Bretylium tosylate binds preferentially to muscarinic receptors labelled with [3H]oxotremorine M (SH or 'high affinity' receptors) in rat heart and brain cortex.

Bretylium tosylate is an antiarrhythmic agent. In guinea pig atria it showed the properties of a competitive muscarinic (cholinergic) antagonist and could distinguish between two muscarinic receptor classes or states in cardiac membranes. We decided to further investigate its binding properties at muscarinic cholinergic receptors of the rat heart and brain (cortex), keeping in mind the recently discovered heterogeneity of muscarinic receptor protein. Bretylium tosylate recognized two receptor classes or states in the heart with Ki values of 0.9 and 11 microM. All cardiac membrane receptors showed a homogeneous (11 microM) Ki value for the drug in the presence of GTP in the incubation medium, or after in vivo pretreatment with islet activating protein (IAP). Bretylium tosylate was able (but only at a high concentration, 1 mM) to slow the dissociation kinetics of the tracer, which suggests that it also bound to an allosteric site on the muscarinic receptor, or that it affected the receptor environment. In the brain cortex, as in the heart, bretylium tosylate displayed a high affinity for receptors labelled with the agonist [3H]oxotremorine M (Ki value: 0.8 microM for the SH-or cardiac-type high-affinity receptors), and a 8- to 10-fold lower affinity for cortex M and L receptors. These data suggest that the antagonist bretylium tosylate had binding properties in rat cardiac membranes analogous to those of the partial agonist pilocarpine and that it interacted with a single type of receptor.

Inactivation of acetylcholinesterase with a bretylium tosylate photoaffinity probe.

Azidobretylium tosylate (ABT), the p-azido analogue of bretylium tosylate, has been synthesized to serve as a photoaffinity probe for bretylium binding sites. Bretylium tosylate has antiarrhythmic action and also interacts with amiloride-sensitive sodium ion transport sites. Acetylcholinesterase was used as a model protein, and both bretylium and ABT are reversible inhibitors of this enzyme. The kinetic inhibition constants (Ki) were determined to be 40 microM for bretylium tosylate and 6 microM for ABT. The azido compound is photochemically labile and apparently irreversibly inactivates the enzyme. The rate was retarded by the addition of bretylium tosylate or 4-oxo-N,N,N-trimethylpentanaminium iodide (OTI). Sephadex G-25 chromatography further demonstrated the irreversible nature of the photoinactivation. Since ABT binds at or near the acetylcholinesterase active site, it may be a useful probe for the characterization of the enzyme active site.

Antiarrhythmic drug therapy. Recent advances and current status.

A number of conventional and newer antiarrhythmic agents are available for the treatment and prophylaxis of ventricular tachycardia and sudden death. Using a multifaceted approach of programmed electrical stimulation studies, drug level determinations, exercise tolerance testing, and 24-hour ambulatory electrocardiographic monitoring, the physician can identify those patients who require therapy and then predict the likelihood of efficacy with each antiarrhythmic agent. This approach affords evaluation of both aspects of the sudden death equation-ectopy frequency (triggering mechanism) and vulnerability to development of sustained ventricular tachycardia (substrate). After institution of therapy, careful follow-up is necessary to document sustained drug efficacy and detect side effects. Serious adverse reactions necessitate a change in antiarrhythmic therapy, as opposed to lowering drug dosage to an ineffective level. The unacceptably high incidence of sudden death due to electrical instability can be reversed only by a rigorous and dedicated long-term approach to the management of serious ventricular arrhythmias.

Bretylium tosylate: profile of the only available class III antiarrhythmic agent.

Bretylium tosylate, the only approved class III antiarrhythmic agent, is a unique quaternary ammonium compound with prominent experimental and clinical antifibrillatory effects. Intravenous bretylium causes a biphasic hemodynamic response; initial norepinephrine release is followed by sympathetic ganglionic blockade. Cardiac output is well maintained. Electrocardiographic intervals are unchanged, and global conduction unchanged or facilitated. With long-term experimental use, proportionate lengthening of ventricular action potential and refractory period occurs. Bretylium is largely eliminated unchanged in the urine, with a long terminal half-life of about 13 hours. Bretylium demonstrates substantial activity in several animal models and clinical circumstances of ventricular fibrillation, including those in which standard antiarrhythmic therapy is ineffective. Bretylium is thus currently approved as a first-line agent for prophylaxis and treatment of ventricular fibrillation, and as a second-line agent for ventricular tachycardia and other prefibrillatory ventricular arrhythmias. In contrast, bretylium's weak antiectopic activity and limited oral absorption make it a poor choice for management of simple ventricular ectopy. Side effects of bretylium are generally limited to its hemodynamic actions (eg, postural hypotension). Nausea may occur with rapid intravenous administration. Emerging clinical concepts emphasize the clinical importance of antifibrillatory action over antiectopic effects alone. Bretylium is thus likely to continue to find increasing usage in the acute management of malignant ventricular arrhythmia.

Nomogram for bretylium dosing in renal impairment.

Bretylium (Bretylol), an antiarrhythmic agent, is currently being used in the prophylaxis and treatment of patients with life-threatening ventricular fibrillation and tachycardia not responsive to conventional therapy. Because bretylium has a delayed onset of action that commonly causes hypotension and may increase ventricular irritability, its use in patients (especially patients with renal impairment) must be exercised with caution. Our results show that the maximum plasma concentration (Cmax) observed at the end of bretylium infusion, when normalized to the dose, increases significantly as renal function diminishes. Significant reductions in renal and total body clearance of bretylium have been observed in patients with renal insufficiency. In order to minimize the risk of potential toxicity following multiple dosing in such patients, dosage adjustments are necessary. Based on correlations developed between the total body clearance of bretylium and renal function, we present a nomogram herein that can be effectively used for adjusting the dosage of bretylium in patients with renal impairment.

Interaction of bretylium tosylate with rat cardiac muscarinic receptors. Possible pharmacological relevance to antiarrhythmic action.

The interaction of the antifibrillatory antiarrhythmic drug, bretylium tosylate, with the muscarinic receptor in tissue homogenates from regions of rat brain and heart was investigated. Competition-binding experiments were carried out with the highly specific tritiated antagonist N-methyl-4-piperidyl benzilate. Bretylium tosylate competitively displaced the labeled antagonist from the muscarinic receptor. The binding of the drug to the two brain preparations was found to be best fitted by a one-site model in each case. On the other hand, in the case of both heart preparations, a two-site model yielded a significantly better fit for the binding data than that given by a single-site model. The low affinity-binding constants in the atrium and the ventricle were similar (approximately 10 microM) to those in the brain regions examined, namely, the cortex and the medullapons. Sites with relatively higher affinity for the drug were detected in the heart only, with equilibrium-binding constants of 0.24 +/- 0.12 microM and 0.97 +/- 0.27 microM for the atrium and the ventricle, respectively. The drug also exerted anti-acetylcholine activity (K1 = 14 +/- 2 microM) measured physiologically in the guinea pig atrium, which correlated well with the concentration of the drug observed to be efficacious clinically (approximately 10 microM).

Tissue distribution of [14C]bretylium tosylate in rats.

The distribution of [14C]bretylium tosylate in the body and the relationship between tissue and plasma concentrations was determined following intravenous administration of the drug to Charles River rats. The renal excretion of bretylium was rapid in rats and follows an active process. On the average, 50% of the administered dose was excreted in the urine within 1 hr. In the postequilibrium phase, the plasma concentration declined with a half-life of 5 hr. Bretylium concentrations in all tissues, except the heart, declined rapidly according to a triexponential equation. The liver and kidney bretylium concentrations declined in parallel to the plasma concentration with mean tissue-plasma concentration ratios of 6.04 and 12.3, respectively, in the beta phase. However, the concentration of bretylium in the heart increased gradually and peaked at 2 hr, with a tissue-plasma concentration ratio of 121, which, in turn, declined to a value of greater than 60 after 8 hr. The data indicated that (a) bretylium is rapidly distributed into the liver and kidney immediately after reaching the systemic circulation; (b) the distribution into the heart occurs at a slower rate compared with the other organs, and the drug has a high affinity to the myocardium; and (c) since the heart is the site of action and there is no direct correlation between the concentrations in myocardium and plasma, the antiarrhythmic effect of bretylium may not be related to the plasma concentration.

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.

Pharmacokinetics of bretylium in dogs and the effect of hemoperfusion on elimination.

The pharmacokinetics of bretylium in dogs and the efficacy of hemoperfusion with a resin column in its removal from the body following intravenous administration of bretylium tosylate were investigated. Five mongrel dogs weighing 18-26 kg were given a bolus dose of 15 mg/kg. Serial blood samples were taken for 24 hr. Hemoperfusion, through a resin column, was then initiated and continued for 4 hr under pentobarbital anesthesia. During hemoperfusion, arterial and venous blood samples were collected several times; venous blood samples were then withdrawn for an additional 8 hr. Urine was collected from each dog in three portions for up to 48-54 hr. Pharmacokinetics of bretylium in dogs could be characterized by a two-compartment open model with a distribution half-life of 7 min and biological half-life of 15.9 +/- 1.9 hr. Plasma levels declined rapidly from approximately 20 microgram/ml at 6 min to less than 2 microgram/ml within 1 hr. The ratio of intercompartmental rate constants, k12/k21, was 16.7, and the volume of the central compartment and apparent volume of distribution were 0.245 and 5.22 liter/kg, respectively, indicating a wide distribution of bretylium into the tissues. Plasma dialysis clearance averaged 29.7 ml/min, which is 30% of the total body clearance (98.8 ml/ min). These data suggest that resin hemoperfusion may not be useful in the treatment of bretylium intoxication.

Bretylium pharmacokinetics and bioavailabilities in man with various doses and modes of administration.

The pharmacokinetics and bioavailabilities of bretylium tosylate were studied in 9 male normal volunteers by 60 min constant rate intravenous infusions of 200, 300, and 400 mg, by intramuscular injection of 300 and 400 mg, by oral administration of 100, 200, and 400 mg in solution, and by oral administration of 200 mg tablets. The latter studies were repeated in the same 5 volunteers which were also studied by all modes of administration and at several doses. Intravenous studies showed a sum of 3 exponentials to characterize plasma level-time studies with a terminal half-life of 535 +/- 32 (S.E.M.) min (n = 12). The urinary recovery of unchanged drug was 77 +/- 4(S.E.M.)(n = 14). Half-lives within a subject were correlated and independent of dose. Intramuscular administration showed an apparent half-life of first-order invasion of 79 +/- 13 (S.E.M.) min (n = 6) with no apparent dose dependency and a urinary recovery of unchanged drug of 95.4 +/- 3.2 (S.E.M.) per cent with a terminal half-life similar to the intravenous studies. Oral solutions had smaller lag times of absorption [17 +/- 4(S.E.M.) min] than tablets [56 +/- 9 (S.E.M.) min] and longer apparent half-lives of first-order absorption [231 +/- 23 (S.E.M.) min] than tablets [87 +/- 15 (S.E.M.) min]. The tablets had slightly greater bioavailabilities [27 +/- 2.3 (S.E.M.) per cent] than the oral solutions [22.1 +/- 2.2 (S.E.M.) per cent] but with no apparent dose dependencies. Renal clearances were the same for all modes of administration. Means +/- S.E.M. were 735 +/- 32, i.v., 686 +/- 38, i.m., and 623 +/- 57 ml min-1, p.o. Apparent overall volumes of distribution were 589 +/- 401, i.v. and 450 +/- 671 (S.E.M.), i.m. The i.v. studies in three dogs confirmed the three-compartment body model and the high overall volumes of distribution, had terminal half-lives similar to humans and had renal clearances of 84, 164, and 207 ml min-1 that were in excess of glomerular filtration. There were no significant changes of cardiovascular parameters with the time course of the drug in the body and no significant drug-affected clinical parameters. The only consistent side effect was a generally transient nasal congestion at plasma peak time on intravenous administration.

Pharmacokinetics of [14C]bretylium tosylate in rats.

The pharmacokinetics of bretylium tosylate were investigated in eight male Charles River rats. Each animal received an intravenous dose (10 mg/kg) of [14C)bretylium tosylate. Serial blood samples, urine, and feces were collected for up to 72 hr. Bretylium concentrations in plasma and amounts excreted in urine and feces were determined by scintillation counting. On the average, 88 and 95% of the dose were recovered in urine and feces in 24 and 72 hr, respectively. Urinary recovery accounted for 65.6 of the dose while 29.7% was excreted in the feces. Bretylium concentrations in plasma declined triexponentially and were fitted to a three-compartment open model. Bretylium has a very high apparent volume of distribution (15 liters/kg), and its beta half-life averaged 5.5 hr. Mean values of the apparent volume of the central compartment, plasma clearance, renal clearance, and excretion rate constants of bretylium in rats were 1 liter/kg, 1.93 liters/hr/kg, 1.27 liters/hr/kg, and 1.24 hr-1, respectively. The results indicate that: (a) bretylium is strongly bound to the tissues and is eliminated by active urinary secretion and by biliary excretion in rats, and (b) there are strong similarities between the pharmacokinetics of bretylium in humans and rats and that this animal model might be suitable for interaction studies with other drugs.

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.

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.

Pharmacokinetics of bretylium in man after intravenous administration.

The pharmacokinetic profile of bretylium was studied in four normal male volunteers using a new sensitive EC-GC procedure for its quantitative in biological fluids. The plasma concentrations and urinary excretion rates following the constant i.v. infusion of a single 4 mg/kg dose of bretylium tosylate declined biexponentially and the data were fitted to a two-compartment model with a renal and a nonrenal route of elimination. The drug had a mean half-life (t1/2 beta) of 7.8 hr and apparent volume of distribution (Vd, beta) of 8.18 liters/kg. The renal clearance, which was 6 times that of the glomerular filtration rate, accounted for almost 84% of the total body clearance and correlated linearly with the subjects' creatinine clearance. The observed side effects of bretylium were mild and similar to those of other adrenergic blocking agents.

Bretylium tosylate: a review.

The chemistry, pharmacology, pharmacokinetics, clinical uses, adverse effects, drug interactions and dosage of bretylium tosylate, a recently approved antiarrhythmic agent, are reviewed. Bretylium tosylate is used to treat life-threatening ventricular arrhythmias, principally ventricular fibrillation and ventricular tachycardia, that have not responded to treatment with first-line antiarrhythmic agents. The drug has a direct positive inotropic effect on the myocardium and blocking effect on postganglionic sympathetic nerve transmission. The drug is poorly absorbed orally, requiring either i.m. or i.v. administration. Drug excretion occurs primarily through the kidney, necessitating dosage modification in renal disease. Hypotension is the most commonly observed adverse reaction to bretylium tosylate. Rapid i.v. administration may cause severe nausea and vomiting, and i.m. injection at the same site may cause atrophy and necrosis of muscle tissue. Quinidine and procainamide may potentiate the hypotensive effects of bretylium. Bretylium will aggravate digitalis-induced arrhythmias. Bretylium's use in resistant ventricular tachyarrhythmias requires close clinical monitoring.

Bretylium tosylate: a newly available antiarrhythmic drug for ventricular arrhythmias.

Bretylium tosylate (Bretylol) has recently been approved for parenteral use against resistant ventricular arrhythmias. The pharmacologic action of bretylium is complex, and its antiarrhythmic action differs significantly from other drugs. Bretylium is an adrenergic neuronal blocking agent taken up selectively at peripheral adrenergic nerve terminals, where it initially releases norepinephrine (sympathomimetic effect) and then produces adrenergic neuronal blockade. It has direct cardiac membrane effect to prolong action potential duration and effective refractory period but, unlike other membrane active antiarrhythmic agents, does not depress conduction velocity or automaticity. Bretylium increases ventricular fibrillation threshold and prevents the decrease in ventricular fibrillation threshold associated with myocardial ischemia. It does not depress myocardial contractility. Clinical studies have shown parenteral bretylium to be effective in suppressing ventricular arrhythmias, particularly recurrent, drug resistant ventricular tachycardia or ventricular fibrillation.

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.

[Bretylium tosylate as an anti-arrhythmic drug]. / Bretylium tosylat als Antiarrhythmikum

With the help of an analysis of the world literature pharmacological, pharmacokinetic and electrophysiological properties as well as the possibilities of the clinico-therapeutic use of Bretylium tosylat are demonstrated. The pharmacon is of increasing interest as antiarrhytmic, especially in the commandment of otherwise therapy-refractory ventricular disturbances of rhythm. A positively inotropic effect is proved. More severe side effects, such as arterial hypotension and increase of the pulmonary vascular resistance have an objection to routine application. The antifibrillatory effect needs particular consideration. This effect might promote this pharmacon to the "chemical defibrillator" in the emergency situation.