Comparative mechanisms of action of antiarrhythmic drugs.
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Action Potentials↗
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Bretylium: a prototype for future development of antidysrhythmic agents.
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Anti-Arrhythmia Agents↗
Prevention of ventricular fibrillation by bretylium in a conscious canine model of sudden coronary death.
In anesthetized dogs, a silver wire electrode was inserted into the lumen of the circumflex coronary artery (LCX) and myocardial infarction was produced by a temporary 90-minute occlusion of the left anterior descending coronary artery (LAD) followed by reperfusion. Four days later while in the ambulatory state, a 150 microA current was applied to the intimal surface of the LCX of saline (n = 10) and bretylium (n = 10) treated animals. Intimal injury and coronary thrombosis produced ST segment changes at 138 +/- 39 minutes (chi +/- SEM), followed by premature ventricular beats (at 142 +/- 37 minutes), ventricular tachycardia (at 156 +/- 49 minutes), and ventricular fibrillation (at 163 +/- 51 minutes) in 9 of 10 saline-treated animals. In bretylium-treated animals, ST segment changes appeared at 128 +/- 35 minutes, with six animals surviving for 24 hours (p less than 0.03 vs saline). LAD infarction was present in both saline (14.1 +/- 2.3%) and bretylium (15.1 +/- 2.1% of left ventricle) treated animals with only bretylium-treated animals developing LCX infarcts (16.1 +/- 2.1%). Bretylium prevents ventricular fibrillation (VF) resulting from ischemia at a site distant to prior myocardial infarction in the conscious dog and deserves further attention as a potential antifibrillatory agent for prevention of sudden coronary death in man.
Animals↗
Failure of bretylium to suppress inducible ventricular tachycardia.
Five patients with recurrent, life-threatening ventricular arrhythmias were given bretylium tosylate intravenously for a minimum of 4 days. Arrhythmias were not related to acute ischemia in any patient. Four patients had inducible ventricular tachycardia, and one patient had inducible ventricular fibrillation requiring cardioversion while taking no medications. Programmed electrical stimulation was then repeated to assess the ability of bretylium to suppress inducible ventricular tachycardia. Bretylium tosylate, at a mean dose of 2.3 mg intravenously per minute, did not suppress inducible ventricular arrhythmias in any patient. Rapid ventricular tachycardia was induced in all patients, and ventricular fibrillation was induced in one patient. Two patients required external cardioversion to terminate their arrhythmias. Bretylium tosylate, given in relatively large doses chronically, did not suppress inducible ventricular arrhythmias in these five otherwise drug-refractory patients with chronic recurrent ventricular tachycardia. This failure to suppress inducible ventricular arrhythmias cannot be attributed to the initial catecholamine release which occurs in the first hour or two after the drug is administered.
Adult↗
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.
Animals↗
Electrophysiologic testing of bretylium tosylate in sustained ventricular tachycardia.
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.
Administration, Oral↗
Effect of quinidine and bretylium on defibrillation energy requirements.
We examined the effect of bretylium and quinidine on the energy requirements for internal defibrillation in 14 pentobarbital-anesthetized dogs. Bretylium, 6 or 10 mg/kg (n = 6), did not affect the relation between energy and the likelihood of successful defibrillation. The mean energy required to achieve 50% success (E50) or 90% success (E90) in defibrillation was not significantly altered; E50 was 5.3 +/- 1.9 J (X +/- s.d) before and 6.1 +/- 3.5 J after bretylium (n.s.), and E90 was 7.2 +/- 2.1 J before and 8.6 +/- 3.3 J after drug (n.s.). Quinidine was administered in a series of two loading and maintenance infusions to achieve mean plasma concentrations of 2.4 +/- 0.63 and 2.95 +/- 0.88 microgram/ml, respectively (n = 8). No significant effect on defibrillation energy requirement was observed; mean E50 before and after treatment was 6.3 +/- 3.3 J and 6.2 +/- 2.9 J, respectively, and mean E90 was 8.3 +/- 4.4 J and 8.3 +/- 4.1 J, respectively. Similarly, saline administration to control dogs (n = 12) resulted in no change in E50 or E90. At concentrations or doses similar to those in patients with serious arrhythmias, neither quinidine nor bretylium appears to have consistent effects on the energy requirements for internal defibrillation in our dog model.
Animals↗
Comparison of bretylium tosylate and lidocaine in management of out of hospital ventricular fibrillation: a randomized clinical trial.
Bretylium tosylate was compared with lidocaine hydrochloride as initial drug therapy in 146 victims of out of hospital ventricular fibrillation in a randomized blinded trial. An organized rhythm was achieved in 89 and 93 percent and a stable perfusing rhythm in 58 and 60 percent of the patients who received bretylium and lidocaine, respectively. After initiation of advanced life support, an organized rhythm was first established after an average of 10.4 minutes and 10.6 minutes in the two respective groups, requiring an average of 2.8 defibrillatory shocks in those who received bretylium and 2.4 in the lidocaine-treated patients. Comparable numbers of patients were discharged from the hospital: 34 percent of those given bretylium and 26 percent of the patients whose initial therapy was lidocaine. No instance of chemical defibrillation was observed with either drug. In this study, bretylium afforded neither significant advantage nor disadvantage compared with lidocaine in the initial management of ventricular fibrillation.
Bretylium Compounds↗
Bretylium tosylate in patients with acute myocardial infarction.
Experience with bretylium tosylate accumulated during a period of over 10 years, during which time greater than 1,500 patients with acute myocardial infarction were treated, is summarized. On the diagnosis of acute infarction, the agent was given by continuous intravenous drip at a rate of 10 mg/kg/24 hours for 5 to 7 days for prophylaxis of ventricular fibrillation. Bretylium administration prevented primary ventricular fibrillation in about 99% of these patients. No undesirable side effects were observed with this protocol, which lessens the initial sympathomimetic effect of the drug while allowing sufficient time for the adrenergic neuronal blocking effect to develop. The beneficial effects of the drug are believed to be due, in part, to a direct electrophysiologic effect on both normal and ischemic myocardium. This effect equalizes the duration of both the effective refractory periods and the ventricular action potentials, and it creates conditions capable of blocking reentrant pathways. Bretylium stabilizes the duration of electrical systole in patients with acute myocardial infarction. Hemodynamic studies during bretylium treatment further confirm the effectiveness of this drug and have prompted additional studies to evaluate its potential as an agent capable of decreasing impedance in acute myocardial infarction.
Animals↗
Management of ventricular dysrhythmias in the prehospital and emergency department setting.
Each year approximately 1,500,000 people experience acute myocardial infarction. About 40% of them die, half before they reach the hospital. Ventricular fibrillation (VF) is a major cause of cardiac arrest, and delay in administering antiarrhythmic agents contributes to the incidence of out-of-hospital deaths. The 3 antiarrhythmic drugs currently used by paramedics for cardiac arrest are bretylium, lidocaine, and procainamide. The early use of bretylium tosylate is stressed in Advanced Cardiac Life Support protocols because of the agent's antifibrillatory properties, that is, its ability to increase the VF threshold and to block reentry. Evidence indicates that early, aggressive use of bretylium tosylate as a first-line agent improves the likelihood of successful resuscitation. Preliminary data are presented from an ongoing comparative study of prehospital use of bretylium tosylate and lidocaine for VF. One hundred seventeen cardiac arrests have occurred, 55 of which were associated with VF and are included in the study. Resuscitation was not attempted in 3 of the 55 patients at the request of the family and physician. Of the remaining 52 patients, 17 received bretylium tosylate plus lidocaine, 12 lidocaine alone, and 7 only bretylium tosylate. There were 16 patients who did not receive medications. According to the study protocol, the choice of antiarrhythmic agents was determined by the paramedic shift during which arrest occurred. Of the 52 patients treated, 16 (30%) survived. It is too soon to draw any conclusions.
Arrhythmias, Cardiac↗
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)
Adult↗
Mechanism of the effect of bretylium on the ventricular fibrillation threshold in dogs.
Experiments were performed to determine the importance of sympathetic blockade vs a direct myocardial effect as a mechanism for the antifibrillatory action of bretylium. The ventricular fibrillation (VF) threshold was determined in open-chest, anesthetized dogs by scanning the vulnerable period with either a single electrical stimulus (10 ms) or a train of electrical stimuli (14 pulses, 4 ms, 100 Hz). Using the train-of-pulses technique, the VF threshold increased from 6.8 +/- 0.6 mA to 29.7 +/- 6.4 mA 15 minutes after a 10-mg/kg intravenous bolus of bretylium (p less than 0.001, n = 8). There was no further significant change in the train-of-pulses VF threshold at 2 or 4 hours. Beta-adrenergic blockade with timolol (0.2 mg/kg) increased the train-of-pulses VF threshold from 6.7 +/- 1.6 mA to 24.5 +/- 5.2 mA (p less than 0.01 n = 8) and prevented any further significant change in response to bretylium. When single electrical pulses were used to scan the vulnerable period, bretylium at doses of 10 mg/kg (n = 8) and 100 mg/kg (n = 6) did not alter the VF threshold over a 4-hour observation period. The administration of timolol, alone or in combination with bretylium, did not significantly alter the single-pulse VF threshold. The failure of bretylium to alter the single-pulse VF threshold was not dependent on the site of stimulation. Stimulation of the right sympathetic cardiac nerves showed that 15 minutes of bretylium treatment was sufficient to completely inhibit adrenergic neuronal transmission to the myocardium.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Comparison between bretylium and diphenylhydantoin interaction with mucosal sodium-channels.
The antifibrillatory drug bretylium and the antiepileptic drug diphenylhydantoin cause an increase in the potential different and in the short-circuit current (SCC) across frog skin when added to the outer surface. The effect of both drugs depends upon the presence of sodium ions in the outer medium and is blocked by the specific sodium channel blocker, amiloride. Quantitative analysis shows that amiloride binds to open as well as closed mucosal sodium channel with the same affinity. The effects of diphenylhydantoin and bretylium differ with respect to their dependence on external pH. The diphenylhydantoin or the bretylium stimulatory effects are additive to the effects of oxytocin. In most cases the diphenylhydantoin and bretylium effects are also additive. It is concluded that the external side of the mucosal Na+ channels contains sites which interact specifically with either bretylium or diphenylhydantoin and thus remove the sodium induced closure of the channels.
Amiloride↗
Cardiac arrhythmias produced by bretylium in cats anesthetized with halothane.
Bretylium given by rapid intravenous injection into cats anesthetized solely with halothane precipitates severe and unusually long-lasting ventricular arrhythmias. They are observed 20-70 sec following doses of bretylium ranging from 0.8 mg/kg to 15 mg/kg and last for 60 sec to just over half an hour. Bretylium also manifests signs of sympathetic involvement since it raises blood pressure and heart rate just prior to the onset of arrhythmias. Propranolol pretreatment prevents bretylium arrhythmias. From these results and from those of other investigations, it is concluded that bretylium arrhythmias are mediated through the release of endogenous noradrenaline stored in adrenergic neurons of the heart. These results call attention to the arrhythmogenic potential of bretylium in the presence of halothane anesthesia.
Anesthesia↗
The action of reserpine, 6-hydroxydopamine, and bretylium on digitalis-induced cardiotoxicity.
This study determined whether the protective effect of reserpine against ouabain-induced ventricular arrhythmias in the cat is due to an action of the drug on the adrenergic nerve terminal. Reserpine (5 mg/kg i.p.) administered 24 h prior to ouabain (2 micrograms/kg per min i.v., until death) increased the dose of ouabain to produce premature ventricular contractions, ventricular tachycardia, and death from 77.3 +/- 5.2 to 105.0 +/- 6.0; 84.9 +/- 5.2 to 132.7 +/- 9.1; and 108.8 +/- 4.0 to 165.7 +/- 10.4 micrograms/kg, respectively (P less than 0.05). When 6-hydroxydopamine (6OHDA; 20 mg/kg i.v.) was given 3 days prior to the experiment, the protective effect of reserpine was not evident. When bretylium (20 mg/kg i.v., 2 h prior to ouabain) was administered to animals previously treated with reserpine, the dose of ouabain which produced premature ventricular contractions, ventricular tachycardia, and death was increased to 109.0 +/- 7.2; 146.1 +/- 12.6; and 165.8 +/- 7.6 micrograms/kg, respectively (P less than 0.05). However, the magnitude of this protective action was similar to that produced by reserpine alone. Lathers et al. (Fed. Proc. 40, 672, 1981) reported that bretylium alone provides protection of a similar order of magnitude as reserpine. Thus, the effects of reserpine and bretylium were not additive; this indicates that the two agents may be acting on the same locus or they may be acting at different sites with the action of one drug masking or blocking the action of the other. Since 6OHDA prevented the action of reserpine on ouabain-induced ventricular arrhythmia and since 6OHDA only produces degeneration of adrenergic nerve terminals, it is probable that the protective effect of both reserpine and bretylium is due to an action at the adrenergic nerve terminal. The heart rate and blood pressure were not involved in the antiarrhythmic effects of reserpine.
Animals↗
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.
Animals↗
Bretylium tosylate enhances salt taste.
Bretylium tosylate (BT), an antifibrillary drug, was found to potentiate the taste of NaCl and LiCl in both humans and rats. Application of 1 mM BT (pH 6.3) to the human tongue statistically potentiated the taste of 0.2 M NaCl and 0.2 M LiCl by 33.5% and 12.5% respectively. Electrophysiological taste responses from nucleus tractus solitarius (NTS) in rat for both hyposmotic and hyperosmotic concentrations of NaCl and 0.1 M LiCl were also increased by 30 to 40% after application of 1 mM BT. This potentiation induced by BT was reduced by amiloride in both humans and rats. Furthermore, amiloride became ineffective in inhibiting taste responses to NaCl in the presence of BT.
Adolescent↗
Prophylaxis and therapy of ventricular fibrillation: bretylium reviewed and lidocaine refuted.
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Animals↗