Keywords

Microtubules are present in all eukaryotic cells. They are responsible for movement of vesicles within cells, motion of cilia and flagella, and chromosome separation in mitosis. In neurons, microtubules serve as tracks for protein particles and organelles that move up and down the axon. They also can direct proteins for repair of cellular injury. Antitubulin agents, including colchicine, vincristine, vinblastine, and podophyllin, inhibit the construction of microtubules, which accounts for the therapeutic and the toxic actions of these agents.

Colchicine

Colchicine is an alkaloid derived from Colchicum autumnale , a member of the family Liliaceae [1], and from Gloriosa superba ( glory lilly ) [2, 3]. C. autumnale is a perennial plant that is known commonly as autumn crocus , wild saffron, meadow saffron, naked lady, naked boy, and son before the father. This plant is indigenous to temperate areas of Europe, Asia, and America. It is unusual because it flowers after the long, lanceolate leaves wither back and fall off (hence the “son before the father”). All parts of the plant contain colchicine, but the highest concentration is in the bulb, which is rooted underground [1]. Accidental and intentional ingestion of Colchicum autumnale has led to fatal poisoning despite supportive measures [4, 5]. Intentional ingestion of Gloriosa superba has also been reported to result in significant toxicity that is indistinguishable from poisoning with colchicine [6].

Colchicine has been used since the sixth century A.D., when it was introduced by Alexander of Tralles as a treatment for gout. It is said that Benjamin Franklin also used colchicine as a remedy for his gouty arthritis and possibly introduced it into the United States [1, 7]. Purified colchicine later was isolated from C. autumnale tubers in 1820 by Syng Dorsey and became widely known as a treatment for gouty arthritis [2].

In 2009, the US Food and Drug Administration (FDA) approved oral colchicine for the treatment of gouty arthritis, preventing gout attacks, and managing familial Mediterranean fever [8]. Previously, oral colchicine had been used for many years in the United States as an unapproved drug without FDA-approved prescribing information, dosage recommendations, or drug interactions. Over the years, colchicine has also been advocated for pseudogout, sarcoidosis [9], scleroderma [10], amyloidosis [11], Behçet’s disease [12, 13], psoriasis [14], systemic sclerosis [15], Paget’s disease, condyloma acuminatum [16], brown recluse spider envenomation [17], alcoholic cirrhosis [18], primary biliary cirrhosis [19], Sweet’s syndrome [20], and low back pain [21, 22].

Despite being available since the 1950s, the FDA withdrew marketing approval for IV colchicine after numerous deaths were associated with its use were reported. In fact, 20 adult deaths were reported between 1983 and 2000 after IV administration of colchicine [23]. In addition, in 2007 a compounding error lead to 3 deaths in the US states of Washington and Oregon after patients received IV colchicine for back pain at an alternative medicine clinic [24, 25].

Biochemistry and Pharmacokinetics

Colchicine has a complex structure (Fig. 1). Tropolones have a hydrogen ion, which resonates between an oxygen and methyl group. Wallace [26] identified five colchicine analogues. It was found that one analogue lacked a tropolone structure; that particular analogue failed to have antigout activity (Table 1).

Fig. 1
figure 1

Chemical structure of colchicine

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Table 1 Colchicine pharmacokinetics [27]
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The kinetics of colchicine are variably reported, but the most frequently cited observations regarding absorption from the gastrointestinal tract show the occurrence of a peak plasma concentration in 30 min to 3 h. Approximately 10–50% of the drug is protein bound, and its volume of distribution is estimated to be 2–12 L/kg. This information allows for an understanding of the limited efficacy of hemodialysis as a means of enhancing drug clearance. The major route of elimination of colchicine is through hepatic metabolism and biliary excretion. Colchicine undergoes extensive first-pass metabolism, which explains its decreased bioavailability of 25–50%. It is believed that enterohepatic recirculation may prolong exposure of the intestinal mucosa to colchicine [1]. Twenty percent of unchanged drug is excreted in the urine [28]. In the setting of preexisting renal or hepatic impairment, these elimination percentages may change. Thus, patients with impaired hepatic or renal function are at significant risk for toxicity even on conventional dosing.

Colchicine has been reported to have a half-life of 4.4 to 16 h with therapeutic dosing and can reach 11–32 h in overdose. Colchicine has been found in white blood cells and in urine 9 days after a single intravenous bolus [7, 29, 30]. Because colchicine is metabolized through cytochrome P-450 CYP3A4, its breakdown may be inhibited or induced. Inhibitors of CYP3A4, such as clarithromycin, cimetidine, ketoconazole, erythromycin, diltiazem, ritonavir, verapamil ER, and grapefruit juice, frequently produce increases in serum concentrations of colchicine. Inducers of CYP3A4 include rifampin, St. John’s wort, phenobarbital, and phenytoin, which tend to lower serum colchicine concentrations. Multiple studies have demonstrated that drugs which inhibit P-glycoprotein, such as clarithromycin and cyclosporine, increase the risk of toxicity by increasing colchicine concentrations [31]. The combination of colchicine and statin medications has become a concern as numerous anecdotal reports have described cases of acute myopathy including rhabdomyolysis [32–35]. In 2010, the AGREE (The Acute Gout Flare Receiving Colchicine Evaluation) study concluded “low-dose colchicine yielded both maximum plasma concentration and early gout flare efficacy comparable with that of high-dose colchicine, with a safety profile indistinguishable from that of placebo.” This conclusion has led to recommendations for using low-dose colchicine for the treatment of gout. The use of low-dose colchicine decreases gastrointestinal side effects and should also reduce potential drug–drug interactions (Table  2) [36].

Table 2 Drug interactions [37, 38]
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Pathophysiology

Microtubules are formed by polymerization of protein subunits, G actin and tubulin. Tubulin is present in α, β, and γ forms; α and β tubulin combine as dimers that serve as the building blocks of microtubules, and γ tubulin seems to play a role in the organization of these dimers during the assembly of a tubulin sheet. The sheet connects end to end to form the cylindrical origin of the microtubule [39]. The microtubule is composed of repeating α and β tubulin subunits in a helical array measuring 24 nm in diameter (Fig. 2) [40]. The tubulin dimer has oppositely charged ends. Because the dimers are aligned repetitively, the microtubule they form has a positive end and a negative end. This alignment confers polarity to microtubules, which is crucial to their function. They are connected in elaborate networks depending on the function they serve within the cell. Microtubules form a diverse array of permanent (stable) and transient (unstable) structures. Stable microtubules are found when long-lived microtubules are needed, such as the axoneme in the flagellum of sperm and the marginal band of microtubules in most red blood cells and platelets or nerve cells. Unstable microtubules are found when cell structures composed of microtubules need to disassemble and assemble quickly. During mitosis, the cytosolic microtubule network that occurs in interphase disappears, and the tubulin from it is used to form the spindle-shaped apparatus that partitions chromosomes equally into daughter cells. Neurons must maintain long axons and do this with the aid of microtubules that continue to assemble (polymerize), and add to the chain. Disassembly of these stable structures has catastrophic effects, such as nonmobile sperm, nonpliable red blood cells, and retracting axons [39].

Fig. 2
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Microtubule assembly occurs at the positive end, whereas disassembly occurs at the negative end. Antitubulin compounds prevent the addition of tubulin at the positive end and stop assembly

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Vinca alkaloids, colchicines, and podophyllin all inhibit the construction of microtubules that compose spindles in metaphase. This inhibition interrupts migration of the chromosomes toward the poles during mitosis but does not affect chromosome condensation. Because of this ability, colchicine is used in research to produce metaphase chromosomes for cytogenic study. Each dimer of tubulin has a single high-affinity binding site for colchicine. When one or two vinca alkaloid-bound, podophyllin-bound, or colchicine-bound tubulin dimers attach to the end of the developing microtubule, additional assembly stops. Although these compounds inhibit spindle formation, they do not cause their disassembly at lower doses. When assembly is halted at the positive end of the microtubule, naturally occurring disassembly at the negative end continues. At high doses, however, some of these compounds also may enhance disassembly [41].

Microtubule formation is regulated by the number of tubulin dimers. As the number of “free” dimers within the cell increases, they bind to ribosomes and shut down the production of tubulin mRNA. The antitubulin compounds, via their inhibition of tubulin dimer polymerization, increase the number available to inhibit mRNA production. They do not seem to affect the more permanent microtubules because at therapeutic doses their impact is primarily on the assembly of the microtubule .

Vincristine and vinblastine also inhibit the formation of mitotic spindles, interrupting cell division. They appear to crystallize free tubulin dimers. As a result of this action, they preferentially kill rapidly dividing cells, such as tumor cells. This effect also causes cell death in gut and hair cells because of their rapid division. Although the vinca alkaloids bind to tubulin, preventing polymerization in a fashion similar to that of colchicine and podophyllotoxin, they seem to have a different binding site [40].

The mechanisms of action of colchicine have been studied extensively but remain unclear. Colchicine’s action seems to depend on its rings, which are believed to bind microtubules, inhibiting the movement of intracellular granules. This inhibition disturbs the excretion of various components to the cell exterior. Colchicine inhibits multiple aspects of neutrophil activity, including adhesiveness, ameboid activity, mobilization, and degranulation of lysosomes, but the most studied is the inhibition chemotaxis [28]. Colchicine is thought to work primarily through this inhibited chemotactic mechanism in the treatment of gout (Table 3) [42, 43].

Table 3 Stages of colchicine toxicity
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Clinical Presentation

Cases of overdose of colchicine are not common but are associated with significant morbidity and mortality. Mortality overall is approximately 10% but approaches 100% for cases in which the ingestion is 0.8 mg/kg or greater [2]. A review by Baum and Meyerowitz found that although about 90% of persons treated with colchicine for gout are men, the intentional use of this drug in overdose occurs more often in women [44].

Acute ingestion of colchicine is heralded by gastrointestinal symptoms for the first 24 h. Profound nausea, vomiting, and diarrhea are common [29]. Abdominal cramping and melanotic stools are reported in several cases [3, 45, 46]. These symptoms can cause circulatory collapse due to fluid losses and electrolyte abnormalities. Gastrointestinal symptoms are used as an end point of therapy in the treatment of gout. Typically, these symptoms ensue within minutes of ingestion. The cause is believed to be a direct toxic effect of colchicine on the gut epithelial cells [1]. Emesis may be centrally mediated as well, however, as suggested by an animal study by Ferguson [47] in which gastrectomized animals vomited anyway.

Beginning at 24–36 h, the second stage consists of multiple organ failure. Hematopoietic changes begin with noticeable peripheral leukocytosis [1, 16, 30], which reverses quickly and is followed by pancytopenia. Hemorrhage may develop secondary to hepatic dysfunction and thrombocytopenia. Hepatotoxicity and adult respiratory distress syndrome are described in multiple cases. Death during this stage is often secondary to hemodynamic collapse and arrhythmias. Disseminated intravascular coagulation is frequently reported [3, 29, 30, 46, 48]. Systemic abnormalities may include pancytopenia, coagulopathy, hepatic transaminase elevation, acidemia, renal insufficiency, and electrolyte abnormalities, such as hypophosphatemia, hypomagnesemia, hypocalcemia, and hypokalemia. Serum creatine phosphokinase or urine myoglobin concentrations initially should be monitored serially. Septic workup, including blood cultures, is indicated for unexplained fever. Chest radiographs may show interstitial lung changes. Colchicine plasma concentration may confirm the presence of the drug but in many cases does not correlate with the patient’s condition [16]. Without preexisting colchicine levels, interpretation of these values is limited. Hepatic and renal dysfunction may prolong drug metabolism and elimination [30].

Bradycardia and irregular rhythms have been seen with intravenous colchicine administration. Hemodynamic profiles of cardiac failure in acute ingestions have been described in several case reports [2]. Cardiac profiles obtained by Sauder and coworkers [49] in a study of eight patients revealed that four patients had declining cardiac index and rising systemic vascular resistance; these patients subsequently died. Asystole has been reported within 24 h of ingestion. In one case, the ingestion of 0.4 mg/kg resulted in death. Eight of 12 deaths due to colchicine, according to poison center statistics from 1985 to 1997, indicated the cause of death to be cardiac [50].

Oliguric renal failure is a common problem in severe colchicine poisoning. One likely cause of renal dysfunction is the profound hypovolemia from sensible gastrointestinal fluid losses and accumulation of fluids that results from paralytic ileus and marked gastrointestinal tract edema [1, 3]. Volume depletion, combined with hypoxia and myoglobinuria secondary to colchicine-induced rhabdomyolysis, has resulted in azotemia, proteinuria, and hematuria [1, 29, 46].

Reported electrolyte abnormalities include hypokalemia, hyponatremia, hypocalcemia, and hypophosphatemia [30, 46, 49]. Hypocalcemia may be due to a direct effect of colchicine on bone resorption. Animal studies have shown that colchicine inhibits the rise of serum calcium after injection of parathyroid hormone [51].

Neurologic complications reflect central nervous system (CNS) and peripheral nervous system involvement. Mental status changes, including sedation, delirium, and coma, are the most common CNS manifestations. However, the incidence is very rare as colchicine does not cross the blood–brain barrier easily due to P-glycoprotein. Seizures also have been reported. Peripheral nervous system involvement includes myoneuropathy and axonopathy as consequences of chronic and acute overdose [52]. Ascending paralysis and loss of deep tendon reflexes typically occur [53]. Myelin degeneration found on postmortem pathologic examination was thought to be the underlying peripheral manifestation in colchicine poisoning [1, 3].

Metabolic derangements also are well described in cases of colchicine intoxication. Lactic acidosis secondary to shock and tissue hypoxia is associated with colchicine toxicity; however, a more disruptive effect on cell metabolism also may contribute to the acid–base disturbance seen in many cases [30]. Rhabdomyolysis occurs fairly commonly in colchicine poisoning, manifested by myalgia, weakness, and marked elevation in serum creatine phosphokinase concentrations[27].

Alopecia marks the third stage of toxicity, which may be seen as early as day 6 and as late as day 14. Alopecia is due to the inhibition of mitotic activity in the hair follicles. Most commonly, alopecia begins on the scalp, then involves the axillae, trunk, extremities, and genital area. Regrowth generally occurs after several months, but failure of regrowth has been reported [54–56]. Rebound leukocytosis also occurs in phase III (Table 4).

Table 4 Clinical features of antitubulin agent overdose
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Diagnosis

The diagnosis of colchicine toxicity is straightforward if a history of exposure is obtained. However, the signs and symptoms of colchicine toxicity could be easily mistaken for other conditions without a known exposure. These conditions might include enterocolitits, sepsis, toxicity due to heavy metals (iron, arsenic, thallium, mercury), or chemotherapeutic agents. The typical toxidrome seen with colchicine poisoning would include gastroenteritis, hypotension, lactic acidosis, and prerenal azotemia [27].

Treatment

Intensive monitoring of vital physiologic parameters is imperative in a patient with colchicine intoxication. After initial resuscitative measures, attempts may be made to delay absorption. Activated charcoal (1 g/kg) can be administered (evidence level III). However, it is unknown if doing so alters the clinical course of colchicine overdoses. Colchicine undergoes enterohepatic recirculation; however, current evidence does not support the use of multi-dose-activated charcoal in the treatment of its toxicity [23]. Additionally, patients with colchicine toxicity may develop a paralytic ileus, which is a contraindication to this intervention. Hemodialysis has not proved to be beneficial for colchicine poisoning. Any patient with a suspected toxic ingestion of colchicine should be observed for symptoms or signs of toxicity for a minimum of 12 h. If signs of toxicity develop (see section on “Clinical Presentation”), intensive care unit admission is warranted.

Supportive care is the mainstay of treatment. Intravascular volume and blood product replacement may be necessary, especially if coagulation parameters are abnormal or bleeding is noted. Fluid requirements may be underestimated due to gastrointestinal loss. It is important to maintain renal clearance to enhance colchicine elimination. Ventilatory status should be monitored closely, with intubation and mechanical ventilation provided as indicated. Hemodynamic monitoring also should be performed in a critical care setting initially and on a continuing basis as needed. Vasopressor support and electrolyte replacement may be necessary. Urine output should be followed closely and adjustments made accordingly. As clinical toxicity progresses, patients should be watched for signs of infection, as they become neutropenic and susceptible to opportunistic pathogens. Seizures should be treated with benzodiazepines or barbiturates (Grade III recommendation), and the possibility of underlying acidosis, hypoxia, or electrolyte abnormalities should be considered and corrected aggressively (Grade III recommendation) [3].

Injections of granulocyte colony-stimulating factor (G-CSF) have been used in several cases to treat bone marrow suppression (Grade III recommendation). Dramatic increases have been reported in some but not all cases [29, 57, 58].

The development of colchicine-specific Fab fragment antibodies is a promising therapy but remains unavailable commercially. These antibodies bind to colchicine and restore tubulin activity in vitro [59]. Studies performed in mice, using thermoregulation as an end point, showed a significant improvement in the group that received colchicine-specific IgG [60]. Anticolchicine antibodies were used successfully in a 25-year-old woman who presented 24 h after ingesting 60 mg (0.96 mg/kg) of colchicine, phenobarbital, and opium extract. She was hemodynamically unstable and required vasopressor support. Colchicine-specific Fab fragments derived from goats were administered intravenously 40 h after the ingestion. The patient’s blood pressure began to increase 30 min after Fab administration. During the 6-h infusion of the maintenance dose of Fab fragments, fluid replacement continued, and urine output improved [61].

Some authors have advocated for considering early initiation of either whole blood or plasma exchange in patients presenting with lethal-dose colchicine intoxication. However, more research needs to be done investigating these therapies [62].

Indications for ICU Admission in Colchicine

Any patient with clinical signs of poisoning or confirmed ingested toxic dose.

Special Populations

Colchicine must be used cautiously in elderly patients owing to their increased risk of underlying hepatic or renal dysfunction [26]. Patients with impaired hepatic or renal function have reduced colchicine clearance. Pediatric patients may be administered colchicine during therapy for conditions such as familial Mediterranean fever [8, 63], acne vulgaris [64], renal amyloidosis [65], or pericarditis [66], to mention only a partial list. There are reports of colchicine toxicity involving children, the first case appearing in the English literature in 2000. Unfortunately, fatal poisoning has occurred in the pediatric population [62, 67–69].

Pregnancy

Colchicine is classified as FDA pregnancy category C, meaning that the benefits may exceed the risks. However, well-controlled studies with colchicine in pregnant women have not been conducted. Colchicine has been shown to cross the placenta.

Key Points in Colchicine Overdose

  • Narrow therapeutic index.

  • Be aware of interactions between colchicine and CYP3A4 and P-glycoprotein inhibitors.

  • Toxicological emergency requiring admission for any known or suspected overdose.

  • Toxidrome includes gastroenteritis, hypotension, lactic acidosis, and prerenal azotemia.

  • Cornerstone of treatment is supportive care.

Vinca Alkaloids

The vinca alkaloids are derived from the Madagascar periwinkle (Catharanthus roseus), a perennial evergreen herb found in most warm regions of the world. Native to Madagascar, it has been naturalized in most tropical countries including the southern part of the United States. Interest in C. roseus among Western researchers began in 1949, when they studied its use in a tea made by Jamaicans for the treatment of diabetes mellitus. Although its use as a hypoglycemic agent did not evolve as a result of this investigation, bone marrow suppression was observed. Many alkaloids eventually were extracted from the plant, including vincristine, vinblastine, vindesine, and vinorelbine. Semisynthetic vinca alkaloids are also in use or under development. Although structurally similar (Fig. 3), these compounds vary in their clinical effects and application in the treatment of neoplastic diseases. The mechanism of action of these compounds is similar to that of colchicine and podophyllin, although with different binding sites on the tubulin dimer. Vincristine is used in combination therapy to treat solid tumors, lymphoma, and leukemia. Vinblastine is used in combination to treat bladder and breast cancers as well as Hodgkin’s disease. Vinorelbine has been used for treatment of small cell lung cancer. Recommended doses for vincristine are shown below:

Fig. 3
figure 3

Chemical structures of vincristine and vinblastine

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  • Vincristine recommended dose for pediatric patients: 1.5–2 mg/m2.

  • Vincristine recommended dose for adults: 1.4 mg/m2.

  • A 50% reduction in the dose is recommended for patients with direct serum bilirubin concentrations exceeding 3 mg/dL [70].

Pharmacokinetics

The vinca alkaloids commonly are injected intravenously and seem to follow a three-compartment model (see Fig. 3). When ingested, vinca alkaloids’ absorption is unpredictable, although vinorelbine is frequently administered orally. When administered intravenously, vincristine rapidly distributes into tissue of the ileum, skeletal muscle, and kidney. It penetrates the blood–brain barrier poorly. Metabolism of these compounds is primarily hepatic. They are excreted in the bile, and less than 1% of vincristine and vinblastine are excreted in the urine. Renal elimination accounts for 18% of vinorelbine excretion.

Pharmacokinetics of Vinca Alkaloids

Table 5
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Vincristine, and probably all the vinca alkaloids, inhibit the CYP3A subfamily. Troleandomycin, ketoconazole, nifedipine, erythromycin, cyclosporine, and vindesine all seem to increase serum concentrations of the vinca alkaloids. Calcium channel blockers, such as verapamil, seem to decrease protein binding of the vinca alkaloids, increasing the risk of neurotoxicity [72].

Pathophysiology

The nervous system is the primary target organ of vincristine toxicity. Vincristine disrupts the normal process of microtubule formation, interfering with axoplasmic transport, which accounts for the prevalence of neural injury associated with its administration [73, 74]. At therapeutic doses of vincristine of 1.5 mg/m2 (0.06 mg/kg), the onset of peripheral neuropathies may begin within 2 weeks and occurs with a nearly 100% incidence [75].

Vinblastine and vinorelbine seem to depolymerize microtubules at the negative terminus while stabilizing the positive terminus [41]. They cause less inhibition of microtubular polymerization and are less neurotoxic than vincristine. Their primary toxicity is bone marrow, which is often the dose-limiting factor during therapy with either drug.

Clinical Presentation

Acute Toxicity

Vincristine. Paresthesias usually begin in the hands, followed by sensory loss in the feet. Loss of ankle-jerk reflex occurs soon thereafter [76]. Although the sensory loss may progress, it seldom results in more proximal stocking-glove distribution deficits. Motor symptoms follow, with weakness of the extensors of the hands and feet being most pronounced. Nerve conduction studies may show slowing of nerve conduction velocity with decreased amplitude. Electromyelography may rarely show signs of denervation in distal muscle. Morphological changes include demyelination with “die-back” pattern of axonal loss and dorsal root ganglion damage [77]. Cranial neuropathies are rare; however, ototoxicity with sudden transient hearing loss has been reported [78]. Sensory and motor symptoms usually abate within a few weeks of discontinuation of therapy, although mild distal sensory loss and absence of ankle-jerk reflexes may persist.

Although CNS penetration at therapeutic doses is relatively low, encephalopathy and seizures have been reported [79, 80]. In rare cases, they are the presenting sign of intravenous overdose and frequently occur a few days to a week after exposure. Initial signs and symptoms of overdose may include bone or muscle pain, abdominal pain, bleeding, or marrow depression [81–83]. Other adverse effects of vincristine use include autonomic dysfunction, mucositis, paralytic ileus, bladder atony, fever, bone marrow suppression, alopecia, and hypertension [75, 83]. Trinkle and Wu [84] reviewed 18 cases of intravenous vincristine overdose in children (average age 10 years). There were four fatalities with a dose range of 0.2–0.6 mg/kg. The major lethal risk factors were hemorrhage due to thrombocytopenia and neutropenia-related infection. Paresthesias and loss of deep tendon reflexes occurred as early as 24 h. Nausea, vomiting, diarrhea, and abdominal pain usually occurred within 48 h. Paralytic ileus occurred in 66% of patients within a mean of 5 days. Thrombocytopenia and leukocytopenia occurred in most cases [84]. Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) has been a relatively frequent occurrence after vincristine overdose [81, 83, 85].

Accidental intrathecal injection accounts for a large portion of the fatalities, and survival from such exposures is rare regardless of therapy [86]. (See “Intrathecal Exposure” below.) These therapeutic mishaps usually involve vincristine administration by personnel unfamiliar with the drug or confusion with other antineoplastic drugs that may be administered via that route. Dermal extravasation of vinca alkaloids has been associated with tissue loss [87]. (See “Extravasation” below.)

Vinblastine and Vinorelbine . These vinca alkaloids are less potent inhibitors of microtubular polymerization and are less neurotoxic than vincristine. Their primary toxicity is bone marrow suppression, which often is the dose-limiting factor during therapy with either drug and is the most common toxic effect of these drugs (see Table 1). Granulocytopenia occurs frequently. There are relatively few reports of overdose [88–91]. After overdose, onset of fever and diarrhea has been reported within a few hours. Pulmonary edema developed in one reported case at day 4 [91]. Vinorelbine also has been associated with bronchospasm and respiratory failure, but concurrent disease may have played a significant role [92].

Chronic Adverse Effects

Myocardial ischemia has been reported after therapeutic doses of the vinca alkaloids [93–96]; however, this patient population tends to be at greater age-related cardiovascular risk. Delayed (24 h) onset of epithelial keratopathy was reported after ocular exposure to vinblastine solution; it resolved over 2 weeks without treatment. Ototoxicity also has been reported (with vincristine and vinblastine). Tinnitus occurred in a 29-year-old man within hours of treatment with vinblastine, doxorubicin, bleomycin, and dacarbazine and lasted 7–10 days after each of multiple treatments; mild sensorineural hearing loss persisted in the high-decibel range [97]. Pancreatitis has been reported after therapeutic doses of vinorelbine [98, 99]. As these cases show, predicting the toxicity of the vinca alkaloids frequently is confounded by coexistent disease and the presence of other chemotherapeutic agents. Similar to vincristine, vinblastine and vinorelbine also have been associated with SIADH [100, 101]. Hepatotoxicity including veno-occlusive disease has been reported particularly in pediatric patients during combination therapy with vincristine (see section “Special Populations”).

Treatment

Intravenous Exposure

Supportive measures are the mainstay of care. Peripheral neuropathies usually resolve or improve on withdrawal of the drug. Seizures usually respond to benzodiazepines or barbiturates or both (Grade III recommendation). Phenytoin would not be expected to be efficacious (see Chap. 20, “Toxicant-Induced Seizures”). Additionally, a theoretical concern with the use of phenytoin is that it seems to potentiate the effects of vincristine and vinblastine by interfering with tubulin polymerization [102]. SIADH is managed most appropriately by fluid restriction. Vincristine has a large volume of distribution due to tissue uptake and is highly protein bound. Hemodialysis is of little benefit with regard to enhancement of drug clearance. Plasmapheresis has been performed with a favorable outcome [103], but data supporting its use are inadequate. Folinic acid has been used in humans [104] and studied in animals [105], but its efficacy is controversial. If used, a suggested dosing schedule is “100 mg IV every 3 h for 24 h and then every 6 h for at least 48 h” [70]. Finally, glutamate also has been studied as a preventive intervention against neurotoxicity. In patients receiving therapeutic doses, neurotoxicity seemed to be reduced [106]. This particular intervention, too, is based on limited data.

Indications for ICU Admission in Vinca Alkaloid Overdose

  1. 1.

    The maximum tolerated doses of these drugs are not established. Patients who have received excessive amounts should be admitted for observation on a cardiac monitor.

  2. 2.

    The length of observation after intravenous overdose with one of the vinca alkaloids should be 3–4 days because the onset of symptoms may involve that degree of delay. This is dose dependent, with high-dose exposures reportedly causing onset of symptoms within only a few hours [81, 83].

Intrathecal Exposure

With few exceptions [107, 108], the accidental intrathecal or intraventricular injection of vincristine has resulted in death [86, 109, 110]. Autopsy results have shown evidence of an ascending chemical leptomeningitis; ventriculitis; and necrosis of the spinal cord, brainstem, and cerebellum [111, 112]. Folinic acid [110, 111, 113, 114] and glutamic acid [114, 115] have been administered in many of these cases despite the relative paucity of supporting data and in response to the devastating and typically lethal nature of this injury. CNS washout involves removal of cerebrospinal fluid and replacement by Ringer’s lactate. Ferayan et al. [116] reported significant motor and sensory impairment in a 7-year-old patient who ultimately survived. They employed a technique first described by Dyke [115]. During a routine admission for chemotherapy, 0.5 mg of vincristine accidentally was injected intrathecally. The error was recognized before the injection was complete, and 75 mL of cerebrospinal fluid was withdrawn immediately thereafter. That volume was replaced with Ringer’s lactate via an additional lumbar puncture. In less than 2 h, a catheter was placed in the right lateral ventricle by way of a burr hole; 1 L of Ringer’s lactate was infused through the ventricular catheter at a rate of 100 mL/h. Afterward, 15 mL of fresh frozen plasma was mixed with each liter of Ringer’s lactate, and the rate was reduced to 55 mL/h. That infusion was continued for 24 h with the effluent passing through the lumbar catheter. Glutamic acid (250 mg every 8 h) was administered via nasogastric tube, and then continued orally for 1 month. The patient became symptomatic 7 days postexposure with urinary retention and sensorimotor impairment of the lower extremities. There was significant residual impairment at follow-up 34 months after exposure [116]. Aggressive replacement and lavage washout is not always successful [86, 110], but at present it seems to be the only viable therapy (Grade III recommendation).

Extravasation

Extravasation typically causes pain, swelling, and erythema within minutes. While blister formation may occur over the subsequent days, skin ulceration usually does not occur [117]. Subcutaneous injection of 250 U of hyaluronidase in 6 mL of normal saline circumferentially at the site has been recommended; this should be followed by the application of heat for 1 h in the event of extravasation of vincristine or vinblastine. This procedure should be repeated four times daily for 3–5 days. Boman et al. (1996) demonstrated significant reduction of dermal toxicity when vincristine was administered in liposomes [118].

Special Populations

Children are the most common victims of accidental overdose or intrathecal injection. This is usually due to lack of familiarity with the drug or confusing it with another agent. It is imperative that stringent protocols for identification and administration of these compounds be followed because toxicological treatment, particularly after intrathecal administration, is of limited efficacy.

  • Hepatic veno-occlusive disease has been reported in several pediatric and some adult patients [119]. Bisogno et al. studied 41 patients with veno-occlusive disease and found a higher percentage of patients in children less than 1 year of age. Risk factors appear to be young age and concomitant radiotherapy [120].

  • Renal Failure: Vinblastine 14%, vincristine 12%, and vinorelbine 18% are eliminated in the urine. This is primarily the parent drug and a smaller amount of the metabolite.

  • Vincristine can induce severe peripheral neuropathy in patients with Charcot–Marie–Tooth syndrome. Vindesine has been successfully used as a substitute [121].

  • Vinblastine, vincristine, and vinorelbine are rated FDA Category D (risks may exceed benefit) for pregnancy and breast-feeding. Human data are limited but animal studies suggest high risk [122–124].

  • Patients taking drugs that inhibit CYP3A subfamilies such as itraconazole and ketoconazole are at increased risk of developing toxic concentrations (Grade III recommendation) (see Table 2) [113, 114, 125].

  • Occupational Exposures: Some studies have raised concerns regarding potential occupational exposures to vinca alkaloid in veterinary and human health-care workers. However, serious adverse health effects outside of allergic reactions have yet to be demonstrated [126–129].

Key Points in Vinca Alkaloid Overdose

  1. 1.

    Fatal exposures are almost always the result of iatrogenic administration.

  2. 2.

    People inexperienced with the use of these compounds should work under close direct supervision of medical professionals with substantial training and experience in the use of these compounds.

  3. 3.

    Therapeutic errors have been avoided by the institution of strict protocols for identification and administration of these drugs.

  4. 4.

    Administration via mini-bags may reduce intrathecal injection [130]

Podophyllin and Podophyllin Derivatives

Podophyllotoxin (Fig. 4) is found in the rhizome and roots of Podophyllum peltatum, also known as mandrake or May apple . Native Americans used podophyllotoxin as an emetic, and the Chinese used it (gui jiu) as an abortifacient, as treatment for snakebites, and as an aid to purging intestinal parasites [131–133]. Podophyllin was included in the United States Pharmacopeia in 1820 [134]. Purification and isolation of podophyllotoxin was first accomplished in 1880 [132, 133]. Podophyllotoxin resin, or podophyllin, was used widely in the United States as a cathartic and an ingredient in proprietary medicines (e.g., Carter’s Little Liver Pills) and topically in a 20–25% solution for condylomata until such uses were associated with reports of serious toxicity [135–144].

Fig. 4
figure 4

Podophylllin and derivatives

Full size image

Herbal remedies erroneously may contain podophyllin because mandrake also is used to refer to Mandragora officinarum, which has anticholinergic properties [145]. Poisoning also has been reported with herbal remedies obtained in countries outside the United States [146–149].

In 1942, podophyllin was reported to treat venereal warts successfully, and in 1947 podophyllin-induced mitotic arrest was shown, leading to the investigation of its use for cancer treatment [132, 134]. In response to the high toxicity and low water solubility of purified podophyllin, chemical modification of the compound was carried out, and many of the resulting compounds were studied. In the 1960s, synthesis and biologic testing of the podophyllin derivatives teniposide and etoposide were initiated. Currently, prescription ointment containing 0.5% podophyllin (Podofilox©, Condylox©) (US brand names are given in examples. These may vary depending upon the country.) and physician-applied 25% podophyllin solution (Podocon −25©) are used for the treatment of anogenital warts [150, 151]. Podophyllin also is used topically to treat oral hairy leukoplakia [152]. Etoposide (VePesid, Etopophos) and teniposide (Vumon) are used in chemotherapy regimens for cancers, including testicular cancer, small cell lung cancer, lymphoma, and acute lymphoblastic leukemia [40, 132, 134, 153–155].

Pharmacokinetics of Podophyllin and Podophyllin Derivatives

Podophyllin [143, 156, 157] Available in topical preparation from 0.5% to 25% in alcohol or benzoin tincture

Highly lipid soluble

Well absorbed across friable tissue

Dermal application of 0.1–1.5 mL of 0.5% topical preparation led to peak serum concentrations of 1–17 ng/mL 1–2 h after application with an elimination half-life of 1–4.5 h

Oral and intravenous pharmacokinetic data unavailable

Etoposide [150, 155, 158] Oral formulation with polyethylene glycol, citrate, and glycerin

Intravenous formulation with polyethylene glycol, polysorbate 80, and 30% ethanol

Poor water solubility

Renal elimination (significant in children, 55% recovery in urine at 24 h)

Oral bioavailability of 50%

No significant first-pass effect

97% protein bound

Volume of distribution highly variable between 7 and 17 L/m2

Terminal half-life 3–11 h after intravenous infusion

Teniposide

Intravenous formulation with ethanol, which is reconstituted before infusion

Greater than 99% protein bound

Volume of distribution highly variable between 3 and 44 L/m2

Half-life variable between 6 and 48 h, depending on the model

Biliary excretion 10% of elimination

Some central nervous system penetration

Pathophysiology

The cell cycle consists of four phases: G1 (growth), S (DNA duplication), G2 (preparation for cell division), and M (mitosis – cell division). Interphase consists of all phases except mitosis [159]. Although the spindle poisons, such as colchicine, podophyllin, and the vinca alkaloids, act in mitosis (specifically, causing metaphase arrest), podophyllin derivatives (etoposide and teniposide) act in interphase and prevent mitosis.

Podophyllin, similar to colchicine, binds reversibly to tubulin at the colchicine-binding site, resulting in mitotic arrest [40, 131]. Microscopically, this activity results in metaphase arrest with clumped chromosomes because the mitotic spindle is unable to form without microtubules [132]. Disruption of microtubules also causes decreased cellular transport. Podophyllotoxin also inhibits the incorporation of labeled thymidine and uridine into cells by inhibiting nucleoside transport [160]. Neurotoxicity is thought to be related to microtubule binding and inhibition of axoplasmic flow [161].

Podophyllotoxin derivatives have a mechanism of action distinct from that of the parent compound. Etoposide does not inhibit microtubule assembly compared with podophyllin [160, 161]. Cells treated with etoposide, teniposide, and similar derivatives were found to have a low mitotic index, indicating that cells were inhibited from entering mitosis [162]. Time analyses indicated that the cells likely arrest in late S or early G2 phase [162, 163]. Later analyses showed that these derivatives may bind to tubulin, but this effect is seen at much higher and clinically impractical doses [132].

Radiolabeled nucleoside (thymidine) incorporation into DNA is inhibited with etoposide and teniposide [162, 164]. This mechanism of action is shared with podophyllin. Inhibition of cell proliferation is not linked to this mechanism, however [162, 165].

In 1974, DNA fragmentation by etoposide and teniposide was reported and represented a breakthrough in the understanding of the mechanism of action of podophyllin derivatives [160]. Podophyllin itself has no effect on DNA. Structure–activity studies indicated that derivatives with a hydroxyl group at the C-4′ position are required for this activity [160, 166]. DNA breakage was found to correlate well with the cytotoxic effects of the drugs [167]. Subsequently, podophyllin derivative–induced DNA fragmentation has been correlated with inhibition of topoisomerase type II, which is essential for uncoiling of DNA before replication [168]. Topoisomerase II inhibition is now believed to represent the primary mechanism of action of these drugs, and they are classified today as topoisomerase interactive agents along with anthracyclines, such as doxorubicin [132, 134, 155]. Current research is ongoing regarding the antitumor potential of novel podophyllin derivatives, some of which have reached clinical trials [169–172].

Clinical Presentation

During therapeutic administration of etoposide and teniposide, the most significant dose-limiting effect is bone marrow suppression (seen in 90% of patients), with granulocyte nadirs occurring in 7–14 days and platelet nadirs occurring in 9–16 days after administration. Marrow recovery usually occurs within 20 days [134, 153, 158, 173]. Nausea, vomiting, anorexia, and diarrhea are reported but are milder when caused by other chemotherapeutic agents [134]. At high doses, mucositis may be dose limiting. Anaphylaxis may occur. CNS depression and hypotension have been reported during intravenous infusion (see Table 1). Transient elevations in liver function tests have been reported. In children with acute lymphocytic leukemia, treatment has been associated with the development of secondary leukemias [174, 175]. Hemolysis and renal failure have been reported in conjunction with teniposide-related antibody [176]. CNS depression, hypotension, and metabolic acidosis have been reported in children treated with teniposide; however, they also had clinically significant ethanol concentrations due to the high ethanol concentration in the infusion [177]. Neurologic manifestations, such as peripheral neuropathy, are less common after administration of the topoisomerase II inhibitors than with the spindle poisons, but they have been reported as well, often in high-dose use and in conjunction with drugs such as vincristine [178, 179]. Neurologic signs and symptoms, such as somnolence and seizures, have been reported after high-dose etoposide therapy for malignant glioma [180]. One case report of inadvertent supratherapeutic use of oral etoposide for 25 days detailed a reduction in T lymphocytes and blastic transformation that persisted at 57 months along with relapse-free remission [181]. Etoposide treatment induces other malignancies such as acute myelocytic leukemia and myelodysplastic syndrome [182].

Podophyllin is far more toxic than its derivatives and has clinical effects similar to those of colchicine. Fatality has been reported after ingestion of 350 mg [183], and survival has been reported after ingestion of 2.8 g [98]. Toxicity has occurred from ingestion [136, 140, 144, 149, 153, 183–187], cutaneous absorption [132, 141, 143, 161, 188, 189], subcutaneous injection [190], and intramuscular injection [191]. Cases of toxicity from cutaneous absorption typically involved prolonged contact, large surface areas, or friable mucosa. Death has been reported after cutaneous application [185, 192].

The hallmarks of toxicity include nausea, vomiting, altered mental status progressing to coma, rapidly progressive peripheral neuropathy with paresis and areflexia, and delayed myelosuppression. These effects have been reported to be delayed 10 h after ingestion [136] and 20 h after topical application [188]. Review of the case reports indicates, however, that the patients initially developed gastrointestinal symptoms (one was given Syrup of Ipecac) and alteration in mental status (one also was ethanol intoxicated), followed by delayed and profound CNS depression and coma. Several reports of toxicity after cutaneous exposure detailed vomiting 12–13 h post application followed by a coma within 30 h of application [141, 189]. Other reports included early gastrointestinal symptoms followed by delayed (24 h) coma. Some patients may present primarily with peripheral neurologic symptoms, such as neuropathy and paresthesia [137, 146, 147, 191, 193]. Patients may recover fully from coma, which may last 10 days [135, 138, 141, 143, 188]. Electroencephalogram may show diffuse slowing, with cerebrospinal fluid findings typically normal but, at times, showing elevated protein [138, 194]. Fever, seizure activity, and visual/auditory hallucinations also have been reported.

Patients often present with tachycardia and tachypnea. Hypotension has been reported. In fatal cases, renal failure and circulatory collapse may occur [144, 187, 189, 192]. Status epilepticus occurred shortly after ingestion in a pediatric case [186]. Noncardiogenic pulmonary edema and idioventricular bradycardia have been reported in a fatal case [192]. Necrotizing myopathy has been reported in a patient who died 9 weeks after podophyllin ingestion owing to sepsis [187].

Survivors may have neurologic sequelae, such as persistent peripheral neuropathy lasting months to several years, that may manifest after the initial encephalopathy has resolved [184, 195]. Some patients have developed persistent lower extremity paralysis and encephalopathy and radiologic findings of cerebral atrophy [149, 186, 196]. Dorsal radiculopathy, manifesting as profound loss of position sense, is reported [184]. Podophyllin has been proposed as an experimental model for deafferentation [146]. Absence of alopecia is notable in that it clinically differentiates podophyllin from acute colchicine or vinca alkaloid toxicity.

Diagnosis

Initially, leukocytosis may be seen (55,000/mm3 [143]. Granulocytopenia and thrombocytopenia are delayed by 5 days and typically resolve over 2–3 weeks. Peripheral leukocytes may show enlarged nuclei with dense chromatin granules and cytoplasmic and nuclear vacuolization [136]. Bone marrow examination may reveal evidence of mitotic arrest [142, 143, 188] and vacuolization of erythroblasts and plasma cells [157]. Lactic acidosis has been described in a fatal case in a patient who had concomitant alcoholic cirrhosis [136]. Hypocalcemia has been reported [140], along with elevated serum hepatic transaminase and uric acid concentrations.

Autopsy findings include mitotic arrest in granulocytes and intestinal mucosal cells; diffuse petechial hemorrhages; pulmonary, renal, and hepatic congestion; and cerebral edema [136, 144, 189]. The bone marrow is hypocellular with cytoplasmic vacuolization of myeloid precursors [197].

Abnormalities on computed tomography or magnetic resonance imaging show cerebral atrophy in some survivors [149, 196]. Some patients have developed persistent lower extremity paralysis; nerve biopsy specimens may reveal axonal degeneration and loss of large myelinated fibers, with gradual regeneration as recovery occurs [110, 112, 149].

Because of its prominent early gastrointestinal effects, toxicity with podophyllin and derivatives may be confused with gastrointestinal disorders. In addition, podophyllin use may not be reported to the treating physician if it is applied as an ointment or applied by the patient’s physician in the office. The common presentation of fever, lethargy, and leukocytosis mimics CNS infection. The presentation of hypotension, altered mental status, and fever mimics septic shock. Podophyllin toxicity may present with ascending paralysis and loss of reflexes similar to Guillain–Barré syndrome. Delayed bone marrow suppression leads to thrombocytopenia, granulocytopenia, and anemia, which may cause the treating physician to suspect other causes of bone marrow suppression, such as infection or malignancy.

Treatment

Gastrointestinal decontamination with activated charcoal may be beneficial after an acute suicidal podophyllin ingestion if given within the first hour postingestion. However, it is not known if this intervention alters the clinical course or outcome. Decontamination of skin should be performed if topical preparation has been applied. The mainstay of treatment is supportive care, including prevention of infection and screening for delayed bone marrow suppression. Blood products should be used if needed. Hemoperfusion has been used for podophyllin toxicity with variable results [136, 142, 143, 149, 185, 188, 192]. Because of the high lipid solubility, volume of distribution, and degree of protein binding (97–99%) of podophyllin and its derivatives, hemodialysis is not likely to be useful.

Indications for ICU Admission in Podophyllin or Podophyllin Derivatives Poisoning

  1. 1.

    Because of delayed and profound central nervous system effects, observation in an ICU setting for at least 24 h should be considered for any patient with a significant exposure to podophyllin or podophyllin derivatives, particularly patients with evidence of altered mental status and rapidly progressive neuropathy.

  2. 2.

    Hemodynamic instability, seizures, or respiratory distress.

Although G-CSF has been used with some success to treat colchicine-induced neutropenia, its use has not been reported in podophyllin poisoning. G-CSF has been used in combination chemotherapy, including etoposide, for the prevention and treatment of hematopoietic toxicity and to facilitate more intensive chemotherapy regimens [198–203]. There is no specific antidotal therapy for podophyllin toxicity or that of its derivatives, etoposide and teniposide.

Key Points in Podophyllin Toxicity

  1. 1.

    Podophyllin poisoning is typically reported after ingestion or large surface dermal application to friable mucosa.

  2. 2.

    Severe symptoms can be delayed up to 20 h, particularly after dermal application.

  3. 3.

    Treatment is primarily supportive.

Special Populations

Pregnant Patients

These drugs are not intended for use in pregnancy. Podophyllin has been used to induce abortion. Reports link podophyllin to intrauterine fetal demise and birth defects [137, 204, 205].

Oncology Patients

In addition to increased risks of infection associated with immunosuppression and bone marrow suppression, after single-agent administration, concomitant cytotoxic medication use may lead to a synergistic increase in neurologic and hematologic toxicity.