Colchicine poisoning: the dark side of an ancient drug.
BACKGROUND
Colchicine is used mainly for the treatment and prevention of gout and for familial Mediterranean fever (FMF). It has a narrow therapeutic index, with no clear-cut distinction between nontoxic, toxic, and lethal doses, causing substantial confusion among clinicians. Although colchicine poisoning is sometimes intentional, unintentional toxicity is common and often associated with a poor outcome.


METHODS
We performed a systematic review by searching OVID MEDLINE between 1966 and January 2010. The search strategy included "colchicine" and "poisoning" or "overdose" or "toxicity" or "intoxication."


METHODS
Colchicine is readily absorbed after oral administration, but undergoes extensive first-pass metabolism. It is widely distributed and binds to intracellular elements. Colchicine is primarily metabolized by the liver, undergoes significant enterohepatic re-circulation, and is also excreted by the kidneys. THERAPEUTIC AND TOXIC DOSES: The usual adult oral doses for FMF is 1.2-2.4 mg/day; in acute gout 1.2 mg/day and for gout prophylaxis 0.5-0.6 mg/day three to four times a week. High fatality rate was reported after acute ingestions exceeding 0.5 mg/kg. The lowest reported lethal doses of oral colchicine are 7-26 mg.
CYP 3A4 and P-glycoprotein inhibitors, such as clarithromycin, erythromycin, ketoconazole, ciclosporin, and natural grapefruit juice can increase colchicine concentrations. Co-administration with statins may increase the risk of myopathy.
Colchicine's toxicity is an extension of its mechanism of action - binding to tubulin and disrupting the microtubular network. As a result, affected cells experience impaired protein assembly, decreased endocytosis and exocytosis, altered cell morphology, decreased cellular motility, arrest of mitosis, and interrupted cardiac myocyte conduction and contractility. The culmination of these mechanisms leads to multi-organ dysfunction and failure. REPRODUCTIVE TOXICOLOGY AND LACTATION: Colchicine was not shown to adversely affect reproductive potential in males or females. It crosses the placenta but there is no evidence of fetal toxicity. Colchicine is excreted into breast milk and considered compatible with lactation.


METHODS
Colchicine poisoning presents in three sequential and usually overlapping phases: 1) 10-24 h after ingestion - gastrointestinal phase mimicking gastroenteritis may be absent after intravenous administration; 2) 24 h to 7 days after ingestion - multi-organ dysfunction. Death results from rapidly progressive multi-organ failure and sepsis. Delayed presentation, pre-existing renal or liver impairment are associated with poor prognosis. 3) Recovery typically occurs within a few weeks of ingestion, and is generally a complete recovery barring complications of the acute illness.


METHODS
History of ingestion of tablets, parenteral administration, or consumption of colchicine-containing plants suggest the diagnosis. Colchicine poisoning should be suspected in patients with access to the drug and the typical toxidrome (gastroenteritis, hypotension, lactic acidosis, and prerenal azotemia).


RESULTS
Timely gastrointestinal decontamination should be considered with activated charcoal, and very large, recent (<60 min) ingestions may warrant gastric lavage. Supportive treatments including administration of granulocyte colony-stimulating factor are the mainstay of treatment. Although a specific experimental treatment (Fab fragment antibodies) for colchicine poisoning has been used, it is not commercially available.


CONCLUSIONS
Although colchicine poisoning is relatively uncommon, it is imperative to recognize its features as it is associated with a high mortality rate when missed.
Finkelstein
Yaron
Y
Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada. yaron.finkelstein@sickkids.ca
Aks
Steven E
SE
Hutson
Janine R
JR
Juurlink
David N
DN
Nguyen
Patricia
P
Dubnov-Raz
Gal
G
Pollak
Uri
U
Koren
Gideon
G
Bentur
Yedidia
Y
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000328:Adult; D002606:Charcoal / Q000627:therapeutic use; D017291:Clarithromycin / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D003078:Colchicine / Q000009:adverse effects* / Q000506:poisoning* / Q000627:therapeutic use; D003115:Colony-Stimulating Factors / Q000627:therapeutic use; D004347:Drug Interactions; D062787:Drug Overdose / Q000188:drug therapy; D064420:Drug-Related Side Effects and Adverse Reactions / Q000139:chemically induced / Q000188:drug therapy; D010505:Familial Mediterranean Fever / Q000188:drug therapy; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000627:therapeutic use; D006801:Humans; D008297:Male
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003115:Colony-Stimulating Factors; D016179:Granulocyte Colony-Stimulating Factor; D002606:Charcoal; D017291:Clarithromycin; D003078:Colchicine