Paracetamol

Mechanism of Action

Although paracetamol is widely used, its exact mechanism of action remains incompletely understood.

Paracetamol shares some similarities with non-steroidal anti-inflammatory drugs (NSAIDs) but exerts only weak cyclo-oxygenase (COX) inhibition within the central nervous system. This action is believed to reduce prostaglandin synthesis and interfere with pain signalling pathways.

The antipyretic effect results from reduced prostaglandin E2 production within the hypothalamus, leading to a lowering of the body’s temperature set-point.

Unlike NSAIDs, paracetamol has minimal peripheral anti-inflammatory activity.

Pharmacokinetics

Absorption

Paracetamol is well absorbed following oral and rectal administration, with a Tmax of approximately 30-60 minutes and 2-3 hours respectively.

Distribution

Paracetamol is widely distributed throughout body tissues and fluids. Paracetamol crosses into breastmilk but exposure to a breastfeeding infant is not expected to be clinically significant. Plasma protein binding is negligible at therapeutic doses but may increase with increasing concentrations.

Metabolism

Paracetamol is extensively metabolised (90-95%) in the liver, partly by CYP1A2 and also by CYP2E1, which is the same enzyme involved in alcohol metabolism.

N-acetyl-p-benzoquinone imine (NAPQI) is a highly reactive and toxic metabolite of paracetamol. Accumulation of NAPQI can lead to acute liver injury.

Normally, NAPQI is detoxified through conjugation with glutathione. However, when glutathione stores become depleted, NAPQI accumulates in the liver and renal tubular cells, resulting in cellular injury.

Increased NAPQI production may occur following paracetamol overdose or when paracetamol is administered alongside enzyme-inducing substances such as chronic alcohol consumption, phenytoin and carbamazepine.

Excretion

Paracetamol is primarily excreted by the kidneys.

The elimination half-life is approximately 2-4 hours. In toxicity, the half-life may be prolonged to 4–8 hours.

Cautions

There are no absolute contraindications to paracetamol use when administered appropriately; however, several patient groups require caution.

Liver Toxicity

Certain patients are at increased risk of paracetamol-induced hepatotoxicity, even outside of overdose situations.

Low Body Weight

The Health Services Safety Investigations Body (HSSIB) has issued guidance regarding paracetamol dosing in adults weighing less than 50 kg who are admitted to hospital.

These patients may have reduced glutathione stores and are at greater risk of paracetamol-induced liver toxicity. A reduced intravenous dose of 15 mg/kg four times daily (maximum 60 mg/kg/day) is recommended.

Malnutrition and Hepatic Impairment

Patients who are malnourished or have severe hepatic impairment may also have reduced glutathione reserves, increasing susceptibility to toxicity.

Chronic Alcohol Consumption

Paracetamol should be used cautiously in chronic alcohol users due to CYP enzyme induction, particularly CYP2E1, which increases NAPQI formation.

Intravenous Paracetamol Administration

For patients receiving regular intravenous paracetamol at the maximum dose, a dose reduction should be considered after 48 hours or less, due to the risk of accumulation of NAPQI. In patients >51kg with risk factors for hepatotoxicity, the BNF recommends a maximum dose of 3g daily.

Overdose

In the UK, paracetamol is  the most common drug involved in deliberate overdose.

At toxic doses (typically >10–15 g in adults), excessive NAPQI formation can result in severe hepatotoxicity and nephrotoxicity.

Early symptoms include:

• Nausea
• Vomiting
• Pallor
• Sweating

After 24-48 hours, evidence of liver injury may develop, which can progress to acute liver failure and death if untreated.

Management

Intravenous acetylcysteine (N-acetylcysteine; NAC) is the main treatment for paracetamol overdose.

Acetylcysteine, a precursor for glutathione, replenishes glutathione stores, allowing detoxification of NAPQI and reducing the risk of liver injury.

Monitoring during treatment commonly includes:

• INR
• Alanine aminotransferase (ALT)
• Creatinine

Acetylcysteine is typically administered as a series of intravenous infusions over approximately 12–21 hours.

By Fvasconcellos - Own work based on: Henry, John (1995) "Poisoning" in Marshall, William Leonard, ed. Clinical biochemistry: metabolic and clinical aspects, Edinburgh: Churchill Livingstone, pp. 666 Retrieved on 18 January 2009. ISBN: 9780443043413. and Hendrickson, Robert G.; Bizovi, Kenneth E. (2006) "Acetaminophen" in Goldfrank's toxicologic emergencies, New York City: McGraw-Hill, pp. 525 Retrieved on 18 January 2009. ISBN: 9780071437639., Public Domain, https://commons.wikimedia.org/w/index.php?curid=5739908

Fig 1: paracetamol metabolism

Adverse Effects

Adverse effects are uncommon when paracetamol is used at therapeutic doses.

Unlike NSAIDs, paracetamol does not significantly inhibit COX-1 and therefore does not commonly cause:

• Gastric ulceration
• Gastrointestinal bleeding
• Renal vasoconstriction associated with NSAID use

The most significant adverse effect is liver damage, particularly in overdose.

Paracetamol may have a minor inhibitory effect on platelet aggregation; however, this effect is generally not clinically significant.

Rare cases of blood dyscrasias have been reported, although a direct causal relationship has not been definitively established.

Pregnancy

Recent evidence from a large systematic review and meta-analysis published in The Lancet Obstetrics, Gynaecology & Women’s Health found no evidence that maternal paracetamol use during pregnancy increases the risk of autism spectrum disorder (ASD), attention-deficit hyperactivity disorder (ADHD), or intellectual disability in offspring. Consequently, the MHRA continues to recommend paracetamol as the first-line option for managing pain and fever during pregnancy when required.

Interactions

CYP enzyme inducers may increase the risk of paracetamol toxicity by increasing NAPQI production.

Examples include:

• Chronic excessive alcohol consumption
• Phenytoin
• Carbamazepine

References

1. HSSIB (2021). Unintentional overdose of paracetamol in adults with low bodyweight. [online] HSSIB. Available at: https://www.hssib.org.uk/patient-safety-investigations/unintentional-overdose-of-paracetamol-in-adults-with-low-bodyweight/.
2. Hitchings BSc, M., Lonsdale, D., Burrage, D., Baker, E. (2022). The Top 100 Drugs – E-Book. Netherlands: Elsevier.
3. Ritter JM, Flower RJ, Henderson G, Loke YK, MacEwan DJ. Rang & Dale’s Pharmacology. 9th ed. London: Elsevier; 2019. 
4. Poisoning or overdose | Health topics A to Z | CKS | NICE  Accessed 19/6/26.
5. Scenario: Paracetamol | Management | Analgesia – mild-to-moderate pain | CKS | NICE  Accessed 19/6/26
6. Paracetamol 125mg Suppositories – Summary of Product Characteristics (SmPC) – (emc) | 8080 Accessed 19/6/26
7. MHRA statement on new review of paracetamol safety during pregnancy – GOV.UK Accessed 19/6/26