Question 1

College Answer

Main points expected for a pass included:

· Actions and mechanism of actions of paracetamol. These include inhibition of cyclooxygenase (COX) activity and prevention of prostaglandin (PG) production. More marks were given for mention of a central COX 1 variant as the possible enzyme responsible for paracetamol’s central versus peripheral effects. Knowledge of the central sites of action was expected.

· Outline of toxicity. Candidates were expected to demonstrate knowledge of toxic doses, conditions enhancing toxicity (alcohol intake, chronic use etc), and the mechanism of hepatic toxicity and other organ toxicity (especially renal). A detailed list of clinical features of toxicity was not required.

· Management of toxicity. Candidates performed well in this section with good knowledge of timing, toxic doses, use of paracetamol levels and the nomogram to determine whether N-acetylcysteine should be administered. Mechanism of action of NAC was expected. Mention of monitoring (liver failure) and supportive therapy gained marks, but detailed explanations were not required

Syllabus G2e2c
Stoelting 4th edition page 285
Rand Dale 5th page 244

Discussion

We forgive the examiners for their unfair expectations here, as this was one of the first CICM primary exam papers, and they were still trying to determine exactly how unfair they could expect to be. Certainly "describe the pharmacological effects" sounds like a pharmacodynamics question, but paracetamol is one of those drugs that defies classification, and there are about ten different explanations for its analgesic and antipyretic effects. 

• 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.