Paracetamol

Usage

• Paracetamol is prescribed for the relief of mild to moderate pain (analgesic) and the reduction of fever (antipyretic). It is commonly used to treat headaches, muscle aches, backaches, toothaches, menstrual cramps, and fever associated with colds or flu.
• Pharmacological Classification: Analgesic, Antipyretic, Non-opioid, Non-steroidal anti-inflammatory drug (NSAID) - although its anti-inflammatory effects are weak compared to other NSAIDs.
• Mechanism of Action: Paracetamol’s precise mechanism of action is not fully understood. It is thought to inhibit cyclooxygenase (COX) enzymes in the central nervous system, reducing prostaglandin synthesis, which plays a key role in pain and fever. It has minimal effect on peripheral COX enzymes, hence its weak anti-inflammatory action and lack of gastrointestinal side effects associated with traditional NSAIDs.

Alternate Names

• Acetaminophen (primarily used in the United States, Canada, Japan, South Korea, Hong Kong, and Iran).
• Brand Names: Crocin, Calpol, Dolo, Panadol, Tylenol (and many others - brand names vary significantly by region).

How It Works

• Pharmacodynamics: Paracetamol exerts its analgesic and antipyretic effects centrally by inhibiting COX enzymes, primarily COX-3, a variant found predominantly in the brain. This reduces the formation of prostaglandins, which mediate pain and fever signals. Paracetamol’s weak peripheral COX inhibition minimizes effects on platelet function and inflammation.
• Pharmacokinetics:
  • Absorption: Rapidly absorbed from the gastrointestinal tract after oral administration. Peak plasma concentrations reached within 30-60 minutes. Rectal administration has slower and less predictable absorption. Intravenous administration delivers 100% bioavailability.
  • Metabolism: Primarily metabolized in the liver by conjugation with glucuronic acid and sulfate. A small portion is metabolized by CYP450 enzymes, forming a potentially hepatotoxic metabolite, N-acetyl-p-benzoquinone imine (NAPQI). At therapeutic doses, NAPQI is detoxified by conjugation with glutathione.
  • Elimination: Excreted mainly in the urine as glucuronide and sulfate conjugates. A small amount is excreted as unchanged paracetamol. Elimination half-life is typically 1-4 hours, prolonged in patients with liver disease or overdose.
• Mode of Action: Paracetamol’s primary mode of action involves central COX inhibition, particularly COX-3, reducing prostaglandin synthesis. It also may affect endogenous cannabinoid and serotonergic pathways.
• Receptor Binding/Enzyme Inhibition/Neurotransmitter Modulation: Primarily COX-3 inhibition within the CNS. Possible modulation of the endocannabinoid and serotonergic systems.
• Elimination Pathways: Primarily renal excretion of glucuronide and sulfate conjugates. Hepatic metabolism plays a crucial role, especially in detoxifying NAPQI.

Dosage

Standard Dosage

Adults:

• 500mg-1000mg every 4-6 hours as needed.
• Maximum daily dose: 4000mg (4g) in 24 hours.

Children:

• 15mg/kg/dose every 4-6 hours as needed.
• Maximum daily dose: 60mg/kg/day (not exceeding 4g/day).
• Use weight-based dosing and appropriate formulations (e.g., syrups, suspensions) for children.

Special Cases:

• Elderly Patients: Standard dosage, but monitor for adverse effects and consider lower doses for frail elderly patients. Avoid exceeding 3g daily in patients at risk for hepatotoxicity.
• Patients with Renal Impairment: Adjust dosing interval to every 6-8 hours if creatinine clearance is <30 mL/min. Reduce daily dose to 2-3 grams, especially with long-term use.
• Patients with Hepatic Dysfunction: Reduce daily dose based on severity of impairment. Avoid exceeding 2-3g daily in patients with chronic liver disease or history of alcohol abuse. Contraindicated in severe liver failure.
• Patients with Comorbid Conditions: Consider dose reductions in malnourished, dehydrated, and chronically ill patients. Consult specialists if necessary.

Clinical Use Cases

• Intubation: Paracetamol can be used as part of a multimodal analgesic regimen to manage post-intubation pain.
• Surgical Procedures: Commonly used for postoperative pain management, often in combination with opioids and/or NSAIDs. Intravenous paracetamol is preferred in the immediate postoperative period when oral intake is restricted.
• Mechanical Ventilation: May be used to control fever and discomfort associated with mechanical ventilation.
• Intensive Care Unit (ICU) Use: Frequently used for analgesia and fever control in critically ill patients. Dosage adjustments are crucial in this population.
• Emergency Situations: Limited role in most emergencies. Not the first-line agent for status epilepticus or cardiac arrest but may be used to treat fever if present.

Dosage Adjustments

• Always consider renal and hepatic function when adjusting dosages.
• Reduce doses in malnourished, chronically ill patients.

Side Effects

Common Side Effects

• Generally well-tolerated. Rarely, allergic skin reactions (rash, itching) may occur.

Rare but Serious Side Effects

• Hepatotoxicity (liver damage) with overdose or in susceptible individuals.
• Severe allergic reactions (anaphylaxis, Stevens-Johnson syndrome).
• Blood disorders (thrombocytopenia, neutropenia).

Long-Term Effects

• Potential for renal impairment with chronic high-dose use.

Adverse Drug Reactions (ADR)

• Hepatotoxicity, severe allergic reactions, blood dyscrasias require immediate attention.

Contraindications

• Hypersensitivity to paracetamol.
• Severe liver failure.
• Acute alcohol intoxication.

Drug Interactions

• Alcohol: Chronic excessive alcohol use increases the risk of hepatotoxicity.
• Warfarin: May enhance anticoagulant effects.
• Anticonvulsants (e.g., phenytoin, carbamazepine): May increase the risk of hepatotoxicity.
• Isoniazid: Increased risk of hepatotoxicity.
• Cholestyramine: May decrease paracetamol absorption.

Pregnancy and Breastfeeding

• Considered safe for use during pregnancy and breastfeeding at recommended doses.
• Use the lowest effective dose for the shortest duration.

Drug Profile Summary

• Mechanism of Action: Central COX inhibition, reducing prostaglandin synthesis.
• Side Effects: Generally well-tolerated. Rarely, allergic reactions and hepatotoxicity (with overdose).
• Contraindications: Hypersensitivity, severe liver failure.
• Drug Interactions: Alcohol, warfarin, anticonvulsants, isoniazid.
• Pregnancy & Breastfeeding: Generally safe at recommended doses.
• Dosage: Adults: 500mg-1000mg q4-6h (max 4g/day); Children: 15mg/kg/dose q4-6h (max 60mg/kg/day).
• Monitoring Parameters: Liver function tests (LFTs) in patients with liver disease or taking high doses.

Popular Combinations

• Paracetamol + Codeine: Enhanced analgesia for moderate to severe pain.
• Paracetamol + Ibuprofen: Synergistic analgesic and antipyretic effects.
• Paracetamol + Caffeine: Enhanced analgesia, particularly for headaches.

Precautions

• General Precautions: Assess liver and kidney function in patients with pre-existing disease. Avoid exceeding maximum daily dose.
• Specific Populations: Use with caution in patients with liver or kidney disease. Standard doses are considered safe in pregnancy and breastfeeding.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Paracetamol?

A: Adults: 500mg-1000mg every 4-6 hours as needed (max 4g/day). Children: 15mg/kg/dose every 4-6 hours (max 60mg/kg/day).

Q2: How does Paracetamol work?

A: It inhibits COX enzymes in the CNS, reducing prostaglandin production, which mediates pain and fever.

Q3: What are the common side effects of Paracetamol?

A: Generally well-tolerated, with rare allergic skin reactions.

Q4: Is Paracetamol safe during pregnancy?

A: Yes, at recommended doses.

Q5: Can I take Paracetamol with alcohol?

A: Chronic excessive alcohol use should be avoided as it increases the risk of liver damage.

Q6: What should I do if a patient overdoses on Paracetamol?

A: Immediate medical attention is required. N-acetylcysteine is the antidote.

Q7: Can Paracetamol be given intravenously?

A: Yes, IV paracetamol is available for patients who cannot tolerate oral administration.

Q8: What are the signs of Paracetamol toxicity?

A: Nausea, vomiting, abdominal pain, jaundice, hepatic encephalopathy.

Q9: Does Paracetamol have anti-inflammatory properties?

A: It has weak anti-inflammatory effects compared to other NSAIDs.

Q10: Can Paracetamol be used for children?

A: Yes, weight-based dosing is essential. Use appropriate formulations like syrups. Pediatric safety considerations should always be considered.