Anticholinesterases and Organophosphate Poisoning

Anticholinesterases and Organophosphate Poisoning

1. Definition, scope & terminology

• Anticholinesterases (anti-ChEs) are agents that inhibit cholinesterase, protect acetylcholine (ACh) from hydrolysis, produce cholinergic effects in vivo, and potentiate ACh both in vivo and in vitro (KDT 8e Ch.7, p.116).
• They are properly termed anti-ChEs or cholinesterase (ChE) inhibitors because they inhibit both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE); they are also loosely called AChE inhibitors (G&G 14e Ch.12, p.221).
• Mechanistically they cause ACh to accumulate near cholinergic nerve terminals, producing effects equivalent to excessive stimulation of cholinergic receptors throughout the CNS and PNS (G&G 14e Ch.12, p.221).
• The class spans therapeutic agents (myasthenia gravis, glaucoma, ileus/atony, Alzheimer's, reversal of competitive neuromuscular block, anticholinergic-overdose antidote) and the most clinically important toxicological problem — organophosphate (OP) and carbamate insecticide poisoning + chemical-warfare nerve agents (G&G 14e Ch.12, pp.221, 228).
• Historical anchor: physostigmine (eserine) — alkaloid of the Calabar/ordeal bean (Physostigma venenosum), West African "ordeal poison"; isolated 1864, first therapeutic use 1877 (Laqueur, glaucoma). Neostigmine introduced 1931. OP compounds developed by Schrader's group pre-/during WWII, first as insecticides (parathion) then as nerve agents (tabun, sarin, soman) (G&G 14e Ch.12, p.221 Box 12-1).

Two-tier "reversible vs irreversible" — a quantitative, not absolute, distinction

• The terms reversible (carbamates) and irreversible (organophosphates) reflect only quantitative differences in rates of decarbamoylation / dephosphorylation of the conjugated enzyme — both chemical classes react covalently with the active-centre serine in essentially the same manner as ACh forms the transient acetyl-enzyme (G&G 14e Ch.12, p.224).
• ⚠ Katzung explicitly states the molecular mechanisms "do not support this simplistic [reversible/irreversible] description" — edrophonium, donepezil and carbamates are called reversible and OPs irreversible purely on duration-of-action grounds (Katzung 16e Ch.7, p.122).