Tolerability of Paracetamol*

Abstract

Paracetamol (acetaminophen) is a well-tolerated drug at therapeutic doses and this safety profile is a major factor in the very wide use of the drug. It is well known that paracetamol is converted by the hepatic cytochrome P450 system to reactive compounds. Less well known is that paracetamol is also metabolized to the same reactive compounds by myeloperoxidase and the peroxidase function of cycloxygenase (COX)-1. The reactive metabolites lead to hepatotoxicity following overdosage. Similar hepatotoxicity has been reported after therapeutic doses, but critical analysis indicates that most patients with alleged toxicity from therapeutic doses have taken overdoses. Associations between the use of paracetamol and chronic renal diseases, gastrointestinal toxicity and asthma may be due to biases in case-control studies. In particular, biases may be caused by the perceived safety of paracetamol in these diseases. Selective inhibition of the delayed pathway of prostaglandin synthesis is consistent with the gastrointestinal safety of paracetamol and its safety in the majority of aspirin-sensitive asthmatics. Despite the conversion of paracetamol to reactive compounds, hypersensitivity reactions are rare, although urticaria is produced in occasional patients.