Paracetamol (Acetaminophen)

Mechanism of Action

• Weak COX-1 and COX-2 inhibitor in peripheral tissues - less potent than NSAIDs, which is why it lacks meaningful anti-inflammatory effects
• Central COX inhibition - inhibits prostaglandin synthesis in the CNS, mediating antipyresis and analgesia centrally
• Endogenous system interactions - analgesic effects also involve the endogenous opioid, cannabinoid (endocannabinoid), and serotonergic systems
• Result: Analgesic + antipyretic, but no significant anti-inflammatory effect

Pharmacokinetics

Indications

• Mild to moderate pain: headache, myalgia, postpartum pain, dental pain, fever
• Preferred over aspirin in patients with:
  • Aspirin allergy
  • Peptic ulcer disease
  • Hemophilia
  • Aspirin-induced bronchospasm
  • Children (avoids Reye syndrome risk)
• Part of multimodal analgesia - often combined with NSAIDs or opioids for post-operative pain

Dosing

Note: Even 4 g/day can cause mild liver enzyme elevations in some patients. Caution in malnutrition, fasting, and significant alcohol use.

Adverse Effects

• Therapeutic doses: Generally very safe; mild, reversible hepatic enzyme elevation possible
• Overdose (>7.5-10 g acutely, or 15 g potentially fatal):
  • NAPQI accumulates when glucuronidation/sulfation pathways saturate
  • Causes centrilobular hepatic necrosis - can progress to acute liver failure
  • Sometimes associated with acute renal tubular necrosis
  • Early symptoms: nausea, vomiting, diarrhea, abdominal pain (within hours)
  • Delayed hepatotoxicity: 24-72 hours post-ingestion
• CNS (high doses): Dizziness, excitement, disorientation
• Rare: hemolytic anemia, methemoglobinemia, anaphylaxis, severe skin reactions (e.g. SJS)
• Unlike phenacetin (its prodrug predecessor), does NOT cause interstitial nephritis or papillary necrosis at therapeutic doses

Overdose Management

• N-acetylcysteine (NAC) - the antidote. Replenishes glutathione, neutralizes NAPQI
• Liver transplant criteria (King's College Criteria) may be applied in fulminant hepatic failure
• Use Rumack-Matthew nomogram to guide treatment decisions based on paracetamol levels and time post-ingestion

Key Drug Interactions

• NSAIDs (combined): Potentiates GI toxicity of the NSAID
• Warfarin: Paracetamol can potentiate anticoagulant effect (often underappreciated)
• Alcohol / CYP2E1 inducers: Increase NAPQI production, raising hepatotoxicity risk
• Anticonvulsants (CYP inducers): May worsen outcome in paracetamol-induced hepatic failure

Comparison: Paracetamol vs NSAIDs