Adverse effects antipsychotic drugs

There is an increased risk of sedation and delirium with increased age. There is also an increased risk of antidopaminergic effects such as parkinsonism due to antipsychotic drugs. Many other drugs that pass the blood-brain barrier may cause adverse effects in the elderly. The response of opioids may be increased in the elderly, resulting in oversedation (Turnheim 1998). 

Clozapine and olanzapine are atypical antipsychotic drugs used in the treatment of schizophrenia. Their strnctnres are depicted in Scheme 2.36. The use of clozapine and olanzapine, which are more effective than standard neuroleptic drugs in the treatment of refractory schizophrenia, is, however, limited becanse of their adverse effects. These adverse effects are ascribed to the formation of the corresponding cation-radicals in living organisms under oxidation by bone marrow cells. These cation-radicals eliminate protons from the NH fragments and generate their nitrenium cations. The nitreninm cations are covalently bonnd to the life-important proteins. This results in the toxic effects of clozapine and olanzapine (Sikora et al. 2007). 

Despite the widespread use of neuroleptics in maintenance treatment of bipolar disorder, there have not been any systematic studies of their suitability for this role. Through clinical experience it has been widely accepted that neuroleptics are useful adjunctive treatments to lithium and related drugs. Treatment refractory patients frequently respond to atypical antipsychotics such as clozapine or risperidone. Such adverse effects as EPS, cognitive dysfunction and weight gain frequently limit the long-term use of classical neuroleptics. For this reason, the atypical neuroleptics such as olanzapine and risperidone should now be considered as alternatives for maintenance treatment. 

Agranulocytosis Because of a significant risk of agranulocytosis, a potentially life-threatening adverse reaction, reserve clozapine for use in the treatment of severely ill schizophrenic patients who fail to show an acceptable response to adequate courses of standard antipsychotic drug treatment because of insufficient effectiveness or the inability to achieve an effective dose due to intolerable adverse effects from those drugs. Consequently, before initiating treatment with clozapine, it... 

Haddad PM, Sharma SG. Adverse effects of atypical antipsychotics differential risk and clinical implications. CNS Drugs 2007 21(ll) 911-36. 

TABLE 34.2 Significant Adverse Effects of Antipsychotic Drugs... 

Tardive dyskinesia is a late-occurring syndrome of abnormal movements of the face and tongue with widespread choreoathetosis. It is the most serious adverse effect of the antipsychotic drugs. It can be expected to occur in 20 to 40% of chronically treated patients there is no established treatment, and reversibility may be limited. These reactions are more frequent and severe in the elderly. 

A related issue is pharmacogenetics, which considers genetic factors (e.g. and adverse effects to drugs such as the antipsychotics ( 57). 

The revolutionary idea that drugs could exert a specific antipsychotic effect, coupled with a growing recognition of their significant drawbacks, led to the search for other substances with similar beneficial properties and fewer adverse effects. Thus, pharmacological animal screens, followed by systematic clinical investigations with chemically or structurally related compounds, has led to a variety of effective, better tolerated drugs for schizophrenia and other major psychotic disorders. 

One common denominator of all antipsychotics is the biockade of centrai dopamine (DA) receptors. As a result, extrapyramidal reactions, particularly parkinsonian symptoms, are a major adverse effect of many of these drugs, as well as an important clue to their mechanism of action. True Parkinson s disease is caused by a DA deficiency in the nigrostriatal system. Further, crystallographic data have demonstrated that CPZ s molecular configuration is similar to that of DA, which could explain its ability to block this neurotransmitter s receptors. Drugs with similar structures that do not block DA receptors (e.g., promethazine, imipramine) do not have antipsychotic activity. Another example is the isomer of flupenthixol, which blocks DA receptors is an effective antipsychotic, but the isomer that does not is ineffective (7). The other family of dopamine receptors, D and Dg, have not yet been implicated in psychosis. 

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