Comparative electrophysiology of lorcainide and norlorcainide in the dog

Electrophysiologic effects of intravenous lorcainide and its major metabolite, norlorcainide, were examined in 18 anesthetized dogs, using intracardiac electrophysiologic measurements and programmed stimulation. Lorcainide and norlorcainide were studied separately, using six dogs for each experiment. Each compound was administered by a series of 5 one-h graded infusions each involving a loading dose over 15 min followed by a 45-min maintenance infusion. Plasma concentrations ranged from 94 +/- 34 to 1345 +/- 471 ng/ml for lorcainide and 81 +/- 22 to 1344 +/- 458 ng/ml for norlorcainide. Six additional dogs were studied, using a combination of a constant lorcainide infusion and four progressively increasing doses of norlorcainide. Both lorcainide and norlorcainide caused concentration-dependent prolongation of PR interval, QRS duration, AH and HV intervals, atrial and ventricular effective refractory periods, and the atrioventricular nodal functional refractory period. For each electrophysiologic parameter, plots of percent change as a function of log plasma concentration were nearly superimposable for lorcainide and norlorcainide. Plots for the combined treatment group using the total plasma concentration of lorcainide and norlorcainide were similar to those for each compound alone. We conclude that in dogs norlorcainide has considerable electrophysiologic activity, and is approximately equieffective and equipotent when compared with lorcainide, and that the electrophysiologic effects of the two compounds appear additive.