**1. The neuron and pharmacology of local anaesthetics**

#### **1.1. Introduction**

Local anaesthetics are drugs that block conduction of electrical impulses in excitable tissues. These tissues include the nerve cells and myocytes (both cardiac and skeletal muscles). Analgesia and anaesthesia occur as a result of the blockage of electrical impulses. Other local anaesthetics like lidocaine also possess Class I antiarrhythmic properties. Before a detailed venture into the physi‐ cal‐chemical properties and mechanism of action of this class of drugs, a brief overview of the nerve anatomy is discussed. This will aid in the overall understanding of how these agents work and how their efficacy and safety can be improved by the use of appropriate doses and adjuncts.

#### **1.2. Nerve anatomy**

Neurons are the primary cells in the nervous system. The nervous system is made up of the central and peripheral nervous system. It can also be looked at in terms of parasympathetic and sympathetic nervous system. A group of neurons bundled together make up *peripheral nerves*. The basic structure of a neuron is illustrated in **Figure 1**.

**Figure 1.** Structure of a neuron. Source: http://www.vce.bioninja.com.au/aos‐2‐detecting‐and‐respond/coordination‐‐ regulation/nervous‐system.html. Used with permission 05/11/2016.

Peripheral nerves contain both afferent and efferent fibres, which are bundled into one or more fascicles as illustrated in **Figure 2**. Individual nerve fibres within the fascicle are sur‐ rounded by a layer of loose connective tissue called the endoneurium. The endoneurium houses the glial cells, fibroblasts and blood vessel capillaries, all of which are integral to the function of the nerve fibre. The fascicle is in turn surrounded by a dense layer of collag‐ enous connective tissue called the perineurium. A cylindrical sheath called the epineurium forms the outermost layer of a peripheral nerve. The main function of these layers is to pro‐ tect the nerve fibres and also act as barriers to agents acting on the nerves including local anaesthetics.

**Figure 2.** Peripheral nerve. Source: https://www.studyblue.com/#flashcard/review/8819508.

#### **1.3. Electrophysiology of nerve conduction**

**4.** Factors that influence the efficacy of local anaesthetics are the pH, pKa, lipid solubility, pro‐ tein binding and the length of the intermediate chain. Efficacy can be augmented by use of ad‐ juncts such as adrenaline, opioids, alpha 2‐adrenergic agonists (clonidine) and alkalinisation. **5.** Toxicity is related to the site of injection, the vascularity of the site and the injected dose. The use of vasoconstrictors may reduce toxicity due to reduction in systemic absorption. **6.** From the local anaesthetics in clinical use, racemic bupivacaine has the highest affinity for the sodium channels and is the most difficult to manage in the event of systemic toxicity.

Local anaesthetics are drugs that block conduction of electrical impulses in excitable tissues. These tissues include the nerve cells and myocytes (both cardiac and skeletal muscles). Analgesia and anaesthesia occur as a result of the blockage of electrical impulses. Other local anaesthetics like lidocaine also possess Class I antiarrhythmic properties. Before a detailed venture into the physi‐ cal‐chemical properties and mechanism of action of this class of drugs, a brief overview of the nerve anatomy is discussed. This will aid in the overall understanding of how these agents work and how their efficacy and safety can be improved by the use of appropriate doses and adjuncts.

Neurons are the primary cells in the nervous system. The nervous system is made up of the central and peripheral nervous system. It can also be looked at in terms of parasympathetic and sympathetic nervous system. A group of neurons bundled together make up *peripheral* 

**Figure 1.** Structure of a neuron. Source: http://www.vce.bioninja.com.au/aos‐2‐detecting‐and‐respond/coordination‐‐

**1. The neuron and pharmacology of local anaesthetics**

*nerves*. The basic structure of a neuron is illustrated in **Figure 1**.

regulation/nervous‐system.html. Used with permission 05/11/2016.

**1.1. Introduction**

4 Current Topics in Anesthesiology

**1.2. Nerve anatomy**

The resting membrane potential of a nerve cell is in the range of −60 to −70 mV. At rest, neurons are more permeable to potassium ions due to the presence of potassium leak chan‐ nels. This explains why the resting neuronal membrane potential is closer to the equilib‐ rium potential of potassium of −80 mV. The ionic disequilibria acts as the energy needed for propagation of action potentials on the cell surface [1]. The intracellular milieu of the nerve cell is negatively charged relative to the extracellular. Upon excitation of the nerve fibres, the electrical impulse propagates along the axon as a result of changes occurring in the adjacent membrane alternating from negative to positive values of about +50 mV due to rapid influx of sodium ions. At an electrical potential of +50 mV, there is rapid efflux of potassium ions in an attempt to maintain electrical neutrality of the cell. To restore the resting membrane potential, the sodium/potassium ATPase pumps sodium extracellularly, while the opposite happens to the potassium ions. The conduction of impulses along nerve fibres occurs as small brief, localised spikes of depolarisation on the surface of the cell membrane. Impulses travel in one direction as the axonal membrane that has just under‐ gone depolarisation remains in the refractory state until the resting potential is restored by the Sodium/Potassium ATPass pumps on [2]. **Figure 3** illustrates the sequence of events occurring during the propagation of the action potential.

**Figure 3.** Sequence of events occurring during the propagation of the action potential. Source: http://www.vce.bioninja. com.au/aos‐2‐detecting‐and‐respond/coordination‐‐regulation/nervous‐system.html. Used with permission 05/11/2016.

#### **1.4. Pharmacology of local anaesthetics**

#### *1.4.1. Structure-activity relationship of local anaesthetics*

Local anaesthetics consist of a hydrophilic amine and a lipophilic aromatic ring connected by an intermediate chain. The structural bond in the intermediate chain determines whether the local anaesthetic will be classified as an ester or an amide. Furthermore, the bond in the inter‐ mediate chain determines the pathway of metabolism of the compound. Ester local anaesthet‐ ics are metabolised by plasma pseudocholinesterases, whereas the amides are metabolised in the liver by the cytochrome family of enzymes.

**Figure 4** illustrates the structure of an ester and amide local anaesthetic showing clearly the bonds in the intermediate chains.

Pharmacology of Local Anaesthetics and Commonly Used Recipes in Clinical Practice http://dx.doi.org/10.5772/67048 7

**Figure 4.** The structure of an ester and amide local anaesthetic showing clearly the bonds in the intermediate chains. Source: Student's Manual, Department of Anaesthesia and Perioperative Medicine. University of Cape Town, South Africa. Used with permission, 16/11/2016.

#### *1.4.2. Mechanism of action of local anaesthetics*

of potassium ions in an attempt to maintain electrical neutrality of the cell. To restore the resting membrane potential, the sodium/potassium ATPase pumps sodium extracellularly, while the opposite happens to the potassium ions. The conduction of impulses along nerve fibres occurs as small brief, localised spikes of depolarisation on the surface of the cell membrane. Impulses travel in one direction as the axonal membrane that has just under‐ gone depolarisation remains in the refractory state until the resting potential is restored by the Sodium/Potassium ATPass pumps on [2]. **Figure 3** illustrates the sequence of events

occurring during the propagation of the action potential.

6 Current Topics in Anesthesiology

**1.4. Pharmacology of local anaesthetics**

*1.4.1. Structure-activity relationship of local anaesthetics*

the liver by the cytochrome family of enzymes.

bonds in the intermediate chains.

Local anaesthetics consist of a hydrophilic amine and a lipophilic aromatic ring connected by an intermediate chain. The structural bond in the intermediate chain determines whether the local anaesthetic will be classified as an ester or an amide. Furthermore, the bond in the inter‐ mediate chain determines the pathway of metabolism of the compound. Ester local anaesthet‐ ics are metabolised by plasma pseudocholinesterases, whereas the amides are metabolised in

**Figure 3.** Sequence of events occurring during the propagation of the action potential. Source: http://www.vce.bioninja. com.au/aos‐2‐detecting‐and‐respond/coordination‐‐regulation/nervous‐system.html. Used with permission 05/11/2016.

**Figure 4** illustrates the structure of an ester and amide local anaesthetic showing clearly the

Local anaesthetic blocks the transmission of nerve impulses by reversibly blocking the fast volt‐ age‐gated sodium channels, thereby inducing analgesia and anaesthesia. Physicochemically, local anaesthetics are weak bases that are formulated in an acidic milieu, hence containing a larger proportion of the drug in the ionised state. However, it is the unionised fraction that is able to cross the lipid bilayer neuronal membrane and block the voltage‐gated sodium channels from the inside of the axoplasm. This blockade renders the sodium channel inactive, and hence, no further conduction of impulses occurs. Diagramatically this is well demonstrated by **Figure 5**.

**Figure 5.** Mechanism of action of local anaesthetics. Source: http://www.esciencecentral.org/ebooks/minimally‐invasive/ anesthesia‐cosmetic‐procedures.php. Used with permission 05/11/2016.

#### *1.4.3. Determinants of physiological activities of local anaesthetics*

The activity of local anaesthetics is influenced by a number of factors. These include the pH of the surrounding tissue, the lipid solubility of the local anaesthetic, pKa, the bond in the interme‐ diate chain and its length and the protein binding of the particular local anaesthetic in question. Details of how each of these factors influence the activity of local anaesthetics is discussed below:


Depending on the type of nerves and their fibres, the sequence of blockade of the nerve fibres is illustrated in **Table 1**.


**Table 1.** Classification of nerve fibres and sequence of blockade.

#### **1.5. Specific local anaesthetics**

*1.4.3. Determinants of physiological activities of local anaesthetics*

any given pH and hence *the faster the onset of action.*

is much lower than the physiological pH of 7.4.

create a 'depot' of the drug from within the axoplasm.

acaine is three to four times more potent than lidocaine.

er duration of action.

is illustrated in **Table 1**.

8 Current Topics in Anesthesiology

**Fibre type Myelin Diameter** 

**(μm)**

A‐β Yes 5–12 Light touch and pressure A‐γ Yes 3–6 Muscle spindle (stretch)

B Yes 1–3 Preganglionic autonomic

C No 0.3–1.3 Pain (nonlocalising ache),

**Table 1.** Classification of nerve fibres and sequence of blockade.

A‐δ Yes 1–4 Firm touch, pain (fast‐localising) and

The activity of local anaesthetics is influenced by a number of factors. These include the pH of the surrounding tissue, the lipid solubility of the local anaesthetic, pKa, the bond in the interme‐ diate chain and its length and the protein binding of the particular local anaesthetic in question. Details of how each of these factors influence the activity of local anaesthetics is discussed below:

**1.** pKa: The pKa is the pH at which the number of ionised and unionised fractions of the drug is in equilibrium. *The lower the pKa, the* more the unionised fraction is present for

**2.** pH: *The lower the pH, that is, acidic milieu, the less the potency because in* acidic conditions the ionised fraction predominates, there is less of the unionised fraction, and there is less of the local anaesthetic available to cross the lipid bilayer and block the voltage‐ gated sodium channels. This explains why local anaesthetic does not have much effi‐ cacy in reducing pain in infected tissues like abscesses in which the pH of such tissues

**3.** Lipid solubility: The more lipid soluble the local anaesthetic is, the higher the potency, the faster the onset of action and the longer the duration of action. This is because there are more drug molecules able to cross the lipid bilayer of the neuronal membrane and

**4.** Intermediate chain: The longer the intermediate chain, the more potent the local an‐ aesthetic. Bupivacaine has a longer intermediate chain compared to lidocaine. Bupiv‐

**5.** Protein binding: Local anaesthetics with higher degrees of protein binding have long‐

**Function Conduction** 

temperature, touch, postganglionic autonomic

**velocity**

Slow Fast

**Onset of block**

Depending on the type of nerves and their fibres, the sequence of blockade of the nerve fibres

A‐α Yes 12–20 Somatic motor and proprioception Fast Slow

temperature

As discussed above, local anaesthetics are classified as ester and amides. Amethocaine also known as tetracaine and cocaine is the ester of clinical importance.

*Cocaine* was first introduced into clinical practice in 1884. It was first used in ophthalmic surgery and later in dental surgery. Currently, it is mainly used topically in ear, nose and throat (ENT) surgeries at a concentration of 4–10%. The onset of action is fast and lasts 20–30 min. Due to its ability to sensitise adrenergic receptors, it is relatively contraindicated in patients known with hypertension and ischaemic heart diseases. Concurrent use of adrenaline is contraindicated because cocaine is a potent vasoconstrictor.

*Amethocaine* (tetracaine) is another ester used widely in clinical practice. It was introduced in 1930 for ophthalmics/ophthalmology and as a cream for use to locally anaesthetise venepunc‐ ture sites, especially in the paediatric population. The onset of action is relatively fast with a long duration of action. A maximum dose of 1 mg/kg is recommended. It is the least metabo‐ lised of ester local anaesthetics and hence possesses a higher risk of toxicity. Other ester local anaesthetics in use include benzocaine, prilocaine and 2‐chloroprocaine.

Some of the amide local anaesthetics exhibit isomerism. Previously, sold drugs were racemic mixtures containing both the levo and dextro enantiomers. The levorotatory enantiomers of local anaesthetics are typically less neural and cardiotoxic than dextrorotatory enantiomers. For this reason, most clinicians had a preference/opted for pure enantiomers. With the intro‐ duction of better monitoring and ultrasound‐guided blocks, the racemic mixtures are making their way back into clinical practice as they tend to have a longer duration of action [3].

*Lidocaine* was the first amid local anaesthetics to be introduced in 1948. It remains one of the most widely used anaesthetics as it can be used intravenously, intrathecally and as a local infiltration. It is also a Class 1b antiarrhythmic drug. It has a fast onset of action due to its pKa of 7.8, which is closer to the physiological pH of 7.4, and is moderately water and lipid solu‐ ble. It has a moderate duration of action and is the least toxic of all amides probably due to its relatively low protein‐binding capacity of 64%. The addition of adrenaline, a vasoconstrictor, reduces its toxicity allowing for higher doses to be used for local tissue infiltrations. The rec‐ ommended doses are 3 mg/kg without adrenaline and 7 mg/kg with adrenaline, respectively. Concerns have been raised over neurotoxicity with lidocaine making it much less popular in recent years for intrathecal usage. For localised procedures such as hand surgeries, 0.5% lidocaine intravenously post‐exsanguination of the limb is still a widely used technique intro‐ duced by August Biers in 1908.

*Mepivacaine* is an intermediate duration of action compared to lidocaine and bupivacaine. It was introduced in 1957. It has a p*K*<sup>a</sup> of 7.6. It has similar pharmacokinetic and dynamic proper‐ ties with lidocaine except for some concerns of it being neurotoxic in the neonate. However, its properties of low rates of systemic toxicity, rapid onset and dense motor block make mepivacaine attractive for procedures such as shoulder surgery**.**

*Ropivacaine* was introduced in 1976. It has a p*K*<sup>a</sup> of 8.2. Its chemical structure is similar to both mepivacaine and bupivacaine. Ropivacaine is available as a pure levorotatory stereoisomer only. It is a pure enantiomer and less cardiotoxic compared with racemic mixtures of other local anaesthetics. With respect to its better safety profile, ropivacaine has become a preferred long‐acting local anaesthetic for peripheral nerve block anaesthesia for many providers. The motor block sparing properties associated with ropivacaine spinal and epidural analgesia may provide an advantage over bupivacaine. Despite its safety profile, all standard precau‐ tions pertaining to use of local anaesthetics are encouraged as they have been incidences of cardiovascular collapse reported with its use [4].

*Bupivacaine* exists as levo and dextro enantiomer. Its racemic form was introduced in 1963, while levobupivacaine was introduced in 1995. It has a p*K*<sup>a</sup> of 8.1 and a protein binding of 96%. The higher degree of protein binding makes bupivacaine the longest acting and most cardiotoxic local anaesthetic if inadvertently administered intravenously. It has been used successfully over the years since its introduction and has become the yardstick for all other long‐acting local anaesthetics. Interestingly, at low concentration, bupivacaine has the pro‐ pensity for sensory blocks while mildly sparing the motor blocks (differential sensitivity). This property allows for 'walking epidural' in labour analgesia. The maximum recommended dose is 2 mg/kg with or without adrenaline as there is only a modest increase in the duration of action when combined with a vasoconstrictor. It is three to four times more potent than lidocaine, but the onset of action is much slower.
