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Mnemonic

Paracetamol Overdose Biochemistry

A memory aid for the mechanism and monitoring of paracetamol toxicity.

Biochemistry Pharmacology Emergency Clinical Biochemistry Toxicology and Antidotes Toxicology and Overdose
Expansion

NAPQI depletes glutathione, causing centrilobular necrosis

Mnemonic

“Normal routes saturate, then NAPQI accumulates, and glutathione runs out”:

  • Normally, about 90 per cent is conjugated by glucuronidation and sulphation
  • About 5 to 10 per cent is oxidised by CYP2E1 to the toxic metabolite NAPQI
  • NAPQI is neutralised by glutathione
  • In overdose the conjugation pathways saturate, more goes down CYP2E1, and glutathione is depleted, so NAPQI binds hepatocyte proteins and causes centrilobular (zone 3) necrosis

“N-acetylcysteine replenishes glutathione”, which is why it works and why it is most effective within 8 hours.

Higher risk at lower doses: chronic alcohol and enzyme inducers such as carbamazepine, phenytoin, rifampicin and St John’s wort (more CYP2E1), and malnutrition, anorexia, HIV and cystic fibrosis (less glutathione).

King’s College criteria for transplant: pH under 7.3 after resuscitation, or the triad of INR over 6.5, creatinine over 300 and grade III or IV encephalopathy.

Expansion

Mechanism

  1. Most paracetamol is conjugated with glucuronide and sulphate
  2. A small fraction is oxidised by CYP2E1 to the toxic metabolite NAPQI
  3. NAPQI is normally detoxified by glutathione
  4. In overdose, conjugation saturates and glutathione is consumed. Below about 30 per cent of normal stores, NAPQI binds hepatocyte proteins
  5. Centrilobular (zone 3) necrosis, since CYP2E1 is concentrated there

Higher risk: chronic alcohol use, enzyme-inducing drugs, malnutrition, anorexia and HIV, all of which either induce CYP2E1 or deplete glutathione.

Time course: often asymptomatic for the first 24 hours, with transaminases rising at 24 to 48 hours and peak hepatic failure at 72 to 96 hours. This latent period is why treatment must not await symptoms.

N-acetylcysteine replenishes glutathione and is most effective within 8 hours, but is given at any time if there is evidence of toxicity.

Prognostic markers (King’s College criteria): pH below 7.3, or the combination of prothrombin time above 100 seconds, creatinine above 300 micromol/l and grade III or IV encephalopathy. Note that the prothrombin time and pH, not the transaminases, determine prognosis.