Paracetamol/Acetaminophen

Usage

Paracetamol is prescribed for the relief of mild to moderate pain, such as headaches, muscle aches, menstrual cramps, backache, toothache, and pain associated with colds and flu. It also reduces fever. Its pharmacological classifications include analgesic (pain reliever) and antipyretic (fever reducer). Paracetamol’s mechanism of action is thought to involve inhibition of prostaglandin synthesis in the central nervous system, affecting the hypothalamic heat-regulating center and pain threshold. However, it lacks significant anti-inflammatory effects.

Alternate Names

• International Nonproprietary Name (INN): Paracetamol
• United States Adopted Name (USAN) and British Approved Name (BAN): Acetaminophen
• Brand Names: Panadol, Tylenol, Calpol (and many others depending on region and formulation)

How It Works

Pharmacodynamics: Paracetamol exerts its analgesic and antipyretic effects primarily through central inhibition of prostaglandin synthesis. It raises the pain threshold and acts on the hypothalamic heat-regulating center.

Pharmacokinetics:

• Absorption: Paracetamol is readily absorbed from the gastrointestinal tract, reaching peak plasma concentrations within 30-60 minutes after oral administration.
• Distribution: It distributes widely throughout most body tissues. Plasma protein binding is minimal at therapeutic doses.
• Metabolism: Paracetamol is extensively metabolized in the liver, primarily via glucuronidation and sulfation pathways. A minor pathway involves a hepatotoxic intermediate metabolite, N-acetyl-p-benzoquinone imine (NAPQI). At therapeutic doses, NAPQI is detoxified by conjugation with glutathione.
• Elimination: Paracetamol metabolites are excreted primarily in the urine. Less than 5% is excreted unchanged. The elimination half-life is typically 1-4 hours.

Mode of Action: Paracetamol is believed to act primarily within the central nervous system by inhibiting cyclooxygenase (COX) enzymes, particularly COX-2, though the exact mechanism of action is not fully understood. The inhibition of COX-3, a variant of COX-1, is also considered. This leads to reduced prostaglandin synthesis in the brain, which affects the hypothalamic temperature-regulating center for antipyresis and pain perception pathways for analgesia.

Dosage

Standard Dosage

Adults: 500-1000 mg orally every 4-6 hours, not to exceed 4000 mg (4g) in 24 hours.

Children: 15 mg/kg orally every 4-6 hours, not to exceed 60mg/kg in 24 hours. For neonates and infants under 1 month, specialist advice should be sought.

Special Cases:

• Elderly Patients: The standard adult dose is usually appropriate, but some sources recommend considering lower doses or increased dosing intervals for frail or low-weight elderly patients.
• Patients with Renal Impairment: Dose adjustment might be necessary depending on the severity of impairment. Increased dosing interval is generally recommended.
• Patients with Hepatic Dysfunction: Dose reduction or increased dosing intervals are necessary due to impaired metabolic capacity.
• Patients with Comorbid Conditions: Consider underlying conditions (e.g., malnutrition, chronic alcohol use) that may increase the risk of hepatotoxicity. Dose adjustments may be necessary.

Clinical Use Cases

Dosing recommendations for specific clinical settings such as intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations should be guided by the patient’s condition, weight, and organ function, always staying within the maximum daily dose and considering potential drug interactions. The drug can be administered intravenously in these settings if oral administration is not feasible.

Dosage Adjustments

Dosage adjustments are often based on patient-specific factors, including age, weight, renal or hepatic function, concomitant medications, and other health conditions. Genetic polymorphisms affecting drug metabolism should also be considered if known.

Side Effects

Common Side Effects:

Generally well-tolerated. Nausea, vomiting, and constipation have been reported, as well as injection site reactions with IV administration.

Rare but Serious Side Effects:

Rare allergic reactions (skin rash, itching, swelling), hepatotoxicity (liver damage) with excessive doses.

Long-Term Effects:

Chronic liver damage can result from prolonged high doses.

Adverse Drug Reactions (ADR):

Severe allergic reactions (anaphylaxis), Stevens-Johnson syndrome (rare), toxic epidermal necrolysis (rare), acute liver failure (with overdose).

Contraindications

Hypersensitivity to paracetamol, severe hepatic impairment, severe active liver disease.

Drug Interactions

• Warfarin: Chronic, high-dose paracetamol may enhance warfarin’s anticoagulant effect.
• Alcohol: Chronic excessive alcohol use increases the risk of hepatotoxicity.
• Enzyme-inducing drugs: Drugs that induce liver enzymes, such as carbamazepine, phenytoin, rifampicin, and St. John’s Wort, can increase the formation of NAPQI and elevate the risk of hepatotoxicity.
• Cholestyramine: Reduces paracetamol absorption.
• Metoclopramide, domperidone: May enhance paracetamol absorption.
• Isoniazid: May increase the risk of hepatotoxicity.

Pregnancy and Breastfeeding

Paracetamol is generally considered safe during pregnancy and breastfeeding. It is the preferred analgesic and antipyretic in these situations. However, it’s crucial to use the lowest effective dose for the shortest duration and consult a healthcare professional before use.

Drug Profile Summary

• Mechanism of Action: Central inhibition of prostaglandin synthesis.
• Side Effects: Generally well-tolerated; rare allergic reactions and hepatotoxicity (with overdose).
• Contraindications: Hypersensitivity, severe hepatic impairment.
• Drug Interactions: Warfarin, alcohol, enzyme-inducing drugs, cholestyramine.
• Pregnancy & Breastfeeding: Generally considered safe.
• Dosage: Adults: 500-1000 mg every 4-6 hours (max 4g/day); Children: 15 mg/kg every 4-6 hours.
• Monitoring Parameters: Liver function tests (if prolonged use or high doses).

Popular Combinations

Paracetamol is often combined with other analgesics like codeine or ibuprofen to provide enhanced pain relief. It may also be included in formulations for cold and flu relief.

Precautions

Assess liver and kidney function, especially in patients with existing impairment or risk factors. Caution is advised in individuals with malnutrition, dehydration, or chronic alcohol use. Avoid exceeding the maximum daily dose.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Paracetamol/Acetaminophen?

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

Q2: Can I take Paracetamol while pregnant or breastfeeding?

A: Paracetamol is generally considered safe during pregnancy and breastfeeding. However, consult your doctor before taking any medication.

Q3: How does Paracetamol work?

A: It primarily works by inhibiting prostaglandin synthesis in the central nervous system, reducing pain and fever.

Q4: What are the common side effects of Paracetamol?

A: Paracetamol is generally well-tolerated. Side effects are uncommon but can include nausea, vomiting, and constipation.

Q5: What are the signs of a Paracetamol overdose?

A: Signs of overdose can include nausea, vomiting, abdominal pain, loss of appetite, sweating, and confusion. Severe overdose can lead to liver failure.

Q6: What should I do if I suspect a Paracetamol overdose?

A: Seek immediate medical attention. Early treatment is crucial to minimize the risk of liver damage.

Q7: Can I take Paracetamol with other medications?

A: Some medications can interact with paracetamol. Consult your doctor or pharmacist about potential drug interactions.

Q8: Is Paracetamol an anti-inflammatory drug?

A: Paracetamol has minimal anti-inflammatory effects. It is primarily an analgesic and antipyretic.

Q9: How long does it take for Paracetamol to work?

A: Paracetamol typically starts working within 30-60 minutes after oral administration.

Q10: What should I tell my patients about Paracetamol use?

A: Advise patients to adhere to the recommended dosage, avoid exceeding the maximum daily dose, and be aware of potential drug interactions. Inform them to seek medical advice if they have any concerns or experience any adverse effects.