Calcium Channel-Blocking Drugs

CALCIUM CHANNEL-BLOCKING DRUGS

It has been known since the late 1800s that transmembrane cal-cium influx is necessary for the contraction of smooth and cardiac muscle. The discovery of a calcium channel in cardiac muscle was followed by the finding of several different types of calcium channels in different tissues (Table 12–4). The discovery of these chan-nels made possible the measurement of the calcium current, I_Ca, and subsequently, the development of clinically useful blocking drugs. 

Although the blockers currently available for clinical use in cardiovascular conditions are exclusively L-type calcium channel blockers, selective blockers of other types of calcium channels are under intensive investigation. Certain antiseizure drugs are thought to act, at least in part, through calcium channel (espe-cially T-type) blockade in neurons .

Chemistry & Pharmacokinetics

Verapamil, the first clinically useful member of this group, was the result of attempts to synthesize more active analogs of papaverine, a vasodilator alkaloid found in the opium poppy. Since then, doz-ens of agents of varying structure have been found to have the same fundamental pharmacologic action (Table 12–5). Three chemically dissimilar calcium channel blockers are shown in Figure 12–4. Nifedipine is the prototype of the dihydropyridine family of calcium channel blockers; dozens of molecules in this family have been investigated, and several are currently approved in the USA for angina and other indications. Nifedipine is the most extensively studied of this group, but the properties of the other dihydropyridines can be assumed to be similar to it unless otherwise noted.The calcium channel blockers are orally active agents and are characterized by high first-pass effect, high plasma protein bind-ing, and extensive metabolism. Verapamil and diltiazem are also used by the intravenous route.

Pharmacodynamics

A. Mechanism of Action

The voltage-gated L-type calcium channel is the dominant type in cardiac and smooth muscle and is known to contain several drug receptors. It consists of α1 (the larger, pore-forming sub-unit), α2, β, γ, and δ subunits. Four variant α1 subunits have been recognized. Nifedipine and other dihydropyridines have been demonstrated to bind to one site on the α1 subunit, whereas verapamil and diltiazem appear to bind to closely related but not identical receptors in another region of the same subunit. Binding of a drug to the verapamil or diltiazem receptors allosterically affects dihydropyridine binding. These receptor regions are ste-reoselective, since marked differences in both stereoisomer-bind-ing affinity and pharmacologic potency are observed for enantiomers of verapamil, diltiazem, and optically active nife-dipine congeners.

Blockade of calcium channels by these drugs resembles that of sodium channel blockade by local anesthetics. The drugs act from the inner side of the membrane and bind more effectively to open channels and inactivated channels. Binding of the drug reduces the frequency of opening in response to depolarization. The result is a marked decrease in transmem-brane calcium current, which in smooth muscle results in long-lasting relaxation (Figure 12–3) and in cardiac muscle results in reduction in contractility throughout the heart and decreases in sinus node pacemaker rate and atrioventricular node conduction velocity.^∗ Although some neuronal cells harbor L-type calcium channels, their sensitivity to these drugs is lower because the chan-nels in these cells spend less time in the open and inactivated states.

Smooth muscle responses to calcium influx through ligand-gated calcium channels are also reduced by these drugs but not asmarkedly. The block can be partially reversed by elevating the concentration of calcium, although the levels of calcium required are not easily attainable in patients. Block can also be partially reversed by the use of drugs that increase the transmembrane flux of calcium, such as sympathomimetics.

Other types of calcium channels are less sensitive to blockade by these calcium channel blockers (Table 12–4). Therefore, tissues in which these other channel types play a major role—neurons and most secretory glands—are much less affected by these drugs than are cardiac and smooth muscle. Mibefradil is a selective T-type calcium channel blocker that was introduced for antiar-rhythmic use but has been withdrawn. Ion channels other than calcium channels are much less sensitive to these drugs. Potassium channels in vascular smooth muscle are inhibited by verapamil, thus limiting the vasodilation produced by this drug. Sodium channels as well as calcium channels are blocked by bepridil, an obsolete antiarrhythmic drug.

B. Organ System Effects

1. Smooth muscle— Most types of smooth muscle are depen-dent on transmembrane calcium influx for normal resting tone and contractile responses. These cells are relaxed by the calcium channel blockers (Figure 12–3). Vascular smooth muscle appears to be the most sensitive, but similar relaxation can be shown for bronchiolar, gastrointestinal, and uterine smooth muscle. In the vascular system, arterioles appear to be more sensitive than veins; orthostatic hypotension is not a common adverse effect. Blood pressure is reduced with all calcium channel blockers . Women may be more sensitive than men to the hypotensive action of diltiazem. The reduction in peripheral vascular resistance is one mechanism by which these agents may benefit the patient with angina of effort. Reduction of coronary artery spasm has been demonstrated in patients with variant anginaImportant differences in vascular selectivity exist among the calcium channel blockers. In general, the dihydropyridines have a greater ratio of vascular smooth muscle effects relative to cardiac effects than do diltiazem and verapamil. The relatively smaller effect of verapamil on vasodilation may be the result of simultane-ous blockade of vascular smooth muscle potassium channels described earlier. Furthermore, the dihydropyridines may differ in their potency in different vascular beds. For example, nimodipine is claimed to be particularly selective for cerebral blood vessels. Splice variants in the structure of the α1 channel subunit appear to account for these differences.

2. Cardiac muscle—Cardiac muscle is highly dependent on cal-cium influx during each action potential for normal function. Impulse generation in the sinoatrial node and conduction in the atrioventricular node—so-called slow-response, or calcium-dependent, action potentials—may be reduced or blocked by all of the calcium channel blockers. Excitation-contraction coupling in all cardiac cells requires calcium influx, so these drugs reduce cardiac contractility in a dose-dependent fashion. In some cases, cardiac output may also decrease. This reduction in cardiac mechanical function is another mechanism by which the calcium channel blockers can reduce the oxygen requirement in patients with angina. 

Important differences between the available calcium channel blockers arise from the details of their interactions with cardiac ion channels and, as noted above, differences in their relative smooth muscle versus cardiac effects. Sodium channel block is modest with verapamil, and still less marked with diltiazem. It is negligible with nifedipine and other dihydropyridines. Verapamil and diltiazem interact kinetically with the calcium channel receptor in a different manner than the dihydropyridines; they block tachycardias in calcium-dependent cells, eg, the atrioventricular node, more selec-tively than do the dihydropyridines. On the other hand, the dihydropyridines appear to block smooth muscle calcium channels at concentrations below those required for significant cardiac effects; they are therefore less depres-sant on the heart than verapamil or diltiazem.

3. Skeletal muscle—Skeletal muscle is not depressed by thecalcium channel blockers because it uses intracellular pools of calcium to support excitation-contraction coupling and does not require as much transmembrane calcium influx.

4. Cerebral vasospasm and infarct following subarach-noid hemorrhage—Nimodipine, a member of the dihydropyri-dine group of calcium channel blockers, has a high affinity for cerebral blood vessels and appears to reduce morbidity after a subarachnoid hemorrhage. Nimodipine was approved for use in patients who have had a hemorrhagic stroke, but it has recently been withdrawn. Nicardipine has similar effects and is used by intravenous and intracerebral arterial infusion to prevent cerebral vasospasm associated with stroke. Verapamil as well, despite its lack of vasoselectivity, is used by the intra-arterial route in stroke. Some evidence suggests that calcium channel blockers may also reduce cerebral damage after thromboembolic stroke.

5. Other effects—Calcium channel blockers minimally interferewith stimulus-secretion coupling in glands and nerve endings because of differences between calcium channel type and sensitivity in different tissues. Verapamil has been shown to inhibit insulin release in humans, but the dosages required are greater than those used in management of angina and other cardiovascular conditions.

A significant body of evidence suggests that the calcium chan-nel blockers may interfere with platelet aggregation in vitro and prevent or attenuate the development of atheromatous lesions in animals. However, clinical studies have not established their role in human blood clotting and atherosclerosis.

Verapamil has been shown to block the P-glycoprotein respon-sible for the transport of many foreign drugs out of cancer (and other) cells ; other calcium channel blockers appear to have a similar effect. This action is not stereospecific. Verapamil has been shown to partially reverse the resistance of cancer cells to many chemotherapeutic drugs in vitro. Some clinical results sug-gest similar effects in patients . Animal research suggests possible future roles of calcium blockers in the treatment of osteoporosis, fertility disorders and male contraception, immune modulation, and even schistosomiasis. Verapamil does not appear to block transmembrane divalent metal ion transport-ers such as DMT1.

Toxicity

The most important toxic effects reported for calcium channel blockers are direct extensions of their therapeutic action. Excessive inhibition of calcium influx can cause serious cardiac depression, including bradycardia, atrioventricular block, cardiac arrest, and heart failure. These effects have been rare in clinical use.

Retrospective case-control studies reported that immediate-acting nifedipine increased the risk of myocardial infarction in patients with hypertension. Slow-release and long-acting dihydro-pyridine calcium channel blockers are usually well tolerated. However, dihydropyridines, compared with angiotensin-converting enzyme (ACE) inhibitors, have been reported to increase the risk of adverse cardiac events in patients with hypertension with or without diabetes. These results suggest that relatively short-acting calcium channel blockers such as prompt-release nifedipine have the potential to enhance the risk of adverse cardiac events and should be avoided. Patients receiving β-blocking drugs are more sensitive to the cardiodepressant effects of calcium channel block-ers. Minor toxicities (troublesome but not usually requiring dis-continuance of therapy) include flushing, dizziness, nausea, constipation, and peripheral edema. Constipation is particularly common with verapamil.

Mechanisms of Clinical Effects

Calcium channel blockers decrease myocardial contractile force, which reduces myocardial oxygen requirements. Calcium channel block in arterial smooth muscle decreases arterial and intraven-tricular pressure. Some of these drugs (eg, verapamil, diltiazem) also possess a nonspecific antiadrenergic effect, which may con-tribute to peripheral vasodilation. As a result of all of these effects, left ventricular wall stress declines, which reduces myocardial oxy-gen requirements. Decreased heart rate with the use of verapamil or diltiazem causes a further decrease in myocardial oxygen demand. Calcium channel-blocking agents also relieve and pre-vent focal coronary artery spasm in variant angina. Use of these agents has thus emerged as the most effective prophylactic treat-ment for this form of angina pectoris.

Sinoatrial and atrioventricular nodal tissues, which are mainly composed of calcium-dependent, slow-response cells, are affected markedly by verapamil, moderately by diltiazem, and much less by dihydropyridines. Thus, verapamil and diltiazem decrease atrio-ventricular nodal conduction and are often effective in the man-agement of supraventricular reentry tachycardia and in decreasing ventricular responses in atrial fibrillation or flutter. Nifedipine does not affect atrioventricular conduction. Nonspecific sympa-thetic antagonism is most marked with diltiazem and much less with verapamil. Nifedipine does not appear to have this effect. Significant reflex tachycardia in response to hypotension occurs most frequently with nifedipine and less so with diltiazem and verapamil. These differences in pharmacologic effects should be considered in selecting calcium channel-blocking agents for the management of angina.

Clinical Uses of Calcium Channel-Blocking Drug

In addition to angina, calcium channel blockers have well-documented efficacy in hypertension  and supraventricular tachyarrhythmias . They also show moderate efficacy in a variety of other conditions, including hypertrophic cardiomyopathy, migraine, and Raynaud’s phenomenon. Nifedipine has some efficacy in preterm labor but is more toxic and not as effective as atosiban, an investigational oxytocin antagonist .

The pharmacokinetic properties of these drugs are set forth in Table 12–5. The choice of a particular calcium channel-blocking agent should be made with knowledge of its specific potential adverse effects as well as its pharmacologic properties. Nifedipine does not decrease atrioventricular conduction and therefore can be used more safely than verapamil or diltiazem in the presence of atrioventricular conduction abnormalities. A combination of vera-pamil or diltiazem with β blockers may produce atrioventricular block and depression of ventricular function. In the presence of overt heart failure, all calcium channel blockers can cause further worsening of failure as a result of their negative inotropic effect. Amlodipine, however, does not increase mortality in patientswith heart failure due to nonischemic left ventricular systolic dys-function and can be used safely in these patients.

In patients with relatively low blood pressure, dihydropyri-dines can cause further deleterious lowering of pressure. Verapamil and diltiazem appear to produce less hypotension and may be better tolerated in these circumstances. In patients with a history of atrial tachycardia, flutter, and fibrillation, verapamil and dilti-azem provide a distinct advantage because of their antiarrhythmic effects. In the patient receiving digitalis, verapamil should be used with caution, because it may increase digoxin blood levels through a pharmacokinetic interaction. Although increases in digoxin blood level have also been demonstrated with diltiazem and nifedipine, such interactions are less consistent than with verapamil.

In patients with unstable angina, immediate-release short-acting calcium channel blockers can increase the risk of adverse cardiac events and therefore are contraindicated (see Toxicity, above). However, in patients with non–Q-wave myocardial infarc-tion, diltiazem can decrease the frequency of postinfarction angina and may be used.