Mibefradil is the prototype of a new class of
calcium antagonists that selectively block T-type voltage-gated plasma membrane
calcium channels in vascular smooth muscle. The
drug is structurally and pharmacologically different from traditional
calcium antagonists. It does not have negative inotropism at therapeutic concentrations, and is not associated with reflex activation of neurohormonal and sympathetic systems. In clinical studies of
hypertension,
mibefradil 50 and 100 mg/day reduced trough sitting diastolic and systolic blood pressures in a dose-related manner. Dosages exceeding 100 mg/day generally did not result in significantly greater efficacy, but were associated with a higher frequency of adverse events. No first-dose hypotensive phenomenon was observed.
Mibefradil has antiischemic properties resulting from dilation of coronary and peripheral vascular smooth muscle, and a slight reduction in heart rate. In clinical studies of
chronic stable angina pectoris, dose-related increases in exercise duration, time to onset of angina, and time to 1-mm ST-segment depression during exercise tolerance tests occurred.
Mibefradil reduced the number and duration of ischemic events recorded by 48-hour ambulatory electrocardiograph (ECG) monitoring, as well as number of anginal episodes and
nitroglycerin consumption. Favorable hemodynamic and clinical profiles are reported, including high trough:peak ratios (> 80%), high oral bioavailability, and long elimination half-life (17-25 hrs) permitting once/day dosing.
Dizziness,
headache, leg
edema, and
lightheadedness are frequently reported, but overall the agent is well tolerated. First-degree
atrioventricular block and sinus
bradycardia are the most frequent ECG changes caused by the
drug. In vitro studies indicate
mibefradil inhibits
cytochrome P450 1A2, 2D6, and 3A4, resulting in elevated plasma concentrations of drugs metabolized by those
isoenzymes. Therefore, it is contraindicated in patients receiving
terfenadine,
astemizole,
cisapride,
lovastatin, or
simvastatin.