|Paracetamol has been available as an over the counter medication for over 50 years and continues to be widely used for acute and chronic pain. Despite its ubiquity in pain management, its exact mode of action is still not clear.
Theories for mechanism of action
A variant of the cyclo-oxygenase (COX) 1 enzyme (COX-3) has been described in the brain and spinal cord and is proposed to be the site of action for the antipyretic and analgesic effects. In animal models, paracetamol has been shown to block the actions of COX-3; however, this has not been proven in humans.
Other theories include:
• Inhibition of prostaglandin synthesis via inhibition of prostaglandin H2-synthase.
• Modulation of pain via stimulation of descending pain pathways.
Absorption: good, mainly small intestine (oral bioavailability 80%)
Distribution: low protein binding, high volume of distribution
Metabolism: hepatic (see below)
Excretion: Inactive metabolites excreted in urine
Metabolism and overdose
Paracetamol undergoes hepatic metabolism (glucuronidation) mainly to two inactive products that are excreted in the urine unchanged. In normal conditions, a very small amount of the toxic compound N-acetyl-p-benzoquinone imine (NAPQI) is produced but this is rapidly inactivated by glutathione (conjugation) to non-toxic metabolites that are also excreted in the urine.
This system can be rapidly saturated in the case of overdose or abnormal liver function, and increased quantities of NAPQI are produced. If glutathione stores are low (e.g. due to malnutrition, chronic alcohol use, co-morbid liver disease and some medications such as phenytoin and carbamazepine) or a sufficiently large dose of paracetamol has been taken, the NAPQI cannot be inactivated and it may cause hepatocellular and renal necrosis.
N-acetylcysteine (NAC) is used in acute overdose, acting like glutathione to neutralise the NAPQI by binding to it. It is very effective within 8 hours of overdose; however, this decreases as the hours pass beyond 15. Treatment is usually based on paracetamol levels and reference to a nomogram of plasma paracetamol concentration (mmol/L), time (hours) and plasma paracetamol concentration (mg/L). In the case of staggered overdose or where ingestion time is unclear, NAC treatment may be started without using the nomogram.
Side effects • Hypotension, flushing, tachycardia with intravenous (IV) infusion (1/1000-1/10000).
• Deranged liver function tests (1/1000-1/10000), liver damage and failure with overdose.
• Hypersensitivity reactions (<1/10000).
• Skin reactions: Stevens–Johnson syndrome, toxic epidermal necrolysis, acute generalised exanthematous pustulosis (1/10000)
Due to the risk of toxicity, a reduction in the dose of the IV formulation may be required in the case of liver or renal failure, chronic alcohol misuse, malnutrition and dehydration.
Table 1. MHRA dosing of children and adults for IV paracetamol. (Adapted from Safe Anaesthesia Liaison Group. Intravenous Paracetamol. May 2013)
|| <10 kg
|| 33–50 kg
| Risk factors for toxicity?|
| YES NO|
|Max. single dose
|| 7.5 mg/kg
|| 15 mg/kg
|| 15 mg/kg
|| 1 g 1 g|
| Max. dose in 24 h
|| 30 mg/kg
|| 60 mg/kg
(max 2 g/day)
| 60 mg/kg
(max 3 g/day)
| 3 g 4 g|
Author: Dr Sarah Hudson