Colchicine

COLCHICINE

Although NSAIDs are now the first-line drugs for acute gout, colchicine was the primary treatment for many years. Colchicine is an alkaloid isolated from the autumn crocus, Colchicumautumnale. Its structure is shown in Figure 36–6.

Pharmacokinetics

Colchicine is absorbed readily after oral administration, reaches peak plasma levels within 2 hours, and is eliminated with a serum half-life of 9 hours. Metabolites are excreted in the intestinal tract and urine.

Pharmacodynamics

Colchicine relieves the pain and inflammation of gouty arthritis in 12–24 hours without altering the metabolism or excretion of urates and without other analgesic effects. Colchicine produces its anti-inflammatory effects by binding to the intracellular protein tubulin, thereby preventing its polymerization into microtubules and leading to the inhibition of leukocyte migration and phago-cytosis. It also inhibits the formation of leukotriene B₄. Several of colchicine’s adverse effects are produced by its inhibition of tubulin polymerization and cell mitosis.

Indications

Although colchicine is more specific in gout than the NSAIDs, NSAIDs (eg, indomethacin and other NSAIDs [except aspirin]) are sometimes used in its stead because of the troublesome diarrhea associated with colchicine therapy. Colchicine is now used between attacks (the “intercritical period”) for prolonged prophylaxis (at low doses). It is effective in preventing attacks of acute Mediterranean fever and may have a mild beneficial effect in sarcoid arthritis and in hepatic cirrhosis. (Although it has been givenintravenously, this route is no longer approved by the FDA [2009].)

Adverse Effects

Colchicine often causes diarrhea and may occasionally cause nau-sea, vomiting, and abdominal pain. Hepatic necrosis, acute renal failure, disseminated intravascular coagulation, and seizures have also been observed. Colchicine may rarely cause hair loss and bone marrow depression, as well as peripheral neuritis, myopathy, and, in some cases, death. The more severe adverse events have been associated with the intravenous administration of colchicine. Acute overdose is characterized by burning throat pain, bloody diarrhea, shock, hematuria, and oliguria. Fatal ascending central nervous system depression has been reported. Supportive care is the mainstay of treatment.

Dosage

In prophylaxis (the most common use), the dosage of colchicine is 0.6 mg one to three times daily. For terminating a gouty attack, traditional dosing has been an initial colchicine dose of 0.6 or 1.2 mg, followed by 0.6 mg every 2 hours until pain resolves, or nau-sea and diarrhea appear. However, a regimen of 1.2 mg followed by a single 0.6 mg oral dose was shown to be as effective as the higher dose therapy noted above. Adverse events were less with this lower dose regimen. In February 2008, the FDA requested that intravenous preparations containing colchicine be discontin-ued in the USA because of their potential life-threatening adverse effects. Therefore, intravenous use of colchicine is not recom-mended.

In July 2009, the FDA approved colchicine for the treatment of acute gout, allowing Colcrys (a branded colchicine) marketing exclusivity in the USA. Colchicine, per se, rather than Colcrys, is available throughout the rest of the world in a generic form.