Pharmacokinetics and pharmacodynamics of verapamil in combination with atenolol, metoprolol and propranolol.

Abstract

Treatment of angina pectoris with beta‐adrenoceptor antagonists and verapamil in combination is effective and increasingly common. The study reported here was designed to show whether the pharmacokinetics of verapamil are influenced by concurrent treatment with three different beta‐adrenoceptor blockers, and whether there is any pharmacodynamic interaction between these drugs. Twelve healthy volunteers (eight men, four women) aged 21‐25 years and weighing 48‐82 kg consented to participate in the study. They received verapamil 50 mg three times daily for four 1‐week periods, each separated by a 1 week ‘washout’ period. During three of the four treatment periods, the subjects took either atenolol 100 mg once daily, metoprolol 100 mg twice daily or propranolol 80 mg twice daily; in the remaining period they took verapamil alone. The concentration/time curve and plasma elimination half‐life of verapamil and norverapamil, its major metabolite, were not influenced by 1 weeks co‐administration atenolol, metoprolol or propranolol. As expected, co‐administration of each of the beta‐adrenoceptor blockers significantly reduced exercise heart rate when compared with verapamil alone.

The effect of combined therapy on the pharmacokinetics and pharmacodynamics of verapamil and propranolol in patients with angina pectoris.

“…As in studies with healthy volunteers (Warrington et al, 1984;Maclnnes et al, 1985Maclnnes et al, , 1986 we did not observe significant differences in the pharmacokinetics of verapamil during 1) combined treatment with propranolol compared with that with atenolol or 2) when verapamil was given alone compared with combined treatment with propranolol, in patients with stable angina pectoris. Confidence intervals for these data are wide ( Table 1) and proof of no effect of 3adrenoceptor treatment would require a study with larger numbers of subjects.…”

“…Recent studies have not detected any pharmacokinetic interaction between verapamil and 3-adrenoceptor antagonists (Warrington et al, 1984: McInnes et al, 1985. However, these investigations involved the administration of single and sub-therapeutic doses of the drugs to young, healthy volunteers.…”

“…Furthermore, there is strong evidence that verapamil inhibits its own metabolism (Schwartz et al, 1985) and also that of antipyrine (Bach et al, 1986;Rumiantsev et al, 1986), quinidine (Edwards et al, 1987), carbamazepine (MacPhee et al, 1986) and cyclosporin (Lindholm & Henricsson, 1987 (Warrington et al, 1984: McInnes et al, 1985 The aim of this study was to investigate the effect of propranolol on the pharmacokinetics and pharmacodynamics of verapamil.…”

??-Blockers Drug Interactions of Clinical Significance

“…[28,29] In terms of pharmacokinetic interactions, there are conflicting reports. Warrington et al [30] reported no interaction of verapamil in combination with atenolol, metoprolol or propranolol. However, other investigators[31] have noted that blood concentrations of propranolol and metoprolol,[32] and the area under the plasma concentration-time curve (AUC) of atenolol are increased with the concurrent use of verapamiJ.l33] Propranolol decreased When combined with a ~-blocker, ACE inhibitors can cause hypotension, especially in the setting of acute myocardial infarction.…”

Evaluation of potential pharmacodynamic and pharmacokinetic interactions between verapamil and propranolol in normal subjects.

“…Furthermore, each has been reported to alter hepatic blood flow (Meredith et al, 1985;Price et al, 1967), an action which could alter the bioavailability and clearance of the other (McLean et al, 1978;Wilkinson & Shand, 1975). Increased bioavailability of metoprolol (Keech et al, 1986) and propranolol (McGourty et al, 1988) has been reported after addition of verapamil although the pharmacokinetics of oral verapamil do not appear to be altered by co-administration of P-adrenoceptor antagonists (McGourty et al, 1988;Warrington et al, 1984). However, the designs of these studies did not allow an adequate description of the putative drug interaction.…”