Pharm 101: N-Acetyl-Cysteine (NAC)

Class

Antidote

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

• Buttner R. Pharm 101: Paracetamol. LITFL

References

• Katzung BG. Basic and Clinical Pharmacology. 14e. 2018: 1040-1041