PharmacologyTier 1Medical Sciences concept

N-acetylcysteine mechanism in paracetamol toxicity

Core concept

Therapeutic dose: ~90% glucuronidation, ~5-10% sulfation, <5-10% CYP oxidation (CYP2E1 > CYP3A4, CYP1A2) to NAPQI
- NAPQI is immediately conjugated by glutathione -> mercapturic acid -> renal excretion
Overdose: the conjugation pathways saturate -> a far greater fraction is shunted to CYP -> NAPQI production overwhelms GSH
- Hepatic GSH falls below ~30% of baseline -> free NAPQI arylates cysteine residues on hepatocyte proteins
- Mitochondrial dysfunction, oxidative stress, centrilobular (zone 3) necrosis - zone 3 has the highest CYP2E1 and the lowest GSH
NAC replenishes cysteine, the rate-limiting substrate for glutathione synthesis
- Restores GSH -> NAPQI conjugated before it binds protein
- Also acts as a direct GSH substitute, a free radical scavenger, and inc hepatic microcirculation and O2 delivery after injury is established

NAC is fully protective if started within 8 hours of an acute ingestion; efficacy falls progressively thereafter but is never zero
- Late presentation, staggered ingestion, or established hepatotoxicity -> still give NAC
Australian regimen: two-bag, 200 mg/kg over 4 h then 100 mg/kg over 16 h (total 300 mg/kg / 20 h)
- Two-bag protocol markedly reduces anaphylactoid reactions vs the older three-bag
Anaphylactoid reactions are non-IgE histamine release, dose-rate dependent - flushing, urticaria, bronchospasm
- Slow or pause the infusion, antihistamine; rarely a reason to abandon NAC
Nomogram line 150 mg/L at 4 h, applies to a single acute ingestion with a known time, 4-16 h post
Risk threshold: >200 mg/kg or >10 g (whichever is less) in an acute ingestion
Higher risk of toxicity where GSH is low or CYP2E1 induced
- Malnutrition, anorexia, alcoholism, cystic fibrosis, chronic illness
- Enzyme inducers - carbamazepine, phenytoin, rifampicin, isoniazid, chronic alcohol
Paracetamol also causes acute kidney injury independent of hepatic failure (renal CYP and prostaglandin synthase)

ALT is the marker of hepatotoxicity; the paracetamol level decides who needs NAC
- Give NAC empirically at >8 h post-ingestion, on unknown timing, or on staggered ingestion, while awaiting levels
Ceasing NAC: paracetamol undetectable and ALT normal or falling and INR <2
King's College criteria for transplant referral in paracetamol ALF
- Arterial pH <7.3 after resuscitation, OR
- All three of INR >6.5, creatinine >300 micromol/L, grade III-IV encephalopathy
- Lactate and phosphate are additional adverse markers
Paracetamol level in massive ingestion may need double-dose NAC - discuss with the Poisons Information Centre (13 11 26)
NAC also used for contrast nephropathy prevention (weak evidence) and as a mucolytic

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