Pralidoxime is ineffective when administered late in severe organophosphate poisoning. The pharmacological basis for this time dependence is:

• A Progressive depletion of presynaptic acetylcholine stores
• B Irreversible 'aging' of the phosphorylated cholinesterase enzyme complex ✓
• C Downregulation of nicotinic receptors at the neuromuscular junction
• D Conversion of pralidoxime to an inactive metabolite by plasma cholinesterase

Explanation

Pralidoxime works by nucleophilic attack on the phosphorus atom of the organophosphate bound to cholinesterase, regenerating free enzyme. With time the enzyme-inhibitor bond loses an alkyl group, a process called aging, after which the bond becomes irreversible and pralidoxime can no longer reactivate it. Aging occurs within minutes for some agents such as soman and within hours for most agricultural organophosphates. Receptor downregulation and acetylcholine depletion are not the limiting factors.

Reference: Goodman and Gilman's The Pharmacological Basis of Therapeutics, 14th ed.

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