Why do patients still die from paracetamol poisoning?

The numbers of deaths from paracetamol poisoning have risen steadily in England and Wales since the first cases of fulminant hepatic failure caused by paracetamol poisoning were reported in 1966.'-3 In 1984 there were 176 deaths from paracetamol alone and a further 305 from paracetamol with other drugs, notably dextropropoxyphene.4 Adults account for most of the serious and fatal cases; young children rarely ingest enough paracetamol to cause more than minimal liver damage. On the first day after taking a hepatotoxic dose of paracetamol patients may have no symptoms, but anorexia, nausea, and vomiting are usual. Patients who absorb more than 15 g (150-200 mg/kg) may develop abdominal pain and hepatic tenderness on the second day. Peak disturbance of liver function occurs two to four days after an overdose, but then recovery is usually rapid and complete. In a few severely poisoned patients fulminant hepatic failure, with increasing jaundice and encephalopathy, develops by the third to fifth day. In addition, acute renal failure may occur, usually but not invariably with severe liver damage.6 Hyperlactataemia and metabolic acidosis may also be observed, particularly in severe paracetamol intoxication78 and in association with liver failure.9 10 Without treatment nearly two thirds of patients with a plasma paracetamol concentration above the so called "treatment line" (which on a semilog graph joins plots of 1 32 mmol/l (200 mg/l) at 4 hours and 0-33 mmol/l (50 mg/l) at 12 hours after ingestion) will develop severe liver damage and about 5% will die." Until recently the explanation for paracetamol induced toxicity has been that a small fraction of the drug is metabolised by cytochrome P450 dependent mixed function oxidases to a reactive intermediate, N-acetyl-p-benzoquinoneimine,'2 which is detoxified by conjugation with glutathione.'0 Most of a dose of paracetamol is eliminated as glucuronide and sulphate derivatives. But with a large dose the sulphate conjugation pathway becomes saturated, an increasing amount of N-acetyl-p-benzoquinoneimine is formed, and hepatic glutathione stores become depleted. N-acetyl-p-benzoquinoneimine is then free to bind covalently to nucleophilic cell macromolecules to cause hepatic necrosis. Increasing experimental evidence suggests, however, that covalent binding is insufficient in itself to explain para-cetamol induced cellular toxicity.'4 '5 None the less, early work on the mechanism of paracetamol toxicity stimulated the development of protective agents designed to reduce or prevent covalent binding of paracetamol, and empirically these have proved effective. The first agent used was cysteamine,'6 which inhibits the conversion of paracetamol …