Medical Disclaimer
- Educational Only: Not for clinical decision-making.
- Verify Information: Always consult protocols and authoritative sources.
AI Assistance Notice
AI was used to assist in organizing and formatting this information. All content is reviewed for accuracy.
Bedside Snapshot
- Primary Role: Antidote for acetaminophen (APAP) overdose—most effective if started within 8–10 hours of ingestion, but still beneficial in late presenters and established liver injury
- Mechanism: Replenishes glutathione, directly detoxifies NAPQI (toxic APAP metabolite), and improves hepatic microcirculation and oxygen delivery
- Formulations: Available in IV and oral forms; most ED/ICU settings favor the IV 21-hour protocol, with extensions for massive ingestions or ongoing injury
- Safety Profile: Generally very safe; main adverse effects are anaphylactoid reactions during IV loading (especially at low APAP levels) and severe nausea/vomiting with oral NAC
- Beyond APAP: Also used (off-label) in some cases of non-APAP acute liver failure and other oxidative injury states under hepatology/toxicology guidance
Brand & Generic Names
- Generic Name: N-acetylcysteine
- Brand Names: Acetadote (IV), Mucomyst (oral solution), generics
Medication Class
Antidote for acetaminophen toxicity; mucolytic; antioxidant
Pharmacology
Mechanism of Action:
- In acetaminophen overdose, CYP-mediated metabolism generates N-acetyl-p-benzoquinone imine (NAPQI), a reactive metabolite detoxified by glutathione conjugation; in overdose, glutathione stores are overwhelmed
- NAC replenishes glutathione stores and also acts as a glutathione substitute, enhancing non-toxic conjugation and clearance of NAPQI
- Additionally, NAC may improve hepatic blood flow, oxygen delivery, and act as a free radical scavenger, which can be beneficial in acute liver failure even when APAP is no longer detectable
Pharmacokinetics:
- Absorption (oral): Rapidly absorbed but with significant first-pass metabolism; bioavailability ~6–10% but sufficient for antidotal effect when dosed appropriately
- Distribution: Distributes into extracellular fluid; protein binding low to moderate
- Metabolism: Undergoes hepatic metabolism to cysteine and other metabolites that participate in glutathione synthesis
- Elimination: Renal excretion of metabolites; elimination half-life ~5–6 hours, but treatment duration is guided more by APAP kinetics and hepatic recovery than NAC half-life
- IV Administration: Produces rapid therapeutic levels; the classic 21-hour regimen provides 300 mg/kg total dose, though extended or modified regimens exist for massive overdoses
Indications
- Acute acetaminophen overdose: Known or suspected single acute overdose above treatment threshold on the Rumack–Matthew nomogram when time of ingestion is known
- Unknown ingestion time: Elevated acetaminophen level and/or evidence of liver injury (elevated AST/ALT, INR)
- Chronic supratherapeutic ingestion: Elevated liver enzymes or concerning APAP levels
- Acute liver failure: When acetaminophen toxicity is suspected or cannot be excluded, even if serum APAP is undetectable (per hepatology/toxicology guidance)
- Other oxidative injuries: Occasionally used for other causes of acute liver failure (e.g., some mushroom poisonings), guided by a poison center or specialist
Dosing & Administration
Available Forms:
- IV solution (Acetadote): Supplied in vials with concentrations such as 200 mg/mL; diluted in D5W or other compatible fluid for infusion
- Oral solution (Mucomyst): 10% or 20% solutions intended for nebulization or oral use; very unpleasant sulfurous odor/taste, typically diluted in juice or soft drinks for oral administration
- Nebulized NAC: For mucolytic use but less relevant to ED/ICU toxicology indications
IV NAC for Acetaminophen Toxicity (Adult) – Classic 21-Hour Regimen:
| Step | Dose (mg/kg) | Infusion Duration | Typical Diluent/Volume |
|---|---|---|---|
| 1: Loading dose | 150 mg/kg | Over 1 hour | Often in 200 mL D5W (adjust in fluid-sensitive patients) |
| 2: Second infusion | 50 mg/kg | Over 4 hours | Commonly in 500 mL D5W |
| 3: Third infusion | 100 mg/kg | Over 16 hours | Often in 1,000 mL D5W; total 300 mg/kg over 21 hours |
| Extended infusion (massive overdose or ongoing injury) | 6.25–12.5 mg/kg/hr | Continuous infusion after 21h | Continue until APAP undetectable and AST/ALT and INR improving |
| Weight cap (practical) | Often capped at 100–110 kg; follow local protocol or poison center guidance | ||
Oral NAC for Acetaminophen Toxicity (Adult) – 72-Hour Regimen:
| Step | Dose (mg/kg) | Schedule | Notes |
|---|---|---|---|
| Loading dose | 140 mg/kg | Once | Dilute to ~5% solution; administer PO or NG |
| Maintenance dose | 70 mg/kg | Every 4 hours × 17 doses | Total duration ~72 hours; repeat dose if emesis within 1 hour |
| If persistent vomiting or encephalopathy | Switch to IV regimen or give via NG with aspiration precautions | ||
| Pediatrics (outline) | Same mg/kg doses; weight-based; use pediatric-specific references | ||
Anaphylactoid Reactions: IV NAC frequently causes anaphylactoid reactions during the loading dose, especially in patients with low or undetectable APAP levels. Monitor closely and manage with temporary infusion pause, antihistamines, and slower restart rate.
Always Follow Local Protocol: Dosing regimens may vary by institution. Always consult local toxicology protocols or poison center guidance for complex cases.
Contraindications
Contraindications:
- True anaphylactic reaction to NAC (rare); in life-threatening APAP toxicity, desensitization or cautious re-challenge may still be considered with specialist guidance
Major Precautions:
- IV NAC frequently causes anaphylactoid reactions, especially during the loading dose and in patients with low or undetectable APAP levels (paradoxically); symptoms include flushing, pruritus, wheezing, and hypotension
- These reactions are usually managed by temporarily stopping or slowing the infusion and giving antihistamines ± bronchodilators; NAC can often be restarted at a slower rate once symptoms resolve
- Oral NAC is strongly emetogenic and foul-tasting; use antiemetics and consider NG administration in high-risk patients
- Adjust total infusion volume for patients with heart failure, renal failure, or other fluid-sensitive conditions
- In encephalopathic patients or those with poor airway protection, oral NAC increases aspiration risk—IV NAC is preferred
Adverse Effects
Common:
- Nausea and vomiting (especially with oral NAC)
- Flushing, pruritus, and mild rash during IV administration
- Headache or dizziness
Serious:
- Anaphylactoid reactions: bronchospasm, angioedema, hypotension, chest tightness
- Severe vomiting with risk of aspiration (oral NAC)
Monitoring
Laboratory Monitoring:
- Acetaminophen serum level, AST/ALT, bilirubin, INR, and creatinine at baseline and at key time points (often at 12–21 hours and as clinically indicated)
Clinical Monitoring:
- Mental status, signs of hepatic encephalopathy (asterixis, confusion), hemodynamics, and signs of multiorgan failure
- For IV NAC, monitor closely during the loading dose for signs of anaphylactoid reactions and treat promptly if they occur
- Continue NAC until acetaminophen is undetectable and hepatic injury is clearly improving (labs and clinical picture), guided by toxicology/hepatology
Clinical Pearls
When in Doubt, Treat: The risk of giving NAC is far lower than the risk of missing a treatable overdose. Start NAC while clarifying history and waiting for labs.
Late Presenters Still Benefit: Patients with established liver injury still benefit from NAC, particularly if there is any chance acetaminophen played a role.
Anaphylactoid Reactions Are Manageable: These reactions are common but usually mild. Don't abandon therapy prematurely in a clear overdose scenario—pause, treat symptoms, and restart at slower rate.
Coordinate with Toxicology: Contact a poison center or toxicologist early for complex cases (massive ingestions, staggered overdoses, co-ingestions, pregnancy, or liver failure).
Document Stop Criteria: In patients on continuous IV NAC beyond 21 hours, be explicit in your notes about stop criteria (APAP level, AST/ALT trend, INR) to avoid indefinite infusions by inertia.
References
- 1. Lexicomp. (2024). Acetylcysteine: Drug information. Wolters Kluwer.
- 2. Heard, K. J. (2008). Acetylcysteine for acetaminophen poisoning. New England Journal of Medicine, 359(3), 285–292. https://doi.org/10.1056/NEJMct0708278
- 3. Dart, R. C., Erdman, A. R., Olson, K. R., et al. (2006). Acetaminophen poisoning: An evidence-based consensus guideline. Clinical Toxicology, 44(1), 1–18. https://doi.org/10.1080/15563650500394571
- 4. Rumack, B. H., & Matthew, H. (1975). Acetaminophen poisoning and toxicity. Pediatrics, 55(6), 871–876. https://doi.org/10.1542/peds.55.6.871
- 5. Prescott, L. F., Illingworth, R. N., Critchley, J. A., et al. (1979). Intravenous N-acetylcysteine: The treatment of choice for paracetamol poisoning. British Medical Journal, 2(6198), 1097–1100. https://doi.org/10.1136/bmj.2.6198.1097