Colchicine

 

Introduction. Colchicine is a unique antiinflammatory agent in that it is largely effective only against gouty arthritis. It provides dramatic relief of acute attacks of gout, and is an effective prophylactic agent against such attacks.

History. Colchicine is an alkaloid of Colchicum autumnale (autumn crocus, meadow saffron). Although the poisonous action of colchicum was known to Dioscorides, preparations of the plant were not recommended for pain of articular origin until the sixth century A.D. Colchicum was introduced for the therapy of acute gout by von Storck in 1763, and its specificity for this syndrome soon resulted in its incorporation in a number of "gout mixtures" popularized by charlatans. Benjamin Franklin, himself a sufferer from gout, is reputed to have introduced colchicum therapy in the United States. The alkaloid colchicine was isolated from colchicum in 1820 by Pelletier and Caventou.

Pharmacological Properties. The antiinflammatory effect of colchicine in acute gouty arthritis is relatively selective for this disorder. Colchicine is only occasionally effective in other types of arthritis; it is not an analgesic and does not provide relief of other types of pain.

Colchicine is an antimitotic agent and is widely employed as an experimental tool in the study of cell division and function.

Effect in Gout. Colchicine does not influence the renal excretion of uric acid or its concentration in blood. By virtue of its ability to bind to tubulin, colchicine interferes with the function of the mitotic spindles and causes depolymerization and disappearance of the fibrillar microtubules in granulocytes and other motile cells. This action is apparently the basis for the beneficial effect of colchicine, namely, the inhibition of the migration of granulocytes into the inflamed area and a decreased metabolic and phagocytic activity of granulocytes. This reduces the release of lactic acid and proinflammatory enzymes that occurs during phagocytosis and breaks the cycle that leads to the inflammatory response.

Neutrophils exposed to urate crystals ingest them and produce a glycoprotein, which may be the causative agent of acute gouty arthritis. Injected into joints, this substance produces a profound arthritis that is histologically indistinguishable from that caused by direct injection of urate crystals. Colchicine appears to prevent the elaboration by leukocytes of this glycoprotein.

Effect on Cell Division. Colchicine can arrest plant and animal cell division in vitro and in vivo. Mitosis is arrested in metaphase, due to failure of spindle formation. Cells with the highest rates of division are affected earliest. High concentrations may completely prevent cells from entering mitosis, and they often die. The action also is characteristic of the vinca alkaloids (vincristine and vinblastine), podophyllotoxin, and griseofulvin.

Other Effects. Colchicine inhibits the release of histamine-containing granules from mast cells, the secretion of insulin from beta cells of pancreatic islets, and the movement of melanin granules in melanophores. Although it is questionable whether these effects occur at clinically achieved concentrations of colchicine, all of these processes may involve the translocation of granules by the microtubular system.

Colchicine also exhibits a variety of other pharmacological effects. It lowers body temperature, increases the sensitivity to central depressants, depresses the respiratory center, enhances the response to sympathomimetic agents, constricts blood vessels, and induces hypertension by central vasomotor stimulation. It enhances gastrointestinal activity by neurogenic stimulation but depresses it by a direct effect, and alters neuromuscular function.

Pharmacokinetics and Metabolism. Colchicine is rapidly absorbed after oral administration, and peak concentrations occur in plasma by 0.5 to 2 hours. Large amounts of the drug and metabolites enter the intestinal tract in the bile and intestinal secretions, and this fact, plus the rapid turnover of intestinal epithelium, probably explains the prominence of intestinal manifestations in colchicine poisoning. The kidney, liver, and spleen also contain high concentrations of colchicine, but it is apparently largely excluded from heart, skeletal muscle, and brain. The drug can be detected in leukocytes and in the urine for at least 9 days after a single intravenous dose.

Colchicine is metabolized to a mixture of compounds in vitro. Most of the drug is excreted in the feces; however, in normal individuals, 10% to 20% of the drug is excreted in the urine. In patients with liver disease, hepatic uptake and elimination are reduced and a greater fraction of the drug is excreted in the urine.

Toxic Effects. The most common side effects reflect the action of colchicine on the rapidly proliferating epithelial cells in the gastrointestinal tract, especially in the jejunum. Nausea, vomiting, diarrhea, and abdominal pain are the most common and earliest untoward effects of colchicine overdosage. To avoid more serious toxicity, administration of the drug should be discontinued as soon as these symptoms occur. There is a latent period of several hours or more between the administration of the drug and the onset of symptoms. This interval is not altered by dosage or route of administration. For this reason, and because of individual variation, adverse effects may be unavoidable during an initial course of medication with colchicine. However, since patients often remain relatively consistent in their response to a given dose of the drug, toxicity can be reduced or avoided during subsequent courses of therapy by reducing the dose. The drug is equally effective when given intravenously; the onset of the therapeutic effect may be faster, and the gastrointestinal side effects may be almost completely avoided.

In acute poisoning with colchicine, there is hemorrhagic gastroenteritis, extensive vascular damage, nephrotoxicity, muscular depression, and an ascending paralysis of the CNS.

Colchicine produces a temporary leukopenia that is soon replaced by a leukocytosis, sometimes due to a striking increase in the number of basophilic granulocytes. The site of action is apparently directly on the bone marrow. Myopathy and neuropathy also have been noted with colchicine treatment, especially in patients with decreased renal function. Long-term administration of colchicine entails some risk of agranulocytosis, aplastic anemia, myopathy, and alopecia; azoospermia has also been described.

Therapeutic Uses. Colchicine provides dramatic relief from acute attacks of gout. The effect is sufficiently selective that the drug has been used for diagnostic purposes, but the test is not infallible. Colchicine also has an established role to prevent and to abort acute attacks of gout. However, its toxicity and the availability of alternative agents that are less toxic have substantially lessened its usefulness.

Acute Attacks. When colchicine is given promptly within the first few hours of an attack, fewer than 5% of patients fail to obtain relief. Pain, swelling, and redness abate within 12 hours and are completely gone in 48 to 72 hours. Although for many years colchicine was administered orally, current practice is to administer the drug intravenously (see Wallace and Singer, 1988). Although a number of regimens have been used, a single dose of 2 mg, diluted in 10 to 20 ml of 0.9% sodium chloride solution, usually is adequate; a total dose of 4 mg should not be exceeded. To avoid cumulative toxicity, treatment with colchicine should not be repeated within 7 days.

Great care should be exercised in prescribing colchicine for elderly patients, and for those with cardiac, renal, hepatic, or gastrointestinal disease. In these patients and in those who do not tolerate or respond to colchicine, indomethacin or another NSAID is preferred.

Prophylactic Uses. For patients with chronic gout, colchicine has established value as a prophylactic agent, especially when there is frequent recurrence of attacks. Prophylactic medication also is indicated upon initiation of long-term medication with allopurinol or the uricosuric agents, since acute attacks often increase in frequency during the early months of such therapy.

The prophylactic dose of colchicine depends upon the frequency and severity of prior attacks. As small an oral dose as 0.5 mg two to four times a week may suffice; as much as 1.8 mg per day may be required by some patients. Colchicine should be taken in larger abortive doses immediately upon the first twinge of articular pain or the appearance of any prodrome of an acute attack. Before and after surgery in patients with gout, colchicine should be given for 3 days (0.5 or 0.6 mg, three times a day); this greatly reduces the very high incidence of acute attacks of gouty arthritis precipitated by operative procedures.

Daily administration of colchicine is useful for the prevention of attacks of familial Mediterranean fever (familial paroxysmal polyserositis) and for prevention and treatment of amyloidosis in such patients (Zemer et al., 1991). Colchicine appears to benefit patients with primary biliary cirrhosis in terms of improvement of liver function tests and perhaps of survival (Warnes, 1991). Colchicine also has been employed to treat a variety of skin disorders, including psoriasis and Behcet's syndrome.