36: Colchicine, Podophyllin, and the Vinca Alkaloids

History

The origins of colchicine and its history in poisoning can be traced 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 is often used plants of the Liliaceae family to poison her victims, one of which is Colchicum autumnale.^25,144,192 The use of colchicum for medicinal purposes is reported in Pedanius Dioscorides De Materia Medica, an ancient medical text, written in the 1st century a.d.^25,144,192 and subsequently in the 6th century a.d. by Alexander of Trallis, who recommended it for arthritic conditions.^{25,40,181,192,176} However, colchicum fell out of favor, perhaps because of its pronounced gastrointestinal (GI) effects, until it was reintroduced for dropsy and various other nonrheumatic conditions in 1763.^25,192 In the late 18th century, a colchicum containing product known as Eau Medicinale reportedly had strong antigout effects.¹⁹² Colchicine, the active alkaloidal component in colchicum, was isolated in 1820 and rapidly became popular as an antigout medication.^144,192 Benjamin Franklin reportedly had gout and is credited with introducing colchicine in the United States.¹⁴⁴ Colchicine is still used in the treatment of gout and has been used in a multitude of other disorders, including amyloidosis, Behçet syndrome, familial Mediterranean fever, chronic pericarditis, arthritis, pulmonary fibrosis, vasculitis, biliary cirrhosis, microcrystalline arthritis, certain spondyloarthropathies, calcinosis, and scleroderma.^{12,25,133,137} Unfortunately, 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).¹⁹² Colchicine is not distributed evenly in the autumn crocus with the highest concentrations found in the bulb and seeds (0.8%) followed by the corm or underground stem (0.6%) and the flowers (0.1%).^144,169,181 Colchicine concentrations within the plant peak during the summer months.¹⁴⁴ The leaves of C. autumnale closely resemble those of the Allium ursinum or wild garlic and have been mistaken for them.^44,45,110 The tubers of G. superba may be confused with Ipomoea batatas (sweet potatoes).¹⁹²

There is a dearth of epidemiologic data on colchicine poisoning. The American Association of Poison Control Centers records several hundred overall exposures annually (Chap. 136). Most of these exposures are in adults and are categorized as unintentional. Approximately 10% of the cases with a recorded outcome typically have evidence of moderate or major toxicity or resulted in death.⁴¹ Although a limited number of cases are due to intentional suicidal ingestions, recent work suggests that therapeutic colchicine administration contributes to adverse health effects and in some cases death among hospitalized patients (probably related to failure to adjust dosing for renal impairment).¹⁶⁵ At least 50 adverse events (23 of which were fatalities) are linked to the use of intravenous (IV) colchicine.⁴ The US Food and Drug Administration announced its intent to stop the marketing of unapproved injectable drug compounds containing colchicine in 2009.⁴ Although all approved IV formulations in the United States were subsequently withdrawn, it may in theory be obtainable from compounding pharmacies and from other countries. Serious questions remain about the safety of colchicine in light of its extremely narrow therapeutic index.

Pharmacology

Colchicine is a potent inhibitor of microtubule formation and function, and thereby interferes with cellular mitosis, intracellular transport mechanisms, and maintenance of cell structure and shape.^137,192 The ubiquitous presence of microtubules in cells throughout the body presents a wide variety of targets for colchicine poisoning.^137,192 Colchicine accumulates in leukocytes and has inhibitory effects on leukocyte adhesiveness, ameboid motility, mobilization, lysosome degranulation, and chemotaxis.^{25,51,61,88,95,186, 187, and 188} At doses used clinically, colchicine inhibits neutrophil and synovial cell release of chemotactic glycoproteins.^195,218 Colchicine also inhibits microtubule polymerization, which disrupts inflammatory cell-mediated chemotaxis and phagocytosis.¹⁹⁹ It reduces expression of adhesion molecules on endothelial and white blood cells and affects polymorphonuclear cell cytokine production.^10,26,161 Colchicine also acts as a competitive antagonist at GABAA receptors in a human ex-vivo model.²⁴³

Pharmacokinetics and Toxicokinetics

Oral colchicine is rapidly absorbed in the jejunum and ileum and has a bioavailability generally between 25% and 50%.^25,203 It is highly lipid soluble^19,25,192 with a volume of distribution that ranges from 2.2 to 12 L/kg, which may increase to 21 L/kg in overdose.^{168,196,197,230} Colchicine binding to plasma proteins approaches 50%.^{25,137,160,192} Protein binding is principally to albumin, although some binding to α1-glycoprotein acid and other lipoproteins is reported.²⁰³ During the first several hours after acute overdose, colchicine is sequestered in white and red blood cells in concentrations five to 10 times higher than in serum.²⁰³ Peak serum concentrations after ingestion occur between 1 to 3 hours.¹³⁷ Toxic effects usually do not occur with concentrations less than 3 ng/mL.^89,160,239

Colchicine is primarily metabolized through the liver with up to 20% of the ingested dose excreted unchanged in the urine.²³⁰ Colchicine undergoes demethylation by CYP3A4.^120,229 Detoxification mainly occurs through deacetylation, demethylation, biliary secretion, and excretion in the stool.^201,203 Enterohepatic recirculation of colchicine occurs.^3,192

Serum elimination half-lives ranging from 9 to 108 minutes are reported.^{17,107,192,203,240} However, upon closer examination, 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.^{3,93,192,197,201,203,230} These values are on the same order as, and probably reflect the tubulin–colchicine complex disassociation time.¹⁷⁶ Individuals with stage 5 chronic kidney disease (CKD) and liver cirrhosis may have elimination half-lives that are prolonged up to tenfold.¹³⁷ 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.^88,192 Colchicine can cross the placenta and is secreted in breast milk, but it is not dialyzable.¹³⁷ Postmortem examination of colchicine-poisoned patients reveals high concentrations within the bone marrow, testicles, spleen, kidney, lung, brain, and heart.¹⁹⁶

Drug Interactions.

Colchicine metabolism is susceptible to drug interactions. Because colchicine is metabolized through CYP3A4, serum concentrations are susceptible to xenobiotics that alter the function of this enzyme, such as erythromycin, clarithromycin, and grapefruit juice.^53,80,99,137 In particular, coadministration of clarithromycin and colchicine, especially in patients with CKD, increases the risk of fatal interaction.^5,119 P-glycoprotein (PGP) expels and clears colchicine; therefore, PGP inhibitors directly affect the amount of colchicine eliminated and hence, toxicity.¹⁷⁶ For example, cyclosporine increases colchicine toxicity.^{85,137,216,217} Coadministration of colchicine with statin or fibrate drugs, nephrotoxins such as nonsteroidal antiinflammatory drugs and angiotensinogen-converting enzyme inhibitors, and fluindione (antivitamin K anticoagulant) can result in colchicine poisoning.²³³

Pathophysiology

Microtubules play a vital role in cellular mitosis and demonstrates significant dynamic instability.^{22,87,127,210} Microtubules are made up of tubulin protein subunits, of which three are known to exist: α, β, and γ.^127,154,210 These structures are highly dynamic with α–β-tubulin heterodimers, constantly being added at one end and removed at the other.^127,128 Microtubules undergo two forms of dynamic behavior: dynamic instability, in which microtubule ends switch between growth and shortening phases, and tread milling, in which there is a net growth (addition of heterodimers) at one end and a shortening (loss) at the other.³⁰ Assembly and polymerization dynamics are regulated by additional proteins known as stabilizing microtubule-associated proteins (MAPs) and destabilizing MAPs.³⁰ These dynamic behaviors and a resultant equilibrium are needed for multiple cell functions, including cell support, transport, and mitotic spindle formation for cell replication.¹²⁷ Xenobiotics that bind to specific regions on tubulin can interfere with microtubule structure and function, thereby causing mitotic dysfunction and arrest.^154,210 This leads to cellular dysfunction and death.²¹⁰ Xenobiotics that target microtubules can be generally divided into two categories: polymerization inhibitors (ie, vinca alkaloids, colchicine) and polymerization promoters (ie, taxanes, laulimalides).³⁰

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.^{30,111,127,182,210,234} This binding is relatively slow, temperature dependent, and generally irreversible, resulting in an alteration of the secondary structure of the protein.^{111,127,143,182,204} Colchicine binds at a second reversible but lower-affinity site on tubulin.^127,143 The colchicine–tubulin complex binds to the microtubule ends and prevents further growth by sterically blocking further addition of dimers.³⁰ Conformational changes in the tubulin and colchicine complex also result as colchicine concentrations increase, which weakens the lateral bonds at the microtubule end.^{30,154,196,210} 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.³⁰ All of these processes may prevent adequate binding of the next tubulin subunit and result in cessation of microtubule growth.^154,210 At low concentrations, colchicine arrests microtubule growth, whereas at high concentrations, colchicine can actually cause microtubule depolymerization through disassociation of tubulin dimers.³⁰

These conformational changes ultimately result in disassembly of the microtubule spindle in metaphase of cellular mitosis, cellular dysfunction, and death.^{91,111,127,182,204,210} Colchicine also inhibits microtubule-mediated intracellular granule transport.^25,137 Some in vitro animal studies also show that colchicine might inhibit DNA synthesis by changing cell regulatory events at a critical time during the mitotic cycle.^{86,92,113,140}

Toxic Dose

The toxic dose for colchicine is not well established. An early case series suggested that patients who ingested greater than 0.8 mg/kg uniformly died and those who ingested above 0.5 mg/kg but less than 0.8 mg/kg would survive if given supportive care.³³ This information was based on a limited series of patients and is not generalizable.¹⁶⁶ More recent literature suggests that severe toxicity and even death may occur with doses smaller than 0.5 mg/kg, and patients can survive ingestions reported to be in excess of 0.8 mg/kg.^{16,81,100,163,166,220} 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. Furthermore, many comorbid conditions (eg, CKD, liver disease) and other pharmaceuticals, which, when coadministered, can enhance the adverse effects of colchicine, complicating the determination of a minimal toxic dose.

Clinical Presentation

The clinical findings in patients poisoned with colchicine are commonly described as triphasic (Table 36–1).^{115,150,168,220} GI irritant effects, such as nausea, vomiting, abdominal distress, and diarrhea, occurring within several hours of an overdose^{8,43,45,71,79,129,150,155,236} and may lead to severe volume depletion.^{99,118,146,166,168,170,220,242} This first stage usually persists for the first 12 to 24 hours following ingestion.^118,150 The second stage is characterized by widespread organ system dysfunction, particularly the bone marrow, and lasts for several days.^{45,81,166,168,220} The final phase is characterized by recovery or death, and the progression can usually be defined within one week.^{115,118,150,220}

After overdose, the hematopoietic effects of colchicine are characterized by an initial leukocytosis, which may be as high as 30,000/mm³. This is followed by a profound leukopenia, which may be lower than 1000/mm³ and is commonly accompanied by pancytopenia, usually beginning 48 to 72 hours after overdose.^{25,43,93,99,114,150,172} The hematopoietic manifestations occur as a result of the effects of colchicine on bone marrow cell division.^{40,118,153,196,242} 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.^{40,115,118,150,168} Sudden cardiovascular collapse from colchicine typically occurs between 24 to 36 hours after ingestion.^{40,52,150,153,166} Profound hypovolemia and shock may contribute to this collapse,^{25,99,166,168,220} but colchicine also has direct toxic effects on skeletal and cardiac muscle.^{36,62,148,156,167,237,242}

Myopathy,^{46,47,209,247} neuropathy,^13,140 and combined myoneuro­pathy^{11,64,72,84,135,136,193,215,253} result from both long-term therapy and acute ­poisoning.¹⁴⁰ Combined myoneuropathy is reported more often, with myopathy dominating the clinical picture.^{11,64,72,135,136,193,215,253} Myoneuropathy is often initially misdiagnosed as polymyositis or uremic neuropathy (caused by coexistent kidney failure).^13,136 Myoneuropathy usually develops in the context of chronic, therapeutic dosing in patients with some baseline CKD,^{11,64,72,84,134,136,193,215,253} although it may also occur in the presence of normal kidney function.¹⁹⁰ Patients may present with proximal limb weakness, distal sensory abnormalities, distal areflexia, and nerve conduction problems consistent with an axonal neuropathy.^136,185 A small amount of myelin degeneration is reported on autopsy, which suggests a myelinopathic component.⁴² The myopathy is characterized by vacuolar changes on biopsy and accompanied by lysosome accumulation.^{11,84,136,253} An elevated serum creatine kinase concentration is present concurrently with symptoms.^136,168 Weakness usually resolves within several weeks of drug discontinuation.¹³⁶ Myopathy may also occur when hydroxymethylglutaryl–coenzyme A reductase inhibitors are concomitantly used in patients with renal insufficiency.⁶ Myopathy symptoms typically resolve within 4 to 6 weeks, although it may take up to 6 to 8 months in some patients.²⁴⁷

Acute respiratory distress syndrome occurs with colchicine toxicity.^{18,71,114,158,208,211} The etiology is not well understood but may result from several factors, including respiratory muscle weakness, multisystem organ failure, and possibly direct pulmonary toxicity.^{71,150,158,208,228} Other indirect effects of colchicine include acute kidney injury (AKI) and various electrolyte abnormalities resulting from fluid loss and impaired glomerular filtration rate.^{25,81,99,140,168}

Alopecia, which is usually reversible, is a well-described complication that occurs 2 to 3 weeks after poisoning.^{12,25,93,99,100,118,143,227} Dermatologic complications range in severity from epithelial cell atypia to toxic epidermal necrolysis.^{9,15,91,98,200} 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.^{46,172,192,211} The cause of seizures is unclear but it might be partly attributable to antagonism of GABAA receptors.²⁴³ Other reported complications of colchicine poisoning include bilateral adrenal hemorrhage,^66,224 disseminated intravascular coagulation,^118,192,211 pancreatitis,^172,232 and liver dysfunction.^46,168,192

Although uncommon, poisoning from IV colchicine administration has occurred. Clinical and laboratory manifestations are similar to those that occur after oral exposure including multisystem organ dysfunction and cytopenias.⁵⁵

Colchicine does not appear to be a significant human teratogen but the limited work on this subject is not definitive.⁷⁶

Diagnostic Testing

Colchicine concentrations in body fluids are not available in a clinically relevant time frame 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 µg/L.¹⁶⁰ Concentrations > 3.0 µg/L can be associated with toxicity depending on the clinical situation and concentrations > 24 µg/L are definitely associated with toxicity.^{89,160,239,249} Serum concentrations do not correlate well with ingested dose in massive oral overdose settings.⁷⁵ Initial laboratory monitoring should include a complete blood count (CBC), serum electrolytes, renal and liver function tests, creatine kinase, phosphate, calcium, and magnesium. A prothrombin time, activated partial thromboplastin time, urinalysis, and other focused testing can be considered depending on clinical suspicion for different end-organ injury. The need for other laboratory studies, such as a troponin, arterial or venous blood gas, lactate, fibrinogen, and fibrin split products, should be considered, depending on the clinical situation. Following significant overdose or in any case 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.^96,237 Electrocardiography and chest radiography should also be obtained. Serial CBCs are indicated (at least every 12 hours) to evaluate for the development of depression in cell lines. Bile appears to be the biologic matrix of choice for postmortem testing, probably due to normal postmortem biologic processes that can increase blood colchicine concentration.^28,171 One colchicine-associated fatality who had a premortem blood colchicine concentration of 50 μg/L, also had a postmortem femoral blood concentration of 137 μg/L and a bile concentration above 600 μg/L.²⁴⁹ Another reported a postmortem blood concentration of 60 µg/L.² Two IV colchicine-associated fatalities had postmortem blood colchicine concentrations of 32 µg/L and 44 µg/L.⁵⁵

Management

Treatment for patients with colchicine toxicity is mainly supportive, which includes IV fluid replacement, vasopressor use, hemodialysis (as indicated for acute kidney injury), antibiotics for suspected secondary infection, colony-stimulating factors, and adjunctive respiratory therapy (endotracheal intubation, positive end-expiratory pressure), as necessary. Consultation with nephrologists and hematologists may be useful. In severe poisoning, intraaortic balloon pump therapy and extracorporeal membrane oxygenation therapy may be of help but there is no proof of clinical benefit.¹⁷⁹

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 should be considered in patients who present within 1 to 2 hours of ingestion and are not already vomiting.^1,35,235 A dose of activated charcoal (AC) should be administered after lavage, or in its place if lavage is not appropriate or possible in the judgment of the physician. Since limited ­evidence suggests that colchicine undergoes some enterohepatic recirculation, administration of a single dose of AC to a patient presenting to a health care facility beyond 2 hours following ingestion can be considered if no contraindications exist. Multiple-dose AC (MDAC) can also be considered in these patients for the same reason.^3,192 The delay in presentation to a health care facility coupled with the fact that patients often have GI symptoms such as vomiting limits the potential benefit of using MDAC. ­However, antiemetic medications can be given to control emesis and facilitate AC administration (Antidotes in Depth: A1).

Experimentally, colchicine-specific antibodies can restore colchicine-affected tubulin activity in vitro and were successfully used in a single case of severe colchicine poisoning.²¹ 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.²¹ Unfortunately, this therapy is not commercially available.

Granulocyte-colony stimulating factor (G-CSF) is useful in the treatment of patients with colchicine-induced leukopenia and thrombocytopenia.^{69,109,131,252} The dose of G-CSF, the dosing frequency, and the route of administration were variable in the reported cases.^{69,109,131,252} G-CSF should be started if the patient develops leukopenia. Dosing should be in accordance with the manufacturer’s instructions.

Hemodialysis and hemoperfusion are not viable options to enhance colchicine clearance based on its large volume of distribution, but hemodialysis may be required if AKI is severe.^{24,31,32,196,197,230,242} Whole blood and plasma exchange have been suggested for cases presenting with lethal-dose colchicine exposures, but evidence of efficacy is lacking, and therefore these procedures are not recommended at this time.¹⁷⁹

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 hours¹⁶⁶ intensive care unit monitoring is recommended for at least this initial time period. Troponin should be checked every 6 to 12 hours during this period because increasing results may suggest an increased risk of cardiotoxicity and cardiovascular collapse.^96,237 CBCs should be followed at least daily to evaluate for cytopenias. 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.

History

Podophyllin is the name often used to refer to a resin extract from the rhizomes and roots of certain plants of the genus Podophyllum.^74,103 Examples include the North American perennial Podophyllum peltatum (May apple or mandrake), the related Indian species Podophyllum emodi, and the Taiwanese Podophyllum pleianthum.⁷⁴ It is more descriptive to refer to it as podophyllum resin.^74,103 Podophyllum resin, or podophyllin, contains at least 16 active compounds.^57,74,103 These include a variety of lignins and flavonols, including podophyllotoxin, picropodophyllin, α- and β-pellatins, desoxypodophyllotoxin, and quercetin.^54,57,74,103 Podophyllotoxin, a component of podophyllin, is a potent microtubular poison, similar to colchicine, and causes similar effects in overdose.⁷⁴

The first reported modern era medicinal use of podophyllin preparations was as a laxative in the 19th century.^54,57,188 Its cathartic properties, and its potential toxicity, were noted as early as 1890, when the first fatality from podophyllin was recorded.^212,246 Podophyllin was used to treat individuals with a variety of other health issues, including liver disease, scrofula, syphilis, warts, and cancer.⁷⁴ Etoposide and teniposide are semisynthetic derivatives of podophyllotoxin used as chemotherapeutics.⁷⁴

Poisoning usually is caused by systemic absorption after topical application, after ingestion of the resin or plant, and after consumption of a commercial preparation of the extract. Systemic toxicity is described after unintentional dispensing of the incorrect herb, and after ingestion of herbal preparations containing podophyllin.^58,59,78

Pharmacology

Podophyllin is primarily used in modern pharmacopeia as a topical treatment for patients with verruca vulgaris and condyloma acuminatum.^54,90,139 The active ingredient is believed to be podophyllotoxin.^{19,74,130,212,226,238,248} Podophyllotoxin exists in the plant as a β-d-glucoside.^90,130,212 Numerous synthetic and semisynthetic derivatives of podophyllotoxin exist; however, the most important are probably the chemotherapeutics etoposide and teniopside.⁷⁴ The antitumor effect of etoposide and teniposide results from their interaction with topoisomerase II and free radical production, leading to DNA strand breakage, an effect not shared by podophyllin and colchicine.^50,74 Etoposide and teniposide also arrest cell growth in the late S or early G2 phase of the cell cycle.^50,74,97 Further discussion of these xenobiotics can be found in Chap. 52.

Pharmacokinetics and Toxicokinetics

Very limited information exists regarding the pharmacokinetics of podophyllin as a preparation or for its major active ingredient, podophyllotoxin. Podophyllotoxin is highly lipid soluble and can easily cross cell membranes.^{90,101,175,212} It can be eliminated through the bile with a half-life of 48 hours.^54,65 However, review of the referenced articles failed to adequately support this elimination half-life and may have been based solely on observed clinical course.⁶⁵

Absorption of podophyllotoxin was measured in seven men after application of various amounts of a 0.5% ethanol podophyllotoxin preparation for condylomata acuminata.²³⁸ Peak serum concentrations of 1 to 17 µg/L were achieved within 1 to 2 hours after administration of doses ranging from 0.1 to 1.5 mL (0.5–7.5 mg).²³⁸ Patients treated with 0.05 mL or less had no detectable podophyllotoxin in their serum. Administration of 0.1 mL yielded peak serum concentrations up to 5 µg/L within 1 to 2 hours and up to 3 µg/L at 4 hours. Administration of 1.5 mL yielded peak serum concentrations ranging from 5 to 9 µg/L within 1 to 2 hours; 5 to 7 µg/L at 4 hours; 3 to 4.5 µg/L at 8 hours; and 3.5 µg/L at 12 hours.²³⁸

Pathophysiology

The components of podophyllin have numerous actions within the cell, including inhibition of purine synthesis, inhibition of purine incorporation into RNA, reduction of cytochrome oxidase and succinoxidase activity, and inhibition of microtubule structure and function.^54,97,241 Podophyllotoxin causes toxicity similar to colchicine^74,248 because of binding to tubulin subunits and interference with subsequent microtubule structure and function.^74,248 Radiolabeled podophyllotoxin inhibits colchicine binding to tubulin, suggesting that their binding sites overlap.⁷⁴ Podophyllotoxin binds more rapidly than colchicine, and in contrast to colchicine, binding is reversible.⁷⁴ Podophyllotoxin also inhibits fast axoplasmic transport similar to colchicine by interference with microtubule structure and function.^185,233 Many other compounds, such as the vinca alkaloids, cryptophycins, and halichondrins, also inhibit microtubule polymerization in a similar manner.¹²⁸

Toxic Dose

The minimum toxic dose associated with podophyllin ingestion is unknown. Limited information on the situations surrounding the few case reports of podophyllin poisoning that do exist does not provide sufficient detail from which to estimate it.

Clinical Presentation

Podophyllin poisoning is described after both ingestion,^{49,60,78,94,116,151,202,245} and absorption following cutaneous application.^{152,159,162,183,194,221,223} Toxicity also is reported following IV administration of podophyllotoxin¹⁰⁶ and ingestion of mandrake root or herbal remedies containing podophyllin.^78,94,246 Nausea, vomiting, abdominal pain, and diarrhea usually begin within several hours after ingestion.^{65,101,106,116,152,157,159,194,202,212,221,245,246} Symptoms of poisoning might be delayed for 12 hours or more after cutaneous exposure to podophyllin and are often caused by improper usage (excessive cutaneous exposure, interruption in skin integrity, or failure to remove the preparation after a short time period).^{152,157,162,212} Initial clinical findings are not necessarily determined by the route of exposure.¹⁵²

Alterations in central and peripheral nervous system function tend to predominate in podophyllin toxicity. Some patients present with, or rapidly progress to, confusion, obtundation, and coma.^{49,65,78,151,157,159,162,194,202,221,223,226,245}

Delirium and both auditory and visual hallucinations occur during the initial presentation.^67,90,223 Patients develop paresthesias, lose deep tendon reflexes, and might develop plantar extension.^{49,57,60,65,78,151,159,162,177,212,223,233} Cranial nerve involvement, including diploplia,⁵⁷ nystagmus,⁶⁵ dysmetria,⁶⁰ dysconjugate gaze,²²³ and facial nerve paralysis,⁶⁷ are all reported. Patients who recover from the initial event are at risk of developing a peripheral sensorimotor axonopathy.^{60,65,78,90,151,159,175,177,194,212,223} The reported duration for recovery from podophyllin-induced axonopathy is variable but can take several months.^{65,78,159,175} Dorsal radiculopathy¹⁰¹ and autonomic neuropathy are also reported.¹³⁹ There may be a mild myelopathic component in the neuropathy.⁵⁹

Hematologic toxicity from podophyllin most likely results from its antimitotic effects. A review of the limited literature suggests that it is similar to colchicine but is not nearly as consistent in its pattern, severity, and frequency. An initial leukocytosis^{159,162,194,212} may occur after poisoning, which can be followed by leukopenia, thrombocytopenia, or generalized pancytopenia.^{116,139,157,159,212,221} In patients who recover, cell lines tend to reach their nadir within 4 to 7 days after exposure.^{90,116,159,194,221}

Other complications of poisoning include fever,¹⁵⁷ ileus,^90,157,223 elevated liver function tests,^{78,116,159,221,245} and hyperbilirubinemia,¹¹⁶ coagulopathy,¹¹⁶ seizures,^67,202 and AKI.^157,245 Teratogenic effects resulting from exposure during pregnancy may also occur.^57,130

Diagnostic Testing

Podophyllin or podophyllotoxin concentrations are not readily available. Routine testing for suspected or known podophyllin poisoning should include routine laboratory tests and other targeted testing, as needed. Serial CBCs should be obtained in cases of poisoning to evaluate for pancytopenia.

Management

Management primarily consists of supportive and symptomatic care. Orogastric lavage may be considered following recent ingestion based on its high toxicity profile.^35,235 If the patient presents within the first several hours of ingestion, then a dose of AC should be given. Any cutaneously applied podophyllin should be removed and the area thoroughly cleansed. Supportive and symptomatic care should be instituted as needed. Patients either progress to multisystem organ dysfunction and death or recover. CBCs should be monitored similarly to colchicine poisoning (at least daily).

A few case reports of treatment with extracorporeal elimination techniques exist. These reports include resin hemoperfusion¹¹² and charcoal hemperfusion.^159,212 The role these procedures played in the clinical courses is unclear. As a result, firm recommendations regarding the use of these techniques cannot be made at this time.

Patients with significant ingestions of podophyllin develop GI symptoms within a few hours,^{60,94,116,177,245,246} but patients may also present with primarily neurologic symptoms, such as confusion or obtundation.^49,54,90,152 An isolated number of cases suggest the onset of toxicity can be delayed for as long as 12 hours.^49,54,65,78 Cutaneous exposure might result in even further delayed toxicity because systemic absorption is delayed and symptom onset is more insidious.^{90,139,162,194,212,221,223} Patients probably should be observed for toxicity for at least 12 hours after ingestion and perhaps even longer after dermal exposures. Asymptomatic patients with unintentional exposures and good follow up that are discharged after 12 to 24 hours should have scheduled follow up with their primary care physician and a repeat CBC obtained within 24 hours.

History

More than 150 different alkaloidal compounds can be isolated from the periwinkle plant (Catharanthus roseus), most of which have been used to manage illness from a variety of medical disorders including cancer, scurvy, diabetes, toothache, and hypertension.²⁵⁰ Among these 150 are about 20 different compounds that have antineoplastic activity. Vincristine and vinblastine are pharmaceuticals derived from compounds in the periwinkle plant and are probably among the most commonly used vinca alkaloid derivatives in medicine.¹⁹¹ They are typically used as part of a chemotherapy regimen for various cancers. Both are administered intravenously and should never be administered intrathecally. Intrathecal administration of vinblastine or vincristine is always the result of an error, is a neurosurgical emergency, and is associated with life-threatening complications⁷ (Special Considerations: SC3). There are a few case reports of intramuscular administration of these chemotherapeutics but they will not be discussed since there are so few and the reader is referred to the primary literature for further information.^20,184 Although other vinca derivatives exist, and sharing similar modes of action (causing microtubule dysfunction); this section will focus primarily on vincristine and vinblastine. Regardless, the pathophysiology of disease, clinical manifestations of illness and management of poisoning from similar compounds and the plant itselfis similar to vincristine and vinblastine.²⁵⁰

Pathophysiology

Vincristine and vinblastine are used specifically for the treatment of patients with leukemias, lymphomas, and certain solid tumors. Their mechanism of activity is similar to that of colchicine, podophyllotoxin, and the taxoids (eg, paclitaxel, docetaxel).^73,180 These chemotherapeutics disrupt microtubule assembly from tubulin subunits by either preventing their formation or depolymerization, both of which are necessary for routine cell maintenance. Vinblastine binds to the β-subunit of the tubulin heterodimer at a specific region known as the vinblastine-binding site.¹⁸² Mitotic metaphase arrest is commonly observed because of the inability to form spindle fibers from the microtubules. Cell death quickly ensues because of the interruption of these homeostatic functions, accounting for the clinical manifestations.

The mechanism of neurotoxicity is not well understood but is probably related to inhibition of microtubular synthesis, which leads to axonal degeneration in the peripheral nervous system.^102,178 Brain biopsy of a patient who experienced a vincristine-related death showed neurotubular dissociation, which is characteristic of vincristine damage in experimental animals.^38,63

Pharmacokinetics

After IV administration, vincristine is rapidly distributed to tissue stores and highly bound to proteins and red blood cells.⁴⁸ Plasma protein binding ranges from 50% to 80%.¹⁸⁹ In more than 50% of children given IV vincristine, serum concentrations were not detected 4 hours after administration.¹⁶⁴ Elimination of vincristine occurs via the hepatobiliary system,⁴⁸ and it has a terminal half-life of about 24 hours.¹⁷⁴ Patients with hepatic dysfunction are susceptible to toxicity. Vincristine overdose is the most frequently reported antineoplastic overdose in the literature. This is because there are at least four different potential inappropriate ways to dose and administer vincristine, including confusing it with vinblastine, misinterpreting the dose, administering it by the wrong route, and confusing two different-strength vials. The normal dose of vincristine is 0.06 mg/kg, and a single dose is should not exceed 2 mg for either an adult or child.

Drug Interactions.

Administration of itraconazole with therapeutic doses of intravenously administered vincristine can cause toxicity probably for two reasons: (1) itraconazole-induced inhibition of certain cytochrome P450 enzymes (most likely the CYP3A subfamily) delays vincristine metabolism in vivo, and (2) inhibition of PGP mediated efflux of vincristine from inside cells, where it then accumulates.¹⁴ Coadministration of other azole antifungals, cyclosporine, isoniazid, erythromycin, mitomycin C, phenytoin, and nifedipine are also implicated in vincristine toxicity for the same aforementioned reasons.^77,206,207

Toxic Dose

The minimum toxic doses associated with adverse health effects from a single dose of vincristine and vinblastine are not well established. However, chemotherapeutic regimens tend to keep single doses at or below 2 mg to decrease the likelihood of peripheral neuropathy. Unfortunately, toxicity occurs with cumulative dosing over time, as which typically occurs with chemotherapeutic regimens. Peripheral neuropathy tends to begin after a cumulative dose (administered over multiple sessions, not all at once) of 30 to 40 mg.²⁹

Clinical Presentation

Despite their similarity in structure, vincristine and vinblastine differ in their clinical toxicity. Vincristine produces less bone marrow suppression and more neurotoxicity than does vinblastine. During the therapeutic use of vincristine, myelosuppression occurs in only 5% to 10% of patients.¹¹⁷ However, this effect is common in the overdose setting, and when it occurs, the need for blood products and concern for overwhelming infection is apparent.¹⁴² The decrease in cell counts begins within the first week and may last for up to 3 weeks. Other manifestations of acute vincristine toxicity are mucositis, central nervous system disorders, and syndrome of inappropriate antidiuretic hormone secretion (SIADH; Chap. 19).

Central nervous system disorders are varied and unusual during therapeutic vincristine therapy because of its poor penetrance of the blood–brain barrier. However, they are more common when there is delayed elimination, damage to the blood–brain barrier, overdose, or inadvertent intrathecal administration. Generalized seizures may occur from 1 to 7 days following exposure.^{121,126,132,222} Other manifestations are depression, agitation, insomnia, and hallucinations. Vincristine stimulation of the hypothalamus may be responsible for the fevers and SIADH noted in overdosed patients.¹⁹⁸ The fevers begin 24 hours after exposure and last 6 to 96 hours. Serum electrolytes must be monitored, typically for 10 days.

Autonomic dysfunction may occur, and it commonly includes ileus, constipation, and abdominal pain. Paraparesis, paraplegia, atony of the bladder, cranial nerve palsies (specifically ptosis), hypertension, and hypotension may also occur.^{77,83,132,254}

Ascending peripheral neuropathies can occur following inadvertent large ingestions and during routine chemotherapy. The risk can be limited somewhat by keeping the total for a single dose below 2 mg.²¹³ Neuropathy may appear after an overdose, starting at about 2 weeks and lasting for 6 to 7 weeks. Paresthesias, neuritic pain, ataxia, bone pain, wrist drop, foot drop, involvement of cranial nerves III to VII and X, and diminished reflexes may be observed.²⁴⁴ The incidence of paresthesia increases with dose and is reported to be 56% in patients treated at doses between 12.5 and 25 μg/kg.¹¹⁷ At a dose of 75 μg/kg, the incidence of patients with a sensory disorder increased by sixfold. The loss of reflexes, the earliest and most consistent sign of vincristine neuropathy, is maximal at 17 days after a single massive dose. Muscular weakness is a limiting point in therapy and typically involves the distal dorsiflexors of the extremities, although laryngeal involvement is also reported.^138,205 These severe neurologic symptoms may be reversed by either withholding therapy or reducing dosage upon manifestation of these findings.¹³⁸ Unlike the vinca alkaloids, taxol-induced peripheral neuropathy is predominantly sensory and resolves faster with discontinuation.¹⁴¹ This is because of the different effects on microtubule assembly by these chemotherapeutics.

Vincristine-associated myocardial infarctions are reported, but their cause is not understood.^{147,214,225,251} They may be related to vinca alkaloid–induced platelet aggregation, coronary artery spasm, or increased sensitivity of myocardium to hypoxia.

Although rare, IV vincristine administration may be associated with an allergic-type cutaneous reaction.¹⁷³

Diagnostic Testing

Determination of vincristine and vinblastine concentrations is not readily available at most hospitals (Table 36–2). Routinely available laboratory tests such as electrolyte panels, kidney function tests, and others can be used as needed to assess the patient as indicated.

Management

Generalized seizures can be a life-threatening complication of vincristine or vinblastine overdose (Table 36–2). Treatment with benzodiazepines or phenobarbital is usually successful; phenytoin was used successfully in a patient with known barbiturate hypersensitivity.¹³² Prophylactic phenobarbital and benzodiazepines were used to prevent seizures in two patients.^56,134 Dysrhythmias and alterations in blood pressure may also be expectantly managed. Calcium channel blockers (nifedipine and amlodipine) were used to control hypertension in a patient with vincristine overdose.⁵⁶ Blood counts must be monitored daily, and G-CSF may be used to treat neutropenia.^56,142,222 However, the red blood cell response from the use of erythropoietin may be limited because of the induction of metaphase arrest in the erythroblasts.¹⁴⁹

The symptoms of acute toxicity usually last for 3 to 7 days, and the neurologic sequelae may last for months before some resolution is observed. Nerve conduction studies are helpful in assessing the extent of any clinical signs and symptoms of peripheral neuropathy.

Clinical findings of a peripheral neuropathy may appear following an excessive dose or after multiple small doses in which the cumulative dose exceeds 30 to 40 mg.²⁹ Treatment for this condition is variable and includes pain and paresthesia management with various medications, including opioids, nonsteroidal antiinflammatory drugs, cyclic antidepressants, vitamin E, and other drugs such as gabapentin and lamotrigine.²⁹ In a controlled clinical trial for vincristine-induced peripheral neuropathy, glutamic acid therapy had some efficacy. Patients receiving vincristine therapy were given glutamic acid as 500 mg orally three times a day.¹²⁴ There was a decreased incidence in loss of the Achilles tendon reflex and a delayed onset of paresthesias in the glutamic acid–treated group. No reported adverse events with glutamic acid were observed in this investigation. Animal studies involving the administration of glutamic and aspartic acid to mice poisoned with either vinblastine or vincristine demonstrate increased survival and decreased sensorimotor peripheral neuropathy.^37,70,123 Although the exact mechanisms of these observed effects with glutamic acid remain unclear, several authors have suggested the ability of glutamic acid to competitively inhibit a common cellular transport mechanism for vincristine.^34,68 It may assist in the stabilization of tubulin and promote its polymerization into microtubules.^39,108 Finally, glutamic acid may improve cellular metabolism by overcoming vinca alkaloid-associated inhibition in the Krebs cycle.^82,125 Although the role of glutamic acid in acute toxicity needs further study, it is likely not harmful and should be considered. Glutamic acid may be initiated as 500 mg orally three times a day and should be continued for at least 5 days following exposure (approximately 95% of the drug should be eliminated after five half-lives) and possibly longer in very large exposures.^124,174 l-Glutamic acid is the preferred stereoisomer because it is biologically active, and this product is available as a powder from various distributors in the United States.

Leucovorin may shorten the course of vincristine-induced peripheral neuropathy¹⁰⁴ and myelosuppression.¹³⁴ The mechanism is attributed to the ability of leucovorin to overcome the vincristine-mediated block of dihydrofolate reductase and thymidine synthetase.¹⁰⁴ However, neither leucovorin^23,122,231 nor pyridoxine¹²² has been definitely shown to be effective. An initial experimental investigation evaluating the efficacy of antibody therapy to limit vinca alkaloid toxicity shows promise.¹⁰⁵ Unfortunately, vinca alkaloid specific antibodies for human poisoning are not commercially available.

The rapid distribution and high protein binding characteristics of vincristine favor early intervention with methods other than hemodialysis. Double-volume exchange transfusion was performed at 6 hours post-exposure in three children who were overdosed with 7.5 mg/m² of IV vincristine.¹³⁴ Of the two survivors, their respective postexchange serum vincristine concentrations were 57% and 71% lower than their preexchange concentrations. The amount of vincristine removed was not determined. Although these patients developed peripheral neuropathies, myelosuppression, and autonomic instability, the author noted that the duration of illness was shorter than previously reported. Thus, based on the pharmacokinetic profile of vincristine and these two reports, exchange transfusion in children is the preferred method of enhanced elimination when the patient presents soon after the administration of the drug, and plasmapheresis is the preferred method in adults.

Plasmapheresis was attempted with vinca alkaloid overdoses.^142,189 In an 18 year-old patient who received two 8 mg IV doses of vincristine at 12 hour intervals, the procedure was performed 6 hours after the second dose, and 1.5 times the plasma volume was plasmapheresed.¹⁸⁹ Postplasmapheresis serum vincristine concentration was 23% lower than the starting concentration. The patient survived with myelosuppression, neurotoxicity, and SIADH.

One case of IV vinblastine overdose was reported to be successfully managed with plasma exchange procedures performed at 4 hours and 18 hours after vinblastine administration resulting in markedly less toxicity than what was expected.²¹⁹

Patients receiving an overdose of vincristine intravenously should be admitted to a cardiac-monitored bed and observed for 24 to 72 hours.¹⁴⁵ If patients remain asymptomatic during the observation period, then they can be discharged with follow-up for bone marrow suppression and SIADH; otherwise, depending on the patient’s clinical condition, continual observation for progression of neurologic symptoms is warranted.²⁷

• Colchicine toxicity manifests within several hours after ingestion and consists of severe nausea, vomiting, diarrhea, and abdominal pain followed by pancytopenia several days later.

• Colchicine poisoned patients are at risk of sudden cardiac death, especially during the period between 24 and 36 hours after ingestion; increasing serial troponin concentrations may be predictive of that risk.

• Podophyllum toxicity is less pronounced than colchicine toxicity but may occur after dermal application.

• When excessive doses of intravenously administered vincristine or vinblastine are likely to cause severe toxicity exchange transfusion, plasmapheresis and plasma exchange should be considered.

• Intrathecal administration of vincristine or vinblastine constitutes a life-threatening neurosurgical emergency.

• Management of patients with toxicity from ingested colchicine, podophyllotoxin, and vinca alkaloid derivatives is similar. Early GI decontamination and supportive treatment are the mainstays of therapy. G-CSF may be of benefit in patients who develop neutropenia.

Disclaimer

The findings and conclusions in this chapter are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention or the Agency for Toxic Substances and Disease Registry.

Acknowledgment

Richard Wang contributed to this chapter in previous editions.

References