Antipsychotic drugs orthostatic hypotension

A number of medications have been associated with an increased risk of falling, including drugs affecting mental status such as antipsychotics, benzodiazepines, tricyclic antidepressants, sedative-hypnotics, anticholinergics, and corticosteroids. Some cardiovascular and antihypertensive drugs also can contribute to falls, especially those causing orthostatic hypotension.9... 

Most patients are able to tolerate the antimuscarinic adverse effects of antipsychotic drugs. Those who are made too uncomfortable or who develop urinary retention or other severe symptoms can be switched to an agent without significant antimuscarinic action. Orthostatic hypotension or impaired ejaculation—common complications of therapy with chlorpromazine or mesoridazine—should be managed by switching to drugs with less marked adrenoceptor-blocking actions. 

Midodrine (ProAmatine). Midodrine can be administered orally to treat resistant cases of orthostatic hypotension. This drug can also prevent hypotension in patients undergoing dialysis, and it can offset the hypotensive effects of certain psychotropic drugs (e.g., antipsychotic medications). 

The introduction of the phenothiazine derivative, chlorpromazine, has started a dramatic improvement in the clinical treatment of schizophrenia. During the past four decades, beside phenothiazines, various antipsychotics having different chemical structures have been identified and introduced into clinical practice (e.g., butyrophenones and benzamides). These drugs ( typical antipsychotics ) decreased the duration of hospitalizations and, with maintenance treatment, reduced the risk of relapse and re-hospitalization. However, they had significant adverse side effects such as tardive dyskinesia, orthostatic hypotension, prolactin increase, and QT prolongation. 

Because of the risk of orthostatic hypotension, clozapine is usually titrated more slowly than other antipsychotics. If a 12.5-mg test dose does not produce hypotension, then 25 mg of clozapine at bedtime is recommended, increased to 25 mg twice daily after 3 days, and then increased in 25- to 50-mg/day increments every 3 days until a dose of at least 300 mg/day is reached. Augmentation therapy involves the addition of a non-antipsychotic drug to an antipsychotic in a poorly responsive patient, while comhination treatment involves using two antipsychotics simultaneously. 

Antidepressants are commonly used in combination with antipsychotics to treat depressive symptoms in individuals with schizophrenia. Different antidepressants have been reported to inhibit metabolism of different P450 pathways. Table 66-10 summarizes the potential metabolic drug interactions between antidepressants and SGAs. Potential enzyme inhibitor interactions with clozapine are the most clinically significant. Increased clozapine serum concentrations with a CYP 1A2 inhibitor such as fluvoxamine may precipitate seizures. With the newer atypical antipsychotics, enzyme inhibitors are more likely to cause side effects such as increased sedation, orthostatic hypotension, or increased risk of akathisia and other extrapyramidal side effects. 

Figure 29-1. Reiative extrapyramidai and autonomic toxicities of representative antipsychotic drugs. Ex-trapyramidai toxicities take the form of parkinsonism, akathisias, and dystonias. Autonomic toxicities are manifested as aipha-adrenoceptor blockade (orthostatic hypotension) or muscarinic blockade (dry mouth, blurred vision, urinary retention).

Metabolic and cardiovascular adverse events were further studied by the same authors in the same sample of children and adolescents [7 ]. Compared with the controls, the treated cohort had a higher prevalence of obesity (OR = 2.1), type 2 diabetes mellitus (OR = 3.2), cardiovascular conditions (OR = 2.7), and orthostatic hypotension (OR = 1.6). In the treated cohort, those who had been exposed to multiple antipsychotic drugs had a significantly higher risk of incident obesity/weight gain (OR = 2.3), type 2 diabetes mellitus (OR = 2.4), and dyslipidemia (OR = 5.3). Incident cardiovascular events were more likely with the use of conventional antipsychotic drugs (OR = 4.3) and mood stabilizers (OR = 1.3). Incident orthostatic hypotension h os more prevalent in those co-prescribed selective serotonin reuptake inhibitors (OR = 1.8) and mood stabilizers (OR = 1.3). 

---