Originally tested as an antihistamine and then proposed as a drug for combating helminth infections, chlorpromazine emerged as an effective treatment for psychotic illness in the 1950s. Chlorpromazine-like drugs were originally termed 'neuroleptics' or 'major tranquillisers' but the class adopted the name 'antipsychotics' as over 20 compounds were brought to market during the next 30 years. Classification is by chemical structure (e.g. phenothiazines, butyrophe-nones). Within the large phenothiazine group, compounds are divided into three types on the basis of the side chain since these tend to predict adverse effect profiles (Table 19.3).

The continuing search for greater efficacy and better tolerability led researchers and clinicians to reinvestigate clozapine, a drug which was originally licenced in the 1960s but subsequently withdrawn because of serious haematological effects. Clozapine appeared to offer greater effectiveness in treatment-resistant schizophrenia, to have efficacy against negative in addition to positive psychiatric symptoms (see Table 19.4), and to be less likely to cause extrapyramidal motor symptoms. It regained its licence in the early 1990s with strict requirements on dose titration and haematological monitoring. The renewed interest in clozapine and its unusual efficacy and tolerability stimulated researchers to examine similar 'atypical' antipsychotic drugs.

Thus the most important distinction in modern-day classification of antipsychotic drugs is between

Antipsychotics the classical (typical) agents such as chlorproma-zine, haloperidol and zuclopenthixol, and the atypical antipsychotics, which include clozapine, and now risperidone, olanzapine and quetiapine. These latter are 'atypical' in their mode of action, effects on experimental animals (lack of extrapyramidal motor symptoms in rats) and adverse effect profiles. Categorisation of atypical agents by their chemical structure is of limited value clinically as they are very heterogenous. A classification by receptor binding profiles is likely to emerge with growing evidence on the clinical importance of their actions on inter-related transmitter systems.

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