52: Miscellaneous Chemotherapeutics

The anthracyclines,^24,120 nitrogen mustards,^{1,38,55,60,90,130} and platinum-based complexes^{32,35,59,64,68,83,108,111,124} are discussed in this chapter because of their increased likelihood for overdose based on past reports and current clinical use.

Daunorubicin and doxorubicin share many common indications for cancer therapy, but they differ in that doxorubicin is used in solid tumors such as breast carcinoma, and daunorubicin is used in hematogenous malignancies, such as acute myelogenous leukemia and acute lymphocytic leukemia. The clinical toxicity of the older anthracyclines is limited by the use of less toxic structural analogs (eg, epirubicin, idarubicin) and liposome-encapsulated formulations (pegylated liposomal doxorubicin).

Pharmacology

The chemotherapeutics derived from the bacterium Streptomyces are dactinomycin, daunorubicin, doxorubicin, bleomycin, mitomycin, and plicamycin. Only plicamycin crosses the blood–brain barrier. Doxorubicin has a protein binding of 75% to 80%, a volume of distribution of 28.0 ± 3.3 L/kg, and a terminal elimination half-life of approximately 30 hours.⁴³ The liposome encapsulated formulation of doxorubicin has a prolonged terminal half-life of 50 hours because of a slower clearance compared with the nonencapsulated formulation. Doxorubicin and daunorubicin are both eliminated by the liver, and their dosages are decreased in patients with hepatic insufficiency. Delayed drug elimination contributes to increased area under the concentration versus time curve and peak concentration, both of which are associated with myelosuppression and cardiac toxicity, respectively.⁶⁶ The mechanism of therapeutic action of the anthracyclines is attributed to DNA intercalation¹⁰¹ and inactivation of topoisomerase II.¹¹⁷ These xenobiotics are metabolized to active metabolites, which have lesser degrees of activity than their parent compounds. The liposomal-encapsulated formulation of doxorubicin has limited selective activity at the tumor compared to nontumor sites in the body, such as the heart and bone marrow because of its particle size (100 A°).^86,98 A typical dose schedule for daunorubicin is 30 to 60 mg/m² daily for 3 days; for doxorubicin, 45 to 60 mg/m² every 18 to 21 days; and for pegylated liposomal doxorubicin, 50 mg/m² every 28 days.

Pathophysiology

The red anthracycline antibiotics—dactinomycin and doxorubicin—are associated with cardiotoxicity, which limits their therapeutic use. The associated toxicity is caused by a different mechanism than the therapeutic effects.¹¹⁷ The purported mechanism of cardiac toxicity is from the formation of free radicals and impaired intracellular calcium.^84,91 Doxorubicin and dactinomycin are quinone derivatives and can be reduced to free radicals. These metabolites are extremely cytotoxic through the promotion of lipid peroxidation in a manner similar to paraquat and bleomycin. The limited efficacy of free radical scavengers (α-tocopherol, N-acetylcysteine) for anthracycline cardiotoxicity led to an understanding of the importance of iron as a cofactor for these free radical-producing reactions.⁸⁵ The anthracyclines have a high affinity for metal ions. Doxorubicin has an iron (Fe³⁺) binding constant of 10⁴¹, which is comparable to deferoxamine.⁴¹ The heart’s increased susceptibility to free radicals is attributed to its lack of sufficient enzyme activity responsible for free radical scavenging.²⁹

Clinical Manifestations

The cardiotoxic manifestations can be divided into those occurring acutely or those of late onset. Acute toxicity is characterized by dysrhythmias, ST and T-wave changes on the electrocardiogram (ECG), diminished ejection fraction that usually resolves over 24 hours, or sudden death.^12,113 Abnormal findings on ECG are present in 41% of patients receiving doxorubicin.^103,113 These abnormalities are neither dose related nor associated with the development of cardiomyopathy. Acute pericarditis and myocarditis resulting in conduction defects and congestive heart failure (CHF) are also reported.¹³ Animal studies with doxorubicin demonstrate beneficial effects of adrenergic antagonists for toxicity because of elevated concentrations of catecholamines.¹³

Significant cardiotoxicity results from elevated peak serum concentrations and led to therapeutic decisions based on continuous or periodic infusion delivery. The anthracycline antibiotics can cause a congestive cardiomyopathy with systolic dysfunction that typically presents at 1 to 4 months after exposure.⁵³ The condition is irreversible and is associated with a 48% mortality.⁹⁴ This drug induced CHF is associated with pathognomonic changes on electron microscopy that can distinguish this type of cardiomyopathy from that of infectious and ischemic etiologies. These histologic changes include reduced numbers of myocardial fibrils, and mitochondrial and cellular degeneration.¹⁰ The incidence of late onset cardiotoxicity for doxorubicin is between 1% and 10% when the cumulative dose is less than 450 mg/m², and this incidence becomes greater than 20% when more than 550 mg/m² (comparable to dactinomycin, 950 mg/m², and epirubicin, 720 mg/m²) is administered.^79,127 Daunorubicin and mitoxantrone are associated with a 2% incidence at the cumulative doses of 600 mg/m² and 140 mg/m², respectively.

The best way of monitoring cardiac function during therapy is to measure the left ventricular ejection fraction (LVEF) by radionuclide cineradiography or echocardiography.⁴ However, the radionuclide method is more sensitive to small decreases in the LVEF than the method using sonography.³⁶ Therapy should be discontinued when the ejection fraction falls below 50%. Two dimensional echocardiography can demonstrate left ventricular wall thickening and fractional shortening from anthracycline overexposure. Newer approaches used to determine early or subclinical signs of cardiac dysfunction include the evaluation of cardiac specific contractile protein, troponin, cardiacnatriuretic peptide, and radionuclide tagged monoclonal antibody imaging.^37,65,71

Factors associated with an increased risk of cardiotoxicity include mediastinal irradiation, preexisting cardiac disease in children, age older than 70 years, and the concomitant use of cyclophosphamide, paclitaxel, and other anthracyclines.¹³ The recent therapeutic use of the monoclonal antibody to human epidermal growth factor receptor 2 (HER2), trastuzumab, with anthracyclines appears to enhance cardiac toxicity.²⁶ Children are at risk for developing increased left ventricular afterload from doxorubicin toxicity because of the ability of the drug to inhibit myocardial growth, which can lead to a disproportionate ratio of left ventricular wall thickness to left ventricular chamber size.⁶⁹ Fatalities are reported with minimum doses of 150 to 333 mg/m² and occur within 1 to 16 days following exposure.²⁴

Myelosuppression and mucositis from the use of the anthracyclines typically occur in 1 to 2 weeks.⁷ The white cells are affected more than either the red cells or platelets. Patients with diminished drug clearance due to hepatic failure are at risk for the development of these findings.

Mitoxantrone is less toxic than doxorubicin and daunorubicin. Major organs of toxicity remain the heart, bone marrow, and gut. ­Gastrointestinal effects are less severe and less frequent with mitoxantrone than with doxorubicin.¹¹⁰ Four cases of mitoxantrone overdose are reported in the literature.^45,110 Common to these events is a 10-fold error in dosing (100 mg/m² instead of 10 mg/m²), early onset of nausea with vomiting, and myelosuppression with fever. Acute decreased cardiac contractility was observed by echocardiography in an asymptomatic patient.⁴⁵ No patients developed dysrhythmias, congestive heart failure, ECG changes, or elevated creatine phosphokinase concentrations. Unfortunately, three patients developed fatal CHF from 1 to 4 months later.¹¹⁰

Management

Patients receiving anthracyclines require monitoring for cardiotoxicity and pancytopenia. A baseline chest radiograph, ECG, and echocardiography to determine LVEF (at rest and/or with stress) are necessary. Endomyocardial biopsy and cardiac catheterization can assist in distinguishing other causes of cardiac dysfunction. Left ventricular function is the best predictor for cardiomyopathy.^34,104 A 10% absolute decrease in the LVEF or a decrease in LVEF of 50% from baseline is an indication to discontinue anthracycline therapy.¹⁰⁴ Treatment is largely supportive and includes the use of dexrazoxane, which is a specific antidote for doxorubicin toxicity. Dexrazoxane is a cardioprotectant that limits the adverse cardiac effects of doxorubicin by chelating intracellular iron, which mediates the formation of free radical cellular damage.

In clinical trials, patients receiving dexrazoxane had smaller decreases in LVEF per dose of doxorubicin or epirubicin, had fewer histologic changes on cardiac biopsy, were better able to tolerate doxorubicin doses greater than 600 mg/m², and had a lower occurrence of CHF than did patients who were not pretreated with dexrazoxane.^{40,71,72,112,115,116,123} The current role of this chelator is to limit cardiotoxicity in patients receiving more than 300 mg/m² of doxorubicin.¹⁰⁶ It is administered 30 minutes before doxorubicin in a ratio not greater than 10:1 to limit dexrazoxane-induced granulocytopenia and thrombocytopenia.^112,115,116 The early institution of β-adrenergic antagonists (carvedilol) or angiotensin-converting enzyme inhibitors can reduce cardiac dysfunction from anthracycline therapy, but they are less effective than dexrazoxane.^42,58,70 Further investigations are required to determine the optimal use of dexrazoxane in patients with unintentional excessive exposures.

Enhanced Elimination

The anthracyclines are highly protein bound and have a large volume of distribution, which limits the use of hemodialysis. However, the early institution of hemoperfusion may enhance elimination. In an animal model, serum doxorubicin clearance could be enhanced up to 20 fold with hemoperfusion.¹²⁹ Factors determining this were duration of therapy, rate of flow, and the use of a 2% acrylic hydrogel coated cartridge. Three patients with a doxorubicin overdose were treated with hemoperfusion, one with an Amberlite cartridge, and all had a rapid reduction in their serum ­concentrations.²⁴ One survived a 10 fold error in dosing. In a patient with an intravenous mitoxantrone overdose of 98 mg, hemoperfusion was begun within hours, but in two sessions, only 0.287 and 0.236 mg of drug were removed.⁴⁵ The role of double-filtration plasmapheresis to enhance the elimination of liposomal encapsulated doxorubicin in the overdosed patient remains exploratory.⁹⁵

Pharmacology

The nitrogen mustards include cyclophosphamide, ifosfamide, chlorambucil, mechlorethamine, and melphalan. Their indicated uses include immunosuppression (eg, controlling graft-versus-host rejection, collagen vascular diseases) and chemotherapy. The tumoricidal activity of these xenobiotics results from the formation of reactive intermediates that bind to chemotherapeutic moieties on DNA, which inactivates DNA synthesis. Mechlorethamine is the original compound from which all of the others were derived. It is highly reactive when it comes in contact with water and undergoes rapid chemical transformation. Local reactions caused by mechlorethamine spillage (eg, extravasation) include tissue injury and thrombophlebitis (Special Considerations: SC4). Nonenzymatic hydrolysis is the major route by which the nitrogen mustards are metabolized, thus accounting for their relatively short elimination half-lives (<3 hours).⁹ Unlike the other xenobiotics in this class, cyclophosphamide and ifosfamide are prodrugs and require cytochrome P450 (CYP2B6 and CYP3A4) activation to achieve their alkylating properties. The pharmacokinetic parameters estimated for ifosfamide are elimination half-life in blood, 4.5 hours (range, 3.4–6.1); volume of distribution, 0.56 L/kg (range, 0.29–0.82); clearance, 79 mL/min (range, 59–116); and protein binding, 20%.⁶⁷ Cyclophosphamide, ifosfamide, and chlorambucil have active metabolites, which prolong their alkylating activity after administration.⁵⁶

Clinical Manifestations

Chlorambucil and ifosfamide can cause altered mental status and myoclonic or tonic-clonic seizures from therapeutic use or from an overdose.^15,16,38 Both chemotherapeutics undergo hepatic N-dechloroethylation to produce chloroacetaldehyde, which is a presumed nervous system toxin.⁶³ Encephalopathy occurs in 9% of patients receiving 5 g/m² of ifosfamide and is more frequent with oral than with intravenous (IV) administration because of the first-pass effect and increased chloroacetaldehyde production.⁷⁸ Seizures are more commonly associated with chlorambucil than other nitrogen mustards. Acute overdoses reported from oral exposures range from 1.5 to 6.8 mg/kg (therapeutic is 0.1–0.2 mg/kg).^5,16 The seizures occur within 6 hours, can appear as generalized tonic–clonic activity or staring spells, and last for up to 24 hours. However, in one instance in which therapeutic dosing was increased, seizures occurred 17 hours later. This delay can be attributed to a lower serum concentration, a slower time to peak than in the overdose setting, or accumulation of active metabolites. A similar reasoning could explain why a patient with a chronic overdose of 4.1 mg/kg over 5 days did not demonstrate central nervous system toxicity.³¹ Patients with increased likelihood for seizures include those with underlying seizure disorders or with nephrotic syndrome, which can alter pharmacokinetics.¹⁰¹ Myelosuppression can present as late as 41 days postexposure in patients with acute or chronic overdoses. Hematopoietic recovery is expected within one week of the nadir, and granulocyte colony stimulating factor treatment may be necessary.⁵⁵ Kidney failure from an acute overdose with ifosfamide is reversible following the immediate institution of hemodialysis.³⁸

Cyclophosphamide and its analog ifosfamide are metabolized to acrolein, which can result in cellular damage from the production of reactive oxygen and nitrogen species^61,97 and cause hemorrhagic cystitis in approximately 5% to 10% of patients receiving therapy.^15,23 The incidence of cystitis does not appear to be related to the total dose and administration route, age, or sex. The condition is usually self limiting, although blood transfusions can be required. Water retention is typically observed in patients within 6 to 8 hours of receiving more than 50 mg/kg of cyclophosphamide. However, it can occur at a lower dose.^27,52 This effect is attributed to the activity of the alkylating metabolite on the renal tubule or the release of endogenous vasopressin (syndrome of inappropriate antidiuretic hormone). The patient typically develops decreased urinary output, increased urine osmolality, and decreased serum osmolality, which is self-limiting and lasts for about 12 to 16 hours.

In overdose, cyclophosphamide can cause dysrhythmias, myocardial necrosis, hemorrhagic pericarditis, and death. ECG changes tend to occur at doses of 120 mg/kg, with heart failure and myocarditis at doses greater than 150 mg/kg.^6,81 Diminished QRS voltage on the ECG is attributed to myocardial edema or hemorrhage. An ordering error led to the death of one patient and to irreversible cardiac damage in another patient from cyclophosphamide overdose. These two patients received 6520 mg daily for four consecutive days, as opposed to that amount divided over 4 days.¹⁰⁰ The onset of heart failure can be sudden, and patients older than 50 years of age and those with a history of cardiac dysfunction or prior treatment with anthracyclines are at greatest risk for cardiac toxicity.¹¹⁴

Management

Recommendations for patients with an acute oral chlorambucil overdose include routine gastrointestinal decontamination, 6 hour observation, determination of a complete blood count (CBC) and hepatic enzymes, and weekly CBCs for 4 weeks during follow-up.¹²² Ifosfamide-induced encephalopathy can be managed with the early administration of methylene blue (1–2 mg/kg IV as a 1% solution), although the mechanism by which methylene blue acts is unknown.^63,132 Potential explanation for the role of methylene blue is as a free radical scavenger⁹³ and an inhibitor of guanylyl cyclase,^76,102 which can limit the loss of cerebral vascular autoregulation and edema caused by nitric oxide synthesis and cyclic guanosine monophosphate production from the administration of ifosfamide^61,102,118 (Antidotes in Depth: A42). Seizures are reported to be more effectively managed with benzodiazepines and barbiturates than with phenytoin.^5,130

When gross hematuria from cyclophosphamide or ifosfamide therapy persists, treatments can include electrocauterization, systemic vasopressin,⁹⁶ intravesical administration of silver nitrate,⁶⁹ formalin,^39,107 prostaglandin F2,¹⁰⁹ and hydrostatic pressure.⁵⁰ Strategies to preventive hematuria include adequate hydration for dilution effect, frequent bladder emptying, IV administration of 2-mercaptoethane sulfonate sodium (MESNA), and intravesical administration of N-acetylcysteine.¹⁵ The thiol group of N-acetylcysteine is believed to directly interact with acrolein and limit its irritating effect on the bladder epithelium. MESNA is believed to work by inactivating acrolein to an inert thioether.⁵¹ The IV dose of MESNA is 20% of the cyclophosphamide or ifosfamide amount (wt/wt) and administered during therapy and at 4 and 8 hours after chemotherapy. In overdose, MESNA does not protect patients from nephrotoxicity and hemodialysis is indicated. Hemodialysis effectively enhances the elimination of ifosfamide and its metabolites when instituted soon after exposure, and it is more effective than hemoperfusion (Adsorba 300 C, Gambro 300 g active carbon) in removing ifosfamide.³⁸

Patients with excessive exposures to cyclophosphamide require baseline ECGs and echocardiograms. IV fluid restriction, a cardiac inotrope (digoxin), and furosemide were successfully used to treat a patient with cyclophosphamide induced congestive cardiomyopathy.¹²⁶

Pharmacology

The cytotoxic effects of the platinum based complexes were first recognized in 1965. Of the many types developed, cisplatin, carboplatin, and oxaliplatin are of clinical utility.⁸² The latter two were designed to reduce the incidence of nephrotoxicity and to counter drug resistance to cisplatin. Cisplatin is an inorganic and carboplatin an organic compound. Similarities exist in their mechanism of toxicity, which is the binding of platinum to DNA to form inter- and intrastrand bonds, resulting in DNA dysfunction and strand breakage. These xenobiotics are eliminated from the body primarily in the urine. The amount eliminated at 24 hours is 25% for cisplatin and 90% for carboplatin. Patients with decreased creatinine clearance (<30 mL/min) have prolonged elimination half-lives of these complexes.³⁰

Pathophysiology

Kidney failure from renal tubular necrosis occurs with cisplatin in a dose-dependent manner. Upon entering the cell, cisplatin forms a cationic reactive complex, which covalently binds to DNA to disrupt replication and transcription, resulting in cell death. The formation of the hydrated platinum complex is favored by a low chloride concentration in the environment; thus, a sodium chloride infusion promotes the native state of cisplatin by preventing hypochloremia. The presence of α1-microglobulin, β2-microglobulin, retinol-binding protein, alanine aminopeptidase, or N-acetyl-d-­glucosaminidase in the urine can be early indicators of renal tubular damage.^25,46

The sensory neuropathy associated with platinum containing chemotherapeutics that commonly are attributed to their accumulation and toxicity at the dorsal root ganglion, which is due to the water solubility and chemical reactivity of these xenobiotics.¹⁰⁵ Pathologic evaluation demonstrates increased platinum content at the dorsal root ganglion following cisplatin therapy, which suggests that the increased vascularity and fenestration of the endothelium at this tissue site contributes to the uptake of cisplatin.^44,54

Clinical Manifestations

The more common manifestations of toxicity with cisplatin with therapeutic dosing are kidney dysfunction, auditory impairment, and peripheral sensory neuropathy. The other chemotherapeutics that commonly cause a peripheral neuropathy are the Vinca alkaloids and the taxoids. Oxaliplatin induced neuropathy is triggered or enhanced by exposure to cold and can resolve over several months.³³ Myelosuppression is a dose-limiting factor for carboplatin and iproplatin, but it does not occur with cisplatin. At a carboplatin dose of 800 mg/m², 25% of patients develop bone marrow toxicity.⁸⁸ The marrow effects are delayed, with the nadir occurring 3 to 5 weeks after the start of therapy. Patients developing an anemia within the first week of ­cisplatin therapy should be evaluated for hemolysis.²⁰

The types of therapeutic dosing errors associated with cisplatin are frequency of administration (total dose versus divided dose), confusing cisplatin for carboplatin, and ordering an inappropriate dose.^21,92 Manifestations in the overdose setting include neurologic, visual, hearing, bone marrow, pancreatic, and kidney disorders.¹⁰⁸ The most common kidney disorder is kidney failure, which is dose-related; it begins at 50 mg/m² and typically occurs at 1 to 2 weeks posttreatment. At this dose, approximately 30% of patients treated with cisplatin develop acute kidney injury (AKI) and a rise in serum blood urea nitrogen and creatinine concentration with subsequent electrolyte disorders, including hypomagnesemia, hypocalcemia, and hyponatremia.³² Hyponatremia is an uncommon finding with cisplatin exposure and is attributed to sodium-wasting nephropathy from renal tubular dysfunction (Chap. 19). At doses greater than 200 mg/m², seizures, encephalopathy, and irreversible peripheral sensory neuropathy are of concern.^{8,22,48,87, 88, and 89} In addition, visual impairment, including temporary visual loss with permanent loss of color discrimination, can occur within the first week of therapy at this dose.^19,75,128 Physical examination of the anterior chamber and fundus of the eye will be normal; however, an electroretinogram can demonstrate postphotoreceptor neural dysfunction.⁵⁹ Other possible ocular disorders are papilledema and retrobulbar neuritis. High-frequency (2000 Hz) hearing loss is evident 2 to 3 days after exposure to doses greater than 500 mg/m².¹⁷

Management

Renal protection and enhanced elimination of platinum are the goals in the initial management of a cisplatin overdose, followed by expectant management for myelosuppression and neurotoxicity. Hydration with 0.9% sodium chloride solution and an osmotic diuretic, such as mannitol, should be administered to achieve a high urine output (eg, 1–3 mL/kg/h) for 6 to 24 hours postexposure. Sodium chloride diuresis both promotes the inactive state of cisplatin and decreases the urine platinum concentration, which can limit nephrotoxicity.^2,125 In the setting of nonoliguric AKI, careful hydration is recommended to maintain urinary output, because renal platinum excretion is directly related to urinary flow and independent of creatinine clearance.¹⁹ Kidney function can be monitored by determining the creatinine clearance or glomerular filtration rate.^99,119

Amifostine (Ethyol) and sodium thiosulfate are effective nephroprotectants. Amifostine is approved by the US Food and Drug Administration to prevent cisplatin induced nephrotoxicity, and additional benefits can include the limitation of myelosuppression, mucositis, and neurotoxicity.³ Unlike thiosulfate, amifostine is activated intracellularly by alkaline phosphatase to scavenge free radicals, regenerate glutathione, prevent cisplatin-DNA adduct formation, and facilitate DNA repair.⁶² The patient requires adequate hydration during amifostine infusion because hypotension can occur. Sodium thiosulfate is effective postexposure. Thiosulfate remains in the extracellular space to bind free platinum and limit cellular damage at the renal tubules. Little or no renal toxicity occurred in patients receiving as much as 270 mg/m² of cisplatin when thiosulfate was given as an IV bolus of 4 g/m² followed by infusion of 12 g/m² over 6 hours.^47,90 In a 14 year-old patient with AKI from cisplatin, thiosulfate was continued at 2.7 g/m² a day until urinary platinum concentration was below 1 μg/mL.³² Thiosulfate can offer the additional benefit of limiting neurotoxicity^74,121 and should be administered to all patients within 1 to 2 hours after a platinum-based complex chemotherapeutic overdose for it to be most effective (Antidotes in Depth: A40). N-Acetylcysteine and BNP7787 (2,2′-dithio-bis-ethanesulfonate) are under investigation as alternative rescue xenobiotics for cisplatin toxicity.^11,28,80 BNP7787 also is under clinical investigation to limit peripheral neuropathy from paclitaxel therapy.⁷⁷

Hemodialysis is ineffective in patients with cisplatin overdoses, likely as a result of high protein binding.¹⁴ Plasmapheresis with plasma exchange was performed in five adults, and there was a decline in blood and plasma platinum concentrations with clinical improvement.^{18,19,49,57,131} In one incident, a patient received an overdose of 280 mg/m² and was plasmapheresed on day 12 of exposure.¹⁹ After three daily treatments, the serum platinum concentration decreased from 2900 to 200 ng/mL, and the patient had noticeable improvement in gastrointestinal and visual symptoms. On day 20, the serum platinum concentration rebounded to 700 ng/mL, and the symptoms worsened. Further plasmapheresis lowered the concentration to 290 ng/mL by day 27, and symptoms improved. In another event, a patient received 300 mg/m² of cisplatin and received four daily treatments of plasmapheresis starting on day 6 postexposure.⁵⁷ The serum platinum concentration declined from 2979 to 430 ng/mL, and the patient became more awake and less nauseated. On day 11, platinum concentrations rebounded to 834 ng/mL and fell to 279 ng/mL on reinstitution of plasmapheresis. The amount of platinum removed by three trials in this patient was approximately 4.6 mg. The author of the paper contends that plasmapheresis prevented the need for hemodialysis in kidney failure. Other reports have noted an improvement in patients’ mental status and hearing loss following the decline in the serum cisplatin (platinum) concentration from plasmapheresis.^18,49 Thus, plasmapheresis with plasma exchange should be immediately considered after a cisplatin overdose. Patients who remain symptomatic days later also may benefit.

• Anthracyclines, nitrogen mustards, and the platinum based complexes are common chemotherapeutic overdoses.

• The primary clinical manifestations of toxicity for these xenobiotics include dilated cardiomyopathy (anthracyclines), encephalopathy and seizures (nitrogen mustards), and kidney failure (platinum based xenobiotics).

• The management for patients with these overdoses includes supportive care, enhanced elimination using plasmapheresis with plasma exchange for cisplatin, and antidotal therapy, such as dexrazoxane for anthracyclines and amifostine for platinum based complexes.

• Specialists in poison information and medical toxicologists must maintain a current level of understanding of these exposures so they can better assist their patients and provide consultation to other healthcare professionals.

Disclaimer

The findings and conclusions in this chapter are those of the author and do not necessarily represent the views of Centers for Disease Control and Prevention.

Acknowledgment

Paul Calabresi, MD, (deceased) contributed to this chapter in previous editions.

References