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Colchicine - complete information


Introduction:
Colchicine is an alkaloid isolated from the autumn crocus, Colchicum autumnale. It is actually present in the corm of the plant, the underground swollen part of the stem.

Pharmacokinetics:
Colchicine is absorbed readily when taken in orally. It reaches peak plasma levels within 2 hours. 
It has a serum half-life of 9 hours. 
Colchicine is partially deacetylated in the liver and the unchanged drug and its metabolites are excreted in the bile and undergo intestinal reabsorption. Colchicine is found in high concentrations in leucocytes, kidneys, the liver and spleen. Most of the drug is excreted in the feces but 10 to 20% is excreted in the urine and this proportion rises in patients with liver disorders. For patients with creatinine clearance of < 50 mL/min, colchicine must be avoided or used at a lower dose. Colchicine is also distributed into breast milk.

Pharmacodynamics:
Colchicine relieves the pain and inflammation of gouty arthritis in 12-24 hours. It does not alter the metabolism or excretion of urates. It also does not have other analgesic effects.
It is an anti-inflammatory agent. 
The mechanism of action is that it binds to the intracellular protein tubulin, thereby preventing its polymerization into microtubules. This causes the inhibition of leukocyte migration and phagocytosis. It also inhibits the formation of leukotriene B4. Colchicine also blocks cell division by binding to mitotic spindles and arrests the cell division at metaphase. Several of colchicine's adverse effects are produced by its inhibition of tubulin polymerization and cell mitosis.

Indications:
NSAIDs have replaced colchicine in the treatment of acute gout because of the troublesome diarrhea associated with colchicine therapy and because of its low therapeutic index. Previously it was used to treat an acute attack. It relieved the pain in more than 95% of cases and also provided a diagnostic confirmation because it is more or less specific for relief of pain due to acute gout. Non-gouty arthritis are unaffected.
1) Colchicine is now used for the prophylaxis of recurrent episodes of gouty arthritis. Its effectiveness is up to 80%.
2) It is also effective in reducing frequency of attacks in acute Mediterranean fever. It also prevents amyloidosis and reverses proteinuria
3) It may have a mild beneficial effect in sarcoid arthritis and in hepatic cirrhosis.
Although it can be given intravenously, this route should be used cautiously because of increased bone marrow toxicity.

Adverse Effects:
Colchicine often causes diarrhea and may occasionally cause nausea, vomiting and abdominal pain. The GIT is most commonly affected because it is the route of intake and of major excretion. Rarely chronic use of colchicine may cause hair loss and bone marrow depression (aplastic anemia, neutropenia) as well as peripheral neuritis and myopathy.

Acute intoxication after overdoses is characterized by burning throat pain, bloody diarrhea, shock, hematuria and oliguria. Fatal ascending central nervous system depression has been reported. Treatment is supportive. The fatal dose is as low as 7 mg.

Dosage:
1) The prophylactic dose of colchicine is 0.5-0.6 mg 1-3 times daily.
2) If used to terminate an attack of gout, the traditional initial dose of colchicine is usually 0.6 or 1.2 mg, followed by 0.6 mg every 2 hours until pain is relieved or nausea and diarrhea appear. A lower dose regimen of 1.2 mg initially, followed by 0.6 mg oral is as effective as the high dose regimen.
Normally we should not exceed 6 mg per acute attack and the dose should not be repeated within 7 days.
3) For Mediterranean fever, 1-1.5 mg 3 times/day is the prophylactic dose.


N.B:
1) IV use of colchicine is not recommended.
2) Colchicine use is contraindicated in pregnancy.
3) 0.6 mg/day for a creatinine clearance of 35-50 mL/min, 0.6 mg every 2 to 3 days for creatinine clearances of 10-35 mL/min and avoidance in those with creatinine clearance of less than 10 mL/min or with combined hepatic and renal disease.
4) Use of colchicine with clarithromycin, erythromycin or tolbutamide may cause colchicine toxicity. Thiazide diuretics may increase serum uric acid and interfere with the activity of colchicine.
5) Colchicine may impair the absorption of vitamin B12.
6) Acute myopathy has been reported in patients with chronic renal impairment given colchicine with Simvastatin. This is so because both drugs are metabolized by the cytochrome P450 isoenzyme CYP3A4.
7) Tetraparesis developed in a patient who took colchicine with verapamil. This was considered to be due to a pharmacokinetic interaction which increased serum and CSF concentrations of colchicine. 

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