Chapter 54

The anthracyclines,31,70,118 nitrogen mustards,1,27,45,64,65,70,95,112,118,129 and platinum-based antineoplastics23,24,41,44,57,68,73,76,80,88,97,108 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. The clinical toxicity of the anthracyclines is limited by the use of structural analogs (eg, epirubicin, idarubin) and liposomal encapsulated formulations (pegylated liposomal doxorubicin).

### Pharmacology

The antineoplastics derived from the bacterium Streptomyces are dactinomycin, daunorubicin, doxorubicin, bleomycin, mitomycin, and plicamycin. Only plicamycin crosses the blood—brain barrier. The terminal elimination half-life for doxorubicin is about 30 hours.50 Doxorubicin and daunorubicin are both eliminated by the liver and patients with hepatic dysfunction should have their dosage decreased. Delayed drug elimination contributes to increased drug area under the drug concentration versus time curve (AUC) and peak concentration, which are associated with myelosuppression and cardiac toxicity, respectively.75 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. 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.

### Pathophysiology

The red anthracycline antibiotics—dactinomycin and doxorubicin—can be associated with cardiotoxicity, which limits their therapeutic use. The mechanism responsible for their therapeutic effects is different from that which causes cardiotoxicity.117 The purported mechanism of cardiac toxicity is from the formation of free radicals and impaired intracellular calcium.89,96Doxorubicin and dactinomycin are quinone derivatives and can be reduced to free radicals. These metabolites are extremely cytotoxic through the promotion of lipid peroxidation. Paraquat and bleomycin have similar mechanisms of toxicity. 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 radical-producing reactions.90 The anthracyclines have a high affinity for metal ions. Doxorubicin has an iron (Fe3+) binding constant of 1041, which is comparable to deferoxamine.48 The heart's increased susceptibility to free radicals is attributed to its lack of sufficient enzyme activity responsible for free radical scavenging.38

### Clinical Manifestations

The cardiotoxic manifestations can be divided into acute and late-onset categories. The various findings described with acute toxicity include dysrhythmias, ST and T-wave changes on the electrocardiogram (ECG), diminished ejection fraction that usually resolves over 24 hours, and sudden death.16,114 Abnormal findings on ECG are present in 41% of patients receiving doxorubicin....

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