Question 5

Describe the pharmacological effects of paracetamol. (40% of marks)

Outline its toxic effects and their management. (60% of marks)

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College Answer

This question was generally well answered with narrow variance; very few candidates  discussed factors predisposing to hepato-toxicity or renal toxicity. Discussion of pharmacokinetics only gained marks when relevant to toxicity


To be fair, "discuss the pharmacological effects" is a fairly unambiguous pharmacodynamics question.

  • Pharmacological effects of paracetamol
    • COX-2 dependent peripheral mechanism (weak anti-inflammatory)
    • COX-1 and COX-3 dependent central mechanism (prevention of PGE2 synthesis)
    • Other receptor systems implicated:
      • Endocannabinoid system
      • Transient receptor potential (TRP) channels
      • Cav3.2 calcium channels 
      • Nitric oxide (as neurotransmitter)
      • Kv7 potassium channels 
      • Seroton receptors
  • Paracetamol toxicity
    • Most paracetamol is metabolised by glucouronidation and sulfation
    • Some (~5%) is metabolised by CYP2E1
    • In the course of this, superoxide and NAPQI are generated
    • In the presence of ample glutathione, NAPQI is rapidly detoxified by conjugation
    • In the presence of massive overdose (more than 10g, or more than 200mg/kg), glutathione is rapidly depleted
    • As NAPQI levels increase, it binds covalently to numerous proteins, causing toxicity
    • Of particular interest is the uncoupling of oxidative phosphorylation, which results in a failure of ATP synthesis, lactic acidosis, and the release of ionised calcium from mitochondrial stores
    • The consequence of this is hepatocellular apoptosis and necrosis.
  • Management of paracetamol toxicity:
    • Supplementation with N-acetylcysteine replenishes glutathione and permits rapid NAPQI detoxification
    • A recommended dosage schedule for N-acetylcysteine:
      • 150mg/kg in the first hour
      • 50mg/kg in the next 4 hours
      • 100mg/kg in the next 16 hours


Graham, Garry G., et al. "The modern pharmacology of paracetamol: therapeutic actions, mechanism of action, metabolism, toxicity and recent pharmacological findings." Inflammopharmacology 21.3 (2013): 201-232.

Jefferies, Sarah, Manoj Saxena, and Paul Young. "Paracetamol in critical illness: a review." Critical Care and Resuscitation 14.1 (2012): 74-80.

Prescott, L. F. "Kinetics and metabolism of paracetamol and phenacetin." British journal of clinical pharmacology 10.S2 (1980): 291S-298S.