Mibefradil

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Abstract
Mibefradil belongs to a new class of calcium antagonists, the tetralol derivatives. It selectively blocks T-type calcium channels in contrast to other calcium antagonists which block only L-type channels. Mibefradil relaxes coronary arteries without suppressing myocardial contractility and causes a dose-related decrease in heart rate. When given orally once daily to patients with hypertension mibefradil produces a dose-related decrease in blood pressure which is sustained for 24 hours and improves exercise performance in patients with stable angina pectoris. In patients with generally mild to moderate hypertension oral mibefradil was superior to nifedipine SR and diltiazem CD, tended to be more effective than nifedipine GITS and had similar efficacy to amlodipine. Mibefradil 50 to 100mg once daily also has antianginal and anti-ischaemic effects. The drug improves the duration of symptom-limited exercise and the time to onset of ischaemia, and reduces the frequency of anginal attacks and consumption of nitroglycerin. Its efficacy is similar to that of diltiazem and tends to be greater than that of amlodipine in patients with stable angina. Mibefradil is generally well tolerated and is associated with a lower incidence of leg oedema than amlodipine and nifedipine. Thus, mibefradil is a calcium antagonist with a predictable cardiovascular profile, which, on the basis of available clinical data, is an effective alternative to other drugs widely used in the treatment of hypertension and stable angina pectoris. Mibefradil is a member of a new class of calcium antagonists that preferentially block T-type calcium channels as well as act at the L-type channels blocked by other calcium antagonists. Mibefradil shares characteristics with both the dihydropyridine and non-dihydropyridine classes of calcium antagonists. Mibefradil is as vasoactive as the dihydropyridine derivatives in dilating coronary and peripheral arteries. On the other hand, like verapamil and diltiazem, mibefradil treatment is associated with dose-related decreased chronotropy, but not negative inotropy. Mibefradil is associated with slowing of AV conduction and prolongation of AV nodal refractoriness, and prolongation of PQ interval is comparable with mibefradil 100mg and sustained release (SR) verapamil 240mg daily after 4 weeks’ administration. Mibefradil is an arterial vasodilator that acts directly on vascular smooth muscle to cause an increase in coronary blood flow and a reduction in peripheral resistance. The decrease in blood pressure produced by mibefradil in animals was similar to that seen with diltiazem, verapamil or amlodipine, but mibefradil caused significantly less suppression of left ventricular contractility than verapamil or diltiazem in the presence or absence of induced heart failure. Once daily dosages of mibefradil 25 to 150mg caused a dose-related decrease in heart rate and blood pressure in otherwise healthy patients with hypertension. Blood pressure reduction was greater on day 8 than on day 1 and the decrease in heart rate reached a maximum of 8 beats per minute. In patients with angina pectoris, resting and exercise heart rate and blood pressure were not affected by single oral doses of mibefradil 50, 100 or 200mg, but exercise duration increased, as did ejection fraction with the largest dose. Mibefradil 50 to 200mg once daily caused small nonsignificant changes in plasma renin activity and plasma levels of adrenaline (epinephrine) and aldosterone. Plasma noradrenaline (norepinephrine) levels increased transiently only with the highest dose. In rat and dog models of ischaemia, mibefradil reduced infarct size to a similar extent to verapamil. Mibefradil, like enalapril and cilazapril, decreased aortic medial thickness in spontaneously hypertensive rats and attenuated aortic intimal dysfunction. The effect of mibefradil and cilazapril in decreasing intimal proliferation in response to balloon-induced injury was comparable in normotensive rats, but only mibefradil inhibited intimal proliferation in rats given desoxycortone when treatment began after vascular injury. Mean peak plasma mibefradil concentrations (Cmax) increased linearly after intravenous administration to healthy volunteers, but disproportionately after single oral doses of 10 to 320mg. After 4 weeks’ oral administration, however, there appeared to be proportionality between dose and trough plasma concentrations (Cmin) in patients with hypertension given mibefradil 25 to 200mg daily. In these patients, Cmin values were 193 to 230 and 438 to 507 µg/L, respectively, after dosages of 50 and 100mg daily. Cmax was reached 1 to 2 hours after ingestion and bioavailability increased with increasing oral doses from 37% to >90% after 10 and ≥160mg, respectively. Available data from animals suggest that mibefradil is metabolised predominantly in the liver. In healthy volunteers, total plasma clearance values for mibefradil were between 11.8 and 16.7 L/h after single intravenous doses, but decreased with increasing single oral doses from 68.3 L/h after 10mg to 15.9 L/h after 160mg. In single-dose studies, elimination half-life was between 9.8 and 21.3 hours after oral administration to healthy volunteers. After multiple dosing elimination half-life was between 17 and 25 hours. Dose-finding studies reported a dose-related decrease in sitting diastolic blood pressure (DBP) compared with placebo in patients treated orally with mibefradil 25mg to 150mg once daily. The lowest clinically effective dosage was 50mg once daily and the antihypertensive effect was near maximal within 1 to 2 weeks of starting treatment. Once daily mibefradil controlled blood pressure throughout the day and night after 4 weeks’ treatment. In double-blind comparisons with other calcium antagonists, mibefradil 100mg once daily for 6 to 12 weeks was more effective than diltiazem CD 360 mg/day and of similar efficacy to amlodipine 10 mg/day in reducing elevated blood pressure. Mibefradil 50 to 150mg once daily was at least as effective as nifedipine gastrointestinal therapeutic system (GITS) 30 to 90mg once daily, and in patients with concomitant renal disease mibefradil 25 to 100mg once daily was more effective than nifedipine SR 10 to 40mg twice daily. In addition, it had similar efficacy to enalapril 20 to 40mg daily. The antihypertensive effect of mibefradil has been sustained for at least 4 months in patients who continued to receive active drug during a randomised withdrawal phase. Mibefradil was superior to nifedipine GITS in reducing DBP during ambulatory monitoring. Coadministration of lisinopril with mibefradil further decreased blood pressure in patients in whom it was not adequately controlled by mibefradil alone. Similarly, a combination of mibefradil and hydrochlorothiazide was more effective than the diuretic alone, increasing the percentage of responders (DBP ≤90mm Hg or a decrease of ≥10mm Hg) from 32 to 63 and 82% after the addition of mibefradil 50 and 100mg, respectively. In patients with chronic stable angina pectoris, mibefradil 50mg consistently increased time to onset of ischaemia and angina and was superior to placebo in improving exercise duration in 3 of 5 studies. Mibefradil 100 and 150mg once daily significantly increased exercise duration, time to onset of anginal symptoms and ST-segment depression compared with placebo. When assessed by these efficacy criteria, mibefradil 100mg and diltiazem SR 240mg daily were similarly effective, whereas mibefradil 100 and 150mg was more effective than amlodipine 10mg in improving exercise performance and reducing the time to ischaemia. The administration of mibefradil 100mg in patients with stable angina receiving treatment with a β-blocker increased the percentage of patients with a ≥60-second increase in exercise duration compared with placebo (41.7 vs 17.4%). Addition of mibefradil 50mg to existing long-acting nitrate therapy increased exercise time and time to ischaemia. At daily doses of 50 or 100mg, mibefradil is generally well tolerated. Adverse events associated with mibefradil are dose related and usually result from the vasodilatory action of the drug. With the 50mg dose, the incidence of each adverse event was similar to that in placebo recipients. Treatment with the 100mg dose was associated with slightly higher incidence compared with placebo of dizziness (2.1 vs 1.8%), leg oedema (3.5 vs 1.4%) and fatigue (2.1 vs 1.4%). The overall withdrawal rate because of adverse events was 6.4%. In comparisons with other calcium antagonists, leg oedema occurred more often with amlodipine (25.7%) and nifedipine (17.4%) than mibefradil (5.1%). Mibefradil 50 and 100mg, respectively, caused a decrease in resting heart rate of about 5 and 9 beats per minute. Sinus bradycardia tended to occur more frequently with mibefradil than with the comparators. The incidence of first degree AV block tended to be more frequent with mibefradil than with nifedipine GITS, but was similar with mibefradil, diltiazem and verapamil. Second degree AV block was rare in patients receiving recommended dosages. Mean QT interval tended to decrease slightly with mibefradil 50 and 100mg, although there have been rare reports of transient prolongation of QT interval. Mibefradil 50mg once daily is the recommended initial dosage for the treatment of patients with hypertension or angina pectoris. Depending on individual response after 1 to 2 weeks, dosage can be increased to 100mg once daily. The same dosage recommendations apply to all populations including the elderly and patients with chronic renal failure. However, caution is required in patients with severe hepatic impairment. Mibefradil should not be coadministered with terfenadine, cisapride or astemizole to minimise the risk of cardiac dysrhythmias.