After administration of a neuroleptic, there is at first only psychomotor dampening. Tormenting paranoid ideas and hallucinations lose their subjective importance (A, dimming of flashy colors); however, the psychotic processes still persist. In the course of weeks, psychic processes gradually normalize (A); the psychotic episode wanes, although complete normalization often cannot be achieved because of the persistence of negative symptoms. Nonetheless, these changes are significant because the patient experiences relief from the torment of psychotic personality changes; care of the patient is made easier and return to a familiar community environment is accelerated.
The conventional (or classical) neu-roleptics comprise two classes of compounds with distinctive chemical structures: 1. the phenothiazines derived from the antihistamine promethazine (prototype: chlorpromazine), including their analogues (e.g., thioxanthenes); and 2. the butyrophenones (prototype: haloperidol). According to the chemical structure of the side chain, phenothiazines and thioxanthenes can be subdivided into aliphatic (chlorpromazine, triflupromazine, p. 239 and piperazine congeners (trifluperazine, fluphenazine, flupentixol, p. 239).
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
- dopamine receptors in the nigrostria-tal system ^ extrapyramidal motor disturbances; in the area postrema ^ antiemetic action (p. 330), and in the pituitary gland ^ increased secretion of prolactin (p. 242);
- histamine receptors in the cerebral cortex ^ possible cause of sedation.
These ancillary effects are also elicited in healthy subjects and vary in intensity among individual substances.
Other indications. Acutely, there is sedation with anxiolysis after neurolep-tization has been started. This effect can be utilized for: "psychosomatic uncoupling" in disorders with a prominent psychogenic component; neurolepta-nalgesia (p. 216) by means of the buty-rophenone droperidol in combination with an opioid; tranquilization of overexcited, agitated patients; treatment of delirium tremens with haloperidol; as well as the control of mania (see p. 234).
It should be pointed out that neuroleptics do not exert an anticonvulsant action, on the contrary, they may lower seizure thershold.
Because they inhibit the thermoregulatory center, neuroleptics can be employed for controlled hypothermia (p. 202).
Adverse Effects. Clinically most important and therapy-limiting are extrapyramidal disturbances; these result from dopamine receptor blockade. Acute dystonias occur immediately after neuroleptization and are manifested by motor impairments, particularly in the head, neck, and shoulder region. After several days to months, a parkinso-nian syndrome (pseudoparkinsonism) or akathisia (motor restlessness) may develop. All these disturbances can be treated by administration of antiparkinson drugs of the anticholinergic type, such as biperiden (i.e., in acute dysto-nia). As a rule, these disturbances disappear after withdrawal of neuroleptic medication. Tardive dyskinesia may become evident after chronic neurolep-tization for several years, particularly when the drug is discontinued. It is due to hypersensitivity of the dopamine receptor system and can be exacerbated by administration of anticholinergics.
Chronic use of neuroleptics can, on occasion, give rise to hepatic damage associated with cholestasis. A very rare, but dramatic, adverse effect is the malignant neuroleptic syndrome (skeletal muscle rigidity, hyperthermia, stupor) that can end fatally in the absence of intensive countermeasures (including treatment with dantrolene, p. 182).
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 extrapyramidal adverse effects. The latter depends on relative differences in antagonism towards dopamine and ace-tylcholine, respectively (p. 188). Thus, the butyrophenones carry an increased risk of adverse motor reactions because they lack anticholinergic activity and, hence, are prone to upset the balance between striatal cholinergic and dop-aminergic activity.
Derivatives bearing a piperazine moiety (e.g., trifluperazine, fluphena-zine) have greater antipsychotic potency than do drugs containing an aliphatic side chain (e.g., chlorpromazine, triflu-promazine). However, their antipsychotic effects are qualitatively indistinguishable.
As structural analogues of the phenothiazines, thioxanthenes (e.g., chlorprothixene, flupentixol) possess a central nucleus in which the N atom is replaced by a carbon linked via a double bond to the side chain. Unlike the phe-nothiazines, they display an added thy-moleptic activity.
Clozapine is the prototype of the so-called atypical neuroleptics, a group that combines a relative lack of extrapyramidal adverse effects with superior efficacy in alleviating negative symptoms. Newer members of this class include risperidone, olanzapine, and ser-tindole. Two distinguishing features of these atypical agents are a higher affinity for 5-HT2 (or 5-HT6) receptors than for dopamine D2 receptors and relative selectivity for mesolimbic, as opposed to nigrostriatal, dopamine neurons. Clozapine also exhibits high affinity for dopamine receptors of the D4 subtype, in addition to H1 histamine and musca-rinic acetylcholine receptors. Clozapine may cause dose-dependent seizures and agranulocytosis, necessitating close hematological monitoring. It is strongly sedating.
When esterified with a fatty acid, both fluphenazine and haloperidol can be applied intramuscularly as depot preparations.
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