Poisoning antidotes and toxicology pharmacology — formative SAQs

1. Mechanism of hepatotoxicity and how NAC prevents it

At therapeutic doses paracetamol is cleared by glucuronidation and sulfation, with only a small fraction metabolised by cytochrome P450 2E1 into the reactive intermediate NAPQI, which is immediately detoxified by glutathione. After an overdose the conjugation pathways saturate, more paracetamol is shunted into the P450 pathway, NAPQI accumulates, glutathione is depleted, and free NAPQI binds hepatocyte proteins and causes centrilobular necrosis. N-acetylcysteine works by replenishing glutathione and supplying sulfhydryl groups that directly detoxify NAPQI — but only while the hepatocyte is still salvageable, which is why timing governs its use. ^{[1] [2]}

2. The IV regimen and when to start regardless of level

For a 14-kilogram child the intravenous N-acetylcysteine regimen is 150 mg per kilogram over one hour (about 2.1 g), then 50 mg per kilogram over four hours (about 0.7 g), then 100 mg per kilogram over sixteen hours (about 1.4 g) — a 21-hour total course. I would start it regardless of the level whenever the ingestion is staggered or timed-unknown (as here, where the time and number are uncertain), for sustained-release preparations, or when there is any evidence of hepatotoxicity, because the Rumack-Matthew nomogram cannot be applied in those situations and the default is to treat. A level at four hours or later plotted against a known time selects treatment when on or above the line. ^[1]

3. The commonest adverse reaction and its management

The commonest adverse reaction is an anaphylactoid reaction — rash, flushing, urticaria, and occasionally bronchospasm — which is rate-related rather than a true IgE allergy. I would manage it by pausing or slowing the infusion and treating the symptoms with an antihistamine, and then resuming the N-acetylcysteine at a slower rate, because the reaction is rarely a reason to abandon a life-saving course. In a small child I would also adjust the diluent volume to avoid fluid overload from the large weight-based dose. ^{[1] [2]}