Describe the pharmacology of paracetamol and the management of paracetamol poisoning.

Pharmacology

• Mechanism — inhibits cyclo-oxygenase chiefly in the central nervous system, where peroxide tone is low; peripheral inhibition is weak because high peroxide levels at inflamed sites overcome it. This explains the whole clinical profile
• Well absorbed orally; also available intravenously and rectally
• Metabolised in the liver — about 90% by glucuronidation and sulphation to inactive conjugates, and about 5 to 10% by CYP2E1 to the toxic metabolite NAPQI
• NAPQI is normally detoxified by conjugation with glutathione

Advantages and Uses

• Does not cause gastric ulceration, bleeding, renal impairment or bronchospasm at therapeutic doses — hence its place as the first-line analgesic and antipyretic
• Safe in children, in pregnancy and in breastfeeding, and in aspirin-sensitive asthma and peptic ulcer
• Does not cause Reye syndrome, so it replaces aspirin in children
• Uses — fever, headache, musculoskeletal pain, osteoarthritis, and as a component of multimodal analgesia; it has a genuine opioid-sparing effect
• Adult dose 500 mg to 1 g up to 6-hourly, maximum 4 g a day; less in the malnourished, in alcoholics and in the frail elderly

Paracetamol Poisoning

A large dose saturates glucuronidation and sulphation → More paracetamol is diverted through CYP2E1 to NAPQI → glutathione stores are depleted → Unconjugated NAPQI binds covalently to hepatocyte proteins → centrilobular (zone 3) hepatic necrosis — zone 3 has the highest CYP activity and the lowest oxygen → Also acute tubular necrosis of the kidney

• Clinical course — Phase 1 (0–24 h): nausea, vomiting, or nothing at all — the patient often looks deceptively well. Phase 2 (24–72 h): right upper quadrant pain, rising transaminases. Phase 3 (72–96 h): peak hepatic necrosis, jaundice, encephalopathy, coagulopathy, hypoglycaemia, lactic acidosis, renal failure. Phase 4: recovery or death
• The absence of symptoms early is the great danger — treatment must be based on the dose and the level, not on how the patient looks
• Higher risk in chronic alcoholics, the malnourished and anorexic (depleted glutathione), and those on enzyme inducers such as rifampicin, phenytoin and carbamazepine

Management of Poisoning

• Activated charcoal if presentation is within an hour or two
• Measure the paracetamol level at 4 hours or later after ingestion and plot it on the treatment nomogram; a level taken earlier cannot be interpreted
• N-acetylcysteine, intravenous or oral — started immediately if the dose was large, presentation is late, the timing is uncertain, or the ingestion was staggered
• Anaphylactoid reactions to intravenous acetylcysteine are common (rash, bronchospasm) but are rate-related and managed by slowing the infusion, not by abandoning it
• Monitor INR, transaminases, creatinine, glucose and lactate; the INR is the best early marker of severity
• King’s College criteria identify patients needing liver transplantation — arterial pH below 7.3, or the combination of high INR, raised creatinine and encephalopathy

Applied Aspects

• Paracetamol is in dozens of combination preparations — cold remedies, analgesic combinations, opioid combinations — and inadvertent therapeutic overdose from taking several at once is a real cause of liver failure
• Ask specifically what else the patient has taken, by brand as well as by name
• Do not wait for symptoms; by the time jaundice appears the damage is largely done
• Warn alcoholic and malnourished patients that their safe dose is lower, and prescribe accordingly
• Paracetamol poisoning is common in India, both deliberate and accidental, and N-acetylcysteine is cheap and widely available — the limiting factor is usually delayed presentation and failure to consider the diagnosis