CALCIUM+CHANNEL+BLOCKERS

Calcium-channel blockers
 * History:** Verapamil, a diphenylalkylamine, was introduced in 1962 as a coronary vasodilator with negative inotropic and chronotropic effects unique from other coronary vasodilators available at that time. Although initially it was believed that verapamil worked by blocking beta-adrenergic receptors, it was subsequently determined that verapamil interfered with excitation-contraction coupling by inhibiting the movement of calcium ions into the cell. The next two "first-generation" calcium-channel blockers (CCBs) to be released, although similar in mechanism of action to verapamil, were completely unrelated chemically. Nifedipine (1981) is a dihydropyridine, while diltiazem (1982) is structurally similar to the benzodiazepines. Although all three inhibit calcium entry, no two were related chemically. Since then, many nifedipine-like dihydropyridines (amlodipine, felodipine, isradipine, nicardipine, and nimodipine) have been released. These are also called "second-generation" agents. Finally, bepridil is chemically and pharmacologically unique among the CCBs.

In general, all of the CCBs are effective antihypertensives and anti-anginals. Although as a class the drugs exhibit efficacy, recent evidence suggests that all may not be equal, with nifedipine having perhaps slightly less efficacy. The most serious challenge to the efficacy of CCBs is their use postinfarction. A recent meta-analysis examined the relative effects of the calcium antagonists and their outcomes when used in patients with acute myocardial infarction and angina. Little, if any, benefit was seen when mortality, infarct development, reinfarction, and unstable angina outcomes were examined.[210] Although some positive trends were seen with verapamil, no overall benefit on mortality was found. These data are less impressive when compared with the efficacy of beta-blockers in treating ischemia and preventing secondary events postinfarction (see beta-blocker Overview).

The lipophilic agent nimodipine was approved in 1988 for the treatment of patients with subarachnoid hemorrhage and neurological deficits. The lipophilic nature of nimodipine allows passage across the blood-brain barrier. Once in the central nervous system, the mechanism of its activity is not fully understood.


 * Mechanism of Action:** Calcium-channel blockers inhibit the influx of extracellular calcium across the myocardial and vascular smooth muscle cell membranes. Despite this biochemical alteration, serum calcium levels remain unchanged. Calcium channels in myocardial and vascular smooth muscle cell membranes are selective and allow a slow inward flow of calcium, which contributes to excitation-contraction coupling and electrical discharge (e.g., plateau phase of the action potential) of conduction cells in the heart and vasculature. These drugs inhibit this influx, possibly by deforming the channel, inhibiting ion-control gating mechanisms, and/or interfering with the release of calcium from the sarcoplasmic reticulum. The resultant decrease in intracellular calcium inhibits the contractile processes of the myocardial smooth muscle cells, resulting in dilation of the coronary and systemic arteries. These actions improve oxygen delivery to the myocardial tissue, decrease total peripheral resistance, decrease systemic blood pressure, and decrease afterload. Verapamil, like diltiazem and nifedipine, effectively increases coronary blood flow. Therefore, calcium-channel blockers are useful in the management of angina and hypertension.

It should be noted that not all agents in the calcium-channel blocker group are identical. While pharmacodynamic differences among members of the dihydropyridine subgroup (amlodipine, felodipine, nicardipine, nifedipine, etc.) are few, verapamil is unique. Of the class, verapamil exerts the most pronounced pharmacodynamic effects on nodal tissue of the heart; smooth muscle cells of the vasculature, especially the arterioles; and the GI tract.

The electrophysiologic effects of verapamil and diltiazem make them favorable agents for controlling and/or converting certain supraventricular arrhythmias (see Class IV Antiarrhythmic Overview). Nifedipine exerts fewer negative inotropic effects than does either diltiazem or verapamil. Verapamil is also less potent as a peripheral vasodilator than are nifedipine and related dihydropyridine analogs.[295]

The decrease in intracellular calcium also affects smooth muscle cells, inhibiting the contractile process and resulting in dilation of the coronary and systemic arteries. These effects lead to increased oxygen delivery to myocardial tissue, decreased total peripheral resistance, decreased systemic and coronary vascular resistance, and decreased afterload. This reduction in myocardial oxygen demand, cardiac workload, and vascular tone are believed to be responsible for the drug's beneficial effects in angina and its antihypertensive activities.[295]


 * Distinguishing Features:** It should be noted that not all agents in the calcium-channel blocker group are identical. Although pharmacodynamic differences among members of the dihydropyridine subgroup (amlodipine, felodipine, nicardipine, nifedipine, etc.) are few, verapamil and diltiazem are unique. These calcium-channel blockers exert the most pronounced pharmacodynamic effects on nodal tissue of the heart; smooth muscle cells of the vasculature, especially the arterioles; and the smooth muscle of the GI tract.

All of the CCBs are approved for treating coronary spasm and hypertension except bepridil, which is not approved for hypertension. All agents except felodipine and isradipine are FDA-approved for the treatment of angina. Diltiazem and verapamil are the only two calcium-channel blockers approved for treating supraventricular arrhythmias (see Class IV Antiarrhythmics Overview), even though bepridil is known to have Class I (fast sodium channel) effects and Class III (potassium channel) antiarrhythmic activity. Unfortunately, bepridil has been shown to be proarrhythmic; it can worsen existing arrhythmias or induce torsade de pointes.

Amlodipine, bepridil, and felodipine are the only calcium-channel blockers with a duration of activity long enough to allow for once-daily dosing. Sustained-release preparations of diltiazem, nifedipine, and verapamil also permit once-daily dosing in the treatment of hypertension. Diltiazem, verapamil, and nicardipine are each available in intravenous formulations and all are used for control of arrhythmias. In addition, intravenous nicardipine can be administered by continuous infusion when rapid reduction of blood pressure is necessary.

A unique use for calcium-channel blockers is the treatment of bone pain associated with cyclosporine therapy in transplant patients. Although the mechanism of bone pain is uncertain, it may be related to cyclosporine-mediated vasoconstriction. The dihydropyridine group of calcium-channel blockers has been successful in a series of transplant patients with bone pain thought to be related to cyclosporine therapy.[581]


 * Adverse Effects:** The most serious adverse effects associated with verapamil or diltiazem therapy are extensions of their therapeutic effects on the AV node and the vasculature. These effects include bradycardia; AV block of any degree, which can require atropine therapy when severe; and excessive hypotension. Although all of the dihydropyridines possess negative inotropic characteristics, the risk of developing or worsening congestive heart failure or pulmonary edema during therapy with these agents is somewhat offset by afterload reduction, particularly with amlodipine. Tachycardia, including ventricular fibrillation, can occur in patients with accessory AV pathways who are given verapamil. The vasodilatory action of the calcium-channel blockers results in many adverse effects including dizziness, flushing, and peripheral edema. Lethargy, headache, and fatigue have also been reported. About 1—3% of patients report adverse GI effects such as nausea/vomiting, anorexia, constipation, weight gain, thirst, dyspepsia, and dysgeusia. Moderate to marked transient elevations in liver-function tests and hepatocellular injury have been reported, usually occurring within 1—8 weeks following initiation of therapy. These changes resolve after discontinuation of therapy.