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The function of acetylcholinesterase (AChE) in terminating the action of acetylcholine (ACh) at the junctions of the various cholinergic nerve endings with their effector organs or postsynaptic sites is considered in Chapter 8. Drugs that inhibit AChE are called anticholinesterase (anti-ChE) agents. They cause ACh to accumulate in the vicinity of cholinergic nerve terminals and thus are potentially capable of producing effects equivalent to excessive stimulation of cholinergic receptors throughout the central and peripheral nervous systems. In view of the widespread distribution of cholinergic neurons across animal species, it is not surprising that the anti-ChE agents have received extensive application as toxic agents, in the form of agricultural insecticides, pesticides, and potential chemical warfare "nerve gases." Nevertheless, several compounds of this class are widely used therapeutically; others that cross the blood-brain barrier have been approved or are in clinical trials for the treatment of Alzheimer's disease.

Prior to World War II, only the "reversible" anti-ChE agents were generally known, of which physostigmine is the prototype. Shortly before and during World War II, a new class of highly toxic chemicals, the organophosphates, was developed first as agricultural insecticides and later as potential chemical warfare agents. The extreme toxicity of these compounds was found to be due to their "irreversible" inactivation of AChE, which resulted in prolonged enzyme inhibition. Since the pharmacological actions of both the reversible and irreversible anti-ChE agents are qualitatively similar, they are discussed here as a group. Interactions of anti-ChE agents with other drugs acting at peripheral autonomic synapses and the neuromuscular junction are described in Chapters 9 and Chapter 11.

History. Physostigmine, also called eserine, is an alkaloid obtained from the Calabar or ordeal bean, the dried, ripe seed of Physostigma venenosum, a perennial plant found in tropical West Africa. The Calabar bean once was used by native tribes of West Africa as an "ordeal poison" in trials for witchcraft, in which guilt was judged by death from the poison, innocence by survival after ingestion of a bean. A pure alkaloid was isolated by Jobst and Hesse in 1864 and named physostigmine. The first therapeutic use of the drug was in 1877 by Laqueur, in the treatment of glaucoma, one of its clinical uses today. Accounts of the history of physostigmine have been presented by Karczmar (1970) and Holmstedt (2000).

After basic research elucidated the chemical basis of the activity of physostigmine, scientists began systematic investigations of a series of substituted aromatic esters of alkyl carbamic acids. Neostigmine was introduced into therapeutics in 1931 for its stimulant action on the GI tract and subsequently was reported to be effective in the symptomatic treatment of myasthenia gravis.

Remarkably, the first account of the synthesis of a highly potent organophosphorus anti-ChE, tetraethyl pyrophosphate (TEPP), was published by Clermont in 1854. It is even more remarkable that the investigator survived to report on the compound's taste; a few drops should have been lethal. ...

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