Introduction
Acetaminophen (also known as paracetamol) is one of the most widely used over-the-counter analgesic and antipyretic medications worldwide. First introduced in clinical practice in the 1950s, it has become a cornerstone of pain management and fever reduction. Unlike NSAIDs, acetaminophen lacks significant anti-inflammatory properties but offers an excellent safety profile when used appropriately.
Mechanism of Action
Acetaminophen exerts its analgesic and antipyretic effects primarily through central nervous system actions. The drug inhibits prostaglandin synthesis by blocking cyclooxygenase (COX) enzymes, particularly the COX-2 isoform, within the central nervous system. Unlike NSAIDs, it has minimal effects on peripheral COX enzymes, explaining its lack of significant anti-inflammatory activity. Additional mechanisms may include modulation of the endocannabinoid system and effects on serotonergic pathways.
Indications
- Mild to moderate pain management (musculoskeletal pain, headache, dysmenorrhea, dental pain)
- Fever reduction
- Often used as first-line therapy for pain in patients with contraindications to NSAIDs
- Commonly included in combination products for cold and flu symptoms
Dosage and Administration
Adults: 325-650 mg every 4-6 hours or 1000 mg every 6-8 hours Maximum daily dose: 4000 mg in healthy adults (3000 mg daily recommended for certain populations) Pediatric dosing:- 10-15 mg/kg/dose every 4-6 hours
- Maximum: 75 mg/kg/day (not to exceed 4000 mg)
- Hepatic impairment: Reduce dose or avoid; maximum 2000 mg/day in significant impairment
- Renal impairment (CrCl <30 mL/min): Extend dosing interval to every 6-8 hours
- Elderly: Consider reduced dosing due to potential decreased hepatic metabolism
- Alcoholics: Maximum 2000 mg/day
Pharmacokinetics
Absorption: Rapid and nearly complete from GI tract; peak concentrations reached within 30-60 minutes Distribution: Widely distributed throughout body fluids; volume of distribution approximately 0.9 L/kg Metabolism: Primarily hepatic via glucuronidation (45-55%) and sulfation (20-30%); minor pathway (5-15%) involves CYP2E1 oxidation to toxic metabolite NAPQI Elimination: Half-life 1-4 hours; eliminated primarily in urine as conjugated metabolites Protein binding: 20-50% at therapeutic concentrationsContraindications
- Known hypersensitivity to acetaminophen
- Severe hepatic impairment or active liver disease
- Patients with G6PD deficiency (relative contraindication due to hemolysis risk)
Warnings and Precautions
Boxed Warning: Risk of severe liver injury and acute liver failure with overdose- Hepatotoxicity risk increased with:
- Chronic alcohol use - Pre-existing liver disease - Malnutrition or fasting states - Concomitant use of other hepatotoxic drugs
- Use with caution in patients with chronic alcoholism
- Risk of serious skin reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis)
- Use caution in patients with severe renal impairment (CrCl <30 mL/min)
Drug Interactions
Significant interactions:- Warfarin: Chronic high-dose acetaminophen may potentiate anticoagulant effect
- Alcohol: Chronic use increases risk of hepatotoxicity
- Isoniazid: Increases formation of toxic metabolite
- Barbiturates, carbamazepine, phenytoin: May enhance metabolism to toxic metabolite
- Cholestyramine: May decrease absorption if taken concomitantly
- Propranolol: May decrease metabolism of acetaminophen
Adverse Effects
Common (≥1%):- Nausea
- Constipation
- Pruritus
- Rash
- Hepatotoxicity (dose-dependent)
- Acute liver failure
- Blood dyscrasias (neutropenia, thrombocytopenia)
- Stevens-Johnson syndrome
- Toxic epidermal necrolysis
- Renal impairment (with massive overdose)
- Hypersensitivity reactions
Monitoring Parameters
- Hepatic function tests (with chronic use or in high-risk patients)
- Renal function in patients with pre-existing renal impairment
- Signs of hypersensitivity reactions
- Assessment of pain relief and functional improvement
- Monitoring for signs of overdose (nausea, vomiting, abdominal pain)
- INR monitoring in patients on warfarin with chronic acetaminophen use
Patient Education
- Adhere strictly to recommended dosing (do not exceed 4000 mg/day)
- Recognize that many combination products contain acetaminophen
- Avoid concurrent use with other acetaminophen-containing products
- Seek immediate medical attention if overdose suspected
- Avoid alcohol consumption during therapy
- Do not use for more than 10 days for pain or 3 days for fever without medical supervision
- Store safely away from children to prevent accidental ingestion
- Report any signs of allergic reaction (rash, itching, swelling)
- Understand that this medication does not reduce inflammation
References
1. FDA. Acetaminophen Prescribing Information. 2021. 2. Dart RC, Bailey E. Does therapeutic use of acetaminophen cause acute liver failure? Pharmacotherapy. 2007;27(9):1219-1230. 3. Graham GG, Davies MJ, Day RO, et al. The modern pharmacology of paracetamol: therapeutic actions, mechanism of action, metabolism, toxicity and recent pharmacological findings. Inflammopharmacology. 2013;21(3):201-232. 4. Watkins PB, Kaplowitz N, Slattery JT, et al. Aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily: a randomized controlled trial. JAMA. 2006;296(1):87-93. 5. American College of Gastroenterology Guidelines on Liver Chemistry Tests. Am J Gastroenterol. 2017;112(1):18-35. 6. Lexicomp Online, Acetaminophen Monograph. Wolters Kluwer Clinical Drug Information. 2023. 7. Micromedex Solutions, Acetaminophen Drug Information. IBM Watson Health. 2023.