Colchicine adverse effects

Assess the patient s subjective complaints and objective information for adverse effects. For NSAID therapy, be alert for new-onset epigastric pain, dark or tarry stools, blood in vomitus, dizziness or light-headedness, development of edema, decreased urine output by more than 50% over a 24-hour period, or shortness of breath. For colchicine, monitor for nausea or vomiting, diarrhea, easy bruising, cold or flulike symptoms, light-headedness, muscle weakness, or pain. Counsel the patient to inform you of any new medications started or stopped while taking colchicine. 

Oral colchicine causes dose-dependent GI adverse effects (nausea, vomiting, and diarrhea) in 50% to 80% of patients before relief of the attack. Non-GI adverse effects include neutropenia and axonal neuromyopathy, which may be worsened in patients taking other myopathic drugs (e.g., statins) or in those with renal insufficiency. Colchicine should not be used concurrently with macrolide antibiotics (especially clarithromycin) because reduced biliary excretion may lead to increased plasma colchicine levels and agranulocytosis. 

IV colchicine should be avoided because it is associated with serious adverse effects (e.g., bone marrow suppression, tissue necrosis from local extravasation, disseminated intravascular coagulation, hepatocellular toxicity, and renal failure). If considered necessary, the recommended initial IV dose is 2 mg (if renal function is normal) diluted in 10 to 20 mL of normal saline administered slowly over 10 to 20 minutes in a secure, free-flowing IV line to avoid extravasation. This may be followed by two additional doses of 1 mg each at 6-hour intervals, with the total dose not exceeding 4 mg. After a full IV course, patients should not receive colchicine by any route for at least 7 days. 

The contractile proteins of the spindle apparatus must draw apart the replicated chromosomes before the cell can divide. This process is prevented by the so-called spindle poisons (see also colchicine, p. 316) that arrest mitosis at metaphase by disrupting the assembly of microtubules into spindle threads. The vinca alkaloids, vincristine and vinblastine (from the periwinkle plant. Vinca rosea) exert such a cell-cycle-specific effect. Damage to the nervous system is a predicted adverse effect arising from injury to microtubule-operated axonal transport mechanisms. 

If properly controlled, simple gout may have few adverse effects. However, the severe neurological symptoms of Lesch-Nyhan syndrome (Section E,2 of text)6 cannot be corrected by medication. Colchicine (Box 7-D), in a manner which is not understood, alleviates the painful symptoms of gout caused by the deposits of sodium urate in joints and tissues. It is also important to keep the dietary purine intake low and it is often necessary to inhibit xanthine oxidase. A widely used and effective inhibitor is the isomer of hypoxanthine known as allopurinol, which is taken daily in amounts of 100 -600 mg or more. 

Colchicine is cleared by a different CYP450 isozyme than fluvastatin and pravastatin are, but another possible mechanism is synergistic myotoxicity, since colchicine causes myopathy by disrupting tubular function with subsequent vacuolization. Patients taking colchicine should be informed about possible muscular and gastrointestinal adverse effects and advised to stop. 

Most common adverse effects include nausea, vomiting, diarrhea, abdominal pain, bone marrow depression with agranulocytosis, thrombocytopenia, and aplastic anemia. Cumulative toxicity is possible in elderly patients, hence it should be used cautiously. Care also should be exercised in patients with cardiac, hepatic, and renal dysfunctions. Colchicine causes teratogenicity in animals, and there are evidences of the risk of fetal chromosomal damage in humans. Colchicine should not be administered by the parenteral route as it causes severe local irritation. 

Adverse effects Colchicine treatment may cause nausea, vomiting, abdominal pain, and diarrhea (Figure 39.15). Chronic administration may lead to myopathy, agranulocytosis, aplastic anemia, and alopecia. The drug should not be used in pregnancy, and should be used with caution in patients with hepatic, renal or cardiovascular disease. 

Adverse effects may be severe with abdominal pain, vomiting and diarrhoea which may be bloody. Renal damage may result and rarely, blood disorders. Large doses cause muscle paralysis. Many patients are unable to tolerate colchicine and use NSAIDs such as indomethacin or diclofenac for an acute attack of gout some patients require oral corticosteroid. 

Acute reversible ciclosporin toxicity occurred in a renal transplant patient a few days after colchicine was administered for an acute attack of gout (SEDA-16, 115). Other potential adverse effects of combining colchicine with ciclosporin include diarrhea, increases in serum liver enzymes, bilirubin, and creatinine, and less often severe myalgia (SEDA-19, 101). Acute myopathy, associated with neuropathy in one case, has been observed in two young renal transplant recipients (SEDA-22, 119). 

Acute inflammatory episodes are treated with colchicine, NSAIDS, and intraarticular steroids. The mode of colchicine s action and its adverse effects are considered. 

This mode of action is not unique since the natural product colchicine, from the autumn crocus Colchicum autumnale (once used as a treatment for gout), also binds to tubulin and disrupts microtubule assembly. It was never seriously considered as an anti-cancer drug owing to its low therapeutic index that is, the dose required to produce clinical benefit was not much greater than the dose causing serious adverse effects or even death. A third plant product with similar biological properties, podophyllotoxin from the American Mayapple, provided the stimulus for research that led to the discovery of another excellent anti-cancer drug - etoposide. 

Colchicine has a narrow therapeutic index (i.e., the amount of drug that produces the desirable therapeutic effect is not much lower than the amount that produces an adverse effect). Its therapeutic effect depends on inhibiting tubulin synthesis in neutrophils, but it can also prevent tubulin synthesis (and, thus, cell division and other cellular processes) in other cells. Fortunately, neutrophils concentrate colchicine, so they are affected at lower intakes than other cell types. Neutrophils lack the transport protein P-glycoprotein, a member of the ABC cassette family (which includes the CFTR channel). In most other cell types, P-glycoprotein exports chemicals such as colchicine, thus preventing their accumulation. 

Use of intravenous colchicine to circumvent adverse gastrointestinal effects is discouraged due to the increased risk of serious and potentially fatal systemic effects with this route. The intravenous form should not be used in patients with moderate or more severe renal impairment (creatinine clearance less than or equal to 50 mL/minute), and total doses should not exceed 4 mg in a 7-day period. The potential extravasation of intravenous colchicine is also a concern. 

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