Comparative Pharmacological Properties among Calcium Channel Blockers: T-Channel versus L-Channel Blockade

Abstract

Calcium antagonists are potent vasodilators and are widely used in the treatment of hypertension and angina pectoris. The currently available compounds belong to three classes: (1) dihydropyridines (e.g. nifedipine, amlodipine and felodipine), (2) phenylalkylamines (e.g. verapamil) and (3) benzothiazepines (e.g. diltiazem). The three classes differ in their pharmacological profile and safety. For example, verapamil and diltiazem lower heart rate, while dihydropyridines increase it or leave it unchanged. With most of the latter compounds, a marked activation of the sympathetic nervous system has been noted. Most compounds exhibit negative inotropic effects, particularly the first-generation molecules, which is disadvantageous in patients with impaired left-ventricular function. The most common side effects of these drugs are flushing, headache and edema. With verapamil, constipation may represent a problem in certain patients. Hence, in spite of a large number of calcium antagonists available, there remains a need for new compounds with enhanced efficacy and improved tolerability. A new compound should lack any negative inotropism, avoid any increase in sympathetic outflow or heart rate and exhibit a high degree of vascular selectivity. Furthermore, a low incidence of side effects, particularly ankle edema and optimal pharmacokinetics allowing once-daily dosing would be desirable. Mibefradil is a new calcium antagonist with promising pharmacological and clinical properties. The compound has a high bioavailability, lacks negative inotropic effects at therapeutic concentrations, does not exhibit reflex tachycardia during vasodilation and actually slightly decreases heart rate. It is a potent direct vasodilator efficacious in hypertension and chronic angina pectoris, elicits endothelium-dependent relaxations and facilitates the effects of nitric oxide in vascular smooth muscle. The drug is a particularly efficacious vasodilator in intramyocardial coronary arteries which may be important for its anti-ischemic effects and the lack of steal in the coronary circulation. Furthermore, mibefradil has antiproliferative properties in human vascular smooth muscle cells in culture. As a unique property, mibefradil blocks T-type calcium channels and hence represents a new class of calcium channel blockers. In patients with hypertension, mibefradil has a high efficacy in controlling blood pressure. The drug does not cause constipation and has a low incidence of ankle edema. A large trial is under way to further delineate the properties of this new calcium antagonist in patients with heart failure.