Colchicine By Chaim

Intoxication: Clinical Pharmacology, Features, and Management Putterman,

Eldad Ben-Chetrit,

The use of colchicine for acute gouty atihritis dates to ancient times. In recent years, colchitine also has been used successfully for various other rheumatic and nonrheumatic conditions. Colchicine is a safe drug when used according to established therapeutic guidelines. However, toxicity can be considerable if ingested intentionally or if the recommended doses are exceeded. Colchicine intoxication is characterized by multiorgan involvement and by the poor prognosis associated with administration of large amounts of the drug. Therapy is basically supportive and symptomatic because of the rapid distribution

M

ANY REPORTS have stressed the efficacy and safety of colchicine in the treatment and prophylaxis of acute gouty arthritis’,’ and familial Mediterranean fever (FMF).7~h Nevertheless, severe complications can occur from using this drug, at times resulting in death. Mortality and morbidity have resulted with ordinary therapeutic use of colchicine or with overdosage (either iatrogenic or in suicide attempts). Colchicine use has been on the rise, with an increased number of suggested and approved indications.‘.” In addition to gout and FMF, a beneficial effect of colchicine has been reported in primary biliary cirrhosis,” alcoholic cirrhosis,“’ psoriasis,” palmar and plantar pustulosis,” necrotizing vasculitis,” Bechet’s disease,14 amyloidosis,” sarcoidosis,‘h and scleroderma.” It is therefore appropriate to review and summarize various aspects of the use of colchicine. We will particularly emphasize the protean manifestations of colchicine toxicity and recent experimental techniques for treating intoxication. HISTORY OF COLCHICINE

The Latin name for the meadow saffron is Colchicum, derived from the name of the ancient district of Colchis, which was situated on the eastern shore of the Black Sea. Colchis was the original source of this plant, or of one similar to it. Its medical use is mentioned in Pedanius Dioscotides De Materia Medica, written in the first century AD. Alexander of Trallis, who

Seminars m Arthritis and Rheumatism,

Yoseph

Risk Factors,

Caraco, and Micha Levy

and binding of colchicine to the affected tissues. Use of anticolchicine antibodies is a novel approach that has shown promise in experimental models. Important research questions pertain to the effect of liver and kidney disease on colchitine metabolism, use of colchicine levels in the diagnosis of intoxication and for prognostication, and application of immunotoxicotherapy for colchicine poisoning in humans. Copyright 0 1991 by W. B. Saunders Company INDEX WORDS: Colchicine; colchicine intoxication; gout; familial Mediterranean fever.

lived in the sixth century AD, is regarded as the first to recommend colchicine as a cathartic in the treatment of gout. After a period in which the use of colchicine fell into disfavor (possibly due to gastrointestinal toxicity), the drug was reintroduced by Baron von Storck of Vienna in 1763, but for dropsy and other nonrheumatic conditions rather than for podagra. In 1770, Hussan introduced Eau Medicinale, which he claimed possessed extraordinary effects in a staggering list of diseases and afflictions. In 1810, Jones reported that Hussan’s preparation had remarkable effects in gout. After its isolation from the Colchicum autumnale tuber in 1820 by Pelletier and Caventou, colchicine gained rapid popularity as being effective in gout, as well as in other related and nonrelated disorders.“~“’

From the Division of Medicine, Rheumatology Unit und FMF Clinic, and Climcal Phamtacologv Unit, Hudu.ssah UniversiQ Hospital, Ein-Kerem, Jerusalem, Isruel. The uuthors ucknowledge the supparr of the Ado&r und Evelyn Blum Research Fund for Arthritis. Chaim Putterman, MD: Resident in Medicine, D/vision of Medicine; Eldad Ben-Chetrit, MD: Senior Lecturer in Medicine, Division of Medicine, Rheumatology Unit and FMF Clinic; Yoseph Caraco. MD: Lecturer in Medic,ine, Division of Medicine and Clinical Pharmacology Umt: Micha Levy, MD: Professor and Chairman, Division of Medicine. Address reprint requests to Michu Levy, MD, Depurtment of Medicine A, Hadassah liniversity Hospital, POR 12000. Jerusalem 41IZ0, Israel. Copyright o 1991 by W.B. Saunders Cornpam 0049.037219112103-0003$5.0010

Vol21, No 3 (December).1991: pp 143-155

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CHEMISTRY

AND STRUCTURE

Colchicine is an alkaloid that can be extracted from two plants of the lily family: Colchicium autumnale (autumn crocus, meadow saffron) and Gloriosa superba (glory lily). Some cases of overdose have resulted from the resemblance of the tubers of the glory lily to the yams of sweet potatoes. The chemical formula of colchicine is N-(5,6,7,9-tetrahydro-1,2,3,10-tetramethoxy-9oxobenzo[a]hep-taien-7-yl) acetamide, and the structure of the drug is shown in Fig 1. The subject of the structure-activity relationship of colchicine has been reviewed by Wallace.*’ PHARMACOKINETICS

Colchicine is most commonly administered by mouth, formulated in tablets of 0.5 or 0.6 mg. Intravenous (IV) administration is also possible in the form of a 0.5 mg/mL solution. Colchicine concentration in the plasma is well described by a two-compartment open model with zero-order input.** When administered orally, colchicine is rapidly absorbed from the gastrointestinal tract. The bioavailability of colchicine was never accurately measured, but different studies have estimated it to be in the range of 25% to 40%.** Large amounts of colchicine affect jejunal and ileal function,*” the most likely foci of absorption. Wallace and Erte124 measured colchicine levels serially after oral administration of 1 mg of colchicine to healthy volunteers. Peak colchicine concentration averaged 0.3 ug/mL, but with wide individual variation. Two disparate populations in the distribution of the drug were identified in this study: one group had peak levels after 30 minutes, whereas the other had peak levels 2 hours after ingestion. A recent study*’ found

ET AL.

that oral administration of colchicine as tablets or in oral solution did not result in different pharmacokinetics. The volume of distribution of colchicine is calculated as about 2.2 L/kg body weight.26 This volume is greater than total body water, indicating significant peripheral binding. Approximately 50% of circulating colchicine is bound to plasma proteins.*’ Colchicine is excreted and undergoes extensive metabolism by the liver. Metabolism involves mainly deacetylation, followed by biliary excretion.28 The role of colchicine metabolites in the biological effects of the drug is unclear.29 Up to 20% of the dose administered is excreted unchanged in the urine.25,26The presence of large amounts of both the parent drug and its metabolites in the bile and the intestinal secretions points to the existence of enterohepatic recirculation.25 In patients with liver disease,*’ the fraction of the drug excreted unchanged in the urine increases. Wallace et al*’ also found a shorter initial half-life in these patients, attributed to the lack of enterohepatic circulation. The plasma clearance of colchicine appears rapid. Initially, the plasma elimination half-life after IV administration was reported to be less than 20 minutes.3” Other studies have reported values of 9 minutes*’ and 65 minutes.3’ As the method of measurement became more sensitive, it was evident that these determined halflives actually reflected the initial distribution phase, which was followed by a slower and more prolonged terminal elimination phase. The terminal half-life averaged 19.4 hours in seven healthy subjects (range, 3.6 to 20.9 hours)** and 9.3 hours in another study of 12 healthy subjects (range, 1.73 to 14.4 hours).25 Measurable colchicine concentrations are present in urine 7 to 10 days after a single IV dose. Significant colchicine concentrations are found in white blood cells after 10 days.“’ In summary, colchicine is rapidly absorbed but remains for protracted periods in certain tissues.

BH30 SIDE EFFECTS

Fig 1: Chemical structure of colchicine.

The frequency of side effects from colchicine depends on the dose and route of administration. Gastrointestinal side effects occur in up to 80% of patients receiving colchicine in full therapeutic doses.33 Gastrointestinal distur-

COLCHICINE INTOXICATION

bances also are a common and well-recognized feature of colchicine toxicity,34 and administration of the drug is usually discontinued on the appearance of severe symptoms. This is a built-in safety feature of oral colchicine administration. Because gastrointestinal symptoms are much less common with IV colchicine?3 additional risk is created, which may be one of the reasons this formulation is no longer available in Great Britain. Gastrointestinal side effects of colchitine include crampy abdominal pain, nausea, vomiting, and diarrhea (all caused by hyperperistalsis). Race et al”’ found that all of their subjects receiving 1.9 to 3.6 mg colchicine daiIy developed diarrhea, with various disturbances in absorption. Conversely, of 54 patients treated with 1 mg colchicine daily for cirrhosis,‘” only 9 reported reversible diarrhea, which in no case necessitated discontinuation of the study medication. Twelve patients with FMF receiving colchicine prophylaxis (1 to 2 mg daily) for 3 years or more were evaluated for the presence of gastrointestinal side effects.36 Three patients had mild steatorrhea with decreased jejunal Na-,K--adenosine triphosphatase (Na’,K’ATPase) activity, yet colchicine was discontinued in only one patient. The antimitotic effects of colchicine have raised concerns regarding chromosomal and gonadal side effects. However, it should be kept in mind that the toxic effects of colchicine in cell and animal models were usually seen with concentrations one or two magnitudes larger than those reached in therapeutic dosing in humans. Cohen et a13’performed a cytogenetic evaluation in patients receiving long-term colchicine therapy for prophylaxis of FMF. Mitotic rates, percentage of tetraploidy, and chromosomal breakage rates were determined in lymphocyte cultures. No statistically significant differences were found between the control and patient groups. As for gonadal side effects, rabbits treated with relatively large doses of colchicine showed various degenerative changes upon histological examination of the testes, including loss of differentiation from spermatogonia to spermatozoa. The interstitial cells were unaffected, and the Leydig cells were intact.38 Also in rabbits, incubation of sperm cells with colchicine (10 to

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100 p,g/mL) did not adversely affect fertilization rates.3y In men, Merlin4” described azoospermia in a patient receiving 1.2 mg colchicine daily; sperm counts were normal with 0.6 mg of colchicine daily or no treatment. OvulationJ1 was not affected in women receiving 1.2 mg of colchicine daily. All 34 male patients receiving colchicine prophylaxis for gout fathered healthy children.“’ On the other hand, children with trisomy 21 have been born to fathers treated with colchitine for gout at the time of conception.4’ Some years ago we summarized our experience regarding the effect of long-term colchitine prophylaxis on fertility in both men4’.” and women.46 In a preliminary report regarding six men receiving long-term colchicine therapy,44 no effects of colchicine on fertility were noted, and levels of spermatograms, testosterone, follicle-stimulating hormone (FSH), luteinizing hormones (LH), and prolactin were all within normal limits. In a larger patient population,J’ however, 4 of 19 men had fertility problems when receiving 0.5 to 2 mg of colchicine daily. One patient had azoospermia, and while in 3 patients the spermatogram was normal but sperm penetration was pathological. In women,‘(’ obstetric histories were obtained for 36 subjects receiving long-term colchicine therapy. Miscarriage and infertility rates were high but similar to those reported for women with FMF before colchicine therapy was instituted. All 16 infants born to mothers who had taken colchicine during pregnancy were normal. Formerly, it was believed that neuromuscular side effects were a rare manifestation of colchitine intoxication, usually appearing in combination with damage to other organ systems. Recently, Kuncl et a14’ described neuromuscular toxicity of colchicine in 12 patients, all of whom were receiving customary doses of colchicine for gout. A feature common to all these patients was some degree of renal impairment. Myopathy, at times severely incapacitating, usually presented as proximal weakness and was always accompanied by elevated serum creatine kinase levels of muscular origin, both features remitting within a month after stopping the drug. The clinical picture of the myopathy was initially confused with polymyositis, but muscle strength returned to normal after drug discontinuation.

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PUTTERMAN

A mild, slowly resolving polyneuropathy accompanied the muscular manifestations. Histological studies of involved muscles implied disruption of a microtubule-dependent cytoskeletal network which interacts with lysosomes as the responsible pathophysiological mechanism. An additional case was described recently4x in which colchicine neuromyopathy appeared after renal transplantation. It was postulated that besides renal dysfunction, concurrent use of colchicine with immunosuppressive drugs also may predispose to this particular adverse effect. Other rare side effects of chronic colchicine administration included bone marrow depression with leukopenia (even agranulocytosis), aplastic anemia, rash, and depilation.34 Nevertheless, it is commonly thought that maintenance therapy with colchicine is associated with a notably low prevalence of serious side effects. (For a summary of the side effects of colchicine therapy, see Table 1.)

Table 1: Manifestations

ET AL.

of Colchicine Toxicity

Gastrointestinal Abdominal

pain

Nausea/vomiting Diarrhea Paralytic ileus Hepatocellular

damage

Pancreatitis Respiratory Respiratory distress ARDS Hematological Leukocytosis (first stage) Bone marrow hypoplasia Coagulopathy Hemolytic anemia Skin Rash Alopecia Cardiovascular Hypovolemia Hypotension Depressed myocardial contractility Peripheral vasodilation

COLCHICINE

INTOXICATION

Less than 50 cases of colchicine toxicity have been reported in the English and American literature since the review by MacLeod and Phillips in 1947.49 The French journals, however, report more extensive experience with this entity.50.51In the following sections, data available from case reports and series regarding clinically relevant aspects of intoxication with natural or purified colchicine are reviewed. Bismuth et al” reported that all 38 patients who ingested less than 0.5 mg/kg of colchicine survived with supportive therapy only, whereas all patients ingesting more than 0.8 mg/kg died of irreversible shock within 72 hours. However, the correlation between the amount of drug ingested, severity of clinical manifestations, and prognosis is not straightforward. Fatality from colchicine overdose has been reported with 74y and 7.5 mg, 52whereas survival eventuated even after ingestion of an estimated 350 mg.53 Toxic effects can result from the ingestion of plants containing colchicine. However, severe manifestations of intoxication are rare, probably due in part to the large volume of plant material needed to cause toxicity. The colchitine content of meadow saffron is about 0.1%. In one case, fatality was reported from the ingestion of the equivalent of 270 mg of colchi-

Arrhythmias Myocarditis Renal Proteinuria/hematuria Acute renal failure Metabolic Metabolic acidosis Hyponatremia Hypocalcemia Hypophosphatemia Hypomagnesemia Neuromuscular Mental status changes Coma Ascending paralysis Seizures Peripheral neuropathy Rhabdomyolysis Fertility Azoospermia Sterility Miscellaneous Fever Hypothermia

cine.s4 The tubers of the glory lily contain about 0.4% colchicine, with severe toxicity reported from 12.5g of tubers, but also from 60 mg.” IV administration of colchicine can be dangerous because of the relative lack of gastrointesti-

COLCHICINE INTOXICATION

nal warning signs of toxicity. The doses of colchicine causing toxicity when administered IV recently have been evaluated by Wallace and Singer.“’ Examples of colchicine doses that were fatal when administered IV were 18 mg in 11 days,“’ 10 mg in 5 days,” and 8 mg in 3 days.” When colchicine was administered IV in combination with an oral dose, 7.5 mg (plus 1.8 mg orally) and 7.2 mg (plus 1.2 mg orally) were lethal.‘“~“” Wallace and Singer’” stated that all reported cases of severe toxicity arising from IV administration represent inappropriate drug use. Adherence to published recommendations?” can potentially abolish severe colchicine intoxication by this route, even when preceded by oral therapy. The lowest oral doses causing lethal colchitine toxicity have been 7 mg over 3 days in a 3%year-old man” and single doses of 7.5 mg in a 41 -year-old woman,’ 8 mg in an 18-year-old and 11 mg in a 13-year-old boy.“’ woman.” Bismuth et al” reported that an oral dose of 0.8 mgikg was uniformly fatal in their series. Gaultier et al,‘” in their series of 23 patients, noted no deaths in the 10 patients ingesting less than 20 mg. Colchicine overdose was lethal in 1 of 3 patients ingesting 30 mg, 2 of 5 ingesting 40 mg, and all 5 ingesting more than 40 mg. Hill et al” conclude that the lethal dose seems to be about 41) mg in adults with normal renal function. In seven cases of intoxication occurring in patients receiving the drug orally,4’~h2~64~hh the average dose associated with a lethal outcome was only 16 mg. On the other hand, patients may survive after ingesting 40 to 60 mg orally.h’.h” Colchicine toxicity may occur when exposure is by other than oral or IV routes. Nadius et alh7 reported a 20-year-old man with life-threatening multisystem dysfunction from a large single dose (50 mg) of colchicine instilled into the urethra for the treatment of condyloma acuminata. Baldwin et alhXtreated a young man who insufflated nasally (“snorted”) approximately 200 mg of colchicine powder, mistaking it for methamphetamine. For technical reasons, there are few studies of colchicine intoxication in which colchicine levels were measured in blood, its components (white blood cells), or urine. Therefore, it is not possible to predict the severity of poisoning, except by using the amount supposedly in-

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gested. With improvements in technique, a more accurate predictive tool may develop based on tissue drug levels. In summary, we concur with Stapczynski et al” that it is not plausible to clearly separate the nontoxic, toxic, and lethal doses of colchicine. In general, the risk of a severe reaction correlates directly with the dose administered, with a high case-fatality rate associated with oral doses exceeding 40 mg in adults. However, considerable variability exists among individuals. There may be a population subset with an increased sensitivity to the toxic effects to the drug” who have severe toxic reactions even at low doses, although evidence of idiosyncratic “hypersensitivity” is lacking. The toxic dose decreases when given acutely (loading doses) or when there is associated excretory organ failure. Ingestion of natural colchicine (as in plants) or the purified drug by nonoral or IV routes is associated with survival even in very large doseS.“.i~.h~ The two main circumstances in which colchicine intoxication occurs are suicide attempts and therapeutic overdoses. Unintentional intoxication has also occurred because of the similiarity of Gloriosa superba tubers to the yams of sweet potatoe? and when colchicine powder was insufflated when mistaken for methamphetamine.4x Baum and Meyerowitz7” highlighted the use of colchicine as a suicidal poison. Of the cases they reviewed in which the definitive reasons for taking colchicine were known (suicide or attempted suicide), all 10 patients were female and between 15 and 25 years old, with two thirds younger than 20. In most cases, no prior suicidal gestures had been made and the act was not intended to result in death-but death not infrequently resulted. In contrast, paracetamol ingestion is usually intended to have a fatal result,” but death is uncommon. Several authors have suggested that fatality from therapeutic colchicine is largely preventable and may be eliminated by rigid adherence to recommended indications and dosages. Simons and Kingman7” recently described a 21year-old patient with an acute attack of FMF who was given 1 mg of colchicine IV every 8 hours. Colchicine was discontinued when hypotension and respiratory distress developed after

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PUnTERMAN

a cumulative dose of 11 mg. In the subsequent correspondence, it was noted that dosage recommendations for colchicine in many standard textbooks and review articles are vague and misleading. Doses are commonly expressed as maximal daily doses, which is taken to mean a dose that can be repeated safely on successive days. Instead, recommendations should state the total dose of colchicine that can be given safely over one course of treatment.” IV administration of colchicine seems particularly prone to hazard, and the appropriate IV dose “. . . should total no more than half of the equivalent oral dose.“” After IV dosage, no further colchicine should be administered (orally or IV) for 1 or 2 weeks.74 RISK FACTORS

Colchicine and its metabolites are normally excreted into bile” and urine.” The influence of hepatic and renal dysfunction on the pharmacokinetics of colchicine is of interest. A 2-mg oral dose of colchicine was administered to three patients with severe chronic hepatocellular dysfunction.27 Initial plasma levels of colchicine were higher, the apparent volume of distribution was lower, and urinary colchicine excretion in 24 hours was greater in these patients than in patients with normal liver function. Leighton et al75 studied the effects of liver dysfunction on colchicine pharmacokinetics in a rat model. Hepatic injury, both hepatocellular and cholestatic, significantly impaired colchicine pharmacokinetics, supporting data indicating that the liver is an important organ for colchicine elimination. After bile duct ligation (extrahepatic cholestasis), and to a lesser extent after druginduced intrahepatic cholestasis or hepatocellular injury, there was a significant decrease in colchicine clearance and a prolongation of the terminal half-life. Volume of distribution increased significantly in the experimental models of hepatocellular dysfunction and extrahepatic cholestasis and decreased in rats with intrahepatic cholestasis. Boruchow76 described a patient with obstructive jaundice due to carcinoma of the pancreas who received colchicine postoperatively for prophylaxis of gout. After administration of a. total of 14 mg of colchicine (4.5 mg IV and 9.5 mg orally over I1 days), fatal agranulocytosis and

ET AL.

thrombocytopenia, with marrow hypoplasia developed. Burochow hypothesized that the toxicity of colchicine in this case was related to concomitant hepatic dysfunction. However, fatalities from colchicine have been described with lesser doses, even in patients without liver disease or cholestasis. Renal disease significantly affects colchicine elimination. Following a single oral dose, patients with severe chronic renal failure had more prolonged plasma half-lives than patients with normal renal function.” Bennet et al” recommend avoidance of prolonged use of colchicine if the glomerular filtration rate is less than 50 mL/min. Doses for short-term therapy need not be altered for glomerular filtration rates above 10 mL/min but should be halved below this level. Wallace and Singer33 suggest even more conservative guidelines for the use of colchicine in renal failure, namely halving the dose if the creatinine clearance is below 50 mL/min and not using the drug at all with clearances less than 10 mL/min. Interestingly, all patients in the series of Kuncl et a14’who developed neuromuscular toxicity from low doses of prophylactic colchicine had some degree of renal insufficiency. Other dosage considerations are the patient’s age and previous colchicine therapy. ElderIy patients may require less colchicine and probably develop toxic side effects at lower doses, even with normal liver and kidney function.6” Cells previously exposed to the drug are more sensitive to its effects, so patients receiving maintenance therapy may be at a higher risk for toxicity from an acute dose.74 As to possible drug interactions, little data exist regarding drugs affecting colchicine metabolism. Leighton et al75 showed the effect of cimetidine, a known cytochrome P-450 inhibitor, on the pharmacokinetics of colchicine. Cimetidine caused a decrease in colchicine clearance and an increase in plasma elimination half-life. Besana et a178 described a case of neuromyopathy appearing 16 days after initiation of daily therapy with 1.5 mg colchicine. The authors suggested that the microsomal enzymeinhibiting activity of tolbutamide, taken concurrently by their patient, might have played a role in the rapid onset of neuromyopathy. We recently treated a patient with FMF in

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COLCHICINE INTOXICATION

whom a therapeutic dose of erythromycin seemed to precipitate toxicity from long-term, prophylactic low-dose colchicine administration (Caraco et al, data on file). This possible interaction seems reasonable, taking into consideration the ability of erythromycin to inhibit oxidative liver metabolism of several compounds, including carbamazepine, theophylline, and warfarin.” (For a summary of risk factors for colchicine toxicity, see Table 2.) ORGAN SYSTEM INVOLVEMENT

IN

COLCHICINE TOXICITY

Colchicine toxicity is a relatively distinct clinical syndrome, characterized by multiorgan involvement. It is convenient to divide the presentation of significant colchicine toxicity into three sequential and usually overlapping stages.“.” The first stage occurs during the first 24 hours after ingestion and is dominated by gastrointestinal symptomatology. In addition, there is significant fluid loss leading to volume depletion and peripheral leukocytosis. Multiorgan failure dominates the second stage, developing from 24 to 72 hours after ingestion. Derangements in organ-system function include bone marrow depression, renal failure, the adult respiratory distress syndrome (ARDS), arrhythmias and heart failure, fever, disseminated intravascular coagulation (DIC), acid-base and electrolyte disturbances, and neuromuscular involvement. If the patient survives the second stage, a recovery phase ensues. This third stage is characterized by recovery of the bone marrow with rebound leukocytosis, resolution of organ system derangement, and development of alopecia. Table 2: Risk Factors for Colchicine Toxicity IV use Use of loading doses Use in elderly patients Prior maintenance Excretory

colchicine

use

organ failure:

Renal insufficiency Hepatic dysfunction

(hepatocellular

cholestatic) Drug interactions: Cimetidine Other P-450 inhibitors Tolbutamide

(?)

or

Gastrointestinal symptoms are early and common manifestations of colchicine toxicity. These symptoms are used as a warning end-point when colchicine is administered therapeutically in an acute clinical situation. The patient may suffer from diffuse abdominal pain, nausea, vomiting, and severe diarrhea. Paralytic ileus may develop.” These dramatic effects are related to the effect of colchicine on intestinal mucosal cells, which have a rapid turnover rate.“,” Histologically, profound changes in cell structure of the intestinal epithelium are seen.56 Gastrointestinal damage may be prominent because the intestinal mucosal cells are exposed to high concentrations of the drug for prolonged periods due to enterohepatic circulation.” Liver damage’h,S4.hK.X0 is an uncommon manifestation of toxicity. Hepatomegaly with liver tenderness and increased serum hepatocellular enzyme levels are seen. On histological examination, hepatocytes may contain “colchicine figures,” which are bizarre condensed nuclear chromatin forms.” Nadius et a167found evidence of pancreatitis, with abdominal pain and tenderness, and increased serum amylase levels. Although isoenzymes were not studied, colchicine was thought to have provoked the pancreatitis. Pancreatic injury also has been described by Baldwin et al.” Respiratory involvement occurs in about one third of cases of colchicine toxicity.” Increasing respiratory distress leads to hypoxemic respiratory failure. Chest x-rays show diffuse interstitial and alveolar edema. In 1975, Hill et al””first described pulmonary involvement indistinguishable from ARDS in colchicine poisoning. This association has since been confirmed.h2.“4.h’.“‘~K2 ARDS may develop as a complication of hypovolemic shock or sepsis occurring in the course of poisoning or through direct damage to the pulmonary vasculature.h4.65 Neuromuscular involvement (see below) may also contribute to respiratory insufficiency due to respiratory muscle weakness.‘” Hematological manifestations appear in all three stages of colchicine toxicity. In the early stage, peripheral leukocytosis appears, sometimes with early myeloid forms, Pelger-Huet cells, and damaged cells with karyorrhexis.‘“~” During the second stage, hematological compli-

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PUUERMAN

ET AL.

cations include bone marrow hypoplasia and nent, with negligible hair regrowth after the coagulation abnormalities. Initially, lymphopeexpected period of recovery.s4.69 Fever may be a manifestation of colchicine nia is observed,57 followed by granulocytopenia, toxicity or a sign of complicating infection.hx.x6 reticulocytopenia, and thrombocytopenia, reaching a nadir 4 to 8 days after ingestion.57,76,8”~83 Fever occurs commonly, being documented in 16 of 26 patients (62%) reviewed by Baldwin et Bone marrow examination shows hypocelhuara16’ Murray et a126and others58,65,X”,83 hold that ity with numerous abnormal megakaryocytes fever can result from a direct drug effect. In (colchicine figures). Leukopenia is one of the animals, colchicine increases body temperature more serious problems of colchicine toxicity, in some experimental modelsx” However, bepredisposing to severe infection with pathocause of the accompanying leukopenia and the genic bacteria, especially gram-negative rods.@’ predisposition to infection, the diagnosis of Sepsis was the direct cause of death in 6 of 16 fever caused by colchicine toxicity per se refatal cases of colchicine toxicity gathered by mains one of exclusion. Interestingly, hypotherStahl et a1.62 Eight to 10 days after acute mia also was repoTteds and associated with a ingestion, the bone marrow shows signs of grave prognosis. recovery, initially manifested by rebound leukoCardiovascular collapse is an important cause cytosis, before normalization of the platelet of mortality during colchicine intoxication. The count.“.” most detailed hemodynamic studies to date Severe coagulation disturbances were promihave been performed by Sauder et aL8’ who nent in a French series of patients with colcollected data on eight patients studied bechicine toxicity. Bismuth et a15’ reported that tween 6 and 72 hours after acute colchicine consumptive coagulopathy occurred commonly, ingestion. The mean colchicine dose was 39 mg. with elevation of fibrinogen degradation prodHypovolemia was present in all patients, with an ucts, decrease in fibrinogen, prolongation of average pulmonary capillary wedge pressure of coagulation time, and abnormal bleeding. 8 mm Hg. Hemodynamic monitoring distinThrombocytopenia may contribute to the coagguished between two groups of patients. In the first group, there were four patients with a ulation disturbance noted, resulting from conhyperdynamic circulation, as expressed by high sumption of pIatelets in the disseminated coagcardiac output and low systemic vascular resisulative process. Although less common in reports tance. The second group had slightly decreased from other countries, coagulopathy was also cardiac output and increased peripheral resisnoted to complicate the course of some patance, consistent with cardiogenic shock. Plasma tients, especially the critically i11.26~5s~h’~64~67~R’~X2 expansion did not improve left ventricular stroke Other rare hematological side effects of colwork in the latter group, but the wedge pressure chicine toxicity include Heinz-body hemolytic increased dramatically. All patients with cardioanemia, reported in three cases,N.h5~b6 and polygenie shock subsequently died. morphonuclear cell inclusions. These intracytoThe mechanism of cardiovascular dysfuncplasmatic inclusions and vacuoles in peripheral tion seen in colchicine toxicity is unclear. The neutrophils were thought to represent an early hyperkinetic hemodynamics observed in some manifestation of acute colchicine toxicity.“’ cases suggested to Bismuth et a15’that sepsis is Alopecia is a common,““.66.8”well-documenthe cause of cardiovascular deterioration. Howtcd82.84manifestation of colchicine poisoning. ever, the cardiac impairment described by Although usually appearing during the late Sauder et al*’ also is consistent with myocardial recovery phase, alopecia has developed as early depression. Colchicine may have a direct toxic as the sixth day after acute ingestion.85 Hair loss effect on myocardial function resulting in cardiois generally confined to the scalp, but total genie shock, while a postulated specific vasodilaalopecia has been reported.” Most cases of tatory effect would explain the hyperkinetic alopecia are reversible, regrowth being noted 3 state that has been noted.55’x7 to 12 weeks after drug discontinuation.*’ HowAdditional features of the cardiovascular effect of colchicine deserve mention. Two paever, in at least two cases hair loss was perma-

COLCHICINE INTOXICATION

tients described by Stapczynski et alhh died of sudden cardiac standstill at a time when both blood pressure and oxygenation were within reasonable limits. Stahl et aP2 observed sequential heart rhythm changes from sinus tachycardia to sinus bradycardia progressing to sinus arrest. One of three patients described by Stemmermann and Hayash? developed complete atrioventricular block in the terminal phase of his hospital course. These reports suggest that colchicine can seriously impair impulse generation and cardiac conduction. Recently, Mendi?’ reported that colchicine ingestion (in plant form) caused diffuse ST-segment elevation followed by T-wave inversion, increased cardiac enzyme levels, and acute left ventricular failure, all indicative of acute myocarditis. Myocardial damage, as expressed by ST-segment elevation and enzyme increase, also was described by Murray et al.‘(’ Renal complications during colchicine toxicity include azotemia, proteinuria, and hematuria. i,h~hK~8” These alterations may progress to oliguria and, in severe intoxication, to acute renal failure.“’ However, kidney dysfunction can be reversible even in severe cases, although dialysis may be required in the interim.6” A recently described parameter of renal damage is the plasma alkaline phosphatase level. Rosalki and FooXX described a patient who ingested 12.5 mg colchicine. The serum alkaline phosphatase increased more than fivefold within 2 days, paralleled by increases in serum urea and creatinine concentrations. An unusual alkaline phosphatase isoenzyme was found and indentified as of possible renal origin, presumably resulting from the toxic effect of colchicine on the kidney. Renal involvement during colchicine toxicity probably is multifactorial. Besides a postulated direct drug effect, other potential causes of renal dysfunction include rhabdomyolysis and myoglobinuria, prolonged hypotension, complicating sepsis, and hypoxemia.hh Several metabolic derangements appear during the course of colchicine intoxication. Metabolic acidosis is a frequent finding in patients with severe toxicity. Because of inhibition of intracellular metabolism caused by the drug, organic acids, which contribute to the observed acidosis, increase.6”~hK.XiLactic acidosis, with high

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levels of lactate and an increased anion gap, was seen in several cases.‘h.M.6h.X’ Asymptomatic hypocalcemia of a modest degree, often associated with hyponatremia and metabolic acidosis, was reported in 5 of 21 cases reviewed in 1981.” Other associated electrolyte disorders are hypophosphatemia2’.” and hypomagnesemia.“‘.” Frayha et al” reported a patient with colchicine intoxication whose clinical features included irritability, carpopedal spasm, tetany, ileus, and repeated generalized convulsions. The blood calcium level was low, and treatment with IV calcium gluconate resulted in full neurological recovery. Because the hypocalcemia appeared together with hypomagnesemia and hypophosphatemia in the setting of vomiting and diarrhea, it is possible that gastrointestinal losses were responsible for the electrolyte deficits seen. In 1972, Heath et al”” showed that colchicine has a calcitonin-like effect on bone and inhibits bone resorption, possibly through microtubular inhibition in bone tissue. The findings by Heath et al suggest that hypocalccmia may result from a direct toxic effect of colchicine, independent of gastrointestinal tract loss. In any case, calcium levels should be followed closely in patients with colchicine toxicity, especially those with neurological symptomatology. Toxic doses of colchicine have profound effects on the nervous system. Among the effects described are mental status changes (delirium, stupor, coma), transverse myelitis and ascending paralysis,” and loss of deep tendon reflexes.X” Seizures also may figure prominently in the clinical picture.“i7’.X” In one of our patients with colchicine toxicity, convulsions progressed to status epilepticus, necessitating muscular paralysis by pharmacological means, mechanical ventilation, and high doses of anticonvulsants. Similar neurological side effects were seen in animals given colchicine experimentally.x” Myelin degeneration reported from one autopsy series”’ explains the peripheral neuropathy reported in animals and in several cases of human poisoning.h’.X” Rats given colchicine develop an acute myopathy.“‘Ultrastructurally, this myopathy is accompanied by degenerative changes in skeletal muscles. Similarly, acute rhabdomyolysis with

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myoglobinuriaz6@~65may appear in human intoxication and contribute to renal dysfunction. MANAGEMENT

Clinical management of colchicine toxicity can be difficult because of widespread involvement of various vital organs. Therapy is basically supportive and symptomatic. Gastric lavage or emetics are indicated initially because removal of even small amounts of colchicine may significantly affect the severity of intoxication and the ultimate prognosis. In plant ingestion, these measures may be useful even 24 hours after acute ingestion. Ellwood and Robb54 reported that a postmortem examination performed more than 30 hours after meadow saffron ingestion recovered more than two thirds of the amount of colchicine ingested. Keeping in mind the enterohepatic circulation of colchitine, serial dosing with activated charcoal may theoretically be useful as a method for enhancing elimination. At times, intentional overdoses with suicidal intent may include other drugs, with possible potentiation of toxicity, another reason to recommend the use of activated charcoal. However, if paralytic ileus develops as a complication of colchicine poisoning,*‘j the latter method has limited usefulness. Cathartics also may be used but may be unnecessary if gastrointestinal toxicity has resulted in diarrhea. Because of colchicine’s rapid distribution into tissues and its high affinity to intracellular binding sites, hemodialysis, charcoal hemoperfusion, and plasma exchange are not effective in colchicine intoxication. Presently, no convincing evidence exists to support the use of these modalities.26.64.67 In one case,54 exchange transfusion of 4 L was performed 5 hours after ingestion of 25 to 30 mg of colchicine, but no cause-and-effect relationship could be established between this measure and the resultant survival. Symptomatic patients, patients ingesting an unknown amount of colchicine, or patients ingesting a dose thought to be in the toxic range should be hospitalized for observation. Fluid deficit due to gastrointestinal loss should be closely followed and liberally replaced. Hemodynamic and respiratory monitoring is of particu-

ET AL.

lar importance, preferably in an intensive care unit, because acute circulatory insufficiency during the initial 24 to 72 hours postingestion is a common cause of death. Until recently there were no specific measures successful in colchicine intoxication. Recent experimental work suggests that specific therapy may soon be possible. Immunotoxicotherapy is currently approved as effective therapy for acute poisoning with digoxin. Although intracellular binding of colchicine was expected to limit the efficacy of immunotoxicotherapy for colchicine poisoning, a reversible effect was found in vitro.93 Preliminary work in mice, found to be a suitable animal model for the study of colchicine poisoning, showed that administration of specific anticolchicine immunoglobulin G (IgG), even after the distribution phase, significantly decreased the mortality rate.94.9”In further studies by the same group of French investigators,96 IgG colchicine antibodies were produced in goats and given to mice who received an LD,, dose of colchicine intraperitoneally. Despite a relatively low dose of antibody, a beneficial effect was shown, and colchicine pharmacokinetic parameters were altered favorably. The steady-state volume of distribution decreased significantly in the treated mice. There was sequestration of free colchicine in the intravascular space (low free plasma toxin) and a decrease in colchicine concentration in most tissues of antidote-treated mice, indicating a tissue extraction process. The practicality of immunotoxicotherapy for colchicine poisoning also was examined using an active immunization approach.97 A dose of 3 mg/kg of colchicine (above LD,,) was given to rabbits previously actively immunized with the drug. Five of the six control rabbits died within 27 hours, compared with only two of the six rabbits previously immunized. The protective effects of immunization depended on the anticolchicine antibody titer. Promising preliminary results using immunotoxicotherapy recently have been reported by Edmond-Rouan et a19*They prepared a specific high-affinity colchicine-binding monoclonal antibody and investigated its ability to reverse in vitro the effects of colchicine on ovary cells of the Chinese hamster. Colchicine-induced

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changes of polyploidy and chromosomal aberrations were reversible even when the antibody was administered up to 6 hours after colchicine exposure. SUMMARY Colchicine is a useful drug for a variety of clinical situations. Although it is relatively safe when properly used, colchicine overdosage can result in severe toxicity. The affects of colchitine on various organ systems are well defined. Despite its widespread use, several important questions remain unanswered. Data concerning the kinetics of colchicine are incomplete or unclear, as is the nature of its affinity for

different organs. Although hepatic and renal diseases affect the metabolism and excretion of colchicine and necessitate dose adjustments, research is needed to clarify this relationship more precisely. The ability of drugs in common use to elevate colchicine levels and induce toxicity requires further delineation. The most important question yet to be answered pertains to appropriate therapy of colchitine intoxication. Currently, treatment is primarily supportive. Anticolchicine antibodies, particularly when administered early in the clinical course, may prove in the future to significantly decrease morbidity and mortality associated with colchicine intoxication.

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