What are the indications and uses of N-acetyl cysteine (NAC)?

N-Acetylcysteine: Indications and Uses

Primary Indication: Acetaminophen Overdose

N-acetylcysteine (NAC) is the definitive antidote for acetaminophen overdose and should be administered immediately when overdose is known or suspected, ideally within 8-10 hours of ingestion but still beneficial up to 24 hours. 1

When to Initiate NAC for Acetaminophen Overdose

• Administer NAC immediately if acetaminophen levels plot in the possible or probable risk zones on the Rumack-Matthew nomogram 1
• Start NAC without delay when presenting >24 hours after ingestion when the nomogram cannot be used 1
• Do not wait for confirmatory acetaminophen levels if there is strong suspicion of significant overdose—initiate treatment immediately 2, 3
• Treat empirically in cases of suspected acetaminophen ingestion even without confirmatory history, particularly when very high aminotransferases are present 1

Dosing Regimens

Two equally acceptable routes exist:

• Oral regimen: 140 mg/kg loading dose, followed by 70 mg/kg every 4 hours for 17 doses (total 72 hours) 1, 3
• Intravenous regimen: 150 mg/kg loading dose over 15 minutes, followed by 50 mg/kg over 4 hours, then 100 mg/kg over 16 hours 1, 3

The oral protocol may preserve more hepatocytes than the 21-hour intravenous protocol, though both are effective when initiated early 4

Special Populations at Higher Risk

• Chronic alcoholics may develop toxicity at lower acetaminophen doses and should receive NAC even if levels are below typical treatment thresholds 1
• Fasting patients are at increased risk and may warrant NAC at lower acetaminophen levels 1, 2
• Extended-release or repeated supratherapeutic ingestions (>4g per 24 hours) require NAC treatment with standard dosing, though monitoring may need extension 1, 2

---

Secondary Indication: Acetaminophen-Associated Acute Liver Failure

The American Gastroenterological Association strongly recommends NAC for all patients with acetaminophen-associated acute liver failure. 5

• NAC reduces mortality in acetaminophen-related acute liver failure (relative risk 0.65,95% CI 0.43-0.99) 5
• Treatment should be initiated even when acetaminophen history is uncertain but suspected based on clinical presentation 1
• Use the standard intravenous or oral dosing protocols as described above 1

---

Emerging Indication: Non-Acetaminophen Acute Liver Failure

While the American Gastroenterological Association officially recommends NAC only in clinical trials for non-acetaminophen acute liver failure, recent high-quality evidence demonstrates significant benefit, particularly in early-stage hepatic encephalopathy. 5, 6

Evidence Supporting Use

• Improved transplant-free survival: 41% versus 30% (OR 1.61,95% CI 1.11-2.34, P=0.01) in non-acetaminophen acute liver failure 6
• Overall survival benefit: 76% versus 59% (OR 2.30,95% CI 1.54-3.45, P<0.0001) 6
• Greatest benefit in early hepatic encephalopathy (grades I-II), with post-hoc analysis showing mortality benefit specifically in stage 1 or 2 encephalopathy 5, 6

Practical Approach

• Consider NAC administration in non-acetaminophen acute liver failure, especially when the cause is indeterminate (may be occult acetaminophen) 5
• Initiate early in the course of drug-induced hepatic failure without waiting for laboratory confirmation 6
• Use the same IV regimen: 150 mg/kg loading dose over 15 minutes, followed by 50 mg/kg over 4 hours, then 100 mg/kg over 16 hours 6
• Minimal toxicity profile supports use even when benefit is uncertain 5, 6

---

Established Indication: Mucolytic Agent

NAC is indicated as adjuvant therapy for abnormal, viscid, or inspissated mucous secretions in various respiratory conditions. 3

Respiratory Indications

• Chronic bronchopulmonary disease: chronic emphysema, emphysema with bronchitis, chronic asthmatic bronchitis, tuberculosis, bronchiectasis 3
• Acute bronchopulmonary disease: pneumonia, bronchitis, tracheobronchitis 3
• Cystic fibrosis pulmonary complications 3
• Tracheostomy care and post-traumatic chest conditions 3
• Atelectasis due to mucous obstruction 3
• Diagnostic bronchial studies (bronchograms, bronchospirometry) 3

Mechanism and Precautions

• NAC "opens" disulfide linkages in mucus, lowering viscosity through its sulfhydryl group 3
• Watch asthmatics carefully—bronchospasm may occur unpredictably; most respond quickly to nebulized bronchodilators 3
• Discontinue immediately if bronchospasm progresses despite bronchodilator use 3
• When cough is inadequate, maintain airway patency with mechanical suction 3

---

Other Potential Applications

NAC shows promise in conditions characterized by decreased glutathione or oxidative stress, though evidence is less robust: 7, 8

• HIV infection (as antioxidant support) 7, 8
• Heavy metal toxicity (as chelating agent and hepatorenal protectant) 7
• Sjögren's syndrome 8
• Hepatitis C 8

---

Critical Timing Considerations

Efficacy is time-dependent for acetaminophen overdose:

• Optimal window: Within 8 hours of ingestion provides maximum hepatoprotection 1, 9
• Still beneficial: Up to 24 hours post-ingestion, though efficacy decreases with time 1, 9
• Mortality prevention: Treatment initiated within 8-24 hours significantly reduces mortality regardless of route (IV or oral) 9

---

Common Adverse Effects

NAC is generally well-tolerated with manageable side effects:

• Oral route: Nausea, vomiting, gastrointestinal symptoms (may aggravate vomiting from acetaminophen overdose itself) 3
• Intravenous route: Anaphylactic reactions (most common), cutaneous reactions 9
• Both routes: Rash with or without mild fever (rare), generalized urticaria (rare) 3
• Overall incidence: Nausea/vomiting <5%, skin rash <5%, bronchospasm 1-2% 6

---

Key Clinical Pitfalls to Avoid

• Never delay NAC while awaiting acetaminophen levels if overdose is suspected 1, 2, 3
• Activated charcoal may be given prior to NAC within 4 hours of presentation, but do not delay NAC administration 2
• Do not discontinue NAC prematurely—the 21-hour IV protocol is often too short; consider extending based on clinical response and ALT trends 4
• Monitor for bronchospasm in respiratory patients receiving nebulized NAC, particularly asthmatics 3
• Discontinue NAC if encephalopathy due to hepatic failure becomes evident to avoid further nitrogenous substance administration 3