Pharmacology & TherapeuticsPending review

Paracetamol Overdose

A toxic metabolite overwhelms the liver's glutathione defences once conjugation pathways saturate, causing centrilobular hepatocyte necrosis that the antidote works by replenishing.

First principles

Normal disposal versus the toxic shunt

At therapeutic doses, most paracetamol is safely conjugated by glucuronidation and sulfation, with only a small fraction oxidised by cytochrome P450 (mainly CYP2E1) to the reactive metabolite NAPQI, which is immediately neutralised by conjugation with glutathione. In overdose, the conjugation pathways saturate, so a much larger fraction is shunted through CYP2E1 to NAPQI, and glutathione stores become progressively depleted.

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Educational content pending clinical review. Not medical advice.