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PubMed1985

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.

Adult↗
PubMed1981

Comparative studies of (--)-, (+/-)-propranolol, atenolol, guanethidine, bretylium and tetracaine on adrenergic transmission.

1 Effects of (--)-, (+/-)-, and (+)-propranolol, atenolol, guanethidine, bretylium and tetracaine were studied on relaxation responses of rabbit ileum and contractile responses of rabbit pulmonary artery and guinea-pig vas deferens to electrical nerve stimulation (2 to 50 Hz). 2 In the ileum, inhibition by tetracaine 3.3 x 10(-6) M occurred at high frequencies of stimulation, while bretylium 1.2 x 10(-4) M and guanethidine 2 x 10(-5) M inhibited responses at all frequencies, the latter producing greater inhibition at low frequencies. 3 (+/-)-Propranolol 10(-5) M produced a tetracaine-type inhibition after 1 h and a bretylium-pattern after 2 h in the ilea and pulmonary arteries and a transition from bretylium- to guanethidine-pattern in the vas deferens, while atenolol 2 x 10(-5) to 10(-4) M produced guanethidine-type inhibition in all preparations. 4 (--)-, (+/-)-, and (+)-Propranolol 3 x 10(-6) to 3.3 x 10(-5) M were equipotent in the vas deferens and ileum. However, inhibition by (--)-propranolol 3.3 x 10(-5) M persisted in the ileum, while that by the (+)-isomer was partially restored by washing. 5 (--)- or (+)-Propranolol 3.3 x 10(-5) M or atenolol 2 x 10(-5) M did not inhibit relaxation of the ileum after the bath temperature was maintained at 4 degrees C for 2 h during drug application. 6 In conclusion, propranolol and atenolol both have gradually developing guanethidine-like adrenergic neurone blocking actions.

Animals↗
PubMed1976

Effect of adrenergic neuron inhibitors on the vascular response to sympathetic nerve stimulation.

In anesthetized cats, the lumbar sympathetic trunk was stimulated, and the responses of the resistance and capacitance vessels of the hindlimb were recorded (by resistography and plethysmography, respectively). The drugs used were reserpine, methyldopa and bretylium tosylate. It was found that reserpine and methyldopa inhibit the response of the resistance vessels to a greater extent than that of the capacitance vessels, while bretylium tosylate has a greater effect on the transmission of constrictor impulses to the capacitance vessels. Reserpine mainly suppresses responses to low-frequency stimulation and bretylium tosylate--those to high-frequency stimulation, while methyldopa affects them to the same degree at all frequencies.

Animals↗
PubMed1977

Experience with bretylium tosylate by a hospital cardiac arrest team.

The effect of bretylium tosylate (BT) was determined in 27 consecutive cases of resistant ventricular fibrillation (VF) encountered by a hospital cardiac arrest team. The VF was sustained and completely resistant to multiple injections of lidocaine, sequential DC shocks at 400 watt-sec and one or a combination of intravenous propranolol, diphenylhydantoin or procainamide. Following 30 min of sustained cardiac massage, BT (5 mg/kg i.v.) was administered. In 20 patients, VF was terminated within 9-12 min after DC shock. Eight of these patients failed to recover while 12 (44%) of all patients resuscitated survived to be discharged from hospital. Eleven out of 20 (55%) of all patients who had a cardiac arrest outside the CCU were survivors; only one out of seven in the CCU were successfully resuscitated. While receiving maintanance BT post-resuscitation (5 mg/kg i.m. q 8-12 hrs x 48 hrs), half the patients developed hypotension and three required vasopressors and/or fluid replacement. The data indicate that BT is a useful agent in patients with sustained VF refractory to repeated lidocaine injections, some other antiarrhythmic agents, and multiple DC shocks.

Bretylium Compounds↗
PubMed1981

Prevention of chronic canine ventricular tachyarrhythmias with bretylium tosylate.

The ability of chronic bretylium tosylate treatment to prevent the induction of ventricular tachycardia was assessed in the conscious dog subjected to serial programmed ventricular stimulation on days 3-6 after acute myocardial infarction. In 34 untreated control dogs, programmed ventricular stimulation produced nonsustained ventricular tachycardia in 11 dogs (32%), sustained ventricular tachycardia in 10 (29%), and ventricular fibrillation in 10 (29%) on the third and fourth day after occlusion and reperfusion of the left anterior descending coronary artery. Bretylium tosylate, 5 mg/kg i.v., was given every 12 hours to a separate group of seven dogs after the induction of ischemic myocardial injury. Programmed ventricular stimulation on the third and fourth days after the induction of myocardial ischemic injury failed to elicit ventricular arrhythmias. Induction of arrhythmias by programmed electrical stimulation could be induced in each of the seven dogs; however, 36 hours after discontinuing bretylium tosylate, two dogs (29%) had non-sustained ventricular tachycardia and five (71%) had sustained ventricular tachycardia. When retested at 60 hours after withdrawal of bretylium tosylate, five (71%) had sustained ventricular tachycardia and two (28%) developed ventricular fibrillation. Readministration of bretylium tosylate (5 mg/kg, i.v.) to four of the five surviving dogs prevented the induction of ventricular arrhythmias in response to programmed ventricular stimulation. The results of these investigations suggest that bretylium tosylate may be effective in preventing the onset of reentrant ventricular rhythms after myocardial ischemic damage, and therefore may be of value in preventing sudden coronary death.

Animals↗
PubMed1984

A method for quantitating antifibrillatory effects of drugs after coronary reperfusion in dogs: improved outcome with bretylium.

We developed a quantitative approach to assess the antifibrillatory effects of short-term interventions in a canine preparation of ventricular fibrillation caused by coronary reperfusion, and applied it to evaluate the antifibrillatory effects of bretylium tosylate. Twenty-five dogs were given 10 mg/kg infusions of bretylium over 10 min, subjected to a 20 min proximal left anterior descending coronary artery ligation followed by sudden release, and compared with 25 animals given saline placebo. Drug infusion was begun 90 min before reperfusion to avoid evaluation of outcome during the phase of drug-induced catecholamine release and to allow adequate time for bretylium uptake in the myocardium. The relationship between the likelihood of ventricular fibrillation during reperfusion and the amount of myocardium perfused by the occluded vessel (myocardium at risk) was analyzed with the logistic risk-regression model. This model was developed to control for the effects of amount of myocardium at risk on outcome. For both the bretylium and the placebo groups the incidence of ventricular fibrillation correlated significantly with amount of myocardium at risk. However, animals treated with bretylium had an improved outcome for a given amount of myocardium at risk. In other words, the curve relating outcome to myocardium at risk was shifted significantly to the right. The amount of myocardium at risk required for half the placebo-treated animals to fibrillate was 20.3 g and that required for half the bretylium-treated animals to fibrillate was 27.9 g, or 37% more than that for the placebo group. This logistic risk-regression analysis format permits quantification of treatment effects while accounting for variability in amount of myocardium at risk.

Animals↗
PubMed1984

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).

Animals↗
PubMed1990

Cerebroventricular calcitonin gene-related peptide inhibits rat duodenal bicarbonate secretion by release of norepinephrine and vasopressin.

Proximal duodenal bicarbonate secretion is an important factor in humans and animals protecting the mucosa against acid-peptic damage. This study examined the mechanisms responsible for the central nervous system regulation of duodenal bicarbonate secretion by calcitonin gene-related peptide (CGRP) in unrestrained rats. Cerebroventricular administration of rat CGRP significantly inhibited basal duodenal bicarbonate secretion as well as the stimulatory effects of vasoactive intestinal peptide, neurotensin, a luminal PGE1 analogue, misoprostol, and hydrochloric acid. The inhibitory effects of cerebroventricular CGRP were abolished by ganglionic blockade with chlorisondamine, significantly attenuated by noradrenergic blockade with bretylium, and enhanced by vagotomy. Inhibition of duodenal bicarbonate secretion induced by CGRP coincided with significant increases in plasma norepinephrine (NE) and vasopressin concentrations. The alpha adrenergic receptor antagonist, phentolamine, and the vasopressin V1 receptor antagonist, (1-deaminopenicillamine, 2-[O-methyl]Tyr, 8-Arg)-vasopressin, given intravenously reversed the central inhibitory effect of CGRP by approximately 50% each. Pretreatment of the animals with both phentolamine and the vasopressin antagonist completely abolished the central inhibitory effect of CGRP. Peripheral vasopressin and NE significantly decreased duodenal bicarbonate secretion, and their inhibitory effects were additive and prevented by phentolamine and the vasopressin antagonist, respectively. We conclude that cerebroventricular CGRP inhibits rat duodenal bicarbonate secretion by activation of sympathetic efferents and subsequent release of NE and vasopressin that act on alpha adrenergic and vasopressin receptors, respectively.

Adrenalectomy↗
PubMed1979

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.

Action Potentials↗