A9: Antidotes in Depth

INTRODUCTION

Physostigmine is a carbamate that reversibly inhibits cholinesterases in the peripheral nervous system and central nervous system (CNS).⁴⁶ The tertiary amine structure of physostigmine permits CNS penetration and differentiates it from neostigmine and pyridostigmine, which are quaternary amines that have limited ability to enter the CNS. The inhibition of cholinesterases prevents the metabolism of acetylcholine, allowing acetylcholine to accumulate and antagonize the antimuscarinic effects of xenobiotics such as atropine, scopolamine, and diphenhydramine.⁵⁴ Although physostigmine previously was used as an antagonist to the antimuscarinic effects of cyclic antidepressants and phenothiazines, this use is no longer recommended because of a poor risk-to-benefit ratio, given the potential for exacerbation of life-threatening cardiotoxicity. Similarly, physostigmine has a poor risk-to-benefit ratio in the management of presumed γ-hydroxybutyric acid (GHB) toxicity.^4,48,55 Atypical antipsychotics have complex pharmacologic effects. Although some atypical antipsychotics, such as olanzapine, have significant antimuscarinic side effects, the benefit of treating these anticholinergic effects with physostigmine must be weighed by the potential risks of exacerbating cardiotoxicity.^19,47,53

HISTORY

The history of physostigmine dates to antiquity and the Efik people of Old Calabar in Nigeria.^17,21,24,46 The chiefs in this area used a poisonous concoction made from the beans of an aquatic leguminous perennial plant found in the area to create a judicial test the esere ordeal. Esere was the word used to represent both the bean and the ritual used to test the innocence or guilt of an accused person. They also believed that the esere had the power to detect and kill persons practicing witchcraft. Supposedly, innocent persons quickly swallowed the poison, which resulted in immediate emesis.²⁴ Vomiting allowed the innocent to survive without therapy or to be given an antidote of excrement in water. The guilty, however, hesitated swallowing, leading to speculation that sublingual absorption led to severe systemic symptoms without the benefit of vomiting. These persons were noted to develop mouth fasciculations and died foaming at the mouth. Daniell, a British medical officer stationed in Calabar, brought samples of the bean and the plant back to England in 1840.²⁴ John Balfour, a professor of medicine and botany at the Edinburgh Medical School, characterized the plant, which became known as Physostigma venenosum Balfour (family Leguminoseae), in 1857. The active alkaloid was isolated by Jobst and Hesse in 1864 and was named physostigmine. Independently, one year later Vee and Leven also isolated and named the active alkaloid eserine.

Christison performed the first toxicologic studies, including self-experimentation with increasing doses of the seed. Fraser, Christison’s student and successor, originated the concept of antagonism from his experiments with physostigmine and atropine. Fraser plotted the dose relationships between the effects of atropine versus physostigmine on various organs such as the eye and the heart, demonstrating the antidotal effects of atropine for the lethal effects of physostigmine.^...