What are the indications, dosing regimens (adult and pediatric), contraindications, and adverse effects of N‑acetylcysteine for mucolytic therapy and acetaminophen overdose?

N-Acetylcysteine (NAC): Clinical Indications, Dosing, and Safety Profile

Primary Indication: Acetaminophen Overdose

N-acetylcysteine is the definitive antidote for acetaminophen overdose and must be initiated immediately when overdose is known or suspected, ideally within 8-10 hours of ingestion, with demonstrated mortality reduction from 80% to 52% in established hepatic failure. 1, 2, 3

When to Initiate NAC

• Start immediately without waiting for acetaminophen levels if there is strong clinical suspicion of significant overdose 2, 3
• Administer when acetaminophen levels plot above the treatment line on the Rumack-Matthew nomogram 2, 3
• For presentations >24 hours post-ingestion where the nomogram cannot be used, initiate NAC based on clinical suspicion 2
• In acute liver failure with suspected acetaminophen ingestion, start NAC even without confirmatory history 1, 2, 3

Dosing Regimens

Oral Protocol (72-hour regimen): 2, 3, 4

• Loading dose: 140 mg/kg
• Maintenance: 70 mg/kg every 4 hours for 17 additional doses (total 18 doses)

Intravenous Protocol (21-hour regimen): 2, 3, 5

• Loading dose: 150 mg/kg over 15 minutes
• Second dose: 50 mg/kg over 4 hours
• Third dose: 100 mg/kg over 16 hours

Alternative 48-hour IV protocol: 5

• Loading dose: 140 mg/kg
• Maintenance: 70 mg/kg every 4 hours for 12 doses

Treatment Efficacy by Timing

• Within 8 hours: Only 2.9% develop severe hepatotoxicity; no deaths when treatment started this early 2, 4
• 8-10 hours: 6.1% develop hepatotoxicity 2, 4
• 10-24 hours: 26.4% develop hepatotoxicity 2, 4
• 16-24 hours (high-risk patients): 41-58% develop hepatotoxicity 4, 5

Special Populations Requiring Lower Treatment Thresholds

• Chronic alcoholics: May develop toxicity at lower acetaminophen doses; treat even if levels are below standard thresholds 2, 3
• Fasting patients: At increased risk; warrant NAC at lower acetaminophen levels 2, 3
• Malnourished cirrhotic patients: Particularly vulnerable to paracetamol hepatotoxicity even at therapeutic doses 3

Critical Clinical Scenarios

• Extended-release formulations: Use standard dosing but extend monitoring period 2
• Repeated supratherapeutic ingestions (>4g/24 hours): Apply standard 3-day protocol 2
• Unknown time of ingestion: Initiate NAC immediately 2
• Established hepatic failure: Use IV NAC regardless of time since ingestion 2

Interaction with Activated Charcoal

• Activated charcoal may be given within 4 hours of presentation but do not delay NAC administration 2
• Charcoal may adsorb up to 96% of oral NAC, but this should not prevent treatment 6

Secondary Indication: Acute Liver Failure (Non-Acetaminophen)

NAC should be administered in all cases of acute liver failure regardless of etiology, with demonstrated improvements in transplant-free survival (64% vs 26%, OR 4.81) and overall survival (76% vs 59%, OR 2.30). 1, 3

Evidence for Non-Acetaminophen ALF

• Liver transplant-free survival: 41% vs 30% (OR 1.61,95% CI 1.11-2.34, P=0.01) 1, 3
• Post-transplant survival: 85.7% vs 71.4% (OR 2.44,95% CI 1.11-5.37, P=0.03) 1
• Overall survival: 76% vs 59% (OR 2.30,95% CI 1.54-3.45, P<0.0001) 1, 3
• Benefits confined to patients with grades I-II coma; start as early as possible 1

Dosing for ALF

Use the same IV protocols as for acetaminophen overdose, though varying doses were used in clinical trials 1

Tertiary Indication: Mucolytic Therapy

NAC is NOT recommended for routine use as a mucolytic agent in chronic bronchitis or cystic fibrosis based on insufficient evidence of clinical benefit. 1

Evidence Against Routine Mucolytic Use

• Chronic bronchitis: Oral NAC may reduce exacerbations but has not been systematically studied for cough; not FDA-approved in the United States 1
• Cystic fibrosis: No demonstrated clinical benefit or improvement in lung function; insufficient evidence to recommend for or against (Grade I recommendation) 1
• COPD: May reduce acute exacerbations with modest health status improvement, but this is not the primary indication 7

Contraindications and Precautions

Absolute Contraindications

• Known hypersensitivity to NAC (rare) 6, 8

Relative Contraindications and Cautions

• Active bronchospasm: May worsen transiently (1-2% incidence) 1, 8
• Pregnancy: NAC is safe and strongly recommended for acetaminophen overdose in pregnancy 3

Adverse Effects Profile

Common Adverse Effects (Overall incidence 46.7% with IV NAC) 8

Gastrointestinal (most common): 1, 3, 6, 8

• Nausea and vomiting (<5% to common)
• Diarrhea or constipation

Dermatologic: 1, 3, 8

• Skin rash (<5%)
• Flushing (significantly associated with IV NAC, p<0.001)
• Pruritus (significantly associated with IV NAC, p<0.001)

Respiratory: 1, 3, 8

• Transient bronchospasm (1-2%)
• Coughing (p=0.01 with IV NAC)

Cardiovascular: 8

• Hypotension (p=0.001 with IV NAC)
• Chest pain (p=0.001 with IV NAC)

Neurologic: 8

• Headache (p=0.001 with IV NAC)
• Dizziness (p<0.001 with IV NAC)
• Convulsion (rare, p=0.03)

Severity Classification 8

• Mild: 43.2% of patients with adverse effects
• Moderate: 13.6%
• Severe: 9.6%
• All adverse reactions were easily managed and did not require treatment discontinuation in 91% of cases 8, 5

Anaphylactoid Reactions

• Most commonly occur during the IV loading dose 5
• Manifest as transient patchy skin erythema or mild urticaria in 14.3% of patients 5
• Rarely require discontinuation of therapy 5

Pediatric Considerations

Use the same weight-based dosing protocols as adults for acetaminophen overdose. 2, 4

• Oral: 140 mg/kg loading, then 70 mg/kg every 4 hours for 17 doses 2, 4
• IV: 150 mg/kg loading over 15 minutes, then 50 mg/kg over 4 hours, then 100 mg/kg over 16 hours 2
• Treatment within 8 hours results in no severe hepatotoxicity in pediatric studies 2

Pharmacokinetics 6

• Peak plasma concentration: 0.35-4 mg/L achieved within 1-2 hours after oral dosing
• Volume of distribution: 0.33-0.47 L/kg
• Protein binding: ~50% at 4 hours post-dose
• Terminal half-life: 6.25 hours (oral reduced form)
• Renal clearance: 0.190-0.211 L/h/kg (~30% of total clearance)
• Major excretory product: Inorganic sulfate

Critical Pitfalls to Avoid

1. Never delay NAC while awaiting confirmatory levels if there is strong suspicion of significant overdose 2
2. Do not withhold NAC because activated charcoal was given 2
3. Do not assume NAC is ineffective after 10 hours—it still provides benefit up to 24 hours and beyond in established liver failure 1, 2, 4
4. Do not use lower treatment thresholds for general population—but DO use them for alcoholics, fasting patients, and malnourished cirrhotics 2, 3
5. Do not discontinue NAC for mild anaphylactoid reactions—these are transient and manageable 8, 5