Toxicity cardiovascular effects

Side Effects and Toxicity. Adverse effects to the tricycHc antidepressants, primarily the result of the actions of these compounds on either the autonomic, cardiovascular, or central nervous systems, are summarized in Table 3. The most serious side effects of the tricycHcs concern the cardiovascular system. Arrhythmias, which are dose-dependent and rarely occur at therapeutic plasma levels, can be life-threatening. In order to prevent adverse effects, as weU as to be certain that the patient has taken enough dmg to be effective, the steady-state semm levels of tricycHc antidepressant dmgs are monitored as a matter of good practice. A comprehensive review of stmcture—activity relationships among the tricycHc antidepressants is available (42). 

Imipramine3 10-25 75-250 cardiovascular effects delayed onset of action may precipitate mania sexual side effects toxic in overdose weight gain... 

Target Organ Toxicity. This section focuses on mechanisms for sensitive health effects of major concern for lead—cardiovascular effects, hematological effects, and neurological effects, particularly in children. Bone is a major sink for lead, and there is some limited information regarding the effects of lead on bone and potential mechanisms of action. Renal effects occur at relatively high blood lead levels and evidence of renal carcinogenicity has been demonstrated only in animals mechanisms for these effects will be discussed briefly. 

Cardiovascular Effects. Only limited reports of cardiovascular toxicity of endrin were located. Diffuse degenerative lesions of the heart were observed in dogs administered lethal doses of endrin (Treon et al. 1955), and enlarged hearts were observed at sublethal doses. The health significance of these finding is unclear, as the effects were not observed in other animal species. 

Cardiovascular Effects. Reports of cardiovascular effects in humans or animals after exposure to 3,3 -dichlorobenzidine by any route were not foimd in any of the existing epidemiological and animal studies, suggesting that the cardiovascular system is not a target of 3,3 -dichlorobenzidine toxicity. It is unlikely that cardiovascular effects will occm in humans exposed to 3,3 -dichlorobenzidine at levels foimd at hazardous waste sites. 

One of the pollutants known to interfere with cardiovascular development is 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD). TCDD is a persistent, bioaccumulative environmental contaminant, as well as a potent developmental toxicant and human carcinogen [30]. Piscine, avian, and mammalian cardiovascular systems are sensitive to TCDD toxicity, with effects including cardiac enlargement, edema, and several dysfunctions. In zebrafish embryos, these effects include areduction in cardiomyocyte number at 48 hpf, decreased heart size, altered vascular remodeling, pericardial edema, and decreased ventricular contraction culminating in ventricular standstill [31-34]. 

The synthesis [214] of debrisoquine, its cardiovascular effects (in animal preparations), acute toxicity and biochemistry [201] and clinical pharmacology [215] have been reported (see also p. 167—168 of this volume). 

Embryotoxic effects have occurred in rabbits exposed to hydroxylamine hydrochloride by intracoelomic injection. Subcutaneous or intravenous injection of pregnant rabbits with 50-650mg of hydroxylamine hydrochloride on gestational day 12 caused death or euthanasia of all rabbits within 30 hours. All maternally injected rabbits exhibited severe cyanosis, presumably due to methemoglobinemia. At 8 hours all embryos were dead from cardiovascular effects, which are considered to be secondary to the severe maternal toxicity. 

Following intravenous injection of Thorotrast, cirrhosis of the liver was the primary systemic effect in humans and animals. Hematological disorders (aplastic anemia, leukemia, myelofibrosis, and splenic cirrhosis), cardiovascular effects (myocardial infarction, severe coronary luminal narrowing and internal alteration of the carotid artery), and Thorotrastoma (localized fibrosis surrounding deposits of Thorotrast) were also found in patients injected with Thorotrast. The effects of Thorotrast were a result of the radiological toxicity of thorium. 

Cardiovascular Effects. Most studies of humans exposed to carbon tetrachloride by inhalation have not detected significant evidence of cardiovascular injury, even at exposure levels sufficient to markedly injure the liver and/or kidney. Changes in blood pressure, heart rate, or right- sided cardiac dilation have sometimes, but not always, been observed (Ashe and Sailer 1942 Guild et al. 1958 Kittleson and Borden 1956 Stewart et al. 1961 Umiker and Pearce 1953), and are probably secondary either to fluid and electrolyte retention resulting from renal toxicity, or to central nervous system effects on the heart or blood vessels. Carbon tetrachloride also may have the potential to induce cardiac arrhythmias by sensitizing the heart to epinephrine, as has been reported for various chlorinated hydrocarbon propellants (Reinhardt et al. 1971). 

Cardiovascular Effects. Inhalation and oral studies in humans and animals have not revealed any treatment-related histopathological lesions of heart tissue, or impairment of cardiac functions, even at dose levels causing severe liver and kidney damage (Adams et al. 1952 Stewart et al. 1961 Umiker and Pearce 1953). It is possible that high-level carbon tetrachloride exposure may produce cardiac arrhythmias by sensitization of the heart to catecholamines (Reinhardt et al. 1971). Accordingly, there is some concern for cardiovascular toxicity following substantial exposure to carbon tetrachloride. 

Halogenated hydrocarbon inhalation anesthetics may increase intracranial and CSF pressure. Cardiovascular effects include decreased myocardial contractility and stroke volume leading to lower arterial blood pressure. Malignant hyperthermia may occur with all inhalation anesthetics except nitrous oxide but has most commonly been seen with halothane. Especially halothane but probably also the other halogenated hydrocarbons have the potential for acute or chronic hepatic toxicity. Halothane has been almost completely replaced in modern anesthesia practice by newer agents. 

Infrequent reactions to interferon therapy include proteinuria, renal toxicity, autoimmune disease, thyroid disease, ophthalmic toxicity, pulmonary dysfunction (pulmonary infiltrates, pneumonitis, and pneumonia), and cardiovascular effects (tachycardia, arrhythmia, hypotension, cardiomyopathy, and myocardial infarction). Rarely, the body may develop antibodies against interferons that inhibit their effectiveness. 

The adverse effects of TCAs are also similar to those reported in adults (see Chapter 7). The secondary amine TCAs (e.g., desipramine, nortriptyline) are generally as well tolerated as newer antidepressants. Increased blood pressure may be more likely to occur in children than in adults but hypertension per se is rare ( 135). The most common cardiovascular effect is mild tachycardia. Despite their generally favorable adverse effect profile, secondary amine TCAs can cause serious toxicity in children and adolescents just as in adults when a taken in an overdose or when a high TCA plasma level occurs as a result of slow metabolism ( 136). For that reason, most clinicians reserve TCAs for the child or adolescent who has at least a moderate depressive disorder unresponsive to a trial of one or more newer antidepressants. In such instances, TDM should be done at least once to ensure plasma concentrations greater than 450 ng/mL do not develop ( 137). Such levels are associated with an increased risk of the following ... 

Cardiovascular Effects. Limited information on the cardiovascular toxicity of HDl was available. 

The net cardiovascular effects of moderate doses of cholinesterase inhibitors therefore consist of modest bradycardia, a fall in cardiac output, and an increased vascular resistance that result in a rise in blood pressure. (Thus, in patients with Alzheimer s disease who have hypertension, treatment with cholinesterase inhibitors requires that blood pressure be monitored to adjust antihypertensive therapy.) At high (toxic) doses of cholinesterase inhibitors, marked bradycardia occurs, cardiac output decreases significantly, and hypotension supervenes. 

Digoxin has multiple direct and indirect cardiovascular effects, with both therapeutic and toxic consequences. In addition, it has undesirable effects on the central nervous system and gut. 

At doses up to those causing hypnosis, no significant effects on the cardiovascular system are observed in healthy patients. However, in hypovolemic states, heart failure, and other diseases that impair cardiovascular function, normal doses of sedative-hypnotics may cause cardiovascular depression, probably as a result of actions on the medullary vasomotor centers. At toxic doses, myocardial contractility and vascular tone may both be depressed by central and peripheral effects, leading to circulatory collapse. Respiratory and cardiovascular effects are more marked when sedative-hypnotics are given intravenously. 

Toxicities include elevation of liver enzymes with some risk of liver damage, renal impairment, and teratogenic effects. A low frequency of cardiovascular effects (angina, tachycardia) was reported in clinical trials of leflunomide. 

Calcium antagonists can cause serious toxicity or death with relatively small overdoses. These channel blockers depress sinus node automaticity and slow AV node conduction (see Chapter 12). They also reduce cardiac output and blood pressure. Serious hypotension is mainly seen with nifedipine and related dihydropyridines, but in severe overdose all of the listed cardiovascular effects can occur with any of the calcium channel blockers. 

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