Introduction
Paracetamol (also known as acetaminophen) is one of the most widely used over-the-counter analgesic and antipyretic medications worldwide. First introduced into clinical practice in the 1950s, it has become a first-line treatment for mild to moderate pain and fever across all age groups. Unlike NSAIDs, paracetamol possesses minimal anti-inflammatory properties and is generally better tolerated with fewer gastrointestinal side effects.
Mechanism of Action
The exact mechanism of paracetamol's analgesic and antipyretic effects is not fully understood, but it is believed to work primarily through central nervous system actions. The drug is thought to inhibit prostaglandin synthesis by blocking cyclooxygenase (COX) enzymes, particularly the COX-2 isoform, within the central nervous system. Unlike NSAIDs, paracetamol has minimal effects on peripheral COX enzymes, explaining its lack of significant anti-inflammatory activity. Additional proposed mechanisms include modulation of the descending serotonergic pathways and potential effects on the endocannabinoid system.
Indications
- Management of mild to moderate pain (including headache, musculoskeletal pain, dysmenorrhea)
- Reduction of fever
- Off-label use as an adjunct for postoperative pain management
- Part of multimodal analgesia regimens
Dosage and Administration
Adults: 325-1000 mg every 4-6 hours as needed, not to exceed 4000 mg daily Maximum daily dose: 4000 mg (lower in specific populations) Special Populations:- Hepatic impairment: Reduce dose or avoid; maximum 2000 mg daily in significant impairment
- Renal impairment (CrCl 10-50 mL/min): Dosing interval every 6 hours
- Elderly: Consider reduced dosing due to possible decreased clearance
- Pediatrics: 10-15 mg/kg/dose every 4-6 hours, not to exceed 75 mg/kg/day or 4000 mg/day
Pharmacokinetics
Absorption: Rapid and nearly complete from GI tract; peak concentrations within 30-60 minutes (oral) Distribution: Widely distributed throughout most body tissues; Vd ≈ 0.9 L/kg; crosses placenta and enters breast milk Metabolism: Primarily hepatic via glucuronidation (40-67%) and sulfation (20-46%); minor pathway (5-15%) involves CYP450 enzymes (mainly CYP2E1) producing toxic metabolite NAPQI Elimination: Half-life 1-4 hours; 85-95% excreted in urine as metabolites within 24 hoursContraindications
- Known hypersensitivity to paracetamol or any product components
- Severe hepatic impairment (Child-Pugh Class C)
- Patients with severe active liver disease
- Use of other paracetamol-containing products (risk of overdose)
Warnings and Precautions
Hepatotoxicity: Risk of serious liver injury with overdose; early signs may be nonspecific Alcohol use: Chronic alcoholics should not exceed 2000 mg daily due to increased hepatotoxicity risk Malnutrition: Patients with chronic malnutrition or hypovolemia at increased risk G6PD deficiency: Use with caution due to potential hemolytic risk IV formulation: Monitor for hypersensitivity reactions, especially with initial infusionDrug Interactions
Enzyme inducers: Rifampin, carbamazepine, phenytoin, barbiturates - may increase formation of toxic metabolite Warfarin: Chronic high-dose paracetamol may potentiate anticoagulant effect (monitor INR) Isoniazid: May increase hepatotoxicity risk Cholestyramine: Reduces absorption if taken within 1 hour Probenecid: May decrease paracetamol conjugation Alcohol: Chronic use increases hepatotoxicity riskAdverse Effects
Common (>1%): Nausea, vomiting, constipation, headache, insomnia Rare but serious:- Hepatotoxicity (dose-dependent)
- Stevens-Johnson syndrome, toxic epidermal necrolysis
- Agranulocytosis, thrombocytopenia
- Acute renal failure (with overdose)
- Hypersensitivity reactions including anaphylaxis
- Metabolic acidosis (with massive overdose)
Monitoring Parameters
- Hepatic function (especially with chronic use or high doses)
- Renal function in susceptible patients
- Signs of overdose (nausea, vomiting, abdominal pain)
- Analgesic efficacy and pain scores
- Fever reduction in antipyretic use
- Adherence to dosing limits in at-risk populations
Patient Education
- Do not exceed recommended dosage (read all product labels)
- Recognize maximum daily limits (4000 mg for healthy adults)
- Avoid concurrent use of multiple paracetamol-containing products
- Seek immediate medical attention if overdose suspected, even if asymptomatic
- Do not use with alcohol (three or more drinks daily)
- Store safely away from children
- Report any signs of allergic reaction or liver problems (yellowing skin/eyes, dark urine, abdominal pain)
- Understand that paracetamol does not reduce inflammation like NSAIDs
References
1. 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. 2. FDA. Acetaminophen Information. https://www.fda.gov/drugs/information-drug-class/acetaminophen-information 3. Prescott LF. Paracetamol: past, present, and future. Am J Ther. 2000;7(2):143-147. 4. Dart RC, Bailey E. Does therapeutic use of acetaminophen cause acute liver failure?. Pharmacotherapy. 2007;27(9):1219-1230. 5. Hodgman MJ, Garrard AR. A review of acetaminophen poisoning. Crit Care Clin. 2012;28(4):499-516. 6. Micromedex® Healthcare Series. Acetaminophen Drug Monograph. IBM Watson Health. 7. UpToDate. Acetaminophen (paracetamol): Drug information. Wolters Kluwer Clinical Drug Information.