1. Drug Name
Generic Name: Paracetamol
Brand Names: Tylenol, Panadol, Calpol, Dolo, Crocin
2. Drug Classification
Class: Analgesic, Antipyretic
Subclass: Para-aminophenol derivative
3. Mechanism of Action
Paracetamol’s precise mechanism of action is not entirely understood, but it is thought to exert its analgesic and antipyretic effects primarily in the central nervous system.
It inhibits the cyclooxygenase (COX) enzymes, particularly COX-2, and acts centrally to decrease the production of prostaglandins, which mediate pain and fever.
Unlike NSAIDs, paracetamol has minimal peripheral anti-inflammatory activity, as it does not inhibit COX enzymes in peripheral tissues to a significant extent.
It may also act on the cannabinoid (CB1) receptors indirectly and increase serotoninergic (5-HT) pathways in the brain, contributing to its analgesic effects.
4. Pharmacokinetics
Absorption: Paracetamol has good oral bioavailability (generally 70-90%), with peak plasma concentration achieved within 30 minutes to 2 hours after administration.
Distribution: Volume of distribution (Vd) is approximately 0.9 L/kg, with modest plasma protein binding (10-25%).
Metabolism: Primarily metabolized in the liver through glucuronidation and sulfation. A small fraction is metabolized via the CYP2E1 enzyme to form NAPQI (N-acetyl-p-benzoquinone imine), a toxic metabolite.
Excretion: Half-life (t½) is around 1-4 hours in healthy individuals; excreted mainly in the urine as conjugated metabolites.
Special Considerations: In cases of overdose or liver disease, paracetamol’s metabolism shifts, increasing NAPQI production, which can lead to hepatotoxicity.
5. Indications
Primary Indications:
Management of mild to moderate pain (e.g., headache, dental pain, osteoarthritis).
Reduction of fever in conditions like infections or post-vaccination.
Off-Label Uses:
As an adjunct in severe pain when combined with opioids or NSAIDs.
Specific Populations: Safe and effective in children, adults, and older adults when used within recommended doses; preferred antipyretic for pregnant women.
6. Dosage and Administration
Adults:
Typical dose is 500-1000 mg every 4-6 hours as needed; maximum dose should not exceed 4 grams per day.
Pediatric:
Dosage is typically weight-based, around 10-15 mg/kg every 4-6 hours, with a maximum of 60 mg/kg/day.
Route: Oral, rectal, and intravenous (IV) forms are available.
Dosing Adjustments:
Hepatic impairment: Reduce dose and increase dosing interval due to the risk of toxicity.
Renal impairment: Caution is needed in severe renal impairment with dose adjustment.
Maximum Safe Dose: Up to 4 grams per day in adults; lower in hepatic impairment (up to 2 grams per day recommended).
7. Contraindications
Absolute Contraindications:
Known hypersensitivity to paracetamol or its components.
Severe hepatic impairment or active liver disease.
Relative Contraindications:
Caution in chronic alcohol use, liver disease, or renal impairment due to the risk of toxicity.
8. Warnings and Precautions
Black Box Warning: There is a significant risk of severe liver injury at high doses or with chronic use.
Special Warnings:
Pregnancy: Generally considered safe but used at the lowest effective dose.
Lactation: Safe in breastfeeding as minimal amounts are transferred to breast milk.
Monitoring Parameters:
Liver function tests in patients using high doses or those with risk factors for hepatotoxicity (e.g., chronic alcohol use, malnutrition).
9. Adverse Effects
Common Adverse Effects (≥10%): Generally well-tolerated at therapeutic doses.
Less Common but Clinically Significant:
Nausea, rash, and hypersensitivity reactions.
Rare/Serious Adverse Reactions:
Hepatotoxicity, particularly in overdose.
Severe skin reactions (e.g., Stevens-Johnson Syndrome, toxic epidermal necrolysis), although rare.
10. Drug Interactions
Major Drug Interactions:
Warfarin: Chronic use may increase INR and bleeding risk.
Phenytoin, Carbamazepine, Rifampin: May induce CYP enzymes, increasing NAPQI production and hepatotoxicity risk.
Food-Drug Interactions: None significant, though absorption may be delayed with high-fat meals.
Interactions with Lab Tests: May cause minor increases in liver enzymes.
11. Clinical Pharmacology
Paracetamol’s pharmacodynamics are focused on its central analgesic and antipyretic effects without significant peripheral anti-inflammatory effects.
It lacks the gastrointestinal and platelet effects seen with NSAIDs due to its minimal COX-1 inhibition.
12. Special Populations
Pregnancy: Generally safe, with no evidence of teratogenic effects; however, use cautiously and at the lowest effective dose.
Lactation: Considered safe with minimal drug transfer to breast milk.
Geriatrics: Standard dosing generally safe; reduce dose if liver function is compromised.
Renal/Hepatic Dysfunction: Dose adjustments necessary in hepatic impairment; avoid or use cautiously in severe liver disease.
13. Therapeutic Uses
First-Line Therapy: Analgesic and antipyretic for mild pain and fever.
Second-Line or Adjunctive Therapy: Often combined with opioids for moderate to severe pain management, especially in postoperative or cancer pain.
14. Monitoring and Follow-Up
Recommended Lab Tests: Liver function tests for patients on long-term use or high doses.
Patient-Reported Symptom Checklists: Any signs of liver dysfunction (jaundice, fatigue, dark urine) should be reported.
Monitoring of Therapeutic and Toxic Levels: Clinically evaluate symptoms of toxicity if overdose is suspected.
15. Overdose Management
Symptoms of Overdose: Nausea, vomiting, abdominal pain, elevated liver enzymes, jaundice, and in severe cases, liver failure.
Treatment Protocols:
Activated charcoal within 1-2 hours of ingestion for recent overdose.
N-acetylcysteine (NAC) as an antidote; it replenishes glutathione to detoxify NAPQI.
Supportive care and frequent monitoring of liver function and coagulation status.
16. Patient Counseling Information
Warn patients about the maximum safe daily dose and the risks of combining with other paracetamol-containing medications.
Inform patients of early signs of liver damage, such as fatigue, loss of appetite, nausea, and jaundice, and advise them to seek medical attention if these occur.
Emphasize the importance of taking paracetamol with caution if they consume alcohol or have liver disease.