FIGURE 36–5 Pathophysiologic events in a gouty joint. Synoviocytes phagocytose urate crystals and then secrete inflammatory mediators, which attract and activate polymorphonuclear leukocytes (PMN) and mononuclear phagocytes (MNP) (macrophages). Drugs active in gout inhibit crystal phagocytosis and polymorphonuclear leukocyte and macrophage release of inflammatory mediators. PG, prostaglandin; IL-1, interleukin-1; LTB4, leukotriene B4.
Although NSAIDs, corticosteroids, or colchicine are now first-line drugs for acute gout, colchicine was the primary treatment for many years. Colchicine is an alkaloid isolated from the autumn crocus, Colchicum autumnale. Its structure is shown in Figure 36–6.
1.
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.
2.
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 phagocytosis. It also inhibits the formation of leukotriene B4 and IL-1β. Several of colchicine’s adverse effects are produced by its inhibition of tubulin polymerization and cell mitosis.
3.
Indications: Colchicine is indicated for gout and is also used between attacks (the “intercritical period”) for prolonged
FIGURE 36–6 Colchicine and uricosuric drugs.
prophylaxis (at low doses). It prevents attacks of acute Mediterranean fever and may have a mild beneficial effect in sarcoid arthritis and in hepatic cirrhosis. Colchicine is also used to treat and prevent pericarditis, pleurisy, and coronary artery disease, probably due to its anti-inflammatory effect. Although it has been given intravenously, this route is no longer approved by the FDA (2009).
4.
Adverse Effects: Colchicine often causes diarrhea and may occasionally cause nausea, 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.
5.
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, a regimen of 1.2 mg followed by a single 0.6-mg oral dose was as effective as higher dose regimens, and adverse events were less frequent. In 2008, the FDA requested that intravenous preparations containing colchicine be discontinued in the United States because of their potential life-threatening adverse effects. Therefore, intravenous colchicine is no longer available.
In 2009, the FDA approved a new oral formulation of colchicine for the treatment of gout, allowing Colcrys (a branded colchicine) marketing exclusivity in the United States. Generic colchicine rather than Colcrys is available throughout the rest of the world.