Antiarrhythmic and Antifibrillatory Actions of Bretylium Tosylate.

Abstract

This study was undertaken to evaluate the potential of bretylium tosylate as an agent capable of preventing sudden coronary death. To determine the possible efficacy of bretylium for the prevention of sudden coronary death, it was necessary to answer the following three questions. (1)Can bretylium suppress the continuous electrical instability associated with myocardial ischemic injury, and thereby prevent the development of reentrant ventricular tachyarrhythmias and ventricular fibrillation? (2)What is the relationship between the electrophysiologic actions of bretylium and concentrations of bretylium in plasma and ventricular myocardium? (3)Is the oral administration of bretylium efficacious for the long term suppression of ventricular tachyarrhythmias and ventricular fibrillation in man? The ability of bretylium to suppress myocardial electrical instability associated with myocardial ischemic damage was evaluated in two canine models of myocardial ischemic injury and in patients resuscitated from previous episodes of sustained ventricular tachycardia or sudden coronary death. The uptake of bretylium into canine myocardium from plasma after intravenous administration and the relationship between the electrophysiologic actions of bretylium and concentrations of bretylium in ventricular myocardium and plasma were studied in the dog. The oral absorption, disposition, and clearance of bretylium from plasma were evaluated in normal human volunteers and in patients resuscitated from prior episodes of sustained ventricular tachycardia or sudden coronary death. The following results were obtained. (1)Acute and chronic bretylium administration prevented ventricular tachyarrhythmias that were initiated by programmed electrical stimulation in conscious dogs, 3 to 14 days after myocardial infarction. The beneficial response to chronic bretylium administration was accompanied by an increase in ventricular effective refractory periods and no alteration in ventricular activation times. (2)Bretylium administration significantly reduced the incidence of ventricular fibrillation occurring in conscious dogs due to the development of acute myocardial ischemia distant to a site of myocardial ischemic injury produced by a prior ischemic event. (3)Chronic oral bretylium administration prevented the recurrence of ventricular tachyarrhythmias and sudden coronary death in some patients resuscitated from prior episodes of sustained ventricular tachyarrhythmias or sudden coronary death. (4)The slow onset of the increase in ventricular effective refractory periods and the ventricular fibrillation threshold observed after acute intravenous bretylium administration were not accounted for by delayed myocardial uptake of bretylium. Myocardial bretylium uptake was more rapid than the onset of the electrophysiologic actions of bretylium. After the acute administration of bretylium tosylate, the electrophysiologic actions of the drug did not correlate directly with either plasma or myocardial drug concentrations. (5)Bretylium was rapidly removed from the plasma by the kidney. Clearance was more rapid after oral administration than after intravenous administration. Elimination of bretylium from plasma did not become a first-order process until serum concentrations less than 70 ng/ml were reached. Oral absorption of bretylium was incomplete, but a therapeutic response was maintained with chronic oral administration in most patients. These results suggest that bretylium tosylate can effectively suppress ventricular tachyarrhythmias associated with ischemically injured ventricular myocardium. Chronic oral bretylium administration prevents the recurrence of ventricular tachyarrhythmias in many patients and dem and s further study as an possible agent for the prevention of sudden coronary death.