N-Acetylcysteine ​​(NAC)

Mechanism

Pharmacological Group and Molecular Target

Donor of sulfhydryl groups, precursor of L-cysteine and intracellular glutathione. Direct modulator of oxidation-reduction processes in hepatocytes.

Detailed Mechanism of Action

In cases of paracetamol (acetaminophen) overdose, the normal metabolic pathway of sulfate and glucuronide conjugation is saturated. This redirects excess paracetamol toward cytochrome P450 (mainly the CYP2E1 isoenzyme), producing the highly reactive and hepatotoxic metabolite N-acetyl-p-benzoquinoneimine (NAPQI). Under normal conditions, NAPQI is rapidly neutralized by cellular reduced glutathione (GSH). When cellular GSH stores fall below 30%, free NAPQI covalently binds to cellular proteins in hepatocytes, triggering lipid peroxidation, mitochondrial dysfunction, and centrilobular hepatic necrosis.

N-Acetylcysteine acts by restoring hepatic glutathione reserves through two main pathways:

1. It serves as a precursor to L-cysteine, which is the limiting amino acid in the synthesis of new cellular GSH.
2. It binds directly to the reactive NAPQI in a non-enzymatic manner, acting as a surrogate nucleophile for glutathione to neutralize the toxin before it damages cellular proteins.

Pharmacokinetics

Pharmacokinetic and Toxicokinetic Profile

• Absorption: Rapid oral administration, although it undergoes intense first-pass hepatic metabolism that reduces its bioavailability to approximately 4-10%.
• Distribution: It is 80% bound to plasma proteins. It effectively penetrates the hepatic cytosol.
• Metabolism: Deacetylated in the intestinal wall and liver to form cysteine, which is directly incorporated into the cellular synthesis of glutathione.
• Excretion: Mostly renal in the form of inactive metabolites; only 15-20% of the unchanged drug is eliminated in the urine.
• Elimination half-life: 5.6 hours in adults; It is significantly prolonged in newborns (up to 11 hours) and end-stage liver failure.

Indicators and dose

Specific Clinical Indications

• Acute or chronic Paracetamol poisoning: Indicated according to the evaluation of the Rumack-Matthew nomogram or in cases of well-founded suspicion with intakes greater than 150 mg/kg in children or 7.5 g in adults.
• Acute Liver Failure not related to Paracetamol: Used to improve microvascular oxygen delivery and systemic tissue perfusion.
• Prevention of contrast nephropathy (controversial): Renal antioxidant adjuvant.

Dosage Scheme and Infusion Protocols

Three Bag Intravenous Protocol (Classic 21 hours)

1. Loading Dose (Bag 1): 150 mg/kg diluted in 200 mL of 5% dextrose to infuse over 60 minutes (1 hour).
2. Maintenance Dose (Bag 2): 50 mg/kg diluted in 500 mL of 5% dextrose to infuse over the next 4 hours.
3. Second Maintenance Dose (Bag 3): 100 mg/kg diluted in 1000 mL of 5% dextrose to infuse over the next 16 hours.

*In patients with low body weight (<40 kg) or with strict fluid restriction, dilution volumes must be accurately calculated to avoid acute dilutional hyponatremia.*

Security

Contraindications and Precautions

• There are no absolute contraindications due to the lethal nature of fulminant acute liver failure.
• Precautions: Asthmatic patients or patients with a history of severe bronchospasm. NAC infusion may trigger a non-immunological histaminergic anaphylactoid reaction.

Adverse Effects (ADR)

• Anaphylactoid reactions (up to 15% of patients): Pruritus, diffuse skin rash, facial flushing, peripheral angioedema, mild-moderate bronchospasm, transient arterial hypotension. These reactions are usually associated with the high rate of the loading infusion and resolve when the drug is temporarily suspended and antihistamines are administered.
• Gastrointestinal: Intense nausea, reflex vomiting (especially orally due to its sulfur smell).

Use in Special Populations

Pregnancy: Highly recommended. Paracetamol freely crosses the placental barrier and is hepatotoxic to the fetus. Treatment with NAC prevents fetal death and abortion induced by the toxin. It is safe during breastfeeding.