PREVENTION OF PHYSOSTIGMINE-INDUCED LETHALITY IN RATS - A PHARMACOLOGICAL ANALYSIS

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  • 1 January 1982
    • journal article
    • research article
    • Vol. 259  (1) , 153-165
Abstract
A systematic study of a large number of compounds from various pharmacological classes were performed to better define their interaction with the cholinergic nervous system. An in vivo test procedure called physostigmine antagonism in rats was used; it involved the administration of the test compouds, measurement of the pupil diameter and recording of the survival time after injection of a lethal dose of physostigmine. Known peripherally acting anticholinergics, such as isopropamide and methylscopolamine did not protect from physostigmine lethality at doses up to > 150 times the mydriatic dose. Known centrally acting anticholinergics, such as dexetimide and benztropine, protected from lethality at doses equal to or slightly higher than the mydriatic dose. Penetration into the brain of a muscarinic blocking agent thus appeared to be a sufficient condition to significantly reduce the cholinergic overstimulation of the CNS that results from inhibition of acetylcholine hydrolysis. Drugs of other pharmacological classes having anticholinergic activity in addition to their more characteristic action, were also active in the physostigmine test. They include most of the tricyclic antidepressants, some antihistamines such as diphenhydramine and cyproheptadine, some ganglion blocking agents such as mecamylamine and the neuroleptic clozapine. Drugs with hpnotic or anticonvulsant properties, sedative neuroleptics and high doses of some members of other pharmacological classes protected from physostigmine-induced lethality by a mechanism not based on anticholinergic activity. A number of pharmacological actions, dopamine, histamine H1 and serotonin S2 antagonism, MAO[monoamine oxidase]-inhibition, .alpha.-adrenergic blockade, etc., are all insufficient to produce physostigmine antagonism.