Colchicine is an alkaloid medication derived from the autumn crocus plant, primarily used to treat and prevent gout attacks by reducing inflammation. It is also prescribed for the management of Familial Mediterranean Fever (FMF). The drug has a very narrow therapeutic index, meaning the difference between an effective dose and a toxic or lethal dose is extremely small. This narrow margin makes accidental or intentional overdose profoundly dangerous and frequently fatal.
The Mechanism Behind Colchicine Toxicity
Colchicine’s toxic action is an extension of its intended pharmacological effect at the cellular level. The drug functions by binding to tubulin, a protein subunit necessary for forming microtubules. Microtubules are structural components within cells responsible for maintaining cell shape, facilitating intracellular transport, and enabling cell division.
When colchicine binds to tubulin, it prevents the protein from assembling into functional microtubules. This disruption arrests mitosis, or cell division, which is devastating for rapidly dividing cells. Tissues with high cellular turnover, such as the lining of the gastrointestinal tract and the cells of the bone marrow, are the most severely affected.
This molecular disruption causes widespread cellular dysfunction, impairing protein assembly, decreasing cellular motility, and interrupting cardiac myocyte conduction. Because colchicine is metabolized by the liver and excreted by the kidneys, its concentration can become dangerously elevated when co-administered with drugs that inhibit the CYP3A4 enzyme or the P-glycoprotein transporter. These drug interactions can push a standard therapeutic dose into the toxic range, causing unintentional poisoning.
Clinical Progression of a Lethal Overdose
A lethal colchicine overdose progresses through three distinct phases, reflecting the systemic damage caused by cellular disruption.
Phase 1: Gastrointestinal Phase
This phase typically begins between 2 and 24 hours after ingestion. It is characterized by severe gastrointestinal symptoms, including intense nausea, vomiting, abdominal pain, and profuse, often bloody, watery diarrhea. The massive fluid loss leads quickly to hypovolemic shock and hypotension, which is an early cause of death. Initial blood work may show a temporary elevation in white blood cells (peripheral leukocytosis) before the more severe systemic effects manifest.
Phase 2: Multi-Organ Failure Phase
This phase represents the peak of toxicity, occurring between 24 hours and seven days after ingestion. Damage to rapidly dividing cells becomes overwhelming, leading to systemic failure. Severe bone marrow suppression results in pancytopenia, marked by profound drops in white blood cells (leukopenia), red blood cells, and platelets. Consequences during this stage include:
- Acute renal failure
- Rhabdomyolysis (muscle breakdown)
- Severe cardiac dysfunction, including arrhythmias and cardiovascular collapse
- Acute respiratory distress syndrome
- Liver failure and sepsis
Death during this phase often results from rapidly progressive multi-organ failure and intractable shock.
Phase 3: Recovery or Death Phase
This phase begins after seven days. If the patient survives the multi-organ failure of the second phase, a prolonged recovery is expected, with hematologic recovery taking several weeks. Patients who recover may experience transient alopecia (temporary hair loss), along with myopathies and neuropathies. However, ingestion exceeding 0.8 mg per kilogram of body weight is associated with near-certain mortality.
Emergency Care and Determining Survival
The management of colchicine poisoning is supportive, as there is currently no commercially available specific antidote. Immediate medical intervention focuses on rapid gastrointestinal decontamination to limit drug absorption. Activated charcoal should be administered as soon as possible, especially in patients who present early after ingesting a toxic dose.
Supportive measures are the mainstay of treatment, aimed at managing the cascading organ failures caused by the drug. Aggressive intravenous fluid resuscitation is necessary to combat hypovolemic shock resulting from massive fluid loss through the gastrointestinal tract. Vasopressors are often required to maintain adequate blood pressure and tissue perfusion in cases of shock.
For hematological complications, such as severe bone marrow suppression, granulocyte colony-stimulating factor (G-CSF) may be administered to stimulate white blood cell production. Patients with renal failure may require hemodialysis to manage electrolyte and acid-base disturbances, although dialysis does not effectively remove colchicine due to its large volume of distribution.
Several factors serve as prognostic indicators that predict a poor outcome. Ingestion of a dose greater than 0.5 mg per kilogram of body weight significantly increases the risk of mortality. Other markers associated with a worse prognosis include:
- Early onset of severe leukopenia
- Elevated prothrombin time (indicating coagulopathy)
- Development of cardiogenic shock within the first 72 hours of ingestion