Paracetamol (Acetaminophen)

Mechanism

💊 Common Business Names

Tylenol, Gelocatil, Panadol, Efferalgan, Termalgin, Tempra.

🔬 Pharmacological Group

Derived from para-aminophenol. Non-anti-inflammatory analgesic and antipyretic.

Mechanism of Action

Although its exact action remains under investigation, it is known that its analgesic effect is due to a preferential central action:

• Inhibition of prostaglandin synthesis at a central level: It acts by reducing the active site of the cyclooxygenase enzyme (specifically the COX-3 variant or the central pool of COX) by acting as an electron donor, preventing the propagation of the tyrosyl radical necessary for the oxygenation of arachidonic acid. This inhibition is easily reversed in conditions of high concentrations of peroxides (a characteristic of inflamed peripheral tissues, where neutrophils are abundant, which explains its null peripheral anti-inflammatory action).
• Interaction with the endogenous cannabinoid system: Metabolized in the brain by fatty acid amide hydrolase (FAAH) to form AM404 (N-acetyl-p-aminophenylamine-arachidonyl). AM404 acts as an anandamide reuptake inhibitor and as an agonist of transient receptor potential vanilloid-like 1 (TRPV1), reinforcing descending serotonergic analgesic pathways.

Pharmacokinetics

Key Pharmacokinetics

Indicators and dose

Dosage and Adjustment

• Adults: 500 mg to 1000 mg orally or intravenously every 4 to 6 hours as needed. Absolute maximum dose: 4000 mg/day in healthy patients; limit to 2000 - 3000 mg/day in the elderly, malnourished or chronic alcoholics.
• Pediatrics: 10 - 15 mg/kg/dose every 4 to 6 hours orally or rectally. Do not exceed 60 mg/kg/day or 5 doses in 24 hours.
• Adjustment in Kidney Failure:
  • Cl_cr ≥ 50 mL/min: Administer standard doses every 4 hours.
  • Cl_cr 10-50 mL/min: Extend the dosing interval to a minimum of every 6 hours.
  • Cl_cr < 10 mL/min: Extend the dosing interval to a minimum of every 8 hours (and limit the maximum daily dose to 2000 mg).
• Adjustment in Liver Failure: Contraindicated in severe failure. In stable chronic liver disease or compensated cirrhosis, strictly limit the maximum dose to ≤ 2000 mg/day and avoid prolonged treatments.

Security

Pathophysiology of Paracetamol Overdose

Under conditions of paracetamol overdose (generally single doses greater than 150 mg/kg or greater than 7.5 - 10 grams in adults), the normal glucuronidation and sulfation pathways are rapidly saturated. Consequently, a substantially larger fraction is metabolized by the CYP2E1 system, generating massive amounts of , which depletes intracellular hepatic glutathione stores.. Intrahepatic glutathione reserves are completely depleted (fall below 30% of the basal limit). Excess free NAPQI covalently binds to the sulfhydryl groups of hepatocyte mitochondrial proteins, inducing dysfunction of the cellular respiratory chain, lipid peroxidation, massive entry of intracellular calcium and hepatocyte cell death due to centrilobular necrosis (Rappaport Zone 3).

Contraindications

• Absolute: Hypersensitivity to the active ingredient or its excipients; severe hepatocellular insufficiency or active decompensated liver disease (Child-Pugh C).
• Relative: Chronic alcohol consumption (induction of CYP2E1 and basal reduction of glutathione stores); severe malnutrition, cachexia and anorexia (glutathione depletion); glucose-6-phosphate dehydrogenase deficiency (G6PD - risk of hemolysis with extreme doses); severe renal failure (Cl_cr < 10 mL/min).

Adverse Effects (ADR)

• Frequent / Mild: Transient and reversible elevation of transaminases (ALT/AST), dizziness, drowsiness, post-dosing nausea.
• Rare / Serious: Severe cutaneous hypersensitivity reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis, acute generalized exanthematous pustulosis). Thrombocytopenia, leukopenia and isolated neutropenia.
• Specific Toxicity: Acute fulminant hepatic failure in overdose. Acute renal tubular necrosis (secondary to local synthesis of NAPQI in renal tubular cells).

Treatment of Liver Failure by Paracetamol: N-Acetylcysteine (NAC)

N-acetylcysteine ​​(NAC) constitutes the specific antidote. It acts through three integrated mechanisms: 1) Provides cysteine, the limiting substrate for endogenous glutathione synthesis; 2) It binds directly to free NAPQI acting as a substitute for glutathione; 3) Improves microvascular oxygen supply to tissues through its vasodilatory action. Maximum effectiveness is obtained if administered within the first 8 hours of ingestion. It is prescribed using the Rumack-Matthew protocol or the simplified 20-hour infusion regimen (150 mg/kg in 1 hour, followed by 50 mg/kg in 4 hours and 100 mg/kg in 16 hours).

Drug Interactions

• Enzyme Inducers (Rifampin, Phenytoin, Carbamazepine, Phenobarbital): They increase the rate of NAPQI formation by induction of the CYP2E1 pathway, drastically increasing the risk of hepatotoxicity even at doses considered therapeutic.
• Alcohol (Ethanol): Acute consumption competes for CYP2E1 and can temporarily mitigate toxicity, but chronic consumption stably induces CYP2E1 and reduces hepatic glutathione storage, amplifying the hepatotoxic risk profile.
• Oral Anticoagulants (Warfarin / Acenocoumarol): Prolonged administration of high doses of paracetamol (>2 g/day for more than 5 days) can competitively inhibit the metabolism of coagulation factors and induce a modest but clinically relevant increase in INR.

Pregnancy and Breastfeeding

Historically classified in FDA Category B. It is considered the analgesic of choice during all trimesters of pregnancy if used at the lowest recommended doses and for short periods of time. However, recent epidemiological studies suggest possible associations of its prolonged in utero use with childhood neurodevelopmental disorders (ADHD) and male urogenital anomalies, so it should be used with strict medical indication. Breastfeeding: Compatible; It is excreted in breast milk at clinically insignificant concentrations (less than 1% of the weight-adjusted maternal dose).