Heart failure doxorubicin

The anthracycline antibiotics, which include doxorubicin, daunorubicin, bleomycin, and mitomycin C, inhibit DNA and RNA synthesis. Doxorubicin also interfers with topoisomerase II (a DNA gyrase), the activity of which is markedly increased in proliferating cells. Structurally related to doxorubicin are epirubicin and mitozantrone. The cytotoxic antibiotics are used to treat leukaemias and lymphomas and also for solid tumours in the breast, lung, thyroid and ovary. Cardiotoxicity is the major dose-limiting factor, with arrhythmias and myocardial depression (Bacon and Nuzzo 1993). The chronic phase of cardiotoxicity is a dose-dependent cardiomyopathy that leads to congestive heart failure in 2-10% of patients. Myocardial injury is the result of oxygen free radical formation. Children are particularly sensitive to these cardiotoxic reactions and may require a heart transplant in their later years. Epirubicin is less cardiotoxic than doxorubicin. 

When the heart can no longer pump an adequate supply of blood to meet the metabolic needs of the tissues or in relation to venous return, cardiac failure may ensue. The causes of cardiac failure are complex, but stem from mechanical abnormalities (e.g., pericardial tamponade), myocardial failure (e.g., cardiomyopathy and inflammation), and arrhythmias. In high-output failure, the cardiac output, which may be normal or even higher than normal, is not sufficient to meet the metabolic requirement of the body. Cardiac failure may predispose a patient to congestive heart failure, which is a state of circulatory congestion. Toxic injury, caused by agents such as doxorubicin, the alkaloid emetine in ipecac syrup, cocaine, or ethyl alcohol, is another way by which the functional integrity of the heart may also be compromised. 

The main dose-limiting toxicity of all anthracyclines is myelosuppression, with neutropenia more commonly observed than thrombocytopenia. In some cases, mucositis is dose-limiting. Two forms of cardiotoxicity are observed. The acute form occurs within the first 2-3 days and presents as arrhythmias or conduction abnormalities, other electrocardiographic changes, pericarditis, and myocarditis. This form is usually transient and is asymptomatic in most cases. The chronic form results in a dose-dependent, dilated cardiomyopathy associated with heart failure. The chronic cardiac toxicity appears to result from increased production of free radicals within the myocardium. This effect is rarely seen at total doxorubicin dosages below 500-550 mg/m2. Use of lower weekly doses or continuous infusions of doxorubicin appear to reduce the incidence of cardiac toxicity. In addition, treatment with the iron-chelating agent dexrazoxane (ICRF-187) is currently approved to prevent or reduce anthracycline-induced cardiotoxicity in women with metastatic breast cancer who have received a total cumulative dose of doxorubicin of 300 mg/m2. All anthracyclines can produce "radiation recall reaction," with erythema and desquamation of the skin observed at sites of prior radiation therapy. 

Heart Propranolol, doxorubicin, Heart failure, dysrhythmia,... 

CALCIUM CHANNEL BLOCKERS DOXORUBICIN t serum concentrations and efficacy of doxorubicin when co-administered with verapamil, nicardipine and possibly diltiazem and nifedipine however, no cases of doxorubicin toxicity have been reported Uncertain however, verapamil is known to inhibit intestinal P-gp, which may t the bioavailability of doxorubicin Watch for symptoms/signs of toxicity (tachycardia, heart failure and hand-foot syndrome)... 

Cardiotoxicity, which can lead to congestive heart failure and death, is a toxic effect of the anticancer drug, doxorubicin. A cumulative dose-effect analysis demonstrated that doxorubicin cardiotoxicity is related to the lifetime dose of the drug (Figure 18.12) and provided the basis for the definition of safe lifetime dose levels (7). The lifetime dose of doxorubicin is now limited to less than 400-450 mg/m, which is associated with a <5% risk of developing congestive heart failure. 

FIGURE 18.12 Cumulative risk of developing congestive heart failure (chfi as a function of the lifetime dose of doxorubicin. (Reproduced with permission from Van Hoff DD, Layard MW, Basa P et al. Ann Intern Med 1979 91 710-7.)... 

Of 682 patients, 144 who were over 65 years of age all had doses up to but not exceeding the usual cumulative dose for doxorubicin (14). The authors concluded that older patients without cardiovascular co-morbidity are at no greater risk of congestive heart failure. 

The authors of a study of the use of MRI scans to assess the subclinical effects of the anthracyclines concluded that increased MRI enhancement equal to or greater than 5 on day 3 compared with the baseline predicted significant reduction in ejection fraction at day 28 (32). In 1000 patients given doxorubicin chemotherapy and irradiation there were six cases of congestive heart failure and three cases of myocardial infarction there was a cumulative cardiac mortality of 0.4% in all anthracycUne-exposed patients (33). 

Ibrahim NK, Hortobagyi GN, Ewer M, Ah MK, Asmar L, Theriault RL, Fraschini G, Frye DK, Buzdar AU. Doxorubicin-induced congestive heart failure in elderly patients with metastatic breast cancer, with long-term... 

Cardiac adverse events that have been considered probably or possibly related to pegylated liposomal doxorubicin have been reported in 3-9% of patients (14-16). These include hypotension, pericardial effusion, thrombophlebitis, heart failure, and tachycardia (14,15). 

The combination of doxorubicin plus paclitaxel is cardio-toxic. Various authors have suggested that after a median cumulative dose of 480 mg/m, 50% of patients will have a reduced left ventricular ejection fraction and 20% will develop congestive heart failure. 

Doxorubicin (adriamycin) An increased incidence of late onset congestive heart failure has been seen in patients treated with mitomycin that had previously been given doxorubicin. 

These toxicides are not related to the mechanism of antitumor activity and in point of fact are not completely understood. What is known is that patients treated with doxorubicin can display an acute type of cardiac alteration and/or a chronic type of cardiac toxicity. The acute toxicides are most often expressed as myocardial arrhythmias and decreased left ventricular ejection fraction. Both effects are reversible once drug administration stops and are not considered to be a reason to discontinue the use of doxorubicin. Whether there is a correlation between these acute events and subsequent chronic cardiac toxicity is not known since individuals who never displayed acute toxicides ultimately developed chronic toxicides including fatal congestive heart failure. A reversible... 

Numerous neuroendocrine biomarkers correlate with severity of cardiac dysfunction. Heart failure is associated with increase in peripheral vascular resistance due to increases in sympathetic tone, norepinephrine, renin, angiotensin II, arginine vasopressin, and endothelin-1. The increased venous pressure causes atrial distension that stimulates production and release of atrial and brain natriuretic peptides (ANP, BNP) from the atria and ventricles, respectively. ANP inhibits the renin-angiotensin-aldosterone system. In humans and mammals, BNP has been found to be an early biomarker of left ventricular hypertrophy developing with doxorubicin cardiotoxicity, congestive heart failure, or occult dilated cardiomyopathy (Erkus et al. 2006 Walker 2006 Oyama, Sisson, and Solter 2007). 

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