What are the uses and effects of N-acetylcysteine (NAC)?

What N-Acetylcysteine Does

N-acetylcysteine (NAC) is a medication with three primary clinical uses: as a life-saving antidote for acetaminophen (paracetamol) overdose, as a chronic preventive therapy to reduce exacerbations in patients with moderate-to-severe COPD, and as a mucolytic agent that breaks down thick respiratory secretions.

Primary Mechanism of Action

NAC works through multiple distinct pathways:

• Mucolytic effect: NAC reduces the viscosity of respiratory secretions by cleaving disulfide bonds in mucoproteins, making thick secretions easier to clear from the airways 1, 2
• Antioxidant activity: NAC serves as a precursor for glutathione synthesis and directly scavenges reactive oxygen species, protecting cells from oxidative damage 1, 3
• Hepatoprotection: In acetaminophen overdose, NAC maintains or restores glutathione levels and acts as an alternate substrate for conjugation with the toxic metabolite of acetaminophen 4

FDA-Approved Clinical Indications

Acetaminophen Overdose (Life-Saving)

• NAC is the definitive antidote for acetaminophen poisoning and must be initiated within 24 hours of ingestion, though earlier treatment (within 8 hours) prevents virtually all hepatotoxicity 4, 5
• The FDA-approved intravenous regimen is 150 mg/kg loading dose over 60 minutes, followed by 50 mg/kg over 4 hours, then 100 mg/kg over 16 hours (total 300 mg/kg over 21 hours) 4
• In patients treated within 8 hours of acetaminophen ingestion, only 4% developed hepatotoxicity (AST/ALT >1000 U/L), compared to 44% when treatment was delayed beyond 15 hours 4
• NAC improves transplant-free survival in acute liver failure from any cause (64% vs 26%, OR 4.81), not just acetaminophen overdose 2

Chronic COPD Exacerbation Prevention

• The American College of Chest Physicians recommends NAC 600 mg orally twice daily for patients with moderate-to-severe COPD (GOLD II-III) who have ≥2 exacerbations per year despite optimal inhaled bronchodilator and corticosteroid therapy 1, 2
• NAC reduces annual exacerbation rates by 22% (1.16 vs 1.49 exacerbations, RR 0.78) in this population 2, 6
• NAC reduces hospitalizations from 18.1% to 14.1% (risk ratio 0.76), with a number needed to treat of 25 patients to prevent one hospitalization 6
• NAC appears more effective in moderate COPD (GOLD II) compared to severe disease (GOLD III), with longer time to first exacerbation in the moderate group 2, 6
• Benefits require at least 6 months of continuous therapy to become significant, and treatment should continue for 1-3 years as benefits accumulate over time 6

Important Clinical Caveats

What NAC Does NOT Do

• NAC is NOT recommended during acute COPD exacerbations—the American College of Chest Physicians assigns a Grade I recommendation (no evidence of effectiveness) for mucolytics during acute exacerbations 6
• While NAC reduces COPD exacerbations, it has not been shown to significantly impact mortality or quality of life, which should inform discussions about indefinite use 2, 6
• For acute exacerbations, use short-acting bronchodilators and systemic corticosteroids for 10-15 days instead 6

Safety Profile

• NAC is generally well-tolerated with rare adverse gastrointestinal effects (nausea, vomiting, diarrhea) even with prolonged use 2, 7
• Rare side effects include skin rash (<5%) and transient bronchospasm (1-2%) 2
• In the largest COPD study of 1,006 patients, adverse effects did not differ significantly between NAC and placebo groups 7
• When used for acetaminophen poisoning, NAC's side effects (including anaphylactoid reactions) should not prevent completion of therapy, as benefits far outweigh risks 7

Pharmacokinetics

• After oral administration, NAC is rapidly absorbed from the GI tract, reaching peak plasma concentrations of 0.35-4 mg/L within 1-2 hours 8
• NAC quickly appears in active form in lung tissue and respiratory secretions after ingestion 1, 6
• Terminal half-life is 5.6 hours intravenously and 6.25 hours orally 4, 8
• Protein binding ranges from 50-87%, and renal clearance accounts for approximately 30% of total body clearance 4, 8
• NAC is metabolized to cysteine, which is further metabolized to glutathione and other metabolites 4

Dosing by Indication

• Acetaminophen overdose (IV): 150 mg/kg loading dose over 60 minutes, then 50 mg/kg over 4 hours, then 100 mg/kg over 16 hours 4
• Acetaminophen overdose (oral): Must be initiated within 24 hours of ingestion 5
• COPD exacerbation prevention: 600 mg orally twice daily (1200 mg total daily dose) for chronic ongoing use 2, 6
• Lower doses (<1200 mg daily) show significantly less benefit and are not recommended 6

Additional Emerging Uses

• NAC has shown promise in treating HIV/AIDS, cancer, heart disease, heavy metal toxicity, and psychiatric disorders, though these remain investigational 9, 10
• NAC inhibits eryptosis (programmed red blood cell death) in vitro and may prolong erythrocyte lifespan in vivo 1