Cardiac toxicity, increased

Ketoconazole can increase the concentrations of astemi-zole and terfenadine by inhibition of CYP3A4. High concentrations of terfenadine can cause cardiac toxicity. Increased plasma concentrations of unmetabohzed terfenadine prolong the QT interval and carry the risk of torsade de pointes and other fatal ventricular arrhythmias (13). 

Halogenated hydrocarbons depress cardiac contractility, decrease heart rate, and inhibit conductivity in the cardiac conducting system. The cardiac-toxicity of these compounds is related to the number of halogen atoms it increases first as the number of halogen atoms increases, but decreases after achieving the maximum toxicity when four halogen atoms are present. Some of these compounds, e.g., chloroform, carbon tetrachloride, and trichloroethylene, sensitize the heart to catecholamines (adrenaline and noradrenaline) and thus increase the risk of cardiac arrhythmia. 

For early-stage diffuse, aggressive NHL, combined-modality therapy was tested versus a longer course of chemotherapy.22 Overall survival favored the CHOP/radiation arm for 5 years (82% versus 72%). There was a trend toward increased toxicity, particularly hematologic and cardiac toxicity, in the CHOP alone arm. The results of this trial have established combined-modality therapy as first-line treatment for early-stage NHL. Unique presentations of NHL, such as CNS primary disease, may incorporate radiation into treatment algorithms.23... 

Before the arrival of the new antidepressants, the older tricyclic antidepressants were widely used to treat depression and agitation in demented patients. They have now largely been abandoned in these patients as their prominent anticholinergic effects tend to worsen dementia and the increased risk for cardiac toxicity can be especially dangerous in geriatric patients. 

Voluntary inhalation of butane has led to numerous deaths. Possible mechanisms for the cause of death included the central respiratory and circulatory sequelae of the anesthetic properties of butane, laryngeal edema, chemical pneumonia, and the combined effects of cardiac toxicity and increased sympathetic activity. ... 

Myocardial toxicity, manifested in its most severe form by potentially fatal CHF, may occur either during therapy with mitoxantrone or months to years after termination of therapy. Mitoxantrone use has been associated with cardiotoxicity this risk increases with cumulative dose. In cancer patients, the risk of symptomatic CHF was estimated to be 2.6% for patients receiving up to a cumulative dose of 140 mg/m. For this reason, monitor patients for evidence of cardiac toxicity and question them about symptoms of heart failure prior to initiation of treatment. Monitor patients with multiple sclerosis (MS) who reach a cumulative dose of 100 mg/m for evidence of cardiac toxicity prior to each subsequent dose. Ordinarily, patients with MS should not receive a cumulative dose greater than 140 mg/m. Active or dormant cardiovascular disease, prior or concomitant radiotherapy to the mediastinal/pericardial area, previous therapy with other anthracyclines or anthracenediones, or concomitant use of other cardiotoxic drugs may increase the risk of cardiac toxicity. Cardiac toxicity with mitoxantrone may occur at lower cumulative doses whether or not cardiac risk factors are present (see Warnings and Administration.and.Dosage). 

Hyperglycemia Precipitation or worsening of depression Exacerbation of glaucoma Increase in blood pressure Cardiac toxicity Dizziness, falls, syncope... 

Quinidine can increase the plasma concentrations of digoxin, which may in turn lead to signs and symptoms of digitalis toxicity. Gastrointestinal, central nervous system (CNS), or cardiac toxicity associated with elevated digoxin concentrations may occur. Quinidine and digoxin can be administered concurrently however, a downward adjustment in the digoxin dose may be required. 

Geriatric Considerations - Summary Bupropion has several advantages as an antidepressant agent for use in older adults. It has neither the anticholinergic or cardiac toxicities of the tricyclic antidepressants, and has fewer sexual side effects than selective serotonin reuptake inhibitors. Because this drug may lower seizure threshold, it should be used with caution in older adults with increased risk of seizures (e.g., previous stroke, early-onset Alzheimer s disease). 

Local anesthetics are frequently coadministered with vasoconstrictor molecules such as epinephrine. Normally, they are applied or injected locally and then taken up by local blood vessels into the systemic circulation, ultimately leading to their metabolic breakdown. The co-administration of a vasoconstrictor decreases the systemic absorption of the local anesthetic, thereby increasing its effective half-life in the area of administration and decreasing the probability of systemic toxicity (i.e., cardiac toxicity) secondary to systemic distribution. 

Bupivacaine is an amide compound with a duration of nerve blocking effect of around 3 hours. It is about four times more potent than lidocaine (lignocaine) and has an intermediate-to-slow onset of action. Bupivacaine is prepared as the hydrochloride salt in aqueous solutions in concentrations of 0.25%, 0.50%, and 0.75%. The incidence of motor block increases with increasing concentration. High doses of bupivacaine are associated with cardiac toxicity. Particular care must be exercised to avoid inadvertent overdosage or when the drug is administered to patients taking concurrent cardioactive medication. 

Theophylline Uncertain phosphodiesterase inhibition t adenosine receptor antagonist Bronchodilation, cardiac stimulation, increased skeletal muscle strength (diaphragm) Asthma, COPD Oral duration 8-12 h but extended-release preparations often used Toxicity. Multiple (see text)... 

SNRIs have many of the serotonergic adverse effects associated with SSRIs. In addition, SNRIs may also have noradrenergic effects, including increased blood pressure and heart rate, and CNS activation, such as insomnia, anxiety, and agitation. The hemodynamic effects of SNRIs tend not to be problematic in most patients. A dose-related increase in blood pressure has been seen more commonly with the immediate-release form of venlafaxine than with other SNRIs. Likewise, there are more reports of cardiac toxicity with venlafaxine overdose than with either the other SNRIs or SSRIs. Duloxetine is rarely associated with hepatic toxicity in patients with a history of liver damage. All the SNRIs have been associated with a discontinuation syndrome resembling that seen with SSRI discontinuation. 

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. 

Cardiotoxic effects are relatively uncommon with mianserin (2). In a placebo-controlled study in 50 patients with a variety of cardiac conditions who were taking anticoagulants, mianserin (up to 30 or 60 mg) had no effects on electrocardiography, blood pressure, or pulse rate after 3 weeks. In a second phase, mianserin (up to 60 mg/day) was compared with amitriptyline (up to 150 mg/day) and placebo in 18 healthy volunteers. Measurements included systolic time intervals, electrocardiography at rest and during exercise, echocardiography, and blood pressure. Amitriptyline had a negative inotropic effect mianserin increased ejection fraction. The results of both these experiments led the authors to conclude that mianserin is an antidepressant with very low cardiac toxicity. 

The cardiac toxicity of antimony has been explored in cultured myocytes (26,27). Potassium antimony tartrate disrupted calcium handling, leading to a progressive increase in the resting or diastolic internal calcium concentration and eventual cessation of beating activity and cell death. An interaction with thiol homeostasis is also involved. Reduced cellular ATP concentrations paralleled toxicity but appeared to be secondary to other cellular changes initiated by exposure to antimony. 

In a randomized study in 390 patients suramin has been given in a fixed low dose (3.192 g/m ), intermediate dose (5.320 g/m ), or high dose (7.661 g/m ) to determine whether its efficacy and toxicity in the treatment of patients with hormone-refractory prostate cancer is dose-dependent (8). There was no clear dose-response relation for survival or progression-free survival, but toxicity increased especially with the higher dose. There were neurological adverse effects in 40% of the patients and cardiac adverse effects in 15%. This raises questions about the usefulness of suramin, particularly in high doses, in advanced prostate cancer. However, in another... 

Cardiomyopathy is the most common chemotherapy-associated cardiac toxicity. Myocardial ischemia, pericarditis, arrhythmias, miscellaneous electrocardiogram (ECG) changes, and angina occur much less frequently. The anthracyclines (da-unorubicin, doxorubicin, epirubicin, and idarubicin) have the highest consistent risk for cardiomyopathy, which is cumulative dose related. There is evidence that high-dose cyclophosphamide, mitoxantrone, and fluorouracil also pose an increased risk of cardiac damage. The concurrent use of traztuzu-mab with an anthracycline and cyclophosphamide is associated with a risk of cardiac dysfunction, but the consequences of sequential use are not yet known. 

Accumulation of the parent drug and resultant QT prolongation may occur following a overdose, a drug interaction that limits metabolism of terfenadine (e.g., concomitant administration with erythromycin or other macrolide antibiotic or with the azole derivatives ketoconazole or itraconazole), or significant hepatic dysfunction that limits metabolism of terfenadine. Patients with preexisting cardiac disease or those with electrolyte abnormalities are also at increased risk for cardiac toxicity. 

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