Paracetamol Pharmacology

Paracetamol is a para-aminophenol derivative with analgesic and antipyretic effect and negligible anti-inflammatory action. It is the most widely used analgesic worldwide, safe at labelled doses and a leading cause of acute liver failure after overdose in many countries. It is the first-line agent for mild pain and fever and the foundation of multimodal analgesia.

Mechanism. Inhibits COX within the central nervous system, especially where peroxide tone is low, and reduces prostaglandin E2 in the hypothalamus to lower fever. Its metabolite AM404 acts on TRPV1 and cannabinoid receptors, and descending serotonergic inhibition contributes to analgesia.

Pharmacokinetics. Oral bioavailability is 60 to 90%; peak 30 to 60 minutes (delayed with slow gastric emptying); intravenous peak at the end of a 15-minute infusion. Protein binding is low (10 to 25%), volume of distribution about 1 L/kg, half-life 1.5 to 3 hours (longer in liver failure, overdose and neonates).

Metabolism. About 50 to 60% is glucuronidated and 20 to 30% sulphated, both inactive and renally cleared. Roughly 5 to 10% is oxidised by CYP2E1 (also 1A2 and 3A4) to N-acetyl-p-benzoquinone imine (NAPQI), detoxified by glutathione.

Mechanism of toxicity. In overdose glucuronidation and sulphation saturate, glutathione falls under about 30% of normal and NAPQI binds hepatocyte proteins, causing centrilobular necrosis. Risk rises with fasting, malnutrition, chronic alcohol use and enzyme inducers such as carbamazepine, phenytoin, rifampicin and isoniazid.

Formulations.

• Oral tablets 500 mg (1 g in some regions), soluble tablets, suspension 120 mg/5 mL and 250 mg/5 mL.
• Rectal suppositories 125 mg to 1 g; absorption is slower and erratic, so rectal dosing suits only patients unable to take oral or intravenous doses.
• Intravenous 10 mg/mL in 50 mL or 100 mL containers.
• Combinations with codeine (500 mg with 8 or 30 mg), tramadol, ibuprofen, caffeine and, for migraine, metoclopramide.

Intravenous administration. Infuse over 15 minutes. Prescribe in mg and state the volume, because confusion of mg with mL has caused tenfold overdoses. There is no loading dose.

• First-line. Mild to moderate pain, post-operative baseline analgesia, fever in distressed patients, and dysmenorrhoea. Evidence for benefit in chronic low back pain and osteoarthritis is weak.
• Alternative. Intravenous route when oral intake is impossible; combination with an NSAID for additive analgesia; combination with a weak opioid when both are needed.
• Specialist. Neonatal patent ductus arteriosus where NSAIDs are contraindicated (15 mg/kg intravenously every 6 hours for 3 days; evidence still developing).
• Emergency. Overdose management.

Overdose thresholds. A single ingestion of 150 mg/kg or 12 g (whichever is less) is potentially toxic; use 75 mg/kg with hepatic risk factors. Take a plasma level at 4 hours or later and plot it against the treatment line.

Acetylcysteine. Give without waiting for a level when presentation is after 8 hours, ingestion is staggered or the time is unknown: 150 mg/kg intravenously over 1 hour, then 50 mg/kg over 4 hours, then 100 mg/kg over 16 hours.

Fever. Treat distress rather than the number. Alternating with ibuprofen is not routinely advised; test for malaria in febrile patients in endemic areas.

Contraindications. Hypersensitivity; intravenous use in severe hepatocellular insufficiency or active hepatic failure.

Adverse effects. Hepatotoxicity in overdose or repeated supratherapeutic dosing; rare Stevens-Johnson syndrome, toxic epidermal necrolysis, thrombocytopenia and neutropenia; hypotension during intravenous infusion; high anion gap metabolic acidosis (5-oxoproline) in malnourished or septic patients on prolonged use.

Interactions.

• Warfarin: regular use of 2 g or more daily raises INR.
• Carbamazepine, phenytoin, rifampicin, chronic alcohol use: more NAPQI.
• Flucloxacillin: high anion gap metabolic acidosis.
• Colestyramine reduces absorption; metoclopramide speeds it.

Common prescribing errors.

• Duplicate paracetamol in cold remedies and combination analgesics.
• Intravenous mg and mL confusion.
• Fixed adult doses in low body weight or malnutrition.
• Staggered overdoses not recognised.
• Co-administering suppository and oral doses.

Special groups.

• Pregnancy: acceptable at the lowest effective dose for the shortest time; reported neurodevelopmental associations are inconsistent and do not justify withholding treatment.
• Breastfeeding: compatible.
• Older adults: use 15 mg/kg dosing if frail or under 50 kg.
• Kidney: interval of at least 6 hours when CrCl is under 30 mL/min, at least 8 hours when under 10 mL/min.
• Liver: 2 g daily at most in decompensated cirrhosis or active alcohol-related liver disease; avoid in acute liver failure from another cause unless directed by a specialist.
• G6PD deficiency: safe at usual doses.
• East Africa: over-the-counter availability makes duplicate use and intentional self-poisoning important; fever should not be treated empirically before malaria is excluded.

Monitoring. Liver enzymes and INR with prolonged high-dose therapy or hepatic risk factors; plasma paracetamol at 4 hours in overdose; repeat ALT and INR at the end of acetylcysteine and continue the infusion until ALT is falling and INR is under 1.5.

Referral and escalation. Any overdose of 150 mg/kg or 12 g or more, uncertain time of ingestion, or ALT rising during treatment; INR over 2, encephalopathy, creatinine rise, lactate over 3 mmol/L or pH under 7.30 need urgent hepatology or transplant-centre contact.

Comparison with alternative classes. Paracetamol avoids the gastric, renal, platelet and cardiovascular harm of NSAIDs and the respiratory depression of opioids, but is weaker for inflammatory pain and has a narrow margin in overdose.