Paracetamol

Paracetamol, also known as acetaminophen, is a widely used over-the-counter (OTC) medication known for its analgesic (pain-relieving) and antipyretic (fever-reducing) properties. It is considered a first-line treatment for mild to moderate pain and fever due to its effectiveness and relatively safe profile when used appropriately. Unlike nonsteroidal anti-inflammatory drugs (NSAIDs), paracetamol has minimal anti-inflammatory activity and is less likely to cause gastrointestinal or cardiovascular side effects.

Indications Paracetamol is indicated for a variety of conditions, including:

• Pain Relief: Effective for mild to moderate pain, including headaches, migraines, toothaches, menstrual pain (dysmenorrhea), and musculoskeletal pain.
• Fever Reduction: Commonly used to manage fever in both adults and children, particularly during viral or bacterial infections.
• Arthritic Conditions: Provides symptomatic relief in osteoarthritis and other non-inflammatory joint disorders.
• Post-operative Pain: Used for managing pain following surgical procedures.
• Pediatric Use: Safe and effective for managing fever and mild pain in children.

Dosages Proper dosing is critical to ensure efficacy while avoiding toxicity.

• Adults:

  • Recommended dose: 500–1000 mg every 4–6 hours as needed.
  • Maximum daily dose: 4000 mg (4 grams).

• Children:

  • Dose: 10–15 mg/kg every 4–6 hours.
  • Maximum daily dose: Not exceeding 60 mg/kg/day.

• Special Populations:

  • In elderly individuals or those with liver impairment, the dose should be reduced to prevent toxicity.
  • Chronic alcohol users or individuals with malnutrition should also adhere to lower doses due to reduced liver function.

Contraindications Paracetamol is contraindicated in the following conditions:

• Allergy: Known hypersensitivity to paracetamol or its excipients.
• Severe Liver Disease: Conditions like cirrhosis or active hepatitis due to the risk of hepatotoxicity.
• Chronic Alcoholism: Increased risk of liver damage due to impaired metabolism.
• Glutathione Deficiency: Conditions such as malnutrition or chronic illnesses that reduce glutathione reserves.

Overdose Paracetamol overdose is a medical emergency that can lead to severe hepatotoxicity and acute liver failure.

• Pathophysiology: Overdose leads to saturation of the usual conjugation pathways (glucuronidation and sulfation), resulting in the accumulation of the toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI). Excessive NAPQI depletes hepatic glutathione, causing oxidative damage to liver cells.

• Symptoms:

  • Early signs (within 24 hours): Nausea, vomiting, abdominal pain, and lethargy.
  • Intermediate stage (24–48 hours): Elevated liver enzymes (AST, ALT), jaundice, and right upper quadrant pain.
  • Late stage (>72 hours): Hepatic encephalopathy, coagulopathy, and multi-organ failure.

Antidote

• N-acetylcysteine (NAC): The primary antidote for paracetamol overdose. NAC replenishes glutathione stores, aiding in the detoxification of NAPQI.
  • Most effective when administered within 8–10 hours of ingestion.
  • Can be given orally or intravenously, depending on clinical circumstances.
• Supportive Care: Includes monitoring of liver function tests, maintaining hydration, and, in severe cases, liver transplantation.

Mechanism of Action Paracetamol acts primarily in the central nervous system (CNS):

• Inhibits the enzyme cyclooxygenase (COX), predominantly COX-2, reducing the synthesis of prostaglandins, which mediate pain and fever.
• Unlike NSAIDs, paracetamol’s action is weak in peripheral tissues, accounting for its minimal anti-inflammatory effect.
• It also acts on serotonergic pathways in the CNS to enhance its analgesic effect.

Plasma Half-Life

• The plasma half-life of paracetamol is approximately 1.5 to 3 hours in healthy individuals.
• In overdose or liver dysfunction, the half-life can extend significantly, leading to prolonged toxicity.

Pharmacodynamics

• Analgesic Effect: Paracetamol effectively reduces pain by decreasing prostaglandin synthesis in the CNS, thereby altering the perception of pain.
• Antipyretic Effect: It lowers fever by acting on the hypothalamic heat-regulating center, leading to increased heat dissipation through sweating and vasodilation.
• Advantages:
  • Does not affect platelet aggregation.
  • Minimal gastrointestinal irritation compared to NSAIDs.

Pharmacokinetics

• Absorption: Rapidly absorbed from the gastrointestinal tract, with peak plasma concentrations occurring 30–60 minutes after oral administration.
• Distribution: Widely distributed throughout body tissues and fluids. Crosses the blood-brain barrier effectively.
• Metabolism:
  • Major pathways: Conjugation with glucuronide and sulfate (90% of metabolism).
  • Minor pathway: Metabolism via cytochrome P450 enzymes to form NAPQI, which is detoxified by glutathione.
• Excretion: Primarily excreted in urine as glucuronide and sulfate conjugates. Less than 5% is excreted unchanged.

Conclusion Paracetamol is a cornerstone medication for managing pain and fever. Its widespread availability and well-tolerated nature make it an essential drug in clinical practice. However, careful adherence to dosing guidelines is vital to avoid severe complications such as hepatotoxicity. Understanding its pharmacology, indications, and the management of overdose ensures its safe and effective use. Regular education about its proper usage can help mitigate the risks associated with misuse.