USE-DEPENDENT ACTIONS AND EFFECTS ON TRANSMEMBRANE ACTION-POTENTIALS OF FLECAINIDE, ENCAINIDE, AND ETHMOZINE IN CANINE PURKINJE-FIBERS

The Cardiac Arrhythmia Suppression Trial implicated flecainide and encainide as proarrhythmic in a specific clinical setting, whereas ethmozine was not. The purpose of the present study was to attempt to understand the cellular basis for these different drug effects by comparing the actions on transmembrane action potential characteristics and onset and offset of use-dependent block in canine Purkinje fibers using standard microelectrode techniques. All drugs caused qualitatively similar changes on action potential characteristics: reduction of action potential amplitude and the maximum rate of depolarization (V(max)) as well as acceleration of repolarization. Ethmozine and the orthodemethyl (O-D) metabolite of encainide had greater effects at all concentrations studied than encainide or flecainide. Although ethmozine induced greater use-dependent reduction of V(max) than flecainide or encainide, it also showed faster onset and recovery from use-dependent block. The time constant of recovery from use-dependent block for O-D encainide was about 5 times that of the parent compound. The rates of onset and recovery from use-dependent block for ethmozine were similar to those reported for class IA drugs like disopyramide and much slower than class IB drugs like lidocaine. The faster on and off rates of ethmozine when compared to flecainide and encainide in this study may provide the basis for the differing effects of these drugs on conduction in situ and their proarrhythmic actions.