Protective action of diazepam and of sympathomimetic amines against amitryptyline-induced toxicity
Follmer, C.H.; Lum, B.K.
Journal of Pharmacology and Experimental Therapeutics 222(2): 424-429
1982
ISSN/ISBN: 0022-3565 PMID: 7097563 Document Number: 195980
Factors that contribute to the lethality of amitriptyline overdosage were studied in cats. Amitriptyline (50 mg/kg) given i.p. to unanesthetized cats produced convulsions in all of the animals and death in 5 of 6 animals; pretreatment with diazepam (5 mg/kg) protected against the convulsions and death. Respiratory depression contributed to be mortality when amitriptyline was given i.v. in cats anesthetized with pentobarbital as indicated by the finding that artifical respiration delayed the time of death induced by a continuous i.v. infusion of the drug. The i.v. infusion of amitriptyline in pentobarbitalized cats under artificial respiration produced death due to cardiovascular colapse. The latter was characterized by hypotension, bradycardia, depression of myocardial contractile force, atrioventricular block, intraventricular conduction delay and cardiac arrhythmias. These effects appear to be due to a direct membrane (quindine-like) cardiotoxic action of amitriptyline. Dopamine and dobutamine were effective in protecting the animals against the acute cardiovascular collapse induced by amitriptyline. The protection was associated with a diminution of the hypotension, the negative inotropic and chronotropic actions and the incidence of atrioventricular block produced by the tricyclic antidepressant drug. Evidently, the positive chronotropic, inotropic and dromotropic actions of the amines may all be contributory factors in their protective action. Isoproterenol and norepinephrine were less effective than the other 2 amines.