Synergistic adverse hemodynamic interaction between oral verapamil and propranolol

The interaction between oral verapamil and propranolol may involve negative chronotropic, inotropic or dromotropic effects. The immediate effects of orally administered verapamil (120 mg) and propranolol (80 mg), alone and combined, on submaximal exercise hemodynamics and on pharmacokinetics were studied in eight healthy male volunteers in a randomized, double-blind, crossover manner. Maximum effects on heart rate, systolic blood pressure, PR interval and rate-adjusted PR prolongation were greatest with the combined administration of verapamil and propranolol. The combination caused a high frequency of adverse drug events, predominantly exercise fatigue. Verapamil increased the AUC and Cmax and shortened the tmax of propranolol. Propranolol decreased the AUC and Cmax of verapamil. The greater reduction of heart rate with the combination of verapamil and propranolol was only partially explained by higher plasma concentrations of propranolol. The combination of propranolol and verapamil produced clinically important synergistic adverse effects during exercise. Negative dromotropic effects occurred primarily by direct AV node inhibition and were more important than previously recognized.