Acetaminophen Mechanism & Effects

• Acetaminophen (US) is also known as Paracetamol internationally
• Brand names include Tylenol, Panadol, Calpol, and Ofirmev (IV form)
• Mnemonic: "PAIN no INFLAMMATION — LIVER loves LIMITS"
  • PAIN relief
  • No anti-inflammatory action
  • LIVER metabolism
  • Must LIMIT dose to prevent toxicity

Mechanism of Action

• Primary mechanism involves inhibiting prostaglandin synthesis in the CNS through weak inhibition of cyclooxygenase (COX)—mainly COX-2 and COX-3
• Reduces perception of pain and fever
• Minimal peripheral COX inhibition results in a lack of anti-inflammatory effects
• Does not significantly inhibit COX-1 in the periphery, unlike NSAIDs, avoiding platelet inhibition or GI mucosa effects
• Acts on the hypothalamic heat-regulating center to lower body temperature
• Inhibits prostaglandin E2 (PGE2) production, resetting the thermoregulatory set point
• High levels of peroxides in inflamed peripheral tissues inhibit acetaminophen’s COX-inhibiting activity, reducing its effectiveness in reducing inflammation

Metabolism

• Primarily metabolized in the liver via:
  • Glucuronidation & sulfation (safe)
  • A small portion via CYP2E1 into NAPQI (toxic)
• NAPQI is detoxified by glutathione; overdose depletes glutathione, leading to hepatotoxicity

Indications

• First-line analgesic and antipyretic, particularly when NSAIDs are contraindicated
  • Mild to moderate pain (headache, muscle pain, osteoarthritis)
  • Fever (especially in children and adults)
  • Osteoarthritis pain (without inflammation)
  • Dental pain
  • Post-vaccination fever or discomfort
• Safe alternative to NSAIDs in:
  • Pregnancy
  • Peptic ulcer disease
  • Anticoagulant users (doesn’t affect platelets)

Side Effects

• Generally well-tolerated, but common side effects include:
  • Nausea
  • Rash (rare)
  • Headache
• Serious (Overdose-Related) Side Effects:
  • Hepatotoxicity (due to NAPQI buildup)
  • Acute liver failure, especially with high doses, chronic alcohol use, or malnutrition (low glutathione stores)
• Signs of Toxicity:
  • Nausea, vomiting, RUQ pain
  • Elevated liver enzymes
  • Jaundice, hepatic encephalopathy
  • Can progress to liver failure and death
• Antidote:
  • N-acetylcysteine (NAC) replenishes glutathione and detoxifies NAPQI

Contraindications

• Severe liver impairment or active liver disease
• Alcohol abuse or chronic alcohol use
• Known hypersensitivity
• Use with caution in:
  • Chronic malnutrition
  • Dehydrated states
  • Long-term use >4g/day

Dosing Cautions

• Max daily dose for adults:
  • 4 g/day (generally); some recommend 3 g/day as safer
• Pediatrics:
  • Weight-based dosing (10–15 mg/kg per dose)