Receptor pharmacology of calcium entry blocking agents

The mechanism of action of calcium channel modulators, a class of drugs that includes 3 chemical groups--1,4-dihydropyridines, phenylalkylamines and benzothiazepines--has been extensively reviewed. The best known representatives of these 3 groups are nifedipine, verapamil and diltiazem, respectively. These drugs bind reversibly, stereospecifically and with high affinity to both the membrane-bound and the purified receptor complex. Non-dihydropyridines allosterically regulate dihydropyridine binding. This has been shown by using (-) [3H]202-791 and (+) [3H]PN200-110 as labeled ligands. The purified receptor complex that possesses binding sites for all 3 chemical groups is likely to be related to the voltage-dependent calcium channel. As the result of a drug-receptor interaction, voltage-dependent calcium channels are either activated or inactivated. The drugs that activate channels act by promoting long-lasting channel openings. The drugs that inhibit calcium channels, the calcium entry-blocking agents, act by preventing channel openings upon membrane depolarization. A complex pharmacologic, electrophysiologic, biochemical, immunologic and molecular genetic approach is required to determine the molecular mechanism of action of calcium channel modulators. Clinically, calcium entry-blocking agents are recommended for the treatment of angina pectoris, hypertension, posthemorrhagic cerebral vasospasm, supraventricular tachycardia, migraine and asthma and the protection of the ischemic myocardium.