The use of MAO inhibitors. MAO inhibitors - what is it? Irreversible selective MAO-B inhibitors

Monoamine oxidase inhibitors (MAOIs, MAOIs)- biologically active substances capable of inhibiting the enzyme monoamine oxidase contained in nerve endings, preventing the destruction of various monoamines (serotonin, norepinephrine, dopamine, phenylethylamine, tryptamines, octopamine) by this enzyme and thereby contributing to an increase in their concentration in the synaptic cleft.

Monoamine oxidase inhibitors include some antidepressants, as well as a number of natural substances.

IMAO classification

According to their pharmacological properties, monoamine oxidase inhibitors are divided into reversible and irreversible, selective and non-selective.

Selective MAOIs inhibit mainly one of the types of MAO, non-selective - both types (MAO-A and MAO-B).

Irreversible MAOIs interact with monoamine oxidase, forming chemical bonds with it. The enzyme is then unable to perform its functions and is metabolized, and instead the body synthesizes a new one, which usually takes about two weeks.

Reversible MAOIs bind to the active site of the enzyme and form a relatively stable complex with it. This complex gradually dissociates, releasing MAOI, which then enters the bloodstream and is excreted from the body, leaving the enzyme intact.

Non-selective irreversible MAOIs

• Iproniazid
• Nialamide
• Isocarboxazid
• Phenelzine
• Tranylcypromine

Strictly speaking, it is not entirely correct to attribute tranylcypromine to this group, since it is a reversible inhibitor, however, it may take up to 30 days for the dissociation of its complex with the enzyme and its complete elimination from the body. In addition, it exhibits some selectivity towards MAO-A.

Currently, non-selective MAO inhibitors are rarely used. This is due to their high toxicity. Unlike most other non-selective MAOIs, iproniazid is not used at all, which is now universally discontinued due to high hepatotoxicity; in many countries, isocarboxazid has also been discontinued for the same reason.

Isoniazid, an anti-tuberculosis drug, historically the first MAOI, also has clinically significant activity: it was the euphoric effect of isoniazid observed in tuberculosis patients that led to the discovery of monoamine oxidase inhibitors. Due to its significant hepatotoxicity and potential to cause pyridoxine-deficient polyneuropathies, isoniazid has ceased to be used as an MAOI, except for its use off-label at high doses in combination with high doses of vitamin B6 in countries where other hydrazine MAOIs are not available.

Reversible selective MAO-A inhibitors

• Moclobemide
• Pirlindol (pyrazidol)
• befol
• Metralindol
• Garmalin
• Derivatives of beta-carbolines

Irreversible selective MAO-B inhibitors

• Selegiline
• Rasagiline
• Pargylin

The division into MAOI-A and MAOI-B is partly arbitrary, since at high doses MAOI-Bs lose their selectivity and begin to block MAO-A as well, and MAOI-A at high doses (exceeding the maximum doses recommended in the instructions) also significantly block MAO-B . The division into irreversible and reversible MAOs is also to some extent arbitrary: only hydrazine derivatives - nialamide, phenelzine, isocarboxazid, iproniazid - are completely irreversible MAOIs. Tranylcypromine and selegiline are partly reversible: after stopping their intake, monoamine oxidase is restored not after 2 weeks, as after stopping the intake of hydrazine MAOIs, but after 5-7 days.

Selegiline and rasagiline are officially registered in Russia only for the treatment of Parkinson's disease. The antidepressant effect of selegiline in monotherapy is observed only at high doses, when it loses its selective effect. However, as potentiators, selegiline and rasagiline can be used in selective MAO-B dosages, in which they act as dopaminergic agents.

Tranylcypromine and selegiline are metabolized to amphetamine to a small extent in the body, which is partly due to their strong stimulant activity.

Therapeutic action

MAOIs, blocking the destruction of monoamines by monoamine oxidase, increase the content of one or more mediator monoamines (norepinephrine, serotonin, dopamine, phenylethylamine, etc.) in the synaptic cleft and enhance monoaminergic (monoamine-mediated) transmission of nerve impulses (neurotransmission). For this reason, for medical purposes, these substances are used mainly as antidepressants. MAOI-Bs are also used in the treatment of parkinsonism and narcolepsy.

Side effects

Non-selective inhibitors

The main undesirable effect is orthostatic hypotension, which occurs in almost all patients taking these drugs, while a hypertensive reaction as a result of the interaction of MAO inhibitors with products or drugs that can provoke a hypertensive crisis is rare.

Non-selective MAO inhibitors have a large number of side effects. These include dizziness, headache, urinary retention, constipation, fatigue, dry mouth, blurred vision, skin rashes, anorexia, paresthesia, swelling of the legs, convulsive epileptiform seizures, hepatitis. In addition, due to a pronounced psychostimulant effect, these drugs can cause euphoria, insomnia, tremors, hypomanic agitation; due to the accumulation of dopamine - delirium, hallucinations and other mental disorders. Perhaps the development of Korsakov's syndrome. The use of non-selective MAO inhibitors often leads to sexual side effects, such as decreased libido, erectile dysfunction, delayed or absent orgasm, delayed or absent ejaculation.

Like other antidepressants, MAOIs can induce a manic episode in predisposed patients. MAOIs are more likely to cause manic episodes than some other antidepressants, and for this reason they are not the drugs of choice for the treatment of depressive episodes with a previous manic episode.

Iproniazid has a pronounced hepatotoxic effect, which predetermines its unsuitability for widespread use in psychiatry. Phenelzine is less liver toxic than iproniazid, but hypotension and sleep disturbances are common side effects, and isocarboxazid can be used in cases where patients respond well to phenelzine treatment but suffer from these side effects.

Tranylcypromine differs from other MAOIs in its combination of MAO inhibition and amphetamine-like stimulant action; this drug is partially metabolized to amphetamine. Some patients become dependent on the stimulant effect of tranylcypromine. Compared with phenelzine, it can more often provoke hypertensive crises, but less affects the liver. For these reasons, tranylcypromine should be administered with great caution.

Selective inhibitors

They are used more widely, as they give significantly fewer side effects. Possible side effects include mild dry mouth, urinary retention, tachycardia, dyspepsia; in rare cases, dizziness, headache, anxiety, restlessness, hand tremors are possible. Skin allergic reactions may also occur.

Interactions

The combination of monoamine oxidase inhibitors with substances that affect the metabolism of monoamines can lead to an unpredictable increase in their action and be life-threatening.

Foods incompatible with MAOIs

Significant danger in the use of MAOIs, especially non-selective irreversible MAOIs, represents the consumption of foods containing various monoamines and their metabolic precursors. First of all, it is tyramine and its metabolic precursor amino acid tyrosine, as well as tryptophan. Tyramine, like amphetamine psychostimulants, causes the release of catecholamines from nerve endings. Its joint intake with MAOIs is fraught with a hypertensive crisis (see tyramine syndrome).

Tryptophan is used by the body to produce serotonin, and eating foods high in tryptophan can lead to serotonin syndrome.

Foods to avoid:

• All cheeses, except for fresh homemade cheese (cottage cheese), especially spicy and aged; milk, cream, sour cream, kefir
• Ice cream with syrup
• Red wine, beer containing yeast (unrefined), ale, liqueurs, whiskey
• Smoked meats, salami, chicken and beef liver, chicken pate, meat broths, marinades, any stale meat products, fried poultry and fried game
• Caviar, smoked fish, herring (dried or salted), dried fish, shrimp pate, marinated fish (fresh fish is relatively safe)
• Yeast extracts and brewer's yeast (regular baker's yeast is safe)
• Protein Supplements
• Legumes (beans, lentils, beans, soy), soy juice
• Sauerkraut
• Overripe fruits, canned figs, bananas, avocados, raisins
• Spices
• All types of cookies

Products to be treated with caution:

• White wine, port
• Strong alcoholic drinks (danger of depression of the respiratory center)
• Certain fruits such as figs, prunes, raspberries, pineapple, coconut
• Dairy products (curdled milk, yogurt, etc.)
• Chocolate
• Soy sauce
• Peanut
• Caffeine, theobromine, theophylline (coffee, tea, mate, coca-cola)
• Spinach

Irreversible, non-selective MAOIs require that these products and the drugs and narcotics listed below be avoided while taking them and for two weeks after the end of the use. In the case of reversible MAOIs, dietary restrictions are usually less severe and apply to the time that the substance remains in the body (no more than a day). The use of drugs and surfactants listed in the list together with reversible MAOIs should also be abstained until they are completely eliminated.

Interaction with drugs and drugs

To prevent tyramine syndrome and serotonin syndrome, the following agents should be avoided during MAOI therapy:

• Psychostimulants of the amphetamine group and related to them - increasing the levels of catecholamines in the synaptic cleft (amphetamine, methamphetamine, sydnocarb, etc.)
• Any empathogens (entactogens)
• Cold remedies containing sympathomimetics (ephedrine, pseudoephedrine, phenylpropanolamine, phenylephrine, chlorpheniramine, oxymetazoline, etc.): coldrex, teraflu, rinza, etc., nasal sprays and drops (naphthyzine, etc.)
• Means for weight loss
• Oral hypoglycemic agents
• Monoamine reuptake inhibitors:
  • Cocaine
  • Cyclic antidepressants, including clomipramine, imipramine
  • Selective serotonin reuptake inhibitors (SSRIs), eg paroxetine, citalopram, fluoxetine
  • Venlafaxine
  • Trazodone, nefazodone
• Herbal antidepressants containing St. John's wort
• 5-hydroxytryptophan, tryptophan
• Lithium preparations
• Dextromethorphan (DXM)
• Metabolic precursors of monoamines: levodopa, methyldopa, 5-hydroxytryptophan
• Antihypertensive drugs (guanethidine, reserpine, pargyline)
• Adrenaline and local anesthetics containing epinephrine (lidocaine and novocaine are harmless)
• Anti-asthma drugs
• Diuretics
• Beta blockers
• Antihistamines
• Barbiturates
• Anticholinergic drugs
• Narcotic analgesics.
• Alcohol.

After discontinuation of fluoxetine before the appointment of an irreversible MAOI, it is necessary to maintain a gap of at least five weeks to prevent serotonin syndrome. In elderly patients, this interval should be at least eight weeks. After the withdrawal of short-acting SSRIs, there should be a break of at least two weeks before the appointment of MAOIs.

When transferring from irreversible MAOIs to SSRIs, a break of four weeks should be maintained; when transferring from moclobemide to SSRIs, 24 hours is sufficient.

The likelihood of developing serotonin syndrome in the interaction of SSRIs with selegiline or moclobemide is significantly lower compared to the risk of its occurrence when SSRIs are combined with non-selective irreversible MAOIs, but such an interaction is still possible. Serotonin syndrome was also noted in monotherapy with moclobemide.

Irreversible MAOIs should not be combined with antihypertensive drugs due to the risk of severe orthostatic hypotension, or the dose of the antihypertensive drug should be reduced.

MAOIs enhance the effects of alcohol, sedatives, anxiolytics, and painkillers, sometimes pushing these drugs beyond the safety limit.

MAOIs can complicate procedures involving anesthesia or analgesia, as they interact with narcotic substances, causing a syndrome manifested by agitation, fever, headaches, convulsions, and coma with the possibility of death. They can cause respiratory depression. Fatal outcomes have been reported with the use of meperidine. Patients who are to undergo surgery should reduce the dose of MAO inhibitors in advance in order to exclude unwanted reactions to medications.

Patients with diabetes who take insulin may experience a more dramatic drop in blood sugar levels. In this case, the dose of insulin can be reduced.

Application restrictions

The presence of irreversible MAOIs of a hypotensive effect and the ability to provoke orthostatic hypotension makes it difficult to use them in patients with initial hypotension and a tendency to fainting, in elderly patients with severe cerebral atherosclerosis, with severe arterial hypertension, when a sharp decrease in blood pressure is dangerous.

Precautionary measures

With a sudden change in body position, a feeling of instability may occur. This can be avoided by rising slowly from a horizontal position. If the tablets are taken with meals, this and other side effects are much less pronounced.

Care should be taken when servicing machinery and when operating a machine, since many patients in the initial period of treatment with MAOIs are prone to increased drowsiness.

Non-medical use

There are a number of reports of abuse of MAO inhibitors. The mechanism of abuse may be due to the similarity of the chemical structure of MAOIs to that of amphetamine; however, the mechanism of action of MAOIs and amphetamines differ significantly. MAOI abusers may be particularly prone to developing hypertensive crises because they use high doses of MAOIs and/or may not be aware of the recommended diet.

Interactions with phenethylamine and tryptamine psychedelics

Most tryptamines are good substrates for MAO-A. DMT and 5-MeO-DMT, when taken orally, are metabolized by it already in the gastrointestinal tract and liver, without having time to get into the blood, so they are inactive when taken orally. 4-hydroxy-DMT (psilocin) is less susceptible to degradation by MAO, since its hydroxyl group in the 4-position makes it difficult for it to bind to the active site of the enzyme, so that it is orally active. Alkyl substituents on the amino group, which are bulkier than methyl (ethyl, propyl, cyclopropyl, isopropyl, allyl, etc.), also make it difficult for tryptamines with such substituents to be metabolized by MAO, so all such tryptamines are active when taken orally. Alpha-methyl in tryptamine molecules like AMT and 5-MeO-AMT significantly impedes their metabolism by MAO and turns them de facto from substrates into weak inhibitors of this enzyme.

Inhibition of peripheral MAO-A in the gastrointestinal tract and liver by strong MAOIs makes tryptamines such as DMT and 5-MeO-DMT orally active as well as enhancing and prolonging the action of other tryptamines such as psilocin and DET. On the other hand, long-term use of MAOIs as antidepressants significantly weakens the effects of psychedelics. This is apparently due to changes in the monoaminergic systems of the brain caused by increased levels of monoamines. The nature of this phenomenon is currently unclear and is not explained by a simple desensitization of the serotonin receptors with which psychedelics interact.

Thus, the use of MAOIs with tryptamines or immediately before the use of tryptamines prolongs and in some cases enhances the effect of the latter, and in addition, makes it possible to use oral tryptamines such as DMT. This is the basis of the principle of action of ayahuasca and similar mixtures, including the so-called pharmacoasca, in which pure DMT is used instead of plant components, and traditional Banisteriopsis Caapi, and Peganum Harmala seeds, or their extracts, or even moclobemide (Aurorix). However, taking an irreversible MAOI a few days before taking a psychedelic will weaken its effect. The same will happen with long-term use of both irreversible and reversible MAOIs before a psychedelic is taken.

It is not safe to use 5-MeO-DMT with MAOIs. Many note the strong and unpleasant side effects of this combination, up to serotonin syndrome. In addition, this experience is psychologically extremely difficult for many people and can be associated with serious mental health risks.

Tryptamines, which significantly increase levels of monoamines in the synaptic cleft (AMT, 5-MeO-AMT, AET, etc.), can be deadly when combined with MAOIs. There is some concern about the safety of using MAOIs with tryptamines such as DPT.

The metabolism of LSD is currently not well understood, but MAO does not seem to play any role in it. However, according to some authors, when used in conjunction with harmala, its effects are enhanced and prolonged. The same applies to other ergolines.

MAO plays a minor role or even practically does not participate in the metabolism of phenylethylamine psychedelics. Therefore, taking MAOIs together with them is devoid of practical meaning. Although, according to some users, both harmala and moclobemide increase the effect of some PEAs, such as 2C-B.

In most cases, the use of MAOIs with phenylethylamine psychedelics does not pose a serious health hazard. However, the use of MAOIs with sulfur-containing phenethylamines such as 2C-T-7 and Aleph-7 should be avoided due to their controversial and little-studied effects on brain monoamine levels and high toxicity. Combinations of MAOIs with TMA-6 and TMA-2 may also be unsafe.

Overdose

MAOI antidepressants are extremely toxic in overdose, and the symptoms of intoxication do not necessarily appear immediately. In acute poisoning with large doses of MAOIs, general weakness, dizziness, ataxia, blurred speech, clonic muscle twitching are observed; this is followed by coma or convulsive seizures (such as generalized epileptiform seizures) followed by coma. After coming out of a coma, the state of stun may persist for some time. In some cases, coma does not occur, while the initial symptoms of an overdose are replaced by a delirious syndrome. Impaired consciousness with an overdose of MAOIs is not always observed; in those cases when they are absent, the depression that caused the appointment of MAOIs is very quickly, paroxysmal, replaced by euphoria.

Overdose manifestations can also be anxiety, confusion, hypertensive crisis, cardiac arrhythmias, rhabdomyolysis, coagulopathy.

Due to the high toxicity of MAOIs in patients with suicidal tendencies, they should be prescribed in quantities sufficient for only a few days of admission.

IMAO classification

According to their pharmacological properties, monoamine oxidase inhibitors are divided into reversible and irreversible, selective and non-selective.

Selective MAOIs inhibit mainly one of the MAO types, non-selective MAOIs inhibit both types.

Irreversible MAOIs interact with monoamine oxidase, forming chemical bonds with it. The enzyme is then unable to perform its functions and is metabolized, and instead the body synthesizes a new one, which usually takes about two weeks.

Reversible MAOIs bind to the active site of the enzyme and form a relatively stable complex with it. This complex gradually dissociates, releasing the MAOI, which then enters the bloodstream and is excreted from the body, leaving the enzyme intact.

Non-selective irreversible MAOIs

Strictly speaking, it is not entirely correct to attribute tranylcypramine to this group, since it is a reversible inhibitor, however, it may take up to 30 days for the dissociation of its complex with the enzyme and its complete elimination from the body. In addition, it exhibits some selectivity towards MAO-A.

Reversible selective MAO inhibitors A

• Derivatives of beta-carbolines

When taking reversible MAOIs, it is not necessary to follow a diet.

Irreversible selective MAO B inhibitors

Pharmacology IMAO

General information

MAOIs, blocking the destruction of monoamines by monoamine oxidase, increase the content of one or more mediator monoamines (norepinephrine, serotonin, dopamine, phenylethylamine, etc.) in the synaptic cleft and enhance monoaminergic (monoamine-mediated) transmission of nerve impulses (neurotransmission). For this reason, for medical purposes, these substances are used mainly as antidepressants. MAOI-Bs are also used in the treatment of parkinsonism and narcolepsy.

Interaction with drugs and some surfactants

The combination of monoamine oxidase inhibitors with substances that affect the metabolism of monoamines can lead to an unpredictable increase in their action and be life-threatening.

List of drugs to avoid:

Foods incompatible with MAOIs

A significant hazard when using MAOIs is the consumption of foods containing various monoamines and their metabolic precursors. First of all, it is tyramine and its metabolic precursor amino acid tyrosine, as well as tryptophan. Tyramine, like amphetamine psychostimulants, causes the release of catecholamines from nerve endings. Its joint intake with MAOIs is fraught with a hypertensive crisis. Tryptophan is used by the body to produce serotonin, and eating foods high in tryptophan can lead to serotonin syndrome.

Foods to avoid:

• Cheeses, especially aged
• Red wine, beer, especially dark (including non-alcoholic), ale, liqueurs, whiskey.
• Smoked products, sausages and any products from stale meat
• Marinated, smoked and dried fish (fresh fish is relatively safe)
• Yeast extracts and brewer's yeast (regular baker's yeast is safe)
• Protein Supplements
• Legumes (beans, lentils, beans, soybeans)

Products to be treated with caution:

• Strong alcoholic drinks (danger of depression of the respiratory center)
• Some fruits, such as bananas, avocados, figs, raisins, prunes, raspberries, pineapples, coconut
• Dairy products (sour milk, kefir, yogurt, sour cream)
• Caffeine, theobromine, theophylline (coffee, tea, mate, coca-cola)

Irreversible non-selective MAOIs require avoidance of the aforementioned substances and products during their use and for two weeks after the end of use. In the case of reversible MAOIs, dietary restrictions are usually less severe and apply to the time that the substance remains in the body (no more than a day). The use of drugs and surfactants listed in the list together with reversible MAOIs should also be avoided until they are completely eliminated.

Interactions with phenethylamine and tryptamine psychedelics

Most tryptamines are good substrates for MAO-A. DMT and 5-MeO-DMT, when taken orally, are metabolized by it already in the gastrointestinal tract and liver, without having time to get into the blood, so they are inactive when taken orally. 4-hydroxy-DMT (psilocin) is less susceptible to degradation by MAO, since its hydroxyl group in the 4th position makes it difficult for it to bind to the active site of the enzyme, as a result of which it is orally active. Alkyl substituents on the amino group that are bulkier than methyl (ethyl, propyl, cyclopropyl, isopropyl, allyl, etc.) also make it difficult for tryptamines with such substituents to be metabolized by MAO, so all such tryptamines are active when taken orally. The alpha-methyl in tryptamine molecules such as AMT and 5-MeO-AMT significantly impairs their metabolism by MAO, and turns them, de facto, from substrates into weak inhibitors of this enzyme.

Inhibition of peripheral MAO-A in the gastrointestinal tract and liver by strong MAOIs makes tryptamines such as DMT and 5-MeO-DMT orally active, as well as enhancing and prolonging the action of other tryptamines such as psilocin and DET. On the other hand, long-term use of MAOIs as antidepressants significantly weakens the effects of psychedelics. This is apparently due to changes in the monoaminergic systems of the brain caused by increased levels of monoamines. The nature of this phenomenon is currently unclear, and is not explained by a simple desensitization of the serotonin receptors with which psychedelics interact.

Thus, taking MAOIs with tryptamines or immediately prior to ingestion of tryptamines prolongs, and in some cases enhances, the effects of tryptamines, and also allows the use of oral tryptamines such as DMT. This is the basis for the action of ayahuasca, and similar mixtures, including the so-called pharmahoasca, in which pure DMT is used instead of plant components, and both traditional Banisteriopsis Caapi and Peganum Harmala seeds, or their extracts, can be used as MAOIs, or even moclobemide (Aurorix). At the same time, taking irreversible MAOIs a few days before taking a psychedelic will weaken its effect. The same will happen with long-term use of both irreversible and reversible MAOIs before a psychedelic is taken.

It is not safe to use 5-MeO-DMT with MAOIs. Many note the strong and unpleasant side effects of this combination, up to serotonin syndrome. In addition, such an experience for many people is psychologically extremely difficult, and can be a serious danger to mental health.

Tryptamines that significantly increase synaptic monoamine levels, such as AMT, 5-MeO-AMT, and AET, can be deadly when combined with MAOIs. There is some concern about the safety of using MAOIs with tryptamines such as DPT.

The metabolism of LSD is currently not well understood, but MAO does not seem to play any role in it. However, according to some participants, when used in conjunction with harmala, its effects are enhanced and prolonged. The same applies to other ergolines.

MAO plays a minor role, or even practically does not participate in the metabolism of phenylethylamine psychedelics. Therefore, taking MAOIs together with them is devoid of practical meaning. Although, according to some users, both harmala and moclobemide enhance the effect of some PEAs, such as 2C-B. In most cases, the use of MAOIs with phenylethylamine psychedelics does not pose a serious health hazard. However, the use of MAOIs with sulfur containing phenethylamines such as 2C-T-7 and Aleph-7 should be avoided due to their controversial and little-studied effects on brain monoamine levels and high toxicity. Combinations of MAOIs with TMA-6 and TMA-2 may also be unsafe.

Other MAOIs

Amphetamines and alpha-methyltryptamines

Nicotiana Rustica

Notes

Links

see also

Antidepressants ( N06A)
Non-selective monoamine reuptake inhibitors	Desipramine * Imipramine Clomipramine Opipramol * Trimipramine * Lofepramine * Dibenzepine * Amitriptyline Nortriptyline * Protriptyline Doxepin * Iprindole Melitracene Butriptyline * Dosuleptine Amoxapine Dimethacrine Amineptine Maprotiline Quinupramine
selective serotonin reuptake inhibitors	Zimeldine Fluoxetine Citalopram Paroxetine Sertraline Alaproclate Fluvoxamine Ethoperidone Escitalopram Trazodone
Non-selective monoamine oxidase inhibitors	Isocarboxazid Nialamide Phenelzine Tranylcypromine Iproniazid * Iprocloside
Monoamine oxidase type A inhibitors	Moclobemide Toloxatone Pyrazidol
Other antidepressants	Oxytriptan Tryptophan Mianserin

This group of short-acting drugs is divided into two groups:

1. selective, blocking MAO type A;
2. non-selective, blocking MAO type A and type B.

Group 2 - non-selective

Indopan (alphamethyltryptamine). A domestic drug that is similar in pharmacological actions to tryptamine and phenamine.
In addition to short-term reversible inhibition of MAO, it has a stimulating effect on the central and peripheral adrenoreactive systems. Therefore, it is sometimes referred to as psychostimulants.

It has a less stimulating effect than others (such as nu-redal), also has a thymoanaleptic effect. Target Syndromes:

1. astheno-depressive;
2. astheno-hypochondriac;
3. astheno-anergic;
4. apato-abulic;
5. different in genesis of depression with lethargy.

Assign in the first half of the day from 5-10 mg / day to 60 mg / day. Duration - several months.
Well tolerated. In case of overdose - agitation, hypomania, insomnia, exacerbation of productive symptoms, hypertensive phenomena and allergic reactions.
The rest is compliance with the rules for prescribing all MAO inhibitors.

Inkazan (Metralindol). Original domestic drug. Tetracycline derivative of carboline.
The effect is associated with pyrazidol: it inhibits the reuptake of serotonin and norepinephrine, reversibly undifferentiated blocks MAO, does not have an anticholinergic effect.
It has a thymoanaleptic and stimulating effect. Inferior to pyrazidol, but has a vegetative-stabilizing effect.
"Small antidepressant".
Indications:

1. asthenic anergic depression on an outpatient basis;
2. asthenodepressive conditions in patients with alcoholism in remission. First, there is a stimulating effect.

Dosage from 25-30 mg / day to 400 mg / day.
Well tolerated. Sometimes causes dyspepsia, fluctuations in blood pressure, bradycardia. Contraindications:

1. acute alcohol withdrawal;
2. together with other MAO inhibitors.

Caroxazone (thymostenil, surodil). Bicyclic derivative of benzoxaline.
"Small antidepressant" balanced action.
Indications:

1. cyclothymia with asthenovegetative symptoms;
2. chronic neuroleptic parkinsonism;
3. prolonged neuroleptic depression. TU2 = 24 hours, dosage 400-1200 mg / day. Well tolerated.

In case of overdose - dyspepsia, fluctuations in blood pressure, sleep disturbances.

Group 1 - electoral

pyrazidol. It blocks the reuptake of norepinephrine and serotonin and reversibly blocks MAO type A. It does not have an anticholinergic effect, but enhances the effects of sympathomimetic amines.

It has a thymoanaleptic effect (weaker than melipramine and amitriptyline), but is a balanced antidepressant, that is, with inhibited depression it has a stimulating effect, and with anxiety it has a sedative effect.
Indications:

1. depression of various origins, including alcoholic depression;
2. somatized depression, as it has a pronounced vegetative-stabilizing effect.

It goes well with neuroleptics in the treatment of apatoabulic syndrome, combined with tranquilizers.
Dosage: 50-100 mg/day - 400-500 mg/day.
Therapeutic improvement - by the 7-14th day. Well tolerated, can be used in debilitated patients, children, the elderly.
Side effects: dry mouth, hand tremor, tachycardia, dizziness.
Contraindications:

1. acute diseases of the liver, kidneys;
2. blood diseases;
3. other MAO inhibitors;
4. sympathomimetic amines (adrenaline, mezaton);
5. acute alcohol withdrawal.

Tetrindol. New original drug.
Tetracyclic blood pressure, close in all respects to pyrazidol. Does not give side effects of MAO, has no anticholinergic properties. Exceeds pyrazidol by the strength of the stimulating effect. Indications:

1. mild depression with lethargy, apatoaboulia, asthenia;
2. dysthymia;
3. cyclothymia;
4. hypochondriacal and obsessive-phobic phenomena;
5. somatized depression;
6. asthenodepressive syndrome in alcoholism. Dosage: 25-50 mg/day - 400 mg/day.

Stimulating effect - by the end of the 1st week, thymoanaleptic - at the 2-4th week. Well tolerated.
In case of overdose - dyspeptic disorders, insomnia, agitation. Contraindications are the same as for pyrazidol.

Moclobemide (Aurorix, Monerix). Monocyclic benzamide.
Selective reversible MAO blocker, has no anticholinergic, hypotensive and cardiotoxic properties.
Pharmacokinetics: rapidly absorbed in the gastrointestinal tract, bioavailability up to 85%. 50% binds to blood proteins. V/ = 1-2 hours, safe.
"Small antidepressant".
Indications:

1. "atypical" depression with obsessive-phobic, hypochondriacal symptoms;
2. somatized depression;
3. panic disorder;
4. hyperactive syndrome in children. Dosage up to 300-600 mg / day.

Side effects are rare, contraindications - like all ADs.

befol. Original domestic drug. Benzamide derivative.
A reversible type A MAO blocker with a selective effect on serotonin deamination, that is, serotonergic blood pressure.
It does not have anticholinergic, antihistamine properties.
Pharmacokinetics: rapidly absorbed in the gastrointestinal tract, T1 / 2 = 3-5 hours. Peak concentration 1 hour after ingestion.
"Small antidepressant". Indications:

1. somatogenic depression;
2. cyclothymia;
3. adynamic depression;
4. somatovegetative depression;
5. anergic depression.

The therapeutic effect - on the 5-6th day. Dosage - 100-500 mg / day. Rarely and few side effects, therefore, it is indicated for children, the elderly. In case of overdose - dyspeptic disorders, tremor, palpitations.

Brofaromin. Bicyclic derivative of piperidine.
Selective reversible MAO inhibitor, serotonin reuptake blocker.
Efficiency approaches classical MAO inhibitors.
Indications:

1. endogenous depression resistant to treatment with tricyclic AD;
2. panic reaction;
3. phobias.

Therapeutic dose - 75-250 mg / day. Well tolerated. Side effects:

1. sleep disorders;
2. hypotension;
3. enhances the action of sympathomimetics.

Toloxatone (humor, humor, renum). Monocyclic derivative of oxazolidinone. Similar in effects to moclobemide. Indications: shallow depression with lethargy. Therapeutic doses - 600-1000 mg / day. T "/2 = 0.5-2.5 hours, safe. It is prescribed 4-6 times a day.
In case of overdose - dyspeptic symptoms, hyperstimulation, exacerbation of productive symptoms, inversion of sleep phases, hypotension, hepatitis.
Contraindications:

1. diseases of the liver and kidneys;
2. the use of irreversible MAO.

Monoamine oxidase inhibitors (MAOIs) are chemicals that inhibit the activity of monoamine oxidase enzymes. They have long been used as drugs to treat depression. These substances are particularly effective in the treatment of atypical depression. These drugs are also used to treat Parkinson's disease and some other conditions. Due to potentially dangerous dietary and drug interactions, monoamine oxidase inhibitors have historically been used as a last resort, and were used only when other antidepressants (eg, selective serotonin reuptake inhibitors and tricyclic antidepressants) have failed. A new MAO study shows that much of the concern about dangerous dietary side effects is due to misconceptions and misinformation, and that despite the proven effectiveness of drugs in this class, they are underused in medicine. The new study also casts doubt on the validity of the perceived severity of food reactions, based on data from outdated studies.

Indications

In the past, MAO inhibitors were prescribed to patients resistant to the effects of tricyclic antidepressants. Newer MAO inhibitors such as selegiline (typically used to treat Parkinson's disease) and the reversible MAO inhibitor moclobemide are safer alternatives to these drugs and are now sometimes used as first-line treatment. However, these substances do not always act as effectively as their predecessors. MAOIs have been found effective in the treatment of panic disorder with agoraphobia, social phobia, atypical depression or mixed anxiety and depression, bulimia and post-traumatic stress disorder, and borderline personality disorder. There is evidence of the effectiveness of MAOIs in the treatment of obsessive-compulsive disorder (OCD), trichotillomania, body dysmorphic disorder, and avoidant personality disorder, however, these data are obtained from uncontrolled clinical sources. MAOIs can also be used in the treatment of Parkinson's disease, acting in particular on MAO-B (thus acting on dopaminergic neurons) and also providing an alternative for migraine prevention. Inhibition of MAO-A and MAO-B is used to treat depression and anxiety. MAO inhibitors are especially commonly prescribed for outpatients with "neurotic depression" complicated by panic disorder or hysteroid dysphoria, which includes repeated episodes of depressed mood in response to feelings of rejection.

Mechanism of action

MAOIs act by inhibiting monoamine oxidase activity, preventing the breakdown of monoamine neurotransmitters, thereby increasing their availability. There are two isoforms of monoamine oxidase, MAO-A and MAO-B. MAO-A predominantly deaminates serotonin, melatonin, epinephrine and norepinephrine. MAO-B preferentially deaminates phenylethylamine and residual amines. Dopamine is equally deaminated by both types of isoforms.

reversibility

First-generation MAOIs irreversibly inhibit monoamine oxidase. In reaction with monoamine oxidase, they permanently deactivate it, and the enzyme cannot function until it is replaced in the body with a new one, which can take about two weeks. Some of the newer MAOIs, most notably moclobemide, are reversible, meaning they can be separated from the enzyme to facilitate normal substrate catabolism. The level of inhibition is thus regulated by the concentration of the substrate and the MAOI. Harmaline, found in the plants harmala vulgaris, ayahuasca, spirit vine, and meat red stratoflower, is a reversible MAO-A inhibitor (RIMA).

Selectivity

In addition to reversibility, MAO inhibitors differ in their MAO receptor selectivity. Some MAO inhibitors can equally inhibit MAO-A and MAO-B, while other MAO inhibitors have been developed for specific purposes. Inhibition of MAO-A reduces the breakdown primarily of serotonin, norepinephrine and dopamine; selective inhibition of MAO-A allows it to be metabolized through MAO-B. Taking drugs that act on serotonin when taken with another drug that increases serotonin levels can lead to a potentially fatal interaction called serotonin syndrome. When taking MAOIs with irreversible and non-selective inhibitors (for example, the older generation of MAOIs), as a result of interaction with tyramine in the diet, it is possible to provoke the development of a hypertensive crisis. Tyramine is degraded by MAO-A and MAO-B, therefore inhibition of this action can lead to its excessive accumulation, so the patient should carefully monitor the intake of tyramine. Inhibition of MAO-B reduces the breakdown of mainly dopamine and phenylethylamine, so there are no associated dietary restrictions. MAO-B will also metabolize since the only differences between dopamine, phenylethylamine and tyramine are the two phenylhydroxyl groups on carbons 3 and 4. 4-OH does not sterically hinder MAO-B on tyramine. Two MAO-B drugs, selegiline and rasagiline, have been approved by the FDA without dietary restrictions except for high dose treatment, in which case they lose their selectivity.

dangers

When administered orally, MAO inhibitors inhibit the catabolism of dietary amines. When eating foods containing tyramine (the so-called "cheese effect"), a person may experience a hypertensive crisis. When consuming foods containing tryptophan, hyperserotonemia may develop. The amount of substance required to develop a reaction varies greatly from person to person and depends on the degree of inhibition, which in turn depends on dose and selectivity. The exact mechanism by which tyramine induces a hypertensive response is not well understood, but it is hypothesized that tyramine displaces norepinephrine from the vesicles in which it is stored. This can cause a cascade of effects in which excessive amounts of norepinephrine can lead to the development of a hypertensive crisis. Another theory suggests that a hypertensive crisis causes the distribution and accumulation of catecholamines. It is tyrosine, not tyramine, that is the precursor of catecholamines. Tyramine is a breakdown product. In the intestines and during fermentation, the amino acid tyrosine is decarboxylated to tyramine. Under normal circumstances, tyramine is deaminated in the liver to inactive metabolites, but when hepatic MAO (predominantly MAO-A) is suppressed, the first pass of tyramine is blocked, which can lead to an increase in circulating levels of tyramine. Tyramine competes in increased amounts for transport across the blood-brain barrier (via aromatic amino acids), where it can enter adrenergic nerve endings. After entering the cytoplasmic space, tyramine is transported by the vesicular monoamine transporter to synaptic vesicles, thereby displacing norepinephrine. The massive movement of norepinephrine from its vesicular storage into the intercellular space can accelerate the development of a hypertensive crisis. Hypertensive crises, if left untreated, can cause stroke or cardiac arrhythmias. Both types of intestinal MAO inhibition can lead to the development of hyperthermia, nausea and psychosis, with the consumption of substances with a high content. Foods and drinks with potentially high levels of tyramine include: liver and fermented substances such as alcoholic beverages and aged cheeses. found in foods such as beans. These dietary restrictions are not necessary for individuals taking selective MAO-B inhibitors at normal or low doses. Of special note is the fact that some meat extracts and yeast extracts (Bovril, Marmite, Vegemite) contain extremely high levels and should also not be consumed while taking such medications.

When MAOIs are first introduced to the market, these risks

nothing was known, and over the next four decades, less than 100 people died from a hypertensive crisis. Presumably due to the sudden onset and violent occurrence of the reaction, MAOIs gained a reputation for being such a dangerous substance that for some time they were completely discontinued in America. However, it is now believed that when using MAOIs under the supervision of a qualified psychiatrist, this class of drugs is a viable alternative, even for long-term use. The most significant risk associated with the use of MAO inhibitors is associated with the possibility of interactions with drugs, both available over the counter and prescription only, illicit drugs or medicines, and certain supplements (eg, St. John's wort). It is very important that the doctor supervise such combinations in order to avoid possible adverse reactions. For this reason, many users have an MAOI card that gives all emergency information about drugs that the patient should avoid (for example, the dose of adrenaline in this case should be reduced by 75%, and the duration of exposure should be increased). The risk of MAOI drugs interacting with other drugs or certain foods is especially dangerous because often patients taking such drugs are in the position that they "don't care if they live or not." MAO inhibitors should not be combined with other psychoactive substances (antidepressants, painkillers, stimulants and illegal substances), except in cases of expert assistance. Certain combinations may be fatal, including combinations with SSRIs, TCAs, MDMA, meperidine, tramadol, and dextromethorphan. Drugs that act on epinephrine, norepinephrine, or dopamine should be administered at much lower doses due to the potentiation and long-term effect. Nicotine, a commonly addictive substance, has a "relatively weak" addictive potential when used alone. With the simultaneous administration of MAOIs, the potential for addiction increases dramatically, which leads to an allergenic musculoskeletal response in rats, which is a measure of the potential of a substance to develop addiction. This can be expressed in the difficulty of quitting smoking, since in addition to nicotine, tobacco contains natural compounds.

Conclusion

Antidepressants, including MAOIs, have addictive properties, the most notable result of which is withdrawal symptoms, which can be severe, especially when MAOIs are stopped suddenly or too quickly. However, the dependence potential of MAO inhibitors or antidepressants in general is not as significant as that of benzodiazepines. To minimize or prevent withdrawal symptoms, you can gradually reduce the dose over several weeks, months or years. MAO inhibitors, like any other antidepressants, cannot change the course of the disease, so it is possible that if the patient stops taking it, he can return to the state that he had before starting treatment. This circumstance significantly complicates the patient's switch from MAOIs to SSRIs, since after taking one drug and before starting to take another, a complete cleansing of the body system is necessary. By gradually tapering the dose, the patient will find himself struggling with depression for several weeks without pharmacological support during the drug-free interval. This may be preferable to the risk of developing interaction effects between the two drugs, but often such a test is not given to the patient so easily.

Interactions

MAO inhibitors are known for numerous drug interactions, including with the following types of substances: 1. Substances that are metabolized by monoamine oxidase, since they can increase their effect several times. 2. Substances that increase the activity of serotonin, norepinephrine, or dopamine, since an excess of any of these neurochemicals can lead to serious acute consequences, including the development of serotonin syndrome, hypertensive crisis and psychosis, respectively. Such substances include: - Phenethylamines: 2C-B, mescaline, phenethylamines, etc. - Amphetamines: amphetamine, MDMA, dextroamphetamine, methamphetamine, DOM, etc. - Tryptamines: DMT, psilocin/psilocybin ("magic mushrooms"), etc. - Lysergamides: ergolines/LSA, LSD ("acid"), etc. - Serotonin, norepinephrine and/or dopamine reuptake inhibitors: - Serotonin reuptake inhibitors (SSRIs): citalopram, dapoxetine, escitalopram, fluvoxamine, paroxetine,. - Serotonin-norepinephrine reuptake inhibitors: dezvenlafaxine, duloxetine, milnacipran,. - Norepinephrine-dopamine reuptake inhibitors: amineptine, bupropion, methylphenidate, nomifensine. - Norepinephrine reuptake inhibitors: atomoxetine, mazindol, reboxetine. - Tricyclic antidepressants (TCAs): butriptyline, clomipramine, dosulepin, doxepin, imipramine, lofepramine, nortriptyline, protriptyline, trimipramine. - Tetracyclic antidepressants: amoxapine, maprotiline. - Phenylpiperidine opioid derivatives: meperidine/pethidine, tramadol, methadone, dextropropoxyphene, propoxyphene. - Others: brompheniramine, chlorpheniramine, cocaine, cyclobenzaprine, dextromethorphan (DXM), ketamine, MDPV, nefazodone, phencyclidine (PCP), pheniramine, sibutramine, trazodone. - Substances that release serotonin, norepinephrine and / or dopamine: 4-methitaminorex (4-MAR), amphetamine, benzphetamine, cathin, cathinone, diethylcathinone, levmethamphetamine, lisdexamphetamine, MDMA ("ecstasy"), methamphetamine, pemoline, phendimetrazine, phenethylamine ( PEA), phentermine, propylhexedrine, pseudoephedrine, phenylephrine, . - Serotonin, norepinephrine and/or dopamine precursors: 5-HTP, L-phenylalanine, L-tyrosine. - Anesthetics used in surgery and dentistry of local and general action, in particular, containing adrenaline. There is no universal practice in dentistry regarding the use of MAO inhibitors such as phenelzine, which is why it is important to inform all physicians, especially dentists, of the potential effect of MAO inhibitors in local anesthesia. In preparation for dental procedures, it is desirable to stop taking phenelzine, however, due to the fact that such a stop takes two weeks, this option is not always desirable or practical. Dentists using local anesthesia are advised to use a non-epinephrine based anesthetic such as 3% carbocaine. Particular attention during the procedure should be paid to blood pressure. The anesthetic level must be replenished regularly and correctly, as non-adrenaline-based anesthetics take longer to act and wear off more quickly. Patients taking phenelzine should notify their psychiatrists before starting any dental treatment. - Some other supplements: Hypericum perforatum (St. John's wort), inositol, Rhodiola rosea, S-adenosyl-L-methionine (SAME), . - Other monoamine oxidase inhibitors.

Story

The heyday of the popularity of the IMAO falls for the most part during the period from 1957 to 1970. The initial popularity of "classic" non-selective irreversible MAO inhibitors has waned due to the presence of dangerous interactions of these drugs with sympathomimetic drugs and products containing tyramine, which can lead to the development of a hypertensive crisis. As a result, physician use of the previous generation of MAOIs has declined. When scientists discovered that there were two different MAO enzymes (MAO-A and MAO-B), they developed selective compounds for MAO-B, such as selegiline, which is used to treat Parkinson's disease, to reduce side effects and serious drug interactions. . Further improvement has come with the development of compounds (moclobemide and toloxatone) that are not only selective but also cause reversible MAO-A inhibition and have a reduced rate of dietary and drug interactions. Irreversible MAO inhibitors are the first antidepressants discovered, but their popularity has declined with the emergence of safe antidepressants; this new class of antidepressants has fewer side effects, especially the dangerous irreversible interaction of MAOIs with food containing tyramine, sometimes called "cheese syndrome", leading to the development of severe hypertension. However, reversible MAO inhibitors do not have these adverse hypertensive effects. Moclobemide was the first reversible MAO-A inhibitor to be introduced into widespread clinical practice. Its features as a reversible inhibitor give it a number of advantages over the previous generation of irreversible MAOIs. On February 28, 2006, the US FDA approved a transdermal MAOI formulation of selegiline called Emsam for the treatment of depression.

List of MAOIs

Mentions in culture

In the episode "The Late Shaft" of the detective TV drama The Castle, Bobby Mann was taking MAO inhibitors. His killer used this fact to cause a negative interaction with the drug, which led to Bobby's death, which appeared to be a normal heart attack. In the Law & Order episode "Cut", a surgeon puts a patient on painkillers that interact with the MAO inhibitors she is taking, resulting in her death. The pilot episode "Law & Order" was based on a true story. Journalist Sidney Sione questioned the sudden death of his daughter Libby Sione in a Manhattan emergency room on October 4, 1984. The cause of death was listed as a "mysterious infection". The father persuaded the authorities to open a criminal case. This was done after it was discovered that his daughter had taken certain medications before her death, including Demerol, which reacted with Nardil, which the victim was taking. The district attorney brought a murder charge against a doctor who approved the use of special equipment and drugs on Libby. This case has led to many reforms in medical education and restrictions on the number of working hours for medical staff. As a result, it turned out that the main cause of death was drug abuse.

Monoamine oxidase inhibitors (MAO) are biological substances that, by reducing the rate of chemical reactions of the monoamine oxidase enzyme, prevent the destruction of various monoamines (this group includes serotonin, norepinephrine, dopamine, phenylethylamine, tryptamine and octamine). This enhances the concentration of the active element between two neurons or between a neuron and an effector molecule (a particle that binds to proteins to increase biological activity).

For medical purposes, MAOIs are used as antidepressants and sometimes to treat Parkinson's disease and narcolepsy attacks, a pathological condition of the nervous system that causes drowsiness and a sudden "attack" of sleep.

According to their pharmacological properties, MAOIs are divided into:

• non-selective irreversible;
• reversible selective;
• irreversible selective.

So, let's take a brief look at each group and learn about the active ingredients, properties and trade names.

Non-selective irreversible MAOIs - inhibit MAO-A and MAO-B

Table 1

№	Active substance	Short description	Tradename
1.	Iproniazid	It has a pronounced hepatotoxic effect. In this regard, it is used and appointed very rarely. Apply no more than 2 weeks.	"Iprazid"
2.	Nialamide	The chemical structure is similar to iproniazid, but has a more gentle toxic effect. Improves general condition and helps to recover from depression. The appearance of a therapeutic effect is observed after 1-2 weeks.	"Nialamid"
3.	Isocarboxazid	Activates some natural components in the brain to maintain mental balance.	"Marplan"
4.	Phenelzine	It is prescribed to reduce depression. Reduces anxiety and anxiety.	"Nardil"
5.	Tranylcypromine	It is recommended in the treatment of mental illnesses that develop against the background of depressive conditions. Has a stimulating effect. May be metabolized to amphetamine.	"Parnat"

Reversible selective MAO-A inhibitors

table 2

№	Active substance	Short description	Tradename
1.	Moclobemide	It is prescribed for depression, as well as social phobia. Blocks the destruction of norepinephrine and serotonin.	"Aurorix"
2.	pyrazidol	It has a therapeutic effect in patients with apathetic attacks and depressive disorders. It is also prescribed for agitation - strong emotional arousal, which is manifested by a feeling of anxiety and fear. The drug is widely used in psychiatric practice.	"Pirlindol"
3.	befol	Indications: depressive syndrome, anxiety and delusional disorders, hallucinations. With alcoholism: asthenosubdepressive syndrome.	"Befol"
4.	Inkazan	Pharmacological properties are similar to pyrazidol. Activates norepinephrine and serotonin in the central nervous system. It is widely used for mental disorders: schizophrenia, manic-depressive psychosis, mood swings, and also to improve blood circulation in the brain. In the treatment of alcoholism, the drug is recommended to be taken in the period of remission.	"Metralindol"
5.	Derivatives of beta-carbolines	The β-carboline backbone is the main structure for many alkaloids that are isolated from plant components. Medicines containing this substance can be used in the fight against alcoholism and depression. Derivatives are also used in antiviral, antibacterial and antitumor therapy. In addition, active compounds help in the fight against rheumatoid arthritis, osteoarthritis, bronchial asthma.	Garman, Garmin

Irreversible selective MAO-B

Table 3

№	Active substance	Short description	Tradename
1.	Selegiline	Pharmacological group: antiparkinsonian agent. Selegin is involved in the metabolism of dopamine (inhibits). Thus, there is an increase in the neurotransmitter in various parts of the brain. The time for which the enzyme is restored is 2 weeks.	Umeks, Stillin
2.	Rasagiline	Antiparkinsonian drug. It is recommended for the treatment of true Parkinson's disease, as well as in the presence of symptoms that indicate this pathology. The tool has an effect due to the accumulation of special natural compounds in the brain. The drug is taken according to the scheme; sudden withdrawal or a sharp increase in dose can lead to serious consequences.	"Azilect"
3.	Pargylin	Antidepressant, recommended for mental and nervous disorders. In combination with the drug Meticlothiazide may lower blood pressure.	"Pargilin"

Surely each of us has been exposed. Due to abrupt life changes, the human body, as it were, develops "mental immunity", thereby increasing its regenerative abilities. Thus, before using psychotropic drugs (monoamine oxidase inhibitors), you should find out whether they are really essential to survive depression or stress.