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

Abstract

Royal Hallamshire Hospital, Sheffield S10 2JF1 The pharmacokinetics and pharmacodynamics of oral verapamil and propranolol were studied in patients with stable angina pectoris during chronic mono-and dual therapy. 2 The peak plasma concentrations (Cmax) and areas under the plasma concentrationtime curves (AUC) of verapamil were similar during combined treatment with propranolol (mean ± s.d.: Cmax = 491 ± 397 ng ml-'; AUC = 2075 ± 1524 ng ml-' h) or atenolol (mean + s.d.: Cmax = 372 ± 320 ng ml-'; AUC = 1985 ± 1660 ng ml-' h).3 No differences in Cmax and AUC were observed during verapamil monotherapy (mean + s.d.: Cmax = 287 ± 105 ng ml-'; AUC = 1375 ± 455 ng ml-' h) vs combined treatment with propranolol (mean ± s.d.: Cmax = 312 ± 55 ng ml-'; AUC = 1566 ± 486 ng ml-' h).4 Treatment with verapamil increased the Cmax (mean ± s.d.: 227 ± 117 vs 116 ± 62 ng ml-', P < 0.05) and AUC (1389 ± 617 vs 837 ± 316 ng ml-' h, P = 0.0625) of propranolol in all subjects. 5 Transient atrioventricular dissociation occurred in two patients 2 h after dosing with verapamil and propranolol or atenolol.6 Close observation of patients is essential when 13-adrenoceptor antagonists and verapamil are used together.

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

“…There may in fact be no interaction; although the relatively small sample size raises the possibility of a Type II statistical error, inhibition of drug metabolism has been observed in populations of the same size (Bax et al, 1985). As has been argued previously (McGourty et al, 1988), the lack of pharmacokinetic interaction may reflect the specificity of the individual isoenzymes of cytochrome P-450, while the capacity of propranolol and verapamil to displace each other from plasma proteins may disguise mutual interference with metabolism. This work was carried out in young healthy males where drug influences on heart rate and cardiac conductivity may be more marked than in patients who have age-related changes in adrenergic tone and sinus automaticity (Dauchot & Gravenstein, 1971); increased sensitivity to both verapamil (Abernethy et al, 1986) and propranolol (Vestal et al, 1979) has been demonstrated in younger age groups.…”

“…No interaction was reported after repeated doses of verapamil, propranolol, metoprolol and atenolol in normals (Warrington et al, 1984) or between verapamil and atenolol in patients with angina (Findlay et al, 1987;Keech et al, 1986). However, increased plasma concentrations of the lipid-soluble ,3-adrenoceptor antagonists metoprolol (Keech et al, 1986;McLean et al, 1985) and propranolol (McGourty et al, 1988) were noted after repeated dosing in combination with verapamil. These studies did not allow investigation of mechanisms or of possible pharmacodynamic consequences.…”

“…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.…”

Heart insufficiency after combination of verapamil and metoprolol: A fatal case report and literature review

“…Worsening of myocardial function, such as hypotension, bradycardia, and AV block, might be expected to occur more often with combination therapy rather than therapy with either drug alone . Some authors found that cardiac risk increases by left ventricular dysfunction, aortic stenosis, low‐pulse rate, or large doses of either drug ; however, other authors describe cases in which the ventricular function was normal or near normal and incidents have often occurred at normal doses of both drugs (Table ) …”

Poisoning Due to Calcium Antagonists

“…Although verapamil may elevate serum concentrations of propranolol (McGourty et al 1988) and increase gastrointestinal absorption and decrease renal clearance of atenolol, no clinically relevant pharmacokinetic interaction has been demonstrated between calcium antagonists and ~-blockers (Kirch et al 1990). However, significant pharmacodynamic effects are common during combination therapy with ~-blockers and calcium entry blockers, particularly verapamil (Carruthers et al 1989;Packer et al 1982;Wayne 1983).…”