What Is of Colchicine ? /Colchicine is an alkaloid isolated from Colchicum autumnale with anti-gout and anti-inflammatory activities? The exact mechanism of action by which colchicines exerts its effect has not been completely established. Colchicine binds to tubulin, thereby interfering with the polymerization of tubulin, interrupting microtubule dynamics, and disrupting mitosis. This leads to an inhibition of the migration of leukocytes and other inflammatory cells, thereby reducing the inflammatory response to deposited urate crystals. Colchicine may also interrupt the cycle of monosodium urate crystal deposition in joint tissues, thereby also preventing the resultant inflammatory response. Overall, colchicine decreases leukocyte chemotaxis/migration and phagocytosis to inflamed areas and inhibits the formation and release of a chemotactic glycoprotein that is produced during phagocytosis of urate crystals.
Colchicine is a plant alkaloid that is widely used for the treatment of gout. Colchicine has not been associated with acute liver injury or liver test abnormalities except with serious overdoses.
Colchicine appears as odorless or nearly odorless pale yellow needles or powder that darkens on exposure to light. Used to treat gouty arthritis, pseudogout, sarcoid arthritis, and calcific tendinitis. (EPA, 1998).
Synonyms
- Colchicin
- Colchicina
- Colchicine
- Colchicinum
Mechanism of Action of Colchicine
HUVEC cells were exposed to various concentrations of colchicine and were harvested at different time points. Ribonucleic acid was extracted, amplified, reverse transcribed and hybridized to complementary deoxyribonucleic acid microarrays containing more than 40,000 probes to human expressed sequence tags. This approach enabled us to have a global look at the transcriptional response induced by colchicine treatment. Colchicine changed the expression of many genes in HUVEC cells following exposure to a concentration of 100 ng/ml or higher. Following short exposure (30 or 120 min), colchicine affected genes known to be involved in the cell cycle and its regulation. However, changes in the expression of genes involved in neutrophil migration or other inflammatory processes were observed mainly after 12 to 24 hr. The anti-inflammatory effect of colchicine may be mediated not only through direct interaction with microtubules but also through changes at the transcriptional level. This latter effect apparently requires a higher concentration and a longer time to occur.
Colchicine, long used to treat gout, arrests microtubule assembly and inhibits many cellular functions. At micromolar concentrations, it suppresses monosodium urate crystal-induced NACHT-LRR-PYD-containing protein-3 (NALP3) inflammasome-driven caspase-1 activation, IL-1beta processing and release, and L-selectin expression on neutrophils. At nanomolar concentrations, colchicine blocks the release of a crystal-derived chemotactic factor from neutrophil lysosomes blocks neutrophil adhesion to endothelium by modulating the distribution of adhesion molecules on the endothelial cells and inhibits monosodium urate crystal-induced production of superoxide anions from neutrophils. Cytochrome P450 3A4, the multidrug transporter P-glycoprotein, and the drugs that bind these proteins influence its pharmacokinetics and pharmacodynamics. Trial evidence supports its efficacy in acute gout and in preventing gout flares, but it has a narrow therapeutic index, and overdosage is associated with gastrointestinal, hepatic, renal, neuromuscular, and cerebral toxicity; bone marrow damage; and high mortality.
Indications of Colchicine
- Colchicine is a plant alkaloid that is widely used for the treatment of gout. Colchicine has not been associated with acute liver injury or liver test abnormalities except with serious overdoses.
- Gout Suppressants
- Colchicine also is used in the prophylactic treatment of recurrent gouty arthritis.
- Colchicine is used in the management of familial Mediterranean fever. The drug has been used effectively for chronic prophylactic therapy to reduce the frequency and severity of the episodic attacks of painful serositis in patients with familial Mediterranean fever.
- Colchicine is a widely used treatment for Behcet’s syndrome, even though in a previous 6-month controlled study, it was shown to be effective only in controlling erythema nodosum and arthralgias.
- Colchicine has been used in the treatment of sarcoid arthritis, arthritis associated with erythema nodosum, and acute inflammatory calcific tendinitis.
- patients have shown improvement in liver fibrosis during therapy with the drug. Colchicine has also been used for the treatment of primary biliary cirrhosis in a limited number of patients.
- Arrest the progression of neurologic disability caused by chronic progressive multiple sclerosis.
- Behcet’s Syndrome
- Familial Mediterranean Fever (FMF )
- Gout Flares
- Pericarditis
- Postpericardiotomy Syndrome
Contraindications of Colchicine
- decreased function of bone marrow
- low blood counts due to bone marrow failure
- decreased blood platelets
- low levels of white blood cells
- low levels of granulocytes
- a type of white blood cell
- a disease with shrinking and weaker muscles called myopathy
- method of removing waste/poison from blood with dialysis
- severe liver disease
- severe renal impairment
- a condition with muscle tissue breakdown called rhabdomyolysis
- vomiting
- diarrhea
- anemia from pyruvate kinase and G6PD deficiencies
- Allergies to Colchicine Analogues
Dosage of Colchicine
Strengths: 0.5 mg; 0.6 mg; 0.5 mg/mL
Acute Gout
- Initial: 1.2 mg orally at first sign of gout flare followed by 0.6 mg 1 hour later
- Maximum dose: 1.8 mg orally over a 1 hour period; higher doses have not been found to be more effective
Familial Mediterranean Fever
- Usual dose: 1.2 mg to 2.4 mg orally daily, administered in 1 or 2 divided doses
- Dose increases should be made in increments of 0.3 mg/day as needed and tolerated to control disease; if intolerable side effects develop, the dose should be decreased in increments of 0.3 mg/day
- Maximum dose: 2.4 mg/day
Gout – Prophylaxis
- 0.6 mg orally once or twice a day
- Maximum dose: 1.2 mg/day
Pediatric Dose for Familial Mediterranean Fever
- Age: 4 to 6 years: 0.3 to 1.8 mg orally daily, administered in 1 or 2 divided doses
- Age: 6 to 12 years: 0.9 to 1.8 mg orally daily, administered in 1 or 2 divided dose
- Age: Older than 12 years: 1.2 to 2.4 mg orally daily, administered in 1 or 2 divided doses
- Dose increases should be made in increments of 0.3 mg/day as needed and tolerated to control disease; if intolerable side effects develop, the dose should be decreased in increments of 0.3 mg/day
Maximum dose: 2.4 mg/day
MAXIMUM DOSAGE
Maximum dosages are dependent on indication for use. Do not exceed the maximum dose recommended for the indication for use.
- 1.8 mg PO per acute gout flare course (tablets); 1.2 mg/day PO for gout prophylaxis (tablets, capsules, oral solution); 2.4 mg/day PO for familial Mediterranean fever (tablets).
- 1.8 mg PO per acute gout flare course (tablets); 1.2 mg/day PO for gout prophylaxis (tablets, capsules, oral solution); 2.4 mg/day PO for familial Mediterranean fever (tablets).
- 2.4 mg/day PO for familial Mediterranean fever (tablets). Rare off-label use for gout prophylaxis has been described, does not exceed 1.2 mg/day PO.
- 4 to 12 years: 1.8 mg/day PO for familial Mediterranean fever (tablets).
- 4 years: Safety and efficacy have not been established.
- Safety and efficacy have not been established.
Side Effects of Colchicine
More common
- Diarrhea
- Abdominal cramps, difficulty breathing, nausea, and vomiting, or swelling of the face and throat
- Nausea, vomiting, diarrhea, loss of appetite, weight loss, yellowing of the skin or whites of the eyes, dark urine, pale stools)
- Stomach pain
- Muscle pain or weakness;
- Numbness or tingly feeling in your fingers or toes;
- The pale or gray appearance of your lips, tongue, or hands;
- Severe or ongoing vomiting or diarrhea;
- Fever, chills, body aches, flu symptoms; or
- Easy bruising, unusual bleeding, feeling weak or tired.
Common
- burning feeling in the stomach, throat, or skin
- convulsions (seizures)
- diarrhea (severe or bloody)
- fast, shallow breathing
- muscle weakness (very severe)
- nausea, stomach pain, or vomiting (severe)
- frequent infections (e.g., frequent colds – may be a sign of low white blood cells)
- hair loss
- infertility (e.g., decreased sperm production)
- itchiness
- muscle aches and weakness
- prickling, tingling, or numbness in the arms or legs
- severe diarrhea
- signs of bleeding (e.g., bloody nose, blood in urine, coughing blood, cuts that don’t stop bleeding)
- signs of kidney problems (e.g., increased urination at night, decreased urine production, blood in the urine, change of urine color)
Rare
- Black, tarry stools
- blood in the urine or stools
- burning, “crawling”, or tingling feeling in the skin
- difficulty with breathing when exercising
- fever with or without chills
- headache
- large, hive-like swellings on the face, eyelids, mouth, lips, or tongue
- muscle weakness
- numbness in the fingers or toes (usually mild)
- pain
- peeling of the skin
- pinpoint red spots on the skin
- redness
- skin rash or hives
- sores, ulcers, or white spots on the lips or in the mouth
- sore throat
Drug Interactions of Colchicine
Colchicine may interact with following drugs, supplements, & may change the efficacy of the drug
- atorvastatin
- azole antifungals (e.g., itraconazole, ketoconazole, voriconazole)
- calcium channel blockers (e.g., amlodipine, diltiazem, nifedipine, verapamil)
- carbamazepine
- carvedilol
- conivaptan
- cyanocobalamin (Vitamin B12)
- cyclosporine
- dasatinib
- desipramine
- dexamethasone
- dronedarone
- fenofibrate
- grapefruit juice
- haloperidol
- hepatitis C antiviral combinations (e.g., ombitasvir – paritaprevir – ritonavir – dasabuvir, ombitasvir – paritaprevir – ritonavir)
- imatinib
- lomitapide
- macrolide antibiotics (e.g., azithromycin, clarithromycin, erythromycin)
- metronidazole
- mifepristone
- mirabegron
- multivitamin supplements
- norfloxacin
- phenobarbital
- phenytoin
- prazosin
- progesterone
- propranolol
- protein kinase inhibitors (e.g., crizotinib, dasatinib, imatinib, nilotinib)
- rifampin
- St. John’s wort
- sertraline
- “statin” cholesterol-lowering medications (e.g., atorvastatin, lovastatin, simvastatin)
- tacrolimus
- tamoxifen
- tetracycline
- trazodone
- vinblastine
Pregnancy Category of Colchicine
FDA Pregnancy Category – C
Pregnancy
This medication should not be used during pregnancy unless the benefits outweigh the risks. If you become pregnant while taking this medication, contact your doctor immediately.
Lactation
This medication passes into breast milk. If you are a breast-feeding mother and are taking colchicine, it may affect your baby. Talk to your doctor about whether you should continue breast-feeding. Colchicine may be used by adolescents older than 12 years of age to treat FMF. The safety and effectiveness of using this medication to treat gouty arthritis for children under 18 years of age have not been determined; it should not be used for that purpose.
Patient advice
- Instruct patients on proper use and inform patients that fatal overdose, both accidental and intentional, have occurred; this drug should be kept out of the reach of children.
- Inform patients that there are a number of potentially serious drug interactions; grapefruit, grapefruit juice, and some herbal products should be avoided; patients should check with their healthcare provider before starting any new medications including short-term medications such as antibiotics.
- Inform patients that bone marrow depression and neuromuscular toxicity may occur; patients should seek medical attention promptly for unusual bleeding or bruising, increased infections, weakness or fatigue, muscle pain or weakness, or numbness or tingling in fingers or toes.
- Inform patients that gastrointestinal adverse events occur, but if these events are severe or persistent, they should be reported promptly to their healthcare provider.
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