Indomethacin

Usage

Indomethacin is prescribed for various medical conditions involving inflammation, pain, and fever. These include:

• Osteoarthritis
• Rheumatoid arthritis
• Ankylosing spondylitis
• Acute gouty arthritis
• Bursitis/Tendinitis
• Acute painful shoulder
• Pain (mild to moderate)
• Dysmenorrhea (period pain)
• Patent ductus arteriosus (in premature infants).

Pharmacological Classification: Non-Steroidal Anti-Inflammatory Drug (NSAID)

Mechanism of Action: Indomethacin inhibits cyclooxygenase (COX) enzymes, primarily COX-1 and COX-2. These enzymes are responsible for producing prostaglandins, which mediate inflammation, pain, and fever. By inhibiting COX, indomethacin reduces prostaglandin synthesis, thereby alleviating these symptoms.

Alternate Names

• Indometacin (International Nonproprietary Name - INN)

Brand Names:

• Indocin
• Indocid
• Tivorbex (for acute pain)

How It Works

Pharmacodynamics: Indomethacin’s primary effect is to reduce inflammation, pain, and fever by inhibiting prostaglandin synthesis. It binds to and inhibits COX-1 and COX-2 enzymes, leading to a decrease in prostaglandin production.

Pharmacokinetics:

• Absorption: Indomethacin is well-absorbed after oral administration. Food can slow down absorption but increases bioavailability. Rectal administration shows good absorption.
• Metabolism: Extensively metabolized in the liver, primarily by O-demethylation. Several metabolites are formed, including desmethylindomethacin.
• Elimination: Primarily eliminated through renal excretion (approximately 60%) as metabolites and unchanged drug. About 33% is excreted in feces.

Mode of Action: Indomethacin competitively inhibits COX-1 and COX-2 enzymes by binding to their active sites. This prevents the conversion of arachidonic acid to prostaglandins, thus reducing inflammation, pain, and fever.

Receptor Binding, Enzyme Inhibition, or Neurotransmitter Modulation: Indomethacin primarily acts through enzyme inhibition (COX-1 and COX-2). It does not directly bind to receptors or modulate neurotransmitters.

Elimination Pathways: Renal excretion (as metabolites and unchanged drug) and hepatic excretion via biliary route.

Dosage

Standard Dosage

Adults:

• Osteoarthritis, Rheumatoid Arthritis, Ankylosing Spondylitis: Initial: 25 mg orally 2-3 times/day. Increase by 25-50 mg weekly intervals as needed, up to a maximum of 200 mg/day. Extended-release capsules: 75 mg once or twice daily, maximum 150 mg/day.
• Acute Painful Shoulder: 75-150 mg/day orally in 3-4 divided doses for 1-2 weeks.
• Acute Gouty Arthritis: 50 mg orally 3 times/day until pain subsides, then taper rapidly. Do not use extended-release.
• Mild to Moderate Acute Pain: 20 mg orally 3 times/day or 40 mg 2-3 times/day (Tivorbex formulation).
• Dysmenorrhea: 25 mg every 8 hours starting with onset of bleeding or cramps.

Children:

• 2-14 years: 1-2 mg/kg/day orally divided every 6-12 hours, not to exceed 4 mg/kg/day or 200 mg/day.
• Over 14 years: Same as adult dosing.
• Patent Ductus Arteriosus: IV administration; dosing varies based on postnatal age.

Special Cases:

• Elderly Patients: Start with lower doses and monitor closely for adverse events.
• Patients with Renal Impairment: Use with caution; dose adjustment may be needed.
• Patients with Hepatic Dysfunction: Use with caution; dose adjustment may be needed.
• Patients with Comorbid Conditions: Close monitoring is advised, especially for those with cardiovascular disease, hypertension, or history of gastrointestinal bleeding.

Clinical Use Cases

Indomethacin is not typically used for intubation, surgical procedures, mechanical ventilation, or routine ICU use. While it might be used for pain management post-operatively, there are typically safer alternatives. It’s not indicated for emergency situations like status epilepticus or cardiac arrest. Its primary use is in the management of inflammatory conditions, pain, and gout as outlined above.

Dosage Adjustments

Dose modifications may be required for patients with renal/hepatic dysfunction, pre-existing medical conditions, or those taking interacting drugs.

Side Effects

Common Side Effects:

• Headache
• Dizziness
• Nausea
• Vomiting
• Heartburn
• Diarrhea
• Constipation
• Abdominal pain

Rare but Serious Side Effects:

• Gastrointestinal bleeding
• Peptic ulcer
• Heart attack
• Stroke
• Stevens-Johnson Syndrome
• Toxic Epidermal Necrolysis
• Renal failure
• Hepatotoxicity

Long-Term Effects: With prolonged use, increased risk of gastrointestinal issues, cardiovascular events, and renal damage.

Adverse Drug Reactions (ADR): Anaphylaxis, angioedema, severe skin reactions, bone marrow suppression.

Contraindications

• Hypersensitivity to indomethacin, aspirin, or other NSAIDs
• History of asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs.
• Active peptic ulcer disease
• History of gastrointestinal bleeding
• Third trimester of pregnancy
• Peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery.

Drug Interactions

Indomethacin interacts with numerous medications. Here’s a partial list:

• Anticoagulants (warfarin): Increased bleeding risk
• Antihypertensives: Reduced effectiveness
• Aspirin and other NSAIDs: Increased risk of gastrointestinal side effects
• Corticosteroids: Increased risk of gastrointestinal ulceration
• Lithium: Increased lithium levels
• Methotrexate: Increased methotrexate toxicity
• Diuretics: Reduced diuretic effect

CYP450 interactions can occur, and indomethacin is metabolized by CYP2C9.

Pregnancy and Breastfeeding

• Pregnancy Safety Category: D (after 30 weeks)
• Fetal Risks: Premature closure of the ductus arteriosus, prolonged labor, increased risk of bleeding.
• Breastfeeding: Small amounts are present in breast milk, potentially causing side effects in infants. Use with caution and only if benefits outweigh the risks.

Drug Profile Summary

• Mechanism of Action: Inhibits COX-1 and COX-2 enzymes, reducing prostaglandin synthesis.
• Side Effects: Headache, dizziness, gastrointestinal issues, serious cardiovascular events, renal damage.
• Contraindications: Hypersensitivity to NSAIDs, peptic ulcer, pregnancy (third trimester), CABG surgery.
• Drug Interactions: Numerous, including anticoagulants, antihypertensives, other NSAIDs.
• Pregnancy & Breastfeeding: Avoid in third trimester; use cautiously during breastfeeding.
• Dosage: Varies by indication and age; see dosage section.
• Monitoring Parameters: Renal function, liver function, blood pressure, signs of gastrointestinal bleeding.

Popular Combinations

Indomethacin is sometimes used in combination with other analgesics for enhanced pain relief, but this must be carefully balanced with the risk of increased side effects. It’s essential to monitor for adverse events and consider alternative strategies when appropriate.

Precautions

• General Precautions: Careful patient selection, pre-screening for conditions like peptic ulcers and bleeding disorders.
• Specific Populations: Avoid in pregnancy (third trimester); caution in elderly, breastfeeding mothers, and children.
• Lifestyle Considerations: Avoid alcohol, monitor blood pressure.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Indomethacin?

A: Dosage varies based on the indication and patient characteristics. See detailed dosage section above.

Q2: What are the most common side effects?

A: Headache, dizziness, nausea, vomiting, heartburn, diarrhea, and constipation are common.

Q3: What are the serious side effects of indomethacin?

A: Gastrointestinal bleeding, peptic ulcers, heart attack, stroke, and allergic reactions are serious potential side effects.

Q4: Can Indomethacin be used in pregnancy?

A: It’s contraindicated in the third trimester. Use with extreme caution earlier in pregnancy.

Q5: How does Indomethacin work?

A: It inhibits COX-1 and COX-2 enzymes, reducing prostaglandin synthesis.

Q6: Can Indomethacin be used with other NSAIDs like aspirin?

A: Combining with other NSAIDs increases the risk of gastrointestinal side effects and is generally avoided.

Q7: Does Indomethacin interact with other medications?

A: It interacts with numerous medications, including anticoagulants, antihypertensives, and lithium. Consult a comprehensive drug interaction resource for details.

Q8: Is Indomethacin safe for long-term use?

A: Long-term use carries increased risks of gastrointestinal and cardiovascular side effects. Use the lowest effective dose for the shortest duration possible.

Q9: What are the contraindications for Indomethacin?

A: Contraindications include hypersensitivity to NSAIDs, active peptic ulcer, pregnancy (third trimester), and CABG surgery.

Q10: What should patients be monitored for while taking indomethacin?

A: Patients should be monitored for signs of gastrointestinal bleeding, renal impairment, changes in blood pressure, and any allergic reactions.