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Antidepressants

The first drugs, which were used as specific agents for the treatment of depression, appeared in the late 50-ies of this century.
In 1957, when studying some derivatives of isonicotinic acid hydrazide, attention was directed to their euphorizing effect as antituberculous agents. 2- Isopropyl-1-isonicotinoylhydrazine caused euphoria and general excitation in patients. The study of this drug in a psychiatric clinic showed that it is effective in treating patients with depressive conditions. Based on the elements of the chemical structure (isopropyl ... nicotinoylhydrazide), it was called << Iproniazid >>. This drug became the ancestor of a new group of psychotropic drugs-antidepressants.
At the same time, antidepressant activity was detected in N- (3-dimethylaminopropyl) iminodibenzyl hydrochloride, which was called "Imipramine".
A study of the mechanism of action of iproniazide showed that it has a characteristic ability to inhibit monoamine oxidase (MAO), an enzyme that causes oxidative deamination and inactivation of monoamines, including norepinephrine, dopamine, serotonin, i.e. The main neurotransmitters, which facilitate the transfer of nervous excitation to the central nervous system. With depressive states, there is a decrease in the activity of noradrenergic and serotonergic synaptic transmission, therefore inhibition of inactivation and accumulation in the brain of these neurotransmitters caused by iproniazide can be considered as a leading component in the mechanism of their antidepressant effect.
Iproniazide and subsequently synthesized drugs made up a group of antidepressants - monoamine oxidase inhibitors (MAOI).
Imipramine differs according to the mechanism of action from iproniazide. It is not an MAO inhibitor, but it also stimulates the processes of synaptic transmission in the brain. This is due to the fact that imipramine blocks the "reverse capture" of neurotransmitter monoamines with presynaptic nerve endings, which results in synaptic cleft and activation of the synaptic transmission. According to the chemical structure, imipramine is a tricyclic compound (see the formula), and therefore this antidepressant and the preparations that were synthesized in the future are called tricyclic antidepressants.
For a long time, antidepressants - MAO inhibitors and tricyclic antidepressants were the two main "typical" antidepressants. Despite the different mechanism of action, their antidepressant efficacy was considered as a result of a similar, namely, activating, effect on the synaptic transmission. Originally believed that the main mechanism of antidepressant action is the activation of noradrenergic transmission, and then began to attach great importance to the activation of serotonergic transmission.
Over time, there were data on new antidepressants that differed from "typical" (MAO inhibitors and tricyclics). There was a need to clarify the classification of drugs of this group.
An important role was played by the establishment of heterogeneity of monoamine oxidases. It turned out that there are two types of this enzyme - MAO type A and type B, differing in substrates that are exposed to their action. MAO type A inhibits mainly deamination of norepinephrine, epinephrine, dopamine, serotonin, tyramine, and MAO type B - deamination of phenylethylamine and some other amines. MAO inhibitors can have either a "mixed" effect, affecting both types of enzyme, or selectively affect one type of enzyme. The inhibition is competitive and non-competitive, reversible and irreversible. All this can significantly affect the pharmacological and therapeutic properties of various MAO inhibitors.
Iproniazide and its closest analogues (isocarboxazide, phenelzine, tranylcypromine and other first-generation drugs) proved to be effective antidepressants, but due to non-selectivity and irreversibility of action, undesirable side effects were observed in their use. It was impossible to use them at the same time as a number of other medicines (due to a violation of their metabolism).
Preparations of this group completely destroy MAO, and for enzyme disintegration it takes at least 2 weeks.
One of the serious side effects when using these drugs is the so-called "cheese" (or rather, tyramine) syndrome. It is expressed in the development of hypertensive crises and other complications with the simultaneous use of iprazide and its analogues with food products containing tyramine or its precursor tyrosine (cheeses, smoked products, etc.), as well as with drugs of tyramine-like structure. The main cause of these complications is the inhibition of enzymatic cleavage of tyramine, which has pressor activity. These complications and general high toxicity (damaging effects on the liver and other organs) led to the fact that almost all first-generation MAO inhibitors were excluded from the nomenclature of drugs. Limited use has only nialamide. Over time, it was found that there are means that have selective inhibitory effect on MAO type A or type B. Thus, selective MAO inhibitor of type A is chlorargil belonging to the group of propargylamines, and selective MAO inhibitor of type B is deprenyl. Chlorigiline has not been used in practice, and deprenyl is used as a limited adjuvant to treat Parkinson's disease (see Deprenil).
A major recent achievement is the creation of a new generation of antidepressants, MAO inhibitors, which have selective and reversible effects on MAO activity. The first representative of this group, the domestic antidepressant pyrazidyl, has found wide application in medical practice. Preparations of this group are characterized by high efficiency, a wide range of action and good tolerability. Some other antidepressants - MAO inhibitors of reversible action (Tetrindol, Inkazan, Befol, Moclobemide, etc.) have been obtained.
Tricyclic antidepressants, as a rule, inhibit the reverse neuronal capture of various neurotransmitter amines (norepinephrine, dopamine, serotonin). At the same time, there are antidepressants that selectively inhibit the capture of different monoamines. Thus, maprolin inhibits the seizure of norepinephrine more actively. In recent years, more attention has been paid to the role of serotonin in the mechanism of action of antidepressants. Antidepressants of new chemical groups (fluoxetine, fluvoxamine, etc.), more selectively inhibiting the neuronal seizure of serotonin, than the capture of noradrenaline and dopamine have been obtained. An selective serotonin reuptake inhibitor is also an antidepressant trazodone.
Along with antidepressants - MAO inhibitors and tricyclic antidepressants, a number of antidepressants are now known, which differ from "typical" both in structure and in the mechanism of action. Antidepressants of the tricyclic structure (<< atypical >>, which do not exert a retarding effect on the neuronal capture of neurotransmitters, as well as on the activity of MAO (mianserin, etc.), antidepressants of bicyclic structure and other chemical structure are also obtained.
The common property of all antidepressants is their timoleptic effect, i.e. Positive influence on the affective sphere of the patient, accompanied by an improvement in mood and general mental state. Different antidepressants differ, however, in the amount of pharmacological properties. Thus, in imipramine, an incanus and some other antidepressants, the timoleptic effect is combined with a stimulating effect, while in the case of amitriptyline, azaphene, and fluoracycin, a sedative component is expressed. In maprotilina antidepressant effect is combined anxiolytic and sedative effects. MAO inhibitor nialamide has a stimulating effect. Pyrazidol affects not only the symptoms of depression, but also has a nootropic effect (see Nootropic drugs), improves << cognitive >> (<< cognitive >> functions of the central nervous system.
When choosing a means for the pharmacotherapy of depression, it is necessary to take into account the pharmacological and toxicological features of a given drug, the symptomatological structure of the disease and the severity level of the depressive state. Antidepressants have found application not only in psychiatric practice. They are used to treat a number of neurovegetative and somatic diseases, which can sometimes be seen as a manifestation of "masked" depressions. There are data on the effectiveness of antidepressants in patients with dyskinesia of the abdominal cavity, IHD, chronic pain syndromes, etc.
When choosing an antidepressant, one should consider its tolerability. Some tricyclic antidepressants (imizin, amitriptyline) in large doses and with prolonged use may have cardiotoxic effects. They should be administered with caution to patients with heart disease. A number of triclinic antidepressants (amitriptyline, fluocyclin, imipramine, etc.) has a pronounced cholinolytic activity, which makes it difficult to use them in patients with prostatic hypertrophy, intestinal and bladder atony, glaucoma, cardiovascular diseases. In connection with pronounced side effects, the majority of "old" antidepressants - MAO inhibitors in medicine is not used, but MAO inhibitors of reversible action (pyrazidol, etc.), which are well tolerated, are widely used in practice.
Tricyclic and other antidepressants are easily absorbed when taken orally, but their therapeutic effect develops, as a rule, gradually. The symptomatic effect is usually manifested after 5-10 days or more from the beginning of the premax of the drug. It is believed that the delayed action is due to the fact that the development of the antidepressant effect is associated not only with the accumulation of neurotransmitters in the field of nerve endings, but also with adaptive changes in the neurotransmitter circuit and the receptivity of the brain that gradually progress under their influence. It should, however, be noted that the curative effect is manifested at different times when using different antidepressants. So, the effect of some new drugs (for example, tetreenol) is manifested after 2 - 3 days from the start of treatment. Given the current knowledge of antidepressants, the following classification is appropriate. 1. Antidepressants - monoamine oxidase inhibitors (MAOI):
A) MAO inhibitors of irreversible action;
B) reversible MAO inhibitors. 2. Antidepressants - inhibitors of neuronal uptake:
A) indiscriminate inhibitors of neuronal seizure;
B) selective inhibitors of neuronal capture. 3. Antidepressants of different groups.

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Subgroup Psychotropic drugs include drugs: