The effect of dextro-, levo-, and racemic verapamil on atrioventricular conduction in humans

Abstract

To study the dromotropic effects of dextro(D)- and levo(L)-verapamil on atrioventricular (AV) conduction in humans, we investigated the prolongation of the PR interval following intravenous administrations of each isomer and racemic preparation (D, 5, 25, and 50 mg; L, 5, 7.5, and 10 mg; racemic, 10 mg). The plasma drug concentration-effect relationship was analyzed by log-linear regression and the sigmoidal E max model. The sigmoidal E max model provided a significantly better fit for the data than log-linear regression ( p < 0.01). Maximum drug effect (E max) and plasma drug concentration associated with 50% E max (EC 50) were calculated by means of the E max model. The dromotropic potency of each isomer was assessed in terms of EC 50 and the drug concentration associated with a 10% PR prolongation from the basal level calculated by the E max model. The results demonstrated that L-verapamil was 10 and 18 times more potent than D-verapamil in terms of EC 50 (D, 188.9 ± 108.4 ng/ml; L, 17.7 ± 11.3 ng/ml; p < 0.05) and drug concentration associated with 10% PR prolongation (D, 166.6 ± 48.1 ng/ml; L, 9.1 ± 2.8 ng/ml; p < 0.01), respectively. A stereospecific difference in plasma protein binding was observed (D, 93.7 ± 2.2%; L, 88.5 ± 1.6%; p < 0.05). When potency was assessed with plasma free drug concentration, L-verapamil was 4.5 and 8 times more potent than D-verapamil in terms of EC 50 (D, 9.17 ± 4.53 ng/ml; L, 2.0 ± 1.36 ng/ml; p < 0.01), respectively. These results suggest that L-verapamil is largely responsible for the negative dromotropic effects on AV conduction in humans.