Acetaminophen (Oral)

• Core Use: First-line analgesic and antipyretic for mild to moderate pain and fever; cornerstone of multimodal analgesia in ED/ICU
• Onset/Duration: Onset within 30–60 minutes, peak at ~1–2 hours, duration 4–6 hours
• Typical Dosing: Adults: 650–1,000 mg PO every 6 hours as needed, strict maximum ≤4 g/day (many institutions: ≤3 g/day)
• Key Danger: Dose-dependent hepatotoxicity; must track total daily dose from all sources (OTC Tylenol, cold meds, combo opioids like Norco/Percocet)
• Special Note: Higher risk in chronic alcohol use, malnutrition, low body weight, and pre-existing liver disease; safe in pregnancy when used within limits

• Generic Name: Acetaminophen (paracetamol)
• Brand Names: Tylenol, Panadol, various generics and combination products

Non-opioid analgesic and antipyretic

Mechanism of Action:

• Primarily central inhibition of prostaglandin synthesis via weak cyclooxygenase (COX) inhibition, possibly COX-2 and variant COX enzymes in the CNS
• Modulation of serotonergic descending pain pathways and potential endocannabinoid system effects contribute to analgesia
• Minimal peripheral anti-inflammatory activity; not an NSAID and lacks platelet inhibition or significant GI mucosal toxicity at therapeutic doses

Pharmacokinetics:

• Absorption: Rapid and nearly complete from the GI tract; onset of analgesia within 30–60 minutes; peak at ~1–2 hours
• Distribution: Volume of distribution ~0.9 L/kg; crosses placenta and appears in breast milk at low concentrations
• Metabolism: Primarily hepatic via glucuronidation and sulfation; ~5–10% via CYP2E1 (and others) to a reactive metabolite (NAPQI) detoxified by glutathione
• Elimination: Renal excretion of conjugated metabolites; elimination half-life ~2–3 hours in healthy adults, prolonged in liver failure or overdose
• Toxicity Mechanism: Develops when glucuronidation/sulfation pathways are saturated and glutathione stores are depleted, leading to accumulation of NAPQI and hepatocellular injury

• Mild to moderate pain: headaches, musculoskeletal pain, dental pain, dysmenorrhea, minor trauma
• Adjunct to opioids/other agents for moderate to severe pain (multimodal analgesia), reducing opioid requirements
• Antipyresis in febrile patients when fever is contributing to discomfort, tachycardia, or increased metabolic demand
• Preferred systemic analgesic/antipyretic in many pregnant patients and those with NSAID contraindications (e.g., peptic ulcer disease, CKD, anticoagulation)

Available Forms:

• Tablets/caplets: 325 mg, 500 mg, 650 mg (extended-release), 1,000 mg in some regions
• Chewable tablets: e.g., 80 mg, 160 mg (varies by manufacturer)
• Oral suspension/solution: commonly 160 mg/5 mL (pediatrics); always verify concentration
• Many combination products (e.g., with hydrocodone, oxycodone, tramadol, cold/flu meds). These all count toward total daily acetaminophen

Dosing – Acetaminophen (Adult Oral):

Pediatric Dosing (outline – use pediatric-specific references):

• Typical short-term oral dosing: 10–15 mg/kg per dose every 4–6 hours as needed
• Maximum: 75 mg/kg/day, not to exceed ~3,000–4,000 mg/day (whichever is lower)
• Adjust for low body weight, chronic illness, or concomitant hepatotoxic drugs
• Avoid long-term scheduled high dosing without specialist input

Absolute Contraindications:

• Severe hepatic impairment or active severe hepatic disease where any additional hepatotoxic exposure is unsafe
• Known serious hypersensitivity to acetaminophen (e.g., anaphylaxis, severe cutaneous adverse reactions)

Major Precautions:

• Chronic alcohol use, malnutrition, low body weight, or chronic liver disease: decreased glutathione and higher risk of hepatotoxicity at lower doses
• Concurrent use of multiple acetaminophen-containing products (OTC cold/flu meds, opioid combinations) – high risk for unintentional overdose
• Induction of CYP2E1 (e.g., chronic alcohol, isoniazid) may increase production of the toxic metabolite NAPQI
• Use caution with prolonged high-dose therapy; monitor LFTs if use extends beyond a few days at higher doses

Common (therapeutic dosing):

• Generally well tolerated; occasional nausea or mild GI upset
• Mild elevations in liver enzymes with repeated dosing

Serious:

• Dose-dependent hepatotoxicity and acute liver failure with supratherapeutic doses or chronic overuse
• Severe cutaneous adverse reactions (SCARs) including Stevens–Johnson syndrome, toxic epidermal necrolysis, and acute generalized exanthematous pustulosis (extremely rare)
• Anaphylaxis and other serious hypersensitivity reactions (rare)

Hepatic Impairment:

• Reduce total daily dose to ≤2,000 mg/day in cirrhosis, chronic alcohol use, or malnutrition
• Use lowest effective dose for shortest duration
• Consider alternative analgesic in severe hepatic disease

Renal Impairment:

• No major dose adjustment for isolated renal impairment
• Consider extending interval to q8h in severe CKD or hemodialysis
• Monitor for accumulation in prolonged use

Geriatric Patients:

• Use lower doses (500–650 mg) in frail or low-body-weight elderly patients
• Maximum often limited to ≤2–3 g/day
• Increase monitoring for adverse effects

Pregnancy & Lactation:

• Generally considered safe in pregnancy at therapeutic doses; preferred analgesic/antipyretic in pregnancy
• Crosses placenta; appears in breast milk at low concentrations
• Use lowest effective dose for shortest duration

Pediatric Considerations:

• Weight-based dosing: 10–15 mg/kg per dose every 4–6 hours
• Maximum: 75 mg/kg/day, not to exceed 3,000–4,000 mg/day
• Always verify concentration of liquid formulations

Clinical Monitoring:

• Track total daily acetaminophen dose from all sources (scheduled, PRN, combination products, OTC medications)
• Assess pain and fever control; taper or discontinue as soon as adequate control or clinical improvement occurs

Laboratory Monitoring:

• In patients on repeated high doses or with liver risk factors, monitor liver function tests (AST/ALT, bilirubin, INR) intermittently
• For suspected overdose, obtain serum acetaminophen level and apply the Rumack–Matthew nomogram; initiate N-acetylcysteine promptly per toxicology guidance

• 1. Lexicomp. (2024). Acetaminophen: Drug information. Wolters Kluwer.
• 2. Dart, R. C., Bailey, E., & Blessy, H. (2019). Acetaminophen. In Goldfrank's Toxicologic Emergencies (11th ed.). McGraw-Hill.
• 3. Heard, K. J. (2008). Acetylcysteine for acetaminophen poisoning. New England Journal of Medicine, 359(3), 285–292.
• 4. Sanford Guide to Antimicrobial Therapy. (2023). Analgesics and antipyretics – acetaminophen.
• 5. Prescott, L. F. (2000). Paracetamol, alcohol and the liver. British Journal of Clinical Pharmacology, 49(4), 291–301.