Colchicine is highly toxic and has no antidote. In severe cases, death may occur even with the highest level of supportive care.
Toxicity can occur following acute overdose, supratherapeutic use, or ingestion of colchicine containing plants – Colchicum autumnale (Autumn Crocus), Gloriosa superba (Glory Lily)
Early efforts at decontamination and ongoing enhanced elimination are paramount in cases of potential toxicity.
Colchicine adversely affects the formation and function of microtubules. These are essential in the metaphase process of cell division during mitosis and for intracellular transport of a variety of substances essential for cell survival. Thus, rapidly dividing cells and other cells with high rates of metabolism are most severely affected.
Colchicine causes dose-dependant toxicity. Doses above 0.5mg/kg can cause severe toxicity, but lower doses can be associated with severe systemic toxicity, especially if risk factors are present (see below). A dose less that 6mg is unlikely to cause toxicity in an adult.
Colchicine containing plants have 0.1-0.8% colchicine in both bulbs and other plant parts.
Colchicine is rapidly absorbed from the small intestine. Peak concentrations occur in therapeutic use within 2 hours. There is probably significant first pass metabolism, though this is likely to be reduced in overdose. It is not known whether the gastrointestinal toxicity alters the bioavailability of colchicine.
Colchicine has a large volume of distribution (1.5-3 L/kg) and crosses the blood brain barrier.
Colchicine is metabolised in the liver to inactive metabolites as well as being excreted unchanged in bile and urine. The half-life in therapeutic use is 20 minutes.
There is significant enterohepatic circulation and P-Glycoprotein inhibitors and CYP3A4 inhibitors are likely to increase toxicity.
Colchicine toxicity follows a fairly predictable, prolonged time course.
2-12 hours: vomiting and diarrhoea leading to dehydration, hypovolaemia and acute kidney injury. Leucocytosis may be seen at this stage.
1 to 7 days: this stage is typified by multi-organ failure including renal failure, liver failure, myocardial depression, arrhythmias and respiratory failure. Other effects include metabolic acidosis, hypocalcaemia, neurotoxicity, consumptive coagulopathy, rhabdomyolysis, potential death.
5 to 10 days: bone marrow suppression, mostly commonly seen as neutropenia but thrombocytopenia may also develop.
>10 days: recovery, potential for rebound leucocytosis, peripheral neuropathy and alopecia.
Key investigations depend on a patient’s clinical condition. Any patient a risk of systemic toxicity should have a set of blood towards to end of their observation period (or earlier if symptoms develop) looking for evidence of organ injury.
Early intervention of airway and breathing are unlikely to be needed but may be required if significant toxicity develops. In large ingestions, where a patient is refusing potential lifesaving decontamination, it may be appropriate to intubate the patient to allow this to occur – this should be decided on a case-by-case basis.
Early hypotension will likely be due to significant fluid losses due to GI toxicity and should be treated with fluid replacement. As toxicity progresses, myocardial depression may develop. A bedside echocardiogram can be helpful in determining if ongoing hypotension is cardiogenic or vasodilatory in nature. If cardiac function is depressed, then adrenaline is first line. If cardiac function is maintained, then target vasoplegia with noradrenaline being first line.
Granulocyte-colony stimulation factor (G-CSF) can be used if neutropenia is prolonged or severe- discuss with a haematologist.
Given the severity of toxicity that may develop and the lack of antidote, early decontamination is a vital intervention. The below table gives the doses ingested and the risk factors present that determine whether decontamination is recommended.
Colchicine undergoes enterohepatic circulation, making it amenable for treatment with multi-dose activated charcoal. The below table gives suggested doses and risk factors that determine whether enhanced elimination if recommended.
| Exposure over 24hr (mg/kg) | Risk of Toxicity | Intervention |
|---|---|---|
| <0.05 or 0.05-0.1 (no risk factors) | Low | None |
| 0.05-0.1 (with risk factors) | Potential for toxicity inc mortality | SDAC |
| 0.1-0.5 (no risk factors) | Potential for toxicity inc mortality | SDAC |
| 0.1-0.5 (with risk factors) | Potential for toxicity inc mortality | MDAC |
| 0.5-0.8 | 10% mortality | MDAC |
| >0.8 | High risk for mortality | MDAC |
SDAC: Single dose activated charcoal 1g/kg (max 50g)
MDAC: Multi-dose activated charcoal: 1g/kg initial dose followed by 0.5g/kg (max 35g), 2 hourly.
Risk factors: Renal failure, liver failure or presence of interacting drug (CYP3A4 or P-gp inhibitors)
Colchicine Fab fragments have been studied in a limited number of trials. They are not commercially available and therefore are not an option for treatment.
Patients with evidence of multiorgan failure or other signs of severe poisoning will need admission to an intensive care environment.
Those exposed to more than 6 mg or 0.1 mg/kg of colchicine should be observed for at least 24 hours, for the development of gastrointestinal effects or severe poisoning.