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Journal of Cardiovascular Pharmacology 1981We studied 12 patients receiving either chronic oral (p.o.) maintenance bretylium and/or acute intravenous (i.v.) bretylium to evaluate drug efficacy and...
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.
Topics: Administration, Oral; Adult; Aged; Arrhythmias, Cardiac; Blood Pressure; Bretylium Compounds; Bretylium Tosylate; Female; Humans; Injections, Intravenous; Kinetics; Male; Middle Aged; Ventricular Fibrillation
PubMed: 6168830
DOI: 10.1097/00005344-198105000-00008 -
American Journal of Hospital Pharmacy Jun 1983The stability of bretylium tosylate when mixed with large-volume parenteral (LVP) solutions was assessed over a four-week period, and the compatibility of bretylium...
The stability of bretylium tosylate when mixed with large-volume parenteral (LVP) solutions was assessed over a four-week period, and the compatibility of bretylium tosylate when mixed with eight frequently used drugs was evaluated. Bretylium tosylate admixtures of approximately 1 mg/ml were prepared in both polyvinyl chloride (PVC) bags and glass bottles of 5% dextrose injection, 0.9% sodium chloride injection, and lactated Ringer's injection. The admixtures were examined visually and stored for four weeks at 25 +/- 0.5 degree C under fluorescent light. The concentrations of bretylium tosylate were determined spectrophotometrically at times 0.25, 0.5, 1, 3, 8, 24, and 48 hours and twice weekly thereafter for four weeks. Spectrophotometric assays were confirmed with high-pressure liquid chromatography. Admixtures of bretylium tosylate were prepared with aminophylline, calcium gluconate, digoxin, regular insulin, lidocaine hydrochloride, phenytoin sodium, procainamide hydrochloride, and quinidine gluconate in 5% dextrose injection and 0.9% sodium chloride injection. The admixtures were examined visually for 48 hours. The concentration of bretylium tosylate did not change appreciably during the four-week study period. There were no signs of haze, precipitation, color change, or evolution of gas. There were no apparent differences in stability when comparing the glass with the PVC containers. Bretylium tosylate was also found to be compatible with all the additives tested except phenytoin sodium; a precipitate formed immediately when the latter drug was added to the bretylium tosylate solution. Bretylium tosylate was stable for four weeks in the LVP solutions studied in both glass and PVC containers. The admixtures of bretylium sodium with the other drugs were all visually compatible except those containing phenytoin sodium.
Topics: Bretylium Compounds; Bretylium Tosylate; Drug Incompatibility; Drug Packaging; Drug Stability; Excipients; Glass; Infusions, Parenteral; Polyvinyl Chloride; Solutions; Time Factors
PubMed: 6869385
DOI: No ID Found -
Archives of Internal Medicine Jul 1969
Topics: Animals; Bretylium Compounds; Dogs; Electrocardiography; Heart; Ventricular Fibrillation
PubMed: 5791492
DOI: No ID Found -
European Journal of Pharmacology Jan 1989Bretylium tosylate is an antiarrhythmic agent. In guinea pig atria it showed the properties of a competitive muscarinic (cholinergic) antagonist and could distinguish...
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.
Topics: Animals; Bretylium Compounds; Bretylium Tosylate; Cerebral Cortex; Guanosine Triphosphate; Heart; In Vitro Techniques; Male; Membranes; Myocardium; N-Methylscopolamine; Oxotremorine; Pilocarpine; Rats; Rats, Inbred Strains; Receptors, Muscarinic; Scopolamine Derivatives
PubMed: 2714357
DOI: 10.1016/0014-2999(89)90660-2 -
British Journal of Pharmacology Apr 19711. The actions of bretylium tosylate on neuromuscular transmission in the rat phrenic nerve diaphragm preparation have been investigated by electrophysiological methods....
1. The actions of bretylium tosylate on neuromuscular transmission in the rat phrenic nerve diaphragm preparation have been investigated by electrophysiological methods. Additional experiments have been made on the effect of the drug on the frog rectus preparation and on the acetylcholinesterase of erythrocytes.2. After bretylium, there was a reduction in the amplitudes of miniature end-plate potentials (mepps), endplate potentials (epps) and acetylcholine potentials recorded in the diaphragm, and also in the contractures of the rectus in response to acetylcholine (ACh) and to carbachol.3. After bretylium, there was a prolongation of the time courses of epps and ACh potentials. Under certain circumstances there was enhancement of the amplitudes of epps and ACh potentials and of the contractile responses to ACh but not to carbachol.4. Bretylium reduced the velocity of hydrolysis of ACh by erythrocyte ghosts. This inhibition was competitive and the Ki of bretylium was 0.053 mM.5. Bretylium did not cause a reduction in the mean quantal content of the epp in junctions blocked with Mg(++).6. It is concluded that bretylium exerts both facilitatory and inhibitory influences on neuromuscular transmission, which, exerted simultaneously, may give the false appearance that the drug has little action at this synapse.
Topics: Acetylcholine; Acetylcholinesterase; Animals; Bretylium Compounds; Carbachol; Diaphragm; Electrophysiology; Erythrocytes; Female; In Vitro Techniques; Magnesium; Male; Membrane Potentials; Muscle Contraction; Muscles; Neuromuscular Junction; Phrenic Nerve; Rats; Receptors, Cholinergic; Receptors, Drug
PubMed: 5103906
DOI: 10.1111/j.1476-5381.1971.tb07069.x -
Journal of Cardiovascular Pharmacology 1983The electrophysiologic and antiarrhythmic actions of bretylium tosylate were studied after acute coronary artery occlusion and reperfusion in pentobarbital-anesthetized...
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.
Topics: Animals; Arrhythmias, Cardiac; Blood Pressure; Bretylium Compounds; Bretylium Tosylate; Coronary Vessels; Dogs; Electrophysiology; Heart; Heart Conduction System; Heart Rate; Male; Myocardial Contraction
PubMed: 6193345
DOI: 10.1097/00005344-198307000-00002 -
American Heart Journal Jun 1983We used programmed ventricular stimulation to test intravenous bretylium tosylate in 10 consecutive patients with inducible sustained ventricular tachycardia (usually...
We used programmed ventricular stimulation to test intravenous bretylium tosylate in 10 consecutive patients with inducible sustained ventricular tachycardia (usually refractory to type I antiarrhythmic agents). These 10 patients had previously documented sustained ventricular tachycardia and/or ventricular fibrillation complicating stable heart disease. Following control inductions of sustained ventricular tachycardia, bretylium 10 mg/kg was infused over 30 minutes. Thirty minutes after this infusion, sustained ventricular tachycardia could be induced in 9 of the 10 patients (one of these nine patients also had bretylium-potentiated spontaneous ventricular tachycardia). Tachycardia induced in the nine patients after bretylium was similar to control tachycardia with respect to morphology and cycle length (333 +/- 16 msec after bretylium versus 330 +/- 16 msec during control). However, five of the nine patients tolerated induced tachycardia less well after bretylium (exacerbated hypotension). In one patient, ventricular tachycardia could not be induced after intravenous bretylium.
Topics: Administration, Oral; Adult; Aged; Anti-Arrhythmia Agents; Bretylium Compounds; Bretylium Tosylate; Cardiac Pacing, Artificial; Electrocardiography; Female; Heart Ventricles; Humans; Infusions, Parenteral; Male; Middle Aged; Tachycardia
PubMed: 6858846
DOI: 10.1016/0002-8703(83)90399-x -
Annals of Internal Medicine Oct 1986
Topics: Adult; Bretylium Compounds; Bretylium Tosylate; Humans; Hypothermia; Male; Ventricular Fibrillation
PubMed: 3752772
DOI: 10.7326/0003-4819-105-4-624_1 -
Clinical Pharmacology and Therapeutics Oct 1980To 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... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
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.
Topics: Administration, Oral; Adult; Blood Pressure; Blood Proteins; Bretylium Compounds; Bretylium Tosylate; Humans; Injections, Intravenous; Kidney; Kinetics; Male; Metabolic Clearance Rate; Middle Aged; Protein Binding
PubMed: 7408407
DOI: 10.1038/clpt.1980.190 -
AANA Journal Jun 1983The impact of psychogenic and physical stressors has been shown to have a negative effect on cardiovascular homeostasis (Figure 2). As CRNAs, we have a responsibility to...
The impact of psychogenic and physical stressors has been shown to have a negative effect on cardiovascular homeostasis (Figure 2). As CRNAs, we have a responsibility to maintain the patient's equilibrium under the stress-provoking conditions of surgery. Experience in coronary care units over the last 16 years has shown that the majority of patients who develop primary ventricular fibrillation during AMI can be rapidly resuscitated by prompt defibrillation. Only in a small number of patients does ventricular tachycardia or ventricular fibrillation become recurrent or resistant to treatment. It is in this small number that bretylium has proven itself to be a life-saving treatment.
Topics: Arrhythmias, Cardiac; Bretylium Compounds; Bretylium Tosylate; Heart Ventricles; Hemodynamics; Humans; Myocardial Contraction; Myocardial Infarction; Stimulation, Chemical
PubMed: 6613506
DOI: No ID Found