Calcium channel-blocking drugs

A. Classification and Pharmacokinetics: Several types of calcium channel blockers are approved for use in angina; these drugs are typified by nifedipine, a dihydropyridine, and several other dihydropyridines; diltiazem; and verapamil. Although calcium channel blockers differ markedly in structure, all are orally active and most have half-lives of 3-6 hours. Nimodipine is another member of the dihydropyridine family with similar properties, but it is approved only for the management of stroke associated with subarachnoid hemorrhage. Bepridil, a drug that is somewhat similar in structure to verapamil, has a longer duration of action but greater cardiovascular toxicity than the older calcium channel blockers.

B. Mechanism of Action: Almost all of these drugs block voltage-dependent "L-type" calcium channels, the calcium channels most important in cardiac and smooth muscle. By decreasing calcium influx during action potentials in a frequency- and voltage-dependent manner, these agents reduce intracellular calcium concentration and muscle contractility. Mibefradil is the newest of the calcium blockers to be approved for use in the USA. It is not a dihydropyridine and is said to block cardiac "T-type" calcium channels as well as "L-type" channels. None of the channel blockers interfere with calcium-dependent neurotransmitter or hormone release because these processes do not utilize "L-" or "T-type" channels.

C. Effects: Calcium channel blockers relax blood vessels, and, to a lesser extent, the uterus, bronchi, and gut. The rate and contractility of the heart are reduced by diltiazem and verapamil. Because they block calcium-dependent conduction in the AV node of the heart, verapamil and diltiazem may be used to treat AV nodal arrhythmias (Chapter 14). Nifedipine and other dihydropyridines evoke greater vasodilation, and the resulting sympathetic reflex prevents bradycardia and may actually increase the heart rate. All the calcium channel blockers reduce blood pressure and reduce the double product in patients with angina.

Table 12-3. Effects of nitrates alone and with beta-blockers or calcium channel blockers in angina pectoris.
	Nitrates Alone	Beta-Blockers or Calcium Channel Blockers Alone	Combined Nitrate and Beta-Blockers or Calcium Channel Blockers
Heart rate	Reflex increase	Decrease	Decrease
Arterial pressure	Decrease	Decrease	Decrease
End-diastolic pressure	Decrease	Increase	Decrease
Contractility	Reflex increase	Decrease	No effect or decrease
Ejection time	Reflex decrease	Increase	No effect
1-Undesirable effects (effects that increase myocardial oxygen requirement) are shown in italics; major therapeutic effects are shown in bold.

D. Clinical Use: Calcium channel blockers are effective as prophylactic therapy in both types of angina; nifedipine can also be used to abort an acute anginal attack. In atherosclerotic angina, these drugs are particularly valuable when combined with nitrates (Table 12-3). In addition to well-established uses in angina, hypertension, and supraventricular tachycardia, these agents are being tried in migraine, preterm labor, stroke, and Raynaud's phenomenon. As noted above, nimodipine is approved for use in hemorrhagic stroke.

E. Toxicity: The calcium channel blockers cause constipation, edema, nausea, flushing, and dizziness. More serious adverse effects include congestive heart failure, atrioventricular blockade, and sinus node depression; these are more common with verapamil than with the dihydropyridines. Bepridil may induce torsade de pointes and other arrhythmias.