About This Page
This is a clinician-written, evidence-based summary aligned to the 2026 MLA Content Map. It is intended for medical students and junior doctors preparing for the UKMLA. Always cross-reference with NICE guidance, local protocols, and clinical judgement.
The Bottom Line
- Commonest drug overdose in the UK — ~100,000 presentations and 150–200 deaths annually
- Toxic dose: ≥75 mg/kg in 24 hours (≈15 tablets of 500 mg in a 70 kg adult)
- Mechanism: glutathione depletion → NAPQI accumulation → hepatocellular necrosis (peak liver damage at 72–96 hours)
- Treatment: IV acetylcysteine (NAC) — near 100% effective if given within 8 hours of ingestion
- Single treatment line on nomogram: plot paracetamol level at 4+ hours post-ingestion — treat if above the line (100 mg/L at 4 hours)
Overview
Paracetamol (acetaminophen) overdose is the commonest cause of acute liver failure in the UK. At therapeutic doses, paracetamol is primarily metabolised by conjugation (glucuronidation and sulphation). In overdose, these pathways become saturated, and more paracetamol is metabolised by CYP2E1 to the toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI). Normally, NAPQI is safely conjugated with glutathione. In overdose, glutathione stores are depleted and NAPQI accumulates, causing centrilobular hepatic necrosis. N-acetylcysteine (NAC) works by replenishing glutathione stores and is virtually 100% hepatoprotective if given within 8 hours of a single acute overdose. Efficacy declines progressively after 8 hours.
Epidemiology
Approximately 100,000 people present to UK emergency departments annually with paracetamol overdose. Around 150–200 deaths occur per year, and 15–20 liver transplants are performed for paracetamol-induced liver failure. Most overdoses are impulsive acts of self-harm in young people. Staggered overdoses (ingestion over >1 hour) and unintentional therapeutic excess carry higher mortality because the nomogram cannot be used and presentation is often delayed.
Clinical Features
Symptoms
Phase 1 (0–24 hours): often asymptomatic, or mild nausea, vomiting, malaise, abdominal pain
Phase 2 (24–72 hours): RUQ pain (hepatic capsular stretching), vomiting, improving general symptoms (deceptive improvement)
Phase 3 (72–96 hours): peak hepatotoxicity — jaundice, coagulopathy, encephalopathy, renal failure, hypoglycaemia
Phase 4 (4–14 days): recovery phase in survivors, or progression to multi-organ failure and death
Signs
Initially patient may appear completely well — do NOT be falsely reassured
RUQ tenderness (hepatomegaly and hepatic inflammation at 24–72 hours)
Jaundice (from 48–72 hours)
Encephalopathy, asterixis (hepatic failure)
Oliguria (renal failure)
Investigations
First-line
Serum paracetamol levelTake at 4 hours post-ingestion (or immediately if ≥4 hours). Plot on the treatment nomogram. Level above the 100 mg/L line at 4 hours = treat with NAC
ALT/ASTBaseline and serial monitoring — rising transaminases indicate liver damage (may be normal initially)
INR/PTBest prognostic marker of liver synthetic function — rising INR indicates severe hepatotoxicity
U&Es, creatinineMonitor for renal failure — paracetamol causes direct renal tubular toxicity
Venous blood gasAssess for metabolic acidosis (lactate) — an ominous sign indicating severe hepatic failure
Second-line
Blood glucoseHypoglycaemia in liver failure (impaired gluconeogenesis) — monitor regularly
FBC and phosphateThrombocytopenia and hypophosphataemia in severe cases
Salicylate levelExclude co-ingestion (common in mixed overdoses)
Specialist
Arterial blood gas and lactateArterial pH <7.3 after resuscitation = poor prognostic marker (King’s College criteria)
1
Acute single ingestion with known time
- Take paracetamol level at 4 hours post-ingestion (or as soon as possible if >4 hours)
- Plot on the MHRA treatment nomogram (SINGLE treatment line at 100 mg/L at 4 hours)
- If above the line: start IV NAC immediately
- If below the line and ALT/INR normal: discharge with safety-net advice
- If presenting <1 hour: consider activated charcoal 50 g (if ≥75 mg/kg ingested)
2
IV acetylcysteine (NAC) protocol
- Standard 21-hour regimen: 150 mg/kg in 200 mL over 1 hour, then 50 mg/kg in 500 mL over 4 hours, then 100 mg/kg in 1 L over 16 hours
- Modified SNAP 12-hour regimen (increasingly used): 100 mg/kg over 2 hours, then 200 mg/kg over 10 hours
- Cap weight at 110 kg for dose calculation in obese patients
- Anaphylactoid reactions to NAC are common (flushing, urticaria, bronchospasm) — slow infusion rate, give IV antihistamine, do NOT stop NAC
3
Staggered overdose or uncertain timing
- Cannot use the nomogram — start NAC immediately if ≥75 mg/kg in any 24-hour period
- Check paracetamol level and ALT — treat with NAC if either is abnormal
- Higher risk of severe liver damage due to delayed presentation
4
Refer to liver unit (King’s College criteria)
- Arterial pH <7.3 after fluid resuscitation (most important single criterion)
- OR all three of: INR >6.5 (PT >100s), creatinine >300 µmol/L, grade III–IV encephalopathy
- Discuss with regional liver transplant centre early if deteriorating despite NAC
Complications
- Acute liver failure: Peak at 72–96 hours — encephalopathy, coagulopathy, hypoglycaemia, metabolic acidosis
- Acute kidney injury: Direct renal tubular toxicity (not just hepatorenal syndrome)
- Multi-organ failure: Hepatic, renal, and metabolic failure in severe untreated cases
- Death: Approximately 150–200 per year in UK despite treatment availability
- NAC anaphylactoid reaction: Common but manageable — do NOT stop NAC
UKMLA Exam Tips
- 1Take paracetamol level at 4 HOURS post-ingestion — levels before 4 hours are unreliable
- 2SINGLE treatment line on the nomogram (100 mg/L at 4 hours) — the old "high-risk" line was removed in 2012
- 3NAC is near 100% effective within 8 hours — efficacy drops significantly after this
- 4Staggered overdose or unknown time of ingestion = cannot use nomogram → start NAC if ≥75 mg/kg ingested
- 5A patient may appear WELL for the first 24 hours — liver damage peaks at 72–96 hours. Do NOT be falsely reassured
- 6INR is the best marker of prognosis — rising INR = worsening liver synthetic failure
- 7King’s College criteria for transplant: pH <7.3 OR (INR >6.5 + Cr >300 + grade III–IV encephalopathy)
- 8Activated charcoal only useful if given within 1 hour of ingestion
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