Mibefradil: a selective T-type calcium antagonist.
Mibefradil is the first of a new class of calcium antagonists with a unique structure and pharmacology. Its novel mechanism of action is characterized by L-type and selective T-type calcium channel blockade. Mibefradil is selective for smooth muscle over cardiac muscle and selectively dilates the coronary vasculature over the peripheral vasculature. In animal studies, mibefradil increases coronary blood flow during induced ischemia. In addition, in vitro studies demonstrated that mibefradil decreases smooth muscle proliferation in response to vascular injury. The most intriguing effects of mibefradil include a lack of negative inotropy and reflex tachycardia, as well as inhibition of pathologic hypertrophy and remodeling in response to vascular injury. In clinical trials, mibefradil (100 mg) was more effective than diltiazem dual-release capsules (360 mg) and as effective as amlodipine (10 mg) in treating mild-to-moderate hypertension; mibefradil (100 mg) also resulted in a greater reduction in sitting diastolic blood pressure than did nifedipine GITS (60 mg) in patients with moderate-to-severe hypertension. In patients with chronic stable angina, mibefradil (100 mg) was as effective as diltiazem SR capsules (120 mg) twice daily and more effective than amlodipine (10 mg) in improving exercise tolerance and reducing ischemic episodes. Mibefradil improved survival in a rat model of heart failure as effectively as the angiotensin-converting enzyme (ACE) inhibitor, cilazapril. The apparent lack of negative inotropic activity and neurohormonal activity with mibefradil, as well as its favorable effects on cardiac remodeling in experimental models, suggest that this agent may be beneficial in congestive heart failure. This hypothesis is being tested in the ongoing Mortality Assessment in Congestive Heart Failure (MACH-1) trial.
Massie
B M
BM
Department of Veterans Affairs Medical Center, San Francisco, California 94121, USA.
D000787:Angina Pectoris / Q000188:drug therapy*; D000818:Animals; D001562:Benzimidazoles / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002121:Calcium Channel Blockers / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006333:Heart Failure / Q000188:drug therapy; D006801:Humans; D006973:Hypertension / Q000188:drug therapy*; D020748:Mibefradil; D013329:Structure-Activity Relationship; D013764:Tetrahydronaphthalenes / Q000493:pharmacokinetics / Q000627:therapeutic use*
D001562:Benzimidazoles; D002121:Calcium Channel Blockers; D013764:Tetrahydronaphthalenes; D020748:Mibefradil