Comparative Effects of Disopyramide and Its Mono- N-Dealkylated Metabolite in Conscious Dogs with Chronic Atrioventricular Block

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Abstract
In animals and humans, the antiarrhythmic agent disopyramide is primarily metabolized by mono-N-dealkylation. The effects of disopyramide and its N-dealkylated metabolite (MND) were investigated in 13 conscious dogs with chronic atrioventricular (A-V) block and implanted atrial pacing electrodes. Our data clearly show that both compounds used within the therapeutic plasma level range induced lengthening of the atrial effective refractory period (AERP) as reflected by the diminution of the maximal atrial frequency determined by pacing. However, at equivalent drug plasma concentrations, disopyramide induced a more marked decrease (1.2-1.7 times) in the maximal atrial frequency than did its metabolite. Both compounds increased mean arterial pressure (MAP) and atrial rate and decreased ventricular rate, but the effects on MAP and atrial rate were more marked with disopyramide than with MND. Thus, with regard to these cardiovascular parameters, the parent drug and MND possess distinct pharmacodynamic profiles, which may in part be related to their respective vagolytic power.