Pharm 101: N-Acetyl-Cysteine (NAC)



Paracetamol metabolism in therapeutic dosing
  • Hepatic metabolism to toxic and non-toxic products:
    • > 95% conjugated by glucuronidation and sulphation (transferase enzymes)
    • 5% undergoes metabolism via CYP 2E1 pathway (phase I hydroxylation reaction) to form toxic metabolite NAPQI (N-acetyl-p-benzoquinone imine)
    • NAPQI is irreversibly conjugated with sulfhydryl groups of glutathione
  • Renal excretion of conjugate, < 5% excreted unchanged
Mechanism of paracetamol toxicity
  • Zero order kinetics
  • In overdose, glucuoronidation and sulphation pathways are saturated and paracetamol is broken down by phase I hydroxylation reaction which forms NAPQI (N-acetyl-p-benzoquinone imine)
  • More NAPQI is formed, depleting glutathione stores and eventually causing accumulation of this toxic metabolite
  • NAPQI reacts with nucleophilic groups of cellular proteins to produce hepatotoxicity
Mechanism of action of NAC
  • NAC prevents paracetamol-induced hepatotoxicity by four possible mechanisms:
    1. Increased glutathione availability (sulfhydryl donor) – glutathione substitute
    2. Direct binding to NAPQI
    3. Provision of inorganic sulphate
    4. Reduction of NAPQI back to paracetamol
Adverse effects
  • Anaphylactoid reactions used to occur in ~15-20%, but are now less common due to changes in administration timing
    • Cease infusion, treat with antihistamine and restart at a reduced rate
Further reading

Pharmacology 101

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MBBS (UWA) CCPU (RCE, Biliary, DVT, E-FAST, AAA) Adult/Paediatric Emergency Medicine Advanced Trainee in Melbourne, Australia. Special interests in diagnostic and procedural ultrasound, medical education, and ECG interpretation. Editor-in-chief of the LITFL ECG Library. Twitter: @rob_buttner

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