Evaluation of the pharmacokinetics and electrocardiographic effects of intravenous verapamil with intravenous calcium chloride pretreatment in normal subjects

Abstract

To evaluate the effects of calcium pretreatment on the disposition and etectrocardiographic effects of verapamil, 8 healthy male volunteers received treatment in each of 3 phases in a randomized, double-blind, crossover manner. Phase I denoted 10 ml of 0.9% intravenous sodium chloride followed by 10 mg of intravenous verapamil; phase II denoted 10 ml of 10% intravenous calcium chloride followed by 4 ml of 0.9% intravenous sodium chloride; and phase III denoted 10 ml of 10% intravenous calcium chloride followed by 10 mg of intravenous verapamil. Blood samples for the determination of verapamil concentrations were drawn at 5, 10, 15, 20, 30, 45, 60 and 90 minutes, and at 2, 4, 6, 10 and 24 hours. Blood pressure, heart rate and PR intervals were also measured at these times. Pretreatment of verapamil with intravenous calcium did not alter the disposition of intravenous verapamil. Blood pressure was not significantly altered in any treatment phase, although calcium tended to increase mean arterial pressure and verapamil abolished this effect. Cakium had no significant affect on verapamil-induced PR prolongation (maximum percent change in PR interval: phase I = 19 ± 11%, phase III = 18 ± 7%; time to maximal prolongation: phase I = 0.38 ± 0.21 hours, phase III = 0.37 ± 0.26 hours; and area under the percent change in PR vs time curve: phase I = 15.5 ± 10, phase III = 21 ± 9). Verapamil caused a reflex increase in heart rate of similar magnitude in both phases I and III (24 ± 10% and 21 ± 7%, respectively). However, calcium in phase III caused an initial decrease in heart rate, such that the net change in heart rate over time was significantly different (p < 0.05) than with verapamil alone (area under the percent change in heart rate vs time curve: phase I = 5 ± 28, phase III = −23 ± 12). In doses frequently used in a clinical setting, calcium and verapamil produce opposing effects on the sinus rate and arterial blood pressure, but not on atrioventricular conduction. These findings show that the atrioventricular nodal and thus antiarrhythmic effects of verapamil are preserved despite pretreatment with calcium.