Paracetamol Overdosage Pharmacological Considerations and Clinical Management

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SummaryParacetamol (acetaminophen), normally a very safe drug, may produce acute centrilobular hepatic necrosis when taken in overdosage. There are no specific early symptoms or signs of paracetamol poisoning and consciousness is not impaired. Plasma aminotransferase (AST or ALT) activity may increase dramatically to 10,000 iu/L or more with prolongation of the prothrombin time ratio and mild jaundice. Acute renal failure is an uncommon complication. Maximum abnormalities of liver function are delayed for at least 3 days, and initially the prognosis can only be determined by estimation of the plasma paracetamol concentration in relation to the time after ingestion. Severe liver damage (plasma aminotransferase activity > 1000 iu/L) occurs in about 60% of patients with paracetamol concentrations above a ‘treatment line’ joining semilogarithmic plots of 200 μg/ml at 4 hours and 30 μg/ml at 15 hours after ingestion. Although recovery of liver function is usually rapid and complete, fulminant hepatic failure develops 3 to 6 days after ingestion in a small minority of severely poisoned patients and is often fatal. Contrary to popular belief, only about 15% of unselected patients taking paracetamol in overdosage are severely poisoned with plasma concentrations above the ‘treatment line’. Without specific therapy, severe liver damage only occurs in about 8%, fatal hepatic failure in 1 to 2%, and renal failure in about 1%.Paracetamol damages the liver through the formation of a highly reactive metabolite which is normally trapped and inactivated by preferential conjugation with hepatic glutathione. Following an hepatotoxic dose, glutathione is depleted and the toxic metabolite binds covalently to vital proteins and enzymes causing cell damage and necrosis. Toxicity depends on the balance between the rate of formation of the reactive metabolite of paracetamol and the rate of glutathione synthesis. Glutathione precursors and other sulfhydryl compounds prevent glutathione depletion, covalent binding and liver damage, probably by facilitation of glutathione conjugation.Cysteamine, methionine and N-acetylcysteine prevent liver damage, renal failure and death following paracetamol overdosage if given within 8 to 10 hours; treatment after 15 hours is of no benefit. Cysteamine has long been abandoned because of its toxicity. N-Acetylcysteine or methionine therapy is indicated in patients with plasma paracetamol concentrations above the ‘treatment line’. Intravenous N-acetylcysteine appears more effective than methionine and is currently the treatment of choice. Oral therapy is unreliable and cannot be recommended.

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