Electrophysiologic actions of O-demethyl encainide: an active metabolite.

Abstract

Differences between the electrophysiologic actions of the antiarrhythmic agent encainide have been reported after short-term intravenous and oral administration. Only prolongation of the HV interval and QRS duration have been described immediately after short-term intravenous administration of encainide in dogs and man. However, during oral therapy or more prolonged infusions, prolongation of the AH interval and atrial and ventricular effective refractory periods have also occurred. In most patients receiving encainide therapy, metabolites (O-demethyl encainide and 3-methoxy-0-demethyl encainide) accumulate during prolonged therapy to concentrations greater than those of the parent drug. We compared the electrophysiologic action of 0-demethyl encainide with that of saline in anesthetized dogs to determine if this metabolite has pharmacologic activity and whether its electrophysiologic effects could account for the disparities noted between effects of intravenous and oral encainide therapy. An initial pharmacokinetic evaluation allowed design of a series of loading and maintenance infusions that produced plasma concentrations similar to those seen during encainide therapy in man (concentration after first maintenance dose, 149 + 27 ng/ml [A+ SE] and after second maintenance dose, 230 + 45 ng/ml). Significant increases in atrial effective refractory period and ventricular refractoriness, and prolongation of AH interval and HV conduction time were observed. These effects are similar to those reported after prolonged oral encainide therapy but are substantially different from those seen after short-term infusions of encainide. These findings indicate that the difference between the electrophysiologic actions of intravenous and oral encainide may be due to pharmacologic effects of at least one encainide metabolite, 0-demethyl encainide. Circulation 68, No. 2, 385-391, 1983. ENCAINIDE is an investigational antiarrhythmic agent that has been found to be effective in the treatment of ventricular arrhythmias.' 6 Differences have been noted between the electrophysiologic actions of encainide observed immediately after an intravenous infusion and those during long-term oral therapy.

Encainide

“…Concurrent measurements demonstrated that the monophasic action potential at 90% recovery was increased (14%), and both the functional and effective refractory periods of the atria {26% to 31c/c) and ventricle (10% to 13%) were prolonged after this high-dose administration. His-bundle observations in anesthetized dogs given ODE at infusion rates to attain steady-state plasma levels comparable to those measured clinically during encainide therapy in humans (149 to 230 ng/ml) support the interpretation that the differences between the electrophysiologic actions of acute intravenous and chronic oral encainide may be due to the pharmacologic effects of its ODE metabolite [31]. Thus unlike other class I antiarrhythmic agents, acute administration of encainide was associated with conduction slowing in the specialized His-Purkinje system without significant alterations in conduction or refractoriness in other areas of the canine myocardium.…”

Antiarrhythmic efficacy, clinical electrophysiology, and pharmacokinetics of 3-methoxy-O-desmethyl encainide (MODE) in patients with inducible ventricular tachycardia or fibrillation.

“…In patients who underwent debrisoquin phenotyping, 10 mg debrisoquin was administered while the patient was receiving no other antiarrhythmic agents (generally the night before planned electrophysiology study), and urine was collected for the subsequent 8 hours. The metabolic ratio, the percent recovery of debrisoquin to that of 4-hydroxy debrisoquin in the 8-hour urine collection, was determined: a metabolic ratio of more than 12 …”

Clinical Pharmacokinetics of Encainide

“…In in vitro test systems (Elharrar & Zipes 1982), animal models Duff et al 1983;Roden et al 1982Roden et al , 1984 and most recently patients (Barbey et aI. 1985), both ODE and MODE have been shown to produce pharmacological effects similar to those seen during encainide therapy, including arrhythmia suppression and QRS prolongation.…”