What are the recommended adult dosing regimens of N‑acetylcysteine for mucolytic therapy, acute acetaminophen overdose, and prevention of contrast‑induced nephropathy?

N-Acetylcysteine Dosing Regimens

Acetaminophen Overdose

For acute acetaminophen overdose, administer N-acetylcysteine using either the oral regimen (140 mg/kg loading dose, then 70 mg/kg every 4 hours for 17 doses) or the intravenous regimen (150 mg/kg over 15 minutes, then 50 mg/kg over 4 hours, then 100 mg/kg over 16 hours). 1, 2

Oral Dosing Protocol

• Loading dose: 140 mg/kg orally as initial dose 1, 2
• Maintenance doses: 70 mg/kg orally every 4 hours for 17 additional doses (total 72-hour treatment course) 1, 2
• Peak plasma concentrations of 0.35 to 4 mg/L are achieved within 1 to 2 hours after oral administration 3

Intravenous Dosing Protocol

• Loading dose: 150 mg/kg IV over 15 minutes 1, 2
• Second infusion: 50 mg/kg IV over 4 hours 1, 2
• Third infusion: 100 mg/kg IV over 16 hours (total 20-hour protocol) 1, 2

Critical Timing Considerations

• Initiate NAC as soon as possible, ideally within 8-10 hours of ingestion 1, 2
• Treatment within 8 hours results in only 2.9% severe hepatotoxicity 1
• Efficacy decreases significantly after 10 hours (26.4% severe hepatotoxicity when treated after 10 hours) 1
• NAC still provides benefit when started up to 24 hours after ingestion, though efficacy is reduced 1, 2
• Do not delay NAC administration while awaiting confirmatory acetaminophen levels if there is strong suspicion of significant overdose 1

Special Populations Requiring Treatment

• Chronic alcoholics should receive NAC even if acetaminophen levels are below typical treatment thresholds due to increased susceptibility 1, 2
• Fasting patients are at higher risk and may warrant NAC at lower acetaminophen levels 1, 2
• Patients on enzyme-inducing medications (anticonvulsants, rifampin) merit NAC treatment even with sub-toxic concentrations 1

Acute Liver Failure

• For established hepatic failure from acetaminophen, administer IV NAC regardless of time since ingestion 4, 1
• NAC reduces mortality in acetaminophen-induced acute liver failure from 80% to 52% 4
• Decreases cerebral edema, need for inotropic support, and progression to coma 4

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Mucolytic Therapy

For chronic bronchitis and pulmonary diseases with viscous mucus, the standard oral dose is 600 mg twice daily. 2, 3

• Oral NAC 200 to 400 mg achieves therapeutic effect for mucolytic purposes 3
• The 600 mg twice daily regimen is well-tolerated with gastrointestinal symptoms occurring at rates comparable to placebo 2
• Adverse events in large COPD trials occurred in 29% receiving NAC versus 26% receiving placebo 2

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Contrast-Induced Nephropathy Prevention

N-acetylcysteine is NOT recommended for prevention of contrast-induced nephropathy based on high-quality evidence showing no benefit. 5

Evidence Against Routine Use

• High-quality randomized controlled trials demonstrated that oral NAC 1,200 mg twice daily for 2 days does not reduce contrast-induced acute kidney injury compared with placebo (relative risk 1.05; 95% CI 0.73–1.53) 5
• Intravenous NAC for contrast prophylaxis is linked to potentially serious adverse effects with no proven benefit 5

Historical Context (Conflicting Evidence)

While older meta-analyses suggested benefit 6, 7, 8, and one 2006 trial in primary angioplasty patients showed dose-dependent reduction in contrast nephropathy 9, the most recent high-quality evidence does not support routine use 5. A 2009 European guideline noted that hydration with sodium bicarbonate plus oral NAC (600 mg twice daily) was no more effective than saline plus NAC 4.

If NAC Is Used Despite Limited Evidence

• The suggested regimen is 1,200 mg orally twice daily for 2 days in addition to intravenous isotonic crystalloid hydration 5
• NAC should never replace adequate fluid therapy 5
• Some older protocols used 600 mg twice daily starting 12 hours before contrast exposure 4, 7

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Common Adverse Effects

• Nausea, vomiting, and diarrhea: <5% incidence 2, 3
• Cutaneous rash: <5% incidence 1, 2
• Bronchospasm: 1-2% incidence 1, 2
• Anaphylactoid reactions: Approximately 10% with IV administration, typically within the first hour of infusion 2

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Important Clinical Caveats

• Activated charcoal may adsorb up to 96% of oral NAC, but do not delay NAC administration even if activated charcoal has been given 1, 3
• For extended-release acetaminophen preparations, use standard dosing regimens but extend monitoring due to prolonged absorption 4, 1
• For repeated supratherapeutic ingestions (>4g per 24 hours or ≥150 mg/kg/day for ≥48 hours), the standard 72-hour oral protocol or 20-hour IV protocol applies 1
• Volume of distribution is 0.33 to 0.47 L/kg with approximately 50% protein binding 3
• Terminal half-life after oral administration is 6.25 hours 3