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Neuroleptics

The term “neuroleptics” (antipsychotics) was proposed as early as 1967, when the first classification of psychotropic drugs was developed. They designated the means intended for the treatment of severe diseases of the central nervous system (psychosis). Recently, in a number of countries, it has become considered appropriate to replace this term with the term “antipsychotics”, since “neuroleptic syndrome” is not the main, but a side effect — undesirable — an effect complicating the therapeutic effect of the drugs of this group. The current challenge is the creation of antipsychotic drugs, devoid of neuroleptic component. Nevertheless, the term "neuroleptics" continues to be widely used to refer to this group of drugs.
The group of neuroleptic drugs includes a number of phenothiazine derivatives (aminazine, etc.), butyrophenones (haloperidol, etc.), derivatives of diphenylbutylpiperidine (flushpyrylene, etc.) and other chemical groups. One of the first antipsychotic drugs was also alkaloid reserpine. Currently, due to the relatively low antipsychotic activity, it has given way to more effective modern drugs, but retained its value as an antihypertensive agent.
Neuroleptics have a multifaceted effect on the body. One of their main pharmacological features is a kind of calming effect, accompanied by a decrease in reactions to external stimuli, a weakening of psychomotor agitation and affective tension, the suppression of fear, a weakening of aggressiveness. Their main feature is the ability to suppress delusions, hallucinations, automatism and other psychopathological syndromes and to have a therapeutic effect in patients with schizophrenia and other mental illnesses.
Neuroleptics do not have a pronounced hypnotic effect in usual doses, but they can cause drowsiness and contribute to the onset of sleep. They enhance the effect of sleeping pills and other sedatives (sedatives), they also potentiate the effects of drugs, analgesics, local anesthetics and weaken the effects of psychoactive drugs (phenamine, etc.).
A number of neuroleptics (phenothiazine group, butyrophenone, etc.) has antiemetic activity; This effect is associated with selective inhibition of chemoreceptor trigger (trigger) zones of the medulla oblongata.
For a number of neuroleptics characterized by the ability to have a cataleptogenic effect.
There are neuroleptics whose antipsychotic action is accompanied by a sedative (aliphatic derivatives of phenothiazine, reserpine, etc.) or an activating (energizing) effect (piperazine derivatives of phenothiazine, some butyrophenones). Some neuroleptics are inherent elements of antidepressant action.
These and other pharmacological properties of various neuroleptic drugs are expressed in varying degrees. The combination of these and other properties with the main antipsychotic effect determines the profile of their actions and indications for use in psychiatry and other areas of medicine.
In the physiological mechanisms of central action of neuroleptics, their effect on the reticular formation of the brain is essential; exerting a depressant effect on this part of the brain, neuroleptics eliminate its activating effect on the cerebral cortex. The action of neuroleptics is not limited, however, to the effect on the reticular formation. Their various effects are also associated with the impact on the occurrence and conduct of excitation in different parts of the central and peripheral nervous system.
Of the neurochemical mechanisms of action of neuroleptics, their effect on mediator processes in the brain has been the most studied. At present, much data has been accumulated on the effects of neuroleptics (and other psychotropic drugs) on adrenergic, dopaminergic, serotonergic, GABAergic, cholinergic and other neurotransmitter processes, including the effect on the neuropeptide systems of the brain.
Different groups of neuroleptics and individual drugs, as well as psychotropic drugs of other groups, differ in their influence on the formation, accumulation, release of the metabolism of various neurotransmitters and their interaction with receptors in different brain structures, which significantly affects their pharmacological properties and therapeutic efficacy.
Recently, much attention has been paid to the interaction of neuroleptics with dopamine brain structures. According to modern data, dopamine, which is a precursor in the process of norepinephrine biosynthesis, has independent significance as a chemical mediator of nerve impulses in certain brain structures and plays an important role in the processes of nervous activity. It has been established that impairment of the dopamine mediator function is one of the pathogenetic mechanisms for the development of parkinsonism and other extrapyramidal disorders (see Dopamine, Parkinsonian treatment drugs). Changes in the formation and function of dopamine are also observed in various psychopathological states. There is reason to believe that the effect on dopaminergic processes plays an important role in the mechanism of action of neuroleptics, although at the same time they act on other mediator systems.
It was shown that neuroleptics of different groups (phenothiazines, butyrophenones, etc.) block dopamine receptors of different brain structures. It is believed that this action causes antipsychotic activity, and the inhibition of central noradrenergic receptors (in particular, in the reticular formation) causes a predominantly sedative effect, as well as the hypotensive effects observed in the clinic.
<< Target >> for neuroleptics are mainly D, -receptors (see Dopamine).
The depression of the mediator activity of dopamine is associated not only with the antipsychotic activity of neuroleptics, but also with the main side effect caused by them - << neuroleptic syndrome >> (extrapyramidal disorders similar to parkinsonism). This action is explained by the blocking effect of neuroleptics on the subcortical formations of the brain (substantia nigra and striatum, bulgaric, interlimbic and mesocortical regions), where a significant number of dopamine-sensitive receptors are localized. Of the most well-known neuroleptics, nomenergic receptors are more strongly influenced by aminazine, levomepromazine, thioridazine, and dopaminergic - fluorophenazine, haloperidol, sulpiride.
Extrapyramidal side effects do not completely correlate with the antipsychotic activity of various neuroleptics, which indicates the unequal sensitivity of various dopaminergic brain structures to different chemical compounds; this creates prospects for the production of antipsychotics with selective antipsychotic action without significant extrapyramidal side effects. It was also noted that a lesser side extrapyramidal effect is usually observed in neuroleptics with greater anticholinergic activity. Indeed, compounds with anticholinergic properties have an anti-Parkinsonian effect.
One of the neuroleptics with a pronounced antipsychotic activity, practically not causing extrapyramidal side effects, is the drug azaleptin (syn .: clozapine, leponex) - a piperazino-dibenzodiazepine derivative.
It should be noted that neuroleptics, which cause more pronounced extrapyramidal phenomena, have the strongest cataleptogenic activity under experimental conditions, which can be explained in blocking dopamine receptors and allows us to foresee the possibility of extrapyramidal disorders on the basis of an experimental study.
The effect on central dopamine receptors explains the mechanism of some endocrine disorders caused by neuroleptic drugs, including lactation stimulation. By blocking the dopamine receptors of the pituitary gland, antipsychotics enhance the secretion of prolactin. Acting on the hypothalamus, neuroleptics also inhibit the secretion of corticotropin and somatotropic hormone.
Pharmacokinetically, most neuroleptics are characterized by good absorption with different routes of administration (by mouth, intramuscularly). They penetrate the blood-brain barrier, but they accumulate in the brain in much smaller quantities than in the internal organs (liver, lungs). Metabolized in the liver and excreted in significant quantities with urine, and partially with feces.
Most of the “ordinary” neuroleptics have a relatively short half-life in the body and have a short-lasting effect after a single injection. Special drugs of prolonged action have been created (see Fluorophenazine decanoate, Flushpirilen, Pimozide, etc.), which have a long-lasting effect upon parenteral administration or ingestion.