Paracetamol at recommended doses is a safe and effective medicine for the relief of mild pain and fever. It is generally available as 500 mg tablets, but is also available in soluble form (also generally 500 mg tablets), and in a variety of combinations. Liquid preparations are also available for young children.
Paracetamol is rapidly absorbed, the soluble form being absorbed faster than the solid tablet form. The peak blood level for both forms is similar and is usually less than 20 mg/litre following a 1000 mg dose. Peak serum levels usually occur 30 minutes to 2 hours after ingestion. Elimination from the body is rapid with a half-life of about two hours.
Paracetamol is primarily metabolised by the liver. Most of it is combined with glucuronide and sulphate, which account for about 90% of the dose excreted. About 5% of the dose is excreted unchanged and a further 5% is oxidised to a benzoquinoneimine, which is then combined with glutathione and metabolised on to cysteine and mercapturate compounds which are safely excreted.
Paracetamol and its two primary metabolites are remarkably safe compounds, and the hepatotoxicity of paracetamol arises only through the 5% that is oxidised. The immediate oxidation metabolite, benzoquinoneimine, is a highly reactive substance that normally combines with glutathione. As the dose of paracetamol increases, the quantity of benzoquinoneimine produced increases too. There then comes a point where the glutathione stores in the liver have been completely used up and the rate of production of new glutathione cannot keep up with the rate of production of the benzoquinoneimine. It is at this point that the benzoquinoneimine attaches to liver protein and causes liver injury.
The time required for the liver to become depleted of glutathione, and for the benzoquinoneimine to build up and cause fatal liver damage, is three to four days. During the early stages of this process, there may be few overt symptoms, and it is important that in cases of suspected overdose the patient does not wait for symptoms to appear before seeking medical help. It is estimated that liver injury may begin to occur at a single dose of paracetamol of 15g (30 standard tablets) or over.
Treatment of overdose consists of skilled hospital management of the patient, including where necessary the administration of an antidote, n-acetylcysteine, which is administered intravenously. The antidote restores the liver's capacity to produce glutathione for combination with the benzoquinoneimine, and appears to have further protective effects on the liver.
The administration of antidote within 12 hours of overdose is highly effective and is able to remove the risk of liver injury. Antidote therapy is also very effective up to 24 hours and there is evidence for benefit from antidote administration up to 48 hours following overdose.
Paracetamol overdose can be successfully treated providing patients receive skilled treatment early, and the early diagnosis and treatment of any suspected overdose is a goal to be pursued.