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ACh: acetylcholine

AChE: acetylcholinesterase

anti-ChE: anticholinesterase

BChE: butyrylcholinesterase

ChE: cholinesterase

CYPs: cytochrome P450s

DFP: diisopropyl fluorophosphate (diisopropyl phosphorofluoridate)

EPA: Environmental Protection Agency

GI: gastrointestinal

2-PAM: pralidoxime


The hydrolytic activity of acetylcholinesterase (AChE) terminates the action of acetylcholine (ACh) at the junctions of the various cholinergic nerve endings with their effector organs or postsynaptic sites (see Chapter 10). Drugs that inhibit AChE are properly termed anti-ChEs or cholinesterase (ChE) inhibitors, since they inhibit both AChE and BChE (butyrylcholinesterase); however, such agents are also referred to as AChE inhibitors. BChE is not abundant in nerve ending synapses but is found in liver and plasma, where it metabolizes circulating esters.

AChE inhibitors 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 and prominence of ACh among neurotransmitters, 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 agents or gases. AChE reactivators are particularly useful in treating poisoning by pesticides or agents of terrorism in controlled ventilation facilities. Several anti-ChEs are 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 (Box 12–1). 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 (Everts, 2016). The extreme toxicity of these compounds was found to be due to their “irreversible” inactivation of AChE, which resulted in prolonged enzyme inhibition. Because 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 11 and 13.


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 and 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. Karczmar ...

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