Paracetamol

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Paracetamol (acetaminophen) is a widely used analgesic and antipyretic. It works centrally by inhibiting prostaglandin synthesis in the CNS, lacks significant peripheral anti-inflammatory activity, and is generally well tolerated at therapeutic doses. Overdose causes hepatotoxicity via accumulation of the toxic metabolite NAPQI.

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paracetamol acetaminophen pharmacology

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Paracetamol (Acetaminophen)

Brand names: Tylenol, Ofirmev (IV formulation) Class: Non-opioid analgesic / antipyretic Metabolite of: Phenacetin

Mechanism of Action

Paracetamol works primarily within the CNS by inhibiting prostaglandin synthesis. Unlike NSAIDs, it has minimal peripheral anti-inflammatory activity. It also inhibits nitric oxide synthesis in murine spinal cord models. The CNS-central action accounts for its analgesic and antipyretic effects without the gastric or platelet-related side effects of NSAIDs.

Dosage

Category	Adults	Children
Therapeutic dose	500-1000 mg/dose (max 4 g/day)	10-15 mg/kg/dose (max 60 mg/kg/day)
Toxic dose	≥150 mg/kg (single ingestion)	≥150-200 mg/kg
Lethal dose	>350 mg/kg	>250-350 mg/kg

The Essentials of Forensic Medicine and Toxicology, 36th ed., p. 543

Pharmacokinetics

Rapidly absorbed from the GI tract; peak plasma concentration in 30-60 minutes
Plasma half-life ~2 hours under normal therapeutic conditions

Metabolism Pathway

Fig. 31.1: Metabolism pathway of paracetamol - The Essentials of Forensic Medicine and Toxicology, 36th ed.

~90% - Conjugated with glucuronic acid and sulfuric acid → non-toxic metabolites (safe excretion)
~10% - Metabolized via CYP2E1 → NAPQI (N-acetyl-p-benzoquinone imine), a highly reactive toxic metabolite

Under normal conditions: NAPQI is neutralized by glutathione → cysteine and mercapturic acid conjugates (safely excreted)

In overdose: Hepatic glutathione reserves are exhausted → NAPQI accumulates → covalent binding to liver cell proteins, especially in the centrilobular region → oxidative stress and hepatocyte necrosis

Clinical Features of Paracetamol Poisoning

Stages

Stage	Timeframe	Clinical Features
Stage I	0-24 hours	Nausea, vomiting, anorexia, malaise, pallor, diaphoresis. Often asymptomatic; LFTs usually normal. Deceptively mild - can give false sense of security.
Stage II	24-72 hours	Right upper quadrant pain, elevated LFTs (ALT, AST), bilirubin rises. Patient relatively pain-free despite ongoing liver damage. Anorexia, epigastric pain, malaise.
Stage III	72-96 hours (peak hepatotoxicity)	Fulminant hepatic failure, coagulopathy, encephalopathy. Acute kidney injury, metabolic acidosis, hypoglycaemia, gastrointestinal haemorrhage, cerebral oedema, cardiomyopathy.
Stage IV	4 days - 2 weeks	Recovery phase: if patient survives Stage III, complete resolution of liver injury typically occurs.

Key point: In overdose, paracetamol does NOT affect acid-base balance, does NOT stimulate respiration, and does NOT have cardiovascular effects in the early stages - unlike aspirin poisoning.

Fatal dose: Ingestion of ~20 tablets of 500 mg (10 g) is usually fatal within 3-5 days.

Management of Paracetamol Overdose

Admission - All suspected overdose patients must be admitted, even if clinically well. A patient appearing well at 12 hours may die of acute hepatic failure up to 5 days later.
Gastric lavage - If admitted within 4 hours of ingestion.
Activated charcoal - Within 1-2 hours post-ingestion to limit absorption. Note: may reduce effectiveness of oral NAC if given together.
N-Acetylcysteine (NAC) - The antidote; most effective within 8-10 hours of overdose (effective up to 16-24 hours):
- Oral NAC: Loading dose 140 mg/kg, then 70 mg/kg every 4 hours. Duration 24-72 hours (6-18 doses). Dilute to ~5% solution.
- IV NAC (FDA-approved protocol): 150 mg/kg over 1 hour → 50 mg/kg over 4 hours → 100 mg/kg over 16 hours (21-hour regimen total). Recommended if vomiting prevents oral administration.
Methionine - Oral glutathione precursor: 2.5 g every 4 hours for 4 doses (10 g total over 12 hours). Useful if NAC unavailable.
Supportive care for hepatic necrosis complications: IV dextrose (hypoglycaemia), IV bicarbonate (metabolic acidosis), Vitamin K1, whole blood/plasma (coagulopathy). Fluid restriction to <2.5 L/day (paracetamol causes fluid retention).
Haemodialysis - For acute renal failure, or severe overdose with metabolic complications.
Liver transplantation - Indications: severe metabolic acidosis, prothrombin time >100 seconds, or serum creatinine >300 µmol/L (King's College Criteria).

Rumack-Matthew Nomogram - Essential tool for guiding treatment decisions based on serum paracetamol level and time since ingestion.

Postmortem Findings

Remains of paracetamol tablets in stomach
Centrilobular hepatic necrosis
Acute tubular necrosis of kidneys
Skin rashes, jaundice
Petechial haemorrhages, GI bleeding
Myocardial damage, cerebral oedema

Drug Interactions / Risk Factors for Increased Hepatotoxicity

Isoniazid, rifampicin, barbiturates (enzyme inducers increase CYP2E1 activity → more NAPQI)
Chronic alcohol use
AIDS / immunocompromised states
Long-term therapeutic use can cause toxic hepatitis in these high-risk groups

Medicolegal Notes

Poisoning is usually accidental (overdosage, indiscriminate use as analgesic/antipyretic)
More common in children
Suicidal ingestion is notable because patients who attempt suicide with paracetamol often regret the choice due to the prolonged and painful course before death
Common in USA and UK; relatively less common in India

Sources: The Essentials of Forensic Medicine and Toxicology 36th ed. (2026), p. 541-543 | Parikh's Textbook of Medical Jurisprudence Forensic Medicine and Toxicology, p. 714-715 | P C Dikshit Textbook of Forensic Medicine and Toxicology | Bailey and Love's Short Practice of Surgery 28th ed.

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