Prevention of physostigmine-induced lethality in rats. A pharmacological analysis.

A systematic study of a large number of compounds from various pharmacological classes was 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 compounds, 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 more than 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 that are known to have 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 hypnotic 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. The results further show that a number of pharmacological actions: dopamine, histamine H1 and serotonin S2 antagonism, MAO-inhibition, alpha-adrenergic blockade etc. are all insufficient to produce physostigmine antagonism.