Colchicine
Colchicine is a medication used to prevent and treat gout, to treat familial Mediterranean fever and Behçet's disease, and to reduce the risk of myocardial infarction. The American College of Rheumatology recommends colchicine, nonsteroidal anti-inflammatory drugs or steroids in the treatment of gout. Other uses for colchicine include the management of pericarditis.
Colchicine is taken by mouth. The injectable route of administration for colchicine can be toxic. In 2008, the US Food and Drug Administration removed all injectable colchicine from the US market.
Colchicine has a narrow therapeutic index, so overdosing is a significant risk. Common side effects of colchicine include gastrointestinal upset, particularly at high doses. Severe side effects may include pancytopenia and rhabdomyolysis, and the medication can be deadly in overdose. Whether colchicine is safe for use during pregnancy is unclear, but its use during breastfeeding appears to be safe. Colchicine works by decreasing inflammation via multiple mechanisms.
Colchicine, in the form of the autumn crocus, was used as early as 1500 BC to treat joint swelling. It was approved for medical use in the United States in 1961. It is available as a generic medication. In 2023, it was the 215th most commonly prescribed medication in the United States, with more than 2million prescriptions.
Colchicine is used in plant breeding to induce polyploidy, in which the number of chromosomes in plant cells are doubled. This helps produce larger, hardier, faster-growing, and in general, more desirable plants than the normally diploid parents.
Medical uses
Gout
Colchicine is an alternative for those unable to tolerate nonsteroidal anti-inflammatory drugs when treating gout. Low doses appear to be well tolerated and may reduce gout symptoms and pain, perhaps as effectively as NSAIDs. At higher doses, side effects limit its use.For treating gout symptoms, colchicine is taken orally, with or without food, as symptoms first appear. Subsequent doses may be needed if symptoms worsen.
There is preliminary evidence that daily colchicine may be effective as a long-term prophylaxis when used with allopurinol to reduce the risk of increased uric acid levels and acute gout flares; adverse gastrointestinal effects may occur, though overall the risk of serious side effects is low.
Risk of cardiovascular disorders
In June 2023, the US FDA approved a low-dose regimen of colchicine to reduce the risk of further disorders in adults with existing cardiovascular diseases. As an anti-inflammatory drug, Lodoco in a dose of 0.5 mg per day reduced the rate of cardiovascular events by 31% in people with established atherosclerosis and by 23% in people with recent myocardial infarction. Colchicine was most effective in combination therapy with lipid-lowering and anti-inflammatory medications. The mechanism for this effect of colchicine is unknown.Other conditions
Colchicine is also used as an anti-inflammatory agent for long-term treatment of Behçet's disease. It appears to have limited effect in relapsing polychondritis, as it may only be useful for the treatment of chondritis and mild skin symptoms. It is a component of therapy for several other conditions, including pericarditis, pulmonary fibrosis, biliary cirrhosis, various vasculitides, pseudogout, spondyloarthropathy, calcinosis, scleroderma, and amyloidosis.Research regarding the efficacy of colchicine in many of these diseases has not been performed. It is also used in the treatment of familial Mediterranean fever, in which it reduces attacks and the long-term risk of amyloidosis.
Colchicine is effective for prevention of atrial fibrillation after cardiac surgery. In people with recent myocardial infarction, it has been found to reduce risk of future cardiovascular events. Its clinical use may grow to include this indication.
Contraindications
Long-term regimens of oral colchicine are absolutely contraindicated in people with advanced kidney failure. About 10–20% of a colchicine dose is excreted unchanged by the kidneys; it is not removed by hemodialysis. Cumulative toxicity is a high probability in this clinical setting, and a severe neuromyopathy may result. The presentation includes a progressive onset of proximal weakness, elevated creatine kinase, and sensorimotor polyneuropathy. Colchicine toxicity can be potentiated by the concomitant use of cholesterol-lowering drugs.Adverse effects
Deaths - both accidental and intentional - have resulted from overdose of colchicine. Typical side effects of moderate doses may include gastrointestinal upset, diarrhea, and neutropenia. High doses can also damage bone marrow, lead to anemia, and cause hair loss. All of these side effects can result from inhibition of mitosis, which may include neuromuscular toxicity and rhabdomyolysis.Toxicity
According to one review, colchicine poisoning by overdose begins with a gastrointestinal phase occurring 10–24 hours after ingestion, followed by multiple organ dysfunction occurring 24 hours to 7 days after ingestion, after which the affected person either declines into multiple organ failure or recovers over several weeks.Colchicine can be toxic when ingested, inhaled, or absorbed in the eyes. It can cause a temporary clouding of the cornea and be absorbed into the body, causing systemic toxicity. Symptoms of colchicine overdose start 2 to 24 hours after the toxic dose has been ingested, and include burning in the mouth and throat, fever, vomiting, diarrhea, and abdominal pain. This can cause hypovolemic shock due to extreme vascular damage and fluid loss through the gastrointestinal tract, which can be fatal.
If the affected persons survive the gastrointestinal phase of toxicity, they may experience multiple organ failure and critical illness. This includes kidney damage, which causes low urine output and bloody urine; low white blood cell counts that can last for several days; anemia; muscular weakness; liver failure; hepatomegaly; bone marrow suppression; thrombocytopenia; and ascending paralysis leading to potentially fatal respiratory failure. Neurologic symptoms are also evident, including seizures, confusion, and delirium; children may experience hallucinations. Recovery may begin within six to eight days and begins with rebound leukocytosis and alopecia as organ functions return to normal.
Long-term exposure to colchicine can lead to toxicity, particularly of the bone marrow, kidney, and nerves. Effects of long-term colchicine toxicity include agranulocytosis, thrombocytopenia, low white blood cell counts, aplastic anemia, alopecia, rash, purpura, vesicular dermatitis, kidney damage, anuria, peripheral neuropathy, and myopathy.
No specific antidote for colchicine is known, but supportive care is used in cases of overdose. In the immediate period after an overdose, monitoring for gastrointestinal symptoms, cardiac dysrhythmias, and respiratory depression is appropriate, and may require gastrointestinal decontamination with activated charcoal or gastric lavage.
Mechanism of toxicity
With overdoses, colchicine becomes toxic as an extension of its cellular mechanism of action via binding to tubulin. Cells so affected undergo impaired protein assembly with reduced endocytosis, exocytosis, cellular motility, and interrupted function of heart cells, culminating in multiple organ failure.Epidemiology
In the United States, several hundred cases of colchicine toxicity are reported annually, about 10% of which end with serious morbidity or mortality. Many of these cases are intentional overdoses, but others were accidental; for example, if the drug were not dosed appropriately for kidney function. Most cases of colchicine toxicity occur in adults. Many of these adverse events resulted from the use of intravenous colchicine. It was used intentionally as a poison in the 2015 killing of Mary Yoder.Drug interactions
Colchicine interacts with the P-glycoprotein transporter, and the CYP3A4 enzyme involved in drug and toxin metabolism. Fatal drug interactions have occurred when colchicine was taken with other drugs that inhibit P-glycoprotein and CYP3A4, such as erythromycin or clarithromycin.People taking macrolide antibiotics, ketoconazole, or cyclosporine, or those who have liver or kidney disease, should not take colchicine, as these drugs and conditions may interfere with colchicine metabolism and raise its blood levels, potentially increasing its toxicity abruptly. Symptoms of toxicity include gastrointestinal upset, fever, muscle pain, low blood cell counts, and organ failure. People with HIV/AIDS taking atazanavir, darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir, ritonavir, or saquinavir may experience colchicine toxicity. Grapefruit juice and statins can also increase colchicine concentrations.
Pharmacology
Mechanism of action
In gout, inflammation in joints results from the precipitation of uric acid as needle-like crystals of monosodium urate in and around synovial fluid and soft tissues of joints. These crystal deposits cause inflammatory arthritis, which is initiated and sustained by mechanisms involving various proinflammatory mediators, such as cytokines. Colchicine accumulates in white blood cells and affects them in a variety of ways - decreasing motility, mobilization, and adhesion.Under preliminary research are various mechanisms by which colchicine may interfere with gout inflammation:
- Inhibits microtubule polymerization by binding to its constitutive protein, tubulin
- As availability of tubulin is essential to mitosis, colchicine may inhibit mitosis
- Inhibits activation and migration of neutrophils to sites of inflammation
- Interferes with the inflammasome complex found in neutrophils and monocytes that mediate interleukin-1β activation, a component of inflammation
- Inhibits superoxide anion production in response to urate crystals
- Interrupts mast cell and lysosome degranulation
- Inhibits release of glycoproteins that promote chemotaxis from synovial cells and neutrophils