Mibefradil dihydrochloride

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Posicor (Roche)

50 mg and 100 mg tablets

Indication: angina, hypertension

Calcium channel antagonists block the entry of calcium into cells via the L channels. Mibefradil is believed to also block the T channels.

The effect of mibefradil on vascular smooth muscle results in peripheral vasodilatation. As peripheral vascular resistance is reduced, the blood pressure falls. The heart rate is reduced and there is no reflex tachycardia.

In trials lasting up to 14 weeks, mibefradil was more effective than placebo at reducing blood pressure. A dose of 50 mg reduced systolic blood pressure by a mean of 13 mmHg and diastolic pressure by 9.3 mmHg. There is some evidence to suggest that mibefradil is as effective as amlodipine and possibly more effective than nifedipine and diltiazem at lowering blood pressure.

In patients with chronic stable angina, mibefradil delays the onset of angina during exercise tests. The mean increase in exercise duration, 24 hours after a 100 mg dose, is 77 seconds. Holter monitoring reveals that mibefradil also significantly reduces the number and duration of episodes of silent ischaemia. Compared to amlodipine, mibefradil has a greater effect on exercise tolerance tests, but a similar effect to diltiazem.

The single daily dose is rapidly absorbed. There is first-pass metabolism which can become saturated so the bioavailability at steady state can reach 90% compared to 70% after a single dose. There are two metabolic pathways, one of which involves cytochrome P450. The metabolites are excreted in the bile and urine. After repeat doses, the half-life is 17-35 hours as mibefradil has non-linear kinetics. This can lead to the development of adverse effects if small increases in dose are made at higher doses.

Some of the adverse reactions to mibefradil are due to its vasodilator effect, e.g. swelling of the legs and dizziness. The most common adverse reaction is headache. Some patients will develop heart block on their ECG. Second or third degree block is a contraindication and mibefradil is not recommended for patients with congestive heart failure.

Mibefradil can affect peak concentrations of digoxin. Cytochrome P450 CYP 3A4 and 2D6 are inhibited by mibefradil resulting in potentially serious interactions. For example, co-administration with terfenadine is contraindicated.

Mibefradil is effective in mild to moderate hypertension and chronic stable angina; however, long-term safety data are limited.