The first medicines which received use as specific means for treatment of depressions appeared in the late fifties our century.
In 1957 when studying some derivatives of hydrazide of isonicotinic acid as antituberculous remedies the attention to their eyforiziruyushchy action was paid. the 2-Izopropil-1-izonikotinoilgidrazin caused euphoria and the general excitement in patients. Studying this drug in psikhoatrichesky clinic showed that it is effective at treatment of patients with depressions. Proceeding from elements of chemical structure (an isopropyl... nicotinoylhydrazide), it received the name<Ипрониазид>. This drug became the ancestor of new group of psychotropic drugs - antidepressants.
Then the antidepressive activity was found in a hydrochloride of N-(3-dimethylaminopropyl) - the iminodibenzyl which received the name<Имипрамин>.
Studying the mechanism of effect of iproniazid showed that it has characteristic ability to inhibit monoamine oxidase (MAO) - the enzyme causing oxidizing deamination and an inactivation of monoamines, including noradrenaline, dopamine, serotonin, i.e. the main neurotransmitters promoting transfer of nervous excitement to central nervous system. In depressions the decrease of the activity of noradrenergichesky and serotonergic synoptic transfer is observed therefore the braking of an inactivation caused by iproniazid and accumulation in a brain of these neurotransmitters can be considered as the leading component in the mechanism of their antidepressive effect.
Iproniazid and the drugs synthesized further similar to it made made group of antidepressants - monoamine oxidase inhibitors (IMAO).
Imipraminum differs on the action mechanism from iproniazid. It is not MAO inhibitor, but too stimulates processes of synoptic transfer in a brain. It is explained by what Imipraminum blocks<обратный захват> neuromediator monoamines presynaptic nerve terminations therefore there is them in a synaptic gap also an activation of synoptic transfer. On chemical structure Imipraminum is tricyclic connection (see a formula) in this connection this antidepressant and the drugs synthesized further close to it received the name of tricyclic antidepressants.
Long time antidepressants - MAO inhibitors and tricyclic antidepressants were two main<типичными> of antidepressants. Despite the different mechanism of action, their antidepressive efficiency was considered as result similar, namely activating, influences on synoptic transfer. Originally considered that the main thing in the mechanism of antidepressive action is activation of noradrenergichesky transfer, then began to attach also great value of activation of serotonergic transfer.
Over time there were data on the new antidepressants differing from<типичных> (MAO inhibitors and tricyclic). There was a need for specification of classification of drugs of this group.
The important role was played by establishment of inhomogeneity of monoaminoxidases. It turned out that there are two types of this enzyme - MAO of A type and type B, differing on the substrates which are treated to their action. MAO of A type inhibits generally deamination of noradrenaline, adrenaline, dopamine, serotonin, tyramine, and MAO of B type - deamination of a feniletilamin and some other amines. MAO inhibitors can<смешанное> affect or, influencing both types of enzyme, or to influence selectively one type of enzyme. Allocate inhibition competitive and noncompetitive, reversible and irreversible. All this can significantly affect pharmacological and medicinal properties of the MAO different inhibitors.
Iproniazid and its next analogs (an isocarboxazid, fenelzin, Tranylcyprominum and other drugs of the first generation) were effective antidepressants, but in connection with not selectivity and irreversibility of action at their use undesirable side effects were observed. Impossible was their use along with some other medicines (owing to disturbance of their metabolism). Drugs of this group completely destroy MAO, and the rezintez of enzyme requires not less than 2 weeks.
One of serious by-effects when using these drugs is so-called<сырный> (more true tiraminovy) the syndrome. He says in development of hypertensive crises and other complications at simultaneous use of Iprazidum and its analogs with the foodstuff containing tyramine or its predecessor tyrosine (cheeses, smoked products, etc.) and also with drugs of tiraminopodobny structure. The inhibition of zymolysis of the tyramine having pressor activity is a basic reason of these complications. These complications and the general high toxicity (the damaging influence on a liver and other bodies) led to the fact that almost all MAO inhibitors of the first generation were excluded from the nomenclature of medicines. Limited use has only Nialamidum. Over time it became clear that there are means having selective inhibiting effect on MAO of A type or type B. So, the MAO selective inhibitor of A type is chlorgilin, belonging to group of propargylamines, and the MAO selective inhibitor of B type - deprenil. Chlorgilin did not receive practical application, and deprenil is used restrictedly as supportive application for treatment of parkinsonism (see Deprenil).
Large achievement of the last time is creation of new generation of antidepressants - the MAO inhibitors having selective and reversible effect on activity of MAO. The first representative of this group pirazidit domestic antidepressant found broad application in medical practice. Drugs of this group differ in high efficiency, a broad spectrum of activity and good tolerance. Some other antidepressants - MAO inhibitors of reversible action are received (tetrindol, inkazan, befol, moklobemid, etc.).
Tricyclic antidepressants, as a rule, inhibit at the same time return neuronalny capture of different neuromediator amines (noradrenaline, dopamine, serotonin). At the same time there are antidepressants which are rather selectively inhibiting capture of different monoamines. So, maprolin slows down capture of noradrenaline more actively. In the last years began to pay bigger attention to a serotonin role in the mechanism of effect of antidepressants. The antidepressants of new chemical groups (fluoxetine, fluvoksamin, etc.) which more selectively are slowing down neuronalny serotonin reuptake, than capture of noradrenaline and dopamine are received. Selective inhibitor of the return serotonin reuptake is also antidepressant Trazodonum.
Along with antidepressants - MAO inhibitors and tricyclic antidepressants a number of the antidepressants differing from<типичных> both in structure, and on the action mechanism is known now. Antidepressants of the tricyclic building (<атипичные>not having the braking impact on neuronalny capture of neurotransmitters, also as on activity of MAO are received (mianserin, etc.). Also antidepressants of the bicyclic building and other chemical structure are received.
The general property of all antidepressants - their timoleptichesky action, i.e. the positive influence on the affective sphere of the patient which is followed by improvement of mood and the general mental state. Different antidepressants differ, however, on the sum of pharmacological properties. So, at Imipraminum, an inkazan and some other antidepressants the timoleptichesky action is combined with the stimulating effect, and at amitriptyline, Azaphenum, a ftoratsizina the sedative component is expressed. At Maprotilinum the antidepressive action is combined anxiolytic and sedative by effects. MAO inhibitor Nialamidum has promoting effect. Pyrazidolum influences not only depression symptoms, but has also nootropic effect (see. Nootropic drugs), improves<когнитивные> (<познавательные>) the central nervous system functions.
When choosing means for pharmacotherapy of depressions it is necessary to consider pharmacological and toxicological features of any given drug, simptomatologichesky structure of a disease and level of weight of a depression. Antidepressants found application not only in psychiatric practice. They are used for treatment of a row neurovegetative and somatopathies which sometimes can be considered as manifestation<маскированных> of depressions. The patients suffering from diskineziya of abdominal organs, an ischemic heart disease have data on efficiency of antidepressants at chronic pain syndromes, etc.
When choosing antidepressant it is necessary to consider its shipping. Some tricyclic antidepressants (imipramine, amitriptyline) in high doses and at prolonged use can have cardiotoxic effect. It is necessary to appoint them with care the patient with heart diseases. A number of triklichesky antidepressants (amitriptyline, ftoratsizin, Imipraminum, etc.) has the significant cholinolytic activity that complicates their use for patients with a prostatauxe, an atony of intestines and bladder, glaucoma, cardiovascular diseases. Due to the expressed by-effects the majority<старых> of antidepressants - MAO inhibitors in medicine is not applied, at the same time practice widely included the MAO inhibitors of reversible action (Pyrazidolum, etc.) differing in good tolerance.
Tricyclic and other antidepressants are easily soaked up at intake, however their therapeutic action develops, as a rule, gradually. The Timoleptichesky effect is shown usually in 5-10 days and more from the beginning of a prem of drug. Believe that the slowed-down action is explained by the fact that development of antidepressive effect is connected not only with accumulation of neurotransmitters in nerve terminations, but also with the adaptation changes in a circulation of neurotransmitters and in sensitivity which are gradually occurring under their influence of brain receptors to them. It should be noted, however, that the medical effect is shown in various time when using different antidepressants. So, effect of some new drugs (for example, a tetrindola) is shown in 2 - 3 days from an initiation of treatment. Taking into account modern knowledge of antidepressants their following classification is appropriate:
1. Antidepressants - monoamine oxidase inhibitors (IMAO):
a) MAO inhibitors of irreversible action;
b) MAO reversible inhibitors.
2. Antidepressants - inhibitors of neuronalny capture:
a) not selective inhibitors of neuronalny capture;
b) selective inhibitors of neuronalny capture.
3. Antidepressants of different groups.