NEUROLEPTICS (Greek neuron a nerve + leptikos capable to take, to apprehend; synonym: nevroleptichesky means, neuroleptics, neuroplegic means, neyrogshegik, antipsychotic means, anti-schizophrenic means, big tranquilizers) — group of the pharmaceuticals rendering diverse, preferential oppressing, action on higher nervous activity, an emotional state and behavior and not breaking at the same time consciousness. N.'s feature of page distinguishing them from other groups of psychotropic drugs is antipsychotic action, i.e. ability to stop psychotic frustration (nonsense, hallucinations). At N.'s use by the village there is the general calm, emotional tension decreases, sensation of fear, concerns considerably decreases, the condition of psychoaffective indifference to surrounding develops.
Classification is based by hl. obr. on chemical structure of the connections possessing antipsychotic action taking into account them pharmakol, properties of N of features a wedge, uses. Allocate the following basic groups of neuroleptics: 1) fenotiazina — dialkylaminoalkyl (subgroup of propazine), piperidylalkyl (subgroup of a ridazin) and alkiliperazinilpropilny (subgroup of pyrazine and phenazine) derivatives; 2) thioxanthenes; 3) tricyclic neuroleptics with various chemical structure (dibenzoksepina, dibenzdiazepines, dibenztiyepina); 4) phenyl propyl ketones; 5) difenilbutilpiperidina; 6) sulfamoylbenzamides; 7) derivatives of an indole and Carbolenum; 8) alkaloids of Rauwolfia and their synthetic analogs. Constitutional formulas of representatives of basic groups of N. of page are given below.
1. Fenotiazina. X = N, Cl, CF3,OCH3, CN, SO2N(CH3)2; R=N (CH3)2, piperidit, alkilpiperazinit, piperazinylethsilt ethers enanthic or decanoic to - t
2. Thioxanthenes. X =Cl, CF3, SO2N (CH2)2; R — N (CH3)2, alkilpiperazinit, piperazinylethsilt ether decanoic to - you
3. Tricyclic neuroleptics with various chemical constitution (dibenz-diazepines)
4. Phenyl propyl ketones. X=4-Cl — a haloperidol X=3-CF3 — Trifluperidolum
8. Alkaloids of Rauwolfia
Chemical constitution of most of N. of page has nek-ry common features, the most important of to-rykh are: 1) three-dimensional (space) structure of a molecule; 2) existence of the sites of a molecule providing specific and nonspecific binding with a receptor; 3) a possibility of binding due to polar and hydrophobic interaction; 4) a relative positioning and a certain distance between functional groups (sites) of a molecule.
as the Beginning of broad use of N. of page discovery of antipsychotic properties of aminazine served in psychiatry after it was applied by A. Labori and P. Hugue-nard in 1951 as one of components of so-called lytic mixes during the training of patients for operation with the purpose of creation of the central and peripheral neurovegetative blockade — a so-called neyrolepsiya. N.'s use by the village significantly expanded possibilities of treatment of mental diseases, allowed to reduce terms of treatment, to reduce the frequency of a recurrence, to return a considerable part of patients to public and work. N of page apply also in pilot studies in the field of psychiatry, psychology, neurology, physiology, a neurochemistry, pharmacology.
For N.'s most the page is characteristic, on the one hand, strengthening of action of many pharmakol, substances of the depriving of bonuses type (the general and local anesthetics, somnolent and analgesic means), with another — antagonistic action in relation to neural activity stimulators (e.g., to the hair dryer-mpnu). Along with this N. pages do not interfere with development of the spasms caused by Corazolum, strychnine, iik-rotoksiny. In high doses of N. of page prevent development of a phase of a tonic ekstenziya at an electroshock, without exerting noticeable impact on a threshold of the convulsive reaction caused by electric current. In N.'s experiment with, oppress conditional - reflexes of avoiding, cause a condition of motive block (katalepsy) that correlates with their property to cause frustration of extrapyramidal system in patients in the course of treatment (pages, nek-ry from N., napr, clozapine and Sulpiridum, have no this property). Page, characteristic of N., is antiemetic action, especially at the vomiting caused by Apomorphinum and a penetrating radiation.
Experience a wedge, N.'s uses by the village allows to allocate the following main components of their action: 1) the calming (sedative) effect which is shown in the form of mental and motive block, slackness, decrease in an initiative, interest to surrounding drowsiness; 2) antipsychotic action, i.e. stopping of psychotic frustration (nonsense, hallucinations, etc.); 3) influence on the somatic sphere and vegetative innervation (decrease in the ABP, delay of a rhythm and depth of breath, oppression of vegetative reactions, decrease in body temperature); 4) the influence on Extrapyramidal system leading to emergence nevrol, frustration like parkinsonism (increase in a muscle tone, a tremor, various motive paroxysms, etc.); 5) the promoting effect which is shown at prolonged use of nek-ry N. of page. At various N. the specified types of action are expressed to page in different degree. The calming (sedative) action is most characteristic for aminazine (see) and similar to it on pharmakol, to properties of drugs, such, as propazine (see), levomepromazinum (see), chlorprothixene (see); also clozapine has the expressed sedative effect. Along with the systemic seda-tpvny effect of N. of page can exert also the selective calming impact on the psychoemotional sphere: to eliminate or reduce feeling of tension, fear, concern (tranquilizing effect). The antipsychotic action inherent to all N. to page, also has qualitative features at various drugs of one class. Distinguish the systemic and selective antipsychotic effect of N. of page. The systemic antipsychotic effect is meant as the weakening N.'s influence by the village on polymorphic psychotic symptomatology. Selective antipsychotic effect comes down preferential to N.'s influence by the village on certain psychopathological syndromes (nonsense, hallucinations, the struporous phenomena, etc.). Thus, each drug possesses own range of psychotropic action, in Krom the general are definitely combined sedative, tranquilizing, and selective antipsychotic effects. Besides, are inherent to each drug greater or smaller influence on the somatovegetativny sphere and various degree of manifestation of extrapyramidal effect. The activating influence on mentality and behavior of patients is found in nek-ry neuroleptics in the course of their prolonged use (they become more live, more active, their mood, the speech improves).
The mechanism of action of neuroleptics
the Mechanism of action of neuroleptics, according to neurochemical and neurophysiological researches, is explained by their influence on exchange of dopamine in a brain, in particular by blocking of postsynaptic dofaminergichesky receptors in certain structures of a brain (a striatum, limbic system), however the mechanism of antipsychotic action of N. of page is found out insufficiently. Fiziol, can form a basis of psychotropic effect of N. of page their influence on a kernel having a tail, the important part in formation of higher nervous activity, emotions, attention and perception is assigned to Krom. Blocking postsynaptic dofaminergichesky receptors of a kernel having a tail and eliminating with that brake control from black substance, N. pages cause strengthening of function of a striatum leading to improvement of striatno-cortical control, restriction of perception of a retikulokortikal-ny afferent flow, decrease in emotional reactivity and locomotory functions. Oppression of a reticular formation of a brainstem has, apparently, smaller value also correlates only with the systemic oppressing (sedative) effect of N. of page
a Certain combination of various components of antipsychotic action at different groups H. of page causes features of their use in clinic.
Derivatives of a fenotiazin, the dialkylaminoalkyl, or aliphatic, including aminazine and levomepromazinum, are characterized by dominance of a psychosedative component, as defines their use at all types of psychomotor and contagious excitation: fear, alarm, tension, sleeplessness. Aminazine is appointed also at the acute psychotic states which are followed by nonsense, hallucinations and other frustration except a depression. Levomepromazinum which unlike aminazine is not causing depressions is shown at alarming and depressive and alarming and crazy states. In general these drugs it is possible to characterize as N. page of not selective type contrary to other subgroups of derivatives of a fenotiazin.
Piperidylalkyl derivatives — thioridazine and pro-Periciazinum (neuleptil) are intermediate between aminazine, on the one hand, and Triphtazinum — with another. Both drugs have the moderate calming effect at rather weak antipsychotic effect that allows to appoint them at conditions of emotional instability, a hyperexcitability, tension. Therapeutic action of a prope-ritsiazin is shown at a behavior disorder owing to psychopathic and psychopatholike frustration. Thioridazine is shown at alarming depressions without the expressed excitement. Theralenum also concerns to this group (a synonym: Trimeprazinum, alimemazin), applied at many psychosomatic frustration (senesthopathias, a hiccups, etc.).
Alkilpiperazinilpropilny derivatives include Metherazinum (see), etaperazin (see), Triphtazinum (see), ftorfenazin (see), Frenolonum, etc. Drugs of this subgroup by 10 — 20 times surpass aminazine in antipsychotic activity, on expressiveness of sedative action concede to it. High kataleptogenny activity in an experiment correlates at them with the expressed extrapyramidal effect observed in clinic. Feature of a psychotropic range of N. of page of this subgroup is the combination well-marked the general and selective (it is preferential on a hallucinatory-dilision syndrome) antipsychotic action. Besides, these drugs exert the expressed activating impact on a mental condition of patients. The promoting effect is most brightly expressed at Frenolonum that allows to recommend it at serious struporous conditions, apatoabulichesky frustration. At the same time drug has rather weak systemic antipsychotic effect, causes moderate tranquilizing effect, exerts positive impact on emotions. Pages of this subgroup on intensity of the systemic antipsychotic effect are the most active N. ftorfenazin and especially Thioproperazinum (majeptil). However Thioproperazinum is more often than other N. the page of this group causes Extrapyramidal, preferential hyperkinetic and Diskinetichesky, nevrol, frustration. Use drug for treatment of acute and chronic psychoses, hl. obr. at schizophrenia with catatonic and gebefrenny symptomatology.
On the basis of synthesis of ethers enanthic and decanoic to - t are received by depot neuroleptics — flufenazindekanoat (Moditenum depot), flupentiksol-dekanoat, etc.; their action continues during 1 — 5 week after a single injection of oil solution. Convenience and reliability of a maintenance therapy of depot neuroleptics is confirmed a wedge, given about considerable decrease in number of a recurrence at mentally sick. Side effects of depot neuroleptics, including frustration of extrapyramidal system, are observed seldom, however in some cases there can be dangerous symptoms of overdose: hyperthermia and heavy Extrapyramidal disturbances.
Tioksanteny on a chemical structure and pharmakol, are close to properties to fenotiazina. Treat drugs of this group chlorprothixene (see), tiotiksen, flupen-tiksol, schizophrenia, effective at gallyu-natorno-crazy and periodic forms. They are applied at all types of psychomotor excitement, including at a depression when aminazine is contraindicated. Have high psychotropic activity tiotiksen (a tioksantenovy analog of Thioproperazinum) and flupentiksol (an analog of a ftorfenazin).
From tricyclic neuroleptics with various chemical structure it is most known and clozapine (leponexum) is widely applied in clinic. On pharmakol, to action it differs from other N. in page lack of the selective oppressing influence on a conditioned reflex of avoiding, antagonistic action in relation to Phenaminum and Apomorphinum, and also katalepto-gene action. Drug renders the expressed page, sedative and stronger in comparison with other N., the central myorelaxation action, blocks reaction of activation of EEG in response to electric irritation of a reticular formation of a trunk of a brain. Value of clozapine as neuroleptic of new type is defined by the fact that thanks to features of the pharmakol, a range drug does not exert noticeable impact on nigrostriarny system and does not cause frustration of extrapyramidal system. It also causes its broad use in clinic, in particular at organic diseases of c. N of page. However it is necessary to consider a possibility of defeat of the hemopoietic bodies, the agranulocytosis can be a consequence of what.
Phenyl propyl ketones and difenilbutilpiperidina are widely used in clinic. From phenyl propyl ketones are most known haloperidol (see), Droperidolum (see), Trifluperidolum (trisedyl). Pimozidum and Fluspirilenum belong to difenilbutilpiperidina. Along with the expressed sedative action phenyl propyl ketones, in particular a haloperidol, significantly do not influence the ABP and functions of century of N of page, the page their antagonistic action in relation to adrenaline and noradrenaline is less expressed in comparison with other N. It is supposed that the haloperidol and its analogs selectively block the central and peripheral dofaminergichesky receptors, as defines specifics them pharmakol, actions. Scope of N. of page of this group is rather wide: they are used not only in psychiatry, but also in anesthesiology (especially Droperidolum), in cardiology for stopping of a pain syndrome at a myocardial infarction, as antiemetics. Antipsychotic action is characteristic of the majority of phenyl propyl ketones selective (preferential on a hallucinatory-dilision syndrome). Besides, phenyl propyl ketones exert also the stimulating impact on mentality. Highly active drug is Trifluperidolum, strongly expressed systemic antipsychotic effect to-rogo is combined with selective influence on psychoses with paranoid symptomatology. However more than in 90% of cases drug causes frustration of extrapyramidal system.
On character pharmakol, actions of a difenilbutilpiperidina Pimozidum and Fluspirilenum (flushpirilen) are close to phenyl propyl ketones, but the effect caused by them at single use is more long owing to their slow absorption. Thanks to duration of action they are applied to a maintenance therapy. Pimozidum surpasses a haloperidol in the activity and approaches Trifluperidolum, but renders the promoting effect which was more expressed in comparison with the last.
Treats group of sulfamoylbenzamides sulyshrid (dogmatit, eglonyl), combining properties of a neuroleptic and antidepressant. Sulpiridum does not exert impact on the maintenance of catecholamines in a brain and at the same time influences metabolism of serotonin. Drug is used at depressive and crazy, depressnvno-hallucinatory and struporous states; the psychosomatic frustration which are followed by disturbance of functions went. - kish. path, dizziness, pain syndrome; for treatment of migraine and at posttraumatic a syndrome (an adynamy, dizziness, a headache).
From derivatives of an indole and Carbolenum found practical application Carbidinum (see), having the properties characteristic both for N. page, and for antidepressants (see). Carbidinum is effective at periodic schizophrenia, especially with a depres-sivno-pas ranoidny symptomatology. Drug is used also for treatment hron, alcoholism.
From group of alkaloids of Rauwolfia in psychiatry it is used Reserpinum (see); synthetic substitutes in psychiatry do not apply it (tetrabenazin, benzkhinamid). The antipsychotic effect of Reserpinum is noted only at purpose of high doses and prolonged use. Therefore drug is appointed by hl. obr. for the purpose of correction of the mental disorders caused by vascular disorders (and in particular at a hypertension).
At N.'s appointment page it is necessary to consider possibility of various side effects. Frustration of extrapyramidal system, a depression, an exacerbation of psychosis, a delirium, disorders of functions of century of N of page, metabolic and endocrine disturbances, allergic reactions, dermatitis, damages of a liver, gematol, changes are most frequent.
Bibliography: Avrutsky G. Ya., Gurovich I. Ya. and Gromova of V. V. Pharmakoterapiya of mental diseases, M., 1974, bibliogr.; Arushanyan E. B. Antipsychotic action of neuroleptics and function basal gangliyev, Pharm, and toksikol., t. 34, page 481, 1973; Mashkovsky M. D. Pharmaceuticals, t. 1, page 40, M., 1978; K. S. Pharmakologiya's Rajevski of neuroleptics, M., 1976, bibliogr.; The pharmacological basis of therapeutics, ed. by L. S. Goodman a. A. Gilman, L., 1975.
K. S. Rayevsky.