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

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 less than 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 micrograms/ml were frequently associated with a short-lived pressor response. There was a significant relation (p less than 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.(ABSTRACT TRUNCATED AT 250 WORDS)

Human blood preservation: effect on in vitro protein binding.

In vitro plasma protein binding for phenytoin, meperidine, and bretylium tosylate was affected by the type of preserved human blood used for its estimation. Fresh heparinized plasma and serum gave equivalent fractions bound at the concentrations studied for all three drugs. However, the in vitro plasma binding of phenytoin and meperidine decreased 9-50% when estimated in fresh citrated plasma or commercially available lyophylized human serum at the concentration levels investigated. The fraction of bretylium tosylate bound to plasma protein decreased 30-40% when estimated in fresh citrated plasma but was unchanged when estimated in the lyophylized human serum.

GI drug absorption in rats exposed to cobalt-60 gamma-radiation II: in vivo rate of absorption.

The rate of absorption of sulfanilamide, bretylium tosylate, sulfisoxazole acetyl, and riboflavin was studied in rats exposed to 850 rad of cobalt-60 gamma-radiation either 1 or 5 days before oral drug administration. Polyethylene glycol 4000 was administered with sulfanilamide; its distribution along the GI tract indicated that the gastric emptying rate was reduced threefold at 1 day postirradiation but returned to normal at 5 days postirradiation; the small intestinal transit rate was not detectably altered by irradiation. At 1 day postirradiation, there was a marked decrease in the absorption rate of sulfanilamide, a smaller, although significant, decrease in the absorption rate of sulfisoxazole acetyl and bretylium, and an increase in the absorption rate of riboflavin. At 5 days postirradiation, the drug absorption rate was normal. The changes in the absorption rate of the drugs were due to a radiation-induced reduction in the gastric emptying rate; the permeability of the GI epithelium did not appear to be affected by radiation. The results indicate that, immediately following irradiation, a marked reduction in the gastric emptying rate causes a pronounced reduction in the absorption rate of rapidly absorbed drugs, a less pronounced reduction in the absorption rate of drugs that are absorbed slowly because of slow dissolution or slow diffusion across the GI epithelium, and an increase in the absorption rate of drugs that are absorbed by a saturable mechanism provided the mechanism is not impaired by irradiation.

Massive intravenous bolus bretylium tosylate.

A 30 mg/kg (2-gm) intravenous bolus of bretylium tosylate was administered to a patient with recurrent ventricular tachycardia and fibrillation. After successful defibrillation the patient exhibited marked hypertension followed by protracted refractory hypotension. There was no further ventricular ectopy in spite of a very low cardiac index. A bretylium level of 8,800 ng/ml is the highest reported in man from a single bolus injection. This case demonstrates the exaggerated hemodynamic response to massive intravenous bolus bretylium tosylate.

Endotracheal bretylium tosylate in a canine model.

This study was conducted to determine whether bretylium tosylate (BT) is effectively and safely absorbed through the endotracheal route in the canine model. Eleven adult mongrel dogs were anesthetized with pentobarbital, were orally intubated, and had continuous blood pressure and electrocardiographic monitoring. Four dogs received 5 mg/kg BT, three dogs received 10 mg/kg BT, two dogs received 20 mg/kg BT, and two control dogs were given volumes of normal saline equal to those given the 5- and 10-mg/kg groups. Each dog received the same dose of BT both endotracheally and intravenously, but in a random order and on different dates. Following each drug administration arterial blood was drawn at various intervals over two hours and sent for immediate gas analysis; serum samples were frozen for future determination of BT levels. Regardless of the amounts delivered, the peak levels of BT in the arterial blood following administration by the endotracheal route were consistently low (4.13 micrograms/mL to 14.00 micrograms/mL) when compared to those levels following intravenously administered BT (120 micrograms/mL to 268 micrograms/mL) (all P less than .002 for the 5- and 10-mg/kg groups). No depot effect was observed during a two-hour period. The arterial blood gases did not change significantly following the administration of BT by the endotracheal route in the 5- and 10-mg/kg groups, and sections of these autopsied dog lungs showed no apparent pathologic changes.

Electrophysiologic effects of bretylium on canine ventricular muscle during acute ischemia and reperfusion.

Electrophysiologic effects of bretylium were assessed on a recently developed animal model for analysis of conduction of premature impulses and excitation threshold. Bretylium was administered intravenously 10 mg/kg over 10 minutes followed by 2 mg/min of infusion immediately after coronary ligation. Conduction of the premature impulse was recorded in the epicardial and endocardial sites both in the base-to-apex and apex-to-base directions, in the normal, in the center, and across the border of ischemic myocardium. Compared to the control group of animals, bretylium did not cause any significant change in the conduction characteristics in the ischemic myocardium; however, it delayed the conduction of premature impulses in the normal myocardium. Thus the disparity in conduction times between the normal and the ischemic myocardium was lessened by bretylium. Further, conduction of impulses from normal tissue across the border of ischemia was also delayed. Bretylium also decreased the excitability threshold in the ischemic myocardium, although the normal myocardial excitation threshold was unaffected. These unique effects of bretylium on conduction and excitability in the normal, in the center, and across the border of ischemic myocardium, when a therapeutic dosage of the drug is used, further validate its antiarrhythmic potential and offer an insight into its mechanism of action in the setting of acute myocardial ischemia.