What ingredients are added to paracetamol (acetaminophen) to reduce its toxicity?

N-acetylcysteine (NAC) is the Primary Ingredient Added to Paracetamol to Reduce its Toxicity

N-acetylcysteine (NAC) is the most effective ingredient added to paracetamol formulations to reduce its toxicity by preventing hepatotoxicity through glutathione restoration and reactive metabolite detoxification. 1, 2

Mechanism of Paracetamol Toxicity and NAC Protection

• Paracetamol (acetaminophen) overdose is the most frequent cause of serious, often lethal, drug-induced hepatotoxicity 1
• Acetaminophen doses of 150 mg/kg or greater have been associated with hepatotoxicity 3
• In overdose, paracetamol is metabolized to a highly reactive alkylating metabolite (N-acetyl-p-benzoquinone imine or NAPQI) that depletes glutathione and binds to vital cell constituents, causing acute hepatic necrosis 4
• NAC protects the liver by:
  • Maintaining or restoring glutathione levels 3
  • Acting as an alternate substrate for conjugation with the reactive metabolite 3
  • Scavenging reactive oxygen/peroxynitrite species 2
  • Supporting mitochondrial bioenergetics 2

Effectiveness of NAC in Preventing Paracetamol Toxicity

• When administered concurrently with paracetamol, NAC effectively prevents liver damage that would otherwise occur with toxic doses 1
• Studies show that co-administration of NAC with paracetamol results in only marginal increases in hepatic transaminases and preservation of liver architecture 1
• NAC is most effective when administered early, ideally within 8-10 hours of paracetamol ingestion 5, 6
• Treatment timing is critical for effectiveness:
  • NAC initiated within 8 hours: 2.9% risk of severe hepatotoxicity 6
  • NAC initiated within 10 hours: 6.1% risk of severe hepatotoxicity 6
  • NAC initiated after 10 hours: 26.4% risk of severe hepatotoxicity 6

NAC Dosing and Administration

• For acetaminophen overdose, NAC can be administered through oral or intravenous routes 7
• Oral NAC regimen: 140 mg/kg loading dose followed by 70 mg/kg every 4 hours for 17 doses 7
• Intravenous NAC regimen: 150 mg/kg loading dose over 15 minutes, followed by 50 mg/kg over 4 hours, then 100 mg/kg over 16 hours 7
• For co-formulation with paracetamol to prevent toxicity, studies suggest equal amounts of NAC and paracetamol may be effective 1

Other Potential Protective Agents

• 4-Methylpyrazole (4MP) has shown effectiveness against paracetamol toxicity by inhibiting cytochrome P450 enzymes and c-Jun N-terminal kinase 2
• Calmangafodipir (CMFP), a SOD mimetic, has potential to be effective after severe overdoses 2
• Methionine is another sulfhydryl compound that can prevent paracetamol-induced damage 4
• Metformin and methylene blue have shown protective effects in animal studies 2

Special Considerations

• Patients with prolonged fasting may be at increased risk for acetaminophen toxicity and may develop toxicity at lower doses 7
• Patients with repeated supratherapeutic ingestions (>4g per 24 hours) may have worse prognosis than those with acute overdose 5
• For high-dose or "massive" paracetamol overdoses, standard NAC dosing may be insufficient, though evidence for higher-dose NAC regimens is still limited 8, 9
• From a public health perspective, replacing current over-the-counter paracetamol with a safe APAP/NAC co-formulation could prevent accidental and intentional paracetamol toxicity 1

Clinical Application

• NAC should be administered to patients with suspected acetaminophen overdose, even without confirmed levels 6
• The Rumack-Matthew nomogram is used to predict hepatic toxicity after acute acetaminophen ingestion and guide treatment decisions 5
• For patients with elevated transaminases who require paracetamol, limiting the dose to 2g/day with daily monitoring is recommended 6