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Saturday, July 26, 2025

Colchicine


Colchicine is a naturally derived alkaloid with anti-inflammatory properties, historically obtained from plants such as Colchicum autumnale (autumn crocus). It is used primarily in the treatment and prevention of gout and familial Mediterranean fever (FMF). Its mechanism of action is unique among anti-inflammatory agents, as it does not involve direct inhibition of prostaglandin synthesis or immune suppression but instead disrupts intracellular microtubule formation and neutrophil function.

Colchicine is a prescription-only oral medication with a narrow therapeutic index, necessitating caution in dosing, especially in patients with hepatic or renal impairment.

1. Classification

  • Pharmacologic class: Anti-gout agent; anti-inflammatory alkaloid

  • Therapeutic class: Antimitotic agent (microtubule inhibitor)

  • Drug class (ATC): M04AC01

  • Source: Alkaloid from Colchicum autumnale or Gloriosa superba

2. Mechanism of Action

Colchicine exerts its pharmacologic effect through:

  • Inhibition of microtubule polymerization by binding to tubulin

  • Disrupts neutrophil chemotaxis and adhesion, limiting migration to inflamed joints

  • Blocks inflammasome activation and IL-1β production

  • Suppresses phagocytosis of urate crystals, reducing activation of inflammatory pathways

  • Reduces superoxide production, prostanoid release, and other mediators

By modulating the innate immune response at the cellular level, colchicine effectively reduces the inflammatory cascade without directly influencing uric acid levels.

3. Indications

A. Approved Indications

  • Acute gout flares

  • Gout flare prophylaxis (e.g., during urate-lowering therapy)

  • Familial Mediterranean fever (FMF)

  • Pericarditis (including idiopathic and post-cardiotomy syndrome)

  • Prevention of pericarditis recurrence

B. Off-label or Investigational Uses

  • Behçet's disease

  • Primary biliary cholangitis

  • Coronary artery disease (as an anti-inflammatory adjunct in atherosclerosis)

  • Dermatologic conditions: leukocytoclastic vasculitis, Sweet’s syndrome

  • COVID-19: evaluated for anti-inflammatory effect in clinical trials (e.g., COLCORONA trial)

4. Available Formulations

  • Oral tablets: 0.5 mg and 0.6 mg (depending on country)

  • Oral solution (some regions): for pediatric or dysphagic patients

  • Brands:

    • Colcrys (US)

    • Colchicine Alkaloid (generic, various manufacturers)

    • Mitigare (prophylactic 0.6 mg capsules)

    • Colgout, Colcrys, Dexacolicin (market-specific)

5. Dosage and Administration

A. Acute Gout Flare

  • Initial dose: 1.2 mg (2 × 0.6 mg tablets) orally, then 0.6 mg after 1 hour

  • Total maximum dose: 1.8 mg in 1 hour

  • Repeat: No earlier than 3 days later due to toxicity risk

B. Prophylaxis of Gout

  • 0.6 mg once or twice daily

  • Adjust based on tolerance, renal/hepatic function

  • Continue prophylaxis when initiating urate-lowering therapy (e.g., allopurinol) for 3–6 months

C. Familial Mediterranean Fever (FMF)

  • Adults: 1.2–2.4 mg/day in 1–2 divided doses

  • Children:

    • 0.3–0.6 mg/day (<5 years)

    • 0.9–1.8 mg/day (>5 years)

D. Pericarditis

  • 0.5–0.6 mg once or twice daily (duration: 3–6 months or longer)

  • Always combined with NSAIDs (e.g., aspirin or ibuprofen)

Dose Adjustment:

  • Renal impairment (CrCl <30 mL/min): reduce frequency

  • Hepatic impairment: use with extreme caution

  • Elderly or low body weight: consider lower doses

6. Pharmacokinetics

  • Absorption: Rapid oral absorption, peak in 1–2 hours

  • Bioavailability: ~45%

  • Distribution: Widely distributed; concentrates in leukocytes and GI tissues

  • Protein binding: Low (~30–50%)

  • Metabolism: Hepatic via CYP3A4

  • Elimination: Biliary and renal excretion

  • Half-life: 9 hours (plasma); intracellular longer

  • Excretion: ~10–20% unchanged in urine

7. Contraindications

  • Hypersensitivity to colchicine or any component

  • Severe renal impairment (CrCl <10 mL/min) without dose adjustment

  • Severe hepatic impairment

  • Concomitant use with strong CYP3A4 inhibitors or P-glycoprotein inhibitors in renal/hepatic dysfunction (e.g., clarithromycin, ketoconazole)

  • Blood dyscrasias or existing bone marrow suppression

  • Pregnancy (caution advised despite limited teratogenicity)

8. Warnings and Precautions

  • Narrow therapeutic index: even minor overdoses can be fatal

  • Bone marrow suppression: monitor with long-term use

  • Neuromyopathy: dose-related; caution with statins or cyclosporine

  • Gastrointestinal toxicity: early sign of overdose (diarrhea, vomiting)

  • Hepatic impairment: increases toxicity risk

  • Renal impairment: reduces clearance; accumulation may occur

  • Elderly: increased sensitivity, risk of toxicity

9. Adverse Effects

A. Common (Dose-limiting)

  • Nausea

  • Vomiting

  • Diarrhea

  • Abdominal cramps

B. Serious (Toxicity or Long-Term)

  • Bone marrow suppression: aplastic anemia, pancytopenia

  • Rhabdomyolysis, myopathy

  • Hepatotoxicity

  • Peripheral neuropathy

  • Alopecia

  • Seizures (rare)

C. Signs of Overdose

  • Early: severe vomiting, bloody diarrhea, dehydration

  • Late: multi-organ failure, bone marrow suppression, death

10. Drug Interactions

Colchicine is a substrate of CYP3A4 and P-glycoprotein (P-gp). Dangerous drug-drug interactions can occur.

A. CYP3A4 Inhibitors (↑ colchicine levels)

  • Strong inhibitors: clarithromycin, ketoconazole, itraconazole, ritonavir → avoid

  • Moderate inhibitors: verapamil, diltiazem → dose adjust or monitor

B. P-glycoprotein Inhibitors

  • Cyclosporine, ranolazine → increase toxicity risk

C. Statins and Fibrates

  • Simvastatin, atorvastatin, gemfibrozil → ↑ risk of myopathy/rhabdomyolysis

D. Other

  • Digoxin → ↑ toxicity due to competition at P-gp

  • NSAIDs → safe co-use for gout but monitor for renal effects

11. Toxicity and Overdose Management

  • Lethal dose: ~0.8 mg/kg (~48 mg in adults), but lower doses can be fatal in renal/hepatic impairment

  • Management:

    • No specific antidote

    • Supportive care: fluid resuscitation, antiemetics, electrolyte correction

    • Activated charcoal: if within 1 hour

    • Filgrastim: in bone marrow suppression

    • Intensive care in severe poisoning

12. Pregnancy and Lactation

  • Pregnancy category:

    • US: Not formally categorized post-2015; animal studies show minimal teratogenicity

    • UK: Use if benefits outweigh risks; often continued in FMF

  • Lactation:

    • Excreted in breast milk in small amounts

    • Generally considered safe with monitoring

13. Monitoring Recommendations

  • CBC: periodically if on long-term therapy (bone marrow toxicity)

  • Renal and hepatic function tests

  • Creatine kinase (CK): if symptoms of myopathy

  • Gout frequency and uric acid levels

  • Signs of neuromuscular toxicity (especially with statins)

14. Special Populations

  • Pediatrics: Used in FMF; dose adjusted by weight

  • Geriatrics: Lower doses required due to decreased renal function

  • CKD patients: Avoid high doses; consider alternative therapies

  • Hepatic impairment: Avoid unless benefit outweighs risk

15. Advantages and Limitations

AdvantagesLimitations
Effective for acute gout flaresNarrow therapeutic window
Can be used in patients with NSAID contraindicationsGI side effects common
No impact on uric acid levels (neutral)

Myopathy and neuropathy risks
Low cost and oral administration


Effective prophylactic in FMF		Dangerous drug interactions


Requires strict adherence to dosing






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