[Tolerability of paracetamol].

Area of Science:

• Pharmacology
• Toxicology
• Biochemistry

Background:

• Paracetamol (acetaminophen) is widely used due to its favorable safety profile at therapeutic doses.
• Hepatic cytochrome P450 enzymes metabolize paracetamol into reactive compounds.
• Myeloperoxidase and cyclooxygenase-1 (COX-1) also metabolize paracetamol into reactive compounds.

Purpose of the Study:

• To investigate the metabolic pathways of paracetamol and their relation to toxicity.
• To critically evaluate reported associations between paracetamol use and chronic diseases.
• To assess the safety of paracetamol in specific patient populations, including those with asthma.

Main Methods:

• Review of existing literature on paracetamol metabolism and toxicity.
• Critical analysis of case-control studies investigating paracetamol's association with renal diseases, gastrointestinal toxicity, and asthma.
• Evaluation of paracetamol's mechanism of action concerning prostaglandin synthesis.

Main Results:

• Reactive metabolites of paracetamol, formed by both hepatic and extrahepatic enzymes, are implicated in hepatotoxicity, primarily following overdose.
• Evidence suggests that alleged toxicity at therapeutic doses is often due to unrecognised overdoses.
• Associations with chronic renal disease, gastrointestinal issues, and asthma may be influenced by study biases, particularly the perceived safety of paracetamol.
• Paracetamol's selective inhibition of prostaglandin synthesis aligns with its gastrointestinal safety and safety in most aspirin-sensitive asthmatics.
• Hypersensitivity reactions to paracetamol are rare, with urticaria being an occasional manifestation.

Conclusions:

• Paracetamol's safety profile is largely maintained at therapeutic doses, with hepatotoxicity predominantly linked to overdose.
• Extrahepatic metabolism of paracetamol contributes to reactive metabolite formation.
• Reported adverse associations with chronic diseases require careful consideration of potential biases.