Introduction
Tylenol (acetaminophen/paracetamol) is one of the most widely used over-the-counter analgesic and antipyretic medications worldwide. First introduced in 1955, it has become a mainstay in pain management and fever reduction due to its favorable safety profile when used appropriately and minimal gastrointestinal side effects compared to NSAIDs.
Mechanism of Action
Acetaminophen exerts its analgesic and antipyretic effects primarily through central nervous system mechanisms. It acts as a weak inhibitor of prostaglandin synthesis in the central nervous system via inhibition of cyclooxygenase (COX) enzymes, particularly the COX-2 variant. Unlike NSAIDs, it has minimal peripheral anti-inflammatory activity. Recent research suggests additional mechanisms may involve modulation of the endocannabinoid system and serotonergic pathways.
Indications
- Mild to moderate pain management (headache, musculoskeletal pain, dental pain, dysmenorrhea)
- Reduction of fever
- Often used as first-line therapy for pain in patients with contraindications to NSAIDs
- May be used in combination with opioids for moderate to severe pain
Dosage and Administration
Adults: 325-650 mg every 4-6 hours or 1000 mg every 6-8 hours Maximum daily dose: 4000 mg (healthy adults); 3000 mg daily recommended for certain populations Special populations:- Hepatic impairment: Reduce dose or avoid use
- Renal impairment (CrCl <30 mL/min): Extend dosing interval to every 8 hours
- Elderly: Consider reduced maximum daily dose (3000 mg)
- Pediatrics: 10-15 mg/kg every 4-6 hours (maximum 75 mg/kg/day)
Available formulations: tablets, capsules, liquid, suppositories, and intravenous (Ofirmev)
Pharmacokinetics
Absorption: Rapid and complete from GI tract; peak concentrations in 30-60 minutes Distribution: Widely distributed throughout body fluids; volume of distribution approximately 0.9 L/kg Metabolism: Primarily hepatic via glucuronidation (55-60%) and sulfation (30-35%); minor pathway via CYP2E1 produces toxic metabolite NAPQI Elimination: Half-life 1-4 hours; excreted primarily in urine as metabolitesContraindications
- Known hypersensitivity to acetaminophen
- Severe hepatic impairment
- Use with other acetaminophen-containing products
Warnings and Precautions
Boxed Warning: Risk of severe liver injury with overdose- Hepatotoxicity may occur with doses exceeding 4000 mg/day
- Risk increased with chronic alcohol use, malnutrition, dehydration, and liver disease
- Use with caution in patients with chronic alcoholism
- Do not use in patients with severe active liver disease
Drug Interactions
- Alcohol: Chronic use increases risk of hepatotoxicity
- Warfarin: May potentiate anticoagulant effect with chronic high-dose acetaminophen
- Isoniazid: Increases risk of hepatotoxicity
- Phenobarbital, carbamazepine: May enhance formation of toxic metabolite
- Cholestyramine: May decrease absorption
Adverse Effects
Common (≥1%):- Nausea
- Constipation
- Pruritus
- Headache
- Insomnia
- Hepatotoxicity (dose-dependent)
- Acute liver failure
- Stevens-Johnson syndrome (rare)
- Toxic epidermal necrolysis (rare)
- Agranulocytosis (rare)
- Thrombocytopenia (rare)
Monitoring Parameters
- Liver function tests (AST, ALT, bilirubin) with chronic use or high doses
- Signs of hepatotoxicity (nausea, vomiting, abdominal pain, jaundice)
- Analgesic efficacy and pain scores
- Fever reduction in antipyretic use
- Renal function in patients with pre-existing impairment
Patient Education
- Do not exceed recommended dosage (maximum 4000 mg/day for most adults)
- Be aware of acetaminophen content in combination products (cold medications, prescription pain relievers)
- Avoid concurrent alcohol consumption
- Seek immediate medical attention if signs of liver problems occur (yellowing skin/eyes, dark urine, abdominal pain)
- Do not use for more than 10 days for pain or 3 days for fever without consulting healthcare provider
- Use appropriate measuring devices for liquid formulations
- Store safely away from children to prevent accidental ingestion
References
1. Acetaminophen. In: Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Updated 2023. 2. FDA Drug Safety Communication: FDA warns of rare but serious skin reactions with the pain reliever/fever reducer acetaminophen. U.S. Food and Drug Administration. 2013. 3. Dart RC, et al. Acetaminophen poisoning: an evidence-based consensus guideline for out-of-hospital management. Clin Toxicol (Phila). 2006;44(1):1-18. 4. Watkins PB, et al. Aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily: a randomized controlled trial. JAMA. 2006;296(1):87-93. 5. Graham GG, et al. The modern pharmacology of paracetamol: therapeutic actions, mechanism of action, pharmacokinetics, and safety. Inflammopharmacology. 2020;28(5):1125-1146. 6. Prescott LF. Paracetamol: past, present, and future. Am J Ther. 2000;7(2):143-147.