The CCBs are discussed here as a group, but differences exist among the drugs of this class. The common property of CCBs is their ability to impede the infl ux of Ca++ through membrane channels in cardiac and smooth muscle cells. Two principal types of voltage-gated Ca ++ channels have been identifi ed in cardiac tissue, termed L and T. The L-type channel is responsible for the Ca entry that maintains phase 2 of the action potential (the “plateau”). The T-type Ca++ channel likely plays a role in the initial depolarization of nodal tissues. It is the L-type channel that is antagonized by currently available CCBs.
Mechanisms of Action
The cellular mechanism of CCBs has been partly delineated. Increased concentrations of intracellular Ca lead to augmented contractile force in both myocardium and vascular smooth muscle. At both sites, the net effect of Ca channel blockade is to decrease the amount of Ca available to the contractile proteins within these cells, which translates into vasodilation of vascular smooth muscle and a negative inotropic effect in cardiac muscle.
Vascular Smooth Muscle
Contraction of vascular smooth muscle depends on the cytoplasmic Ca++ concentration, which is regulated by the transmembrane fl ow of Ca ++ through voltage-gated channels during depolarization.
Intracellular Ca++ interacts with calmodulin to form a Ca ++–calmodulin complex. This complex stimulates myosin light chain kinase, which phosphorylates myosin light chains and leads to cross-bridge formation between myosin heads and actin, causing smooth muscle contraction. CCBs promote relaxation of vascular smooth muscle by inhibiting Ca++ entry through the voltage-gated channels. Other organs possessing smooth muscle (including gastrointestinal, uterine, and bronchiolar tissues) are also susceptible to this relaxing effect.
Cardiac Cells
Cardiac muscle also depends on Ca++ influx during depolarization for contractile protein interactions, but by a different mechanism than that in vascular smooth muscle. Ca++ entry into the cardiac cell during depolarization triggers additional intracellular Ca++ release from the sarcoplasmic reticulum, leading to contraction. By blocking Ca++ entry, CCBs interfere with excitation–contraction coupling and decrease the force of contraction. Because the pacemaker tissues of the heart (e.g., sinoatrial [SA] and AV node) are the most dependent on the inward Ca++ current for depolarization, one would expect that CCBs would reduce the rate of sinus fi ring and AV nodal conduction. Some, but not all, CCBs have this property. The effect on cardiac conduction appears to depend not only on whether the specific CCB reduces the inward Ca++ current, but also on whether it delays recovery of the Ca++ channel to its preactivated state. Verapamil and diltiazem have this property, whereas nifedipine and the other dihydropyridine CCBs do not.
Clinical Uses
As a result of their actions on vascular smooth muscle and cardiac cells, CCBs are useful in
several cardiovascular disorders through the mechanisms summarized. In angina pectoris, they exert benefi cial effects by reducing myocardial oxygen consumption as well as by potentially increasing oxygen supply through coronary dilatation. The latter effect is also useful in the management of coronary artery vasospasm.
CCBs are often used to treat hypertension. More so than B-blockers
or ACE inhibitors, CCBs are particularly effective in elderly patients.
Nifedipine and the other dihydropyridines are the most potent
vasodilators of this class.
CCBs are usually administered orally, and once-a-day formulations
are available for these agents. Routes of excretion vary. For example,
nifedipine and verapamil are eliminated primarily in the urine, whereas
diltiazem is excreted through the liver. Common side effects include
hypotension (owing to excessive vasodilation) and ankle edema (caused by
local vasodilation of peripheral vascular beds). Since verapamil and
diltiazem may result in bradyarrhythmias, they should be used with
caution in
patients already receiving B -blocker therapy.
The safety of short-acting CCBs has been called into question. In
several observational studies, a higher incidence of myocardial
infarction or death has been reported in patients with hypertension or
coronary disease taking such agents. In contrast, these adverse outcomes
have not been demonstrated with long-acting CCBs (i.e., formulations
meant for once-a-day ingestion). Thus, the long-acting versions should
generally be prescribed for extended use. Also, recall from Chapter 6
that B -blockers and/or nitrates are preferred over CCBs for initial
therapy in patients with CAD.
Calcium Channel Blockers
Negative Suppress AV Node
Drug Vasodilation Inotropic Effect Conduction Major Adverse Effects
Verapamil + +++ +++ • Hypotension
• Bradycardia, AV block
• Constipation
Diltiazem ++ ++ ++ • Hypotension
• Peripheral edema
• Bradycardia
Dihydropyridines +++ 0 to + 0 • Hypotension
Amlodipine • Headache, flushing
Felodipine • Peripheral edema
Isradipine
Nicardipine
Nifedipine
Nisoldipine
Clinical Effects of Calcium Channel Blockers
Condition Mechanism
Angina pectoris ↓ Myocardial oxygen consumption
↓ Blood pressure (↓ afterload)
↓ Contractility
↓ Heart rate (verapamil and diltiazem)
↑ Myocardial oxygen supply
↑ Coronary dilatation
Coronary artery spasm Coronary artery vasodilation
Hypertension Arteriolar smooth muscle relaxation
Supraventricular arrhythmias (Verapamil and diltiazem): decrease conduction velocity and
increase refractoriness of atrioventricular node
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