Key Facts

Paracetamol is the first-line analgesic for most pain presentations and is a key component of multimodal analgesia. Its safety profile at therapeutic doses is excellent, but overdose is a major clinical problem and a common exam topic.

Epidemiology

• Most commonly used analgesic in UK; OTC and prescription
• ~100,000 presentations/year to UK EDs with paracetamol overdose
• Leading cause of acute liver failure in UK (~40–50% of cases)
• ~150–200 deaths/year from paracetamol poisoning in UK (declining with NAC and legislation)

Pharmacology

• Absorption: rapidly absorbed orally; peak levels at 30–60 minutes (4 hours with modified-release or co-ingested drugs)
• Metabolism: 90% hepatic conjugation (glucuronidation and sulfation) → non-toxic metabolites; ~5% via CYP2E1 → NAPQI (toxic)
• At therapeutic doses: NAPQI is rapidly conjugated by glutathione → non-toxic
• In overdose: conjugation pathways saturated → excess NAPQI → glutathione depleted → NAPQI binds hepatocyte proteins → centrilobular necrosis

Pathophysiology of Toxicity

• NAPQI accumulation → glutathione depletion → oxidative stress → mitochondrial dysfunction → hepatocyte necrosis
• Centrilobular pattern (zone 3) — highest CYP2E1 activity
• Peak liver damage: 72–96 hours post-ingestion
• May also cause renal tubular necrosis (direct toxicity)
• NAC: replenishes glutathione + direct hepatoprotective effects

Therapeutic Use

• First-line analgesic for mild-moderate pain
• Antipyretic
• Component of multimodal analgesia (reduces opioid requirement by ~30%)
• Safe in pregnancy, breastfeeding, renal impairment

Paracetamol Overdose — Phases

Phase 1 (0–24 hours):

• Often asymptomatic
• Nausea, vomiting, malaise
• Liver function typically normal

Phase 2 (24–72 hours):

• Nausea, vomiting, RUQ pain
• Rising ALT/AST (may reach >10,000 IU/L)
• Rising INR, falling albumin
• AKI may develop

Phase 3 (72–96 hours):

• Peak hepatotoxicity
• Jaundice, coagulopathy, encephalopathy
• Metabolic acidosis, hypoglycaemia
• Multi-organ failure
• Maximum mortality risk

Phase 4 (4 days–2 weeks):

• Recovery phase (if survives) — liver regeneration
• Complete recovery in most survivors

Red Flags

• pH <7.3 (after fluid resuscitation) — poor prognosis, consider transplant listing
• INR >6.5 at 24 hours
• Encephalopathy grade III–IV
• Creatinine >300 μmol/L
• Lactate >3.5 mmol/L at 4 hours or >3.0 after fluid resuscitation

Overdose Assessment

• Paracetamol level: at ≥4 hours post-ingestion — plot on nomogram
• LFTs: ALT, AST (may be normal initially; serial monitoring)
• INR/PT: most important prognostic marker — serial monitoring
• U&Es, creatinine: renal function
• Venous blood gas: pH, lactate — prognostic significance
• Blood glucose: hypoglycaemia in severe hepatotoxicity
• Phosphate: low phosphate is a good prognostic sign (indicates hepatic regeneration)

Timed Monitoring

• Paracetamol level at 4 hours (or as soon as possible after 4 hours)
• LFTs, INR, U&Es: at presentation, then 12-hourly
• pH, lactate: at presentation and serially in severe cases

Special Tests

• King's College criteria: assess need for liver transplant listing
• Serum phosphate: rising phosphate = poor prognosis; falling/normal = recovery
• Arterial ammonia: if encephalopathy
• CT head: if encephalopathy to exclude other causes

Therapeutic Use

• Adults >50 kg: 1 g QDS orally (max 4 g/24 hours)
• Low body weight (<50 kg): 15 mg/kg per dose (max 60 mg/kg/day)
• Liver disease/chronic alcohol: max 2–3 g/day (some guidelines suggest 4 g short-term is acceptable)
• IV paracetamol: 1 g over 15 minutes QDS (max 4 g/24h); weight-based if <50 kg — BEWARE ten-fold dosing errors in neonates/infants

Overdose Management

Immediate:

• Activated charcoal 50 g: if within 1 hour of ingestion (rarely achievable)
• Paracetamol level at ≥4 hours: plot on Rumack-Matthew nomogram using 100 mg/L treatment line (UK)

N-Acetylcysteine (NAC):

• Indicated if: level above treatment line on nomogram; staggered overdose ≥150 mg/kg; uncertain timing; already symptomatic
• New 2-bag regimen (SNAP protocol — 2023): 100 mg/kg in 200 mL over 2 hours, then 200 mg/kg in 1000 mL over 10 hours
• Anaphylactoid reactions to NAC: common (~15%) — flushing, urticaria, bronchospasm; slow/pause infusion, give antihistamine; usually restart at slower rate
• Most effective within 8 hours: virtually 100% hepatoprotective if given within 8 hours

Severe Hepatotoxicity:

• ITU admission: coagulopathy, encephalopathy, acidosis, renal failure
• Continue NAC infusion at 150 mg/kg/16 hours until INR falling and ALT declining
• IV fluids, glucose, correct coagulopathy
• Avoid FFP (unless actively bleeding) — obscures INR prognostic value
• Contact liver transplant centre early if King's College criteria met

Referral Criteria

• Liver transplant centre: King's College criteria or rapidly deteriorating liver function
• Psychiatric assessment: all intentional overdoses
• Toxicology: complex overdoses, late presentation, uncertainty

• NAC within 8 hours: mortality <0.5%
• NAC at 8–24 hours: still beneficial but less effective
• Without NAC: mortality ~5–10% in significant overdose
• King's College criteria met: mortality ~80% without transplant
• Most survivors recover completely — liver regenerates fully
• UK paracetamol pack-size legislation (1998): reduced deaths by ~43%

King's College Criteria (Paracetamol-Induced ALF)

NAC Regimen (SNAP 2-bag Protocol)

Risk Factors for Enhanced Toxicity