| toxicity summary | IDENTIFICATION: Colchicine is an antigout preparations. Colchicine is available as tablets and, in some countries, as injectable solutions. Colchicine is an alkaloid of Colchicum autumnale . Colchicum is also present in Gloriosa superba. Colchicine is a pale yellow odorless powder or scales. It darkens on exposure to light. Colchicine is used for acute gout attacks to reduce pain and inflammation. It may be used on long-term basis to prevent or reduce the frequency of attacks. Colchicine is used on long-term basis to prevent fever and recurrent polyserositis. Colchicine is effective in preventing the amyloidosis in this condition. Colchicine has been showed to be effective in the treatment of articular, cutaneous and mucosal symptoms. Colchicine has been used in the treatment of scleroderma and sarcoidosis. HUMAN EXPOSURE: Main risks and target organs: Colchicine exerts a multiorgan toxicity. The main toxic effects are related to the effects of colchicine on cellular division and account for diarrhea, bone marrow depression, alopecia. Other acute effects are hypovolemia, shock, and coagulation disturbances, which may lead to death. Summary of clinical effects: Toxic manifestations appear after a delay of 2 to 12 hours following ingestion or parenteral administration. Symptomatology progresses in three stages: Stage I gastrointestinal and circulatory phase: Severe gastrointestinal irritation: Nausea, vomiting, abdominal cramps, severe diarrhea. Dehydration, hypovolemia, shock. Cardiogenic shock may occur and may result in death within the first 72 hours. Hypoventilation, acute respiratory distress syndrome. Stage II bone marrow aplasia phase: Bone marrow aplasia with agranulocytosis. Coagulation disorders with diffuse hemorrhages. Rhabdomyolysis, polyneuritis, myopathy, acute renal failure and infections. Stage III: recovery phase: Alopecia. Routes of entry: Oral: Oral absorption is the most frequent cause of intoxication. Parenteral: Intoxications after parenteral administration are rare, however, the toxic dose appears to be lower than the oral toxic dose. A fatal bone marrow aplasia in a 70 year-old man after 10 mg intravenous colchicine over 5 days. Intoxication with multisystemic reactions after instillation of colchicine into the penile urethra for treatment of condyloma acuminata. Absorption by route of exposure: Oral: Rapidly absorbed from the gastro-intestinal tract. Peak plasma concentration is reached 0.5 to 2 hours after ingestion. Half time of absorption is 15 minutes. Absorption may be modified by pH, gastric contents, intestinal motility. Colchicine is not totally absorbed. There is an important hepatic first pass effect. Colchicine distributes in a space larger than that of the body. In severe renal or liver diseases the volume of distribution is smaller. Colchicine accumulates in kidney, liver, spleen, gastro-intestinal wall and leucocytes and is apparently excluded in heart, brain, skeletal muscle. Colchicine crosses the placenta and has also been found in maternal milk. Biological half-life by route of exposure: Parenteral: After a single 2 mg intravenous dose the average plasma half-life is 20 minutes. Plasma half-life is increased in severe renal disease and decreased in severe hepatic disease . Oral: After oral administration plasma concentrations reach a peak within 0.5 to 2 hours and afterwards decrease rapidly within 2 hours. The plasma half-life is 60 minutes. Colchicine may remain in tissues for as long as 10 days. Metabolism: Colchicine undergoes some hepatic metabolism. Colchicine is partially deacetylated in the liver. Large amounts of colchicine and of its metabolites undergo enterohepatic circulation. This may explain the occurrence of a second plasma peak concentration observed 5 to 6 hours after ingestion. Elimination by route of exposure: Colchicine is excreted unchanged or as metabolites. Oral: Urinary excretion amount to 16 to 47% of an administered dose. 50 to 70% of colchicine is excreted unchanged and 30 to 50% as metabolites. 20% of the dose administered is excreted in urine in the first 24 hours and 27.5% in the first 48 hours. Colchicine is detected in urine up to 7 to 10 days after ingestion. Urinary excretion is increased in patients with impaired hepatic function. Bile: 10 to 25% of colchicine is excreted in the bile. Feces: Large amounts of the drug are excreted in the feces. Breast Milk: Colchicine may be eliminated in breast milk. Intravenous: Feces: After intravenous administration 10 to 56% is excreted in the feces within the first 48 hours. Breast Milk: Colchicine may be eliminated in breast milk. Mode of action: Colchicine binds to tubulin and this prevents its polymerization into microtubules. The binding is reversible and the half-life of the colchicine-tubulin complex is 36 hours. Colchicine impairs the different cellular functions of the microtubule: separation of chromosome pairs during mitosis , ameboid movements, phagocytosis. Mitosis blockade accounts for diarrhoea, bone marrow depression and alopecia. Colchicine may have a direct toxic effect on muscle, peripheral nervous system and liver. Inhibition of cellular function does not, however, account for all the organ failures seen in severe overdose. Pharmacodynamics: Gout inflammation is initiated by urate crystals within tissues. The crystals are ingested by neutrophils but this leads to the release of enzymes and the destruction of the cells. Chemotactic factors are released and attract more neutrophils. Colchicine may act by preventing phagocytosis, the release of chemotactic factors and the response of neutrophils. Colchicine has other properties such as antipyretic effects, respiratory depression, vasoconstriction and hypertension. Adults: Oral: The severity and the mortality rate of the poisoning is directly related to the dose ingested. Intravenous: A fatal bone marrow aplasia in a 70-year-old patient is reported. The enhanced toxicity of intravenous colchicine is probably due to the higher bioavailability of colchicine after parenteral administration. Teratogenicity: Colchicine is contraindicated in pregnancy as Down's syndrome and spontaneous abortion have been reported. Colchicine should be discontinued three months prior to conception. Interactions: A case of acute cyclosporin nephrotoxicity induced by colchicine administration has been reported. Colchicine may interfere with cyclosporin pharmacokinetics by increasing cyclosporin plasma levels either by enhancing cyclosporin absorption or by reducing its hepatic metabolism. Main adverse effects: Gastrointestinal symptoms are a common complication of chronic colchicine therapy. Fatal outcomes have been reported after intravenous colchicine therapy. Gastrointestinal: vomiting, diarrhoea, abdominal discomfort, paralytic ileus, malabsorption syndrome with steatorrhea. Hematological: Bone marrow depression with agranulocytosis, acute myelomonocytic leukaemia, multiple myeloma, thrombocytopenia. Neurological: Peripheral neuritis, myopathy and rhabdomyolysis. Dermatological: Allergic reactions are rare urticaria; oedema may be seen. Alopecia has been reported after chronic treatment. Reproductive system: A reversible, complete azoospermia has been reported. Metabolic: Colchicine is capable of producing a reversible impairment of vitamin B12 absorption. Porphyria cutanea tarda has been reported. Others: Hyperglycemia has been reported in a 58-year-old woman who ingested colchicine and developed transient diabetes mellitus has been reported. Hyperlipemia: A transient hyperlipemia has been reported. Hyperuricemia: A transient hyperuricemia has also been noted. Hyperthermia-fever: Occurrence of fever may be relate to an infectious complication, especially during the stage of aplasia. Special risks: Pregnancy: Two cases of Down's syndrome babies have been reported. The obstetric histories of 36 women with familial Mediterranean fever on long-term colchicine treatment between 3 and 12 years have been reported. Seven of 28 pregnancies ended in miscarriage. Thirteen women had periods of infertility. All 16 infants born to mothers who had taken colchicine during pregnancy were healthy. The authors do not advise discontinuation of colchicine before planned pregnancy but recommend amniocentesis for karyotyping and reassurance. Breast-feeding: As colchicine is eliminated in the breast milk breast-feeding should be avoided. |
