Pharmacology Update

Mibefradil: A New Calcium Channel Blocker

By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD

Roche has introduced a new calcium channel blocker that is chemically distinct from currently available agents. Mifefradil (Posicor, Roche) is a tetraline calcium channel blocker as opposed to the dihydropyridines (e.g., nifedipine), phenylalkylamines (e.g., verapamil), and benzothiazepines (e.g., diltiazem). Mibefradil inhibits both L-type and T-type channels and appears to be more selective for T-type channels,1,2 whereas older calcium channel inhibitors primarily block L-type channels. This selectivity may offer some therapeutic advantages and may be associated with a unique side effect profile. The once-a-day drug is approved and is being marketed for the treatment of both hypertension and angina.

Indications

Mibefradil is indicated for the treatment of hypertension or chronic stable angina pectoris. Mibefradil can be used alone or in combination with other antihypertensives or antianginal drugs.

Potential Advantages

Mibefradil has a long elimination half life (17-25 hours) and reduces blood pressure with little trough to peak variation (trough to peak ratio, > 75%).3 In a comparative trial with diltiazem (n = 201), mibefradil 100 mg was more effective than controlled-release diltiazem (Cardizem CD) 360 mg in reducing blood pressure in patients with stage 1 and 2 hypertension. The mean sitting diastolic blood pressure reduction from baseline was -14.0 ± 7.8 mmHg for mibefradil and -9.5 ± 7.5 mmHg. Blood pressures were measured at trough (21-27 hours post dose).4 Mibefradil reduces blood pressure without reflex tachycardia and negative inotropic on the heart.1,3,5

Potential Disadvantages

Mibefradil produces a modest decrease in heart rate. In clinical trials involving doses up to 150 mg/d, sinus bradycardia (heart rate < 55 bpm or change from baseline of > 10 bpm) was reported in 16.3-26% of patients. First degree AV block was reported in 6.1-11%.4,5 Other side effects include headache, fatigue, and lightheadedness, generally with an incidence of 11%.3,4 Mibefradil or its metabolites are inhibitors of cytochrome P450 isoenzymes 2D6, 1A2, and 3A4. Concomitant administration of terfenadine, astemizole, and cisapride are contradindicated.3 Concomitant administration of drugs that are metabolized via isoenzyme 2D6, 1A2, and 3A4 may require dose adjustment and should be monitored. Mibefradil causes a flattening of the T wave and an increase in the voltage of the U wave which may be interpreted as QTc prolongation. This generally occurs in doses above the recommended dosage range.3

Prescribing Information

Mibefradil is supplied as 50 mg and 100 mg tablets. The recommended inital dose is 50 mg for either hypertension or chronic angina. Titration to 100 mg should be based on response. In chronic angina, the benefit of the 50 mg dose was smaller and less consistent than the 100 mg dose. The tablets may be taken without regard to meals. The tablets should not be crushed or chewed. Mibefradil is extensively metabolized by the liver; caution must be exercised when administering this drug to patients with severe hepatic dysfunction.3

Comments

Mibefradil is a new calcium channel blocker that is chemically different from those currently on the market. Once daily administration has been associated with mean difference from placebo of 5-11 mmHg reduction in diastolic blood pressure and a 7-11 mmHg reduction in systolic blood pressure.3 Mibefradil has also been shown to be effective in delaying the time to onset of angina during exercise, reduction in the frequency of episodes of ST segment depression, reduction in the total duration of ST segment elevation, decrease in the rate of anginal attacks, and a decrease in nitroglycerine consumption.3,6,7

In contrast to other calcium channel blockers, mibefradil blocks both L-type and T-type channels with greater selectivity for T-type channels. L-type channels are involved in the initiation of cardiac and smooth muscle, while T-type channels are found in the sinoatrial node and are generally involved in automaticity.8,9 L-type channels are blocked by the prototype calcium channel blockers, dihydropyridine, diltiazem, and verapamil and, to a lesser degree, mibefradil. Mibefradil’s selectively on T-type channels would be expected to produce vasodilation and reduction in heart rate with minimal negative inotropic effect. The safety of mibefradil is currently being assessed in heart failure patients who are in NYHA classes II-IV in the Mortality Assessment in Congestive Heart Failure trial (MACH-1).10

Clinical Implications

Mibefradil is a new calcium channel blocker that appears to differ from current agents due to its selectivity for T-type channels and, to a lesser degree, L-type channels. The clinical significance of calcium channel selectivity has not been established. There are currently no long-term data on the effect of mibefradil on mortality or morbidity. Mibefradil’s wholesale cost is $1.03 per tablet for the 50 mg strength and $1.78 per tablet for the 100 mg strength. It is priced similarly to Novasc and Procardia XL.

References

1. Triggle DJ. Am J Cardiol 1996;78(suppl 9A):7-12.

2. Tsien RW, et al. J Cardiovasc Pharmacol 1996;27(suppl A):S4-10.

3. Posicor Product Information. Roche Pharmaceuticals. June 1997.

4. Massie BM, et al. Clin Cardiol 1997;20:562-568.

5. Lacourciere Y, et al. AJH 1997;10:189-196.

6. Braun S, et al. J Am Coll Cardiol 1997;27:317-322.

7. Bakx AI, et al. Am Heart J 1995;130:748-757.

8. Buhler FR, et al. J Cardiovasc Pharmacol 1996;27(suppl A):S1-3.

9. Hockerman GH, et al. Ann Rev Pharmacol Toxicol 1997;37:361-396.

10. Levine TB, et al. Clin Cardiol 1997;20:320-326.