DRUG EVALUATION
Drugs 44 (5): 835-85 7, 1992 0012-6667/92/ 0011-0835/$11.50/ 0 © Adis International Limited. All rights reserved. DREl142
Bepridil
A Review of its Pharmacological Properties and Therapeutic Use in Stable Angina Pectoris Lisa M. Hollingshead, Diana Faulds and Andrew Fitton Adis International Limited, Auckland, New Zealand
Various sections of the manuscript reviewed by: P. Jaillon, Unite de Pharmacologie Clinique, H6pital SaintAntoine, Paris, France; D. Jewitt, Cardiac Department, King's College Hospital, University of London, London, England; A. Millaire, H6pital Cardiologique, Centre Hospitalier Regional et Universitaire de Lille, Lille, France; K.A. Narahara, Division of Cardiology, Harbor-UCLA Medical Center, Torrance, California, USA; F. NielsenKudsk, 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.
Contents 836 838 838 839 839 840 842 842 843 844 845 845 846 847 847 847 849 849 850 850 852 853 853 853
Summary I. Pharmacodynamic Properties 1.I Cellular Effects 1.2 Haemodynamic Effects 1.2.1 Effects in Animals 1.2.2 Effects in Humans 1.3 Electrophysiological Effects 1.3.1 Effects in Animals \.3.2 Effects in Humans 1.4 Anti-Ischaemic Effects in Animals 2. Pharmacokinetic Properties 2.1 Absorption and Distribution 2.2 Metabolism and Elimination 2.3 Effects of Age and Disease on Pharmacokinetic Properties 3. Therapeutic Use in Stable Angina 3.1 Placebo-Controlled Studies 3.2 Comparative Studies 3.2.1 Comparisons with {3-Blockers 3.2.2 Comparisons with Other Calcium Antagonists 4. Tolerability 5. Drug Interactions 6. Dosage and Administration 6.1 Overdosage 7. Place of Bepridil in Therapy
Drugs 44 (5) 1992
836
Summary 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 oftorsade 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 ofpatients 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, atrioventricular 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 (C max ) occurred
Bepridil: A Review
837
in healthy volunteers receiving oral bepridil.300 mgjday. Cmax was observed after approximately 2 hours (tmax ), and t max 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 Ljkg. Bepridil undergoes extensive hepatic biotransformation, with diltiazem > verapamil. Each agent slowed conduction in the atrioventricular node, increased the atrioventricular nodal refractory period and increased Wenckebach cycle length with the following order of activity: verapamil » diltiazem > bepridil. Cosnier et al. (1977) also observed a decrease in heart rate in dogs with intact or denervated hearts administered bepridil 2.5 mg/kg, accompanied by an increase in coronary sinus blood flow and partial pressure of oxygen in venous blood (pV02). In the unanesthetised dog with chronic heart block, bepridil 1.25 to 5 mg/kg induced a significant initial acceleration in atrial and ventricular rhythm followed by atrial and ventricular bradycardia. As the dose of bepridil was increased from 1.25 to 5 mg/kg bradycardia diminished and was insignificant at the highest dose (Boucher & Duchene-Marullaz 1978). In conscious dogs, heart rate initially increased significantly following administration ofbepridil or diltiazem (by 18 and 27 beats/ min, respectively). Verapamil only slightly elevated heart rate. The positive chronotropic responses were reversed to bradycardia only by diltiazem, and all 3 agents produced negative dromotropic responses (Kantelip et al. 1986). It was concluded that their effects resulted from a reflexmediated increase in sympathetic tone secondary to afterload reduction, followed by a direct depressant action on sinoatrial and atrioventricular nodal conduction (Kantelip et al. 1986). 1.3.2 Effects in Humans The electrophysiological effects of intravenous and oral bepridil (2 to 3 mg/kg over 1 to 15 minutes and 200 to 600 mg/day, respectively) have been investigated in several studies in healthy human volunteers and patients with angina, known or suspected cardiac arrhythmias, and those undergoing endocavitary exploration for various reasons (n =
843
7 to 86) [Duchene- Marullaz et al. 1983; Flammang et al. 1983; Funck-Brentano et al. 1990; Hill & Pepine 1984; Ponsonnaille et al. 1982; Rowland et al. 1985; Singh 1991; Singh et al. 1985; Upward et al. 1985). Although bepridil is primarily a calcium channel blocker with class IV electrophysiological activity, it also displays class I activity, and for this reason cannot be considered either a typical class I or class IV agent. Within class I, bepridil approximates most closely to a class Ia agent, although it has minimal effect on the QRS and HV intervals (Prystowsky 1992) [table I]. When administered to healthy volunteers at incremental doses ranging from 200 to 600 mg/day for 12 days, oral bepridil produced dose-proportional reductions in resting (Duchene-Marullaz et a1.1983) and exercise (Montluc et al. 1984) heart rates. The resting QTc interval was prolonged (5 to 15%) on repeated administration ofbepridil200 to 600 mg/day (Duchene-Marullaz et al. 1983; Lecocq et al. 1990), with the effect being most pronounced at low heart rates, and some repolarisation changes were observed, including a double humped or flattened T-wave or an increase in Uwave amplitude (Duchene-Marullaz et al. 1983). Bepridil 200 to 500 mg/day significantly prolonged the QTc interval by a mean of 17 to 35 msec compared with baseline in patients with stable angina pectoris (Funck-Brentano et al. 1990; Singh 199'1). The effects of bepridil on QT duration were slightly more pronounced in bradycardic patients than in those with higher heart rates, and prolongation of QTc interval was inversely proportional to baseline QTc (Funck-Brentano et al. 1990). This rate-dependent enhancement of QT interval could explain the higher incidence of bepridil-induced torsade de pointes in bradycardic patients. When administered intravenously, bepridil 2 or 3 mg/kg significantly prolonged sinus cycle length (9.2%) and slowed atrioventricular node conduction (15%); Wenckeback cycle length was significantly increased in the anterograde direction (16 to 20%) and, to a greater degree, in the retrograde direction (23 to 26%) [Flammang et al. 1983; Ponsonnaille et al. 1983]. Unlike most calcium
Drugs 44 (5) 1992
844
Table I. Summary of the clinical electrophysiological effects of calcium channel blockers (adapted from Nademanee & Singh 1988) Electrophysiological parameter
Bepridil
Verapamil
Nifedipine
Diltiazem
RR interval aRS interval aTc interval PR interval AH interval HV interval Atrial ERP AV node ERP Ventricular FRP His-Purkinje ERP Bypass tract ERP Ventricular automaticity
t t t t t t t tt tt t t
0 0 0
o
o
o
o
t
+
AV
ttt
0 0
ttt
0 0
±
0
o
o o o
tt o o tt
±
o o o o
o o ±
o = variable effect; 0 = no change;
t = slight increase; tt = moderate increase; ttt = large increase; ± = atrioventricular; ERP = effective refractory period; FRP = functional refractory period.
Symbols and abbreviations:
+= slight decrease;
tt
channel blockers, bepridil increased the effective and functional refractory periods of the right atrium (15 and 14%, respectively), His-Purkinje system (15%) and right ventricle (10 and 11%) in addition to those of the atrioventricular node (13 and 12%) [Ponsonnaille et al. 1982]. 1.4 Anti-Ischaemic Effects in Animals In common with other calcium channel blockers, bepridil preserves cardiac cell viability against calcium injury under anoxic conditions. At very low concentrations « 100 nmolfL) bepridil restored the cellular ATP content and viability ofhypoxic rat ventricular myocytes (Cruz et al. 1987). Bepridil may attenuate ATP depletion in anoxic cells by inhibiting ATP-dependent calcium entry into the mitochondrion. Bepridil has been shown to have a protective effect against veratrine-induced contraction (Lebouef et al. 1992) and ouabain-induced calcium overload (Wilhelm et al. 1990) in the rat atrium. Calcium antagonists such as verapamil, nifedipine and diltiazem have proved beneficial in decreasing damage caused by ischaemia and reperfusion in various experimental models of myocardial ischaemia. These effects are believed to
be due to inhibition of transmembrane calcium influx, thereby reducing ATP depletion and intracellular calcium overload (Hugtenburg et al. 1989). The cardioprotective effects of bepridil were compared with those of other calcium antagonists in the guinea-pig working heart, with respect to cardiac function and high energy phosphate content after 45 minutes of global ischaemia and 25 minutes of reperfusion. All the calcium antagonists produced a negative inotropic effect resulting in a decrease in aortic pressure and cardiac output, and recovery of contractile function after global ischaemia and reperfusion was improved to between 60 and 80% of values in normotoxic. hearts. However, there was no direct relationship between the beneficial effects of bepridil and the other calcium antagonists on contractile activity and their effects on levels of high energy phosphates after ischaemia and reperfusion (Hugtenburg et al. 1989). Other studies demonstrating the cardioprotective effects of bepridil have been performed in rats, dogs, isolated rat myocardium and isolated guinea-pig hearts (Boddeke et al. 1988; Hanaki et al. 1989; Huizer et al. 1987; Lynch et al. 1985; Reifart et al. 1986; Shikano et al. 1986; van Amsterdam et al. 1990a,b; Watts et al. 1987); In the isolated, perfused rat heart, Huizer et al (1987)
Bepridil: A Review
demonstrated that bepridil dose dependently prevented ATP breakdown during ischaemia followed by reperfusion. This was thought to be due to the negative inotropic action of bepridil prior to ischaemia. Guo and Tang (1990) suggested that bepridil protects against myocardial injury during ischaemia/reperfusion via a calmodulin antagonistic action as well as a calcium channel blocking effect. This study also demonstrated the superiority of bepridil over propranolol in protecting against myocardial injury. Calcium antagonists have recently been shown to offer two modes of protection against ischaemic myocardial injury: a negative inotropic, energysaving action conferring protection during ischaemia, and a vasodilatory action, accounting for myocardial recovery during reperfusion. Thus, in the isolated perfused rat heart calcium channel blockers delayed and reduced the development of ischaemic end-diastolic contracture and accelerated recovery of diastolic function during reperfusion (van Amterdam et al. 1990a). In common with other vasoselective calcium channel blockers, bepridil (0.03 to 3 ,.,.molfL) selectively accelerated recovery of ischaemia-induced end-diastolic contracture during reperfusion at concentrations devoid of negative inotropic activity, suggesting that this cardioprotective effect is due to its potent coronary vasodilatory action (van Amsterdam et al. 1990a). The enantiomers of bepridil also showed the same pattern of protection in this model of ischaemic injury (van Amsterdam et al. 1990b). Bepridil has been reported to offer protection against the early ventricular arrhythmias ensuing after acute coronary artery occlusion in anaesthetised animals (Kane & Winslow 1980; Marshall & Muir 1981). Possible mechanisms underlying this action include blockade of sodium channels in ischaemic myocardium, improvement of conduction in re-entrant pathways, preservation of cell integrity in the ischaemic zone, and preservation of blood flow in the area supplied by the infarcted artery (Marshall 1985). Bepridil also protects against reperfusion-induced ventricular tachycardia/fibrillation in the isolated perfused rat heart (Winslow et al. 1983) as well as in the anaesthetised rat, cat
845
and dog (Jackson et al. 1985: Kane et al. 1984; Marshall 1985). In humans, bepridil (2 mg/kg intravenously; 500 to 800 mg/day orally) offered protection against spontaneous (Fauchier et al. 1983; Jullien et al. 1983) and electrically induced (Levy 1983) ventricular arrhythmias associated with myocardial ischaemia, an effect most probably due to its ability to block sodium channels and prolong ventricular refractoriness (Ponsonnaille et al. 1982; Valere et al. 1982).
2. Pharmacokinetic Properties The pharmacokinetic properties of bepridil have been investigated in healthy volunteers and, to a limited extent, in the elderly and in patients with coronary disease, or renal or hepatic dysfunction (table II). Plasma and urinary concentrations of bepridil have been assayed by high performance liquid chromatography (detection limit 10 ,.,.g/L) [Ng et al. 1984] and capillary gas chromatography with nitrogen-phosphorus ionisation detection (detection limit 1 ,.,.g/L) [Holland & Ng 1986]. 2.1 Absorption and Distribution Bepridil is essentially 100% absorbed from the gastrointestinal tract following oral administration, but hepatic first pass metabolism reduces its systemic bioavailability in healthy volunteers to approximately 60%. Maximum plasma bepridil concentrations (C max ) were observed about 2 hours after an oral dose; the time to Cmax was increased about 2-fold when bepridil was administered immediately after a meal, but the extent of absorption was not significantly altered. Plasma bepridil concentrations were linearly related to dose over the therapeutic range (200 to 400 mg/day) with Cmax values of approximately 1.0 to 1.5 mg/L (mean 1.27 mg/L) at steady-state in 11 volunteers receiving bepridil 300 mg/day (Benet 1985). Bepridil is rapidly distributed to body tissues and fluids with a distribution half-life of about 2 hours and an apparent volume of distribution (Vd) of 8 L/kg, probably due in part to its high lipid solubility. The drug is more than 99% bound to
846
Drugs 44 (5) 1992
Table II. Summary of pharmacokinetic parameters of standard formulations of representative calcium antagonists in healthy volunteers (after Benet 1985; Buckley et al. 1990; McTavish & Sorkin 1989; Sorkin et a!. 1985; Wu et al. 1992) Bepridil
Dilitazem
Nifedipine
Verapamil
Oral bioavailability ("!o)
59
30-40
45-68
19
Clearance (ml/min/kg) [IV dose]
5.3
10-20
10.3
11.8
Decrease in clearance on multiple dosing
2-fold
2.4-fold
Not stated
2-2.5-fold
Elimination half-life (h) [single oral dose]
33-48
4.5
2-118
4.8
Urinary clearance of unchanged drug ("!o)
Drugs 44 (5): 835-85 7, 1992 0012-6667/92/ 0011-0835/$11.50/ 0 © Adis International Limited. All rights reserved. DREl142
Bepridil
A Review of its Pharmacological Properties and Therapeutic Use in Stable Angina Pectoris Lisa M. Hollingshead, Diana Faulds and Andrew Fitton Adis International Limited, Auckland, New Zealand
Various sections of the manuscript reviewed by: P. Jaillon, Unite de Pharmacologie Clinique, H6pital SaintAntoine, Paris, France; D. Jewitt, Cardiac Department, King's College Hospital, University of London, London, England; A. Millaire, H6pital Cardiologique, Centre Hospitalier Regional et Universitaire de Lille, Lille, France; K.A. Narahara, Division of Cardiology, Harbor-UCLA Medical Center, Torrance, California, USA; F. NielsenKudsk, 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.
Contents 836 838 838 839 839 840 842 842 843 844 845 845 846 847 847 847 849 849 850 850 852 853 853 853
Summary I. Pharmacodynamic Properties 1.I Cellular Effects 1.2 Haemodynamic Effects 1.2.1 Effects in Animals 1.2.2 Effects in Humans 1.3 Electrophysiological Effects 1.3.1 Effects in Animals \.3.2 Effects in Humans 1.4 Anti-Ischaemic Effects in Animals 2. Pharmacokinetic Properties 2.1 Absorption and Distribution 2.2 Metabolism and Elimination 2.3 Effects of Age and Disease on Pharmacokinetic Properties 3. Therapeutic Use in Stable Angina 3.1 Placebo-Controlled Studies 3.2 Comparative Studies 3.2.1 Comparisons with {3-Blockers 3.2.2 Comparisons with Other Calcium Antagonists 4. Tolerability 5. Drug Interactions 6. Dosage and Administration 6.1 Overdosage 7. Place of Bepridil in Therapy
Drugs 44 (5) 1992
836
Summary 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 oftorsade 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 ofpatients 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, atrioventricular 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 (C max ) occurred
Bepridil: A Review
837
in healthy volunteers receiving oral bepridil.300 mgjday. Cmax was observed after approximately 2 hours (tmax ), and t max 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 Ljkg. Bepridil undergoes extensive hepatic biotransformation, with diltiazem > verapamil. Each agent slowed conduction in the atrioventricular node, increased the atrioventricular nodal refractory period and increased Wenckebach cycle length with the following order of activity: verapamil » diltiazem > bepridil. Cosnier et al. (1977) also observed a decrease in heart rate in dogs with intact or denervated hearts administered bepridil 2.5 mg/kg, accompanied by an increase in coronary sinus blood flow and partial pressure of oxygen in venous blood (pV02). In the unanesthetised dog with chronic heart block, bepridil 1.25 to 5 mg/kg induced a significant initial acceleration in atrial and ventricular rhythm followed by atrial and ventricular bradycardia. As the dose of bepridil was increased from 1.25 to 5 mg/kg bradycardia diminished and was insignificant at the highest dose (Boucher & Duchene-Marullaz 1978). In conscious dogs, heart rate initially increased significantly following administration ofbepridil or diltiazem (by 18 and 27 beats/ min, respectively). Verapamil only slightly elevated heart rate. The positive chronotropic responses were reversed to bradycardia only by diltiazem, and all 3 agents produced negative dromotropic responses (Kantelip et al. 1986). It was concluded that their effects resulted from a reflexmediated increase in sympathetic tone secondary to afterload reduction, followed by a direct depressant action on sinoatrial and atrioventricular nodal conduction (Kantelip et al. 1986). 1.3.2 Effects in Humans The electrophysiological effects of intravenous and oral bepridil (2 to 3 mg/kg over 1 to 15 minutes and 200 to 600 mg/day, respectively) have been investigated in several studies in healthy human volunteers and patients with angina, known or suspected cardiac arrhythmias, and those undergoing endocavitary exploration for various reasons (n =
843
7 to 86) [Duchene- Marullaz et al. 1983; Flammang et al. 1983; Funck-Brentano et al. 1990; Hill & Pepine 1984; Ponsonnaille et al. 1982; Rowland et al. 1985; Singh 1991; Singh et al. 1985; Upward et al. 1985). Although bepridil is primarily a calcium channel blocker with class IV electrophysiological activity, it also displays class I activity, and for this reason cannot be considered either a typical class I or class IV agent. Within class I, bepridil approximates most closely to a class Ia agent, although it has minimal effect on the QRS and HV intervals (Prystowsky 1992) [table I]. When administered to healthy volunteers at incremental doses ranging from 200 to 600 mg/day for 12 days, oral bepridil produced dose-proportional reductions in resting (Duchene-Marullaz et a1.1983) and exercise (Montluc et al. 1984) heart rates. The resting QTc interval was prolonged (5 to 15%) on repeated administration ofbepridil200 to 600 mg/day (Duchene-Marullaz et al. 1983; Lecocq et al. 1990), with the effect being most pronounced at low heart rates, and some repolarisation changes were observed, including a double humped or flattened T-wave or an increase in Uwave amplitude (Duchene-Marullaz et al. 1983). Bepridil 200 to 500 mg/day significantly prolonged the QTc interval by a mean of 17 to 35 msec compared with baseline in patients with stable angina pectoris (Funck-Brentano et al. 1990; Singh 199'1). The effects of bepridil on QT duration were slightly more pronounced in bradycardic patients than in those with higher heart rates, and prolongation of QTc interval was inversely proportional to baseline QTc (Funck-Brentano et al. 1990). This rate-dependent enhancement of QT interval could explain the higher incidence of bepridil-induced torsade de pointes in bradycardic patients. When administered intravenously, bepridil 2 or 3 mg/kg significantly prolonged sinus cycle length (9.2%) and slowed atrioventricular node conduction (15%); Wenckeback cycle length was significantly increased in the anterograde direction (16 to 20%) and, to a greater degree, in the retrograde direction (23 to 26%) [Flammang et al. 1983; Ponsonnaille et al. 1983]. Unlike most calcium
Drugs 44 (5) 1992
844
Table I. Summary of the clinical electrophysiological effects of calcium channel blockers (adapted from Nademanee & Singh 1988) Electrophysiological parameter
Bepridil
Verapamil
Nifedipine
Diltiazem
RR interval aRS interval aTc interval PR interval AH interval HV interval Atrial ERP AV node ERP Ventricular FRP His-Purkinje ERP Bypass tract ERP Ventricular automaticity
t t t t t t t tt tt t t
0 0 0
o
o
o
o
t
+
AV
ttt
0 0
ttt
0 0
±
0
o
o o o
tt o o tt
±
o o o o
o o ±
o = variable effect; 0 = no change;
t = slight increase; tt = moderate increase; ttt = large increase; ± = atrioventricular; ERP = effective refractory period; FRP = functional refractory period.
Symbols and abbreviations:
+= slight decrease;
tt
channel blockers, bepridil increased the effective and functional refractory periods of the right atrium (15 and 14%, respectively), His-Purkinje system (15%) and right ventricle (10 and 11%) in addition to those of the atrioventricular node (13 and 12%) [Ponsonnaille et al. 1982]. 1.4 Anti-Ischaemic Effects in Animals In common with other calcium channel blockers, bepridil preserves cardiac cell viability against calcium injury under anoxic conditions. At very low concentrations « 100 nmolfL) bepridil restored the cellular ATP content and viability ofhypoxic rat ventricular myocytes (Cruz et al. 1987). Bepridil may attenuate ATP depletion in anoxic cells by inhibiting ATP-dependent calcium entry into the mitochondrion. Bepridil has been shown to have a protective effect against veratrine-induced contraction (Lebouef et al. 1992) and ouabain-induced calcium overload (Wilhelm et al. 1990) in the rat atrium. Calcium antagonists such as verapamil, nifedipine and diltiazem have proved beneficial in decreasing damage caused by ischaemia and reperfusion in various experimental models of myocardial ischaemia. These effects are believed to
be due to inhibition of transmembrane calcium influx, thereby reducing ATP depletion and intracellular calcium overload (Hugtenburg et al. 1989). The cardioprotective effects of bepridil were compared with those of other calcium antagonists in the guinea-pig working heart, with respect to cardiac function and high energy phosphate content after 45 minutes of global ischaemia and 25 minutes of reperfusion. All the calcium antagonists produced a negative inotropic effect resulting in a decrease in aortic pressure and cardiac output, and recovery of contractile function after global ischaemia and reperfusion was improved to between 60 and 80% of values in normotoxic. hearts. However, there was no direct relationship between the beneficial effects of bepridil and the other calcium antagonists on contractile activity and their effects on levels of high energy phosphates after ischaemia and reperfusion (Hugtenburg et al. 1989). Other studies demonstrating the cardioprotective effects of bepridil have been performed in rats, dogs, isolated rat myocardium and isolated guinea-pig hearts (Boddeke et al. 1988; Hanaki et al. 1989; Huizer et al. 1987; Lynch et al. 1985; Reifart et al. 1986; Shikano et al. 1986; van Amsterdam et al. 1990a,b; Watts et al. 1987); In the isolated, perfused rat heart, Huizer et al (1987)
Bepridil: A Review
demonstrated that bepridil dose dependently prevented ATP breakdown during ischaemia followed by reperfusion. This was thought to be due to the negative inotropic action of bepridil prior to ischaemia. Guo and Tang (1990) suggested that bepridil protects against myocardial injury during ischaemia/reperfusion via a calmodulin antagonistic action as well as a calcium channel blocking effect. This study also demonstrated the superiority of bepridil over propranolol in protecting against myocardial injury. Calcium antagonists have recently been shown to offer two modes of protection against ischaemic myocardial injury: a negative inotropic, energysaving action conferring protection during ischaemia, and a vasodilatory action, accounting for myocardial recovery during reperfusion. Thus, in the isolated perfused rat heart calcium channel blockers delayed and reduced the development of ischaemic end-diastolic contracture and accelerated recovery of diastolic function during reperfusion (van Amterdam et al. 1990a). In common with other vasoselective calcium channel blockers, bepridil (0.03 to 3 ,.,.molfL) selectively accelerated recovery of ischaemia-induced end-diastolic contracture during reperfusion at concentrations devoid of negative inotropic activity, suggesting that this cardioprotective effect is due to its potent coronary vasodilatory action (van Amsterdam et al. 1990a). The enantiomers of bepridil also showed the same pattern of protection in this model of ischaemic injury (van Amsterdam et al. 1990b). Bepridil has been reported to offer protection against the early ventricular arrhythmias ensuing after acute coronary artery occlusion in anaesthetised animals (Kane & Winslow 1980; Marshall & Muir 1981). Possible mechanisms underlying this action include blockade of sodium channels in ischaemic myocardium, improvement of conduction in re-entrant pathways, preservation of cell integrity in the ischaemic zone, and preservation of blood flow in the area supplied by the infarcted artery (Marshall 1985). Bepridil also protects against reperfusion-induced ventricular tachycardia/fibrillation in the isolated perfused rat heart (Winslow et al. 1983) as well as in the anaesthetised rat, cat
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and dog (Jackson et al. 1985: Kane et al. 1984; Marshall 1985). In humans, bepridil (2 mg/kg intravenously; 500 to 800 mg/day orally) offered protection against spontaneous (Fauchier et al. 1983; Jullien et al. 1983) and electrically induced (Levy 1983) ventricular arrhythmias associated with myocardial ischaemia, an effect most probably due to its ability to block sodium channels and prolong ventricular refractoriness (Ponsonnaille et al. 1982; Valere et al. 1982).
2. Pharmacokinetic Properties The pharmacokinetic properties of bepridil have been investigated in healthy volunteers and, to a limited extent, in the elderly and in patients with coronary disease, or renal or hepatic dysfunction (table II). Plasma and urinary concentrations of bepridil have been assayed by high performance liquid chromatography (detection limit 10 ,.,.g/L) [Ng et al. 1984] and capillary gas chromatography with nitrogen-phosphorus ionisation detection (detection limit 1 ,.,.g/L) [Holland & Ng 1986]. 2.1 Absorption and Distribution Bepridil is essentially 100% absorbed from the gastrointestinal tract following oral administration, but hepatic first pass metabolism reduces its systemic bioavailability in healthy volunteers to approximately 60%. Maximum plasma bepridil concentrations (C max ) were observed about 2 hours after an oral dose; the time to Cmax was increased about 2-fold when bepridil was administered immediately after a meal, but the extent of absorption was not significantly altered. Plasma bepridil concentrations were linearly related to dose over the therapeutic range (200 to 400 mg/day) with Cmax values of approximately 1.0 to 1.5 mg/L (mean 1.27 mg/L) at steady-state in 11 volunteers receiving bepridil 300 mg/day (Benet 1985). Bepridil is rapidly distributed to body tissues and fluids with a distribution half-life of about 2 hours and an apparent volume of distribution (Vd) of 8 L/kg, probably due in part to its high lipid solubility. The drug is more than 99% bound to
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Drugs 44 (5) 1992
Table II. Summary of pharmacokinetic parameters of standard formulations of representative calcium antagonists in healthy volunteers (after Benet 1985; Buckley et al. 1990; McTavish & Sorkin 1989; Sorkin et a!. 1985; Wu et al. 1992) Bepridil
Dilitazem
Nifedipine
Verapamil
Oral bioavailability ("!o)
59
30-40
45-68
19
Clearance (ml/min/kg) [IV dose]
5.3
10-20
10.3
11.8
Decrease in clearance on multiple dosing
2-fold
2.4-fold
Not stated
2-2.5-fold
Elimination half-life (h) [single oral dose]
33-48
4.5
2-118
4.8
Urinary clearance of unchanged drug ("!o)
