Pharmacologic reversal of hypotensive effect complicating antiarrhythmic therapy with bretylium

The value of bretylium for long-term therapy of arrhythmias is slight because of the almost universal development of orthostatic hypotension induced by adrenergic neuron blockade. Blockade of neurotransmission by bretylium depends on its uptake into adrenergic neurons by the norepinephrine pump. The effects of inhibiting the pump with protriptyline were evaluated in five patients with ventricular tachycardia (VT) resistant to conventional therapy but responsive to bretylium. Adrenergic blockade was assessed by measuring the venous reflex response (VRR) and change in blood pressure on standing. Before bretylium, VRR was present and standing blood pressure was normal. The patients received intravenous bretylium in increasing doses until VT was suppressed, at which time the VRR was blocked and all patients were bedridden due to orthostatic hypotension. The dosage of bretylium was tapered as oral treatment was begun and the dosage gradually increased to maintain VT suppression. Protriptyline was then given orally in slowly increasing doses in an attempt to reverse intolerable orthostatic hypotension. Five to 7 days later the VRR was restored and the blood pressure in the standing position returned toward normal, enabling the patients to become ambulatory. In these patients the antiarrhythmic efficacy of bretylium was not altered by protriptyline and was therefore not dependent on adrenergic neuron blockade. As bretylium was withdrawn and protriptyline continued, recurrence of arrhythmia established that protriptyline did not contribute to bretylium's antiarrhythmic efficacy. These findings do not, however, constitute sufficient evidence to support the routine application of this approach to therapy. Rather, it provides a pharmacologic rationale for more extensive evaluation of the safety and efficacy of the combination. The demonstration of dissociation between the antiarrhythmic and adrenergic effects of bretylium in man suggests that structural modification of the molecule might yield an antiarrhythmic drug free of undesirable effects on the adrenergic nervous system. Clinical Pharmacology and Therapeutics (1982) 32, 313–321; doi:10.1038/clpt.1982.166