PARACETAMOL (ACETAMINOPHEN) POISONING

Paracetamol (N-acetyl-p-aminophenol, acetaminophen) is one of the most widely used antipyretic and analgesic medications worldwide and is the commonest cause of drug overdose and acute liver failure globally.

In therapeutic doses, the drug is safely metabolized in the liver. However, in overdose, toxic metabolites accumulate causing centrilobular hepatic necrosis and potentially fatal acute liver failure.

Toxicity may occur after:

• Single acute ingestion

• Repeated supratherapeutic dosing

• Chronic excessive use (especially in malnourished or alcoholic patients)

Early treatment with antidote is highly effective — delayed treatment leads to high mortality.

2. Toxic Dose

3. Pathophysiology

Normally:

• 90% → glucuronidation & sulfation (safe)

• 5% → unchanged renal excretion

• 5% → CYP450 metabolism → NAPQI (toxic metabolite)

NAPQI is detoxified by glutathione.

In overdose:

• Glutathione depleted

• NAPQI binds hepatocytes

• Causes massive hepatic necrosis

Organs affected:

• Liver (primary)

• Kidney (acute tubular necrosis)

• Brain (hepatic encephalopathy)

• Pancreas (rare)

4. Risk Factors

Patient Factors

• Chronic alcohol use

• Malnutrition / fasting

• HIV/AIDS

• Chronic liver disease

• Elderly

• Low body weight

Drug Factors

• Combination cold medications

• Pediatric syrups overdosing

• Extended-release preparations

• Repeated dosing errors

5. Clinical Features

Paracetamol poisoning progresses in four classic stages

Phase I (0.5–24 hours)

Often mild or asymptomatic

• Anorexia

• Nausea

• Vomiting

• Malaise

• Pallor

• Sweating

• Mild tachycardia

Phase II (18–72 hours)

Hepatic injury begins

• Right upper quadrant pain

• Hepatomegaly

• Persistent vomiting

• Tachycardia

• Hypotension

• Oliguria

• Rising AST/ALT

Phase III (72–96 hours) — Critical Stage

Fulminant hepatic failure

• Jaundice

• Coagulopathy (↑INR/PT)

• Hypoglycemia

• Hepatic encephalopathy

• Acute kidney injury

• Metabolic acidosis

• Lactic acidosis

• Death possible

Phase IV (Day 4–3 weeks)

Recovery phase (if survives)

• Liver regeneration

• Gradual normalization of labs

6. Diagnostic Criteria

Diagnosis based on:

• History of ingestion

• Serum paracetamol level (4 hours post ingestion)

• Rumack-Matthew nomogram

• Liver enzyme elevation

7. Investigations

Essential Tests

• Serum paracetamol level (4 hours after ingestion)

• ALT / AST

• PT / INR

• Blood glucose

• Urea & creatinine

• Electrolytes

• ABG

Additional

• Lactate

• Bilirubin

• Phosphate

• Ultrasound liver (if severe)

Interpretation — Rumack-Matthew Nomogram

Used for acute ingestion only

If level above treatment line → start antidote immediately

8. Management

Initial Stabilization (ABCDE)

• Assess airway

• Oxygen if needed

• IV access

• Treat hypoglycemia immediately

• Monitor vitals continuously

9. Treatment

A. Gastrointestinal Decontamination

Activated charcoal

• 1 g/kg (max 50 g)

• Give within 1–2 hours

• Still useful up to 4 hours for sustained-release

B. Antidote Therapy (Most Important Treatment)

N-Acetylcysteine (NAC)

Indications

• Serum level above treatment line

• Unknown ingestion time

• 8 hours after ingestion

• Any evidence of liver injury

IV NAC Regimen (Standard 21-hour protocol)

1. Loading dose150 mg/kg IV in 200 mL 5% dextrose over 20–60 min

2. Second infusion50 mg/kg in 500 mL 5% dextrose over 4 hours

3. Third infusion100 mg/kg in 1 L 5% dextrose over 16 hours

Severe Poisoning

Continue infusion:100 mg/kg over next 24 hours until liver improves

Pediatric <20 kg Regimen

(Volume adjusted weight-based infusion as provided)

Oral Antidote Alternative — Methionine

Use if NAC unavailable and patient conscious:

• <6 years: 1 g every 4 hours × 4 doses

• ≥6 years: 2.5 g every 4 hours × 4 doses

C. Supportive Treatment

• Treat hypoglycemia aggressively

• Correct electrolyte imbalance

• Vitamin K for coagulopathy

• Fresh frozen plasma if bleeding

• Dialysis for renal failure

• ICU monitoring if encephalopathy

D. Liver Transplant Referral Criteria

(King’s College Criteria)

Poor prognosis if:

• pH <7.3 OR

• INR >6.5 + creatinine >300 µmol/L + encephalopathy

10. Monitoring

Repeat every 12–24 hours:

• AST/ALT

• INR

• Glucose

• Creatinine

• Lactate

Continue NAC until:

• Enzymes falling

• INR improving

• Patient clinically stable

11. Complications

• Acute liver failure

• Cerebral edema

• Renal failure

• Pancreatitis

• Death

12. Prevention

Do’s

• Store medicines safely

• Use correct dosing devices

• Educate caregivers

• Avoid duplicate medications

Don’ts

• Do not combine cold medicines unknowingly

• Do not exceed daily dose

• Do not self-medicate prolonged pain

• Do not call medicine candy

13. Prognosis

• Excellent if NAC started within 8 hour

• Poor if delayed beyond 24 hours