**2. Mechanism of action and effects**

Calcium is an essential element for excitation-contraction coupling in muscle cells. The increase in the cytosolic Ca2+ concentration leads to an increased contraction in both cardiac and vascular smooth muscle cells [6]:


Therefore, in striated muscle, free Ca2+ in the cytosol comes only from the sarcoplasmic reticulum, while in smooth muscle, it must enter the cell through transmembrane Ca2+ channels. Cardiac muscle uses both mechanisms.

Four types of transmembrane calcium channels, differing in location and function, have been identified:


**C.** N type is available in neurons and acting in transmitter release.

**D.** P type is in Purkinje cells whose function is unknown currently.

5- Voltage-gated L-type Ca2+ channels (long-acting, high threshold-activated, slowly inactivated) are found in the cell membranes of a large number of excitable cells, including cardiac and vascular smooth muscle. Ca2+ enters the cell through these channels when the cell membrane is depolarized. The cardiac and vascular smooth muscle L-type Ca2+ channels have different subunit structures. L-type channels are essential therapeutically. The L-type calcium channel, acted on by calcium channel blockers, consists of five different subunits (α1, α2, β, δ, γ). **Figure 3** represents the L type of Ca2+ channel [7].

**219**

**Figure 3.**

*Subunits of the L-type calcium channel.*

**Figure 2.**

**Figure 1.**

6- Voltage-gated T-type Ca2+ channels (transient, low threshold-activated, fast inactivated) are found in pacemaker cells of the sinoatrial and atrioventricular nodes and are also present in vascular smooth muscle. Calcium channel blockers

*Mechanism of contraction of the cardiac myocyte by L-type voltage-gated Ca channel.*

*Calcium Channel Blockers*

*DOI: http://dx.doi.org/10.5772/intechopen.90778*

*Regulation of calcium in cardiac myocytes and blood vessels.*

*New Insight into Cerebrovascular Diseases - An Updated Comprehensive Review*

a wide range of structures are now available [5].

tion in both cardiac and vascular smooth muscle cells [6]:

actions at ryanodine receptors (**Figures 1** and **2**).

tive potentials and more rapid than the L type.

**2. Mechanism of action and effects**

Na+/Ca2+ exchanger (**Figure 1**).

represents the L type of Ca2+ channel [7].

function, have been identified:

of muscle cells.

of Ca2+ in the extracellular medium. Hass and Hartfelder reported in 1962 that verapamil, a coronary vasodilator, possessed negative inotropic and chronotropic effects that were not seen with other vasodilatory agents, such as GTN. In 1967, Fleckenstein suggested that the negative inotropic effect resulted from an inhibition of excitation-contraction coupling and that the mechanism involved reduced movement of Ca2+ into cardiac myocytes. Verapamil was the first clinically available Ca2+ channel blocker; it is a congener of papaverine. Many other Ca2+ entry blockers with

Calcium is an essential element for excitation-contraction coupling in muscle cells. The increase in the cytosolic Ca2+ concentration leads to an increased contrac-

2.In striated and cardiac muscle cells, a rise in intracellular free Ca2+ promotes the release of further Ca2+ from the sarcoplasmic reticulum (SR) through

3.Ligand-gated channels linked to G-protein-coupled receptors promote the release of Ca2+ from intracellular stores in the sarcoplasmic reticulum.

4.Ca2+ leaves striated and cardiac muscle cells in exchange for Na + via the

Therefore, in striated muscle, free Ca2+ in the cytosol comes only from the sarcoplasmic reticulum, while in smooth muscle, it must enter the cell through

Four types of transmembrane calcium channels, differing in location and

**A.** L type, located in skeletal, cardiac, and smooth muscles, causing contraction

**B.** T type, found in pacemaker cells, causing Ca2+ entry, inactivated at more nega-

5- Voltage-gated L-type Ca2+ channels (long-acting, high threshold-activated, slowly inactivated) are found in the cell membranes of a large number of excitable cells, including cardiac and vascular smooth muscle. Ca2+ enters the cell through these channels when the cell membrane is depolarized. The cardiac and vascular smooth muscle L-type Ca2+ channels have different subunit structures. L-type channels are essential therapeutically. The L-type calcium channel, acted on by calcium channel blockers, consists of five different subunits (α1, α2, β, δ, γ). **Figure 3**

transmembrane Ca2+ channels. Cardiac muscle uses both mechanisms.

**C.** N type is available in neurons and acting in transmitter release.

**D.** P type is in Purkinje cells whose function is unknown currently.

1.In smooth muscle and cardiac muscle cells, Ca2+ can enter cells through transmembrane voltage-gated and ligand-gated channels (**Figures 1** and **2**).

**218**

#### **Figure 1.** *Regulation of calcium in cardiac myocytes and blood vessels.*

**Figure 2.** *Mechanism of contraction of the cardiac myocyte by L-type voltage-gated Ca channel.*

#### **Figure 3.**

*Subunits of the L-type calcium channel.*

6- Voltage-gated T-type Ca2+ channels (transient, low threshold-activated, fast inactivated) are found in pacemaker cells of the sinoatrial and atrioventricular nodes and are also present in vascular smooth muscle. Calcium channel blockers

have different chemical structures, but their standard action is to reduce Ca2+ influx through voltage-gated L-type Ca2+ channels in smooth cardiac muscle (**Figure 2**).

There are clinically significant differences among the different types of calcium channel blockers, which bind to discrete receptors on the L-type Ca2+ channel. The receptor for verapamil is intracellular, while diltiazem and the dihydropyridines (e.g., nifedipine, amlodipine) have extracellular binding sites; however, the receptor domains for verapamil and diltiazem overlap. Verapamil and diltiazem exhibit frequency-dependent receptor binding and gain access to the Ca2+ channel when it is in the open state; in contrast, the dihydropyridines preferentially bind to the channel in its inactivated state. As more Ca2+ channels are in the inactive state, dihydropyridines selectively bind to Ca2+ channels in vascular smooth muscle. These receptor binding characteristics account for the relative vascular selectivity of the dihydropyridines and the antiarrhythmic properties of verapamil and diltiazem [6].

Calcium concentrations in cardiac cells and vascular smooth muscles are under the influence of different mechanisms. Calcium entry through voltage-gated L-type Ca2+ channels stimulates ryanodine receptors (RyR) in the sarcoplasmic reticulum, releasing stored Ca2+ (a process known as Ca2+ −induced calcium release, CICR). Intracellular Ca2+ is also regulated by exchange with Na + via the Na+/Ca2+ exchangers (NCX) in the cell membrane.

The depolarization phase during the action potential activates the voltage-gated channels, and the influx of Ca2+ into the cell results in myosin phosphorylation and muscle contraction. It also promotes further Ca2+ release from the sarcoplasmic reticulum by stimulation of ryanodine receptors. L-type Ca2+ channels can, therefore, be reduced directly by calcium channel blockers.

#### **3. Pharmacokinetics**

Most calcium channel blockers are lipophilic compounds with similar pharmacokinetic properties. Calcium channel blockers are typically administered in oral dosage forms, but orally administered calcium channel blockers undergo significant first-pass metabolism in the gut and liver, which can significantly reduce bioavailability to 10–30%. Most oral calcium channel blockers have a rapid onset of action between 20 minutes and 2 hours like nifedipine resulting in reflex tachycardia, which can worsen myocardial ischemia due to shortening diastolic phase of the cardiac cycle. Most of the agents typically have short elimination half-lives (2–10 hours), necessitating short dosing intervals or extended-release formations. Amlodipine was developed in an attempt to overcome the pharmacokinetic limitations of nifedipine. This drug has an increased oral bioavailability of 60%. The time of onset is 6 hours, and prolonged elimination half-life is 40 hours. These kinetic properties are likely due, in part, to its lipophilic character and its positive charge at physiologic pH, which leads to increased association with negatively charged plasma membranes. Some of the calcium channel blockers also have intravenous formulations like diltiazem and verapamil, while clevidipine is a dihydropyridine agent that is available only as an intravenous formulation. All calcium channel blockers are metabolized by the liver. Diltiazem is primarily excreted by the liver, while dihydropyridines and verapamil are mainly excreted in the urine [6–8].

## **4. Pharmacological actions**

The main targets of calcium channel blockers are vascular tissue and cardiac cells. Ca2+ channel blockers inhibit the voltage-dependent Ca2+ channels in vascular

**221**

**Table 1.**

*effect).*

*Calcium Channel Blockers*

recovery of the slow channel.

*DOI: http://dx.doi.org/10.5772/intechopen.90778*

smooth muscle and decrease Ca2+ entry. All Ca2+ channel antagonists relax arterial smooth muscle and thereby reduce arterial resistance, blood pressure, and cardiac afterload. Ca2+ channel blockers do not influence cardiac preload significantly when given at regular doses, suggesting that capacitance veins that determine venous return to the heart are resistant to the relaxing effect of Ca2+ channel antagonists. Depolarization in the SA and AV nodes depends mainly on the movement of Ca2+ through the slow channel. The impact of a Ca2+ channel blocker on AV conduction and the rate of the sinus node pacemaker depend on whether the agent delays the

Diltiazem and verapamil decrease the rate of the SA node pacemaker and slow AV conduction at clinically used doses; the latter effect is the basis for their use in

The hemodynamic profiles of the Ca2+ channel blockers approved for clinical use differ and depend mainly on the ratio of vasodilating and negative inotropic and chronotropic effects on the heart (**Table 1**, **Figures 4** and **5**). Although all calcium channel blockers are vasodilators, dihydropyridine derivatives such as nifedipine and amlodipine are the most potent and have the most significant vascular selectivity. Arterial dilation reduces peripheral resistance and lowers blood pressure, which reduces the work of the left ventricle and therefore reduces myocardial oxygen demand. Most dihydropyridines have a rapid onset of action. A rapid reduction in blood pressure can lead to reflex sympathetic nervous system activation and tachycardia. Amlodipine or modified-release formulations of short-acting dihydropyridines are more slowly absorbed and gradually reduce blood pressure with little reflex tachycardia. But generally, the differences between the relatively vaso-selective dihydropyridines and the much less-selective diltiazem and verapamil have essential consequences because the decrease in arterial blood pressure elicits reflex sympathetic activation, resulting in the stimulation of heart rate, AV conduction velocity, and myocardial force, just the opposite of the direct effect of Ca2+ channel blockers. While direct and indirect impacts usually balance each other in the case of verapamil and diltiazem, sympathetic stimulation often prevails in dihydropyridines, causing an increase in heart rate and contractility. Cardiac depressant effects

*Comparative cardiovascular effects of calcium channel blockers graded from 0 (no effect) to 5 (prominent* 

the treatment of supraventricular tachyarrhythmias [6–8].

**5. Cardiovascular effects of different Ca2+ channel blockers**

#### *Calcium Channel Blockers DOI: http://dx.doi.org/10.5772/intechopen.90778*

*New Insight into Cerebrovascular Diseases - An Updated Comprehensive Review*

ers (NCX) in the cell membrane.

**3. Pharmacokinetics**

**4. Pharmacological actions**

fore, be reduced directly by calcium channel blockers.

have different chemical structures, but their standard action is to reduce Ca2+ influx through voltage-gated L-type Ca2+ channels in smooth cardiac muscle (**Figure 2**). There are clinically significant differences among the different types of calcium channel blockers, which bind to discrete receptors on the L-type Ca2+ channel. The receptor for verapamil is intracellular, while diltiazem and the dihydropyridines (e.g., nifedipine, amlodipine) have extracellular binding sites; however, the receptor domains for verapamil and diltiazem overlap. Verapamil and diltiazem exhibit frequency-dependent receptor binding and gain access to the Ca2+ channel when it is in the open state; in contrast, the dihydropyridines preferentially bind to the channel in its inactivated state. As more Ca2+ channels are in the inactive state, dihydropyridines selectively bind to Ca2+ channels in vascular smooth muscle. These receptor binding characteristics account for the relative vascular selectivity of the dihydropyridines and the antiarrhythmic properties of verapamil and diltiazem [6]. Calcium concentrations in cardiac cells and vascular smooth muscles are under the influence of different mechanisms. Calcium entry through voltage-gated L-type Ca2+ channels stimulates ryanodine receptors (RyR) in the sarcoplasmic reticulum, releasing stored Ca2+ (a process known as Ca2+ −induced calcium release, CICR). Intracellular Ca2+ is also regulated by exchange with Na + via the Na+/Ca2+ exchang-

The depolarization phase during the action potential activates the voltage-gated channels, and the influx of Ca2+ into the cell results in myosin phosphorylation and muscle contraction. It also promotes further Ca2+ release from the sarcoplasmic reticulum by stimulation of ryanodine receptors. L-type Ca2+ channels can, there-

Most calcium channel blockers are lipophilic compounds with similar pharmacokinetic properties. Calcium channel blockers are typically administered in oral dosage forms, but orally administered calcium channel blockers undergo significant first-pass metabolism in the gut and liver, which can significantly reduce bioavailability to 10–30%. Most oral calcium channel blockers have a rapid onset of action between 20 minutes and 2 hours like nifedipine resulting in reflex tachycardia, which can worsen myocardial ischemia due to shortening diastolic phase of the cardiac cycle. Most of the agents typically have short elimination half-lives (2–10 hours), necessitating short dosing intervals or extended-release formations. Amlodipine was developed in an attempt to overcome the pharmacokinetic limitations of nifedipine. This drug has an increased oral bioavailability of 60%. The time of onset is 6 hours, and prolonged elimination half-life is 40 hours. These kinetic properties are likely due, in part, to its lipophilic character and its positive charge at physiologic pH, which leads to increased association with negatively charged plasma membranes. Some of the calcium channel blockers also have intravenous formulations like diltiazem and verapamil, while clevidipine is a dihydropyridine agent that is available only as an intravenous formulation. All calcium channel blockers are metabolized by the liver. Diltiazem is primarily excreted by the liver, while dihydropyridines and verapamil are mainly excreted in the urine [6–8].

The main targets of calcium channel blockers are vascular tissue and cardiac cells. Ca2+ channel blockers inhibit the voltage-dependent Ca2+ channels in vascular

**220**

smooth muscle and decrease Ca2+ entry. All Ca2+ channel antagonists relax arterial smooth muscle and thereby reduce arterial resistance, blood pressure, and cardiac afterload. Ca2+ channel blockers do not influence cardiac preload significantly when given at regular doses, suggesting that capacitance veins that determine venous return to the heart are resistant to the relaxing effect of Ca2+ channel antagonists. Depolarization in the SA and AV nodes depends mainly on the movement of Ca2+ through the slow channel. The impact of a Ca2+ channel blocker on AV conduction and the rate of the sinus node pacemaker depend on whether the agent delays the recovery of the slow channel.

Diltiazem and verapamil decrease the rate of the SA node pacemaker and slow AV conduction at clinically used doses; the latter effect is the basis for their use in the treatment of supraventricular tachyarrhythmias [6–8].
