 Bupivacaine**

It is a long-acting amide LA. Intrapulpal anesthesia as long as offers 6 hours and solf tissue up to 12 hours. It is also the most toxic drug, characterized by cardiovascular affection, inducing sudden collapse. In the same way it can induce longer duration of seizures which may be explained by its slower elimination (0.58 L/minute clearance) and a long half-life. It is four times more potent than lidocaine [15]. Although related to mepivacaine because of their molecular composition they differ chemically, it is 35 times more liposoluble, easily crossing the membrane in nerve cells, binding strongly at receptor sites with greater inactivation of sodium channels which make slow recovery, hence the saying that it is not easily uncoupled from the receptor.

Nancarrow et al. studied fatal doses in several LA: for lidocaine 30.8 ± 5.8 mg/ kg/h, ropivacaine 7.3 ± 1.0 mg/kg, and bupivacaine 3.7 ± 1.1 mg/kg. Due to this finding, the toxicity threshold of bupivacaine in dental procedures is low and, an unnoticed injection during infiltration is dangerous and not recommended or approved by the FDA in children [16].

Bupivacaine is available in dental cartridges in 0.5% with 1:200,000. Ropivacaine has demonstrated a 75% safer profile than bupivacaine. It is a longacting LA with the highest pKa (8.1) and binding to plasmatic proteins in 95% compared to the rest of the drugs used in dentistry, which gives a slowest onset, although in dental procedures this is usually not an issue. With a fast onset of 4-8 minutes after injection, 99% of patients reported low sensitivity in the lips vs. 100% reported with lidocaine [17]. The majority of reports of bupivacaine used in third molar extractions and root canal has confirmed its efficiency and security.

It is four times more toxic than lidocaine, so the use in dentistry is in lower doses than other areas in anesthesiology. A low incidence in paresthesia near 0.5% with this LA in combination with epinephrine at 1:200000 in an inferior alveolar nerve

block has been reported [18]. Chapman and Ganendran reported that patients blocked with bupivacaine and epinephrine for the third molar extractions did not need pain medication at 4 hours after surgery compared to the control group (lidocaine 2%) in which all of the patients were given pain medication at the same time. Seventy percent of the bupivacaine group received medication at 8 hours after surgery, versus 100% in the lidocaine 2% group [19].

#### **4.5 Prilocaine**

For dental anesthesia, it is available in 4% concentration with or without epinephrine 1:200,000. Prilocaine by itself induces more vasodilation than mepivacaine and less than lidocaine. It shares the same length of action, although a slower onset. Toxicity is lower than lidocaine. At doses above 600 mg, there is a higher risk of developing methemoglobinemia. In levels below 20%, clinical symptoms such as cyanosis, respiratory distress, and cardiovascular collapse are not seen. Mainstay treatment for methemoglobinemia is 1% methylene blue, 1–2 mg/kg intravenously slow 10-minute drip. Toxicity signs less severe than lidocaine. Prilocaine at 4% is contained in cream form commercially named EMLA (lidocaine-prilocaine) commonly used to produce skin numbness before any type of procedure such as phlebotomy; the downside is the time (30 minutes) to prepare the skin completely. The maximum recommended dose in adults is 600 mg and 400 mg in children. It may provide anesthesia up to 60 minutes in an inferior alveolar block or even 4 hours in soft tissue. It is important to remember that prilocaine is contraindicated in patients with congenital or idiopathic methemoglobinemia, heart failure, or chronic pulmonary disease.

#### **5. Pharmacology of vasoconstrictors**

The LAs commonly used in dental anesthesia are vasodilators, so they increase the blood flow in the injected site and perhaps enhance the concentration of the drug in blood and the probability of anesthetic overdose. The increase in blood flow also results in a short duration of action, although it depends on other factors, such as protein binding capacity.

Vasoconstrictors are adjuvant substances to LA that play an important role in dental anesthesia, producing deeper anesthesia and greater action duration, decreased systemic toxicity possibility, as well as bleeding reduction.

The most used vasoconstrictor in dental anesthesia is epinephrine, available in concentrations of 1:50,000; 1:100,000; and 1:200,000. It is rapidly metabolized by oxidation or conjugation, and its half-life is a few minutes, but its effects can last up to several hours. Malamed et al. showed in experimental animals that the application of 2% lidocaine with epinephrine 1:100,000 around the sciatic nerve reduces the blood flow in 79% (**Table 3**) [20]. Other vasoconstrictors used in this clinical setting are norepinephrine and levonordefrin [21]. Low plasmatic concentrations of adrenaline can raise heart rate, cardiac output, and systemic vasodilation because of its β1 adrenergic effect. The stimulation of adrenergic receptors alpha and beta occurs in 50/50 proportion; so that alpha-adrenergic stimulation causes peripheral vasoconstriction, while beta-adrenergic stimulation produces tachycardia. It is used to prolong the action time of LA, decrease dental bleeding, and improve the visibility of the surgical field. Its effect limits the diffusion of LA from the injection site and its systemic absorption reducing the possibility of systemic toxicity. Although, in general, vasoconstrictors are not contraindicated, the risk level depends on the characteristics of each patient; people with certain cardiac or endocrine diseases or

**141**

total dose.

*Local Anesthetics in Odontology*

having deleterious side effects.

*Vasoconstrictor concentrations in mg/mL.*

**Table 3.**

*DOI: http://dx.doi.org/10.5772/intechopen.91738*

1:100,000 = 0.01 mg/mL or 10 μg/mL 1:200,000 = 0.05 mg/mL or 5 μg/mL 1:50,000 = 0.02 mg/mL or 20 μg/mL 1 epinephrine cartridge 1:200,000 = 9 μg/mL 1 epinephrine cartridge 1:100,000 = 18 μg/mL 1 epinephrine cartridge 1:50,000 = 36 μg/mL 1 levonordefrin cartridge 1:20,000 = 90 μg/mL

taking medicines that affect the sympathetic nervous system have a greater risk of

The LA with epinephrine for dental use are in the following proportions: 1:50,000 (0.02 mg/mL), 1:100,000 (0.01 mg/mL), or 1:200,000 (0.004 mg/mL) [22]. The administration of 2% lidocaine with epinephrine 1:100,000 (a cartridge) produces plasmatic concentration of 240 ± 69ρ g/mL. With the administration of three cartridges of epinephrine or 54 μg, the blood concentration is 302 ± 142 ρg/mL. Usually, the administration of one cartridge of LA with epinephrine is not associated with cardiovascular changes, while the administration of three cartridges of LA with epinephrine at the same concentration is associated with five times the concentration of epinephrine in plasma, and with it there may be systemic cardiovascular alterations. However, it is not necessarily associated with the dose [23]. The umbral value of plasmatic epinephrine to develop hypertension is between 50 and 100 ρg/mL; the umbral value for systolic blood pressure is 75–125 ρg/mL, while the umbral value to rise the diastolic blood pressure is 150–200 ρg/mL. Barkin et al. found that 2% lidocaine 1:100,000 can produce non-serious cardiac arrhythmias in 16% of dental patients. The study does not specify with was the most

frequent arrhythmia or if any treatment was administered [24].

and can be used with or without vasoconstrictors [25].

**6. Local and systemic complications of LA**

less vasoconstrictor than epinephrine and having a shorter half-life.

Local anesthesia is the gold standard for surgical dental procedures; it has defined as a technique that produces loss of sensitivity, without losing

Unfortunately, the vasoconstrictor effects are not always beneficial. In special situations vasoconstrictors can affect the patient; an example of this are the patients with limited cardiovascular systemic reserves, such angina pectoris, previous myocardial infarction, systemic hypertension, and non-controlled hypothyroidism. In such patients, epinephrine can produce indirectly central nervous system excitation, including systemic hypertension, tachycardia, tremors, headache, palpitations, cardiac arrhythmias, and stroke. Comorbidities recommendable to use lidocaine with epinephrine 1:100,000 to epinephrine dose of 0.04 mg = 40 μg as a

Procaine is a potent vasodilator and cannot produce adequate anesthesia if it is used without a vasoconstrictor. Lidocaine is also a vasodilator but has enough potency to be used alone. In contrast, mepivacaine has minor vasodilator properties

Norepinephrine as a vasoconstrictor is seldom used since fatalities due to hypertension have been reported. Another disadvantage at a local level is being a quarter


#### **Table 3.**

*Topics in Local Anesthetics*

**4.5 Prilocaine**

block has been reported [18]. Chapman and Ganendran reported that patients blocked with bupivacaine and epinephrine for the third molar extractions did not need pain medication at 4 hours after surgery compared to the control group (lidocaine 2%) in which all of the patients were given pain medication at the same time. Seventy percent of the bupivacaine group received medication at 8 hours after

For dental anesthesia, it is available in 4% concentration with or without epinephrine 1:200,000. Prilocaine by itself induces more vasodilation than mepivacaine and less than lidocaine. It shares the same length of action, although a slower onset. Toxicity is lower than lidocaine. At doses above 600 mg, there is a higher risk of developing methemoglobinemia. In levels below 20%, clinical symptoms such as cyanosis, respiratory distress, and cardiovascular collapse are not seen. Mainstay treatment for methemoglobinemia is 1% methylene blue, 1–2 mg/kg intravenously slow 10-minute drip. Toxicity signs less severe than lidocaine. Prilocaine at 4% is contained in cream form commercially named EMLA (lidocaine-prilocaine) commonly used to produce skin numbness before any type of procedure such as phlebotomy; the downside is the time (30 minutes) to prepare the skin completely. The maximum recommended dose in adults is 600 mg and 400 mg in children. It may provide anesthesia up to 60 minutes in an inferior alveolar block or even 4 hours in soft tissue. It is important to remember that prilocaine is contraindicated in patients with congenital or idiopathic methemoglobinemia, heart failure, or chronic pulmonary disease.

The LAs commonly used in dental anesthesia are vasodilators, so they increase the blood flow in the injected site and perhaps enhance the concentration of the drug in blood and the probability of anesthetic overdose. The increase in blood flow also results in a short duration of action, although it depends on other factors, such

Vasoconstrictors are adjuvant substances to LA that play an important role in dental anesthesia, producing deeper anesthesia and greater action duration,

The most used vasoconstrictor in dental anesthesia is epinephrine, available in concentrations of 1:50,000; 1:100,000; and 1:200,000. It is rapidly metabolized by oxidation or conjugation, and its half-life is a few minutes, but its effects can last up to several hours. Malamed et al. showed in experimental animals that the application of 2% lidocaine with epinephrine 1:100,000 around the sciatic nerve reduces the blood flow in 79% (**Table 3**) [20]. Other vasoconstrictors used in this clinical setting are norepinephrine and levonordefrin [21]. Low plasmatic concentrations of adrenaline can raise heart rate, cardiac output, and systemic vasodilation because of its β1 adrenergic effect. The stimulation of adrenergic receptors alpha and beta occurs in 50/50 proportion; so that alpha-adrenergic stimulation causes peripheral vasoconstriction, while beta-adrenergic stimulation produces tachycardia. It is used to prolong the action time of LA, decrease dental bleeding, and improve the visibility of the surgical field. Its effect limits the diffusion of LA from the injection site and its systemic absorption reducing the possibility of systemic toxicity. Although, in general, vasoconstrictors are not contraindicated, the risk level depends on the characteristics of each patient; people with certain cardiac or endocrine diseases or

decreased systemic toxicity possibility, as well as bleeding reduction.

surgery, versus 100% in the lidocaine 2% group [19].

**5. Pharmacology of vasoconstrictors**

as protein binding capacity.

**140**

*Vasoconstrictor concentrations in mg/mL.*

taking medicines that affect the sympathetic nervous system have a greater risk of having deleterious side effects.

The LA with epinephrine for dental use are in the following proportions: 1:50,000 (0.02 mg/mL), 1:100,000 (0.01 mg/mL), or 1:200,000 (0.004 mg/mL) [22]. The administration of 2% lidocaine with epinephrine 1:100,000 (a cartridge) produces plasmatic concentration of 240 ± 69ρ g/mL. With the administration of three cartridges of epinephrine or 54 μg, the blood concentration is 302 ± 142 ρg/mL.

Usually, the administration of one cartridge of LA with epinephrine is not associated with cardiovascular changes, while the administration of three cartridges of LA with epinephrine at the same concentration is associated with five times the concentration of epinephrine in plasma, and with it there may be systemic cardiovascular alterations. However, it is not necessarily associated with the dose [23].

The umbral value of plasmatic epinephrine to develop hypertension is between 50 and 100 ρg/mL; the umbral value for systolic blood pressure is 75–125 ρg/mL, while the umbral value to rise the diastolic blood pressure is 150–200 ρg/mL. Barkin et al. found that 2% lidocaine 1:100,000 can produce non-serious cardiac arrhythmias in 16% of dental patients. The study does not specify with was the most frequent arrhythmia or if any treatment was administered [24].

Unfortunately, the vasoconstrictor effects are not always beneficial. In special situations vasoconstrictors can affect the patient; an example of this are the patients with limited cardiovascular systemic reserves, such angina pectoris, previous myocardial infarction, systemic hypertension, and non-controlled hypothyroidism. In such patients, epinephrine can produce indirectly central nervous system excitation, including systemic hypertension, tachycardia, tremors, headache, palpitations, cardiac arrhythmias, and stroke. Comorbidities recommendable to use lidocaine with epinephrine 1:100,000 to epinephrine dose of 0.04 mg = 40 μg as a total dose.

Procaine is a potent vasodilator and cannot produce adequate anesthesia if it is used without a vasoconstrictor. Lidocaine is also a vasodilator but has enough potency to be used alone. In contrast, mepivacaine has minor vasodilator properties and can be used with or without vasoconstrictors [25].

Norepinephrine as a vasoconstrictor is seldom used since fatalities due to hypertension have been reported. Another disadvantage at a local level is being a quarter less vasoconstrictor than epinephrine and having a shorter half-life.

#### **6. Local and systemic complications of LA**

Local anesthesia is the gold standard for surgical dental procedures; it has defined as a technique that produces loss of sensitivity, without losing consciousness. Although anesthetics are defined as safe medications, some complications have been described.

The incidence of complications related to dental anesthesia is 4.5%, and the most common are needle break, paresthesia, transient facial paralysis, hematoma, toxicity and rarely allergy, dizziness 1.3%, tachycardia 1.1%, agitation 1.1%, nausea 0.8%, chills 0.7%, syncope, seizures, and bronchospasm [26].

As the same way, it can be complications related to additional vasoconstrictors of LA. It has been shown that the increases in plasmatic catecholamines observed after the LA infiltration are mainly due to higher doses of vasoconstrictors. Vasoconstrictors increase heart rate in 4.1% of patients and increase 20% with respect to baseline. Coronary insufficiency, arterial hypertension, myocardial infarction (in the last 6 months), congestive heart failure, pheochromocytoma, hyperthyroidism, and diabetes mellitus are risk factors for the use of vasoconstrictors during dental anesthesia [27].

Patients receiving LA are not always healthy; they can have hypertension, history of myocardial infarction, sequelae of diabetic neuropathy, cardiac disease, serious dental infections, are patients in extremes of life. Some are taking aspirin for various reasons: this drug inhibits the secretion of thromboxane, adenosine diphosphate, and serotonin, chemicals mediators necessary to the platelet plug formation. Therefore, all patients taking aspirin should be recommended to suppress it at least 6 or 7 days before the dental intervention. The aspirin binds to the platelet during its half-life of approximately 7 days, so by removing aspirin, the new platelets will function adequately. In arrhythmic patients the use of anesthetics with vasoconstrictors is not recommended.

More than 45% of dental patients have one or more concomitant disease in their medical history, and near 20% of patients will have some disease and drug or food allergy. The secondary effects of LA are mainly present in patients with risk factors; in such patients the secondary effects can raise to 5.7% [28], which may result in greater morbidity. Nowadays, although lidocaine is the most used LA in dentistry, there are other LAs such as articaine that could displace the use of lidocaine.

Complications of LA include local and systemic effects. Local complications include:

#### **6.1 LA failure**

The possibility that local dental anesthesia fails is remote. Timely identification of the reasons of regional anesthesia failure in dental or maxillofacial surgery is essential to adopt the measures required for its correction. Some factors of anesthetic failure involve bifid inferior alveolar nerve, retromolar foramen associated to accessory innervation, double or accessory mental foramen, the relation between the infiltration technique and bone density, accessory innervation in the case of the mylohyoid nerve and first cervical branches, cross innervation of the incisors, inactivity in the presence of tissue inflammation, inactive LA, incorrect technique, and subjective perception on the part of anxious patients [12]. **Table 4** lists other important factors.

#### **6.2 Hematoma**

Damage to blood vessels is usually caused by the tip needle, the blood accumulated inside the oral tissues, and the swelling located in any tissue which acts as an irritant of the tissue and causes pain and trismus. Accumulated blood can

**143**

*Local Anesthetics in Odontology*

2. Insufficient LA dose

5. Use of expired LA

*LA failure in dental practice.*

**Table 4.**

1. Inadequate anatomical selection

3. Insufficient time for the LA diffusion

4. Administration of LA in swelling or infected tissue

immune deficiency.

**6.3 Nerve damage**

involvement [29].

**6.5 Needle rupture**

**6.6 Systemic complications of LA**

*6.6.1 Systemic or local infection*

**6.4 Transient facial nerve paralysis**

*DOI: http://dx.doi.org/10.5772/intechopen.91738*

be a culture medium for oral bacteria, especially in diabetic patients or those with

motor or sensory abnormalities that usually have a full recovery.

The needle can damage a nerve which produces a partial or complete deficit with

This complication is caused by the introduction of LA into the parotid gland capsule, which is located at the back of the edge of the mandibular branch. If the LA is deposited on this site, a transient paralysis of muscles of the face occurs. The LA is applied next to the facial nerve, so the motor blockade would cause a temporary paralysis of the muscles of the face; clinically a modification in the face expression appears. The duration of motor paralysis lasts between 3 and 5 hours, and treatment is not required. An important clinical situation is that patient cannot close the affected eye and is necessary to avoid the dry eye during this period of

Since the introduction of non-reusable needles in dental anesthesia, needle rupture has been an extremely rare complication. Progrel et al. estimated this risk at 1:14 million, more specifically in the case of inferior alveolar nerve block. In the analysis of broken needles, it was found that the majority were short or G30 ultra-short needles (20 and 10 mm). The inferior alveolar nerve block was the most frequent in 79% of the cases and the alveolar superior posterior nerve in the rest of the cases. Additional factors are pre-bending of the needle before injection, the unexpected and sudden movement of the patient at the time the needle is entering

Local anesthetic-related systemic complications are associated with the nature

of the drug and/or their composition. Systemic complications are as followed:

Spreading the potentially dangerous infection within mouth soft tissue to neck or head may be caused by needle trauma. Dental abscess is a great danger to

the soft tissue, and strong contact of the needle with the bone [30].


#### **Table 4.**

*Topics in Local Anesthetics*

cations have been described.

tors during dental anesthesia [27].

strictors is not recommended.

of lidocaine.

**6.1 LA failure**

important factors.

**6.2 Hematoma**

include:

consciousness. Although anesthetics are defined as safe medications, some compli-

The incidence of complications related to dental anesthesia is 4.5%, and the most common are needle break, paresthesia, transient facial paralysis, hematoma, toxicity and rarely allergy, dizziness 1.3%, tachycardia 1.1%, agitation 1.1%, nausea

As the same way, it can be complications related to additional vasoconstrictors of LA. It has been shown that the increases in plasmatic catecholamines observed after the LA infiltration are mainly due to higher doses of vasoconstrictors. Vasoconstrictors increase heart rate in 4.1% of patients and increase 20% with respect to baseline. Coronary insufficiency, arterial hypertension, myocardial infarction (in the last 6 months), congestive heart failure, pheochromocytoma, hyperthyroidism, and diabetes mellitus are risk factors for the use of vasoconstric-

Patients receiving LA are not always healthy; they can have hypertension, history of myocardial infarction, sequelae of diabetic neuropathy, cardiac disease, serious dental infections, are patients in extremes of life. Some are taking aspirin for various reasons: this drug inhibits the secretion of thromboxane, adenosine diphosphate, and serotonin, chemicals mediators necessary to the platelet plug formation. Therefore, all patients taking aspirin should be recommended to suppress it at least 6 or 7 days before the dental intervention. The aspirin binds to the platelet during its half-life of approximately 7 days, so by removing aspirin, the new platelets will function adequately. In arrhythmic patients the use of anesthetics with vasocon-

More than 45% of dental patients have one or more concomitant disease in their medical history, and near 20% of patients will have some disease and drug or food allergy. The secondary effects of LA are mainly present in patients with risk factors; in such patients the secondary effects can raise to 5.7% [28], which may result in greater morbidity. Nowadays, although lidocaine is the most used LA in dentistry, there are other LAs such as articaine that could displace the use

Complications of LA include local and systemic effects. Local complications

The possibility that local dental anesthesia fails is remote. Timely identification of the reasons of regional anesthesia failure in dental or maxillofacial surgery is essential to adopt the measures required for its correction. Some factors of anesthetic failure involve bifid inferior alveolar nerve, retromolar foramen associated to accessory innervation, double or accessory mental foramen, the relation between the infiltration technique and bone density, accessory innervation in the case of the mylohyoid nerve and first cervical branches, cross innervation of the incisors, inactivity in the presence of tissue inflammation, inactive LA, incorrect technique, and subjective perception on the part of anxious patients [12]. **Table 4** lists other

Damage to blood vessels is usually caused by the tip needle, the blood accumulated inside the oral tissues, and the swelling located in any tissue which acts as an irritant of the tissue and causes pain and trismus. Accumulated blood can

0.8%, chills 0.7%, syncope, seizures, and bronchospasm [26].

**142**

*LA failure in dental practice.*

be a culture medium for oral bacteria, especially in diabetic patients or those with immune deficiency.

#### **6.3 Nerve damage**

The needle can damage a nerve which produces a partial or complete deficit with motor or sensory abnormalities that usually have a full recovery.

#### **6.4 Transient facial nerve paralysis**

This complication is caused by the introduction of LA into the parotid gland capsule, which is located at the back of the edge of the mandibular branch. If the LA is deposited on this site, a transient paralysis of muscles of the face occurs. The LA is applied next to the facial nerve, so the motor blockade would cause a temporary paralysis of the muscles of the face; clinically a modification in the face expression appears. The duration of motor paralysis lasts between 3 and 5 hours, and treatment is not required. An important clinical situation is that patient cannot close the affected eye and is necessary to avoid the dry eye during this period of involvement [29].

#### **6.5 Needle rupture**

Since the introduction of non-reusable needles in dental anesthesia, needle rupture has been an extremely rare complication. Progrel et al. estimated this risk at 1:14 million, more specifically in the case of inferior alveolar nerve block. In the analysis of broken needles, it was found that the majority were short or G30 ultra-short needles (20 and 10 mm). The inferior alveolar nerve block was the most frequent in 79% of the cases and the alveolar superior posterior nerve in the rest of the cases. Additional factors are pre-bending of the needle before injection, the unexpected and sudden movement of the patient at the time the needle is entering the soft tissue, and strong contact of the needle with the bone [30].

#### **6.6 Systemic complications of LA**

Local anesthetic-related systemic complications are associated with the nature of the drug and/or their composition. Systemic complications are as followed:

#### *6.6.1 Systemic or local infection*

Spreading the potentially dangerous infection within mouth soft tissue to neck or head may be caused by needle trauma. Dental abscess is a great danger to patient's health and a high risk for airway management by the anesthesiologist due to the possibility of rupturing it during the intubation. It is important to emphasize that LA should not be applied in infected soft tissue.

Bacterial endocarditis is not a complication related to the use of LA per se; however it can be related as a post procedure bacteremia after any type of injection to the mouth. Dental surgery that involves mucosa o contaminated tissue such as a molar extraction can produce a transient bacteremia and facilitate infections at a distance, especially in cardiac valves or endocardium. The most common bacteria is hemolytic streptococcus viridians. Patients with dentures can develop bacteremia from gum ulcers or gingivitis. Numerous studies have shown a possible odontologyrelated etiology of bacterial endocarditis in up to 20% of the patients. Although prophylactic antibiotics are a commonly accepted practice, the American Heart Association (AHA) in 1997 described multiple prophylactic strategies: (a) amoxicillin 2 g, 1 hour prior to the treatment, and (b) clindamycin 600 mg, 1 hour prior to treatment [31].

#### **6.7 Cardiovascular manifestations**

Heart complications related to dental procedures may increase up to a 5.7% in patients with identified risk factors. Patients with coronary heart disease, cardiac surgery, or heart failure show greater plasmatic lidocaine levels; therefore a 50% reduction in maximum dosage of LA is recommended. Potassium levels and acidosis may worsen the adverse effects in the myocardium. High-risk patients should be limited to 30-minute dental surgery; after that time complications may rise up to 15% [32].

Cardiovascular collapse is described as the most severe LA complication, associated with high mortality. It is produced by intravascular injection of AL and is manifested by arrhythmias, heart failure, and arterial hypotension that can end in death if not treated in a timely manner. Usually, the doses of LA used in dentistry rarely exceed the limits to cause cardiovascular problems, although in exceptional cases, small amounts of AL may be capable of cardiac arrest [33]. For more information, we refer the reader to the chapter on LA systemic toxicity included in this book.

#### **6.8 Local anesthetic overdose**

Most overdose reactions occur during LA injection or within the next 5–10 minutes. Clinical symptoms involving the CNS are, for example, generalized numbness, facial numbing, anxiety, restlessness, confusion, chills, seizures, or respiratory arrest [7]. A simple way to avoid LA injection into the blood vessels is to aspirate before and during the injection. Systemic toxicity depends on several factors such as speed of injection, site, and combination with vasoconstrictors. For example, maximum dose of LA in a pediatric patient may be mistaken with an adult and cause an overdose. High concentrations of LA articaine and prilocaine may exacerbate and overdose. Serum concentration of LA less than 5 μg/mL produce moderate sedation and analgesia, but at concentrations as high as 5–10 μg/mL, it can cause incoherent talk, dysphoria, diplopia, muscle contractions, or seizures [34].

#### **6.9 Plasma cholinesterase deficiency**

Esther-type LA should be avoided in patients that may carry this rare enzyme deficiency, due to the metabolism of this anesthetic. Methemoglobinemia is a rare complication associated with excessive metabolites of certain LA, mainly prilocaine, causing oxidation of the ferrous component in the blood to a ferric

**145**

*Local Anesthetics in Odontology*

**6.10 Allergic reactions**

allergic reaction [37, 38].

**6.11 Drug interactions**

*DOI: http://dx.doi.org/10.5772/intechopen.91738*

form, and poorly delivered oxygen to tissues commonly expressed as hypoxia. Unique features, such as a saturation gap and chocolate-brown-colored blood, can raise suspicion for methemoglobinemia. The use of articaine and benzocaine have also been associated with methemoglobinemia and manifests with cyanosis that does not respond with supplemental oxygen. When high methemoglobinemia levels are present, clinical symptoms such as nausea, sedation, seizures, and coma may appear. Treatment is with methylene blue. Thus, patients with congenital or acquired plasma cholinesterase deficiency should avoid exposure to these LAs [34].

These reactions are extremely rare in dentistry. The most common allergic reactions are allergies to latex, acrylates, and formaldehyde. While polymethylmethacrylate and latex trigger delayed hypersensitivity reactions, sodium metabisulphite and nickel cause immediate reactions. Most adverse reactions are caused by systemic complications or anxiety as a result of pain or needles, generating hyperventilation or syncope that may be confused with a faulty allergic reaction. True allergic reactions are caused mainly by ester LA. They are not dose related. Only 0.7–1% of all allergies are authentic hypersensitivity reactions and caused after administering LA [35]. It is fundamental to have previous contact with the allergen, and then a usual latency period occurs until a second exposure. Hypersensitivity reactions related to LA are classified into two types: type I reactions or humoral are immediate and severe such as anaphylactic shock, angioedema, fever, and photo sensibility. Type IV or cellular are delayed and manifested through moderate dermatologic reactions such as hives or cutaneous rash. Anaphylactic shock usually occurs within a short exposure to the antigen, and symptoms include cardiovascular collapse in 76.3%, bronchospasm in 44.2%, and skin in 69.9%. Cardiovascular collapse presents as abrupt drop in blood pressure, bradycardia, and desaturation followed by bronchospasm and redness in thoracic area and face are common. Initial management is epinephrine 1-5 mcg/kg [36]. Intramuscular application, fluid bolus, secured airway, and increase in oxygen concentration. There is a frequently reported contact dermatitis in healthcare workers that are exposed to parabens and bisulfates used as preservatives in local anesthetic preparations which can cause an

There are some well-known interactions with LA, such as tricyclic antidepressants and beta blockers. The first act is by inhibiting the catecholamine reuptake, thus increasing the concentration at the presynaptic sympathetic binding site. In patients taking this kind of medication, it is recommended to limit the amount of epinephrine to a maximum of 0.05 mg/dose. Beta blockers, on the other hand, inhibit arteriolar vasodilation effect of drugs as epinephrine in combination with LA, which increase the predominant vasoconstrictor alpha adrenergic effect. The end result could be an increase of arterial blood pressure and sympathetic effects. Another reported interaction is the diminished metabolism of amide LA. Sedatives, opioids, opioids, antihistamines, magnesium sulfate, and LA may increase CNS depression and respiratory drive which has to be titrated with caution. LA and some antiarrhythmic like quinidine may increase myocardial depression. Antimyasthenic agents such as neostigmine could antagonize the effect or muscle contraction. Anticholinesterase lowers the metabolism of ester LA. Ester LA such as procaine

combined with sulfas could inhibit antimicrobial action [34].

#### *Local Anesthetics in Odontology DOI: http://dx.doi.org/10.5772/intechopen.91738*

form, and poorly delivered oxygen to tissues commonly expressed as hypoxia. Unique features, such as a saturation gap and chocolate-brown-colored blood, can raise suspicion for methemoglobinemia. The use of articaine and benzocaine have also been associated with methemoglobinemia and manifests with cyanosis that does not respond with supplemental oxygen. When high methemoglobinemia levels are present, clinical symptoms such as nausea, sedation, seizures, and coma may appear. Treatment is with methylene blue. Thus, patients with congenital or acquired plasma cholinesterase deficiency should avoid exposure to these LAs [34].

#### **6.10 Allergic reactions**

*Topics in Local Anesthetics*

treatment [31].

**6.7 Cardiovascular manifestations**

**6.8 Local anesthetic overdose**

**6.9 Plasma cholinesterase deficiency**

patient's health and a high risk for airway management by the anesthesiologist due to the possibility of rupturing it during the intubation. It is important to emphasize

Bacterial endocarditis is not a complication related to the use of LA per se; however it can be related as a post procedure bacteremia after any type of injection to the mouth. Dental surgery that involves mucosa o contaminated tissue such as a molar extraction can produce a transient bacteremia and facilitate infections at a distance, especially in cardiac valves or endocardium. The most common bacteria is hemolytic streptococcus viridians. Patients with dentures can develop bacteremia from gum ulcers or gingivitis. Numerous studies have shown a possible odontologyrelated etiology of bacterial endocarditis in up to 20% of the patients. Although prophylactic antibiotics are a commonly accepted practice, the American Heart Association (AHA) in 1997 described multiple prophylactic strategies: (a) amoxicillin 2 g, 1 hour prior to the treatment, and (b) clindamycin 600 mg, 1 hour prior to

Heart complications related to dental procedures may increase up to a 5.7% in patients with identified risk factors. Patients with coronary heart disease, cardiac surgery, or heart failure show greater plasmatic lidocaine levels; therefore a 50% reduction in maximum dosage of LA is recommended. Potassium levels and acidosis may worsen the adverse effects in the myocardium. High-risk patients should be limited to 30-minute dental surgery; after that time complications may rise up to 15% [32]. Cardiovascular collapse is described as the most severe LA complication, associated with high mortality. It is produced by intravascular injection of AL and is manifested by arrhythmias, heart failure, and arterial hypotension that can end in death if not treated in a timely manner. Usually, the doses of LA used in dentistry rarely exceed the limits to cause cardiovascular problems, although in exceptional cases, small amounts of AL may be capable of cardiac arrest [33]. For more information, we refer the reader to the chapter on LA systemic toxicity included in this book.

Most overdose reactions occur during LA injection or within the next 5–10 minutes. Clinical symptoms involving the CNS are, for example, generalized numbness, facial numbing, anxiety, restlessness, confusion, chills, seizures, or respiratory arrest [7]. A simple way to avoid LA injection into the blood vessels is to aspirate before and during the injection. Systemic toxicity depends on several factors such as speed of injection, site, and combination with vasoconstrictors. For example, maximum dose of LA in a pediatric patient may be mistaken with an adult and cause an overdose. High concentrations of LA articaine and prilocaine may exacerbate and overdose. Serum concentration of LA less than 5 μg/mL produce moderate sedation and analgesia, but at concentrations as high as 5–10 μg/mL, it can cause incoherent

Esther-type LA should be avoided in patients that may carry this rare enzyme deficiency, due to the metabolism of this anesthetic. Methemoglobinemia is a rare complication associated with excessive metabolites of certain LA, mainly prilocaine, causing oxidation of the ferrous component in the blood to a ferric

talk, dysphoria, diplopia, muscle contractions, or seizures [34].

that LA should not be applied in infected soft tissue.

**144**

These reactions are extremely rare in dentistry. The most common allergic reactions are allergies to latex, acrylates, and formaldehyde. While polymethylmethacrylate and latex trigger delayed hypersensitivity reactions, sodium metabisulphite and nickel cause immediate reactions. Most adverse reactions are caused by systemic complications or anxiety as a result of pain or needles, generating hyperventilation or syncope that may be confused with a faulty allergic reaction. True allergic reactions are caused mainly by ester LA. They are not dose related. Only 0.7–1% of all allergies are authentic hypersensitivity reactions and caused after administering LA [35]. It is fundamental to have previous contact with the allergen, and then a usual latency period occurs until a second exposure. Hypersensitivity reactions related to LA are classified into two types: type I reactions or humoral are immediate and severe such as anaphylactic shock, angioedema, fever, and photo sensibility. Type IV or cellular are delayed and manifested through moderate dermatologic reactions such as hives or cutaneous rash. Anaphylactic shock usually occurs within a short exposure to the antigen, and symptoms include cardiovascular collapse in 76.3%, bronchospasm in 44.2%, and skin in 69.9%. Cardiovascular collapse presents as abrupt drop in blood pressure, bradycardia, and desaturation followed by bronchospasm and redness in thoracic area and face are common. Initial management is epinephrine 1-5 mcg/kg [36]. Intramuscular application, fluid bolus, secured airway, and increase in oxygen concentration. There is a frequently reported contact dermatitis in healthcare workers that are exposed to parabens and bisulfates used as preservatives in local anesthetic preparations which can cause an allergic reaction [37, 38].

#### **6.11 Drug interactions**

There are some well-known interactions with LA, such as tricyclic antidepressants and beta blockers. The first act is by inhibiting the catecholamine reuptake, thus increasing the concentration at the presynaptic sympathetic binding site. In patients taking this kind of medication, it is recommended to limit the amount of epinephrine to a maximum of 0.05 mg/dose. Beta blockers, on the other hand, inhibit arteriolar vasodilation effect of drugs as epinephrine in combination with LA, which increase the predominant vasoconstrictor alpha adrenergic effect. The end result could be an increase of arterial blood pressure and sympathetic effects. Another reported interaction is the diminished metabolism of amide LA. Sedatives, opioids, opioids, antihistamines, magnesium sulfate, and LA may increase CNS depression and respiratory drive which has to be titrated with caution. LA and some antiarrhythmic like quinidine may increase myocardial depression. Antimyasthenic agents such as neostigmine could antagonize the effect or muscle contraction. Anticholinesterase lowers the metabolism of ester LA. Ester LA such as procaine combined with sulfas could inhibit antimicrobial action [34].

#### **7. Conclusions**

Anxiety, stress, and pain are very frequent characteristics in dentistry. Dental anxiety can be considered as a universal phenomenon with a high prevalence, being one of the main causes of medical emergencies in the dental office, so its prevention is an essential part of patient safety and quality of care. The LA used in this clinical setting must be selective in nerve tissue; be powerful enough to produce complete anesthesia without tissue damage; have a reversible action within a predictable time; have minimal side effects and, also, reduced systemic toxicity, and few hypersensitivity reactions; have a short latency period with the duration of the effect adaptable to the desired; not cause pain during injection; be compatible with other components in the solution and not easily modified by sterilization processes; not be sensitive to variations in pH; be stable in the solution; and have sufficient penetration. Lidocaine and articaine with epinephrine are the most used, although mepivacaine and prilocaine are still options. It is mandatory to monitor side reactions, especially systemic toxicity.

### **Author details**

Enrique Hernández-Cortez1 \*, Cecilia G. Sandoval Larios2 and Juan Carlos Flores-Carrillo3

1 Department of Anesthesia, Federación Mexicana de Colegios de Anestesiología, A.C., León, México

2 Anesthesia and Cardiovascular Anesthesia, Airway Committee Federación Mexicana de Colegios de Anestesiologia AC, Hospital Angeles León, México

3 Anesthesia and Critical Care Medicine, Hospital Angeles Tijuana, México

\*Address all correspondence to: kikinhedz@gmail.com

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**147**

201-2008

*Local Anesthetics in Odontology*

**References**

*DOI: http://dx.doi.org/10.5772/intechopen.91738*

Gow-gates block for beginners. Giornale di Anestesia Stomatologica.

[10] Johnson TM, Badovinac R, Shaefer J. Teaching alternatives to the standard inferior alveolar nerve block in dental education: Outcomes in clinical practice. Journal of Dental Education.

[11] Malamed SF, Reed KL, Okundeye A, Fonner A. Local and regional anesthesia in dental and oral surgery. Complications of Regional Anesthesia. 2017. DOI: 10.1007/978-3-319-49386-2\_21

[12] Boronat López A, Peñarrocha DM. Failure of locoregional anesthesia in dental practice. Review of the literature. Medicina Oral, Patología Oral y Cirugía

Bucal. 2006;**11**(6):E510-E513

2006;**34**(12):971-976

10.1016/j.oooo

[13] Malamed SF. Local anesthetics dentistry's most important drugs, clinical update 2006: CDA. Journal of the California Dental Association.

[14] Batista da Silva C, Berto LA, Volpato MC, Ramacciato JC, Motta RH, Ranali J, et al. Anesthetic efficacy of articaine and lidocaine for incisive/ mental nerve block. Journal of Endodontics. 2010;**36**(3):438-441

[15] Sambrook PJ, Smith W, Elijah J, Goss AN. Severe adverse reactions to dental local anaesthetics: Systemic reactions. Australian Dental Journal. 2011;**56**:148-153. DOI: 10.1111/j.1834-7819.2011.01316.x

[16] Liu W, Yang X, Li C, Mo A. Adverse drug reactions to local anesthetics: A systematic review. Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology. 2013;**115**(3):319-327. DOI:

[17] Sancho-Puchades M, Vilchez-Perez MA, Valmaseda-Castellon E,

1989;**18**(3):7-17

2007;**71**(9):1145-1152

[1] López-Valverde A, de Vicente J, Cutando A. The surgeons Halsted and Hall, cocaine and the discovery of dental anaesthesia by nerve blocking. British Dental Journal. 2011;**2011**:485-487

[2] Lofgren N. Studies on Local

[3] Vree TB, Gielen MJ. Clinical pharmacology and the use of articaine for local and regional anaesthesia. Best Practice and Research in Clinical Anaesthesiology. 2005;**19**(2):293-308

[4] Yagiela JA. Recent developments in local anesthesia and oral sedation. The Compendium of Continuing Education in Dentistry. 2004;**25**(9):697-706

[5] Suresh S, Ecoffey C, Bosenberg A, Lonnqvist PA, De Oliveira GS, De Leon CO, et al. Recommendations ESRA/ASRA on local anesthetics and adjuvants dosage in pediatric Regional anesthesia. The European Society of Regional Anaesthesia and Pain Therapy/American Society of Regional Anesthesia and Pain Medicine. 2018;**43**(2):211-216.

Available from: https://doi.org/10.1097/

[6] De B, Reed KL. Local anesthetics:

considerations. Anesthesia Progress.

[7] Has DA. An update of local anesthetics in dentistry. Journal of the Canadian Dental Association. 2002;**68**(9):546-551

[8] Alcaina-Lorente MA, Cortes-Lillo O, German Cecilia C, Castejon-Navas I. Parestesia con el uso de anestésicos locales. A propósito de dos casos. Odontologia Pediátrica. 2010;**18**(3):

[9] Manani G, Charanda M, Benatti M, Narne S, Zanardi L, Rusca F, et al.

AAP.0000000000000702

Review of pharmacological

2013;**59**:90-102

Anesthetics: Xylocaine, a New Synthetic Drug. Hoeggstroms: Stockhlm; 1948

### **References**

*Topics in Local Anesthetics*

**7. Conclusions**

**146**

**Author details**

A.C., León, México

Enrique Hernández-Cortez1

and Juan Carlos Flores-Carrillo3

tions, especially systemic toxicity.

provided the original work is properly cited.

\*Address all correspondence to: kikinhedz@gmail.com

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

\*, Cecilia G. Sandoval Larios2

Anxiety, stress, and pain are very frequent characteristics in dentistry. Dental anxiety can be considered as a universal phenomenon with a high prevalence, being one of the main causes of medical emergencies in the dental office, so its prevention is an essential part of patient safety and quality of care. The LA used in this clinical setting must be selective in nerve tissue; be powerful enough to produce complete anesthesia without tissue damage; have a reversible action within a

predictable time; have minimal side effects and, also, reduced systemic toxicity, and few hypersensitivity reactions; have a short latency period with the duration of the effect adaptable to the desired; not cause pain during injection; be compatible with other components in the solution and not easily modified by sterilization processes; not be sensitive to variations in pH; be stable in the solution; and have sufficient penetration. Lidocaine and articaine with epinephrine are the most used, although mepivacaine and prilocaine are still options. It is mandatory to monitor side reac-

1 Department of Anesthesia, Federación Mexicana de Colegios de Anestesiología,

2 Anesthesia and Cardiovascular Anesthesia, Airway Committee Federación Mexicana de Colegios de Anestesiologia AC, Hospital Angeles León, México

3 Anesthesia and Critical Care Medicine, Hospital Angeles Tijuana, México

[1] López-Valverde A, de Vicente J, Cutando A. The surgeons Halsted and Hall, cocaine and the discovery of dental anaesthesia by nerve blocking. British Dental Journal. 2011;**2011**:485-487

[2] Lofgren N. Studies on Local Anesthetics: Xylocaine, a New Synthetic Drug. Hoeggstroms: Stockhlm; 1948

[3] Vree TB, Gielen MJ. Clinical pharmacology and the use of articaine for local and regional anaesthesia. Best Practice and Research in Clinical Anaesthesiology. 2005;**19**(2):293-308

[4] Yagiela JA. Recent developments in local anesthesia and oral sedation. The Compendium of Continuing Education in Dentistry. 2004;**25**(9):697-706

[5] Suresh S, Ecoffey C, Bosenberg A, Lonnqvist PA, De Oliveira GS, De Leon CO, et al. Recommendations ESRA/ASRA on local anesthetics and adjuvants dosage in pediatric Regional anesthesia. The European Society of Regional Anaesthesia and Pain Therapy/American Society of Regional Anesthesia and Pain Medicine. 2018;**43**(2):211-216. Available from: https://doi.org/10.1097/ AAP.0000000000000702

[6] De B, Reed KL. Local anesthetics: Review of pharmacological considerations. Anesthesia Progress. 2013;**59**:90-102

[7] Has DA. An update of local anesthetics in dentistry. Journal of the Canadian Dental Association. 2002;**68**(9):546-551

[8] Alcaina-Lorente MA, Cortes-Lillo O, German Cecilia C, Castejon-Navas I. Parestesia con el uso de anestésicos locales. A propósito de dos casos. Odontologia Pediátrica. 2010;**18**(3): 201-2008

[9] Manani G, Charanda M, Benatti M, Narne S, Zanardi L, Rusca F, et al.

Gow-gates block for beginners. Giornale di Anestesia Stomatologica. 1989;**18**(3):7-17

[10] Johnson TM, Badovinac R, Shaefer J. Teaching alternatives to the standard inferior alveolar nerve block in dental education: Outcomes in clinical practice. Journal of Dental Education. 2007;**71**(9):1145-1152

[11] Malamed SF, Reed KL, Okundeye A, Fonner A. Local and regional anesthesia in dental and oral surgery. Complications of Regional Anesthesia. 2017. DOI: 10.1007/978-3-319-49386-2\_21

[12] Boronat López A, Peñarrocha DM. Failure of locoregional anesthesia in dental practice. Review of the literature. Medicina Oral, Patología Oral y Cirugía Bucal. 2006;**11**(6):E510-E513

[13] Malamed SF. Local anesthetics dentistry's most important drugs, clinical update 2006: CDA. Journal of the California Dental Association. 2006;**34**(12):971-976

[14] Batista da Silva C, Berto LA, Volpato MC, Ramacciato JC, Motta RH, Ranali J, et al. Anesthetic efficacy of articaine and lidocaine for incisive/ mental nerve block. Journal of Endodontics. 2010;**36**(3):438-441

[15] Sambrook PJ, Smith W, Elijah J, Goss AN. Severe adverse reactions to dental local anaesthetics: Systemic reactions. Australian Dental Journal. 2011;**56**:148-153. DOI: 10.1111/j.1834-7819.2011.01316.x

[16] Liu W, Yang X, Li C, Mo A. Adverse drug reactions to local anesthetics: A systematic review. Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology. 2013;**115**(3):319-327. DOI: 10.1016/j.oooo

[17] Sancho-Puchades M, Vilchez-Perez MA, Valmaseda-Castellon E, Paredes-Garcia J, Berini-Aytes L, Gay-Escoda C. Bupivacaine 0.5% versus articaine 4% for the removal of lower third molars. A crossover randomized controlled trial. Medicina Oral, Patología Oral y Cirugía Bucal. 2012;**17**(3):e462-e468

[18] Feldman G, Nordenram A. Bupivacaine in oral surgery. Acta Anaesthesiologica Scandinavica. 1983;**23**:409-413

[19] Sisk AL. Long-acting local anesthetics in dentistry. Anesthesia Progress. 1992;**39**:53-60

[20] Malamed SF, Gagnon S, Lebalanc D. Efficacy of articaine: A new amide local anesthetic. Journal of the American Dental Association (1939). 2000;**131**(5):635-642

[21] James O, Ladeinde AL, Ogunlewe MO, Ajuluchukwu JN, Adeyemo WL. Hemodynamic response after injection of local anesthetics with or without adrenaline in adult Nigerian subjects undergoing simple tooth extraction. Journal of Clinical Sciences. 2015;**12**:90-95

[22] Lawaty I, Drum M, Reader A, Nusstein J. A prospective, randomized, double-blind comparison of 2% mepivacaine with 1 :20,000 levonordefrin versus 2% lidocaine with 1 : 100,000 epinephrine for maxillary infiltrations. Anesthesia Progress. 2010;**57**(4):139-144. DOI: 10.2344/0003-3006-57.4.139

[23] Sisk AL. Vasoconstrictors in local anesthesia for dentistry. Anesthesia Progress. 1992;**39**:187-193

[24] Becker DE, Reed KL. Essentials of local anesthetics pharmacology. Anesthesia Progress. 2006;**53**:98-109

[25] Hass DA. Drugs in dentistry. In: Compendium of Pharmaceuticals and Specialties. 37th ed. Canada: Canadian Pharmaceurical Association; 2002. pp. L26-L29

[26] Daublander M, Muller R, Lipp MDW. The incidence of complications associated with local anesthesia in dentistry. American Dental Society of Anesthesiology. 1997;**44**:132-141

[27] Seminario-Amez M, González-Navarro B, Velasco-Ortega E, Jane-Salas E, Lopéz-Lopéz J. Use of local anesthetics associated with vasoconstrictors in dentistry. Is it a safe treatment? A literature update. EC Anesthesia. 2017;**3.2**:50-54

[28] Daublander M, Muller R, Lipp MDW. The incidence of complications associated with local anesthesia in dentistry. American Dental Society of Anesthesiology. 1999;**50**:102-106

[29] Malamed SF. Nerve injury caused by mandibular block analgesia. International Journal of Oral and Maxillofacial Surgery. 2006;**35**:876-877

[30] Progrel MA. Broken local anesthetic needle: A series of 16 patients, with recommendations. Journal of the American Dental Association. 2009;**140**:1517-1522

[31] Tomás-Carmona I, Diz-Dios P, Limeres-Posse J, Outumuro-Rial M, Caamaño-Durán F, Fernández-Feijoo J, et al. Pautas de profilaxis antibiótica de Endocarditis Bacteriana, recomendadas por los odontólogos en España. Medicina Oral. 2004;**9**:56-62

[32] Bahl R. Local anesthesia in dentistry. Anesthesia Progress. 2004;**51**: 138-142

[33] Becker DE, Reed KL. Local anesthetics: Review of pharmacological considerations. Anesthesia Progress. 2012;**59**:90-101

[34] Yagiela JA. Local anesthetics. Anesthesia Progress. 1991;**38**:128-141

**149**

*Local Anesthetics in Odontology*

America. 2010;**54**:655-664

[37] Gaitan-Padron MA,

México. 2013;**25**(S1):25-32

anpr-65-03-06

[38] Bina B, Hersh EV, Hilario M, Alvarez K, McLaughlin B. True allergy to amide local anesthetics: A review and case presentation. Anesthesia Progress. 2018;**65**(2):119-123. DOI: 10.2344/

*DOI: http://dx.doi.org/10.5772/intechopen.91738*

[35] Speca SJ, Boynes SG, Cuddy MA. Allergic reactions to local anesthetic formulations. Dental Clinics of North

[36] Truhlar A, Deakin CD, Soar J, Khalifa GE, Alfonzo A, Bierens JJ. European resuscitation council guidelines for resuscitation. Cardiac arrest in special circumstances. Resuscitation. 2015;**95**:148-201

Hernández-Cortez E. Alergia al latex en el paciente pediátrico. Anestesia en *Local Anesthetics in Odontology DOI: http://dx.doi.org/10.5772/intechopen.91738*

*Topics in Local Anesthetics*

2012;**17**(3):e462-e468

1983;**23**:409-413

Paredes-Garcia J, Berini-Aytes L, Gay-Escoda C. Bupivacaine 0.5% versus articaine 4% for the removal of lower third molars. A crossover randomized controlled trial. Medicina Oral, Patología Oral y Cirugía Bucal.

Pharmaceurical Association; 2002.

The incidence of complications associated with local anesthesia in dentistry. American Dental Society of Anesthesiology. 1997;**44**:132-141

[27] Seminario-Amez M,

Anesthesia. 2017;**3.2**:50-54

1999;**50**:102-106

[28] Daublander M, Muller R, Lipp MDW. The incidence of complications associated with local anesthesia in dentistry. American Dental Society of Anesthesiology.

[29] Malamed SF. Nerve injury caused by mandibular block analgesia. International Journal of Oral and Maxillofacial Surgery. 2006;**35**:876-877

[30] Progrel MA. Broken local anesthetic

needle: A series of 16 patients, with recommendations. Journal of the American Dental Association.

[31] Tomás-Carmona I, Diz-Dios P, Limeres-Posse J, Outumuro-Rial M, Caamaño-Durán F, Fernández-Feijoo J, et al. Pautas de profilaxis antibiótica de Endocarditis Bacteriana, recomendadas por los odontólogos en España. Medicina

[32] Bahl R. Local anesthesia in

[33] Becker DE, Reed KL. Local

[34] Yagiela JA. Local anesthetics. Anesthesia Progress. 1991;**38**:128-141

dentistry. Anesthesia Progress. 2004;**51**:

anesthetics: Review of pharmacological considerations. Anesthesia Progress.

2009;**140**:1517-1522

Oral. 2004;**9**:56-62

138-142

2012;**59**:90-101

[26] Daublander M, Muller R, Lipp MDW.

González-Navarro B, Velasco-Ortega E, Jane-Salas E, Lopéz-Lopéz J. Use of local anesthetics associated with vasoconstrictors in dentistry. Is it a safe treatment? A literature update. EC

pp. L26-L29

[18] Feldman G, Nordenram A. Bupivacaine in oral surgery. Acta Anaesthesiologica Scandinavica.

[19] Sisk AL. Long-acting local anesthetics in dentistry. Anesthesia

[20] Malamed SF, Gagnon S, Lebalanc D. Efficacy of articaine: A new amide local anesthetic. Journal of the American Dental Association (1939).

Progress. 1992;**39**:53-60

2000;**131**(5):635-642

2015;**12**:90-95

[21] James O, Ladeinde AL, Ogunlewe MO, Ajuluchukwu JN, Adeyemo WL. Hemodynamic response after injection of local anesthetics with or without adrenaline in adult Nigerian subjects undergoing simple tooth extraction. Journal of Clinical Sciences.

[22] Lawaty I, Drum M, Reader A, Nusstein J. A prospective, randomized,

[23] Sisk AL. Vasoconstrictors in local anesthesia for dentistry. Anesthesia

[24] Becker DE, Reed KL. Essentials of local anesthetics pharmacology. Anesthesia Progress. 2006;**53**:98-109

[25] Hass DA. Drugs in dentistry. In: Compendium of Pharmaceuticals and Specialties. 37th ed. Canada: Canadian

double-blind comparison of 2% mepivacaine with 1 :20,000 levonordefrin versus 2% lidocaine with 1 : 100,000 epinephrine for maxillary infiltrations. Anesthesia Progress. 2010;**57**(4):139-144. DOI: 10.2344/0003-3006-57.4.139

Progress. 1992;**39**:187-193

**148**

[35] Speca SJ, Boynes SG, Cuddy MA. Allergic reactions to local anesthetic formulations. Dental Clinics of North America. 2010;**54**:655-664

[36] Truhlar A, Deakin CD, Soar J, Khalifa GE, Alfonzo A, Bierens JJ. European resuscitation council guidelines for resuscitation. Cardiac arrest in special circumstances. Resuscitation. 2015;**95**:148-201

[37] Gaitan-Padron MA, Hernández-Cortez E. Alergia al latex en el paciente pediátrico. Anestesia en México. 2013;**25**(S1):25-32

[38] Bina B, Hersh EV, Hilario M, Alvarez K, McLaughlin B. True allergy to amide local anesthetics: A review and case presentation. Anesthesia Progress. 2018;**65**(2):119-123. DOI: 10.2344/ anpr-65-03-06

**151**

**Chapter 9**

**Abstract**

*Basak Keskin Yalcin*

the complications is also emphasized.

need to be aware of were also reported [2].

and ophthalmologic complications [2, 3].

complications, treatment

**1. Introduction**

Complications Associated with

One of the important attempts in clinical oral surgery practice is to maintain safe and effective local anesthesia. Dental procedures are frequently performed under local anesthesia; thus, drug-related complications are often encountered. It is mandatory to have a preoperative evaluation of the patient and choosing the proper local anesthetic agent. Various complications including hypersensitivity, allergy, overdosage, toxicity, hematoma, trismus, paresthesia, or neuralgia can be observed during practice. Therefore, the practitioner should be aware of the possible complications and management methods. The aim of this chapter is to review the preoperative and postoperative complications associated with the local anesthetic in oral and maxillofacial surgery practice. The prevention of measures and treatment of

**Keywords:** local anesthesia, complication, local complications, systemic

Local anesthetic agents have been used in clinical dentistry to allay or eliminate pain associated with invasive operations as early as the nineteenth century [1]. Local anesthetics are used routinely also in oral and maxillofacial surgery. Despite that local anesthetics are reliable and efficient drugs, the risks that practitioners

Complications associated with local anesthetics can be evaluated systemically and locally. Common systemic reactions due to local anesthesia are reported as psychogenic reactions, systemic toxicity, allergy, and methemoglobinemia. Common local complications associated with local anesthesia are reported as pain at injection, needle fracture, prolongation of anesthesia and various sensory disorders, lack of effect, trismus, infection, edema, hematoma, gingival lesions, soft tissue injury,

This chapter is presenting the local and systemic complications associated with

the local anesthetics used in oral and maxillofacial surgery. The prevention of

complications and management methods are also emphasized.

Local Anesthesia in Oral and

Maxillofacial Surgery

#### **Chapter 9**

## Complications Associated with Local Anesthesia in Oral and Maxillofacial Surgery

*Basak Keskin Yalcin*

#### **Abstract**

One of the important attempts in clinical oral surgery practice is to maintain safe and effective local anesthesia. Dental procedures are frequently performed under local anesthesia; thus, drug-related complications are often encountered. It is mandatory to have a preoperative evaluation of the patient and choosing the proper local anesthetic agent. Various complications including hypersensitivity, allergy, overdosage, toxicity, hematoma, trismus, paresthesia, or neuralgia can be observed during practice. Therefore, the practitioner should be aware of the possible complications and management methods. The aim of this chapter is to review the preoperative and postoperative complications associated with the local anesthetic in oral and maxillofacial surgery practice. The prevention of measures and treatment of the complications is also emphasized.

**Keywords:** local anesthesia, complication, local complications, systemic complications, treatment

#### **1. Introduction**

Local anesthetic agents have been used in clinical dentistry to allay or eliminate pain associated with invasive operations as early as the nineteenth century [1]. Local anesthetics are used routinely also in oral and maxillofacial surgery. Despite that local anesthetics are reliable and efficient drugs, the risks that practitioners need to be aware of were also reported [2].

Complications associated with local anesthetics can be evaluated systemically and locally. Common systemic reactions due to local anesthesia are reported as psychogenic reactions, systemic toxicity, allergy, and methemoglobinemia. Common local complications associated with local anesthesia are reported as pain at injection, needle fracture, prolongation of anesthesia and various sensory disorders, lack of effect, trismus, infection, edema, hematoma, gingival lesions, soft tissue injury, and ophthalmologic complications [2, 3].

This chapter is presenting the local and systemic complications associated with the local anesthetics used in oral and maxillofacial surgery. The prevention of complications and management methods are also emphasized.

#### **2. Classification and chemical structure of local anesthetics**

Local anesthetics can be classified according to their chemical structure, a rate of onset, potency, and duration of action. Chemically, they are either amino esters or amino amides (i.e., an aromatic, lipophilic ring connected to a hydrophilic amine group by an intermediate chain containing either an ester or amide linkage). Ester local anesthetics are hydrolyzed in the plasma by pseudocholinesterase into para-aminobenzoic acid (PABA) and other derivatives, whereas amide-type local anesthetics are metabolized by the liver. The rate of hydrolysis has an effect on the potential toxicity of a local anesthetic. Allergic reactions that occur in response to ester local anesthetics usually are related to para-aminobenzoic acid, which is a major metabolic product of many ester local anesthetics. The rates of biotransformation of amide group lidocaine, mepivacaine, etidocaine, and bupivacaine are similar. Articaine, which contains both amide and ester, metabolizes both in the liver and blood. The ester group (cenzoic acid esters) includes cocaine, procaine, chloroprocaine, tetracaine, and benzocaine. The amide group includes lidocaine, mepivacaine (Carbocaine), prilocaine (Citanest), bupivacaine (Marcaine), etidocaine (curanest), dibucaine (nupercaine), and ropivacaine (Naropin).

Ester local anesthetics are not available in dental cartridges essentially because of several reasons such as the lack of efficacy, the potential for allergenicity, and the advantages of amino amides [4–7].

#### **3. Systemic reactions due to local anesthesia**

#### **3.1 Psychogenic reactions**

This psychogenic answer is associated with either the patient's body counterbalance to an anxiety-inducing situation or due to adrenaline secreted by the vasoconstrictor agent. As a result of mood changes, heart rate, respiratory rate, and blood pressure are altered. Patients often have a blush or erythema which mimics allergic reactions, hyperventilation, nausea, and vomiting [3]. It is important to understand the patient and make them relax. In more severe cases, these reactions should be maintained as syncope and hyperventilation. For preventing psychogenic reactions, the patient should be relaxed before administering local anesthetic injections. Using oral sedatives is an efficacious method to manage dental fears. Initial dosage should be dependent on patient health, age, weight, and duration of the operation. For healthy adult patients in short-term operations antihistamine-diphenhydramine (Benadryl) 50 mg 1 hour prior to the operation, moderate length (1–2 hours) operation benzodiazepine, triazolam (Halcion) 0.125–0.5 mg 1 hour before the operation triazolam, for longer duration (2–4 hours) benzodiazepine such as lorazepam (Ativan) 1–4 mg may be given 1–2 hours prior to the operation or 30–60 minutes prior for the sublingual preparation may be described and given. Pharmacologically, mildly and moderately anxious dental patients can be managed using sedation or extremely anxious or phobic patients using general anesthesia [8, 9].

#### **3.2 Systemic toxicity**

Local anesthetic systemic toxicity develops when a sufficient (toxic) concentration of anesthetic drug in the blood level reaches to the central nervous system and cardiovascular systems.

**153**

*Complications Associated with Local Anesthesia in Oral and Maxillofacial Surgery*

Initial symptoms are characterized by central nervous system signs such as excitation, convulsions, followed by loss of consciousness and respiratory arrest. These symptoms are often accompanied by cardiovascular signs such as hypertension, tachycardia, and premature ventricular contractions. The clinical signs and symptoms usually show objective symptoms such as quick talking, flicker, and

Predisposing factors are associated with age, weight, other drugs, gender, the presence of disease, genetics, vasoactivity, concentration, dose, route of administration, the rate of injection, vascularity of the injection site, and the presence of

In order to prevent systemic toxicity, the patient should be evaluated. The volume of local anesthesia should be decreased, young or lightweight patients should not be treated all four quadrants at one visit using local anesthetic alone; accurate and slow injection technique, adjustment of dosage divided administration and aspirating technique, using agents with low toxicity such as ropivacaine and levobupivacaine, and performing an aspiration test are recommended [11]. Preventing from a toxic dose complication, it should be evoked that for healthy adults, the suggested maximum safe dose of 2% lignocaine in 1:80,000 adrenaline is four-and-a-half 2 or 2.2 mL cartridges (180–198 mg lignocaine); for 3% prilocaine and felypressin 0.03 i.u./mL, the maximum safe dose is 400 mg (six 2 mL cartridges) [12]. Another strategy to reduce toxicity is using the guideline of 1/10th

Dentists should be aware that excessive doses of topical anesthetics while these agents are more concentrated to facilitate infiltration may lead to toxic effects,

Treatment at the office includes airway support, administration of 100% oxygen,

Allergy is also known as hypersensitive reactions, initiated by immunological mechanisms acquired through exposure to a specific allergen; re-exposure to which produces a heightened capacity to react. The prevalence of allergic reactions to amide group local anesthetics is rare. It is predicted that less than 1% of all complications are caused by an allergy. Many of the complications doubt to be allergic are

Ester-type local anesthetics are more allergenic than amide-type local anesthetics. Therefore, amide-type anesthetics are broadly used, among which lidocaine is the most commonly used for dental anesthesia epinephrine involving form. Adverse reactions to local anesthesia are caused by preservatives (e.g., methyl-phydroxybenzoate), antioxidants (e.g., bisulfate), antiseptics (e.g., chlorhexidine), vasoconstrictor (e.g., sulfites), and other antigens such as latex, as well as local

supine positioning, and protection from injury in the event of seizure activity, treating convulsions (benzodiazepines or thiopental; propofol cannot be used in patients with unstable blood pressure, heartbeat) [14]. If severe hypotension arrhythmia occurs, administration of the infusion of a 1.5 mL/kg 20% lipid emulsion over approximately 1 minute and then starting with continuous application at 0.25 mL/kg/min = 1000 mL/h. Studies have reported a resuscitation effect at a total dose of ≤10 mL/kg; therefore, 12 mL/kg can be used as an approximate estimate for the maximum dose. The adrenaline dose should be based on resuscitation guidelines such as those of the American Heart Association. The American Society of Regional Anesthesia and Pain Medicine standard of <1 μg/kg does not need to be

cartridge per kilo as a rough guide to the maximum dose [13].

*DOI: http://dx.doi.org/10.5772/intechopen.87172*

tremor in the extremities [10, 11].

vasoconstrictors [7].

particularly in children.

strictly adhered to [11].

actually anxiety-induced reactions [15].

anesthetic drugs themselves [5].

**3.3 Allergy**

#### *Complications Associated with Local Anesthesia in Oral and Maxillofacial Surgery DOI: http://dx.doi.org/10.5772/intechopen.87172*

Initial symptoms are characterized by central nervous system signs such as excitation, convulsions, followed by loss of consciousness and respiratory arrest. These symptoms are often accompanied by cardiovascular signs such as hypertension, tachycardia, and premature ventricular contractions. The clinical signs and symptoms usually show objective symptoms such as quick talking, flicker, and tremor in the extremities [10, 11].

Predisposing factors are associated with age, weight, other drugs, gender, the presence of disease, genetics, vasoactivity, concentration, dose, route of administration, the rate of injection, vascularity of the injection site, and the presence of vasoconstrictors [7].

In order to prevent systemic toxicity, the patient should be evaluated. The volume of local anesthesia should be decreased, young or lightweight patients should not be treated all four quadrants at one visit using local anesthetic alone; accurate and slow injection technique, adjustment of dosage divided administration and aspirating technique, using agents with low toxicity such as ropivacaine and levobupivacaine, and performing an aspiration test are recommended [11]. Preventing from a toxic dose complication, it should be evoked that for healthy adults, the suggested maximum safe dose of 2% lignocaine in 1:80,000 adrenaline is four-and-a-half 2 or 2.2 mL cartridges (180–198 mg lignocaine); for 3% prilocaine and felypressin 0.03 i.u./mL, the maximum safe dose is 400 mg (six 2 mL cartridges) [12]. Another strategy to reduce toxicity is using the guideline of 1/10th cartridge per kilo as a rough guide to the maximum dose [13].

Dentists should be aware that excessive doses of topical anesthetics while these agents are more concentrated to facilitate infiltration may lead to toxic effects, particularly in children.

Treatment at the office includes airway support, administration of 100% oxygen, supine positioning, and protection from injury in the event of seizure activity, treating convulsions (benzodiazepines or thiopental; propofol cannot be used in patients with unstable blood pressure, heartbeat) [14]. If severe hypotension arrhythmia occurs, administration of the infusion of a 1.5 mL/kg 20% lipid emulsion over approximately 1 minute and then starting with continuous application at 0.25 mL/kg/min = 1000 mL/h. Studies have reported a resuscitation effect at a total dose of ≤10 mL/kg; therefore, 12 mL/kg can be used as an approximate estimate for the maximum dose. The adrenaline dose should be based on resuscitation guidelines such as those of the American Heart Association. The American Society of Regional Anesthesia and Pain Medicine standard of <1 μg/kg does not need to be strictly adhered to [11].

#### **3.3 Allergy**

*Topics in Local Anesthetics*

(nupercaine), and ropivacaine (Naropin).

**3. Systemic reactions due to local anesthesia**

phobic patients using general anesthesia [8, 9].

advantages of amino amides [4–7].

**3.1 Psychogenic reactions**

**2. Classification and chemical structure of local anesthetics**

Local anesthetics can be classified according to their chemical structure, a rate of onset, potency, and duration of action. Chemically, they are either amino esters or amino amides (i.e., an aromatic, lipophilic ring connected to a hydrophilic amine group by an intermediate chain containing either an ester or amide linkage). Ester local anesthetics are hydrolyzed in the plasma by pseudocholinesterase into para-aminobenzoic acid (PABA) and other derivatives, whereas amide-type local anesthetics are metabolized by the liver. The rate of hydrolysis has an effect on the potential toxicity of a local anesthetic. Allergic reactions that occur in response to ester local anesthetics usually are related to para-aminobenzoic acid, which is a major metabolic product of many ester local anesthetics. The rates of biotransformation of amide group lidocaine, mepivacaine, etidocaine, and bupivacaine are similar. Articaine, which contains both amide and ester, metabolizes both in the liver and blood. The ester group (cenzoic acid esters) includes cocaine, procaine, chloroprocaine, tetracaine, and benzocaine. The amide group includes lidocaine, mepivacaine (Carbocaine), prilocaine (Citanest), bupivacaine (Marcaine), etidocaine (curanest), dibucaine

Ester local anesthetics are not available in dental cartridges essentially because of several reasons such as the lack of efficacy, the potential for allergenicity, and the

This psychogenic answer is associated with either the patient's body counterbalance to an anxiety-inducing situation or due to adrenaline secreted by the vasoconstrictor agent. As a result of mood changes, heart rate, respiratory rate, and blood pressure are altered. Patients often have a blush or erythema which mimics allergic reactions, hyperventilation, nausea, and vomiting [3]. It is important to understand the patient and make them relax. In more severe cases, these reactions should be maintained as syncope and hyperventilation. For preventing psychogenic reactions, the patient should be relaxed before administering local anesthetic injections. Using oral sedatives is an efficacious method to manage dental fears. Initial dosage should be dependent on patient health, age, weight, and duration of the operation. For healthy adult patients in short-term operations antihistamine-diphenhydramine (Benadryl) 50 mg 1 hour prior to the operation, moderate length (1–2 hours) operation benzodiazepine, triazolam (Halcion) 0.125–0.5 mg 1 hour before the operation triazolam, for longer duration (2–4 hours) benzodiazepine such as lorazepam (Ativan) 1–4 mg may be given 1–2 hours prior to the operation or 30–60 minutes prior for the sublingual preparation may be described and given. Pharmacologically, mildly and moderately anxious dental patients can be managed using sedation or extremely anxious or

Local anesthetic systemic toxicity develops when a sufficient (toxic) concentration of anesthetic drug in the blood level reaches to the central nervous system and

**152**

**3.2 Systemic toxicity**

cardiovascular systems.

Allergy is also known as hypersensitive reactions, initiated by immunological mechanisms acquired through exposure to a specific allergen; re-exposure to which produces a heightened capacity to react. The prevalence of allergic reactions to amide group local anesthetics is rare. It is predicted that less than 1% of all complications are caused by an allergy. Many of the complications doubt to be allergic are actually anxiety-induced reactions [15].

Ester-type local anesthetics are more allergenic than amide-type local anesthetics. Therefore, amide-type anesthetics are broadly used, among which lidocaine is the most commonly used for dental anesthesia epinephrine involving form. Adverse reactions to local anesthesia are caused by preservatives (e.g., methyl-phydroxybenzoate), antioxidants (e.g., bisulfate), antiseptics (e.g., chlorhexidine), vasoconstrictor (e.g., sulfites), and other antigens such as latex, as well as local anesthetic drugs themselves [5].

Allergic reactions may include mild symptoms, such as urticaria, erythema, and intense itching, as well as severe reactions in the form of angioedema and/or respiratory distress. Even more severe life-threatening anaphylactic responses include symptoms of apnea, hypotension, and loss of consciousness [15].

In order to diagnose allergies, the skin prick test is the most endorsed. When skin prick test results are determined to be negative, intradermal testing should be performed for patients who have a history of allergy to local anesthetics intradermal tests become obligatory [15, 16].

The following treatments a local anesthetic patient had tested negative in the allergy tests, should be used.

The initial treatment for an allergic reaction in office at the first step should be the removal of the causative agent. For the management of mild symptoms, oral or intramuscular antihistamine-diphenhydramine (Benadryl), 25 or 50 mg, should be given. Additionally, hydrocortisone cream may be prescribed to relieve skin itching or erythema. In life-threatening cases basic life support, intramuscular or subcutaneous epinephrine 0.3–0.5 mg, and hospitalization services should be given.

Anaphylaxis is an acute potentially life-threatening hypersensitivity reaction. The clinical symptoms of anaphylaxis are depending on the organ systems involved. Uncontrolled co-existing asthma, mast cell disorders, and patients with specific allergens such as peanut and tree nut allergy are the risk factors for anaphylaxis. In emergency management of anaphylaxis in the office, due to guidelines of the Australasian Society of Clinical Immunology and Allergy should be in these steps, the patient should lie flat, but also in the case of breathing difficulty, the patient is allowed to sit. Adrenaline 1:1000 dilution (0.01 mg/kg up to 0.5 mg per dose) should be administered intramuscular with 1-mL syringes, 21 gauge needles, and should be repeated every 5 minutes as needed. Another recommendation for epinephrine is or children and adults who weigh 30 kg or over is 0.3 mg. For those weighing 15 to 30 kg, the epinephrine dose is 0.15 mg. The use of adrenaline auto-injector can also be chosen, which is carried mostly by heavy allergic patients themselves.

Adrenaline should be administered for anaphylaxis by intravenous (IV) route only in the case of profoundly hypotensive patients or patients who develop a cardiopulmonary arrest or those who fail to respond to multiple doses of IM adrenaline because of the potential cardiovascular adverse effects of IV administration of adrenaline [17, 18].

Estelle and Simons evaluated evidence-based pharmacologic treatment of anaphylaxis. They agreed using epinephrine at the first step intramuscular in the treatment of anaphylaxis. But the use of antihistamines and glucocorticoids is controversial. Some authors claim using antihistamines is not effective because they are not effective on upper or lower airway obstruction, hypotension, or shock, while others advocate that these drugs decrease the side effects urticaria, flushing, headache, hypotension, and rhinorrhea. In the World Allergy Organization survey, glucocorticoids were reported to be the second most widely available medications (after epinephrine) for anaphylaxis treatment globally, even though some claim glucocorticoids have no proven benefit in anaphylaxis [19].

As a result first step of treatment must be epinephrine additionally glucocorticoids and antihistamines may use to treat severe systemic reactions.

#### **3.4 Methemoglobinemia**

Methemoglobinemia is a unique dose-dependent reaction where the iron in hemoglobin is stabilized in the ferric (Fe3+) form, unable to attach oxygen, leading

**155**

*Complications Associated with Local Anesthesia in Oral and Maxillofacial Surgery*

to tissue hypoxia and causing a varying degree of cyanosis. Methemoglobinemia

The risk of methemoglobinemia increased in infants and the elderly. Patients with underlying health problems; liver cirrhosis, with underdeveloped hepatic and renal function; heart disease; and pulmonary disease (chronic obstructive pulmonary disease, pneumonia) are under the risk of methemoglobinemia. When administered in excessive doses, the local anesthetics mostly prilocaine and benzocaine (90% of reported cases) and barely lidocaine and articaine may also lead to

Symptoms of cyanosis will be observed in nail beds and mucous membranes. In more severe cases, headache, dizziness, fatigue, dyspnea, and tachycardia are seen. For diagnosis in the dental clinic, pulse oximetry and in-hospital arterial blood

Management of methemoglobinemia begins with supplemental oxygen (100%) immediately. As a guideline, methylene blue, which is a heterocyclic aromatic chemical compound increasing the rate of conversion of methemoglobin to hemoglobin, may be given to a symptomatic patient. For severe cases, hyperbaric oxygenation may also be used if available. Methylene blue should be administrated in 1 to 2 mg/kg doses, given as 0.1 mL/kg of a 1% solution (10 mg/mL) intravenously over 5–10 minutes every hour up to a 7 mg/kg maximum. Repeated doses may be necessary within 30–60 minutes of the initial dose [22, 23]. Guay summarizes 242 cases of methemoglobinemia complications related to dental local anesthetics lidocaine, bupivacaine, cocaine, mepivacaine, prilocaine, and tetracaine in children and adults. He concluded

that benzocaine should be out of usage. In a specific patient group, in children younger than 6 months, in pregnant women, or in patients taking other oxidizing drugs, prilocaine should not be used. The dose should be limited to 2.5 mg/kg [21].

Pain on injection can be due to specific circumstances such a temperate of the solution, velocity of injection, dull needles, needles with barbs, or aggressive insertion of the needle, damaging soft tissues, blood vessels, nerves, or the periosteum

The burning is dependent on the rate of injection and the acidity of the solution. Lidocaine causes an intense burning sensation when injected locally. When the needle penetrates a nerve, the patient may also feel a sudden "electric" shock,

In order to prevent discomfort, topical anesthetic application, warming anesthetics to body temperature, using a smaller-gauge needle (27 gauge), switching to a fresh needle when you have to inject multiple times in the same lesion or when you have multiple injection sites, and injecting slowly and with low pressure which reduces pain are done. A rate of 30 seconds per mL of solution is recommended. An inadequate injection site can lead to an intramuscular or intraneural injection blunting of the needle, side of injection anatomic structure (palate) it is unacceptable to

Needle breakage in the oral cavity after local anesthesia is a rare complication, since the establishment of non-reusable, stainless steel dental local anesthetic

suddenly moving the head, with the risk of self-inflicted damage [24].

**4. Local complications associated with local anesthesia**

and causing more pain and other complications.

feel a little pain during injection [13, 24, 25].

*DOI: http://dx.doi.org/10.5772/intechopen.87172*

can be either inherited or acquired [20].

methemoglobinemia [21].

**4.1 Pain on injection**

**4.2 Needle fracture**

analysis play an essential role [21].

*Complications Associated with Local Anesthesia in Oral and Maxillofacial Surgery DOI: http://dx.doi.org/10.5772/intechopen.87172*

to tissue hypoxia and causing a varying degree of cyanosis. Methemoglobinemia can be either inherited or acquired [20].

The risk of methemoglobinemia increased in infants and the elderly. Patients with underlying health problems; liver cirrhosis, with underdeveloped hepatic and renal function; heart disease; and pulmonary disease (chronic obstructive pulmonary disease, pneumonia) are under the risk of methemoglobinemia. When administered in excessive doses, the local anesthetics mostly prilocaine and benzocaine (90% of reported cases) and barely lidocaine and articaine may also lead to methemoglobinemia [21].

Symptoms of cyanosis will be observed in nail beds and mucous membranes. In more severe cases, headache, dizziness, fatigue, dyspnea, and tachycardia are seen. For diagnosis in the dental clinic, pulse oximetry and in-hospital arterial blood analysis play an essential role [21].

Management of methemoglobinemia begins with supplemental oxygen (100%) immediately. As a guideline, methylene blue, which is a heterocyclic aromatic chemical compound increasing the rate of conversion of methemoglobin to hemoglobin, may be given to a symptomatic patient. For severe cases, hyperbaric oxygenation may also be used if available. Methylene blue should be administrated in 1 to 2 mg/kg doses, given as 0.1 mL/kg of a 1% solution (10 mg/mL) intravenously over 5–10 minutes every hour up to a 7 mg/kg maximum. Repeated doses may be necessary within 30–60 minutes of the initial dose [22, 23]. Guay summarizes 242 cases of methemoglobinemia complications related to dental local anesthetics lidocaine, bupivacaine, cocaine, mepivacaine, prilocaine, and tetracaine in children and adults. He concluded that benzocaine should be out of usage. In a specific patient group, in children younger than 6 months, in pregnant women, or in patients taking other oxidizing drugs, prilocaine should not be used. The dose should be limited to 2.5 mg/kg [21].

#### **4. Local complications associated with local anesthesia**

#### **4.1 Pain on injection**

*Topics in Local Anesthetics*

tests become obligatory [15, 16].

allergy tests, should be used.

should be given.

themselves.

adrenaline [17, 18].

proven benefit in anaphylaxis [19].

**3.4 Methemoglobinemia**

Allergic reactions may include mild symptoms, such as urticaria, erythema, and intense itching, as well as severe reactions in the form of angioedema and/or respiratory distress. Even more severe life-threatening anaphylactic responses include

In order to diagnose allergies, the skin prick test is the most endorsed. When skin prick test results are determined to be negative, intradermal testing should be performed for patients who have a history of allergy to local anesthetics intradermal

The following treatments a local anesthetic patient had tested negative in the

The initial treatment for an allergic reaction in office at the first step should be the removal of the causative agent. For the management of mild symptoms, oral or intramuscular antihistamine-diphenhydramine (Benadryl), 25 or 50 mg, should be given. Additionally, hydrocortisone cream may be prescribed to relieve skin itching or erythema. In life-threatening cases basic life support, intramuscular or subcutaneous epinephrine 0.3–0.5 mg, and hospitalization services

Anaphylaxis is an acute potentially life-threatening hypersensitivity reaction. The clinical symptoms of anaphylaxis are depending on the organ systems involved. Uncontrolled co-existing asthma, mast cell disorders, and patients with specific allergens such as peanut and tree nut allergy are the risk factors for anaphylaxis. In emergency management of anaphylaxis in the office, due to guidelines of the Australasian Society of Clinical Immunology and Allergy should be in these steps, the patient should lie flat, but also in the case of breathing difficulty, the patient is allowed to sit. Adrenaline 1:1000 dilution (0.01 mg/kg up to 0.5 mg per dose) should be administered intramuscular with 1-mL syringes, 21 gauge needles, and should be repeated every 5 minutes as needed. Another recommendation for epinephrine is or children and adults who weigh 30 kg or over is 0.3 mg. For those weighing 15 to 30 kg, the epinephrine dose is 0.15 mg. The use of adrenaline auto-injector can also be chosen, which is carried mostly by heavy allergic patients

Adrenaline should be administered for anaphylaxis by intravenous (IV) route only in the case of profoundly hypotensive patients or patients who develop a cardiopulmonary arrest or those who fail to respond to multiple doses of IM adrenaline because of the potential cardiovascular adverse effects of IV administration of

Estelle and Simons evaluated evidence-based pharmacologic treatment of anaphylaxis. They agreed using epinephrine at the first step intramuscular in the treatment of anaphylaxis. But the use of antihistamines and glucocorticoids is controversial. Some authors claim using antihistamines is not effective because they are not effective on upper or lower airway obstruction, hypotension, or shock, while others advocate that these drugs decrease the side effects urticaria, flushing, headache, hypotension, and rhinorrhea. In the World Allergy Organization survey, glucocorticoids were reported to be the second most widely available medications (after epinephrine) for anaphylaxis treatment globally, even though some claim glucocorticoids have no

As a result first step of treatment must be epinephrine additionally glucocorti-

Methemoglobinemia is a unique dose-dependent reaction where the iron in hemoglobin is stabilized in the ferric (Fe3+) form, unable to attach oxygen, leading

coids and antihistamines may use to treat severe systemic reactions.

symptoms of apnea, hypotension, and loss of consciousness [15].

**154**

Pain on injection can be due to specific circumstances such a temperate of the solution, velocity of injection, dull needles, needles with barbs, or aggressive insertion of the needle, damaging soft tissues, blood vessels, nerves, or the periosteum and causing more pain and other complications.

The burning is dependent on the rate of injection and the acidity of the solution. Lidocaine causes an intense burning sensation when injected locally. When the needle penetrates a nerve, the patient may also feel a sudden "electric" shock, suddenly moving the head, with the risk of self-inflicted damage [24].

In order to prevent discomfort, topical anesthetic application, warming anesthetics to body temperature, using a smaller-gauge needle (27 gauge), switching to a fresh needle when you have to inject multiple times in the same lesion or when you have multiple injection sites, and injecting slowly and with low pressure which reduces pain are done. A rate of 30 seconds per mL of solution is recommended. An inadequate injection site can lead to an intramuscular or intraneural injection blunting of the needle, side of injection anatomic structure (palate) it is unacceptable to feel a little pain during injection [13, 24, 25].

#### **4.2 Needle fracture**

Needle breakage in the oral cavity after local anesthesia is a rare complication, since the establishment of non-reusable, stainless steel dental local anesthetic

needles. In most cases, needle fracture happened with 30-gauge needles and during inferior alveolar nerve block, as a result of either incorrect injection technique, improper choice of hypodermic needle magnitude, or unexpected motion of the patient or assistants [26].

In order to prevent needle fracture, first the injection needles should be checked; 30-gauge and short needles should not be used for inferior alveolar nerve block in adults or children (25–27 should be chosen). Needles should not bend while inserting them into soft tissue [26, 27].

In the case of a broken needle, if visible, it should be removed immediately with a hemostat. If this is inaccessible, computed tomographic (CT) scanning should be taken to ensure the location of the needle, and under general anesthesia, the patient should be operated. In the literature for the removal of the fragment, mostly superficial mucosal incision perpendicular to the trajectory of the needle followed by blunt supra-periosteal dissection to spare vital structures is recommended [28, 29].

Acham et al. in 2018 made an analysis of the literature complication of needle fracture following dental local anesthesia on 36 reports and 59 needle breakage events; they concluded that three-dimensional imaging techniques should be taken to see the broken fragment and also surrounding structures like vessels and the the parotid gland. It is important because 27 out of 57 cannula fragments were located in the pterygomandibular space, and the choice of the removal of the fragment, whether general or local anesthesia, should be dependent on the patient's systemic condition [30].

#### **4.3 Prolongation of anesthesia and various sensory disorders**

Prolonged anesthesia, paresthesia, or neuralgia may occur following dental local anesthetic blocks. This may be temporary, where after a few days, weeks, or months, sensation returns or it may be permanent [31]. This mostly involves nervus lingualis or nervus mandibularis or both [32]. The nerve may be damaged during injection by direct injury, or the needle may damage the intraneural blood supply, resulting in a hematoma, or the needle may traumatize the medial pterygoid muscle which results in trismus. Neurotoxicity of the local anesthetic is another theory for nerve damage [33]. Procaine and tetracaine cause more damage than bupivacaine or lidocaine [34]. Paresthesia or neuralgia complication is mostly transient but may also be permanent if the anesthetic solution is injected directly into the nerve. Due to a numb feeling, the patient may have discomfort such as tongue biting, drooling, loss of taste, and speech impediment. Sullivan et al. conducted a randomized, double-blind, placebo-controlled trial on 496 patients with Bell's palsy. They maintain treatment with steroids within 3 days after onset quite advances the chance for full recovery at 3 or 9 months [35]. Piccinni et al. conducted an analysis of reports to the FDA Adverse Event Reporting System; about 573 cases of paresthesia and dysesthesia after local anesthetics between 2004 and 2011 were performed. They concluded that the use of prilocaine, articaine, or both drugs has a higher risk of paresthesia [36].

If a nerve is damaged due to dental local anesthesia, the first treatment should be managing the pain. In order to decrease local anesthesia-dependent nerve injury, avoiding high concentration of anesthetic agent for inferior alveolar nerve blocks (use 2% lidocaine as standard), preventing iterative injections, and avoiding inferior alveolar nerve blocks are done by using high concentration agents (articaine) infiltrations only. The use of a low daily dose of multivitamin B, to regaining nerve healing and function, has been recommended [37, 38].

**157**

toms disappeared [45].

**4.5 Trismus**

*Complications Associated with Local Anesthesia in Oral and Maxillofacial Surgery*

Reasons for unsuccess in obtaining local anesthesia can be dependent on anatomical variants, pathological and psychological factors, choice of technique and

Anatomical factors comprise accessory nerve supply, alteration in foramen location, atypical development of the nerves (bifid mandibular canals), and bone

mation, and previous surgery or trauma. Inflammatory diseases altering the pharmacokinetics and pharmacodynamics of local anesthetics cause a response to

Pathological reasons for the failure of anesthesia are trismus, infection, inflam-

Local anesthetic failure or difficulty to obtain satisfactory analgesia commonly occurs in the situations with inflammations such as pulpitis and apical periodontitis acute periodontal abscess or pericoronitis [42]. Psychological determinants such as

Poor technique failure mostly occurs to obtain mandibular anesthesia. If the needle is inserted and advanced too deeply and too far dorsally, the terminal branches of the facial nerve within the deep lobe of the parotid gland are affected. Direct anesthesia to the facial nerve can force a rapid onset that occurs while the anesthetic agent is being injected; reflex vasospasms of the external carotid artery can lead to ischemia of the facial nerve, so facial nerve palsy occurs. The patient is unable to wrinkle the forehead, raise the eyebrow, close the upper eyelid, retract the commissure of the lips to smile, and turn down the lower lip on the affected side. The removal of contact lenses and closing of the eye on the affected side in Bell's

In most cases, paralysis occurs immediately after mandibular anesthesia injection, but there are also some cases in which paralysis starts lately. Cakarer et al. have a case report for late paralyses. They extracted simple teeth, without any complication, and 1 day after the patient returned with complaints of a weakness of the muscles of the left side of his face. On the examination, they observed Bell's palsy sign on the left side and unilateral expressionless, and there was no pathologic sign in the wound or any herpetic lesions. They consulted the patient with the Department of Ophthalmology and the Department of Physical Therapy and Rehabilitation. For the treatment lubricant eye drop (4 × 1), tobramycin ophthalmic solution (4 × 1) and lanolin eye ointment (during night) supported by eye patch were used. For 4 weeks, galvanic stimulation of the affected side of the facial nerve was performed, and mime therapy was recommended. In 2 weeks all of the symp-

If the needle is inserted too high and deep, N. auriculotemporalis will be affected, and the feeling of "numbness" will occur. There has been a report of sud-

Trismus is defined as a painful circumstance with inability to open the mouth normally. Several factors cause trismus such as multiple injections in a short period of time in the same area, intramuscular injections inside the muscle or trauma to muscles (either the lateral pterygoid muscle or the temporal muscle) which cause hematoma formation and fibrosis, needle fracture in the muscles inserting to styloid process, inaccurate positioning of the needle when giving the inferior nerve block or maxillary posterior injections or inflammation of the masseter and other

den unilateral deafness following inferior dental nerve anesthesia.

*DOI: http://dx.doi.org/10.5772/intechopen.87172*

decrease and unfavorable effects to increase [41].

palsy prevent corneal abrasion or drying [43, 44].

angst and anxiety can also cause local anesthesia failure [39].

solution, and poor technique [24].

**4.4 Lack of effect**

density [39, 40].

*Complications Associated with Local Anesthesia in Oral and Maxillofacial Surgery DOI: http://dx.doi.org/10.5772/intechopen.87172*

#### **4.4 Lack of effect**

*Topics in Local Anesthetics*

patient or assistants [26].

recommended [28, 29].

condition [30].

ing them into soft tissue [26, 27].

needles. In most cases, needle fracture happened with 30-gauge needles and during inferior alveolar nerve block, as a result of either incorrect injection technique, improper choice of hypodermic needle magnitude, or unexpected motion of the

In order to prevent needle fracture, first the injection needles should be checked; 30-gauge and short needles should not be used for inferior alveolar nerve block in adults or children (25–27 should be chosen). Needles should not bend while insert-

In the case of a broken needle, if visible, it should be removed immediately with a hemostat. If this is inaccessible, computed tomographic (CT) scanning should be taken to ensure the location of the needle, and under general anesthesia, the patient should be operated. In the literature for the removal of the fragment, mostly superficial mucosal incision perpendicular to the trajectory of the needle followed by blunt supra-periosteal dissection to spare vital structures is

Acham et al. in 2018 made an analysis of the literature complication of needle fracture following dental local anesthesia on 36 reports and 59 needle breakage events; they concluded that three-dimensional imaging techniques should be taken to see the broken fragment and also surrounding structures like vessels and the the parotid gland. It is important because 27 out of 57 cannula fragments were located in the pterygomandibular space, and the choice of the removal of the fragment, whether general or local anesthesia, should be dependent on the patient's systemic

Prolonged anesthesia, paresthesia, or neuralgia may occur following dental local anesthetic blocks. This may be temporary, where after a few days, weeks, or months, sensation returns or it may be permanent [31]. This mostly involves nervus lingualis or nervus mandibularis or both [32]. The nerve may be damaged during injection by direct injury, or the needle may damage the intraneural blood supply, resulting in a hematoma, or the needle may traumatize the medial pterygoid muscle which results in trismus. Neurotoxicity of the local anesthetic is another theory for nerve damage [33]. Procaine and tetracaine cause more damage than bupivacaine or lidocaine [34]. Paresthesia or neuralgia complication is mostly transient but may also be permanent if the anesthetic solution is injected directly into the nerve. Due to a numb feeling, the patient may have discomfort such as tongue biting, drooling, loss of taste, and speech impediment. Sullivan et al. conducted a randomized, double-blind, placebo-controlled trial on 496 patients with Bell's palsy. They maintain treatment with steroids within 3 days after onset quite advances the chance for full recovery at 3 or 9 months [35]. Piccinni et al. conducted an analysis of reports to the FDA Adverse Event Reporting System; about 573 cases of paresthesia and dysesthesia after local anesthetics between 2004 and 2011 were performed. They concluded that the use of prilocaine, articaine, or both drugs has a higher risk of

If a nerve is damaged due to dental local anesthesia, the first treatment should be managing the pain. In order to decrease local anesthesia-dependent nerve injury, avoiding high concentration of anesthetic agent for inferior alveolar nerve blocks (use 2% lidocaine as standard), preventing iterative injections, and avoiding inferior alveolar nerve blocks are done by using high concentration agents (articaine) infiltrations only. The use of a low daily dose of multivitamin B, to regaining nerve

healing and function, has been recommended [37, 38].

**4.3 Prolongation of anesthesia and various sensory disorders**

**156**

paresthesia [36].

Reasons for unsuccess in obtaining local anesthesia can be dependent on anatomical variants, pathological and psychological factors, choice of technique and solution, and poor technique [24].

Anatomical factors comprise accessory nerve supply, alteration in foramen location, atypical development of the nerves (bifid mandibular canals), and bone density [39, 40].

Pathological reasons for the failure of anesthesia are trismus, infection, inflammation, and previous surgery or trauma. Inflammatory diseases altering the pharmacokinetics and pharmacodynamics of local anesthetics cause a response to decrease and unfavorable effects to increase [41].

Local anesthetic failure or difficulty to obtain satisfactory analgesia commonly occurs in the situations with inflammations such as pulpitis and apical periodontitis acute periodontal abscess or pericoronitis [42]. Psychological determinants such as angst and anxiety can also cause local anesthesia failure [39].

Poor technique failure mostly occurs to obtain mandibular anesthesia. If the needle is inserted and advanced too deeply and too far dorsally, the terminal branches of the facial nerve within the deep lobe of the parotid gland are affected. Direct anesthesia to the facial nerve can force a rapid onset that occurs while the anesthetic agent is being injected; reflex vasospasms of the external carotid artery can lead to ischemia of the facial nerve, so facial nerve palsy occurs. The patient is unable to wrinkle the forehead, raise the eyebrow, close the upper eyelid, retract the commissure of the lips to smile, and turn down the lower lip on the affected side. The removal of contact lenses and closing of the eye on the affected side in Bell's palsy prevent corneal abrasion or drying [43, 44].

In most cases, paralysis occurs immediately after mandibular anesthesia injection, but there are also some cases in which paralysis starts lately. Cakarer et al. have a case report for late paralyses. They extracted simple teeth, without any complication, and 1 day after the patient returned with complaints of a weakness of the muscles of the left side of his face. On the examination, they observed Bell's palsy sign on the left side and unilateral expressionless, and there was no pathologic sign in the wound or any herpetic lesions. They consulted the patient with the Department of Ophthalmology and the Department of Physical Therapy and Rehabilitation. For the treatment lubricant eye drop (4 × 1), tobramycin ophthalmic solution (4 × 1) and lanolin eye ointment (during night) supported by eye patch were used. For 4 weeks, galvanic stimulation of the affected side of the facial nerve was performed, and mime therapy was recommended. In 2 weeks all of the symptoms disappeared [45].

If the needle is inserted too high and deep, N. auriculotemporalis will be affected, and the feeling of "numbness" will occur. There has been a report of sudden unilateral deafness following inferior dental nerve anesthesia.

#### **4.5 Trismus**

Trismus is defined as a painful circumstance with inability to open the mouth normally. Several factors cause trismus such as multiple injections in a short period of time in the same area, intramuscular injections inside the muscle or trauma to muscles (either the lateral pterygoid muscle or the temporal muscle) which cause hematoma formation and fibrosis, needle fracture in the muscles inserting to styloid process, inaccurate positioning of the needle when giving the inferior nerve block or maxillary posterior injections or inflammation of the masseter and other

masticatory muscles, a low-grade infection, and excessive volumes of local anesthetic solution deposited into a bounded region which cause expansion of tissues. In the acute phase, pain from hemorrhage leads to muscle contraction and limitation of motion.

Once trismus develops, some cases will resolve spontaneously. Progression of trismus to chronic hypomobility and fibrous ankylosis may be prevented by the early institution of treatment consisting of heat therapy; soft diet; prescription of analgesics, anti-inflammatory drugs, antibiotics, muscle relaxants; or physiotherapy. Trismus caused by an infection needs to be treated by antibiotics. Usually, trismus will resolve in 6 weeks, with a range of 4 to 20 weeks.

Awareness of the anatomical landmarks and muscles: palpation of bony anterior ramus for temporalis muscle, pterygomandibular fold for pterygoid muscle, and appropriate angulation of the needle and bone contact before injecting are good methods for avoiding trismus via local anesthesia.

Intraorally the Vazirani-Akinosi technique, the closed-mouth mandibular nerve block technique, or extraoral techniques can provide anesthesia to trismus patients [43, 46].

#### **4.6 Infection**

Infection complication is rare since the usage of disposable needles and glass cartridges. Infection may extend to tissues by penetration of the needle through a contaminated tissue, because of the needle being contaminated before an operation or improper preparation of local anesthetic diluted solutions. On the other hand, a latent viral infection may be reactivated due to the trauma of the procedure which may be responsible for neural sheath inflammation.

The area to be penetrated should be cleaned with a topical antiseptic prior to insertion of the needle. Antiseptic mouthwash solutions such as chlorhexidine gluconate should be considered for all regional techniques. The local anesthesia should not be injected through the infected area.

Injecting local anesthesia during the presence of infection is important to increase the pH of anesthetic agent in order to increase efficiency because the infected tissue is more acidic. This process is called anesthetic buffering and leads to patient comfort during injection, fast onset of anesthesia, and lower postinjection tissue injury. Recommendation for treatment of infection is antibiotics (penicillin V 500 mg every 6 hour for 7–10 days), analgesics, heat, drainage, and physiotherapy [2, 31, 47].

#### **4.7 Edema**

Swelling of tissues can be due to trauma during injection, infection, allergy, hemorrhage, and injection of irritating solutions.

The management of edema is dependent on the cause. Allergy-induced edema treatment consists of intramuscular epinephrine injection as mentioned above and, additionally, antihistamine and corticosteroid administration and consultation with an allergist to determine the precise cause of the edema. Trauma-induced edema should be managed as a hematoma. For the treatment of edema produced by infection, antibiotics should be prescribed [27].

#### **4.8 Hematoma**

Hematoma formation as a complication of local anesthesia is the result of a venous or arterial laceration; intra-arterial blood pressure increase causes effusion of blood into the surrounding soft tissues. While injecting, if there is a high pressure, it may be a warning injecting against the bloodstream. The size of a hematoma

**159**

*Complications Associated with Local Anesthesia in Oral and Maxillofacial Surgery*

depends on the density and compactness of the affected tissue; when a vein rupture is concerned, hematoma does not necessarily occur. Discoloration on the area, a

From the anatomical point of view, different nerve effects cause hematoma on specific regions such as anterior superior alveolar (infraorbital) nerve block below the lower eyelid, incisive (mental) nerve block at the chin area, buccal nerve block or any palatal injection within the mouth, and posterior superior alveolar nerve block extraoral in the lower buccal region of the mandible, intraoral distal to maxil-

Hematoma formation can be prevented by aspirating before injecting the anesthetic solution, by using a short needle and a minimum number of needle penetrations into tissues. When swelling forms immediately after injection, localized pressure should be applied with a minimum of 2 minutes. This will stop the

Both swelling and discoloration usually subside in 10 to 15 days. Ice packs should be held for the first 24 hours after surgery following which intermittent hot moist packs can be used to resolve the condition and massage therapy using a heparin cream. Antibiotics should be prescribed if the hematoma is large in order to prevent

Gingival lesions consist of recurrent aphthous stomatitis, and herpes simplex can occur intraorally after a local anesthetic injection or after any trauma to the intraoral tissues. The exact mechanism is unknown, but any trauma to tissues by a needle may activate the latent form of the disease process that was present in the

No management is necessary until there is severe pain. In order to relieve pain, topical anesthetic solutions (e.g., viscous lidocaine) may be used on affected areas. A concoction of identical amounts of diphenhydramine and milk of magnesia rinsed in the mouth effectively covers the ulcerations and provides relief from pain.

Lip or tongue biting or chewing can occur on children with special needs or disabled patients, following dental local anesthesia with the unfamiliar sensation of being numb [50]. Shorter-acting local anesthetics such as plain mepivacaine should be chosen, and the patient or the guardian should be warned about eating, drinking hot fluids, and biting on the lips or tongue to test for anesthesia; cotton rolls can be placed between the teeth and soft tissues to prevent chewing. In order to accelerate recovery time for sensation, an alpha-adrenergic receptor, phentolamine mesylate (OraVerse), may be injected. For adults, the proposed dosage is 1 to 2 cartridges of phentolamine mesylate (a dose of 0.4 to 0.8 mg), while for children the proposed

Swelling may decay after 2 to 3 days. The lesion will heal over the next 10 to 14 days. For pain complains, analgesics may be prescribed and topical local anes-

The most common complications include diplopia (dual vision), ophthalmoplegia (paralysis or weakening of eye muscles), ptosis, and mydriasis (dilatation of

Triamcinolone acetonide without corticosteroid can remedy pain [14, 27].

dosage is 0.5 to 1 cartridge (0.2 to 0.4 mg) [50, 51] Malamed [52].

*DOI: http://dx.doi.org/10.5772/intechopen.87172*

bruise may accompany hematoma [48].

the development of a wound infection [14, 49].

lary tuberosity.

hemorrhage.

**4.9 Gingival lesions**

tissues with previous injection.

thetic gel may be applied to the area.

**4.11 Ophthalmologic complications**

**4.10 Soft tissue injury**

#### *Complications Associated with Local Anesthesia in Oral and Maxillofacial Surgery DOI: http://dx.doi.org/10.5772/intechopen.87172*

depends on the density and compactness of the affected tissue; when a vein rupture is concerned, hematoma does not necessarily occur. Discoloration on the area, a bruise may accompany hematoma [48].

From the anatomical point of view, different nerve effects cause hematoma on specific regions such as anterior superior alveolar (infraorbital) nerve block below the lower eyelid, incisive (mental) nerve block at the chin area, buccal nerve block or any palatal injection within the mouth, and posterior superior alveolar nerve block extraoral in the lower buccal region of the mandible, intraoral distal to maxillary tuberosity.

Hematoma formation can be prevented by aspirating before injecting the anesthetic solution, by using a short needle and a minimum number of needle penetrations into tissues. When swelling forms immediately after injection, localized pressure should be applied with a minimum of 2 minutes. This will stop the hemorrhage.

Both swelling and discoloration usually subside in 10 to 15 days. Ice packs should be held for the first 24 hours after surgery following which intermittent hot moist packs can be used to resolve the condition and massage therapy using a heparin cream. Antibiotics should be prescribed if the hematoma is large in order to prevent the development of a wound infection [14, 49].

#### **4.9 Gingival lesions**

*Topics in Local Anesthetics*

of motion.

**4.6 Infection**

**4.7 Edema**

**4.8 Hematoma**

masticatory muscles, a low-grade infection, and excessive volumes of local anesthetic solution deposited into a bounded region which cause expansion of tissues. In the acute phase, pain from hemorrhage leads to muscle contraction and limitation

Once trismus develops, some cases will resolve spontaneously. Progression of trismus to chronic hypomobility and fibrous ankylosis may be prevented by the early institution of treatment consisting of heat therapy; soft diet; prescription of analgesics, anti-inflammatory drugs, antibiotics, muscle relaxants; or physiotherapy. Trismus caused by an infection needs to be treated by antibiotics. Usually,

Awareness of the anatomical landmarks and muscles: palpation of bony anterior ramus for temporalis muscle, pterygomandibular fold for pterygoid muscle, and appropriate angulation of the needle and bone contact before injecting are good

Intraorally the Vazirani-Akinosi technique, the closed-mouth mandibular nerve block technique, or extraoral techniques can provide anesthesia to trismus patients [43, 46].

Infection complication is rare since the usage of disposable needles and glass cartridges. Infection may extend to tissues by penetration of the needle through a contaminated tissue, because of the needle being contaminated before an operation or improper preparation of local anesthetic diluted solutions. On the other hand, a latent viral infection may be reactivated due to the trauma of the procedure which

The area to be penetrated should be cleaned with a topical antiseptic prior to insertion of the needle. Antiseptic mouthwash solutions such as chlorhexidine gluconate should be considered for all regional techniques. The local anesthesia

Injecting local anesthesia during the presence of infection is important to increase the pH of anesthetic agent in order to increase efficiency because the infected tissue is more acidic. This process is called anesthetic buffering and leads to patient comfort during injection, fast onset of anesthesia, and lower postinjection tissue injury. Recommendation for treatment of infection is antibiotics (penicillin V 500 mg every 6 hour for 7–10 days), analgesics, heat, drainage, and physiotherapy [2, 31, 47].

Swelling of tissues can be due to trauma during injection, infection, allergy,

Hematoma formation as a complication of local anesthesia is the result of a venous or arterial laceration; intra-arterial blood pressure increase causes effusion of blood into the surrounding soft tissues. While injecting, if there is a high pressure, it may be a warning injecting against the bloodstream. The size of a hematoma

The management of edema is dependent on the cause. Allergy-induced edema treatment consists of intramuscular epinephrine injection as mentioned above and, additionally, antihistamine and corticosteroid administration and consultation with an allergist to determine the precise cause of the edema. Trauma-induced edema should be managed as a hematoma. For the treatment of edema produced by infec-

trismus will resolve in 6 weeks, with a range of 4 to 20 weeks.

methods for avoiding trismus via local anesthesia.

may be responsible for neural sheath inflammation.

should not be injected through the infected area.

hemorrhage, and injection of irritating solutions.

tion, antibiotics should be prescribed [27].

**158**

Gingival lesions consist of recurrent aphthous stomatitis, and herpes simplex can occur intraorally after a local anesthetic injection or after any trauma to the intraoral tissues. The exact mechanism is unknown, but any trauma to tissues by a needle may activate the latent form of the disease process that was present in the tissues with previous injection.

No management is necessary until there is severe pain. In order to relieve pain, topical anesthetic solutions (e.g., viscous lidocaine) may be used on affected areas. A concoction of identical amounts of diphenhydramine and milk of magnesia rinsed in the mouth effectively covers the ulcerations and provides relief from pain. Triamcinolone acetonide without corticosteroid can remedy pain [14, 27].

#### **4.10 Soft tissue injury**

Lip or tongue biting or chewing can occur on children with special needs or disabled patients, following dental local anesthesia with the unfamiliar sensation of being numb [50]. Shorter-acting local anesthetics such as plain mepivacaine should be chosen, and the patient or the guardian should be warned about eating, drinking hot fluids, and biting on the lips or tongue to test for anesthesia; cotton rolls can be placed between the teeth and soft tissues to prevent chewing. In order to accelerate recovery time for sensation, an alpha-adrenergic receptor, phentolamine mesylate (OraVerse), may be injected. For adults, the proposed dosage is 1 to 2 cartridges of phentolamine mesylate (a dose of 0.4 to 0.8 mg), while for children the proposed dosage is 0.5 to 1 cartridge (0.2 to 0.4 mg) [50, 51] Malamed [52].

Swelling may decay after 2 to 3 days. The lesion will heal over the next 10 to 14 days. For pain complains, analgesics may be prescribed and topical local anesthetic gel may be applied to the area.

#### **4.11 Ophthalmologic complications**

The most common complications include diplopia (dual vision), ophthalmoplegia (paralysis or weakening of eye muscles), ptosis, and mydriasis (dilatation of

pupil). In extremely rare instances, amaurosis (partial/total blindness) can be seen. All these complications are transient and disappear on interruption of the anesthetic effects [53].

Intraarterial injection or perforation of the vascular wall would stimulate the sympathetic fibers running alongside the internal maxillary artery until reaching the orbit. The intravenous injection could reach the cavernous sinus via the pterygoid plexus and anesthetize the oculomotor, trochlear, or abducens nerves.

Horner's syndrome may occur after an inferior dental nerve block anesthesia because of penetration of the local anesthetic through the lateral pharyngeal and prevertebral spaces, causing barrier of the stellate ganglion [54, 55].

Alamanos et al. conducted a systematic review in 2016 on ophthalmologic complications following dental local anesthesia with 66 reports and 89 cases. They found that the Gow-Gates technique for mandibular block anesthesia is only associated with diplopia, vision impairment is more associated with inferior alveolar nerve blocks than with posterior superior alveolar nerve blocks, and the latter technique has rarely been reported as a cause of amaurosis. Ocular complications in the literature are mostly with an injection of lidocaine [56].

In order to minimize the possible complications, visualization of the regional anatomy, numerous aspirations while injection, and aspiration on at least two planes before administration local anesthetic are performed.

#### **5. Conclusion**

Administration of a local anesthetic can be associated with complications of adverse events. In order to prevent local anesthetic complications, the medical history of the patients should routinely be evaluated in details, and effective anxiety management should be performed. Doses of local anesthetics should be always strictly assessed with body weight, and the maximum recommended dosages should be considered. While administrating anesthesia, the painless injection should be performed, avoiding intravascular or intramuscular or direct trauma to the nerve. New developments should be followed by the practitioners to reduce possible complications associated with the local anesthesia.

#### **Author details**

Basak Keskin Yalcin Cerrahpasa Vocational School of Health Services, Istanbul University, Turkey

\*Address all correspondence to: dr.basakkeskin@gmail.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**161**

S63626

*Complications Associated with Local Anesthesia in Oral and Maxillofacial Surgery*

management. Acute Medicine & Surgery. 2017;**4**(2):152-160

[11] Safety Committee of Japanese Society of Anesthesiologists. Practical guide for the management of systemic toxicity caused by local anesthetics. Journal of Anesthesia. 2019;**33**:1-8. DOI:

[12] Singh P. An emphasis on the wide usage and important role of local anesthesia in dentistry: A strategic review. Dental Research Journal (Isfahan). 2012;**9**(2):127-132

[13] Meechan JG. Local anaesthesia: Risks and controversies. Dental Update.

[14] Bosack RC, Lieblich S. Anesthesia Complications in the Dental Office. 1st ed. Wiley-Blackwell; 2014. pp. 211-218

[15] Batinac T, Sotosek Tokmadzic V, Peharda V, Brajac I. Adverse reactions and alleged allergy to local anesthetics: Analysis of 331 patients. The Journal of Dermatology. 2013;**40**(7):522-527

[16] Lee J, Lee JY, Kim HJ, Seo KS. Dental anesthesia for patients with allergic reactions to lidocaine: Two case reports. Journal of Dental Anesthesia and Pain

[17] Muraro A, Roberts G, Worm M, Bilo MB, Brockow K, Fern andez Rivas M, et al. Anaphylaxis: Guidelines from the European academy of allergy and clinical immunology. Allergy. 2014;**69**:1026-

Medicine. 2016;**16**(3):209-212

1045. DOI: 10.1111/all.12437

[18] Australasian Society of Clinical Immunology and Allergy guidelines. 2017. Available from: www.allergy.org. au/health-professionals/papers/acutemanagement-of-anaphylaxis-guidelines

[19] Simons FER. Pharmacologic treatment of anaphylaxis: Can the

2009;**36**(5):278-280

10.1007/s00540-018-2542-4

*DOI: http://dx.doi.org/10.5772/intechopen.87172*

[1] Christopher A. Local anesthesia— An insight. International Journal of Oral Health and Medical Research.

[2] Cummings DR, Yamashita DD, McAndrews JP. Complications of local anesthesia used in oral and maxillofacial

surgery. Oral and Maxillofacial Surgery Clinics of North America.

[3] Haas DA. An update on local anesthetics in dentistry. Journal of the Canadian Dental Association. 2002;**68**(9):546-551. DOI: 10.1111/

[4] MacKenzie TA, Young ER. Local anesthetic update. Anesthesia Progress.

pp. 142-160. ISBN:9944564137

[5] Kocak Berberoglu H, Gurkan Koseoglu B, Kasapoglu C. Dis Hekimliginde lokal anestezi. Istanbul: Quintessence; 2007.

[6] Giovannitti JAJR, Rosenberg MB, Phero JC. Pharmacology of local anesthetics used in oral surgery. Oral and Maxillofacial Surgery Clinics of North America. 2013;**25**(3):453-465

[7] Becker DE, Reed KL. Essentials of local anesthetic pharmacology. Anesthesia Progress. 2006;**53**(3):98-108

[8] Donaldson M, Gizzarelli G, Chanpong B. Oral sedation: A primer on anxiolysis for the adult patient. Anesthesia Progress. 2007;**54**(3):118-128

[9] Appukuttan DP. Strategies to manage patients with dental anxiety and dental phobia: Literature review. Clinical, Cosmetic and Investigational Dentistry. 2016;**8**:35-50. DOI: 10.2147/CCIDE.

[10] Sekimoto K, Tobe M, Saito S. Local anesthetic toxicity: Acute and chronic

2016;**3**(3):83-86

**References**

2011;**23**(3):369-377

ors.12252

1993;**40**(2):29-34

*Complications Associated with Local Anesthesia in Oral and Maxillofacial Surgery DOI: http://dx.doi.org/10.5772/intechopen.87172*

#### **References**

*Topics in Local Anesthetics*

thetic effects [53].

**5. Conclusion**

**Author details**

Basak Keskin Yalcin

pupil). In extremely rare instances, amaurosis (partial/total blindness) can be seen. All these complications are transient and disappear on interruption of the anes-

Intraarterial injection or perforation of the vascular wall would stimulate the sympathetic fibers running alongside the internal maxillary artery until reaching the orbit. The intravenous injection could reach the cavernous sinus via the pterygoid plexus and anesthetize the oculomotor, trochlear, or abducens nerves.

Horner's syndrome may occur after an inferior dental nerve block anesthesia because of penetration of the local anesthetic through the lateral pharyngeal and

Alamanos et al. conducted a systematic review in 2016 on ophthalmologic complications following dental local anesthesia with 66 reports and 89 cases. They found that the Gow-Gates technique for mandibular block anesthesia is only associated with diplopia, vision impairment is more associated with inferior alveolar nerve blocks than with posterior superior alveolar nerve blocks, and the latter technique has rarely been reported as a cause of amaurosis. Ocular complications in

In order to minimize the possible complications, visualization of the regional anatomy, numerous aspirations while injection, and aspiration on at least two

Administration of a local anesthetic can be associated with complications of adverse events. In order to prevent local anesthetic complications, the medical history of the patients should routinely be evaluated in details, and effective anxiety management should be performed. Doses of local anesthetics should be always strictly assessed with body weight, and the maximum recommended dosages should be considered. While administrating anesthesia, the painless injection should be performed, avoiding intravascular or intramuscular or direct trauma to the nerve. New developments should be followed by the practitioners to reduce

Cerrahpasa Vocational School of Health Services, Istanbul University, Turkey

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

prevertebral spaces, causing barrier of the stellate ganglion [54, 55].

the literature are mostly with an injection of lidocaine [56].

planes before administration local anesthetic are performed.

possible complications associated with the local anesthesia.

\*Address all correspondence to: dr.basakkeskin@gmail.com

provided the original work is properly cited.

**160**

[1] Christopher A. Local anesthesia— An insight. International Journal of Oral Health and Medical Research. 2016;**3**(3):83-86

[2] Cummings DR, Yamashita DD, McAndrews JP. Complications of local anesthesia used in oral and maxillofacial surgery. Oral and Maxillofacial Surgery Clinics of North America. 2011;**23**(3):369-377

[3] Haas DA. An update on local anesthetics in dentistry. Journal of the Canadian Dental Association. 2002;**68**(9):546-551. DOI: 10.1111/ ors.12252

[4] MacKenzie TA, Young ER. Local anesthetic update. Anesthesia Progress. 1993;**40**(2):29-34

[5] Kocak Berberoglu H, Gurkan Koseoglu B, Kasapoglu C. Dis Hekimliginde lokal anestezi. Istanbul: Quintessence; 2007. pp. 142-160. ISBN:9944564137

[6] Giovannitti JAJR, Rosenberg MB, Phero JC. Pharmacology of local anesthetics used in oral surgery. Oral and Maxillofacial Surgery Clinics of North America. 2013;**25**(3):453-465

[7] Becker DE, Reed KL. Essentials of local anesthetic pharmacology. Anesthesia Progress. 2006;**53**(3):98-108

[8] Donaldson M, Gizzarelli G, Chanpong B. Oral sedation: A primer on anxiolysis for the adult patient. Anesthesia Progress. 2007;**54**(3):118-128

[9] Appukuttan DP. Strategies to manage patients with dental anxiety and dental phobia: Literature review. Clinical, Cosmetic and Investigational Dentistry. 2016;**8**:35-50. DOI: 10.2147/CCIDE. S63626

[10] Sekimoto K, Tobe M, Saito S. Local anesthetic toxicity: Acute and chronic

management. Acute Medicine & Surgery. 2017;**4**(2):152-160

[11] Safety Committee of Japanese Society of Anesthesiologists. Practical guide for the management of systemic toxicity caused by local anesthetics. Journal of Anesthesia. 2019;**33**:1-8. DOI: 10.1007/s00540-018-2542-4

[12] Singh P. An emphasis on the wide usage and important role of local anesthesia in dentistry: A strategic review. Dental Research Journal (Isfahan). 2012;**9**(2):127-132

[13] Meechan JG. Local anaesthesia: Risks and controversies. Dental Update. 2009;**36**(5):278-280

[14] Bosack RC, Lieblich S. Anesthesia Complications in the Dental Office. 1st ed. Wiley-Blackwell; 2014. pp. 211-218

[15] Batinac T, Sotosek Tokmadzic V, Peharda V, Brajac I. Adverse reactions and alleged allergy to local anesthetics: Analysis of 331 patients. The Journal of Dermatology. 2013;**40**(7):522-527

[16] Lee J, Lee JY, Kim HJ, Seo KS. Dental anesthesia for patients with allergic reactions to lidocaine: Two case reports. Journal of Dental Anesthesia and Pain Medicine. 2016;**16**(3):209-212

[17] Muraro A, Roberts G, Worm M, Bilo MB, Brockow K, Fern andez Rivas M, et al. Anaphylaxis: Guidelines from the European academy of allergy and clinical immunology. Allergy. 2014;**69**:1026- 1045. DOI: 10.1111/all.12437

[18] Australasian Society of Clinical Immunology and Allergy guidelines. 2017. Available from: www.allergy.org. au/health-professionals/papers/acutemanagement-of-anaphylaxis-guidelines

[19] Simons FER. Pharmacologic treatment of anaphylaxis: Can the evidence base be strengthened? Current Opinion in Allergy and Clinical Immunology. 2010;**10**(4):384-393. DOI: 10.1097/ACI.0b013e32833c2038

[20] Barash M, Reich KA, Rademaker D. Lidocaine-induced methemoglobinemia: A clinical reminder. The Journal of the American Osteopathic Association. 2015;**115**(2):94-98

[21] Guay J. Methemoglobinemia related to local anesthetics: A summary of 242 episodes. Anesthesia and Analgesia. 2009;**108**(3):837-845. DOI: 10.1213/ ane.0b013e318187c4b1

[22] Chowdhary S, Bukoye B, Bhansali AM, Carbo AR, Adra M, Barnett S, et al. Risk of topical anesthetic–induced methemoglobinemia: A 10-year retrospective case-control study. JAMA Internal Medicine. 2013;**173**(9):771-776

[23] Hegedus F, Herb K. Benzocaineinduced methemoglobinemia. Anesthesia Progress. 2005;**52**(4):136-139

[24] Säkkinen J, Huppunen M, Suuronen R. Complications following local anaesthesia. Den Norske Tannlaegeforenings Tidende. 2005;**115**:48-52

[25] Kudo M. Initial injection pressure for dental local anesthesia: Effects on pain and anxiety. Anesthesia Progress. 2005;**52**(3):95-101

[26] Augello M, Jackowski J, Grätz KW, Jacobsen C. Needle breakage during local anesthesia in the oral cavity—A retrospective of the last 50 years with guidelines for treatment and prevention. Clinical Oral Investigations. 2011;**15**(1): 3-8. DOI: 10.1007/s00784-010-0442-6

[27] Malamed SF, Reed K, Poorsattar S. Needle breakage: Incidence and prevention. Dental Clinics of North America. 2010;**54**(4):745-756. DOI: 10.1016/j.cden.2010.06.013

[28] Brand HS, Bekker W, Baart JA. Complications of local anaesthesia. An observational study. International Journal of Dental Hygiene. 2009;**7**(4):270-272

[29] Zeltser R, Cohen C, Casap N. The implications of a broken needle in the pterygomandibular space: Clinical guidelines for prevention and retrieval. Pediatric Dentistry. 2002;**24**(2):153-156

[30] Acham S, Truschnegg A, Rugani P, Kirnbauer B, Reinbacher KE, Zemann W, et al. Needle fracture as a complication of dental local anesthesia: Recommendations for prevention and a comprehensive treatment algorithm based on literature from the past four decades. Clinical Oral Investigations. 2019;**23**(3):1109-1119. DOI: 10.1007/s00784-018-2525-8

[31] Crean SJ, Powis A. Neurological complications of local anaesthetics in dentistry. Dental Update. 1999;**26**(8):344-349

[32] Pogrel MA. Permanent nerve damage from inferior alveolar nerve blocks-an update to include articaine. Journal of the California Dental Association. 2007;**35**(4):271-273

[33] Smith MH, Lung KE. Nerve injuries after dental injection: A review of the literature. Journal of the Canadian Dental Association. 2006;**72**(6):559-564

[34] Renton T. Oral surgery: Part 4. Minimizing and managing nerve injuries and other complications. British Dental Journal. 2013;**215**(8):393-399

[35] Sullivan FM, Swan IR, Donnan PT, Morrison JM, Smith BH, McKinstry B, et al. Early treatment with prednisolone or acyclovir in Bell's palsy. The New England Journal of Medicine. 2007;**357**(16):1598-1607

[36] Piccinni C, Gissi DB, Gabusi A, Montebugnoli L, Poluzzi E. Paraesthesia

**163**

*Complications Associated with Local Anesthesia in Oral and Maxillofacial Surgery*

[44] Ogle OE, Mahjoubi G. Local anesthesia: Agents, techniques, and complications. Dental Clinics of North America. 2012;**56**(1):133-148. DOI:

[45] Cakarer S, Can T, Cankaya B, Erdem MA, Yazici S, Ayintap E, et al. Peripheral facial nerve paralysis after upper third molar extraction. The Journal of Craniofacial Surgery. 2010;**21**(6):1825-1827. DOI: 10.1097/

[46] Stone J, Kaban LB. Trismus after injection of local anesthetic. Oral

[47] Fonseca RJ, Frost DE, Hersh EV, Levin LM. Oral and Maxillofacial Surgery. Philadelphia, PA: Saunders;

complications: An overview. Journal of Bio Innovation. 2018;**7**(4):526-534

[50] Bendgude V, Akkareddy B, Jawale BA, Chaudhary S. An unusual pattern of self-inflicted injury after dental local anesthesia: A report of 2 cases. The Journal of Contemporary Dental Practice. 2011;**12**(5):404-407. DOI: 10.5005/jp-journals-[10024-1067]

[51] Jung RM, Rybak M, Milner P, Lewkowicz N. Local anesthetics and advances in their administration-an overview. Journal of Pre-Clinical and Clinical Research. 2017;**11**:94-101

[52] Malamed SF. Handbook of Local Anesthesia. 5th ed. St Louis, Missouri: Elsevier Mosby; 2004. pp. 621-655

[48] Baiju A, Krishnakumar K, Panayappan L. Anaesthesia

[49] Biočić J, Brajdić D, Perić B, Đanić P, Salarić I, Macan D. A large cheek hematoma as a complication of local anesthesia: Case report. Acta Stomatologica Croatica. 2018;**52**(2):156-159. DOI: 10.15644/

10.1016/j.cden.2011.08.003

SCS.0b013e3181f43dcf

Surgery. 1979;**48**:29-32

2009

asc52/2/9

*DOI: http://dx.doi.org/10.5772/intechopen.87172*

after local anaesthetics: An analysis of reports to the FDA adverse event reporting system. Basic & Clinical Pharmacology & Toxicology. 2015;**117**(1):52-56. DOI: 10.1111/ bcpt.12357. PMID:25420896

[37] Sambrook PJ, Goss AN. Severe adverse reactions to dental local

anaesthetics: Prolonged mandibular and lingual nerve anaesthesia. Australian Dental Journal. 2011;**56**(2):154-159. DOI: 10.1111/j.1834-7819.2011.01317.x

[38] Vasconcelos BC, Bessa Nogueira RV, Maurette PE, Carneiro SC. Facial nerve paralysis after impacted lower third molar surgery: A literature review and case report. Medicina Oral, Patología Oral y Cirugía Bucal.

[39] Meyer FU. Complications of local dental anesthesia and anatomical causes. Annals of Anatomy. 1999;**181**(1):105-

[40] Wolf KT, Brokaw EJ, Bell A, Joy A. Variant inferior alveolar nerves and implications for local anesthesia. Anesthesia Progress. 2016;**63**(2):84-90. DOI: 10.2344/0003-3006-63.2.84

[41] Siddiqui A, Shenoi R, Sharma HU, Harankhedkar N, Shrivastava A, Vats V, et al. Causes of failure of dental local anaesthesia—A review. International Journal of Contemporary Medical Research. 2015;**2**(2):415-419

[42] Wong MK, Jacobsen PL. Reasons for local anesthesia failures. Journal of the American Dental Association (1939). 1992;**123**(1):69-73. DOI: 10.14219/jada.

[43] Blanton PL, Jeske AH, ADA Council on Scientific Affairs, ADA Division of Science. Avoiding complications in local anesthesia induction anatomical

considerations. The Journal of the American Dental Association.

2006;**11**(2):175 178

106. PMID:10081571

archive.1992.0004

2003;**134**(7):888-893

*Complications Associated with Local Anesthesia in Oral and Maxillofacial Surgery DOI: http://dx.doi.org/10.5772/intechopen.87172*

after local anaesthetics: An analysis of reports to the FDA adverse event reporting system. Basic & Clinical Pharmacology & Toxicology. 2015;**117**(1):52-56. DOI: 10.1111/ bcpt.12357. PMID:25420896

*Topics in Local Anesthetics*

evidence base be strengthened?

10.1097/ACI.0b013e32833c2038

Rademaker D. Lidocaine-induced methemoglobinemia: A clinical reminder. The Journal of the American Osteopathic Association.

[20] Barash M, Reich KA,

2015;**115**(2):94-98

ane.0b013e318187c4b1

Current Opinion in Allergy and Clinical Immunology. 2010;**10**(4):384-393. DOI:

[28] Brand HS, Bekker W, Baart JA. Complications of local anaesthesia. An observational study. International

[29] Zeltser R, Cohen C, Casap N. The implications of a broken needle in the pterygomandibular space: Clinical guidelines for prevention and retrieval. Pediatric Dentistry. 2002;**24**(2):153-156

[30] Acham S, Truschnegg A, Rugani P, Kirnbauer B, Reinbacher KE, Zemann W, et al. Needle fracture as a complication of dental local anesthesia: Recommendations for prevention and a comprehensive treatment algorithm based on literature from the past four decades. Clinical Oral Investigations. 2019;**23**(3):1109-1119. DOI: 10.1007/s00784-018-2525-8

[31] Crean SJ, Powis A. Neurological complications of local anaesthetics in dentistry. Dental Update.

[32] Pogrel MA. Permanent nerve damage from inferior alveolar nerve blocks-an update to include articaine. Journal of the California Dental Association. 2007;**35**(4):271-273

[33] Smith MH, Lung KE. Nerve injuries after dental injection: A review of the literature. Journal of the Canadian Dental Association.

[34] Renton T. Oral surgery: Part 4. Minimizing and managing nerve injuries and other complications. British Dental Journal. 2013;**215**(8):393-399

[35] Sullivan FM, Swan IR, Donnan PT, Morrison JM, Smith BH, McKinstry B, et al. Early treatment with prednisolone

or acyclovir in Bell's palsy. The New England Journal of Medicine.

[36] Piccinni C, Gissi DB, Gabusi A, Montebugnoli L, Poluzzi E. Paraesthesia

2007;**357**(16):1598-1607

1999;**26**(8):344-349

2006;**72**(6):559-564

Journal of Dental Hygiene.

2009;**7**(4):270-272

[21] Guay J. Methemoglobinemia related to local anesthetics: A summary of 242 episodes. Anesthesia and Analgesia. 2009;**108**(3):837-845. DOI: 10.1213/

[22] Chowdhary S, Bukoye B, Bhansali AM, Carbo AR, Adra M, Barnett S, et al. Risk of topical anesthetic–induced

retrospective case-control study. JAMA Internal Medicine. 2013;**173**(9):771-776

Anesthesia Progress. 2005;**52**(4):136-139

[25] Kudo M. Initial injection pressure for dental local anesthesia: Effects on pain and anxiety. Anesthesia Progress.

[26] Augello M, Jackowski J, Grätz KW, Jacobsen C. Needle breakage during local anesthesia in the oral cavity—A retrospective of the last 50 years with guidelines for treatment and prevention. Clinical Oral Investigations. 2011;**15**(1): 3-8. DOI: 10.1007/s00784-010-0442-6

[27] Malamed SF, Reed K, Poorsattar S. Needle breakage: Incidence and prevention. Dental Clinics of North America. 2010;**54**(4):745-756. DOI:

10.1016/j.cden.2010.06.013

[23] Hegedus F, Herb K. Benzocaineinduced methemoglobinemia.

[24] Säkkinen J, Huppunen M, Suuronen R. Complications following local anaesthesia. Den Norske Tannlaegeforenings Tidende.

2005;**115**:48-52

2005;**52**(3):95-101

methemoglobinemia: A 10-year

**162**

[37] Sambrook PJ, Goss AN. Severe adverse reactions to dental local anaesthetics: Prolonged mandibular and lingual nerve anaesthesia. Australian Dental Journal. 2011;**56**(2):154-159. DOI: 10.1111/j.1834-7819.2011.01317.x

[38] Vasconcelos BC, Bessa Nogueira RV, Maurette PE, Carneiro SC. Facial nerve paralysis after impacted lower third molar surgery: A literature review and case report. Medicina Oral, Patología Oral y Cirugía Bucal. 2006;**11**(2):175 178

[39] Meyer FU. Complications of local dental anesthesia and anatomical causes. Annals of Anatomy. 1999;**181**(1):105- 106. PMID:10081571

[40] Wolf KT, Brokaw EJ, Bell A, Joy A. Variant inferior alveolar nerves and implications for local anesthesia. Anesthesia Progress. 2016;**63**(2):84-90. DOI: 10.2344/0003-3006-63.2.84

[41] Siddiqui A, Shenoi R, Sharma HU, Harankhedkar N, Shrivastava A, Vats V, et al. Causes of failure of dental local anaesthesia—A review. International Journal of Contemporary Medical Research. 2015;**2**(2):415-419

[42] Wong MK, Jacobsen PL. Reasons for local anesthesia failures. Journal of the American Dental Association (1939). 1992;**123**(1):69-73. DOI: 10.14219/jada. archive.1992.0004

[43] Blanton PL, Jeske AH, ADA Council on Scientific Affairs, ADA Division of Science. Avoiding complications in local anesthesia induction anatomical considerations. The Journal of the American Dental Association. 2003;**134**(7):888-893

[44] Ogle OE, Mahjoubi G. Local anesthesia: Agents, techniques, and complications. Dental Clinics of North America. 2012;**56**(1):133-148. DOI: 10.1016/j.cden.2011.08.003

[45] Cakarer S, Can T, Cankaya B, Erdem MA, Yazici S, Ayintap E, et al. Peripheral facial nerve paralysis after upper third molar extraction. The Journal of Craniofacial Surgery. 2010;**21**(6):1825-1827. DOI: 10.1097/ SCS.0b013e3181f43dcf

[46] Stone J, Kaban LB. Trismus after injection of local anesthetic. Oral Surgery. 1979;**48**:29-32

[47] Fonseca RJ, Frost DE, Hersh EV, Levin LM. Oral and Maxillofacial Surgery. Philadelphia, PA: Saunders; 2009

[48] Baiju A, Krishnakumar K, Panayappan L. Anaesthesia complications: An overview. Journal of Bio Innovation. 2018;**7**(4):526-534

[49] Biočić J, Brajdić D, Perić B, Đanić P, Salarić I, Macan D. A large cheek hematoma as a complication of local anesthesia: Case report. Acta Stomatologica Croatica. 2018;**52**(2):156-159. DOI: 10.15644/ asc52/2/9

[50] Bendgude V, Akkareddy B, Jawale BA, Chaudhary S. An unusual pattern of self-inflicted injury after dental local anesthesia: A report of 2 cases. The Journal of Contemporary Dental Practice. 2011;**12**(5):404-407. DOI: 10.5005/jp-journals-[10024-1067]

[51] Jung RM, Rybak M, Milner P, Lewkowicz N. Local anesthetics and advances in their administration-an overview. Journal of Pre-Clinical and Clinical Research. 2017;**11**:94-101

[52] Malamed SF. Handbook of Local Anesthesia. 5th ed. St Louis, Missouri: Elsevier Mosby; 2004. pp. 621-655

#### *Topics in Local Anesthetics*

[53] Pandey R, Dixit N, Dixit KK, Roy S, Gaba C. Amaurosis, an unusual complication secondary to inferior alveolar nerve anesthesia: A case report and literature review. Journal of Endodontia. 2018;**44**(9):1442-1444. DOI: 10.1016/j.joen.2018.05.005

[54] Peñarrocha-Diago M, Sanchis-Bielsa JM. Ophthalmologic complications after intraoral local anesthesia with articaine. Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontics. 2000;**90**(1):21-24

[55] von Arx T, Lozanoff S, Zinkernagel M. Ophthalmologic complications after intraoral local anesthesia an analysis of 65 published case reports. Research and Science Swiss Dental Journal. 2014;**124**:784-795

[56] Alamanos C, Raab P, Gamulescu A, Behr M. Ophthalmologic complications after administration of local anesthesia in dentistry: A systematic review. Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology. 2016;**121**(3):39-50

**165**

**Chapter 10**

**Abstract**

anesthetic from cardiac tissue.

to search for new less toxic LA.

lipid emulsion

**1. Introduction**

Local Anesthetic Systemic Toxicity

Local anesthetics are used very often in medicine and dentistry. They have few adverse effects, but the increased use of these drugs has resulted in a higher incidence of local and systemic anesthetic toxicity (LAST). From the initial symptoms to the deleterious effects on cardiac and the central nervous system, LAST is an important consequence of which we should be aware. LAST is known since the introduction and use of local anesthetics; it was originally associated with seizures and respiratory failure. However, in the 1970s, side effects on the heart were also identified, as the fatal cardiac toxicity associated with bupivacaine was discovered in healthy patients. Prevention and safe administration of regional anesthesia remains primary factors in the avoidance of the toxicity of these drugs. When a patient has LAST, treatment should be started immediately to reduce seizures. If there is cardiac arrest, follow ACLS guidelines. Intravenous lipids improve cardiac conduction, contractility and coronary perfusion by removing liposoluble local

**Keywords:** local anesthetic, toxicity, mechanism of action, prevention, management,

Systemic toxicity due to local anesthetics (LAST) is a nightmare for each anesthesiologist. It can have catastrophic outcome in an otherwise simple procedure, such as a regional dental anesthesia, local anesthesia, nerve block either peripheral, intravenous or peridural. The clinical phenomenon of LAST has been known for more than 100 years. Historically, the introduction of cocaine as the first local anesthetic (LA) in late nineteenth century was soon accompanied by reports of its systemic toxicity. The symptoms of systemic toxicity were frequently described as seizures or respiratory failure, but some cases also included reports of adverse cardiac effects [1]. These reasons demanded medical and pharmaceutical industries

At first, manipulation of existing molecular structures after analyzing natural products lead to development of few drugs. It became clear that the development of more LA of ester group did not return the desired results. The main concern was short duration of action due to instability of ester bonds. The drugs were prepared in an oily formulation to increase the duration (which proved neurotoxic locally, or by enhancing the lipophilicity of the molecule which made it more toxic to central nervous system (CNS) as well as cardiovascular system (CVS)). Lidocaine, synthesized in 1944 was the first amide LA drug to be used clinically. It gave a dependable block, but unfortunately was short acting. In search of an LA with a longer duration of action than lidocaine, a family of N-alkylpiperidines 2,6 xylidides was introduced

*Divya Garg, Shikha Soni and Rakesh Karnawat*

#### **Chapter 10**

*Topics in Local Anesthetics*

[53] Pandey R, Dixit N, Dixit KK, Roy S,

[54] Peñarrocha-Diago M, Sanchis-Bielsa JM. Ophthalmologic complications after intraoral local anesthesia with articaine. Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontics. 2000;**90**(1):21-24

[55] von Arx T, Lozanoff S, Zinkernagel M. Ophthalmologic complications after intraoral local anesthesia an analysis of 65 published case reports. Research and Science Swiss Dental Journal.

[56] Alamanos C, Raab P, Gamulescu A, Behr M. Ophthalmologic complications after administration of local anesthesia in dentistry: A systematic review. Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology. 2016;**121**(3):39-50

2014;**124**:784-795

Gaba C. Amaurosis, an unusual complication secondary to inferior alveolar nerve anesthesia: A case report and literature review. Journal of Endodontia. 2018;**44**(9):1442-1444. DOI: 10.1016/j.joen.2018.05.005

**164**

## Local Anesthetic Systemic Toxicity

*Divya Garg, Shikha Soni and Rakesh Karnawat*

#### **Abstract**

Local anesthetics are used very often in medicine and dentistry. They have few adverse effects, but the increased use of these drugs has resulted in a higher incidence of local and systemic anesthetic toxicity (LAST). From the initial symptoms to the deleterious effects on cardiac and the central nervous system, LAST is an important consequence of which we should be aware. LAST is known since the introduction and use of local anesthetics; it was originally associated with seizures and respiratory failure. However, in the 1970s, side effects on the heart were also identified, as the fatal cardiac toxicity associated with bupivacaine was discovered in healthy patients. Prevention and safe administration of regional anesthesia remains primary factors in the avoidance of the toxicity of these drugs. When a patient has LAST, treatment should be started immediately to reduce seizures. If there is cardiac arrest, follow ACLS guidelines. Intravenous lipids improve cardiac conduction, contractility and coronary perfusion by removing liposoluble local anesthetic from cardiac tissue.

**Keywords:** local anesthetic, toxicity, mechanism of action, prevention, management, lipid emulsion

#### **1. Introduction**

Systemic toxicity due to local anesthetics (LAST) is a nightmare for each anesthesiologist. It can have catastrophic outcome in an otherwise simple procedure, such as a regional dental anesthesia, local anesthesia, nerve block either peripheral, intravenous or peridural. The clinical phenomenon of LAST has been known for more than 100 years. Historically, the introduction of cocaine as the first local anesthetic (LA) in late nineteenth century was soon accompanied by reports of its systemic toxicity. The symptoms of systemic toxicity were frequently described as seizures or respiratory failure, but some cases also included reports of adverse cardiac effects [1]. These reasons demanded medical and pharmaceutical industries to search for new less toxic LA.

At first, manipulation of existing molecular structures after analyzing natural products lead to development of few drugs. It became clear that the development of more LA of ester group did not return the desired results. The main concern was short duration of action due to instability of ester bonds. The drugs were prepared in an oily formulation to increase the duration (which proved neurotoxic locally, or by enhancing the lipophilicity of the molecule which made it more toxic to central nervous system (CNS) as well as cardiovascular system (CVS)). Lidocaine, synthesized in 1944 was the first amide LA drug to be used clinically. It gave a dependable block, but unfortunately was short acting. In search of an LA with a longer duration of action than lidocaine, a family of N-alkylpiperidines 2,6 xylidides was introduced in 1950s. It was shown that increasing N-alkyl carbon chain length (to max at C4 or C5) increased lipophilicity, which increases duration of action, but unfortunately also increased systemic toxicity. Derivatives developed for clinical use included mepivacaine, bupivacaine, ropivacaine, levobupivacaine, etc. But in subsequent year's cases of lethal LAST were documented.

Accidental intravascular injection during regional anesthesia is the most common cause of LAST. Some comorbidities may increase the risk of LAST; liver failure, heart disease, pregnancy and metabolic syndromes. In addition, patients at extreme ages have an increased risk factor of toxicity, due to the reduction in anesthetic clearance. Children under 4 months of age have low plasma concentrations of acid glycoprotein, which may result in a lower intrinsic clearance of bupivacaine [2, 3].

The incidence of LAST is extremely variable from zero events after more than 12,000 nerve blocks to 25 per 10,000 nerve blocks. One study reported seizures in 79 of 10,000 brachial plexus block procedures. This complication was due to toxicity of the CNS as a result of intravascular LA injection. Although the published data are inconsistent, the prevailing goal is to prevent LAST, and when it manifests, it must be treated quickly and effectively [4–6].

Cardiac toxicity is the most important component of LAST since, unlike the CNS toxicity, it can end in cardiac arrest and death. It is often due to an intravascular injection not noticed during nerve block. LA bind and inhibit voltage dependent sodium channels. It leads to conduction disorders, contractile dysfunction and ventricular arrhythmias. The incidence of cardiac toxicity increases with bupivacaine due to its affinity for inactive sodium channels during the cardiac action potential at a concentration of 0.2 μg/mL. This is done in a fast/slow manner, which means that bupivacaine binds very rapidly to a large proportion of sodium channels during the potential for cardiac action, but is slowly released from the channels during diastole, which results in a large proportion of medication that accumulates at 60–150 beats per minute. Lidocaine at 5–10 μg/mL will also result in a substantial blockage of sodium channels during a potential for cardiac action. However, in contrast to bupivacaine, lidocaine follows the principle of rapid entry/exit, which means that it is rapidly released from sodium channels during diastole. This allows faster recovery and a lower incidence of cardiac toxicity compared to bupivacaine.

CNS toxicity is another important consequence of LAST. Although it is composed of many initial prodromal features, it is most often manifested as seizures. A mechanistic theory focuses on acid-sensitive K<sup>+</sup> channels. These pH-sensitive channels generate neuronal currents of leakage of potassium. LA inhibition causes membrane depolarization and increased neuronal excitability. As these channels are expressed throughout the brain, this is the suggested mechanism for seizures in this context. Consequently, it became mandatory to understand the mechanism of LAST, so that it could be prevented and managed efficiently.

This chapter reviews the mechanisms, frequency, clinical characteristics, prevention and treatment of LAST.

#### **2. LAST mechanisms**

LA agents are classic sodium channel inhibitors. LAST hypotheses are based primarily on the binding site, ion channels, signaling pathway or enzymes involved in the CNS and cardiac toxicity or its treatment. LA inhibit some components of the oxidative phosphorylation pathway, which affects the myocardium and the CNS that are poorly tolerant of anaerobic metabolism. These deleterious effects differ quantitatively between LA, doses and administration routes. It is appropriate to first review the ion channels implicated in LAST [7–9].

**167**

and that K<sup>+</sup>

the toxic effects of bupivacaine [15].

**2.3 Ca2+ channel blockade**

*Local Anesthetic Systemic Toxicity*

**2.1 Sodium channel blockade**

**2.2 Potassium channel blockade**

*DOI: http://dx.doi.org/10.5772/intechopen.90605*

LA are sodium channel blocking acting on inactivated sodium channel state and blocking it. They affect the initial depolarization phase and slow it down, leading to slow cardiac conduction. The antiarrhythmic property of lidocaine is related to this slowed conduction as it causes fast blockade of the channels. In contrast, bupivacaine and ropivacaine cannot be used as anti-arrhythmic drugs though they have fast blockade, but slow release of sodium channel (lasting longer than 1 s in contrast to lidocaine which lasts 0.15 s) [10]. Slowed conduction leads to widening the QRS complex, prolongation of the PR interval, AV block and, eventually, ventricular fibrillation due to the unidirectional blockade and re-entry phenomenon.

Out of three known organized potassium channels, two groups are of interest where LA toxicity is concerned. Out of these, one group of channels are known as the inward, outward and transient rectifier potassium channels, thus plays an important role in the potassium efflux during phases 2 and 3 of the cardiac muscle action potential [11]. If these channels are blocked, it will lead to prolongation of action potential; i.e. phase 2, delay in repolarization; i.e. phase and shift the resting membrane potential more positive (phase 4) to increase automaticity [12]. The second group of potassium channels of interest are K2p. Previously known as the delayed rectifier channels, these channels are believed to be responsible for the background or leak potassium currents. In this setting, they control the resting membrane potential. A blockade of these channels shifts the resting membrane potential towards spontaneous depolarization. K2p channels are extensively spread in the body. In the CNS they are mainly located in the thalamo-cortical and striatal neurons, where blockade leads to increased neuroexitability [13]. They are also present in high concentrations in the cerebral blood vessels, where blockade leads to vasoconstriction and decreased cerebral blood flow. K2p channels are also present in neurons of the auditory system, where blockade leads to tinnitus. LA agents are also known to have K2p mediated stimulating effect on ventilation [14]. They are located in the brainstem and carotid body, where they regulate the respiratory response to carbon dioxide via sensing the changes of pH and expressed in the oxygen-sensing cells of the glomus body respectively. K2p channels are sensitive to changes in oxygen tension and extracellular pH and are potentiated by volatile anesthetic [13]. In the CVS K2p channel blockade predisposes the patient to re-entry dysrhythmias. It is well known that hyperkalemia exacerbates LAST,

ATP openers (which effectively lowers intracellular K<sup>+</sup>

All voltage-gated Ca2+ channels are comprised of two subunits according to the latest research: α and β subunit. The α subunit has fairly constant chemical structure for all voltage gated Ca2+ channels and is the main pore- forming element of the channel. The β subunit has highly variable structure that depends on the location and function of the channel for e.g. in cardiac conduction tissue β1 subunit completes the ion channel structure. The role of the β1 subunit seems to be the modulation of channel opening and membrane ion trafficking [16]. In terms of their physiological effect, the heart has two distinct types of channels namely the T-type (transient) that are low voltage activated channels (LVA), and L-type (long lasting). On the other hand, are high voltage activated channels (HVA).

levels) attenuate

#### **2.1 Sodium channel blockade**

*Topics in Local Anesthetics*

year's cases of lethal LAST were documented.

it must be treated quickly and effectively [4–6].

A mechanistic theory focuses on acid-sensitive K<sup>+</sup>

review the ion channels implicated in LAST [7–9].

prevention and treatment of LAST.

**2. LAST mechanisms**

LAST, so that it could be prevented and managed efficiently.

in 1950s. It was shown that increasing N-alkyl carbon chain length (to max at C4 or C5) increased lipophilicity, which increases duration of action, but unfortunately also increased systemic toxicity. Derivatives developed for clinical use included mepivacaine, bupivacaine, ropivacaine, levobupivacaine, etc. But in subsequent

Accidental intravascular injection during regional anesthesia is the most common cause of LAST. Some comorbidities may increase the risk of LAST; liver failure, heart disease, pregnancy and metabolic syndromes. In addition, patients at extreme ages have an increased risk factor of toxicity, due to the reduction in anesthetic clearance. Children under 4 months of age have low plasma concentrations of acid glycoprotein, which may result in a lower intrinsic clearance of bupivacaine [2, 3]. The incidence of LAST is extremely variable from zero events after more than 12,000 nerve blocks to 25 per 10,000 nerve blocks. One study reported seizures in 79 of 10,000 brachial plexus block procedures. This complication was due to toxicity of the CNS as a result of intravascular LA injection. Although the published data are inconsistent, the prevailing goal is to prevent LAST, and when it manifests,

Cardiac toxicity is the most important component of LAST since, unlike the CNS toxicity, it can end in cardiac arrest and death. It is often due to an intravascular injection not noticed during nerve block. LA bind and inhibit voltage dependent sodium channels. It leads to conduction disorders, contractile dysfunction and ventricular arrhythmias. The incidence of cardiac toxicity increases with bupivacaine due to its affinity for inactive sodium channels during the cardiac action potential at a concentration of 0.2 μg/mL. This is done in a fast/slow manner, which means that bupivacaine binds very rapidly to a large proportion of sodium channels during the potential for cardiac action, but is slowly released from the channels during diastole, which results in a large proportion of medication that accumulates at 60–150 beats per minute. Lidocaine at 5–10 μg/mL will also result in a substantial blockage of sodium channels during a potential for cardiac action. However, in contrast to bupivacaine, lidocaine follows the principle of rapid entry/exit, which means that it is rapidly released from sodium channels during diastole. This allows faster recov-

ery and a lower incidence of cardiac toxicity compared to bupivacaine.

CNS toxicity is another important consequence of LAST. Although it is composed of many initial prodromal features, it is most often manifested as seizures.

channels generate neuronal currents of leakage of potassium. LA inhibition causes membrane depolarization and increased neuronal excitability. As these channels are expressed throughout the brain, this is the suggested mechanism for seizures in this context. Consequently, it became mandatory to understand the mechanism of

This chapter reviews the mechanisms, frequency, clinical characteristics,

LA agents are classic sodium channel inhibitors. LAST hypotheses are based primarily on the binding site, ion channels, signaling pathway or enzymes involved in the CNS and cardiac toxicity or its treatment. LA inhibit some components of the oxidative phosphorylation pathway, which affects the myocardium and the CNS that are poorly tolerant of anaerobic metabolism. These deleterious effects differ quantitatively between LA, doses and administration routes. It is appropriate to first

channels. These pH-sensitive

**166**

LA are sodium channel blocking acting on inactivated sodium channel state and blocking it. They affect the initial depolarization phase and slow it down, leading to slow cardiac conduction. The antiarrhythmic property of lidocaine is related to this slowed conduction as it causes fast blockade of the channels. In contrast, bupivacaine and ropivacaine cannot be used as anti-arrhythmic drugs though they have fast blockade, but slow release of sodium channel (lasting longer than 1 s in contrast to lidocaine which lasts 0.15 s) [10]. Slowed conduction leads to widening the QRS complex, prolongation of the PR interval, AV block and, eventually, ventricular fibrillation due to the unidirectional blockade and re-entry phenomenon.

#### **2.2 Potassium channel blockade**

Out of three known organized potassium channels, two groups are of interest where LA toxicity is concerned. Out of these, one group of channels are known as the inward, outward and transient rectifier potassium channels, thus plays an important role in the potassium efflux during phases 2 and 3 of the cardiac muscle action potential [11]. If these channels are blocked, it will lead to prolongation of action potential; i.e. phase 2, delay in repolarization; i.e. phase and shift the resting membrane potential more positive (phase 4) to increase automaticity [12]. The second group of potassium channels of interest are K2p. Previously known as the delayed rectifier channels, these channels are believed to be responsible for the background or leak potassium currents. In this setting, they control the resting membrane potential. A blockade of these channels shifts the resting membrane potential towards spontaneous depolarization. K2p channels are extensively spread in the body. In the CNS they are mainly located in the thalamo-cortical and striatal neurons, where blockade leads to increased neuroexitability [13]. They are also present in high concentrations in the cerebral blood vessels, where blockade leads to vasoconstriction and decreased cerebral blood flow. K2p channels are also present in neurons of the auditory system, where blockade leads to tinnitus. LA agents are also known to have K2p mediated stimulating effect on ventilation [14]. They are located in the brainstem and carotid body, where they regulate the respiratory response to carbon dioxide via sensing the changes of pH and expressed in the oxygen-sensing cells of the glomus body respectively. K2p channels are sensitive to changes in oxygen tension and extracellular pH and are potentiated by volatile anesthetic [13]. In the CVS K2p channel blockade predisposes the patient to re-entry dysrhythmias. It is well known that hyperkalemia exacerbates LAST, and that K<sup>+</sup> ATP openers (which effectively lowers intracellular K<sup>+</sup> levels) attenuate the toxic effects of bupivacaine [15].

#### **2.3 Ca2+ channel blockade**

All voltage-gated Ca2+ channels are comprised of two subunits according to the latest research: α and β subunit. The α subunit has fairly constant chemical structure for all voltage gated Ca2+ channels and is the main pore- forming element of the channel. The β subunit has highly variable structure that depends on the location and function of the channel for e.g. in cardiac conduction tissue β1 subunit completes the ion channel structure. The role of the β1 subunit seems to be the modulation of channel opening and membrane ion trafficking [16]. In terms of their physiological effect, the heart has two distinct types of channels namely the T-type (transient) that are low voltage activated channels (LVA), and L-type (long lasting). On the other hand, are high voltage activated channels (HVA).

The T-type channels are mainly located in the pacemaker cells of the sinoatrial node, and the opening of these channels completes the prepotential required for the pacemaker potential. L-type channels are present on the surface of the myocytes of both atrium and ventricle, and are closely associated with the T-tubules. The plateau phase (phase 2) of cardiac muscle action potential is produced by opening of these L-type channels. LA bind to these channels and predispose them to an inactivated state. The consequence of this is prolongation of the action potential (phase 2) and depressed contractility [9].

#### **3. LAST risk factors**

Risk factors to develop LA toxicity are related to kind of LA used, the type of nerve block, and the patient.

#### **3.1 LA related**

The most important and most studied factors in the development of LAST are undoubtedly the type and dose of LA.

#### *3.1.1 Type of LA*

The kind of LA injection influence toxicity risk. Animal studies showed that [17] more levobupivacaine than bupivacaine was required to induce cardiac arrest and levobupivacaine caused fewer convulsions and arrhythmias than bupivacaine, at similar doses [18]. Ropivacaine may cause less motor block, but whether it is clinically significantly less toxic is unknown. Other property differentiating the toxicity of LA is their intrinsic effect on vessels, where levobupivacaine and ropivacaine have intrinsic vasoconstrictors properties (that may prolong duration of action and slow systemic absorption), whereas bupivacaine is an intrinsic vasodilator. The clinical significance of this difference remains unclear. Another important concept in the study of LAST is the ratio of the dose required to produce cardiovascular collapse to that required to induce seizures, the so called CC/CNS ratio (ratio of dose causing cardiovascular collapse to the dose causing seizures). Bupivacaine has a CC/CNS ratio of 2.0 compared with 7.1 for lidocaine. Therefore, progression from CNS signs and symptoms to cardiovascular collapse can occur more readily with bupivacaine than with lidocaine.

#### *3.1.2 Dose of LA*

Determining the optimal dose of LA to use is complex and always a topic of debate. Using the lowest effective dose is always prudent and advisable practice along with consideration of patient characteristics and site of administration. Some may argue that the recommended doses provide a rough guide for clinical use. The maximum weight-based doses have lost rationale in others view as such dosing does not correlate to the resulting blood level and does not take into account relevant patient factors or the site of injection. Other factors that question the maximum weight based doses are variation between different texts and countries, no recommendation whether dose calculation is based on actual body weight or ideal body weight and such hard and fast dosing rules do not take into account the complete clinical context [19]. As a result, if dosing is calculated on actual body weight, the obese, pregnant, or both patients may receive a dangerously high dose.

**169**

*Local Anesthetic Systemic Toxicity*

supportive therapy are essential.

**3.2 Block-related**

*3.2.1 Site of block*

mucosal anesthesia.

*3.2.2 Conduct of the block*

**3.3 Patient-related factors**

*3.3.1 General principles*

concentration of free LA.

according to severity of renal impairment.

placement to give the LA reduces the risk of toxicity.

*DOI: http://dx.doi.org/10.5772/intechopen.90605*

Inadvertent intravenous injection of LA can occur during any regional anesthetic technique, but tends in becoming LAST only if larger volumes (5–10 mL) are injected, or small doses during face and neck procedures. Symptoms usually occur within 3–5 min and can be severe if appropriate measures are not taken. LAST resulting from the gradual systemic absorption of LA is characterized by a late presentation (20–30 min or more after a bolus injection), and usually occurs when a relatively high dose of LA has been administered in the presence of another risk factor. Local anesthetic systemic toxicity may also occur in the context of continuous LA infusion, in which case the onset may be hours to days after starting the infusion. The symptoms last until the drug metabolism reduces concentrations plasma levels below the toxic threshold. Prolonged monitoring and

Blocking site is important since rate of absorption, chances of direct intravascular injections and thus chances of toxicity depends on the anatomical location. For example, interscalene block, stellate ganglion block, intercostal nerve block have a higher risk of direct intravascular injection and other blocks like scalp, bronchial mucosa, inter pleural cavity carry an increased risk of rapid absorption and toxicity due to the injection being in a highly vascularized area. The classic order of sites propensities to lead to toxicity, in order from lowest to highest: subcutaneous injection, brachial plexus, epidural, caudal, and finally intercostal blocks and topical

Performing the block in a safer way decreases the chances of toxicity by manifolds. The practice of giving the dose of LA in incremental injections, after frequent aspiration, adding test dose and most important is using ultrasound-guided needle

Various factors are related to toxicity of LA. Most common being the free peak plasma concentration, perfusion at the site of injection, co-morbidities (renal, liver, metabolic, and cardiac diseases). As already discussed earlier, more the perfusion at the site of injection, more will be the peak plasma concentration as systemic absorption is accelerated. A low α1-acid glycoprotein (AAG) titer results in a higher

In patients with severe renal impairment there may be slightly increased risk of toxicity as these patients typically have a reduced clearance of LA, hyper dynamic circulation but increased AAG. So, it is prudent to reduce the initial dose by 10–20%

In patients with liver disease, single dose blocks are unaffected, but the doses for repeat boluses and continuous infusions should be reduced. Such patients may also have renal or cardiac disease. AAG is synthesized in patients with end-stage liver disease, offering some protection against LAST. Patients with severe cardiac failure are particularly susceptible to LA-induced myocardial depression and arrhythmias.

#### **3.2 Block-related**

*Topics in Local Anesthetics*

depressed contractility [9].

nerve block, and the patient.

undoubtedly the type and dose of LA.

bupivacaine than with lidocaine.

*3.1.2 Dose of LA*

**3. LAST risk factors**

**3.1 LA related**

*3.1.1 Type of LA*

The T-type channels are mainly located in the pacemaker cells of the sinoatrial node, and the opening of these channels completes the prepotential required for the pacemaker potential. L-type channels are present on the surface of the myocytes of both atrium and ventricle, and are closely associated with the T-tubules. The plateau phase (phase 2) of cardiac muscle action potential is produced by opening of these L-type channels. LA bind to these channels and predispose them to an inactivated state. The consequence of this is prolongation of the action potential (phase 2) and

Risk factors to develop LA toxicity are related to kind of LA used, the type of

The most important and most studied factors in the development of LAST are

The kind of LA injection influence toxicity risk. Animal studies showed that [17] more levobupivacaine than bupivacaine was required to induce cardiac arrest and levobupivacaine caused fewer convulsions and arrhythmias than bupivacaine, at similar doses [18]. Ropivacaine may cause less motor block, but whether it is clinically significantly less toxic is unknown. Other property differentiating the toxicity of LA is their intrinsic effect on vessels, where levobupivacaine and ropivacaine have intrinsic vasoconstrictors properties (that may prolong duration of action and slow systemic absorption), whereas bupivacaine is an intrinsic vasodilator. The clinical significance of this difference remains unclear. Another important concept in the study of LAST is the ratio of the dose required to produce cardiovascular collapse to that required to induce seizures, the so called CC/CNS ratio (ratio of dose causing cardiovascular collapse to the dose causing seizures). Bupivacaine has a CC/CNS ratio of 2.0 compared with 7.1 for lidocaine. Therefore, progression from CNS signs and symptoms to cardiovascular collapse can occur more readily with

Determining the optimal dose of LA to use is complex and always a topic of debate. Using the lowest effective dose is always prudent and advisable practice along with consideration of patient characteristics and site of administration. Some may argue that the recommended doses provide a rough guide for clinical use. The maximum weight-based doses have lost rationale in others view as such dosing does not correlate to the resulting blood level and does not take into account relevant patient factors or the site of injection. Other factors that question the maximum weight based doses are variation between different texts and countries, no recommendation whether dose calculation is based on actual body weight or ideal body weight and such hard and fast dosing rules do not take into account the complete clinical context [19]. As a result, if dosing is calculated on actual body weight, the obese, pregnant, or both patients may receive a danger-

**168**

ously high dose.

Inadvertent intravenous injection of LA can occur during any regional anesthetic technique, but tends in becoming LAST only if larger volumes (5–10 mL) are injected, or small doses during face and neck procedures. Symptoms usually occur within 3–5 min and can be severe if appropriate measures are not taken. LAST resulting from the gradual systemic absorption of LA is characterized by a late presentation (20–30 min or more after a bolus injection), and usually occurs when a relatively high dose of LA has been administered in the presence of another risk factor. Local anesthetic systemic toxicity may also occur in the context of continuous LA infusion, in which case the onset may be hours to days after starting the infusion. The symptoms last until the drug metabolism reduces concentrations plasma levels below the toxic threshold. Prolonged monitoring and supportive therapy are essential.

#### *3.2.1 Site of block*

Blocking site is important since rate of absorption, chances of direct intravascular injections and thus chances of toxicity depends on the anatomical location. For example, interscalene block, stellate ganglion block, intercostal nerve block have a higher risk of direct intravascular injection and other blocks like scalp, bronchial mucosa, inter pleural cavity carry an increased risk of rapid absorption and toxicity due to the injection being in a highly vascularized area. The classic order of sites propensities to lead to toxicity, in order from lowest to highest: subcutaneous injection, brachial plexus, epidural, caudal, and finally intercostal blocks and topical mucosal anesthesia.

#### *3.2.2 Conduct of the block*

Performing the block in a safer way decreases the chances of toxicity by manifolds. The practice of giving the dose of LA in incremental injections, after frequent aspiration, adding test dose and most important is using ultrasound-guided needle placement to give the LA reduces the risk of toxicity.

#### **3.3 Patient-related factors**

#### *3.3.1 General principles*

Various factors are related to toxicity of LA. Most common being the free peak plasma concentration, perfusion at the site of injection, co-morbidities (renal, liver, metabolic, and cardiac diseases). As already discussed earlier, more the perfusion at the site of injection, more will be the peak plasma concentration as systemic absorption is accelerated. A low α1-acid glycoprotein (AAG) titer results in a higher concentration of free LA.

In patients with severe renal impairment there may be slightly increased risk of toxicity as these patients typically have a reduced clearance of LA, hyper dynamic circulation but increased AAG. So, it is prudent to reduce the initial dose by 10–20% according to severity of renal impairment.

In patients with liver disease, single dose blocks are unaffected, but the doses for repeat boluses and continuous infusions should be reduced. Such patients may also have renal or cardiac disease. AAG is synthesized in patients with end-stage liver disease, offering some protection against LAST. Patients with severe cardiac failure are particularly susceptible to LA-induced myocardial depression and arrhythmias.

Further, lower liver and renal perfusion slows metabolism and elimination, so safe initial and maintenance doses of LA are correspondingly lower too. On the other hand, poor perfusion at the injection site may decrease peak plasma concentrations.

#### *3.3.2 Age related factors*

Extremes of age have different physiological changes making them different from young and adolescent age group. In elderly patients; there is a safety benefit in dose reduction without altering the clinical efficacy. In the geriatric patient's nerves appears to be more sensitive to LA due to various factors like altered nerve morphology, there is less fat tissue surrounding the nerves, and axonal function is also reduced. Moreover, this age group has multiple co-morbidities and decreased muscle mass; blood flow to organs is reduced, decreased clearance and organ function. In patients older than 65 years' involuntary overdoses being responsible for some cases of LAST. When considering the use of LA in geriatric patients, it is mandatory to pay special attention to the presence of systemic disease and muscle wasting [20].

In neonates and infants, the risk of accumulation of LA with continuous infusions is more than in adults as AAG levels are reduced (about half that of adult at birth). Children have an increased elimination half-life of LA, which in neonates is increased to 2–3 times that of an adult. Bupivacaine accumulates with continuous infusion and 2-chloroprocaine can be used as an alternative. LAST has the highest incidence in infants less than 6 months of age and is associated with bolus dosing and penile nerve blocks [21].

#### *3.3.3 Pregnant patients*

Pregnancy is one of several clinical settings in which LAST can be potentiated. Pregnant patients are at an increased risk of toxicity as they have increased perfusion as well as decreased AAG levels; thus high peak free plasma concentration of LA. Some of the earliest anecdotal reports of LAST-related fatal cardiac arrests involved pregnant women [1]. Notably, several of the original anecdotal reports of LAST-related fatal cardiac arrests involved pregnant women. It has since been proven that pregnancy increases the risk for LAST, and subsequent guidelines preclude use of 0.75% bupivacaine in late gestation because this concentration was involved in cases of fatal toxicity in parturients [22–24].

#### **4. Clinical presentation of LAST**

Most of the LAST events happen a few minutes after the LA injection and present with signs of the CNS, which may or may not be accompanied by changes in the CVS (**Figure 1**). Sometimes, the manifestations are atypical in terms of time and clinical picture. The onset of symptoms may be delayed up to 60 min after a bolus injection, and signs of CVS toxicity may appear in the absence of any CNS characteristics. This last scenario may be more common in patients who are very sedated or under general anesthesia. High plasma concentrations during LAST can occur in three circumstances: inadvertent intra-arterial injection, intravenous injection or systemic absorption, each of which has a characteristic temporal course. LAST associated with intra-arterial injection occurs classically during nerve blockages in the head and neck (stellate ganglion, interscalene or deep cervical plexus blocks) in which there is an involuntary injection of LA in an artery that supplies the brain. The symptoms of the CNS, usually seizures, occur almost immediately. When the injected dose is small, progression to CVS collapse is uncommon. Recovery

**171**

*Local Anesthetic Systemic Toxicity*

**Figure 1.**

**Figure 2.**

*DOI: http://dx.doi.org/10.5772/intechopen.90605*

*Scheme showing the most important clinical manifestations of LAST.*

is equally rapid since LA quickly redistributes from the cerebral circulation [25]. **Figure 2** shows an intra-arterial puncture detected during the blockage of the stel-

*Accidental arterial puncture during a stellate ganglion block in a patient with postherpetic neuropathy.*

Central nervous system toxicity could be presumed as a two-stage process in

ing excitatory neurons to act unopposed which culminates in generalized convulsions. Higher concentrations of LA agent affect all neurons, leading to global CNS depression, which is clinically seen as coma and evident on EEG as slowing and ultimately silent EEG. In most cases, convulsions, although an impressive clinical entity, can be handled safely without permanent brain damage. Clinical manifestations of the systemic neurotoxicity of LA usually occur in stages; in the initial phase there is perioral numbness, confusion, tinnitus followed by an exciting phase that shows seizures and, finally, a depressive phase where there is loss of consciousness

channels occurs in the inhibitory neurons thus allow-

late ganglion in a patient with herpes zoster neuropathy.

**4.1 Central nervous system toxicity**

which initial blockade of Na+

and respiratory depression.

*Local Anesthetic Systemic Toxicity DOI: http://dx.doi.org/10.5772/intechopen.90605*

*Topics in Local Anesthetics*

*3.3.2 Age related factors*

and penile nerve blocks [21].

*3.3.3 Pregnant patients*

Further, lower liver and renal perfusion slows metabolism and elimination, so safe initial and maintenance doses of LA are correspondingly lower too. On the other hand, poor perfusion at the injection site may decrease peak plasma concentrations.

Extremes of age have different physiological changes making them different from young and adolescent age group. In elderly patients; there is a safety benefit in dose reduction without altering the clinical efficacy. In the geriatric patient's nerves appears to be more sensitive to LA due to various factors like altered nerve morphology, there is less fat tissue surrounding the nerves, and axonal function is also reduced. Moreover, this age group has multiple co-morbidities and decreased muscle mass; blood flow to organs is reduced, decreased clearance and organ function. In patients older than 65 years' involuntary overdoses being responsible for some cases of LAST. When considering the use of LA in geriatric patients, it is mandatory to pay

special attention to the presence of systemic disease and muscle wasting [20].

In neonates and infants, the risk of accumulation of LA with continuous infusions is more than in adults as AAG levels are reduced (about half that of adult at birth). Children have an increased elimination half-life of LA, which in neonates is increased to 2–3 times that of an adult. Bupivacaine accumulates with continuous infusion and 2-chloroprocaine can be used as an alternative. LAST has the highest incidence in infants less than 6 months of age and is associated with bolus dosing

Pregnancy is one of several clinical settings in which LAST can be potentiated. Pregnant patients are at an increased risk of toxicity as they have increased perfusion as well as decreased AAG levels; thus high peak free plasma concentration of LA. Some of the earliest anecdotal reports of LAST-related fatal cardiac arrests involved pregnant women [1]. Notably, several of the original anecdotal reports of LAST-related fatal cardiac arrests involved pregnant women. It has since been proven that pregnancy increases the risk for LAST, and subsequent guidelines preclude use of 0.75% bupivacaine in late gestation because this concentration was

Most of the LAST events happen a few minutes after the LA injection and present with signs of the CNS, which may or may not be accompanied by changes in the CVS (**Figure 1**). Sometimes, the manifestations are atypical in terms of time and clinical picture. The onset of symptoms may be delayed up to 60 min after a bolus injection, and signs of CVS toxicity may appear in the absence of any CNS characteristics. This last scenario may be more common in patients who are very sedated or under general anesthesia. High plasma concentrations during LAST can occur in three circumstances: inadvertent intra-arterial injection, intravenous injection or systemic absorption, each of which has a characteristic temporal course. LAST associated with intra-arterial injection occurs classically during nerve blockages in the head and neck (stellate ganglion, interscalene or deep cervical plexus blocks) in which there is an involuntary injection of LA in an artery that supplies the brain. The symptoms of the CNS, usually seizures, occur almost immediately. When the injected dose is small, progression to CVS collapse is uncommon. Recovery

involved in cases of fatal toxicity in parturients [22–24].

**4. Clinical presentation of LAST**

**170**

**Figure 1.** *Scheme showing the most important clinical manifestations of LAST.*

#### **Figure 2.**

*Accidental arterial puncture during a stellate ganglion block in a patient with postherpetic neuropathy.*

is equally rapid since LA quickly redistributes from the cerebral circulation [25]. **Figure 2** shows an intra-arterial puncture detected during the blockage of the stellate ganglion in a patient with herpes zoster neuropathy.

#### **4.1 Central nervous system toxicity**

Central nervous system toxicity could be presumed as a two-stage process in which initial blockade of Na<sup>+</sup> channels occurs in the inhibitory neurons thus allowing excitatory neurons to act unopposed which culminates in generalized convulsions. Higher concentrations of LA agent affect all neurons, leading to global CNS depression, which is clinically seen as coma and evident on EEG as slowing and ultimately silent EEG. In most cases, convulsions, although an impressive clinical entity, can be handled safely without permanent brain damage. Clinical manifestations of the systemic neurotoxicity of LA usually occur in stages; in the initial phase there is perioral numbness, confusion, tinnitus followed by an exciting phase that shows seizures and, finally, a depressive phase where there is loss of consciousness and respiratory depression.

#### **4.2 Cardiovascular system toxicity**

Both the direct and indirect effects of the LA drugs on myocardium are involved in the mechanism of cardiovascular toxicity [26].

Clinical presentation includes hypertension and tachycardia in initial phase (during CNS excitatory phase), followed by intermediate phase showing myocardial depression, decreased cardiac output and thus hypotension, followed by sinus bradycardia, peripheral vasodilatation, conduction defects and dysrhythmias in terminal phase.

#### **5. Management of LAST**

All medical and paramedical personnel working in operating theaters and hospital locations where LA are used should be prepared to recognize, diagnose and treat patients with signs and symptoms of LAST in a timely manner. The ASRA has published and updated the guidelines recommended by experts for the management of LAST (**Table 1**) [4, 5]. The initial treatment of LAST should focus on keeping the airways permeable with adequate ventilation, circulatory support and the reduction of systemic side effects. Immediate ventilation and oxygenation to prevent hypoxia and acidosis can facilitate resuscitation and reduce the likelihood of progression to seizures or cardiovascular collapse [24, 25].

#### **5.1 Preparation**

All patients receiving LA injections in doses potentially to trigger LAST should have oxygen, standard monitoring which is to be continued at least 30 min after completion of injection to detect delayed presentation if any, and intravenous access applied [27, 28]. Immediate access to LAST Management Checklist is advisable, and all medications and resuscitation equipment required should be immediately available, preferably in the form of a "LAST Rescue Kit".

#### **5.2 Immediate management**

Immediate management involves the general safety and resuscitation measures that are essential in any emergency. First, stop LA injection and call for help. The immediate priority is to manage the airway, breathing, and circulation. Avoid factors potentiating LAST like hypoxia, hypercarbia, and acidosis (metabolic or respiratory [24, 25, 29]).

#### *5.2.1 Intravenous lipid emulsion therapy*

Use of intravenous lipid emulsion as a therapeutic modality comes with several advantages. Theories suggest that it improves cardiac conduction, contractility and coronary perfusion by removing the liposoluble LA from cardiac tissue. Better understanding of the mechanism of action of lipid emulsion with recent advances underlines its importance as therapeutic modality in the management of LAST. First advantage is that lipid emulsion may shuttle any LA agent from high blood flow organs to detoxification organs such as the liver [30]. Secondly, lipid emulsion therapy may also improve the cardiac output and blood pressure. Post conditioning myocardial protection may also occur [31–34]. There is an unavailability of large scale data collection and other prospective studies to demonstrate efficacy of lipid

**173**

**Table 1.**

*Local Anesthetic Systemic Toxicity*

**Checklist for LAST treatment**

• Stop injecting local anesthetic

• Airway management

• Control seizures

○ Call for the LAST rescue kit

○ Benzodiazepines preferred

If patient remains unstable:

• Continue monitoring

• Get help

*DOI: http://dx.doi.org/10.5772/intechopen.90605*

Reduce individual epinephrine boluses to ≤1 mcg/kg

• Treat hypotension and bradycardia—if pulseless, start CPR **Lipid emulsion 20% (precise volume and flow rate are crucial)**

○ At least 4–6 h after a cardiovascular event ○ Or, at least 2 h after a limited CNS event

*With permission from www.anestesia-dolor.org.*

*Checklist for LAST treatment [4, 5].*

The pharmacologic treatment of LAST is different from other cardiac arrest scenarios

○ Consider lipid emulsion therapy at the first sign of a serious LAST event

Avoid vasopressin, calcium channel blockers, beta blockers, or other local anesthetics

○ Alert the nearest cardiopulmonary bypass team – resuscitation may be prolonged

○ Avoid large doses of propofol, especially in hemodynamically unstable patients

**Greater than 70 kg patient Less than 70 kg patient**

Bolus 100 mL lipid emulsion 20% rapidly over 2–3 min Bolus 1.5 mL/kg lipid emulsion 20%

• Lipid emulsion infusion 200–250 mL over 15–20 min • Lipid emulsion infusion ~0.25 mL/kg/

• Re-bolus once or twice at the same dose and double infusion rate; be aware of dosing limit (12 mL/kg)

• Total volume of lipid emulsion can approach 1 L in a prolonged resuscitation (e.g., > 30 min)

• Do not exceed 12 mL/kg lipid emulsion (particularly important in the small adult or child)

○ Much smaller doses are typically needed for LAST treatment

rapidly over 2–3 min

min (ideal body weight)

○ Ventilate with 100% oxygen / avoid hyperventilation / advanced airway device if necessary

emulsion therapy due to various difficulties [24, 35, 36]; however various animal studies provide strong support for use of lipid emulsion therapy to reduce mortality when used along with resuscitative measures [37]. Early administration of 20% intravenous lipid emulsion therapy should, therefore, be an immediate priority after airway management in any LAST event that is judged to be potentially serious. A bolus of 1.5 mL/kg of 20% lipid emulsion and the subsequent infusion of 0.25 mL/kg per minute should be administered. The infusion should be continued for 10 min after reaching hemodynamic stability. An additional bolus and an infusion rate increase to 0.5 mL/kg per minute can be administered if stability is not achieved. The maximum recommended dose for initial administration is approximately 10 mL/kg for 30 min (**Table 1**) [4, 37, 38]. Lipid emulsion remains first-line therapy (in conjunction with standard resuscitative measures) in LAST. However,

more research in humans is necessary to establish its real usefulness [36].

*Topics in Local Anesthetics*

terminal phase.

**5.1 Preparation**

**5.2 Immediate management**

respiratory [24, 25, 29]).

*5.2.1 Intravenous lipid emulsion therapy*

**5. Management of LAST**

**4.2 Cardiovascular system toxicity**

in the mechanism of cardiovascular toxicity [26].

seizures or cardiovascular collapse [24, 25].

able, preferably in the form of a "LAST Rescue Kit".

Both the direct and indirect effects of the LA drugs on myocardium are involved

All medical and paramedical personnel working in operating theaters and hospital locations where LA are used should be prepared to recognize, diagnose and treat patients with signs and symptoms of LAST in a timely manner. The ASRA has published and updated the guidelines recommended by experts for the management of LAST (**Table 1**) [4, 5]. The initial treatment of LAST should focus on keeping the airways permeable with adequate ventilation, circulatory support and the reduction of systemic side effects. Immediate ventilation and oxygenation to prevent hypoxia and acidosis can facilitate resuscitation and reduce the likelihood of progression to

All patients receiving LA injections in doses potentially to trigger LAST should have oxygen, standard monitoring which is to be continued at least 30 min after completion of injection to detect delayed presentation if any, and intravenous access applied [27, 28]. Immediate access to LAST Management Checklist is advisable, and all medications and resuscitation equipment required should be immediately avail-

Immediate management involves the general safety and resuscitation measures that are essential in any emergency. First, stop LA injection and call for help. The immediate priority is to manage the airway, breathing, and circulation. Avoid factors potentiating LAST like hypoxia, hypercarbia, and acidosis (metabolic or

Use of intravenous lipid emulsion as a therapeutic modality comes with several advantages. Theories suggest that it improves cardiac conduction, contractility and coronary perfusion by removing the liposoluble LA from cardiac tissue. Better understanding of the mechanism of action of lipid emulsion with recent advances underlines its importance as therapeutic modality in the management of LAST. First advantage is that lipid emulsion may shuttle any LA agent from high blood flow organs to detoxification organs such as the liver [30]. Secondly, lipid emulsion therapy may also improve the cardiac output and blood pressure. Post conditioning myocardial protection may also occur [31–34]. There is an unavailability of large scale data collection and other prospective studies to demonstrate efficacy of lipid

Clinical presentation includes hypertension and tachycardia in initial phase (during CNS excitatory phase), followed by intermediate phase showing myocardial depression, decreased cardiac output and thus hypotension, followed by sinus bradycardia, peripheral vasodilatation, conduction defects and dysrhythmias in

**172**


○ Much smaller doses are typically needed for LAST treatment

*With permission from www.anestesia-dolor.org.*

#### **Table 1.**

*Checklist for LAST treatment [4, 5].*

emulsion therapy due to various difficulties [24, 35, 36]; however various animal studies provide strong support for use of lipid emulsion therapy to reduce mortality when used along with resuscitative measures [37]. Early administration of 20% intravenous lipid emulsion therapy should, therefore, be an immediate priority after airway management in any LAST event that is judged to be potentially serious. A bolus of 1.5 mL/kg of 20% lipid emulsion and the subsequent infusion of 0.25 mL/kg per minute should be administered. The infusion should be continued for 10 min after reaching hemodynamic stability. An additional bolus and an infusion rate increase to 0.5 mL/kg per minute can be administered if stability is not achieved. The maximum recommended dose for initial administration is approximately 10 mL/kg for 30 min (**Table 1**) [4, 37, 38]. Lipid emulsion remains first-line therapy (in conjunction with standard resuscitative measures) in LAST. However, more research in humans is necessary to establish its real usefulness [36].

#### *5.2.2 Seizure management*

Prompt seizure prevention and termination is crucial to avoid injury and acidosis. Benzodiazepines are first line therapy for management of seizures due to their cardio stable profile. Propofol or thiopental can be used in low doses, although these drugs may worsen the hypotension or cardiac depression associated with LAST. It should be avoided in patients with cardiovascular compromise. Neuromuscular blockade can be considered in cases of ongoing seizures; small doses of succinylcholine should be administered intermittently to stop muscle activity and increased acidosis. Early termination of seizure activity helps to avoid metabolic acidosis and hypoxia that occurs due to repeated muscular contractions [24].

#### *5.2.3 Cardiovascular support*

The treatment of LA-induced cardiac arrest focuses on restoring cardiac output, to restore tissue perfusion, prevent and treat underlying acidosis. Chest compressions should be started without delay and to be continued till return of spontaneous circulation (as per ACLS algorithms for cardiopulmonary resuscitation). If epinephrine is used, small initial doses of ≤1 μg/kg are preferred to avoid impaired pulmonary gas exchange and increased afterload [39]. Vasopressin is not recommended, as it can cause pulmonary hemorrhage. If myocardial LA levels is more than the threshold that corresponds to ion channel blocking concentrations, then the ionotropic effect of lipid emulsion therapy remains questionable. Chest compressions ensure the coronary perfusion that is sufficient to reduce tissue LA levels. In the absence of rapid recovery following ACLS measures and intravenous lipid emulsion therapy, early consideration should be given to cardiopulmonary bypass for circulatory support. For other deleterious CVS effects—such as arrhythmias, conduction block, progressive hypotension, and bradycardia – standard ACLS algorithms should be followed with the omission of LA, such as lidocaine and procainamide. Amiodarone is the first-line antiarrhythmic in the event of ventricular dysrhythmia. In addition, calcium channel blockers and B-adrenergic receptor blockers are not recommended.

#### *5.2.4 Post-event management*

Report the case of LAST to the registry at www.lipidrescue.org [39]. Monitoring is mandatory for at least 2 h in isolated and recovering CNS event but for 6 h for LAST with CVS features.

#### **6. Prevention**

The primary objective of every anesthesiologist is always patient safety. Preanesthetic evaluation, patient preparation, complete monitoring before starting administration of LA, and continuing this monitoring during surgery and the immediate postoperative period are mandatory.

#### **6.1 Pre-procedure**

• During preoperative assessment, evaluate the patient for co-morbidities, evaluation of the risks and benefits of regional anesthesia for that individual should be discussed, patient should be explained regarding procedure and appropriate consent to be obtained.

**175**

*Local Anesthetic Systemic Toxicity*

ing all syringes.

tative measures.

**6.2 Intra-procedure**

help nearby.

**6.3 Post-procedure**

to be considered.

**7. Conclusion**

modalities of LAST.

**Acknowledgements**

*DOI: http://dx.doi.org/10.5772/intechopen.90605*

• Preparation includes selection of type of LA, prior calculation of doses, label-

• All monitoring facilities to be available along with LAST rescue kit and resusci-

• Block to be performed with continuous monitoring attached, with a capable

• The method of administration of LA should include the administration of incremental doses with frequent aspiration, ultrasound-guided needle placement, administration of test doses. This can help in the early detection of accidental intravascular placement of the needle or catheter and thus avoid erroneous administration of the LA, avoiding toxic plasma concentrations.

• Continuous communication with the patient to detect early signs of intravas-

Clearly label any kind of spinal/epidural catheter or peripheral nerve block catheter; it should be documented well in patient chart also. Drug and dose already administered or to be administered should be well informed in instructions to the medical staff responsible for post-operative care of the patient. Continuous monitoring of vital signs in the postoperative period in suspected case of delayed LAST

LAST is a serious life-threatening emergency, with protean manifestations, that can happen after administering LA. Anesthesiologists must understand its risks, prevention, and safe management. Promptly recognition and timely management of LAST can dramatically change the clinical course. In addition to the usual advanced cardiac resuscitation maneuvers, the current treatment focuses on the administration of lipid emulsion. While the development of new treatment plans can help limiting the associated morbidity and mortality, prevention remains vitally important. It is mandatory for all the practitioners using LA to understand patho-physiological basis, mechanisms, risk factors, prevention and treatment

We thank www.anestesia-dolor.org for allowing us to publish **Figures 1** and **2**.

cular injection like perioral numbness, tinnitus etc.

#### *Local Anesthetic Systemic Toxicity DOI: http://dx.doi.org/10.5772/intechopen.90605*


#### **6.2 Intra-procedure**

*Topics in Local Anesthetics*

*5.2.2 Seizure management*

*5.2.3 Cardiovascular support*

blockers are not recommended.

*5.2.4 Post-event management*

LAST with CVS features.

immediate postoperative period are mandatory.

appropriate consent to be obtained.

**6. Prevention**

**6.1 Pre-procedure**

Prompt seizure prevention and termination is crucial to avoid injury and acidosis. Benzodiazepines are first line therapy for management of seizures due to their cardio stable profile. Propofol or thiopental can be used in low doses, although these drugs may worsen the hypotension or cardiac depression associated with LAST. It should be avoided in patients with cardiovascular compromise. Neuromuscular blockade can be considered in cases of ongoing seizures; small doses of succinylcholine should be administered intermittently to stop muscle activity and increased acidosis. Early termination of seizure activity helps to avoid metabolic acidosis and

hypoxia that occurs due to repeated muscular contractions [24].

The treatment of LA-induced cardiac arrest focuses on restoring cardiac output, to restore tissue perfusion, prevent and treat underlying acidosis. Chest compressions should be started without delay and to be continued till return of spontaneous circulation (as per ACLS algorithms for cardiopulmonary resuscitation). If epinephrine is used, small initial doses of ≤1 μg/kg are preferred to avoid impaired pulmonary gas exchange and increased afterload [39]. Vasopressin is not recommended, as it can cause pulmonary hemorrhage. If myocardial LA levels is more than the threshold that corresponds to ion channel blocking concentrations, then the ionotropic effect of lipid emulsion therapy remains questionable. Chest compressions ensure the coronary perfusion that is sufficient to reduce tissue LA levels. In the absence of rapid recovery following ACLS measures and intravenous lipid emulsion therapy, early consideration should be given to cardiopulmonary bypass for circulatory support. For other deleterious CVS effects—such as arrhythmias, conduction block, progressive hypotension, and bradycardia – standard ACLS algorithms should be followed with the omission of LA, such as lidocaine and procainamide. Amiodarone is the first-line antiarrhythmic in the event of ventricular dysrhythmia. In addition, calcium channel blockers and B-adrenergic receptor

Report the case of LAST to the registry at www.lipidrescue.org [39]. Monitoring is mandatory for at least 2 h in isolated and recovering CNS event but for 6 h for

The primary objective of every anesthesiologist is always patient safety. Preanesthetic evaluation, patient preparation, complete monitoring before starting administration of LA, and continuing this monitoring during surgery and the

• During preoperative assessment, evaluate the patient for co-morbidities, evaluation of the risks and benefits of regional anesthesia for that individual should be discussed, patient should be explained regarding procedure and

**174**


#### **6.3 Post-procedure**

Clearly label any kind of spinal/epidural catheter or peripheral nerve block catheter; it should be documented well in patient chart also. Drug and dose already administered or to be administered should be well informed in instructions to the medical staff responsible for post-operative care of the patient. Continuous monitoring of vital signs in the postoperative period in suspected case of delayed LAST to be considered.

#### **7. Conclusion**

LAST is a serious life-threatening emergency, with protean manifestations, that can happen after administering LA. Anesthesiologists must understand its risks, prevention, and safe management. Promptly recognition and timely management of LAST can dramatically change the clinical course. In addition to the usual advanced cardiac resuscitation maneuvers, the current treatment focuses on the administration of lipid emulsion. While the development of new treatment plans can help limiting the associated morbidity and mortality, prevention remains vitally important. It is mandatory for all the practitioners using LA to understand patho-physiological basis, mechanisms, risk factors, prevention and treatment modalities of LAST.

### **Acknowledgements**

We thank www.anestesia-dolor.org for allowing us to publish **Figures 1** and **2**.

*Topics in Local Anesthetics*

#### **Author details**

Divya Garg\*, Shikha Soni and Rakesh Karnawat Department of Anaesthesia and Critical Care, Dr. S.N. Medical College, Jodhpur, Rajasthan, India

\*Address all correspondence to: drdivya.garg12@gmail.com

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**177**

pp. 449-469

*Local Anesthetic Systemic Toxicity*

*DOI: http://dx.doi.org/10.5772/intechopen.90605*

[1] Albright GA. Cardiac arrest following regional anesthesia with etidocaine or bupivacaine. Anesthesiology. 1979;**51**(4):285-287. DOI:

impairs proliferative and biosynthetic functions of aged human dermal fibroblasts. Anesthesia and Analgesia. 2016;**123**(3):616-623. DOI: 10.1213/

[9] Graf B. The cardiotoxicity of local anesthetics: The place of ropivacaine.

[10] Ganong WF. Review of Medical Physiology. 18th ed. Stanford,

Connecticut: Appleton and Lange; 1997

[11] Sommers de K. Pharmakologie. 6th ed. Johannesburg: Heinemann; 1999.

[12] Kindler C, Yost CS. Two pore potassium channels: New sites for local anesthetic action and toxicity. Regional Anesthesia and Pain Medicine. 2005;**30**(3):260-274. DOI: 10.1016/j.

[13] Nisenbaum ES, Wilson CJ. Potassium currents responsible for inward and outward rectification in rat spiny projection neurons. The Journal of Neuroscience. 1995;**15**:4449-4463

[14] Gross JB, Cadwell CB, Shaw LM, Laucks SO. The effects of lidocaine on the ventilatory response to carbon dioxide. Anesthesiology. 1983;**59**:521-525

[15] de La Coussaye JE, Eledjam JJ, Peray P, Bruelle P, Lefrant JY, Bassoul B, et al. Lemakalim, a potassium channel agonist, reverses electrophysiological impairments induced by a large dose of bupivacaine in anaesthetized dogs. British Journal of Anaesthesia. 1993;**71**(4):534-539. DOI:

ANE.0000000000001422

Current Topics in Medicinal Chemistry. 2001;**1**:207-214. DOI: 10.2174/1568026013395164

pp. 184-194

rapm.2004.12.001

10.1093/bja/71.4.534

[16] Yue DT. The dawn of high-

resolution structure of the queen of ion channels. Neuron. 2004;**42**:357-361. DOI: 10.1016/s0896-6273(04)00259-4

10.1097/00000542-197910000-00001

[3] Aydin G. Unexpected local anesthesia toxicity during the ultrasonographyguided peripheral nerve block. Journal of Clinical Anesthesia. 2018;**50**:26. DOI:

Harrison TK, The American Society of Regional Anesthesia and Pain Medicine. Checklist for managing local anesthetic

Regional Anesthesia and Pain Medicine. 2018;**43**(2):150-153. DOI: 10.1097/

[5] Neal JM, Barrington MJ, Fettiplace MR, Gitman M, Memtsoudis SG, Mörwald EE, et al. Practice advisory on local anesthetic systemic toxicity: Executive summary 2017. Regional Anesthesia and Pain Medicine. 2018;**43**(2):113-123. DOI: 10.1097/AAP.0000000000000720

[6] Barash PG, Cullen B, Stoelting RK. Clinical Anesthesia. 5th ed. Philadelphia: Lippincott, Williams & Wilkins; 2005.

Boublik J, Wu CL, Sloth E. Focused cardiac ultrasound for the regional anesthesiologist and pain specialist. Regional Anesthesia and Pain Medicine. 2017;**42**(5):632-644. DOI: 10.1097/

[7] Haskins SC, Tanaka CY,

AAP.0000000000000650

[8] Bentov I, Damodarasamy M, Spiekerman C, Reed MJ. Lidocaine

[2] Bina B, Hersh EV, Hilario M, Alvarez K, McLaughlin B. True allergy to amide local anesthetics: A review and case presentation. Anesthesia Progress. 2018;**65**(2):119-123. DOI: 10.2344/

10.1016/j.jclinane.2018.06.039

[4] Neal JM, Woodward CM,

systemic toxicity: 2017 version.

AAP.0000000000000726

anpr-65-03-06

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*Local Anesthetic Systemic Toxicity DOI: http://dx.doi.org/10.5772/intechopen.90605*

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*Topics in Local Anesthetics*

**176**

**Author details**

Jodhpur, Rajasthan, India

Divya Garg\*, Shikha Soni and Rakesh Karnawat

provided the original work is properly cited.

\*Address all correspondence to: drdivya.garg12@gmail.com

Department of Anaesthesia and Critical Care, Dr. S.N. Medical College,

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

[1] Albright GA. Cardiac arrest following regional anesthesia with etidocaine or bupivacaine. Anesthesiology. 1979;**51**(4):285-287. DOI: 10.1097/00000542-197910000-00001

[2] Bina B, Hersh EV, Hilario M, Alvarez K, McLaughlin B. True allergy to amide local anesthetics: A review and case presentation. Anesthesia Progress. 2018;**65**(2):119-123. DOI: 10.2344/ anpr-65-03-06

[3] Aydin G. Unexpected local anesthesia toxicity during the ultrasonographyguided peripheral nerve block. Journal of Clinical Anesthesia. 2018;**50**:26. DOI: 10.1016/j.jclinane.2018.06.039

[4] Neal JM, Woodward CM, Harrison TK, The American Society of Regional Anesthesia and Pain Medicine. Checklist for managing local anesthetic systemic toxicity: 2017 version. Regional Anesthesia and Pain Medicine. 2018;**43**(2):150-153. DOI: 10.1097/ AAP.0000000000000726

[5] Neal JM, Barrington MJ, Fettiplace MR, Gitman M, Memtsoudis SG, Mörwald EE, et al. Practice advisory on local anesthetic systemic toxicity: Executive summary 2017. Regional Anesthesia and Pain Medicine. 2018;**43**(2):113-123. DOI: 10.1097/AAP.0000000000000720

[6] Barash PG, Cullen B, Stoelting RK. Clinical Anesthesia. 5th ed. Philadelphia: Lippincott, Williams & Wilkins; 2005. pp. 449-469

[7] Haskins SC, Tanaka CY, Boublik J, Wu CL, Sloth E. Focused cardiac ultrasound for the regional anesthesiologist and pain specialist. Regional Anesthesia and Pain Medicine. 2017;**42**(5):632-644. DOI: 10.1097/ AAP.0000000000000650

[8] Bentov I, Damodarasamy M, Spiekerman C, Reed MJ. Lidocaine impairs proliferative and biosynthetic functions of aged human dermal fibroblasts. Anesthesia and Analgesia. 2016;**123**(3):616-623. DOI: 10.1213/ ANE.0000000000001422

[9] Graf B. The cardiotoxicity of local anesthetics: The place of ropivacaine. Current Topics in Medicinal Chemistry. 2001;**1**:207-214. DOI: 10.2174/1568026013395164

[10] Ganong WF. Review of Medical Physiology. 18th ed. Stanford, Connecticut: Appleton and Lange; 1997

[11] Sommers de K. Pharmakologie. 6th ed. Johannesburg: Heinemann; 1999. pp. 184-194

[12] Kindler C, Yost CS. Two pore potassium channels: New sites for local anesthetic action and toxicity. Regional Anesthesia and Pain Medicine. 2005;**30**(3):260-274. DOI: 10.1016/j. rapm.2004.12.001

[13] Nisenbaum ES, Wilson CJ. Potassium currents responsible for inward and outward rectification in rat spiny projection neurons. The Journal of Neuroscience. 1995;**15**:4449-4463

[14] Gross JB, Cadwell CB, Shaw LM, Laucks SO. The effects of lidocaine on the ventilatory response to carbon dioxide. Anesthesiology. 1983;**59**:521-525

[15] de La Coussaye JE, Eledjam JJ, Peray P, Bruelle P, Lefrant JY, Bassoul B, et al. Lemakalim, a potassium channel agonist, reverses electrophysiological impairments induced by a large dose of bupivacaine in anaesthetized dogs. British Journal of Anaesthesia. 1993;**71**(4):534-539. DOI: 10.1093/bja/71.4.534

[16] Yue DT. The dawn of highresolution structure of the queen of ion channels. Neuron. 2004;**42**:357-361. DOI: 10.1016/s0896-6273(04)00259-4

[17] Mazoit J, Boico O, Samii K. Myocardial uptake of bupivacaine: II. Pharmacokinetics and pharmacodynamics of bupivacaine enantiomers in the isolated perfused rabbit heart. Anesthesia and Analgesia. 1993;**77**:7-82

[18] Huang Y, Pryor M, Mather L, Veering BT.Cardiovascular and central nervous system effects of intravenous levobupivacaine and bupivacaine in sheep. Anesthesia and Analgesia. 1998;**86**:797-804. DOI: 10.1097/00000539-199804000-00023

[19] Rosenberg PH, Veering BT, Urmey WF. Maximum recommended doses of local anesthetics: A multifactorial concept. Regional Anesthesia and Pain Medicine. 2004;**29**:564-575

[20] Waldinger R, Weinberg G, Gitman M. Local anesthetic toxicity in the geriatric population. Drugs & Aging. 2019. DOI: 10.1007/ s40266-019-00718-0

[21] Boretsky KR. A review of regional anesthesia in infants. Paediatric Drugs. 2019. DOI: 10.1007/s40272-019-00360-8

[22] Santos AC, Pedersen H, Harmon TW, Morishima HO, Finster M, Arthur GR, et al. Does pregnancy alter the systemic toxicity of local anesthetics? Anesthesiology. 1989;**70**(6):991-995. DOI: 10.1097/00000542-198906000-00018

[23] Santos AC, DeArmas PI. Systemic toxicity of levobupivacaine, bupivacaine, and ropivacaine during continuous intravenous infusion to nonpregnant and pregnant ewes. Anesthesiology. 2001;**95**:1256-1264

[24] Bern S, Weinberg G. Local anesthetic toxicity and lipid resuscitation in pregnancy. Current Opinion in Anaesthesiology. 2011;**24**(3):262-267. DOI: 10.1097/ ACO.0b013e32834654df

[25] El-Boghdadly K, Chin KJ. Local anesthetic systemic toxicity: Continuing professional development. Canadian Journal of Anaesthesia. 2016;**63**(3):330- 349. DOI: 10.1007/s12630-015-0564-z

[26] Plowman AN, Bolsin S, Mather LE. Central nervous system toxicity attributable to epidural ropivacaine hydrochloride. Anaesthesia and Intensive Care. 1998;**26**(2):204-206. DOI: 10.1177/0310057X9802600214

[27] Gitman M, Barrington MJ. Local anesthetic systemic toxicity: A review of recent case reports and registries. Regional Anesthesia and Pain Medicine. 2018;**43**(2):124-130. DOI: 10.1097/ AAP.0000000000000721

[28] Vasques F, Behr AU, Weinberg G, Ori C, di Gregorio G. A review of local anesthetic systemic toxicity cases since publication of the American Society of Regional Anesthesia recommendations: To whom it may concern. Regional Anesthesia and Pain Medicine. 2015;**40**(6):698-705. DOI: 10.1097/ AAP.0000000000000320

[29] Mochizuki T, Sato S. Hypocapnia prolongs bradycardia induced by bupivacaine or levobupivacaine in isolated rat hearts. Canadian Journal of Anaesthesia. 2008;**55**(12):836-846. DOI: 10.1007/BF03034055

[30] Fettiplace MR, Lis K, Ripper R, Kowal K, Pichurko A, Vitello D, et al. Multi-modal contributions to detoxification of acute pharmacotoxicity by a triglyceride micro- emulsion. Journal of Controlled Release. 2015;**198**:62-70. DOI: 10.1016/j. jconrel.2014.11.018

[31] Rahman S, Li J, Bopassa JC, Umar S, Iorga A, Partownavid P, et al. Phosphorylation of GSK-3β mediates intralipid-induced cardioprotection against ischemia/reperfusion injury. Anesthesiology. 2011;**115**(2):242-253. DOI: 10.1097/ALN.0b013e318223b8b9

**179**

2009;**21**:73-76

*Local Anesthetic Systemic Toxicity*

*DOI: http://dx.doi.org/10.5772/intechopen.90605*

Guideline: Management of Severe Local Anaesthetic Toxicity. Available at: https://www.aagbi.org/sites/default/ files/la\_toxicity\_2010\_0.pdf [Accessed:

08 July 2018]

[32] Lou PH, Lucchinetti E, Zhang L, Affolter A, Schaub MC, Gandhi M, et al. The mechanism of Intralipid®-mediated cardioprotection complex IV inhibition by the active metabolite, palmitoylcarnitine, generates reactive oxygen species and activates reperfusion injury salvage kinases. PLoS One. 2014;**9**(1):e87205. DOI: 10.1371/journal.pone.0087205

[33] Stehr SN, Ziegeler JC, Pexa A, Oertel R, Deussen A, Koch T, et al. The effects of lipid infusion on

ane.0000248220.01320.58

CCM.0b013e318287f874

aas.12870

myocardial function and bioenergetics in l-bupivacaine toxicity in the isolated rat heart. Anesthesia and Analgesia. 2007;**104**(1):186-192. DOI: 10.1213/01.

[34] Fettiplace MR, Ripper R, Lis K, Lin B, Lang J, Zider B, et al. Rapid cardiotonic effects of lipid emulsion infusion. Critical Care Medicine. 2013;**41**(8):e156-e162. DOI: 10.1097/

[35] Weinberg G. Current evidence supports use of lipid rescue therapy in local anaesthetic systemic toxicity. Acta Anaesthesiologica Scandinavica. 2017;**61**(4):365-368. DOI: 10.1111/

[36] Harvey M, Cave G. Lipid

emulsion in local anesthetic toxicity. Current Opinion in Anaesthesiology. 2017;**30**(5):632-638. DOI: 10.1097/ ACO.0000000000000498

[37] Fettiplace MR, McCabe DJ. Lipid emulsion improves survival in animal models of local anesthetic toxicity: A meta-analysis. Clinical Toxicology (Philadelphia, Pa.). 2017;**55**(7):617-623. DOI: 10.1080/15563650.2017.1288911

[38] Whizar-Lugo VM. Tratamiento de la toxicidad por anestésicos locales. Uso de lípidos intravenosos. Anest Mex.

[39] Association of Anaesthetists of Great Britain and Ireland. AAGBI Safety *Local Anesthetic Systemic Toxicity DOI: http://dx.doi.org/10.5772/intechopen.90605*

*Topics in Local Anesthetics*

[17] Mazoit J, Boico O, Samii K. Myocardial uptake of bupivacaine:

pharmacodynamics of bupivacaine enantiomers in the isolated perfused rabbit heart. Anesthesia and Analgesia. [25] El-Boghdadly K, Chin KJ. Local anesthetic systemic toxicity: Continuing professional development. Canadian Journal of Anaesthesia. 2016;**63**(3):330- 349. DOI: 10.1007/s12630-015-0564-z

Mather LE. Central nervous system toxicity attributable to epidural

ropivacaine hydrochloride. Anaesthesia and Intensive Care. 1998;**26**(2):204-206. DOI: 10.1177/0310057X9802600214

[27] Gitman M, Barrington MJ. Local anesthetic systemic toxicity: A review of recent case reports and registries. Regional Anesthesia and Pain Medicine. 2018;**43**(2):124-130. DOI: 10.1097/

[28] Vasques F, Behr AU, Weinberg G, Ori C, di Gregorio G. A review of local anesthetic systemic toxicity cases since publication of the American Society of Regional Anesthesia recommendations: To whom it may concern. Regional Anesthesia and Pain Medicine. 2015;**40**(6):698-705. DOI: 10.1097/

[29] Mochizuki T, Sato S. Hypocapnia prolongs bradycardia induced by bupivacaine or levobupivacaine in isolated rat hearts. Canadian Journal of Anaesthesia. 2008;**55**(12):836-846. DOI:

[30] Fettiplace MR, Lis K, Ripper R, Kowal K, Pichurko A, Vitello D, et al.

pharmacotoxicity by a triglyceride micro- emulsion. Journal of Controlled Release. 2015;**198**:62-70. DOI: 10.1016/j.

[31] Rahman S, Li J, Bopassa JC, Umar S, Iorga A, Partownavid P, et al. Phosphorylation of GSK-3β mediates intralipid-induced cardioprotection against ischemia/reperfusion injury. Anesthesiology. 2011;**115**(2):242-253. DOI: 10.1097/ALN.0b013e318223b8b9

Multi-modal contributions to detoxification of acute

[26] Plowman AN, Bolsin S,

AAP.0000000000000721

AAP.0000000000000320

10.1007/BF03034055

jconrel.2014.11.018

[18] Huang Y, Pryor M, Mather L, Veering BT.Cardiovascular and central nervous system effects of intravenous levobupivacaine and bupivacaine

Analgesia. 1998;**86**:797-804. DOI: 10.1097/00000539-199804000-00023

[19] Rosenberg PH, Veering BT, Urmey WF. Maximum recommended doses of local anesthetics: A multifactorial concept. Regional Anesthesia and Pain

Medicine. 2004;**29**:564-575

s40266-019-00718-0

[22] Santos AC, Pedersen H,

toxicity of levobupivacaine,

[24] Bern S, Weinberg G. Local anesthetic toxicity and lipid

ACO.0b013e32834654df

resuscitation in pregnancy. Current Opinion in Anaesthesiology. 2011;**24**(3):262-267. DOI: 10.1097/

[20] Waldinger R, Weinberg G, Gitman M. Local anesthetic toxicity in the geriatric population. Drugs & Aging. 2019. DOI: 10.1007/

[21] Boretsky KR. A review of regional anesthesia in infants. Paediatric Drugs. 2019. DOI: 10.1007/s40272-019-00360-8

Harmon TW, Morishima HO, Finster M, Arthur GR, et al. Does pregnancy alter the systemic toxicity of local anesthetics? Anesthesiology. 1989;**70**(6):991-995. DOI:

10.1097/00000542-198906000-00018

[23] Santos AC, DeArmas PI. Systemic

bupivacaine, and ropivacaine during continuous intravenous infusion to nonpregnant and pregnant ewes. Anesthesiology. 2001;**95**:1256-1264

II. Pharmacokinetics and

in sheep. Anesthesia and

1993;**77**:7-82

**178**

[32] Lou PH, Lucchinetti E, Zhang L, Affolter A, Schaub MC, Gandhi M, et al. The mechanism of Intralipid®-mediated cardioprotection complex IV inhibition by the active metabolite, palmitoylcarnitine, generates reactive oxygen species and activates reperfusion injury salvage kinases. PLoS One. 2014;**9**(1):e87205. DOI: 10.1371/journal.pone.0087205

[33] Stehr SN, Ziegeler JC, Pexa A, Oertel R, Deussen A, Koch T, et al. The effects of lipid infusion on myocardial function and bioenergetics in l-bupivacaine toxicity in the isolated rat heart. Anesthesia and Analgesia. 2007;**104**(1):186-192. DOI: 10.1213/01. ane.0000248220.01320.58

[34] Fettiplace MR, Ripper R, Lis K, Lin B, Lang J, Zider B, et al. Rapid cardiotonic effects of lipid emulsion infusion. Critical Care Medicine. 2013;**41**(8):e156-e162. DOI: 10.1097/ CCM.0b013e318287f874

[35] Weinberg G. Current evidence supports use of lipid rescue therapy in local anaesthetic systemic toxicity. Acta Anaesthesiologica Scandinavica. 2017;**61**(4):365-368. DOI: 10.1111/ aas.12870

[36] Harvey M, Cave G. Lipid emulsion in local anesthetic toxicity. Current Opinion in Anaesthesiology. 2017;**30**(5):632-638. DOI: 10.1097/ ACO.0000000000000498

[37] Fettiplace MR, McCabe DJ. Lipid emulsion improves survival in animal models of local anesthetic toxicity: A meta-analysis. Clinical Toxicology (Philadelphia, Pa.). 2017;**55**(7):617-623. DOI: 10.1080/15563650.2017.1288911

[38] Whizar-Lugo VM. Tratamiento de la toxicidad por anestésicos locales. Uso de lípidos intravenosos. Anest Mex. 2009;**21**:73-76

[39] Association of Anaesthetists of Great Britain and Ireland. AAGBI Safety Guideline: Management of Severe Local Anaesthetic Toxicity. Available at: https://www.aagbi.org/sites/default/ files/la\_toxicity\_2010\_0.pdf [Accessed: 08 July 2018]

*Edited by Víctor M. Whizar-Lugo and Enrique Hernández-Cortez*

The fascinating history of local anesthetics was born in the Andean Mountains with the use of *Erythroxylum coca* and has gradually evolved into a group of safe drugs in anesthesiology and pain medicine. Their mechanism of action on the cell membrane produces anesthesia, analgesia, and side effects that can be catastrophic. Other effects such as antimicrobial, anti-inflammatory, antineoplastic, and other therapeutic results have also been found and are still under investigation. Pharmacological advances in local anesthetics, the use of adjuvant drugs, and new regional anesthesia techniques have resulted in greater efficacy and safety for patients.Written by authors from around the world, this book examines selected topics on local anesthetics and their current use in clinical practice.

Published in London, UK © 2020 IntechOpen © PRAIRAT\_FHUNTA / pixabay

Topics in Local Anesthetics

Topics in Local Anesthetics

*Edited by Víctor M. Whizar-Lugo* 

*and Enrique Hernández-Cortez*