Pralidoxime is used as an antidote to neurotoxic organophosp

Pralidoxime is used as an antidote to neurotoxic organophosphorus agents. Suggest a chemical mechanism for such action.

Solution

Organophosphate compounds (OP) are used as commercial insecticides (phorate, dimethoate, parathion, malathion, diazinon, sevin etc), in chemical warfare (as nerve gases tabun and sarin), applied as aerosols or dusts and also in ophthalmology (echothiopate to treat glaucoma). They can be absorbed cutaneously, ingested, inhaled, or injected.

The primary mechanism of action of OP is inhibition of the enzymes, carboxyl ester hydrolases, particularly acetylcholinesterase (AChE). This enzyme has two parts: the neurotransmitter acetylcholine (ACh) binds at both sites of the enzyme, and is cleaved into choline and acetic acid. ACh is present in the central and peripheral nervous system, neuromuscular junctions, and red blood cells.

In organophosphate poisoning, an OP binds to one end of the AChE (esteric site), phosphorylates the serine hydroxyl group, and inactivates the enzyme. The reaction involves loss of an organophosphate group and establishment of a covalent bond with AChE. The binding of OP to acetylcholinesterase, results initially in reversible inactivation of the enzyme. As a result, ACh accumulates throughout the nervous system, disrupt it and cause overstimulation of muscarinic and nicotinic receptors.

Pralidoxime (2-pyridine aldoxime methyl chloride,) or 2-PAM, belongs to the family of oximes. It attaches to the other half (the unblocked, anionic site) of AChE, binds to the organophosphate, changes conformation, and loses its binding to AChE enzyme. The conjoined poison / antidote then unbind from the site, and reactivate the enzyme. Hence within 24 hours of ingestion of OP into the system, pralidoxime administration reactivates the AChE by cleaving the phosphate-ester bond formed between the OP and AChE.

When delayed the inhibitors develop a permanent bond with cholinesterase, known as aging. At this stage pralidoxime cannot reverse the bond.