Generic Name

Acetaminophen

Mechanism

Acetaminophen (the active ingredient in Tylenol) primarily acts as a CNS‑centered inhibitor of cyclo‑oxygenase (COX) enzymes, with a strong preference for COX‑2 over COX‑1 in the brain.
• Inhibition of COX‑2 ↓ prostaglandin synthesis → ↓ nociception and fever.
• Limited peripheral COX inhibition → minimal anti‑inflammatory effect.
• A proposed central mechanism involves acetaminophen metabolites acting on serotonergic pathways, reinforcing analgesia.
• The exact mechanism may involve modulation of transient receptor potential (TRP) channels and endocannabinoid signaling.

Pharmacokinetics

• Absorption: Rapid; oral bioavailability ~95 %. Peak plasma concentration in 30–60 min.
• Distribution: Volume of distribution ≈ 0.5 L/kg, crosses the blood–brain barrier, modest plasma protein binding (~10 %).
• Metabolism:
• Glucuronidation (50–60 %) → A‑Glu.
• Sulfation (30–35 %) → A‑Sul.
• Minor O‑conjugation & CYP‑mediated (CYP2E1, 3A4) → N‑acetyl‑phenyl‑acetamide (NAPQI).
• Elimination: Primarily renal; T½ 1.5–2.5 h.
• Food interactions: No clinically significant effect on absorption.
• Special populations:
• CKD: ↓ renal clearance → 1.5–2 × increase in plasma levels.
• Hepatic disease: → ↑ NAPQI → higher hepatotoxic risk.
• Pediatric: Dose adjusted for weight; 0.5–1 mg/kg every 4–6 h.
• Elderly: Pharmacokinetics unchanged, but impaired hepatic clearance may elevate risk.

Indications

• Analgesia: Mild‑to‑moderate pain (headache, musculoskeletal, postoperative, dental).
• Antipyresis: Fever reduction in infections, post‑vaccination.
• Adjunct: Reduces narcotic requirements in multimodal pain protocols.

> *Note*: Not indicated for inflammatory conditions like rheumatoid arthritis or acute gout due to lack of anti‑inflammatory activity.

Contraindications

• Contraindications:
• Documented hypersensitivity to acetaminophen or any excipient.
• Severe liver disease (e.g., cirrhosis, acute hepatic failure).
• Warnings:
• Hepatotoxicity: Risk ↑ with overdose (>4 g/day) or chronic alcohol use.
• Renal impairment: Monitor serum creatinine when chronic dosing >1 g/day.
• Alcohol interaction: Chronic drinkers have lower CYP2E1 threshold → ↑ NAPQI.
• Drug interactions:
• Warfarin ↑ INR when >1 g/day.
• CYP2E1 inducers (rifampin, carbamazepine) ↓ plasma levels.
• CYP3A4 inhibitors (ketoconazole) ↑ plasma concentration.

Dosing

| CKD (eGFR 1 g/day for >10 days.

Adverse Effects

• Idiosyncratic: Rare hypersensitivity reactions, especially in young children.
• Dose‑related toxicity: NAPQI accumulation → centrilobular necrosis.

Monitoring

• Baseline: LFTs (AST, ALT, total bilirubin), CBC, PT/INR if on warfarin.
• During therapy (>10 days) in high‑risk pts:
• LFTs every 2–3 weeks.
• Monitor for jaundice, dark urine, RUQ pain.
• In CKD: serum creatinine q2–3 weeks if >1 g/day.
• In hepatic disease: Consider 24‑hour urinary NAPQI if high‑dose therapy.

Clinical Pearls

• Rule of 4: Never combine two acetaminophen products; a cumulative total of 4 g/day is the upper limit.
• Alcohol‑Acetaminophen Synergy: Alcohol lowers the NAPQI threshold by inducing CYP2E1, making a 3‑g dose potentially hepatotoxic for chronic drinkers.
• Rectal bioavailability: Only ~60 % of oral dose; use 50 % higher dosing for neonates and infants.
• Pediatric Dosing: Weight‑based dosing is safer than fixed dosing; always use the 65 mg/kg/day limit.
• Drug interactions: Warfarin’s anticoagulation effect is modestly potentiated at >1 g/day—consider INR monitoring.
• Rapid overdose management: Activated charcoal is ineffective; administer N‑acetylcysteine (NAC) within 8 h of ingestion.
• Alternative analgesics: In patients with CKD or severe hepatic disease, consider NSAIDs or opioids with caution; acetaminophen is contraindicated in decompensated cirrhosis.
• Patient education: Instruct patients to watch all OTC medications for acetaminophen content to avoid accidental overdose.

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• *Prepared for medical students & healthcare professionals; all references are current pharmacology texts and regulatory guidance from the FDA and EMA.*