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PubMed1983

Membrane action and catecholamine release action of bretylium tosylate in normoxic and hypoxic canine Purkinje fibers.

Electrophysiologic effects of bretylium tosylate on transmembrane action potentials of canine Purkinje fibers were studied by microelectrode methods. Perfusion of this agent (20 mg/liter) prolonged the action potential duration and the effective refractory period, but did not alter the maximal diastolic potential, upstroke phase of the action potential and membrane responsiveness curve under normal oxygenation. With a hypoxic superfusion, the action potential amplitude, maximal diastolic potential, maximal rate of depolarization and action potential duration were all decreased. Subsequent addition of bretylium antagonized all these effects of hypoxia and restored the action potential variables to control values. However, similar effects of hypoxia observed in Purkinje fibers pretreated with reserpine were not reversed by bretylium except for a prolongation of repolarization. These results suggest that antiarrhythmic effects of bretylium in hypoxic or depressed myocardium are probably due to: 1) increased maximal rate of depolarization (and conduction velocity) caused by membrane hyperpolarization, and 2) prolongation of the effective refractory period. The first electrophysiologic action appears to depend on catecholamine release by bretylium, as hyperpolarization was not observed in reserpine-pretreated Purkinje fibers. The second effect may represent a direct membrane action.

Action Potentials↗
PubMed1986

Effect of lidocaine and bretylium on energy requirements for transthoracic defibrillation: experimental studies.

The purpose of this study was to determine the effect of the antiarrhythmic drugs lidocaine and bretylium on the minimal energy requirement for transthoracic defibrillation--the defibrillation threshold. Closed chest dogs were anesthetized with chloralose or pentobarbital; lidocaine was administered at varying rates for 2 hours and defibrillation threshold periodically redetermined. Similar protocols were followed for bretylium. Serum lidocaine levels from therapeutic to toxic ranges were obtained, and up to a 60% (p less than 0.05) increase in defibrillation threshold in the pentobarbital-anesthetized dogs was demonstrated. In chloralose-anesthetized dogs the lidocaine effect was modest, with only a 10 to 20% rise in defibrillation threshold (p = NS) despite similar increases in serum lidocaine levels. Thus, lidocaine increases the minimal energy requirements for transthoracic defibrillation, but this effect is in part anesthesia-related, indicating a lidocaine-pentobarbital interaction. When phentolamine was administered to chloralose-anesthetized dogs receiving lidocaine, defibrillation threshold rose 13% (p less than 0.05); this suggests that alpha-adrenergic receptor blockade is at least in part the mechanism of the pentobarbital-lidocaine interaction on defibrillation threshold. Bretylium with either anesthetic had no significant effect on defibrillation threshold.

Animals↗
PubMed1980

Oral and intravenous bretylium disposition.

To compare the oral and intravenous disposition of bretylium tosylate in man, 10 normal male subjects were randomly assigned single doses of 5 mg/kg bretylium tosylate either orally or intravenously and crossed over 2 wk later to the opposite route (20 studies). Each experiment included sampling for drug in serum and urine over 48 hr. Bretylium tosylate was assayed by gas chromatography. Kinetic analysis provided the following mean [coefficient of variation] results: 100FPo, 22.6% [40.2%]; ClrIV, 300 ml/min [27.8%]; ClrPo, 1.268 mg/min [54.8%]; ClBIV, 299 ml/min [31.9%]; f, 101% [8.7%]; Vdss, 3.37 l/kg [30.5%]; lambda lIV 0.0510 [12.8%]; lambda lPG, 0.115 [52.7%]hr-1; elimination half-life (t 1/2) after intravenous bretylium tosylate, 13.6 hr, and after oral bretylium tosylate, 6.0 hr (harmonic means). Bretylium tosylate binding to plasma proteins in normal volunteer samples was found to be negligible. The results indicate extensive tissue binding of bretylium tosylate. Oral doses of bretylium tosylate are only partially absorbed. Bretylium tosylate is eliminated entirely by the kidneys as unchanged drug. The greater renal clearance after oral than intravenous bretylium tosylate, and the greater elimination rate constant and shorter oral bretylium tosyulate t 1/2 are of interest but no explanation is available.

Administration, Oral↗
PubMed1983

Bretylium kinetics in renal insufficiency.

Bretylium kinetics were examined in patients with varying degrees of renal impairment after a single intravenous dose of bretylium tosylate. Maximum plasma concentrations achieved at the end of the infusion, when normalized to the dose, correlated strongly with creatinine clearance. Drug disposition from plasma was biexponential, with a short distributive phase, but drug elimination was reduced, especially in patients with creatinine clearance below 30 ml/min X 1.73 m2. There was reduction in renal and total clearance and prolongation of t 1/2, with deteriorating renal function. In one patient who was reevaluated after a year, there was 76% reduction in the total clearance, corresponding to 43% deterioration of renal function. The difference of 33% between these values is due to a reduction of nearly 36% in volume of distribution, caused by the further deterioration of the renal function. Six-hour hemodialysis procedure on two anephric patients, resulted in an apparent one- to threefold increase in the computed bretylium clearance during dialysis, but the fraction of the total body load eliminated during the same period was not proportionally significant. The strong linear relationships between renal and total clearance, beta, and the creatinine clearance, may be helpful in adjusting dosage regimens for bretylium in patients with renal dysfunction.

Adult↗
PubMed1988

Sympatho-endocrine and metabolic responses to exercise under post-ganglionic blockade in rats.

The purpose of this study was to further document the role of locally released norepinephrine (NE) in the control of metabolic and endocrine responses to exercise in rats. Post-ganglionic blockade with bretylium (20 mg.kg-1, i.v.) reduced NE release from sympathetic nerve endings and triggered a compensatory increase in epinephrine (E) release from the adrenal medulla, as reflected by plasma NE and E concentrations at rest and exercise (E/NE ratio = 2.92 +/- 0.53 and 2.48 +/- 0.51 vs 0.62 +/- 0.15 and 1.48 +/- 0.18 in control rats; mean +/- SE). Following bretylium administration a reduction in running time to exhaustion (28 m.min-1, 8% slope: 33 +/- 2 min vs 74 +/- 10 min) was associated with 1) a faster decrease in blood glucose concentration (3.58 +/- 0.80 mM vs 8.09 +/- 0.38 mM in control rats exercised for 33 min); and 2) an increased glycogen store utilization in fast-twitch muscles (superficial vastus lateralis and gastrocnemius lateralis). Glycogen utilization was not modified in soleus muscle and in the liver. Taken together these results suggest that post-ganglionic blockade increased carbohydrate store and peripheral blood glucose utilization. This could reflect an impairment in fat mobilization and utilization which might be secondary to a reduction of NE release in the adipose tissue and/or in the endocrine pancreas.

Animals↗
PubMed1978

Porcine malignant hyperthermia. VI: the effects of bilateral adrenalectomy and pretreatment with bretylium on the halothane-induced response.

The effects of bilateral adrenalectomy, together with the i.v. administration of bretylium tosylate 20 mg kg-1 on halothane-induced malignant hyperthermia (MH), were investigated in six Pietrain pigs. All six animals survived the halothane challenge, and failed to show any signs of increased muscle metabolism. Bilateral adrenalectomy alone prevented halothane-induced MH in three out of four Pietrain pigs, whereas the i.v. administration of bretylium alone protected only one pig out of an additional four animals studied. The results show that complete adrenergic blockade inhibits the susceptibility of Pietrain skeletal muscle to halothane and that the adrenal medulla makes an important contribution to this response.

Adrenalectomy↗
PubMed1984

Lack of effect of bretylium tosylate on electrical ventricular defibrillation in a controlled study.

The threshold stored energy and transthoracic current for electrical defibrillation were determined in dogs anaesthetised with pentobarbitone. Groups were randomly allocated to pre-treatment with either saline or bretylium. The intravenous administration of bretylium tosylate (10 to 30 mg . kg-1) did not significantly alter either measurement. The drug caused large changes in heart rate and arterial blood pressure.

Animals↗
PubMed1985

Effects of bretylium tosylate on inhomogeneity of refractoriness and ventricular fibrillation threshold in canine hearts with quinidine-induced long QT interval.

We studied effects of bretylium tosylate (6 mg X kg-1, injected intravenously over 60s) on ventricular refractoriness and its inhomogeneity, and ventricular fibrillation threshold (VFT) in canine hearts with quinidine-induced long QT interval. In 3 anaesthetised open chest dogs, 30 mg X kg-1 of quinidine sulphate was injected intravenously over 5 min to produce QT prolongation. Effective refractory period (ERP) was determined at 8 test points of the right ventricle using extrastimuli. Temporal dispersion as an expression of inhomogeneity of ventricular refractoriness was estimated as the difference between the longest and the shortest ERP. VFT was determined using a train of pulses, 4 ms in duration and at 10 ms intervals. Effects of bretylium were determined from 30 to 60 min after injection. Quinidine-induced long QT interval did not change after bretylium (358 +/- 37 vs 348 +/- 26 ms) when transiently elevated blood pressure returned to the pre-bretylium level. Bretylium shortened ERP slightly (278 +/- 16 vs 268 +/- 14 ms, p less than 0.02) but did not shorten ERP after premature depolarisation (209 +/- 14 vs 209 +/- 15). However, temporal dispersion was significantly decreased by bretylium. VFT, which was lowered by quinidine (14.5 +/- 5.0 vs 8.5 +/- 2.9 mA, p less than 0.01), was elevated significantly by bretylium (21.9 +/- 6.9, p less than 0.001). These effects of bretylium might be attributed to the combination of its direct electrophysiology and indirect adrenergic actions.

Animals↗
PubMedDate not supplied

Clinical pharmacokinetics of intravenous and oral bretylium tosylate in survivors of ventricular tachycardia or fibrillation: clinical application of a new assay for bretylium.

We studied 12 patients receiving either chronic oral (p.o.) maintenance bretylium and/or acute intravenous (i.v.) bretylium to evaluate drug efficacy and pharmacokinetics. All patients were survivors of ventricular tachycardia or fibrillation. A new assay for bretylium was applied, and it proved sensitive and reliable. After single intravenous dosing, bretylium was eliminated from serum with a mean rate constant of lambda iv1 = 0.0515 hr-1 and a corresponding elimination half-life of tiv1/2 = 13.5 hr (7 studies), similar to previous results in normals. Total body clearance averaged 428 ml/min, of which virtually all was accounted for by renal clearance. Seven patients responding to intravenous bretylium were transferred to oral drug. During chronic therapy (mean dose, 41 mg/kg/day bretylium tosylate), mean minimum steady-state concentration of bretylium was 186 ng/ml (range, 72-461) and was accurately predicted, within experimental error, by using the elimination rate constant determined for oral, but not intravenous, drug in normal subjects (lambda po1 = 0.115 hr-1). Determination of average steady-state concentration (Css) yielded similar conclusions. Mean 24 hr urinary excretion of bretylium during oral therapy was 18.3% (range, 9-13%). These results lend validity to earlier observations in normals and suggest route and concentration dependence of disposition. Transfer to oral bretylium allowed continued control of sustained ventricular tachycardia in all 7 patients and of unsustained ventricular tachycardia in 5. Orthostatic hypotension in 4 responded to protriptyline. Six were discharged on bretylium, with a mean follow-up of 12.2 months (range, 1-25.5). Four maintained a favorable response, and 2 died suddenly at 1 and 3 months. We conclude that further evaluation or oral bretylium is justified; attempts should be made to increase steady-state concentrations during oral therapy.

Administration, Oral↗
PubMedDate not supplied

Role of the adrenergic nerve terminal in digitalis-induced cardiac toxicity: a study of the effects of pharmacological and surgical denervation.

This study determined whether the protective action of bretylium against ouabain-induced ventricular arrhythmia in the cat is related to an action of bretylium on the adrenergic nerve terminal. Bretylium pretreatment (20 mg/kg, i.v.) administered 2 h prior to ouabain (2 micrograms/kg/min, i.v. until death) increased the dose of ouabain to produce premature ventricular contraction, ventricular tachycardia, and death from 77.2 +/- 5.2 to 107.7 +/- 6.7 micrograms/kg; from 84.9 +/- 5.2 to 113.9 +/- 7.1 micrograms/kg; and from 108.8 +/- 4.0 to 146.7 +/- 5.7 micrograms/kg, respectively (p less than 0.05). Surgical denervation 2 weeks prior to the experiment or 6-hydroxydopamine (6OH dopamine), 20 mg/kg, i.v., administered 3 or 14 days prior to the ouabain infusion did not protect against the arrhythmogenic effects of ouabain. When bretylium was administered to cats pretreated with 6OH dopamine 3 days prior to the ouabain infusion or to surgically denervated cats, the protective action against ouabain-induced arrhythmia did not develop. Since 6OH dopamine and surgical denervation prevented the action of bretylium on ouabain-induced ventricular arrhythmia, it appears that bretylium is acting on the adrenergic nerve terminal. Thus, agents like bretylium that act on the adrenergic nerve terminal, leaving it structurally intact but not functional, are effective against ouabain-induced ventricular arrhythmia while procedures which cause the degeneration of the adrenergic nerve terminal, such as 6OH dopamine and surgical denervation, are not. These observations indicate that for the protective effect of sympathectomy against ouabain-induced arrhythmia to develop, the adrenergic nerve terminal must be present, although not functional as far as adrenergic neurotransmission is concerned. Changes in the heart rate or blood pressure did not appear to be a factor in the protective effect of bretylium.

Animals↗
PubMedDate not supplied

Electrophysiologic effects of bretylium tosylate on the canine heart during coronary artery occlusion and reperfusion.

The electrophysiologic and antiarrhythmic actions of bretylium tosylate were studied after acute coronary artery occlusion and reperfusion in pentobarbital-anesthetized dogs. Three groups of animals were studied: Group I (n = 8) served as saline controls, Group II (n = 7) received bretylium tosylate (10 mg/kg i.v.) 60 min prior to coronary artery occlusion, and Group III (n = 5) received bretylium tosylate (30 mg/kg i.v.) in three divided doses over the 24 h prior to coronary artery occlusion. In Groups II and III the effective refractory period of the nonischemic myocardium was not altered by bretylium before or during the occlusion period, nor was it influenced by bretylium during the subsequent reperfusion period. In Group I the effective refractory period of the ischemic myocardium decreased 24 +/- 3.0% after coronary occlusion and increased 12 +/- 3% above the preocclusion level on reperfusion. In Group II the effective refractory period of the ischemic myocardium decreased 28 +/- 3.2% after coronary occlusion but did not overshoot preischemic levels on reperfusion. In Group III the effective refractory period decreased 15 +/- 3.8% following coronary occlusion and did not overshoot preocclusion levels during reperfusion. The ventricular activation times of the normal and ischemic myocardium were not affected by bretylium tosylate during occlusion or reperfusion in Group II or III. Significant reperfusion arrhythmias were observed only in Groups I and II. These data suggest that bretylium tosylate exerts its antiarrhythmic actions in ischemic myocardium by reducing the dispersion of cardiac refractoriness produced by coronary artery occlusion and, consequently, abolishing the abrupt change in cardiac refractoriness that follows coronary artery reperfusion. These antiarrhythmic actions of bretylium are pronounced in the chronically treated group, suggesting an electrophysiologic basis of the delayed antiarrhythmic actions of bretylium.

Animals↗
PubMedDate not supplied

Competitive inhibition of acetylcholinesterase by bretylium: possible mechanism for its induction of norepinephrine release.

The antiarrhythmic drug bretylium tosylate competitively inhibits acetylcholinesterase activity. The Ki values for the inhibition of the purified enzyme (from electric eel), and acetylcholinesterase activity of crude rat ventricular and cortical homogenates were 6 X 10(-5), 3 X 10(-5), and 8 X 10(-5) M respectively. These values are close to the concentrations of the drug known to induce norepinephrine release from cardiac adrenergic presynaptic vesicles. It is suggested that inhibition of acetylcholinesterase activity by bretylium induces norepinephrine release through the effect of accumulated acetylcholine on nicotinic receptors in adrenergic nerve terminals.

Acetylcholinesterase↗
PubMed1989

Ischemia-induced conduction delay and ventricular arrhythmias: comparative electropharmacology of bethanidine sulfate and bretylium tosylate.

Bretylium tosylate and bethanidine sulfate were studied in two models of experimental myocardial ischemia. In anesthetized dogs, left anterior descending coronary artery occlusion during rapid atrial pacing (180-200 min-1) produced ventricular tachycardia and fibrillation within 5 min in 9 of 11 dogs studied. In all cases, arrhythmias were preceded by and appeared to be temporally related to progressive fractionation and delay of electrograms recorded from the ischemic zone. In four dogs, bretylium (10 mg/kg) did not alter the time course of electrogram changes nor the time to onset of arrhythmia. However, in five dogs bethanidine (10 mg/kg) markedly exacerbated conduction changes in the ischemic zone and decreased the time to onset of ventricular arrhythmias (173 +/- 35 vs. 262 +/- 34 s control, mean +/- SEM, p less than 0.05). Bethanidine administration also facilitated ischemia-induced ventricular tachycardia and fibrillation in two dogs that did not exhibit ischemia-induced arrhythmias before receiving the drug. In isolated perfused rabbit hearts, global ischemia produced conduction slowing, depolarization of resting membrane potential, and decreases in amplitude and Vmax that were reproducible in serial 10 min ischemic episodes. Bretylium (10 mg/L) did not affect these parameters under either perfused or ischemic conditions. Although bethanidine (10 mg/L) also did not affect these parameters during perfusion, conduction slowing and depression of Vmax during ischemia were accelerated without affecting the time course of change in resting membrane potential. Both bretylium and bethanidine prolonged action potential duration under perfused conditions, but after 10 min of ischemia this effect was no longer evident. The results demonstrate that differences in the electrophysiologic effects of bretylium and bethanidine are markedly accentuated in the setting of acute ischemia. Although both these agents have been demonstrated to have antifibrillatory effects in other experimental settings, under the conditions of this study, bretylium failed to protect against ischemia-induced arrhythmias and acute bethanidine administration produced a proarrhythmic effect in association with an exacerbation of ischemia-induced conduction changes.

Action Potentials↗