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Paracetamol

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Paracetamol (Acetaminophen)

Other names: Acetaminophen, N-acetyl-p-aminophenol, 4'-hydroxyacetanilide Trade names: Tylenol, Ofirmev (IV), Panadol

Class & Basic Properties

Paracetamol is a non-opioid analgesic and antipyretic. Unlike aspirin and NSAIDs, it has no significant peripheral anti-inflammatory effects and does not inhibit platelet aggregation or irritate the gastric mucosa, making it a preferred alternative to aspirin in many situations.

Mechanism of Action

The full mechanism remains incompletely understood, but the following are established:
  • Central COX inhibition: Paracetamol inhibits prostaglandin endoperoxide H2 synthase (a COX iso-enzyme) predominantly in the CNS, not in peripheral tissues. It is a weak COX-1 and COX-2 inhibitor peripherally.
  • Endogenous system modulation: Interacts with the endogenous opioid, cannabinoid, and serotonergic systems to produce antinociception.
  • Beta-endorphin activation: May centrally activate beta-endorphin pathways.
  • No peripheral anti-inflammatory effect: It does not reduce inflammation at the site of injury.
(Katzung's Basic and Clinical Pharmacology, 16th Ed.; Rosen's Emergency Medicine)

Pharmacokinetics

ParameterDetails
AdministrationOral, rectal, IV (Ofirmev)
Peak plasma level30-60 minutes (oral)
Protein bindingPoor
Half-life2-3 hours (normal); doubled or more in liver disease/overdose
MetabolismLiver - primarily conjugation to sulfate and glucuronide (inactive); minor CYP450 pathway produces NAPQI
Excretion<5% unchanged in urine

Therapeutic Uses

  • Mild-to-moderate pain: headache, myalgia, dental pain, postpartum pain
  • Fever reduction
  • First-line analgesic in children
  • Preferred over aspirin in:
    • Patients with peptic ulcer history
    • Hemophilia
    • Aspirin hypersensitivity
    • Patients at risk for Reye's syndrome (children with viral illness)
  • Combined with NSAIDs or opioids for additive/synergistic analgesia in moderate-to-severe pain

Dosage

PopulationDose
Adults325-1000 mg every 4-6 hours
Maximum adult dose4 g/day (some guidelines 3 g/day in chronic users, elderly)
ChildrenWeight-based dosing (generally 10-15 mg/kg every 4-6 hours)
No increase in analgesic effect has been reported for doses greater than 650 mg per dose.

Toxicity & Overdose

Mechanism of Hepatotoxicity

In therapeutic doses, the small amount of NAPQI (N-acetyl-p-benzoquinone imine) formed by CYP450 is safely neutralised by hepatic glutathione. In overdose:
  1. NAPQI production overwhelms glutathione stores
  2. Glutathione is depleted
  3. NAPQI binds covalently to liver cell proteins
  4. Centrilobular hepatic necrosis results
This shows a threshold phenomenon - toxicity manifests only once glutathione is critically depleted.

Toxic Doses

  • Serious toxicity: >150 mg/kg or >10 g in an adult
  • Potentially lethal: >20 g (or less in combination drugs like codeine/propoxyphene)
  • Chronic alcoholics: even 5-6 g/day for a few days can cause hepatotoxicity
  • Not recommended in premature infants <2 kg

Clinical Stages of Toxicity

TimeManifestations
Early (0-12 hrs)Nausea, vomiting, abdominal pain, liver tenderness; consciousness is preserved
12-18 hrsCentrilobular hepatic necrosis, renal tubular necrosis, hypoglycemia, progression to coma
2-4 daysFulminant hepatic failure, death
Fulminating hepatic failure and death may occur when plasma levels are above 200 µg/mL at 4 hours and 30 µg/mL at 15 hours post-ingestion.

Autopsy Findings in Fatal Overdose

  • Liver: pale yellow to tan, often <1500 g, centrilobular necrosis on microscopy
  • Renal tubular necrosis
  • Possible myocardial fibril damage

Treatment of Overdose

Treatment must begin as early as possible - practically ineffective if started 16+ hours after ingestion.
  1. Gastric lavage / induced emesis (if early)
  2. Activated charcoal (orally or via tube)
  3. N-acetylcysteine (NAC) - the antidote:
    • IV: 150 mg/kg over 15 minutes, then the same dose over the next 20 hours
    • Oral: 75 mg/kg every 4-6 hours for 2-3 days
    • Mechanism: replenishes glutathione stores, prevents NAPQI from binding to cellular proteins
  4. Liver transplantation may be considered using King's College criteria in fulminant hepatic failure

Drug Interactions & Cautions

  • Warfarin: High-dose paracetamol (>9,100 mg/week) can increase INR
  • Anticonvulsants (phenytoin, barbiturates, carbamazepine): Induce CYP enzymes, increasing NAPQI production - use caution
  • Alcohol: Induces CYP2E1, dramatically increasing NAPQI
  • Aspirin hypersensitivity: ~11% cross-reactivity for urticarial reactions
  • Caution in hepatic or renal disease, malnutrition, prolonged fasting, anorexia

Rare Adverse Effects

  • Mild transient rise in liver enzymes (at therapeutic doses)
  • Hemolytic anemia, methemoglobinemia, agranulocytosis (very rare)
  • Interstitial nephritis (rare, less than with phenacetin)
  • Anaphylaxis, serious skin reactions (very rare)
Sources: Katzung's Basic and Clinical Pharmacology 16th Ed., p. 1027; Rosen's Emergency Medicine; P.C. Dikshit Textbook of Forensic Medicine and Toxicology, p. 578; Bailey & Love's Short Practice of Surgery 28th Ed.
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