Introduction:
Colchicine has been used for more than 2000 years, and it is the standard drug for the treatment of acute pericarditis and gout. Plants like autumn crocus and glory lily contain colchicine alkaloids. Nowadays, they are synthetically manufactured for medicinal purposes also. In therapeutic doses, they have a pleiotropic anti-inflammatory effect and anti-cancer effect. But in high doses, they are lethal. The drug has a very narrow therapeutic dose limit with no clear-cut differences between the non-toxic, toxic, and lethal doses. This confuses the clinicians.
What Is the Mechanism of Toxicity?
After an oral administration, it is readily absorbed and metabolized by the liver, and excreted by the kidneys. It binds well with the intracellular elements. The exact mechanism of Colchicine’s therapeutic and toxic effects is not well understood, but at a high level, they bind with the microtubules in cells and disrupt the microtubular network.
Microtubules are essential for the functioning of cardiac cells. They are mitotic inhibitors (stop cell division). This alters the cell morphology and impairs the protein assembly of the cells. The culmination of these mechanisms can result in multi-organ dysfunction and failure. It mainly affects cells with high cellular turnovers like the gastrointestinal tract or bone marrow. The peak levels are reached within 30 minutes to 120 minutes.
What Are the Therapeutic and Toxic Doses of Colchicine?
The usual adult oral dose of Colchicine in acute gout is 1.2 mg/day, and for familial Mediterranean fever will be 1.2 to 2.4 mg/day. It is 0.5-0.6 mg/day three to four times a week for gout prevention. The mortality rate for colchicine toxicity is estimated at ten percent, with ingestions of more than 0.5 mg/kg. The fatality rate may be up to 100% with ingestions greater than 0.8 mg/kg. The lowest reported doses of oral Colchicine are 7 to 26 mg.
What Are the Drug Interactions?
CYP3A4 and P-glycoprotein inhibitor drugs such as Clarithromycin, Erythromycin, Ketoconazole, Cyclosporine, and natural grape juice can increase Colchicine concentration. Administration of Colchicine with statins can increase the risk of myopathy.
What Are the Clinical Features of Colchicine Toxicity?
Colchicine early and late phases of colchicine toxicity. The early stage is seen in the gastrointestinal epithelium within two to twelve hours of ingestion. The symptoms include nausea, abdominal pain, vomiting, and diarrhea. This results in significant fluid loss, electrolyte imbalance, and hypotension. A multi-organ failure follows the initial phase within 24 hours to 72 hours. Systemic shock, pulmonary edema (excess fluid in the lungs), seizures, cardiac dysrhythmia (abnormal rate and rhythm of the heartbeat), heart attack, rhabdomyolysis (death of muscle fibers that result in the release of their contents into the bloodstream), acidosis, hepatic and renal failure may also be seen. From three days to seven days, pancytopenia (decreased red cells, white cells, and platelets). Recovery takes a few weeks or at least ten days after ingestion. In some patients, the symptoms have persisted longer than one year.
How to Diagnose Colchicine Toxicity?
Symptoms of Colchicine toxicity may be delayed by up to 12 hours, and all patients should be monitored for 24 hours. History of ingestion of tablets, parenteral administration, or consumption of colchicine-containing plants helps in the diagnosis. Patients with gout and age over thirty with early gastrointestinal symptoms of nausea, vomiting, and diarrhea should be suspected of Colchicine poisoning.
Laboratory values that are useful in the diagnosis and management include electrolytes, blood urea nitrogen, serum creatinine, glucose, and complete blood count (CBC) with the differential count. If multisystem toxicity develops, arterial blood gases, electrocardiogram, coagulation panel, liver function tests, creatinine phosphokinase (CPK), troponin, and urinalysis should be monitored.
Asymptomatic patients with suspected Colchicine poisoning should be observed for at least eight hours to develop vomiting, diarrhea, and other gastrointestinal symptoms. When a patient is symptomatic, they should be under continuous cardiovascular monitoring. Patients in the recovery phase may need a CBC three to seven days post-ingestion due to the possibility of delayed pancytopenia.
How to Treat Colchicine Toxicity?
There is no specific antidote for Colchicine. Charcoal may be considered, and supportive treatment is given. Gastrointestinal decontamination with activated charcoal should be considered. Administering 50 g of activated charcoal (1 g/kg in children) as soon as possible in any patient who has ingested more than 0.5 mg/kg of Colchicine is followed. Multiple doses of activated charcoal, in theory, may enhance elimination. Still, it is difficult for the vomiting patient.
Hence, it should be given before the onset of gastrointestinal symptoms. Otherwise, it may worsen the situation. A vast and recent intake may require gastric lavage (evacuation of small volumes of liquid through the orogastric tube to remove the toxic substances within the stomach). Due to rapid absorption and extensive distribution area, hemodialysis and hemoperfusion do not effectively remove the drug and are not used. However, this can be used as a supportive measure for patients with kidney failure.
In patients with significant fluid loss, early replenishment by fluid resuscitation and correction of any abnormalities in electrolyte balance is necessary. Other symptoms like cardiac arrhythmias, heart attack, seizures, infections, clotting of blood, renal failure, and hypotension should be treated whenever they appear. To prevent infections, patients who develop bone marrow suppression should be placed on neutropenic (reduced white blood cells) precautions. Colony-stimulating factors such as G-CSF cause new blood cells to form and multiply. But their commercial availability is restricted.
Conclusion:
Colchicine toxicity is difficult to treat with no universally agreed antidote. Many pharmacological improvements have improved the main side effect, including gastrointestinal disturbances, and Colchicine is a promising drug in several cardiac diseases. They require urgent decontamination due to limited therapies if toxic serum level develops. Therefore early diagnosis and prompt treatment can be life-saving. If missed to diagnose, it can be fatal to the patient.
