, Volume 44, Issue 5, pp 835-857

Bepridil

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Abstract

Synopsis

Bepridil is a calcium antagonist with direct negative chronotropic, dromotropic, inotropic and vasodilatory actions which reduces myocardial oxygen consumption and increases coronary blood flow, leading to a significant anti-ischaemic and antianginal effect in the absence of reflex tachycardia. In contrast to other calcium channel blockers, bepridil produces only modest peripheral vasodilatation and displays weak antihypertensive activity. Its plasma elimination half-life of 1 to 2 days permits once daily administration.

Results of short term clinical trials have shown bepridil to be of comparable efficacy to nifedipine, verapamil, diltiazem, propranolol and nadolol in decreasing the frequency of anginal attacks and consumption of nitroglycerin (glyceryl trinitrate) in patients with stable angina. Bepridil is more effective than nifedipine in improving exercise performance in patients with stable angina. Although bepridil proved superior to diltiazem in improving exercise performance in patients refractory to diltiazem, further studies are required to confirm the efficacy of bepridil in patients refractory to, or intolerant of, other antianginal agents.

Bepridil in therapeutic doses is well tolerated, and appears to have a similar adverse effect profile to the established calcium antagonists. However, rate-dependent prolongation of the QTc interval and development of torsade de pointes have been associated with the use of bepridil. Therefore, bepridil is contraindicated in patients with hypokalaemia, those receiving other drugs that may prolong the QT interval, and those with congenital QT interval prolongation. Future clinical research will help to further define the position of bepridil as an antianginal treatment relative to the traditional calcium antagonists; in the interim, bepridil is indicated for the treatment of patients with angina refractory to or intolerant of other agents.

Pharmacodynamic Properties

Bepridil blocks slow calcium channels in the myocardium and vascular smooth muscle, and fast sodium channels in cardiac tissues. In contrast to other calcium channel blockers, bepridil inhibits both receptor-operated and voltage-operated calcium channels in vascular smooth muscle. Bepridil also inhibits the potassium current and the intracellular calcium/calmodulin complex. Studies in humans have shown that the resultant effects are a dose proportional reduction in heart rate, a rate-dependent prolongation of the QTc interval, an increase in atrial and ventricular refractoriness, and coronary vasodilatation. The diminished myocardial oxygen consumption and increased coronary blood flow (47% in patients receiving intravenous bepridil 4 mg/kg) result in attenuation of anginal symptoms. There is evidence that bepridil permits an increase in workload while preserving left ventricular function; patients with ischaemic heart disease have experienced a slight exercise-related increase in ejection fraction (from 60 to 62%) during bepridil therapy compared to a reduction (from 60 to 55%) with placebo.

The negative chronotropic effect of bepridil is thought to be due at least in part to a direct effect of the drug on the sinus node. Experiments in animals and humans have shown that intravenous bepridil increases coronary blood flow, decreases heart rate, and increases Wenckebach periodicity by 16 to 20% in the anterograde and 23 to 26% in the retrograde direction in humans. Bepridil also prolongs the functional and effective refractory periods of atrial myocardium, atrio-ventricular node, His-Purkinje system and right ventricular myocardium.

Preliminary animal findings suggest that bepridil may protect against calcium overload during myocardial ischaemia and reperfusion.

Pharmacokinetic Properties

Although bepridil is virtually completely absorbed from the gastrointestinal tract following oral administration, first pass hepatic metabolism reduces its systemic bioavailability to approximately 60%. Peak steady-state plasma bepridil concentrations of 1.0 to 1.5 mg/L (Cmax) occurred in healthy volunteers receiving oral bepridil 300 mg/day. Cmax was observed after approximately 2 hours (tmax), and tmax was increased about 2-fold when bepridil was administered after food, but the extent of absorption (≈ 100%) was unaltered. Bepridil has a distribution half-life of approximately 2 hours and an apparent volume of distribution of 8 L/kg. Bepridil undergoes extensive hepatic biotransformation, with <0.1% of the parent drug being recovered unchanged in the urine and about 1% in the faeces. At least 17 metabolites of bepridil have been identified, only 1 of which retains pharmacological activity. These metabolites are primarily excreted via the urine. The elimination half-life in healthy volunteers ranges from 1 to 2 days following a single oral 300mg dose, and during maintenance therapy.

In elderly patients, Cmax was increased 3-fold and the elimination half-life increased more than 2-fold compared with values estimated for younger volunteers. Reduced bepridil clearance has been observed in patients with renal or hepatic impairment, and in patients with coronary artery disease.

Therapeutic Efficacy

Bepridil in doses of 200 to 400 mg/day is beneficial in alleviating symptoms of stable angina. Bepridil 200 to 450 mg/day significantly increased total exercise duration, time to onset of angina and time to 1mm ST-segment depression by up to 41, 57 and 43%, respectively, compared with placebo. Furthermore, anginal attack frequency and nitroglycerin (glyceryl trinitrate) consumption decreased by approximately 40 to 80%, and these benefits were maintained for up to 2 years on long term therapy. Results from a limited number of comparative studies indicate that bepridil 400 mg/day is at least as effective as propranolol 220 mg/day, and the combination of bepridil 200 to 400 mg/day plus propranolol 160 to 240 mg/day has proved effective in patients inadequately controlled with propranolol alone. Bepridil has proved as effective as nifedipine, verapamil, nadolol and diltiazem in controlling anginal symptoms, and superior to nifedipine in improving exercise performance. While bepridil has been shown to be more effective than diltiazem in improving exercise performance in patients with stable angina refactory to diltiazem, further comparative trials are required to confirm the efficacy of bepridil in the treatment of patients refractory to other antianginal agents.

Tolerability

Bepridil in doses of up to 400 mg/day has been well tolerated in clinical trials, the most frequently reported adverse effects being gastrointestinal symptoms such as dyspepsia, nausea and diarrhoea, and neurological symptoms such as dizziness and tremor.

Numerous cases of torsade de pointes have been documented since the introduction of bepridil into clinical practice. Proarrhythmic risk factors include bradycardia, excessive prolongation of the QT interval, low serum potassium levels and, possibly, accumulation of bepridil. Since the introduction of more detailed guidelines regarding ECG and serum potassium monitoring, and the use of co-medications, the incidence of bepridil-induced torsade de pointes has declined to about 0.01%. Bepridil has been used safely in conjunction with both short- and long-acting nitrates, anticoagulants, aspirin, oral hypoglycaemics or β-blockers in patients with relatively well-preserved cardiac function. The safety of bepridil plus β-blockers in patients with impaired ventricular function or cardiac conduction abnormalities remains to be fully assessed.

Dosage and Administration

The recommended starting dose and usual maintenance dose of orally administered bepridil is 300 mg/day, and the maximum permitted dose is 400 mg/day. In elderly patients and those with hepatic or renal impairment, the recommended starting dose and usual maintenance dose is 200 mg/day, while the maximum permitted dose in these patients is 300 mg/day. The long elimination half-life of bepridil allows for once daily dosing. Due to their increased risk of ventricular arrhythmias with the drug, elderly patients and those with renal or hepatic impairment should be monitored frequently and dosage adjustments should be performed as necessary.

Various sections of the manuscript reviewed by: P. Jaillon, Unité de Pharmacologie Clinique, Hôpital Saint-Antoine, Paris, France; D. Jewitt, Cardiac Department, King’s College Hospital, University of London, London, England; A. Millaire, Hôpital Cardiologique, Centre Hospitalier Régional et Universitaire de Lille, Lille, France; K.A. Narahara, Division of Cardiology, Harbor-UCLA Medical Center, Torrance, California, USA; F. Nielsen-Kudsk, Institute of Pharmacology, University of Aarhus, Aarhus, Denmark; A.P. Rae, Department of Medical Cardiology, Royal Infirmary, Glasgow, Scotland; C. Schmitt, Department of Internal Medicine, University of Heidelberg, Heidelberg, Federal Republic of Germany; B. Surawicz, Department of Medicine, Krannert Institute of Cardiology, Indiana University, Indianapolis, Indiana, USA; M. Thomas, Cardiac Department, King’s College Hospital, University of London, London, England; J. Zaagsma, University Centre for Pharmacy, University of Groningen, Groningen, The Netherlands.