Skip to main content
British Journal of Clinical Pharmacology logoLink to British Journal of Clinical Pharmacology
. 1988 Mar;25(3):349–357. doi: 10.1111/j.1365-2125.1988.tb03313.x

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

J C McCourty 1, J H Silas 1, G T Tucker 1, M S Lennard 1
PMCID: PMC1386359  PMID: 3358897

Abstract

1. 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 concentration-time curves (AUC) of verapamil were similar during combined treatment with propranolol (mean +/- s.d.: Cmax = 491 +/- 397 ng ml-1; AUC = 2075 +/- 1524 ng ml-1 h) or atenolol (mean +/- s.d.: Cmax = 372 +/- 320 ng ml-1; AUC = 1985 +/- 1660 ng ml-1 h). 3. No differences in Cmax and AUC were observed during verapamil monotherapy (mean +/- s.d.: Cmax = 287 +/- 105 ng ml-1; AUC = 1375 +/- 455 ng ml-1 h) vs combined treatment with propranolol (mean +/- s.d.: Cmax = 312 +/- 55 ng ml-1; AUC = 1566 +/- 486 ng ml-1 h). 4. Treatment with verapamil increased the Cmax (mean +/- s.d.: 227 +/- 117 vs 116 +/- 62 ng ml-1, P less than 0.05) and AUC (1389 +/- 617 vs 837 +/- 316 ng ml-1 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 beta-adrenoceptor antagonists and verapamil are used together.

Full text

PDF
349

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bach D., Blevins R., Kerner N., Rubenfire M., Edwards D. J. The effect of verapamil on antipyrine pharmacokinetics and metabolism in man. Br J Clin Pharmacol. 1986 Jun;21(6):655–659. doi: 10.1111/j.1365-2125.1986.tb05230.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bax N. D., Lennard M. S., Tucker G. T. Inhibition of antipyrine metabolism by beta-adrenoceptor antagonists. Br J Clin Pharmacol. 1981 Dec;12(6):779–784. doi: 10.1111/j.1365-2125.1981.tb01306.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Benaim M. E. Asystole after verapamil. Br Med J. 1972 Apr 15;2(5806):169–170. doi: 10.1136/bmj.2.5806.169-b. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Edwards D. J., Lavoie R., Beckman H., Blevins R., Rubenfire M. The effect of coadministration of verapamil on the pharmacokinetics and metabolism of quinidine. Clin Pharmacol Ther. 1987 Jan;41(1):68–73. doi: 10.1038/clpt.1987.11. [DOI] [PubMed] [Google Scholar]
  5. Eichelbaum M., Ende M., Remberg G., Schomerus M., Dengler H. J. The metabolism of DL-[14C]verapamil in man. Drug Metab Dispos. 1979 May-Jun;7(3):145–148. [PubMed] [Google Scholar]
  6. Freedman S. B., Richmond D. R., Ashley J. J., Kelly D. T. Verapamil kinetics in normal subjects and patients with coronary artery spasm. Clin Pharmacol Ther. 1981 Nov;30(5):644–652. doi: 10.1038/clpt.1981.216. [DOI] [PubMed] [Google Scholar]
  7. Harapat S. R., Kates R. E. Rapid high-pressure liquid chromatographic analysis of verapamil in blood and plasma. J Chromatogr. 1979 Mar 11;170(2):385–390. doi: 10.1016/s0021-9673(00)95464-5. [DOI] [PubMed] [Google Scholar]
  8. Johnston A., Burgess C. D., Hamer J. Systemic availability of oral verapamil and effect on PR interval in man. Br J Clin Pharmacol. 1981 Sep;12(3):397–400. doi: 10.1111/j.1365-2125.1981.tb01233.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Lindholm A., Henricsson S. Verapamil inhibits cyclosporin metabolism. Lancet. 1987 May 30;1(8544):1262–1263. doi: 10.1016/s0140-6736(87)92710-3. [DOI] [PubMed] [Google Scholar]
  10. Livesley B., Catley P. F., Campbell R. C., Oram S. Double-blind evaluation of verapamil, propranolol, and isosorbide dinitrate against a placebo in the treatment of angina pectoris. Br Med J. 1973 Feb 17;1(5850):375–378. doi: 10.1136/bmj.1.5850.375. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Lo M. W., Silber B., Riegelman S. An automated HPLC method for the assay of propranolol and its basic metabolites in plasma and urine. J Chromatogr Sci. 1982 Mar;20(3):126–131. doi: 10.1093/chromsci/20.3.126. [DOI] [PubMed] [Google Scholar]
  12. McGourty J. C., Silas J. H., Solomon S. A. Tolerability of combined treatment with verapamil and beta-blockers in angina resistant to monotherapy. Postgrad Med J. 1985 Mar;61(713):229–232. doi: 10.1136/pgmj.61.713.229. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. McLean A. J., Knight R., Harrison P. M., Harper R. W. Clearance-based oral drug interaction between verapamil and metoprolol and comparison with atenolol. Am J Cardiol. 1985 Jun 1;55(13 Pt 1):1628–1629. doi: 10.1016/0002-9149(85)90987-7. [DOI] [PubMed] [Google Scholar]
  14. Opie L. H. Drugs and the heart. III. Calcium antagonists. Lancet. 1980 Apr 12;1(8172):806–810. doi: 10.1016/s0140-6736(80)91303-3. [DOI] [PubMed] [Google Scholar]
  15. Reimann I. W., Klotz U., Siems B., Frölich J. Cimetidine increases steady state plasma levels of propranolol. Br J Clin Pharmacol. 1981 Dec;12(6):785–790. doi: 10.1111/j.1365-2125.1981.tb01307.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Rumiantsev D. O., Piotrovskii V. K., Riabokon O. S., Slastnikova I. D., Kokurina E. V., Metelitsa V. I. The effect of oral verapamil therapy on antipyrine clearance. Br J Clin Pharmacol. 1986 Nov;22(5):606–609. doi: 10.1111/j.1365-2125.1986.tb02942.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Schneck D. W., Pritchard J. F. The inhibitory effect of propranolol pretreatment on its own metabolism in the rat. J Pharmacol Exp Ther. 1981 Sep;218(3):575–581. [PubMed] [Google Scholar]
  18. Schwartz J. B., Keefe D. L., Kirsten E., Kates R. E., Harrison D. C. Prolongation of verapamil elimination kinetics during chronic oral administration. Am Heart J. 1982 Aug;104(2 Pt 1):198–203. doi: 10.1016/0002-8703(82)90192-2. [DOI] [PubMed] [Google Scholar]
  19. Subramanian B., Bowles M. J., Davies A. B., Raftery E. B. Combined therapy with verapamil and propranolol in chronic stable angina. Am J Cardiol. 1982 Jan;49(1):125–132. doi: 10.1016/0002-9149(82)90286-7. [DOI] [PubMed] [Google Scholar]
  20. Subramanian V. B., Bowles M. J., Khurmi N. S., Davies A. B., Raftery E. B. Rationale for the choice of calcium antagonists in chronic stable angina. An objective double-blind placebo-controlled comparison of nifedipine and verapamil. Am J Cardiol. 1982 Nov;50(5):1173–1179. doi: 10.1016/0002-9149(82)90439-8. [DOI] [PubMed] [Google Scholar]
  21. Tucker G. T., Bax N. D., Lennard M. S., Al-Asady S., Bharaj H. S., Woods H. F. Effects of beta-adrenoceptor antagonists on the pharmacokinetics of lignocaine. Br J Clin Pharmacol. 1984;17 (Suppl 1):21S–28S. doi: 10.1111/j.1365-2125.1984.tb02424.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Warrington S. J., Holt D., Johnston A., Fitzsimons T. J. Pharmacokinetics and pharmacodynamics of verapamil in combination with atenolol, metoprolol and propranolol. Br J Clin Pharmacol. 1984;17 (Suppl 1):37S–44S. doi: 10.1111/j.1365-2125.1984.tb02426.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Wayne V. S., Harper R. W., Laufer E., Federman J., Anderson S. T., Pitt A. Adverse interaction between beta-adrenergic blocking drugs and verapamil--report of three cases. Aust N Z J Med. 1982 Aug;12(4):285–289. doi: 10.1111/j.1445-5994.1982.tb03813.x. [DOI] [PubMed] [Google Scholar]
  24. Weiner D. A., McCabe C. H., Cutler S. S., Ryan T. J., Klein M. D. Plasma verapamil levels and exercise performance. Clin Pharmacol Ther. 1984 Jul;36(1):25–32. doi: 10.1038/clpt.1984.134. [DOI] [PubMed] [Google Scholar]
  25. Wing L. M., Miners J. O., Lillywhite K. J. Verapamil disposition--effects of sulphinpyrazone and cimetidine. Br J Clin Pharmacol. 1985 Mar;19(3):385–391. doi: 10.1111/j.1365-2125.1985.tb02658.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Winniford M. D., Fulton K. L., Corbett J. R., Croft C. H., Hillis L. D. Propranolol-verapamil versus propranolol-nifedipine in severe angina pectoris of effort: a randomized, double-blind, crossover study. Am J Cardiol. 1985 Feb 1;55(4):281–285. doi: 10.1016/0002-9149(85)90361-3. [DOI] [PubMed] [Google Scholar]
  27. Winniford M. D., Fulton K. L., Hillis L. D. Symptomatic sinus bradycardia during concomitant propranolol-verapamil administration. Am Heart J. 1985 Aug;110(2):498–498. doi: 10.1016/0002-8703(85)90181-4. [DOI] [PubMed] [Google Scholar]
  28. Yong C. L., Kunka R. L., Bates T. R. Factors affecting the plasma protein binding of verapamil and norverapamil in man. Res Commun Chem Pathol Pharmacol. 1980 Nov;30(2):329–339. [PubMed] [Google Scholar]

Articles from British Journal of Clinical Pharmacology are provided here courtesy of British Pharmacological Society

RESOURCES