Clozapine cardiovascular effects

Cardiovascular effects. Hypotension and tachycardia occur in most patients taking clozapine. Cases of potentially fatal myocarditis and dilated cardiomyopathy have been reported in association with clozapine (Kilian et al. 1999). Myocarditis typically occurred within 3 weeks of starting clozapine, but cardiomyopathy may not be apparent for several years. Although rare, treatment-emergent myocarditis and cardiomyopathy occur at a reportedly higher incidence with clozapine than with other antipsychotics (Coulter et al. 2001). The mechanism by which clozapine may cause myocarditis has not been established, but some authors have speculated that clozapine may cause an immunoglobuhn E (IgE)-mediated type 1 hypersensitivity reaction (Kihan et al. 1999) or a hypereosinophilic syndrome (Hagg et al. 2001). 

Benzodiazepines are used as hypnotics because they have the ability to increase total sleep time. They demonstrate minimal cardiovascular effects, but do have the ability to increase heart rate and decrease cardiac output. Most CNS depressants, including the benzodiazepines, exhibit the ability to relax skeletal muscles. Clozapine, a dibenzodiazepine, is used in the treatment of schizophrenia. It has both sedative and antipsychotic actions, and is the only FDA-approved medication indicated for treatment-resistant schizophrenia, and for reducing the risk of suicidal behavior in patients with schizophrenia. This drug can have potentially life-threatening side effects, but appears to have no abuse potential and will not be considered further. 

Other adverse cardiovascular and respiratory effects Orthostatic hypotension, with or without syncope, can occur with clozapine treatment. Rarely, collapse can be profound and accompanied by respiratory and/or cardiac arrest. Orthostatic hypotension is more likely to occur during initial titration in association with rapid dose escalation. In patients who have had even a brief interval off clozapine, start treatment with 12.5 mg once or twice daily (see Warnings). Because collapse, respiratory arrest, and cardiac arrest during initial treatment have occurred in patients receiving benzodiazepines or other psychotropic drugs, caution is advised when clozapine is initiated in patients taking a benzodiazepine or any other psychotropic drug. 

Clozapine also has been shown to benefit schizoaffective and bipolar patients with treatment-refractory mania ( 54) patients with Parkinson s disease and those with other neurological disorders with psychoses, such as Huntington s disease. Although clozapine has been shown to be an effective agent in the elderly, its usefulness in this population is limited because of its anticholinergic, sedative, cardiovascular, and potentially toxic effects on the bone marrow ( 55). In a study of 12 elderly female psychotic patients on clozapine (maximal daily dose, 300 mg), for example, five were taken off clozapine because of postural hypotension, one had a nonfatal episode of agranulocytosis, and one had leukopenia ( 56). 

Hypotension is the most commonly observed cardiovascular adverse effect of neuroleptic drugs, particularly after administration of those that are also potent alpha-adrenoceptor antagonists, such as chlorpromazine, thioridazine, and clozapine (34). A central mechanism involving the vasomotor regulatory center may also contribute to the lowering of blood pressure. 

Data from an open study (n = 329) have suggested that patients aged 55-64 years may have a better response to clozapine than those aged 65 and older, but there were no significant differences between the two age groups in the number of patients remaining on clozapine therapy and the number in whom therapy was discontinued (n = 134) (223). The mean duration of clozapine therapy was 278 days. The most common adverse effects that required withdrawal were sedation (n = 12), hematological adverse effects (n = 7), and cardiovascular adverse effects (n = 6). 

Tachycardia is the most common cardiovascular adverse effect of clozapine, and atrial fibrillation has also been reported (SEDA-22, 57) (20). 

Taking into account the results from an epidemiological study of deaths in users and former users of clozapine (32), the cardiovascular mortality risk related to clozapine may be outweighed by the overall lower mortality risk associated with its beneficial effects, since the death rate was lower among current users (322 per 100 000 person years) than among past users (696 per 100 000 person years). The reduction in death rate during current use was largely accounted for by a reduction in the suicide rate compared with past use (RR = 0.25 Cl = 0.10, 0.30). 

Clozapine, which is associated with higher risk of agranulocytosis and seizures, is indicated (25 mg once or twice daily) only in the management of schizophrenic patients who fail to respond adequately to standard antipsychotic drug treatment. On the other hand, it is relatively free from extrapyramidal side effects such as parkinsonism. Approximately 50% of the administered dose is excreted in the urine and 30% in the feces as inactive demethylated, hydroxylated, and N-oxide derivatives. Clozapine has anticholinergic properties and causes tachycardia, and hence poses a serious risk for a patient with compromised cardiovascular function (see also Table 23). 

Other autonomic effects of antipsychotic drugs are probably mediated by the hypothalamus, such as an impairment of the body s abihty to regulate temperature. Clozapine can induce moderate elevations of body temperature that can be confusing clinically central effects on temperatme regulation and cardiovascular and respiratory function probably contribute to the featmes of neuroleptic malignant syndrome (see Table 18-1). 

The combined regimen is safe and effective, although severe cardiovascular or respiratory adverse effects may occur with high doses of clozapine when combined with diazepam and lorazepam. There are no reports of pharmacokinetic interactions between olanzapine and benzodiazepines (studied mainly with diazepam). 

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