Pharmacological antagonism of the toxic manifestations of amitriptyline and protriptyline in dogs

Abstract In unanesthetized dogs intoxication with amitriptyline produced tachycardia and neurologic changes characterized chiefly by agitation and restlessness. The chronotropic actions of such intoxication were reduced by inhibitors of cholinesterase (physostigmine, pyridostigmine), by mecamylamine, a ganglionic blocking agent, and by propranolol, a β-receptor blocking agent. Neurologic patterns were favorably influenced only by physostigmine. Protriptyline, given in toxic doses, produced a lesser degree of tachycardia, did not cause neurologic disturbances and was less susceptible to physostigmine reduction of heart rate changes than amitriptyline. The data suggest that the weak anticholinergic activities of amitriptyline and protriptyline may be responsible for some of the toxic manifestations. Activation of the sympathetic nervous systems may participate to some extent in the tachycardia.