What is the recommended action of Acetylcysteine (N-acetylcysteine) in acetaminophen (paracetamol) overdose?

Acetylcysteine Action in Acetaminophen Overdose

N-acetylcysteine (NAC) is the essential antidote for acetaminophen overdose that prevents or lessens hepatic injury by maintaining or restoring glutathione levels and serving as an alternate substrate for conjugation with the toxic metabolite NAPQI. 1, 2

Mechanism of Action

NAC counteracts acetaminophen toxicity through several mechanisms:

• Functions as a sulfhydryl group donor
• Directly conjugates with the toxic metabolite N-acetyl-p-benzoquinoneimina (NAPQI)
• Reduces hepatocellular toxicity of NAPQI
• Maintains or restores glutathione levels in the liver 1

Treatment Protocol

Timing of Administration

• Early administration is critical - ideally within 8 hours of ingestion
  • Treatment within 8 hours: only 1% risk of severe hepatotoxicity
  • Treatment between 8-10 hours: 6.1% risk of severe hepatotoxicity
  • Treatment between 10-16 hours: 29% risk of severe hepatotoxicity
  • Treatment between 16-24 hours: 62% risk of severe hepatotoxicity 1

Dosing Regimen

• Intravenous administration:

  • Loading dose: 150 mg/kg over 15-60 minutes
  • Maintenance: 300 mg/kg over 21 hours 1

• Oral administration:

  • Loading dose: 140 mg/kg
  • Maintenance: 70 mg/kg every 4 hours for 17 additional doses (72-hour protocol) 1, 3

Risk Assessment

The Rumack-Matthew nomogram determines the risk of hepatotoxicity based on acetaminophen concentration and time since ingestion:

Acetaminophen Concentration (mg/L)	Time Post-Ingestion (hours)	Risk of Hepatotoxicity
>200	4	Probable
100-200	4	Possible
<100	4	No risk

• Acetaminophen levels should be measured at least 4 hours post-ingestion
• If levels fall in "possible" or "probable" risk zones, initiate NAC immediately 1

Special Considerations

High-Risk Patients

Treatment should be considered even with levels in the non-toxic range for patients with:

• Chronic alcoholism
• Malnutrition
• Patients taking CYP2E1 enzyme-inducing drugs 1

Extended-Release Formulations

• Require a second level at 8-10 hours if the 4-hour level is below the toxicity line
• Administer NAC if the second level is at or above the possible toxicity line 1

Treatment Duration

• Continue NAC beyond the initial protocol if:
  • Liver enzymes are elevated or rising
  • Until AST/ALT levels are decreasing
  • INR is <2.0
  • Clinical improvement is observed 1

Monitoring and Supportive Care

• Serial monitoring of:

  • Acid-base status
  • Liver function tests
  • Renal function
  • Coagulation parameters
  • Mental status 1

• Supportive care for hemodynamic instability is essential in severe cases 1

Potential Pitfalls

1. Delayed treatment: Efficacy decreases significantly after 8 hours, but NAC should still be administered up to 24 hours after ingestion 2, 4

2. Allergic reactions: May occur with NAC but should not prevent treatment; manage with antihistamines and epinephrine if needed 1

3. Underestimating risk: Even with early NAC treatment, patients with extremely high acetaminophen levels (>300 mg/L at 4 hours) may still develop hepatotoxicity 5

4. Inadequate duration: Premature discontinuation of NAC before liver enzymes normalize can lead to rebound hepatotoxicity 1

NAC remains the cornerstone of treatment for acetaminophen overdose, with nearly 50 years of clinical use demonstrating its efficacy in preventing hepatic injury when administered promptly 6.