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Define paracetamol poising

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paracetamol poisoning acetaminophen overdose

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Paracetamol (Acetaminophen) Poisoning

Definition

Paracetamol poisoning refers to toxicity - hepatic, renal, and systemic - resulting from ingestion of paracetamol (acetaminophen, N-acetyl-p-aminophenol) in doses exceeding the safe therapeutic range. It is one of the most common causes of deliberate self-poisoning worldwide and a leading cause of acute liver failure.
  • Therapeutic dose: 500-1000 mg/dose in adults (max 4 g/day); 10-15 mg/kg/dose in children (max 60 mg/kg/day)
  • Toxic dose: ≥150 mg/kg (single ingestion) in adults and children
  • Lethal dose: >350 mg/kg in adults; >250-350 mg/kg in children; overdoses of 20 g or more are potentially fatal, though less is required in combination with other drugs
  • The Essentials of Forensic Medicine and Toxicology, 36th Edition, p. 543; P.C. Dikshit Textbook of Forensic Medicine and Toxicology, p. 578

Toxicokinetics

  • Paracetamol is rapidly absorbed from the GI tract; peak plasma concentrations occur within 30-60 minutes
  • Plasma half-life is approximately 2 hours under normal therapeutic conditions
  • Volume of distribution: ~0.8 L/kg; protein binding is low (≥20%)

Mechanism of Toxicity

Under normal conditions, ~90% of paracetamol is conjugated with glucuronic acid and sulfuric acid in the liver to form non-toxic metabolites. The remaining ~10% is oxidized by the cytochrome P450 enzyme system (CYP2E1) to the highly reactive metabolite N-acetyl-p-benzoquinone imine (NAPQI).
In therapeutic doses: NAPQI is quickly neutralized by glutathione, forming cysteine and mercapturic acid conjugates that are safely excreted.
In overdose: Glutathione stores are overwhelmed and depleted. Unbound NAPQI covalently binds to proteins in hepatocytes and renal tubular cells, inducing oxidative stress, centrilobular necrosis, and cell death. This toxicity follows a threshold phenomenon - it manifests only when glutathione is critically depleted.
Risk factors that lower the threshold: chronic alcoholism (5-6 g/day over days can be hepatotoxic), enzyme-inducing drugs, malnutrition, children with low hepatic glucuronide conjugating ability.
  • Brenner and Rector's The Kidney, p. 3950; P.C. Dikshit, p. 578

Clinical Stages

StageTimeframeClinical Features
Stage I0-24 hoursNausea, vomiting, anorexia, malaise, pallor, diaphoresis. Often asymptomatic; LFTs usually normal
Stage II24-72 hoursRight upper quadrant pain, rising liver enzymes (AST, ALT), elevated bilirubin, prolonged PT; possible early renal involvement
Stage III72-96 hoursPeak hepatotoxicity: jaundice, coagulopathy, hypoglycemia, hepatic encephalopathy, renal failure, metabolic acidosis, possible multi-organ failure
Stage IV4-14 daysClinical improvement if patient survives; gradual normalization of liver function; full recovery possible due to liver regeneration
  • The Essentials of Forensic Medicine and Toxicology, 36th Edition, Table 31.2
Hepatotoxicity is defined as a peak AST >1000 IU/L. Severe cases progress to fulminant liver failure with encephalopathy, coagulopathy, hypoglycemia, and death.
Renal involvement (AKI): Due to NAPQI effects on renal tubules (via CYP450, prostaglandin synthetase, and N-deacetylase pathways); can persist 1-3 months after hepatotoxicity resolves.

Diagnostic Assessment

  • Rumack-Matthew Nomogram: Used to assess risk by plotting serum paracetamol concentration against time from ingestion. A serum level of ≥150 mg/L at 4 hours post-ingestion indicates need for NAC treatment
  • Dangerous levels: Plasma level >200 μg/mL at 4 hours and >30 μg/mL at 15 hours signals risk of fulminant hepatic failure
  • Blood levels in significant overdoses (≥10-15 g): 100-400 mg/L (average ~250 mg/L); urine may contain 150-800 mg/L
  • Monitor: LFTs (AST, ALT, bilirubin), PT/INR, renal function, blood glucose, electrolytes, metabolic panel
  • Brenner and Rector's The Kidney, p. 3957; P.C. Dikshit, p. 578

Management and Treatment

1. Decontamination

  • Gastric lavage: Consider only within the first hour of ingestion
  • Activated charcoal: Administer within 1-2 hours of ingestion to limit absorption; however, it can reduce the effectiveness of oral NAC if given concurrently

2. Antidotal Therapy - N-Acetylcysteine (NAC)

NAC is the primary antidote. It replenishes glutathione stores and prevents binding of NAPQI to cellular proteins. Most beneficial within 8-10 hours of overdose; treatment is practically ineffective if started ≥16 hours after ingestion.
Oral NAC:
  • Loading dose: 140 mg/kg
  • Maintenance: 70 mg/kg every 4 hours for 17 doses (total 72 hours); dilute to ~5% using water, soda, or juice
Intravenous NAC (FDA-approved 21-hour regimen):
  • 150 mg/kg over 1 hour (loading)
  • then 50 mg/kg over the next 4 hours
  • then 100 mg/kg over 16 hours
  • IV preferred if oral route is compromised by vomiting
Methionine (alternative): Oral glutathione precursor, 2.5 g every 4 hours up to four doses; useful when NAC is unavailable.

3. Supportive Care

  • Treat hypoglycemia, coagulopathy, and electrolyte disturbances
  • Liver transplantation for fulminant hepatic failure that meets criteria
  • The Essentials of Forensic Medicine and Toxicology, 36th Edition, p. 543; P.C. Dikshit, p. 578; Brenner and Rector's The Kidney, p. 3960

Autopsy Findings (Forensic)

  1. No specific GI tract findings
  2. In massive overdoses, CNS depression may be the direct cause of death
  3. Most deaths are delayed 2-4 days from liver failure; liver may be enlarged but often <1500 g, pale yellow-to-tan colored; centrilobular necrosis is visible microscopically
  4. Renal tubular necrosis may be present
  5. Myocardial fibril damage may be visible histologically
  • P.C. Dikshit Textbook of Forensic Medicine and Toxicology, p. 578

Recent Evidence (2024-2026)

A 2025 systematic review and meta-analysis (PMID 40013897) compared two-bag versus three-bag acetylcysteine regimens and supported simplified dosing protocols. A 2025 consensus statement (PMID 40162912) published standardized consensus definitions of paracetamol poisoning types and clinical outcomes, which are now being adopted in systematic reviews and clinical toxicology guidelines globally.
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