Bretylium: Relations between plasma concentrations and pharmacologic actions in high-frequency ventricular arrhythmias

Abstract

Although it is widely assumed that the early arrhythmogenic and pressor responses to bretylium are caused by catecholamine release from the adrenergic neuron, this assumption has not been systematically studied in humans. Pharmacologic responses to a placebo infusion and 3 separate bretylium infusions (2.5, 5.0, 10 mg/kg over 60 minutes) were assessed in 6 patients with recurrent, nonsustained ventricular tachycardia. Plasma bretylium concentration, blood pressure (BP), plasma norepinephrine (NE) concentration, arrhythmia frequency and adrenergic neuronal blockade (assessed by the presence or absence of reflex venoconstriction) were measured. Adrenergic blockade was seen with every bretylium infusion and at a time when relatively small amounts of bretylium had been administered (range 160 to 750 mg, median 252). Temporal relations (p < 0.03) were noted among the time of onset of adrenergic neuronal blockade, onset of the pressor response, increase in NE plasma concentration and increase in ventricular arrhythmia frequency. BP responses during the infusions were linearly related to change in plasma NE at the time of development of adrenergic neuronal blockade. Bretylium plasma concentrations higher than 3 μg/ml were frequently associated with a short-lived pressor response. There was a significant relation (p < 0.06) between the increase in plasma NE during the infusion and an increase in ventricular arrhythmia frequency. Reduction in arrhythmia frequency was seen in only 1 patient, beginning 6 hours after the development of adrenergic neuronal blockade. In conclusion, soon after bretylium administration to patients with ventricular arrhythmias, a dose-related increase in BP and arrhythmia frequency occurred that were temporally related to catecholamine release and adrenergic neuronal blockade. Lack of antiarrhythmic response in this highly selected population does not detract from the proved efficacy of bretylium in patients with recurrent sustained ventricular tachycardia and fibrillation.