Monograph: |
Bretylium Tosylate
Bretylium Tosilate (rINN) ; ASL - 603. (2-Bromobenzyl)ethyldimethylammonium toluene - 4 - sulphonate.
C11H17BrN, C7H7O3S = 414.4.
A white, crystalline, hygroscopic powder. Freely soluble in water, in alcohol, and in methyl alcohol ; practically insoluble in ether, in ethyl acetate, and in petroleum spirit. A 5% solution in water has a pH of 5.0 to 6.5.
Store in airtight containers. Protect from light.
Adverse Effects, Treatment, and Precautions
The most common adverse effect following administration of bretylium is hypotension which may be severe. Bretylium may also cause a transient initial increase in blood pressure and heart rate, and a worsening of cardiac arrhythmias due to a release of noradrenaline. Nausea and vomiting may occur particularly during rapid intravenous infusion. Intramuscular injection of bretylium can lead to local tissue necrosis and muscle atrophy, which can be avoided by limiting the volume and varying the site of the injection (see Uses and Administration, below). Care should be taken when administering bretylium to patients with impaired renal function and doses should be reduced. Caution is also required in patients with severe aortic stenosis or pulmonary hypertension who may be unable to increase cardiac output in response to the fall in peripheral resistance produced by bretylium.
Effects on body temprature. Bretylium tosylate administered by intravenous infusion was considered to be the cause of hyperthermia in a 59 - year - old. Six similar cause had been reported to the manufacturer in the USA.
Effects on the cardiovascular system. Seven patients with recent myocardial infarction. 3 with and 4 without left ventricular failure, received bretylium tosylate 5 to 10 mg per kg body - weight intravenously. Initial transient tachycardia and hypertension, and late sustained bradycardia, hypotension with decreased vascular resistance, and increased calf blood flow and venous capacitance occurred in all 7 patients. Bretyllum should be used cautiously in patients with hypotension as it might cause a significant reduction in arterial pressure.
Interactions
Bretylium may exacerbate arrhythmias caused by digitalis toxicity. If sympathomimetics are required to reverse bretylium - induced hypotension, great care should be exercised since their effects may be enhanced.
Pharmacokinetics
Bretylium tosylate is incompletely absorbed from the gastro - intestinal tract. It is well absorbed following intramuscular administration. It is not metabolised in the body and is largely excreted unchanged in the urine. The half - life is reported to be between 4 and 17 hours in patients with normal renal function and is prolonged in patients with impaired renal function. Bretylium is dialysabale.
Uses and Administration
Bretylium is a quaternary ammonium agent with class II and class III antiarrhythmic activity ; it causes an initial release of noradrenaline and then blocks adrenergic transmission by preventing noradrenaline release from adrenergic nerve endings. It suppresses ventricular fibrillation and other ventricular arrhythmias, but the exact mode of action has yet to be determined.
It is given parenterally as the tosylate for the treatment of immediately life - threatening ventricular arrhythmias and for the short - term control of ventricular arrhythmias resistant to standard treatment. If a positive response is to be seen in patients with ventricular fibrillation it usually occurs within minutes. However, a delay of up to several hours may occur before peak antiarrhythmic activity is achieved and therefore it should only be used in other ventricular arrhythmias if the arrhythmia is resistant to more rapidly acting drugs.
In immediately life - threatening ventricular arrhythmias such as ventricular fibrillation a suggested dose is 5 mg per kg body - weight as an undiluted 5% (50 mg per ml) solution by rapid intravenous injection, in association with other resuscitative measures and cardioversion, increased to 10 mg per kg if the ventricular fibrillation persists, and repeated as necessary up to a total dose of 30 mg per kg.
For the control of ventricular arrhythmias that are not immediately life - threatening bretylium may be given under ECG monitoring by intramuscular or slow intravenous injection. The patient should be supine or closely observed for postural hypotension. A dose of 5 to 10 mg per kg by either route may be repeated initially every 1 to 2 hours until the arrhythmia is controlled and subsequently every 6 hours intravenously or 6 to 8 hours intramuscularly for maintenance therapy. The patient should be changed to an oral antiarrhythmic as soon as possible. For intramuscular administration an undiluted 5% (50 mg per ml) solution is used ; the site of intramuscular injections should be varied on repeated injection and not more than 5 ml should be given into any one site. Nausea and vomiting during intravenous administration can be avoided by administering the injection over not less than 8 minutes although a period of 15 to 30 mg per ml with glucose 5% or sodium chloride 0.9%. Alternatively an intravenous infusion of 1 to 2 mg per minute has been recommended.
Doses should be reduced in patients with renal impairment.
Bretylium tosylate was originally used in the treatment of hypertension but because of poor gastric absorption and the development of tolerance during long - term therapy it has been superseded by other drugs.
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