Ingestional Paracetamol (Acetaminophen) Poisoning

Epidemiology

Pharmacology & Normal Metabolism

• Rapidly absorbed from the GI tract; peak levels within 30 min - 2 hours
• Volume of distribution ~0.85 L/kg; ~20% protein-bound; half-life ~2.5 hours
• ~90% conjugated as glucuronide (40-67%) or sulfate (20-46%) - both renally excreted
• 5-15% oxidized by CYP450 (mainly CYP2E1) to the reactive metabolite NAPQI (N-acetyl-p-benzoquinoneimine)
• At therapeutic doses, NAPQI is rapidly conjugated by hepatic glutathione (via glutathione-S-transferase) to a non-toxic mercaptate compound, excreted in urine

Recommended Maximum Doses

Mechanism of Toxicity

1. Glucuronidation and sulfation pathways become saturated
2. A larger fraction is shunted through CYP450 to NAPQI
3. NAPQI production depletes hepatic glutathione; when stores fall below 30% of normal, free NAPQI accumulates
4. NAPQI binds covalently to intracellular proteins and organelles, primarily in Zone 3 (centrilobular) hepatocytes - the area furthest from portal blood supply
5. Result: centrilobular hepatic necrosis - the hallmark histological lesion

High-Risk Groups

• Alcoholics - both reduced glutathione stores AND CYP2E1 induction (dual hit)
• Patients on anticonvulsants (phenytoin, carbamazepine) or antituberculous drugs (rifampicin, INH) - CYP450 induction
• Malnourished patients - depleted glutathione
• HIV/AIDS patients
• Children under 6 years are relatively protected - greater capacity for hepatic sulfation

Clinical Features: Four Stages

Extrahepatic Toxicity

• Isolated acute kidney injury (direct renal tubular toxicity)
• Pancreatitis
• Rarely, cardiac toxicity
• In massive overdose (>500 mg/kg or serum level >750 mcg/mL): early metabolic acidosis with elevated lactate and altered mental status, even without liver failure - likely from glutathione depletion generating 5-oxoproline and mitochondrial respiratory inhibition

Diagnosis

When to Suspect Toxic Exposure

The Rumack-Matthew Nomogram

• Plots serum acetaminophen concentration (y-axis) against time post-ingestion (x-axis) to predict hepatotoxicity risk
• Only valid for single acute oral ingestion, serum drawn 4-24 hours post-ingestion
• Original line: 4-hour level of 200 mcg/mL; modified (current) treatment line: 4-hour level of 150 mcg/mL (1000 micromol/L) - to increase safety margin
• Above the treatment line: ~60% risk of hepatotoxicity (ALT >1000 IU/L), 1% renal failure risk, 5% mortality (based on pre-antidote era data)
• Very high levels (parallel line at 4-hour concentration of 300 mcg/mL): near-certain hepatotoxicity, higher mortality

Treatment

1. Initial Resuscitation & GI Decontamination

• Secure airway if GCS impaired
• Activated charcoal (1 g/kg orally) if presentation within 1-2 hours of ingestion and airway is protected - reduces absorption
• IV fluids, antiemetics (paracetamol causes nausea)

2. N-Acetylcysteine (NAC) - The Antidote

• Replenishing glutathione (precursor supply)
• Directly conjugating NAPQI
• Acting as antioxidant

• Given within 8 hours of ingestion: nearly 100% effective at preventing hepatotoxicity
• Effectiveness declines with each hour of delay
• Still beneficial even in late presentation with established hepatic failure (improves cerebral perfusion, reduces oxidative stress)

IV NAC Protocol (Standard 21-hour "Three-Bag" Regimen)

Oral NAC

• Loading dose: 140 mg/kg, then 70 mg/kg q4h x 17 doses (total 72 hours)
• Used when IV not available; limited by vomiting

3. Special Situations

• Nomogram cannot be applied (no single time of ingestion)
• Assume ingestion started at the earliest stated time and plot accordingly (conservative approach)

• Obtain a second acetaminophen level 4-6 hours after the first (at 4-8 hours post-ingestion)
• If second level rises above nomogram line, treat with full NAC course

• Standard 21-hour protocol may be inadequate
• Options: add oral NAC to IV protocol; increase 3rd bag to 200 mg/kg over 16 hours; reload regimen if serum levels remain high at completion

4. Monitoring During Treatment

• LFTs (AST/ALT), bilirubin, PT/INR, creatinine, glucose every 12-24 hours
• Serum lactate, blood gas in severe cases
• Consider stopping NAC when: serum acetaminophen undetectable, ALT/AST normalizing, INR <2, and patient asymptomatic

5. Liver Transplantation

• For fulminant hepatic failure not responding to NAC
• King's College Criteria (KCC) used to stratify transplant candidacy:
  • Arterial pH <7.3 after resuscitation, OR
  • All three of: PT >100 sec, creatinine >300 micromol/L, Grade III-IV encephalopathy

Key Labs to Order

Summary Points

• Paracetamol poisoning is the #1 cause of acute liver failure in the UK and USA
• Toxicity is mediated by NAPQI overwhelming hepatic glutathione stores
• Pathological lesion: centrilobular (Zone 3) necrosis
• Use the Rumack-Matthew nomogram (4-24 h post single ingestion) to guide NAC treatment
• NAC within 8 hours = ~100% prevention of hepatotoxicity
• Monitor for the "Stage 2 trap" - apparent clinical improvement while hepatic necrosis progresses
• Always check serum levels in ALL intentional overdose patients
• In massive overdose, consider augmented NAC dosing or liver transplantation