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Bretylium

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Bretylium

CLINICAL PHARMACOLOGY

Bretylium (bretylium tosylate injection ) tosylate is abromobenzyl quaternary ammonium compound which selectively accumulates in sympathetic ganglia and their postganglionic adrenergic neurons where it inhibits norepinephrine release by depressing adrenergic nerve terminal excitability.

Bretylium (bretylium tosylate injection ) also suppresses ventricular fibrillation and ventricular arrhythmias. The mechanisms of the antifibrillatory and antiarrhythmic actions of bretylium (bretylium tosylate injection ) are not established. In efforts to define these mechanisms, the following electrophysiologic actions of bretylium (bretylium tosylate injection ) have been demonstrated in animal experiments:

  1. Increase in ventricular fibrillation threshold.
  2. Increase in action potential duration and effective refractory period without changes in heart rate.
  3. Little effect on the rate of rise or amplitude of the cardiac action potential (Phase 0) or in resting membrane potential (Phase 4) in normal myocardium. However, when cell injury slows the rate of rise, decreases amplitude, and lowers resting membrane potential, bretylium (bretylium tosylate injection ) transiently restores these parameters toward normal.
  4. In canine hearts with infarcted areas bretylium (bretylium tosylate injection ) decreases the disparity in action potential duration between normal and infarcted regions.
  5. Increase in impulse formation and spontaneous firing rate of pacemaker tissue as well as increase ventricular conduction velocity.

The restoration of injured myocardial cell electrophysiology toward normal, as well as the increase of the action potential duration and effective refractory period without changing their ratio to each other, may be important factors in suppressing re-entry of aberrant impulses and decreasing induced dispersion of local excitable states.

Bretylium (bretylium tosylate injection ) induces a chemical sympathectomy-like state which resembles a surgical sympathectomy. Catecholamine stores are not depleted by bretylium (bretylium tosylate injection ) tosylate, but catecholamine effects on the myocardium and on peripheral vascular resistance are often seen shortly after administration because bretylium (bretylium tosylate injection ) causes an early release of norepinephrine from the adrenergic postganglionic nerve terminals. Subsequently, bretylium (bretylium tosylate injection ) tosylate blocks the release of norepinephrine in response to neuron stimulation. Peripheral adrenergic blockade regularly causes orthostatic hypotension but has less effect on supine blood pressure. The relationship of adrenergic blockade to the antifibrillatory and antiarrhythmic actions of bretylium (bretylium tosylate injection ) is not clear. In a study in patients with bretylium (bretylium tosylate injection ) , peak hypotensive effects were seen within one hour of intramuscular administration, presumably reflecting adrenergic neuronal blockade. However, suppression of premature ventricular beats was not maximal until 6-9 hours after dosing, when mean plasma concentration had declined to less than one-half of peak level. This suggests a slower mechanism, other than neuronal blockade, was involved in suppression of the arrhythmia. On the other hand, antifibrillatory effects can be seen wfthin minutes of an intravenous injection, suggesting that the effect on the myocardium may occur quite rapidly.

Bretylium (bretylium tosylate injection ) has a positive inotropic effect on the myocardium, but it is not yet certain whether this effect is direct or is mediated by catecholamine release.

Bretylium (bretylium tosylate injection ) is eliminated intact by the kidneys. No metabolites have been identified following administration of BRETYLIUM (bretylium tosylate injection ) TOSYLATE INJECTION in man and laboratory animals. In man, approximately 70%-80% of a 14C-labelled intramuscular dose is excreted in the urine during the first 24 hours, with an additional 10% excreted over the next three days.

The terminal half-life in four normal volunteers averaged 7.8±0.6 hours (range 6.9-8.1). In one patient with a creatinine clearance of 21.0 mL/min. x 1.73m2 the half-life was 16 hours. In one patient with a creatinine clearance of 1.0 mL/min. x 1.73m2 the half-life was 31.5 hours. During hemodialysis, this patient†s arterial and venous bretylium (bretylium tosylate injection ) concentrations declined rapidly, resulting in a half-life of 13 hours. During dialysis there was two-fold increase in total bretylium (bretylium tosylate injection ) clearance.

Effect on heart rate: There is sometimes an initial small increase in heart rate when bretylium (bretylium tosylate injection ) tosylate is administered, but this is an inconsistent and transient occurrence.

Hemodynamic effects: Following intravenous administration of 5mg/kg of BRETYLIUM (bretylium tosylate injection ) TOSYLATE INJECTION to patients with acute myocardial infarction, there was a mild increase in arterial pressure, followed by a modest decrease, remaining within normal limits throughout. Pulmonary artery pressures, pulmonary capillary wedge pressure, right atrial pressure, cardiac index, stroke volume index, and stroke work index were not significantly changed. These hemodynamic effects were not correlated with antiarrhythmic activity.

Onset of action: Suppression of ventricular fibrillation is rapid, usually occurring within minutes following intravenous administration. Suppression of ventricular tachycardia and other ventricular arrhythmias develops more slowly, usually 20 minutes to 2 hours after parenteral administration.

Last reviewed on RxList: 12/8/2004
This monograph has been modified to include the generic and brand name in many instances.

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