BLACK BOX WARNING
- hepatotoxicity — risk with doses >4 g/day; risk increased with alcohol use, hepatic disease, or CYP2E1 inducers
acetaminophen
Brand: Tylenol, APAP, Ofirmev (IV), Paracetamol
⚠ BBW Prototype Drug
Drug Class: analgesic / antipyretic
Drug Family: analgesic
Subclass: para-aminophenol derivative
Organ Systems: cnsmusculoskeletal
Mechanism of Action
Exact mechanism incompletely understood; inhibits central COX-3 (a COX-1 splice variant) and activates descending serotonergic pain pathways; has no meaningful peripheral anti-inflammatory activity; robust antipyretic action via central inhibition of prostaglandin synthesis in the hypothalamus.
COX-3 (central)endocannabinoid systemTRPA1 channels
Indications
- mild-to-moderate pain
- fever
- first-line analgesic/antipyretic in pregnancy
- osteoarthritis pain (oral, topical)
- multimodal analgesia (IV Ofirmev)
Contraindications
- severe hepatic impairment
- hypersensitivity to acetaminophen
Adverse Effects
Common
- hepatotoxicity (with overdose or therapeutic use in patients with hepatic disease/alcohol use)
- rarely: rash
Serious
- hepatotoxicity — potentially fatal; N-acetylcysteine is the antidote
- acute liver failure
- rare: severe hypersensitivity reactions including anaphylaxis, SJS
Pharmacokinetics (ADME)
| Absorption | Rapid and complete oral absorption; IV form achieves higher peak CNS levels than oral |
| Distribution | Low protein binding (<20%); Vd ~0.9 L/kg; crosses BBB |
| Metabolism | Primarily glucuronidation (55%) and sulfation (30%) to inactive metabolites; ~5–10% via CYP2E1 (and CYP3A4) to toxic NAPQI, which is detoxified by glutathione |
| Excretion | Renal as glucuronide/sulfate conjugates |
| Half-life | 2–3 hours |
| Onset | 30 minutes (oral); ~5–10 minutes (IV) |
| Peak | 30–60 minutes (oral); 15 minutes (IV) |
| Duration | 4–6 hours |
| Protein Binding | <20% |
| Vd | ~0.9 L/kg |
Drug Interactions
| Drug / Agent | Mechanism | Severity |
|---|---|---|
| warfarin | acetaminophen inhibits warfarin metabolism; INR may increase significantly even at therapeutic doses | moderate |
| alcohol (chronic heavy use) | CYP2E1 induction increases NAPQI formation; glutathione depletion from malnutrition increases hepatotoxicity risk | major |
| isoniazid | CYP2E1 induction increases NAPQI formation | moderate |
Nursing Considerations
- Maximum dose: 4 g/day in healthy adults; 2 g/day maximum in patients with hepatic disease, heavy alcohol use, or malnutrition; check all other OTC/prescription products for acetaminophen content to prevent inadvertent overdose
- In overdose: administer N-acetylcysteine (NAC) within 8–10 hours of ingestion for maximum efficacy; use Rumack-Matthew nomogram to guide NAC therapy
- IV Ofirmev: infuse over 15 minutes; check dose carefully — 10-fold dosing errors have occurred (1000 mg vs 100 mg/mL concentration)
- Patient education: avoid alcohol with acetaminophen; identify all sources of APAP in multi-ingredient OTC products (cold/flu preparations, sleep aids)
Clinical Pearls
- Acetaminophen overdose (intentional or accidental) is the leading cause of acute liver failure in the United States — toxicity is mediated by NAPQI accumulation when glutathione stores are depleted
- Unlike NSAIDs, acetaminophen lacks anti-inflammatory activity and does not inhibit platelet aggregation — it is therefore safe in patients who cannot tolerate NSAIDs (GI bleeding risk, renal insufficiency, anticoagulation) but ineffective for inflammatory pain
Safety Profile
Pregnancy safe
Lactation safe
Renal Adjustment Not required
Hepatic Adjustment Required
TDM Not required
Concordance Terms
Cross-referenced clinical concepts — click any term to see all content where it appears.