Paracetamol

 Common indications

1. Paracetamol is a first-line analgesic for most forms of acute and chronic pain. The WHO pain ladder (originally designed to guide the treatment of cancer pain) uses regular paracetamol as the basis of treatment, with weak then strong opioids added incrementally until pain is controlled.
2. Paracetamol is an antipyretic that can reduce fever and its associated symptoms (e.g. shivering).

 

Mechanisms of action

• The mechanisms of action of paracetamol are poorly understood. Paracetamol is a weak inhibitor of cyclooxygenase (COX), the enzyme involved in prostaglandin metabolism. In the central nervous system, COX inhibition appears to increase the pain threshold and reduce prostaglandin (PGE2) concentrations in the thermoregulatory region of the hypothalamus, controlling fever. 
• Paracetamol has specificity for COX-2 (the isoform induced in inflammation) rather than COX-1 (the isoform involved in protecting the gastric mucosa and regulating renal blood flow and clotting). However, despite its COX-2 selectivity, paracetamol is a weak anti-inflammatory, as its actions are inhibited in inflammatory lesions by the presence of peroxides.

 

Important adverse effects

• At treatment doses, paracetamol is very safe with few side effects.  Its safety makes it a popular choice as a first-line analgesic.
• Lack of COX-1 inhibition means that it does not cause peptic ulceration or renal impairment or precipitate cardiovascular events (unlike NSAIDs).
• Paracetamol is metabolised by cytochrome P450 enzymes to a toxic metabolite (N-acetyl-p-benzoquinone imine [NAPQI]), which is conjugated with glutathione before elimination. 
• After overdose, this elimination pathway is saturated, and NAPQI accumulation causes hepatocellular necrosis. This causes liver failure.
• Hepatotoxicity can be prevented by treatment with the glutathione precursor acetylcysteine.

 

Warnings

• Paracetamol dose should be reduced in people at increased risk of liver toxicity, either because of increased NAPQI production (e.g. in chronic excessive alcohol use, inducing metabolising enzymes) or reduced glutathione stores (e.g. in malnutrition, low body weight (<50 kg) and severe hepatic impairment). This is particularly important where paracetamol is given by IV infusion.

 

Important interactions

• There are few clinically significant interactions between paracetamol and other drugs. 
• Cytochrome P450 inducers, e.g. phenytoin and carbamazepine, increase the rate of NAPQI production and risk of liver toxicity after paracetamol overdose.