INDOMETHACIN

1. Drug Name

• Generic Name: Indomethacin

• Brand Names: Indocin, Tivorbex, Indocin SR, and others.

2. Drug Classification

• Class: Non-Steroidal Anti-Inflammatory Drug (NSAID)

• Subclass: Acetic acid derivative

3. Mechanism of Action

Indomethacin is a potent NSAID that exerts its therapeutic effects primarily by inhibiting the cyclooxygenase (COX) enzymes—COX-1 and COX-2. These enzymes are responsible for the synthesis of prostaglandins, which mediate inflammation, pain, and fever.

• COX Inhibition: Indomethacin inhibits both COX-1 and COX-2 enzymes, although it has a stronger affinity for COX-1. COX-1 is involved in the production of prostaglandins that protect the gastric mucosa, while COX-2 is primarily involved in inflammation. Inhibition of these enzymes reduces prostaglandin synthesis, leading to anti-inflammatory, analgesic, and antipyretic effects.

• Anti-Inflammatory Effect: Indomethacin’s ability to inhibit COX-2 reduces the inflammatory response, making it effective in conditions like arthritis.

• Analgesic Effect: By lowering prostaglandin levels, indomethacin alleviates pain, particularly pain related to inflammation.

• Antipyretic Effect: The drug reduces fever through the inhibition of prostaglandin production in the hypothalamus, thus regulating the body’s temperature set point.

4. Pharmacokinetics

• Absorption: Indomethacin is well-absorbed from the gastrointestinal tract after oral administration, with a bioavailability of approximately 90%. Food intake can delay the absorption but does not significantly affect the overall bioavailability.

• Distribution: The volume of distribution (Vd) of indomethacin is about 0.2 L/kg. It is highly protein-bound (around 99%), mainly to albumin, which means its effects may be altered in patients with low albumin levels or liver dysfunction.

• Metabolism: Indomethacin undergoes extensive hepatic metabolism. The primary metabolic pathways involve cytochrome P450 enzymes, mainly CYP2C9. It is metabolized to its inactive metabolites, which are then excreted in the urine.

• Excretion: The elimination half-life of indomethacin is about 4 to 5 hours. Approximately 60-75% of the drug is excreted in the urine as metabolites, with a small fraction excreted unchanged. Renal impairment can prolong the elimination of the drug.

• Special Considerations: The pharmacokinetics of indomethacin may be altered in elderly individuals or those with liver or renal dysfunction, necessitating dose adjustments.

5. Indications

• Primary Indications:

  • Acute gouty arthritis

  • Osteoarthritis

  • Rheumatoid arthritis

  • Ankylosing spondylitis

  • Bursitis and tendonitis

  • Acute musculoskeletal pain

• Off-Label Uses:

  • Patent ductus arteriosus in premature infants

  • Acute pain following surgery (especially orthopedic surgeries)

  • Temporomandibular joint disorder

• Specific Populations: Indomethacin is beneficial in patients with moderate to severe inflammatory conditions but should be used with caution in elderly patients, those with a history of gastrointestinal disorders, and those with renal or hepatic impairments.

6. Dosage and Administration

• Adult Dosing:

  • Acute conditions (e.g., gout, rheumatoid arthritis): 50 mg 2 to 3 times a day.

  • Chronic conditions (e.g., osteoarthritis, ankylosing spondylitis): 25 mg to 50 mg twice or thrice daily, depending on response.

  • IV administration: For moderate to severe pain, 1 mg/kg IV for 1-2 doses.

• Pediatric Dosing:

  • Patent ductus arteriosus in neonates: 0.2 mg/kg IV every 12 to 24 hours, depending on clinical response.

• Renal/Hepatic Impairment: Dosing adjustments are necessary. Use with caution in patients with severe renal or hepatic dysfunction.

• Maximum Safe Dose: The maximum recommended daily dose is 200 mg. For prolonged use, lower doses should be considered to minimize adverse effects.

7. Contraindications

• Absolute Contraindications:

  • Hypersensitivity to indomethacin or other NSAIDs.

  • Active peptic ulcer disease.

  • History of gastrointestinal bleeding.

  • Severe renal impairment (e.g., anuria).

  • Third-trimester pregnancy (due to risks of premature closure of the ductus arteriosus).

• Relative Contraindications:

  • History of cardiovascular disease or hypertension.

  • Asthma or bronchospasm.

  • Coagulopathies or active bleeding disorders.

8. Warnings and Precautions

• Black Box Warnings:

  • Increased risk of serious cardiovascular events (e.g., MI, stroke) with prolonged use.

  • Risk of serious gastrointestinal events (e.g., bleeding, ulceration, perforation).

• Special Warnings:

  • Pregnancy: Should be avoided in the third trimester due to fetal risks.

  • Lactation: Indomethacin is excreted in breast milk, and its use should be avoided or carefully monitored in breastfeeding mothers.

  • Gastrointestinal: Monitor for signs of GI bleeding, especially in elderly or those with a history of peptic ulcers.

  • Renal Function: Should be used with caution in patients with impaired renal function.

• Monitoring Parameters:

  • Monitor renal function, liver enzymes, and complete blood counts.

  • Regular blood pressure monitoring is advised due to the potential for fluid retention and hypertension.

9. Adverse Effects

• Common Adverse Effects:

  • Gastrointestinal discomfort (nausea, dyspepsia, abdominal pain)

  • Headache

  • Dizziness

• Less Common but Clinically Significant Side Effects:

  • Peptic ulceration

  • Gastrointestinal bleeding

  • Hypertension or fluid retention

  • Renal dysfunction (elevated creatinine, edema)

• Rare/Serious Adverse Reactions:

  • Anaphylaxis

  • Stevens-Johnson syndrome

  • Toxic epidermal necrolysis (TEN)

  • Myocardial infarction, stroke

10. Drug Interactions

• Major Drug Interactions:

  • Anticoagulants (e.g., warfarin): Increased risk of bleeding due to additive effects on platelet aggregation.

  • ACE inhibitors/ARBs: Reduced effectiveness of antihypertensive therapy and an increased risk of renal dysfunction.

  • Diuretics (e.g., furosemide): Increased risk of renal impairment due to reduced renal blood flow.

• Food-Drug Interactions:

  • Food may delay the absorption of indomethacin but does not significantly affect its overall bioavailability.

• Lab Test Interactions:

  • Indomethacin may interfere with liver enzyme tests, increasing AST/ALT levels.

11. Clinical Pharmacology

Indomethacin provides significant anti-inflammatory effects through its inhibition of COX enzymes. Its pharmacodynamic profile includes potent analgesic and antipyretic effects, particularly in conditions of acute and chronic inflammation.

12. Special Populations

• Pregnancy: Category C (may be harmful in the third trimester).

• Lactation: Should be avoided unless the benefit outweighs the risk.

• Pediatrics: Used in neonates for ductus arteriosus closure but should be monitored for renal and cardiovascular status.

• Geriatrics: Increased risk of GI side effects and renal impairment; lower doses may be needed.

13. Therapeutic Uses

• First-Line Indications: Acute gout, rheumatoid arthritis, osteoarthritis.

• Second-Line Indications: Severe musculoskeletal pain.

• Combination Therapy: Often combined with corticosteroids for flare-ups of inflammatory conditions.

Clinical trials have supported the efficacy of indomethacin in reducing inflammation and pain in arthritis, gout, and musculoskeletal disorders.

14. Monitoring and Follow-Up

• Monitor liver function, renal function, and blood pressure at baseline and periodically during therapy.

• Encourage patients to report any signs of gastrointestinal bleeding (e.g., black stools, vomiting blood) or cardiovascular symptoms (e.g., chest pain, shortness of breath).

15. Overdose Management

• Symptoms of Overdose: Nausea, vomiting, headache, dizziness, tinnitus, drowsiness, and in severe cases, seizures or coma.

• Treatment Protocols: Activated charcoal may be administered if the overdose is recent. Symptomatic treatment, including hydration and monitoring of vital signs, is essential.

• Supportive Measures: Intravenous fluids, correction of electrolyte imbalances, and monitoring of renal function are important.

16. Patient Counseling Information

• Advise patients to take indomethacin with food or milk to minimize gastrointestinal irritation.

• Inform patients about the potential risks of GI bleeding and cardiovascular events, especially with prolonged use.

• Patients should report any signs of allergic reactions or GI bleeding immediately.