Neuroleptics antipsychotic action

Unfortunately, few of the studies that have attempted to relate the blood concentrations of neuroleptics to therapeutic response have fulfilled all these criteria. There is a suggestion that a "thera peutic window" exists for some phenothiazine neuroleptics. A therapeutic window is a range of concentrations of a drug measured in the blood that are associated with a good therapeutic response. Plasma concentrations outside this range are either too low to ensure a therapeutic response or so high that they induce toxic side effects. Despite the numerous studies of the relationship between the plasma concentration and the therapeutic response for a number of "standard" neuroleptics, it would appear that such correlations rarely account for more than 25% of the variance in clinical response to treatment. The existence of a therapeutic window for neuroleptics would therefore appear to be unproven. However, there could be ranges of plasma concentrations associated with optimal antipsychotic action, but these... 

The antipsychotic effect is probably due to an antagonistic action at dopamine receptors. Aside from their main antipsychotic action, neuroleptics display additional actions owing to their antagonism at... 

Fluanisone is a neuroleptic with sedative properties and relatively poorly expressed antipsychotic action. It is used as an independent or adjuvant drug for psychomotor excitement in severe and chronic schizophrenia and for manic-depressive disorder. Synonyms of this drug are sedalande, methorin, and others. 

Some 20 years later, Keck et al. (1989) noted that the course of action of neuroleptics, particularly the onset of their specific antipsychotic action, has still not been studied accurately enough. According to these authors there have been hardly any controlled studies in which clear distinction was made between the non-specific calming action and the antipsychotic effects of neuroleptics. 

The first psychotropics of the modern era (e.g., lithium, neuroleptic antipsychotics, tricyclic and monoamine oxidase inhibitor antidepressants) were discovered serendipitously. These agents were not engineered to have selective actions, but instead produce a wide range of central biochemical effects and generally affect more than one neurotransmitter system simultaneously, resulting in multiple repercussions ... 

Many earlier reports considered extrapyramidal side effects unavoidable when treating patients with neuroleptics. There appeared to he a parallel between antipsychotic action and the incidence of unwanted neurological effects. However, the development of newer neuroleptics has changed this view. Drugs like clozapine have a high antipsychotic potency and yet produce few neurological problems. It has therefore been proposed that the DA receptors involved in the beneficial actions of neuroleptics in the treatment of psychiatric disorders are situated in mesolimbic areas, such as the nucleus accumbens, whereas the extrapyramidal effects are mediated by striatal receptors. 

In this chapter I will look at the main body of research on which current beliefs about the nature and efficacy of the so-called antipsychotic or neuroleptic drugs are based. I will attempt to evaluate whether the data from this and other research supports a disease-based theory of neuroleptic drug action in disorders diagnosed as psychosis or schizophrenia. 

The antipsychotic actions of neuroleptic drugs reflect blockade at dopamine and/or serotonin receptors. However, many of these agents also block cholinergic, adrenergic, and histamine receptors, causing a variety of side effects (Figure 13.3). 

This group comprises drugs with antipsychotic actions (i.e. neuroleptics). 

The butyrophenone AL-449 (8) also lacked antiemetic action in animalq in an otherwise typical major neuroleptic profile. In chronic schizophrenics it showed practically no evidence of antipsychotic action 25... 

Neuroleptic activity profiles. The marked differences in action spectra of the phenothiazines, their derivatives and analogues, which may partially resemble those of butyrophenones, are important in determining therapeutic uses of neuroleptics. Relevant parameters include antipsychotic efficacy (symbolized by the arrow) the extent of sedation and the ability to induce ex-trapyramidal adverse effects. The latter depends on relative differences in antagonism towards dopamine and acetylcholine, respectively (p. 188). Thus, the butyrophenones carry an increased risk of adverse motor reactions because Lullmann, Color Atlas of Pharmacology 2000 Thieme All rights reserved. Usage subject to terms and oonditlons of lloense. 

The mechanism of action of neuroleptics is not sufficiently clear. However, it is believed that they are antagonists of dopamine and dopaminomimetics, and that their effect is connected in some way with the blockage of dopamine D receptors, which results in changes of behavioral reactions. Moreover, it is possible that they also block action on the serotonin receptors and M-choline receptors. It also is possible that antipsychotic agents disrupt the process of the release and return neuronal uptake of a number of biogenic amines. 

It also seems plausible that antipsychotic drugs competitively bind with dopamine receptors and block the action of dopamine on corresponding receptor sites, thus lowering psychotic activity. Central dopamine receptors are subdivided into Dj, D2, and according to some sources, Dj receptors. These receptors have a high affinity for dopamine, but they differ in sensitivity to neuroleptics of various chemical classes. For example, drugs of the phenothiazine series are nonselective competitive Dj and D2 antagonists. Unlike phenoth-iazines, antipsychotics of the butyrophenone series such as haloperidol display selective action only on D2 receptors. 

A number of different compounds of the piperidine and piperazine series with p-fluorobuty-rophenone group substitutions at the nitrogen atom display significant neuroleptic activity (haloperidol, trifluperidol, droperidol, methorin). There is a considerable interest in butyrophenone derivatives as antipsychotic agents as well as in anesthesiology. They exhibit pharmacological effects and a mechanism of action very similar to that of phenothiazines and thioxanthenes in that they block dopaminergic receptors. However, they are more selective with respect to D2 receptors. 

The neuroleptic droperidol possesses antipsychotic, sedative, and antishock action. It potentiates the action of drugs for narcosis. In psychiatric practice, droperidol is used for psy-chomotor excitement and hallucinations. The principal use of this drug lies in anesthesiology for neuroleptanalgesia in combination with fentanyl. It is used in premedication as well as in surgical operations and post-operational circumstances. Synonyms of this drug are talam-onal, droleptan, leptofen, innovar, and others. 

Clozapine is a neuroleptic, which expresses antipsychotic and sedative action. It does not cause general depression and extrapyramidal disorders. It is used for severe and chronic... 

Representatives of diphenylbutylpiperidines are pimozide, fluspirilene, and penfluridol, which belong to the powerful neuroleptic drugs with expressed antipsychotic properties similar to haloperidol. The principle distinctive feature of this series of drugs is their prolonged action. The mechanism of their action is not completely known however, it is clear that they block dopaminergic activity. 

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