Pharmacology & Therapeutics

Paracetamol overdose

Paracetamol overdose saturates conjugation and depletes hepatic glutathione, letting the reactive metabolite N-acetyl-p-benzoquinone imine (NAPQI) kill hepatocytes over 24 to 72 hours while the patient still feels well.

In a nutshell

Paracetamol overdose is silent for about 24 hours, then causes hepatic necrosis through the metabolite N-acetyl-p-benzoquinone imine (NAPQI). Treat with intravenous acetylcysteine 100 mg/kg over 2 hours then 200 mg/kg over 10 hours, guided by a 4-hour level or started blind when the timing is unreliable.

Classic presentation

A young adult brought to the emergency department a few hours after taking 30 paracetamol tablets, feeling completely well with a normal examination and normal liver tests.

Key points

Acetylcysteine given within 8 hours of a single ingestion prevents hepatotoxicity in almost all patients; later treatment still helps and is never futile in evolving injury.
Combination products such as co-codamol are a common hidden paracetamol source, and the opioid can depress respiration long before any liver injury appears.
In pregnancy, calculate the toxic dose on pre-pregnancy weight but the acetylcysteine dose on current weight.
On renal replacement therapy the acetylcysteine dose is doubled; discuss with the National Poisons Information Service (NPIS).
Adult under 40 kg: the same 100 then 200 mg/kg, given as a 50 mg/mL solution over 2 hours then a 10 mg/mL solution over 10 hours.
The therapeutic maximum is eight 500 mg tablets in 24 hours; repeated excess above this can be toxic without any single large overdose.

First-line investigation

Plasma paracetamol concentration at 4 hours or later after a single timed ingestion, sent with alanine aminotransferase (ALT), INR, U&E, glucose and a venous gas.

Management

Resuscitate, quantify, and decide on charcoal

ABCDE, capillary glucose, measured weight. Calculate the maximum plausible dose in mg/kg with the weight capped at 110 kg; above 150 mg/kg is potentially toxic.^3,4
Activated charcoal 50 g by mouth only within 1 hour of ingestion, and only if the patient is alert and will drink it. Never give it to a drowsy patient.^9,3
Phone the National Poisons Information Service (NPIS) via its database TOXBASE for children, pregnancy, weight under 40 kg, intravenous paracetamol, dialysis or mixed overdose.^8,1

Take the level at the right time

Single ingestion with a reliable time: if arrival is before 4 hours, wait and sample exactly at 4 hours; from 4 to 8 hours, draw the level immediately.^3,2
Treat if the level is on or above the line joining 100 mg/L at 4 hours to 15 mg/L at 15 hours. Beyond 15 hours the line is unreliable.^2,1
Arrived after 8 hours, staggered over more than 1 hour, or unknown time: start acetylcysteine now. The level then decides only whether you can stop.^1,2

Give the SNAP (Scottish and Newcastle Acetylcysteine Protocol) 12-hour regimen

Adult 40 kg or more: 100 mg/kg in 200 mL glucose 5% intravenously over 2 hours, then 200 mg/kg in 1 litre over 10 hours immediately afterwards.⁵
Total 300 mg/kg over 12 hours. Cap the calculating weight at 110 kg. Use sodium chloride 0.9% if glucose 5% is unsuitable.^5,12
Royal College of Emergency Medicine recommends SNAP as default. Licensed 21-hour alternative: 150 mg/kg over 1 hour, then 50 mg/kg over 4 hours, then 100 mg/kg over 16 hours.^11,12
Flushing, wheeze or hypotension early in the infusion is anaphylactoid, not allergic: pause 30 minutes, chlorphenamine 10 mg intravenously, nebulised salbutamol 5 mg, then restart.^1,2

Stop or continue at 12 hours, and spot liver failure

Send paracetamol, alanine aminotransferase (ALT), INR and U&E at 10 hours so the result is back before the second bag finishes.⁴
Stop only if paracetamol is below 10 mg/L, ALT normal and not doubled, INR 1.3 or less and no symptoms. Otherwise repeat 200 mg/kg over 10 hours.^4,3
Discuss with a liver unit for INR above 2, pH below 7.3, creatinine above 200 micromol/L, hypoglycaemia or encephalopathy. Encephalopathy runs confusion to coma; grade 3 to 4 is drowsy or comatose.⁷
Super-urgent transplant listing uses the King's College criteria, the UK thresholds for prioritising a liver graft.¹⁴
These are pH below 7.25 beyond 24 hours, or INR above 6.5 with creatinine above 300 micromol/L and grade 3 to 4 encephalopathy together.¹⁴

Mental health assessment and safe discharge

Refer every self-harm presentation to liaison psychiatry for psychosocial assessment as soon as possible after arrival. Never use a risk scale to decide discharge.⁶
Discharge needs the blood criteria met and an agreed safety plan. Warn the patient to return for vomiting, abdominal pain, jaundice, drowsiness or bleeding.^15,6

Exam traps

A level taken before 4 hours cannot rule out toxicity, however low it is.
Never plot a staggered or unknown-time ingestion on the nomogram. Treat instead.
Anaphylactoid reactions to acetylcysteine are rate-related, not allergic: pause and restart rather than abandoning treatment, and a previous reaction does not bar a further course.
The 12 hours is a minimum, not a course. The 10-hour bloods decide whether it stops, not the clock.
Normal liver tests at presentation are expected in the first 24 hours and are not reassurance.
Weight above 110 kg is capped at 110 kg for both the toxic-dose calculation and the acetylcysteine dose.

Illustrations

Paracetamol metabolism and glutathione depletionDiagram showing therapeutic conjugation pathways, formation of NAPQI in overdose, glutathione depletion and hepatocyte injury.PassFinals · original

Timed level and acetylcysteine decision pathwayFlow diagram distinguishing a known single acute ingestion suitable for timed nomogram plotting from staggered or uncertain ingestions treated immediately.PassFinals · original

Progression from overdose to acute liver failureClinical timeline from early nonspecific symptoms through hepatic injury, coagulopathy, encephalopathy and critical-care or transplant referral red flags.PassFinals · original

Key sources

This page is exam revision material, not medical advice, and must not be used for patient care. Always check drug doses against the BNF and current guidance. Full disclaimer.