Acetaminophen Poisoning (Paracetamol Overdose)

Metabolic pathways

The liver normally metabolises paracetamol predominantly via conjugation with glucuronic acid and sulphate to form non-toxic metabolites. A small proportion is oxidised by cytochrome P450 enzymes (particularly CYP2E1) to produce a highly reactive toxic metabolite, N-acetyl-p-benzoquinone imine (NAPQI).

Under normal conditions:

• NAPQI is rapidly detoxified by conjugation with glutathione
• This forms non-toxic cysteine and mercapturic acid metabolites

In overdose:

• Glucuronidation and sulphation pathways become saturated
• A greater proportion is metabolised via the P450 system
• This leads to excessive production of NAPQI

When glutathione stores are depleted (typically <30% of normal):

• NAPQI accumulates
• It binds covalently to cellular proteins
• This causes oxidative stress, mitochondrial dysfunction, and hepatocellular necrosis
• Renal tubular injury may also occur

Management

The minority of patients who present within 1 hour may benefit from activated charcoal to reduce absorption of the drug.