The origins of colchicine and its history in poisoning can be traced back to Greek mythology. Medea was the evil daughter (and a known poisoner) of the king of Colchis, a country that lay east of the Black Sea in Asia Minor. After being betrayed by her husband Jason (of Jason and the Argonauts), she killed their children and her husband's lover. Medea often used plants of the Liliaceae family, of which Colchicum autumnale is a member, to poison her victims.17,134,176 The use of colchicum for medicinal purposes is also reported in Pedanius Dioscorides De Materia Medica, an ancient medical text, written in the first century A.D.17,134,176 and subsequently in the 6th century A.D. by Alexander of Trallis, who recommended it for arthritic conditions.17,30,110,176 However, colchicum fell out of favor, perhaps because of its pronounced gastrointestinal (GI) effects, until it was introduced for dropsy and various other nonrheumatic conditions in 1763.17,176 In the late 18th century, a colchicum-containing product known as Eau Medicinale appeared, which reportedly had strong anti-gout effects.176 Colchicine, the active alkaloidal component in colchicum, was isolated in 1820 and rapidly became popular as an anti-gout medication.134,176 Benjamin Franklin reportedly had gout and is credited with introducing colchicine in the United States.134 Colchicine is still used in the treatment of gout and has been used in a multitude of other disorders, including amyloidosis, Behçet 's syndrome, familial Mediterranean fever, pericarditis, arthritis, pulmonary fibrosis, vasculitis, biliary cirrhosis, pseudogout, certain spondyloarthropathies, calcinosis, and scleroderma.7,17,122,127 Systematic data supporting the efficacy of colchicine therapy in many of these other diseases are lacking.
Colchicine is derived from two plants of the Liliaceae family, C. autumnale (autumn crocus, meadow saffron, wild saffron, naked lady, son-before-the-father) and Gloriosa superba (glory lily).176 The autumn crocus may contain different amounts of colchicine by weight, depending on the plant part (bulb, 0.8%; flowers, 0.1%; seeds, 0.8%; and the corm or underground stem, 0.6%).110,134,159 Colchicine concentrations within the plant peak during the summer months.134 The leaves of C. autumnale closely resemble those of the Allium ursinum or wild garlic and have been mistaken for them.33,34,98 The tubers of G. superba may be confused with Ipomoea batatas (sweet potatoes).176
There is a lack of good epidemiologic data on colchicine poisoning. The American Association of Poison Control Centers records several hundred overall exposures annually. The majority of these exposures are in adults and are categorized as unintentional. Of the cases with a recorded outcome, approximately 10% reportedly to have major toxicity or resulted in death (see Chap. 135). At least 50 adverse events (23 of which were fatalities) have been linked to the use of intravenous (IV) colchicine.216 The United States Food and Drug Administration recently announced its intent to stop the marketing of injectable compounds containing colchicine,216 and serious questions remain about the utility of colchicine in light of its extremely narrow therapeutic index.
Colchicine is a potent inhibitor of microtubule formation and function, which interferes with cellular mitosis, intracellular transport mechanisms, and maintenance of cell structure and shape.127,176 The ubiquitous presence of microtubules in cells throughout the body presents a wide variety of targets for colchicine in poisoning.127,176 Colchicine accumulates in leukocytes and has inhibitory effects on leukocyte adhesiveness, ameboid motility, mobilization, lysosome degranulation, and chemotaxis.17,40,49,74,81,127,136,137,ch37rf171,ch37rf172,ch37rf173177 At doses used clinically, colchicine inhibits neutrophil and synovial cell release of chemotactic glycoproteins.180,202 Colchicine also inhibits microtubule polymerization, which disrupts inflammatory cell-mediated chemotaxis and phagocytosis.184 It reduces expression of adhesion molecules on endothelial and white blood cells and affects polymorphonuclear cell cytokine production.5,18,152 Colchicine also acts as a competitive antagonist at GABAA receptors.226
Pharmacokinetics and Toxicokinetics
Colchicine is rapidly absorbed in the jejunum and ileum and has a bioavailability generally between 25% and 50%.17,123,176,188 It is highly lipid soluble12,17,176 with a volume of distribution that ranges from 2.2 to 12 L/kg and that may increase to 21 L/kg in overdose.158,164,176,181,182,214,223 Colchicine binding to plasma proteins approaches 50%.17,127,153,176 Protein binding is principally to albumin, although some binding to α-1-glycoprotein acid and other lipoproteins is reported.188 During the first several hours after acute overdose, colchicine is sequestered in white and red blood cells in concentrations 5-10 times higher than serum.188 Peak serum concentrations after ingestion occur between 1 to 3 hours.127 Toxic effects usually do not occur with concentrations less than 3 ng/mL.75,153,222
Colchicine is primarily metabolized through the liver with up to 20% of the ingested dose excreted unchanged in the urine.108,176,214 Colchicine undergoes demethylation by the cytochrome P450 3A4.108,127,164,213 Detoxification mainly occurs through deacetylation, demethylation, biliary secretion, and excretion in the stool.108,127,150,186,188,213 Enterohepatic recirculation of colchicine occurs.1,164,176
Serum elimination half-lives ranging from 9 to 108 minutes have been reported.10,95,176,188,223 On closer examination, however, these times probably more accurately reflect a rapid initial distribution phase. The drug undergoes a more delayed terminal elimination phase, which ranges from 1.7 to 30 hours, depending on the individual compartment model used to estimate elimination and the amount of colchicine absorbed.1,79,176,182,186,188,214 These values are on the same order as and probably reflect the tubulin—colchicine complex disassociation time.164 Individuals with renal failure and liver cirrhosis may have elimination half-lives that are prolonged up to 10-fold.127 Colchicine can remain in measurable tissue quantities for a long time, as evidenced by its detection in white blood cells after 10 days and in urine 7 to 10 days after exposure.74,176 Colchicine can cross the placenta and is secreted in breast milk, but it is not dialyzable.127 Postmortem examination of colchicine-poisoned patients reveals high concentrations within the bone marrow, testicles, spleen, kidney, lung, brain, and heart.181
Colchicine metabolism is susceptible to drug interactions. Because colchicine is detoxified through CYP3A4, blood concentrations are susceptible to xenobiotics that alter the function of this enzyme, such as erythromycin, clarithromycin, and grapefruit juice.42,67,87,127 In particular, coadministration of clarithromycin and colchicine, especially in patients with renal insufficiency, increases the risk of fatal interaction.107 P-glycoprotein (PGP) expels and clears colchicine, and drugs that inhibit PGP may directly affect the amount of colchicine eliminated and hence, toxicity.164 For example, cyclosporine increases colchicine toxicity.127,200,201
Microtubules play a vital role in cellular mitosis and possess a high amount of dynamic instability.14,73,116,194 Microtubules are made up of tubulin protein subunits, of which three are known to exist: α, β, and γ.116,146,194 These structures are highly dynamic with α-β tubulin heterodimers, constantly being added at one end and removed at the other.116,117 Microtubules undergo two forms of dynamic behavior: dynamic instability, in which microtubule ends switch between growth and shortening phases, and treadmilling, in which there is a net growth (addition of heterodimers) at one end and a shortening (loss) at the other.20 Assembly and polymerization dynamics are regulated by additional proteins known as stabilizing microtubule-associated proteins (MAPs) and destabilizing MAPs.20 These dynamic behaviors and a resultant equilibrium are needed for multiple cell functions, including cell support, transport, and mitotic spindle formation for cell replication.116 Xenobiotics that bind to specific regions on tubulin can interfere with microtubule structure and function, thereby causing mitotic dysfunction and arrest.146,194 This leads to cellular dysfunction and death.194 Xenobiotics that target microtubules can be generally divided into two categories: polymerization inhibitors (ie, vinca alkaloids, colchicine) and polymerization promoters (ie, taxanes, laulimalides).20
Colchicine binds to a tubulin dimer at a specific region known as the colchicine-binding domain, which is located at the interphase of the α and β subunits of the tubulin heterodimer.20,99,116,167,194,217 This binding is relatively slow, temperature dependent, and generally irreversible, resulting in an alteration of the protein's secondary structure.99,116,167,189 Colchicine binds at a second reversible but lower-affinity site on tubulin.116,133 Current evidence suggests that the colchicine—tubulin complex binds to the microtubule ends and prevents further growth by sterically blocking further addition of dimers.20 Conformational changes in the tubulin and colchicine complex also result as colchicine concentrations increase, which weakens the lateral bonds at the microtubule end.20,146,194 Lateral and longitudinal interactions between dimers within a microtubule help stabilize the structure. The number of tubulin—colchicine dimers incorporated into the microtubule determines the stability of the microtubule ends.20 All of these processes may prevent adequate binding of the next tubulin subunit and result in cessation of microtubule growth.146,194 At low concentrations, colchicine arrests microtubule growth, where as at high concentrations, colchicine can actually cause microtubule depolymerization through disassociation of tubulin dimers.20
These conformational changes ultimately result in disassembly of the microtubule spindle in metaphase of cellular mitosis, cellular dysfunction, and death.77,99,116,167,189,194 The effects of colchicine are dose dependent, with high concentrations inhibiting further microtubule polymerization, as well as inducing depolymerization of already formed microtubules.130 Low concentrations can simply affect new microtubule formation and have no effect on preestablished polymer mass.130 Colchicine also inhibits microtubule-mediated intracellular granule transport.17,127 Some in vitro animal studies have also shown that colchicine might inhibit DNA synthesis by changing cell regulatory events at a critical time during the mitotic cycle.72,78,101,130
The toxic dose for colchicine is not well established. An early case series suggested that patients with ingestions of greater than 0.8 mg/kg uniformly died and those with ingestions above 0.5 mg/kg but less than 0.8 mg/kg would survive if given supportive care.23 This information was based on a limited series of patients and is likely not generalizable.156 More recent literature suggests that severe toxicity and even death may occur with smaller doses, and patients may survive ingestions in excess of 0.8 mg/kg.63,81,88,94,156,204 This inability to accurately quantify the toxic dose in humans is likely due in great part to difficulty in dose estimation from the patient's history and significant advances in supportive care.
The clinical findings in poisoned patients is commonly described as triphasic (Table 37–1).103,142,158,204 GI irritant effects, such as nausea, vomiting, abdominal distress, and diarrhea, occur initially within several hours after an overdose3,32,34,59,66,118,142,147,219 and may lead to severe volume depletion.87,106,137,156,158,160,204,225 This first stage usually persists for the first 12 to 24 hours after ingestion.106,142 The second stage is characterized by widespread organ system dysfunction, particularly the bone marrow, and lasts for several days.34,63,156,158,204 The final phase is characterized by recovery or death, and the progression can usually be defined within 1 week.103,106,142,204
Table 37–1. Colchicine Poisoning: Common Clinical Findings, Timing of Onset, and Treatment |Favorite Table|Download (.pdf)
Table 37–1. Colchicine Poisoning: Common Clinical Findings, Timing of Onset, and Treatment
|Phase||Timea||Signs and Symptoms||Therapy/Followup|
|I||0—24 hours||Nausea, vomiting, diarrhea||Antiemetics|
|Consider GI decontamination|
|Leukocytosis||Close observation for leukopenia|
|II||1—7 days||Possible risk of sudden cardiac death (24—36 hours)||ICU admission and appropriate resuscitation|
|Acute respiratory distress syndrome||Oxygen, mechanical ventilation|
|Electrolyte imbalances||Repletion as needed|
|Rhabdomyolysis||IV fluids, hemodialysis|
|III||>7 days||Alopecia||Follow-up within 1—2 months|
|Myopathy, neuropathy, or myoneuropathy||EMG testing, biopsy and neurological follow-up as needed|
After overdose, the hematopoietic effects of colchicine are characterized by an initial peripheral leukocytosis, which may be as high as 30,000/mm3. This is followed by a profound leukopenia, which may be lower than 1000/mm3. It is commonly accompanied by pancytopenia, usually beginning 48 to 72 hours after overdose.17,32,79,87,102,142,161 The hematopoietic manifestations occur as a result of colchicine's effects on bone marrow cell division.30,106,145,181,225 A rebound leukocytosis and recovery of all cell lines occur if the patient survives.
Colchicine toxicity is associated with the development of dysrhythmias and cardiac arrest.30,103,106,142,158 Sudden cardiovascular collapse from colchicine typically occurs between 24 to 36 hours after ingestion.30,41,142,145,156 Profound hypovolemia and shock may contribute to this collapse,17,87,156,158,204 but colchicine has direct toxic effects on skeletal and cardiac muscle, causing rhabdomyolysis.26,50,140,148,157,220,225
Myopathy,35,36,193,229 neuropathy,8,130 and a combined myo-neuropathy6,52,61,70,125,126,178,199,233 are described as a result of both long-term therapy and acute poisoning.130 A combined myoneuropathy is reported more often, with myopathy dominating the clinical picture.6,52,61,70,125,126,178,199,233 The myoneuropathy is often initially misdiagnosed as polymyositis or uremic neuropathy (caused by coexistent renal insufficiency).6,126 Myoneuropathy usually develops in the context of chronic, therapeutic dosing in patients with some baseline renal impairment,6,52,61,70,125,126,178,199,233 although it may also occur in the presence of normal renal function.175 Patients may present with proximal limb weakness, distal sensory abnormalities, distal areflexia, and nerve conduction problems consistent with an axonal neuropathy.126,169 A small amount of myelin degeneration is reported on autopsy, which suggests a myelinopathic component.31 The myopathy is characterized by vacuolar changes on biopsy and accompanied by lysosome accumulation.6,70,126,233 Elevated serum creatine kinase activity is present concurrently with symptoms.126,158 Weakness usually resolves within several weeks of drug discontinuation.126 Myopathy may also occur when concomitant use of hydroxymethylglutaryl—coenzyme A reductase inhibitors are used in patients with renal insufficiency.2 Myopathy symptoms typically resolve within 4 to 6 weeks, although it may take up to 6 to 8 months in some patients.229
Acute respiratory distress syndrome occurs with colchicine toxicity.11,59,102,150,191,195 The etiology is not well understood but may result from several factors, including respiratory muscle weakness, multisystem organ failure, and possibly direct pulmonary toxicity.59,142,150,191,212 Other indirect effects of colchicine include renal failure and various electrolyte abnormalities resulting from fluid loss and impaired kidney function.17,63,87,130,158
Alopecia, which is usually reversible, is a well-described complication that occurs 2 to 3 weeks after poisoning in survivors.17,79,87,88,106,133,211 Dermatologic complications range in severity from epithelial cell atypia to toxic epidermal necrolysis.4,9,77,86,185
Neurologic effects, including delirium, stupor, coma, and seizures, might be at least partly attributable to the multisystem disease caused by poisoning and not necessarily a direct effect of colchicine.35,161,176,195 The cause of seizures is unclear but it might be partly attributable to antagonism of GABAA receptors.226
Other reported complications of colchicine poisoning include bilateral adrenal hemorrhage,54,208 disseminated intravascular coagulation,106,176,195 pancreatitis,161and liver dysfunction.35,158,176
Colchicine concentrations in body fluids are not available in a clinically relevant fashion and have no well-established correlation with severity of illness. However, effective steady-state serum concentrations for treatment of patients with various illnesses are reported as 0.5 to 3.0 ng/mL.153 Concentrations greater than 3.0 ng/mL are generally associated with toxicity.75,153,222 Serum concentrations do not correlate well with the amount of xenobiotic ingested in massive oral overdose settings.62 Initial laboratory monitoring should include a complete blood count (CBC), serum electrolytes, renal and liver function tests, creatine kinase, phosphate, calcium, magnesium, prothrombin time, activated partial thromboplastin time, and urinalysis. The need for other laboratory studies, such as a troponin, arterial blood gases, lactate, fibrinogen, and fibrin split products, should be considered, depending on the clinical situation. If cardiac toxicity is present or suspected, serial troponins (every 6–12 hours) should be performed because increasing concentrations may be predictive of cardiovascular collapse.84,220 An electrocardiogram and chest radiograph should also be obtained. Serial CBCs are indicated (at least every 12 hours) to evaluate for the development of depression in cell lines.
Treatment for patients with colchicine toxicity is mainly supportive, which includes IV fluid replacement, vasopressor use, hemodialysis (for renal failure), antibiotics for suspected secondary infection, colony-stimulating factors and adjunctive respiratory therapy (endotracheal intubation, positive end-expiratory pressure), as indicated. Consultation with nephrology and hematology specialists should be obtained in the case of impaired renal function or evidence of hematotoxicity.
Because most patients with an acute oral colchicine overdose present several hours after their ingestion, vomiting has already begun, and the utility of GI decontamination is inadequately defined. However, given the extensive morbidity and mortality associated with colchicine overdose, orogastric lavage probably should be performed in patients who present within 1 to 2 hours of ingestion and are not vomiting.25,218 A dose of activated charcoal (AC) should be administered after lavage, or in its place, and multiple-dose AC (MDAC) should be considered because of enterohepatic recirculation.1,176 The delay in presentation to a health care facility coupled with the presence of GI symptoms such as vomiting significantly complicates using MDAC. However, antiemetic medications can be given to control emesis and facilitate AC administration.
Experimental colchicine-specific antibodies can restore colchicine-affected tubulin activity in vitro and were successfully used in a single case of severe colchicine poisoning.13 The administration of Fab fragments was temporally associated with a dramatic improvement in clinical and hemodynamic status. This improvement was also associated with a significant increase in serum colchicine concentrations, which suggests a redistribution of drug into the intravascular space.13 Unfortunately, this therapy is not commercially available.
Granulocyte-colony stimulating factor (G-CSF) has been useful in the treatment of patients with colchicine-induced leukopenia and thrombocytopenia.57,97,120,232 The dose of G-CSF, the dosing frequency, and the route of administration were variable in the reported cases.57,97,120,232 G-CSF should be started if the patient begins to manifest evidence of leukopenia. Dosing should be in accordance with the manufacturer's instructions.
Hemodialysis and hemoperfusion are not viable options for patients with colchicine poisoning based on its large volume of distribution, but hemodialysis may be required if renal failure is present.16,21,22,181,182,214,223
Because of the significant morbidity and mortality associated with colchicine toxicity, all symptomatic patients with suspected or known overdoses should be admitted to the hospital for observation. Because these patients have a risk of sudden cardiovascular collapse within the first 24 to 48 hours156 intensive care unit monitoring is recommended for at least this initial time period. Troponin should be ordered every 6 to 12 hours during this period because increasing results may suggest an increased risk of cardiotoxicity and cardiovascular collapse.84,220 Poisoned patients manifest GI signs and symptoms within several hours of ingestion and should be observed for at least 8 to 12 hours. Patients who do not manifest GI signs and symptoms within that time period after ingestion are unlikely to be significantly poisoned.