Spondloarthrosis 

Inhalation steroids Preparations. Pharmacokinetics of inhalation glucocorticosteroids

Currently, bronchial asthma is considered as a chronic inflammatory process in bronchi, leading to hyperreactivity and obstruction of bronchi. In this regard, the main direction in the treatment of bronchial asthma is anti-inflammatory (basic) therapy. The anti-inflammatory means used in the treatment of bronchial asthma include glucocorticoids (inhalation forms) and fraud cell stabilizers (Intal, Lomudal, Nedocromil, Toraly, Ditete).

Anti-inflammatory therapy using inhaled glucocorticoids is recommended as the primary stage of bronchial asthma therapy of medium and severe with the addition of RD-adrenomimetics if necessary.

In the treatment of patients with a slight persistent stream of bronchial asthma, in the absence of an effect from the episodic use of P-adrenomimetics, it is recommended to regularly use glucocorticoid inhalations.

With severe cortic-dependent bronchial asthma after reaching remission using glucocorticoids taken inward, it is recommended to move on inhalation of glucocorticoids using large doses (Salmeron, 1989).

The intake of glucocorticoids in inhalations is the most important stage of the treatment of bronchial asthma, since the inhaled glucocorticoids have an active local anti-inflammatory effect, while systemic side effects Practically do not develop (Utigev, 1993).

Mechanismanti-inflammatory effect of inhalation glucocorticoids:

Preparations have a high affinity for glucocorticoid cell receptors involved in inflammation, and interact with these receptors;

The resulting complex affects the transcription of genes directly through the interaction with the DNA molecule. At the same time, the MRNA function is in charge of the synthesis of inflammation proteins, and a new mRNA molecule is formed, which is responsible for the synthesis of anti-inflammatory proteins (lipocortine or lipomodulin, neutral
peptidase, etc.). The newly synthesized peptides directly depress phospholipase hr, responsible for the products of anticipal prostaglandins, leukotrienes, platelet aggregation factor.

Severe two generations of glucocorticoids in inhalations:

Preparations I generations: Bekotide, Beclomet, Bekodisk;

Preparations II generation: Budesonide, Fluooned, fluctaisone dipropionate.

Inhalation glucocorticoids of the 1st generation

Becklomethasone dipropionate(Beclomet, Bekotide) - this is 9<х-хлор-16-р-метилпреднизолон-17,21-дипропионат. Препарат выпускается в следующих лекарственных формах:

A microeroerosol containing 50-100 μg in one dose;



Suspension for use in a nebulizer (in 1 ml of 50 μg);

Disk forms (Bekodi 100 and 200 μg) inhaled with
The power of the disk inhaler "Discheiler".

Becklomethasone dipropionate is a "propraged". It is metabolized into a more active metabolite of Beklomethasone Monopropionate in many tissues, incl. In the lungs and liver.

When inhalation of the beclometazone dipropionate, 30% of its amount falls into the lungs and is metabolized, about 70% is precipitated in the oral cavity, pharynx, is swallowed and activated in the liver to the beclometazone of the Mo-nopropionate. When using large doses of Becmetazone, systemic side effects are possible.

The becotide (beclomet) in the form of aerosols for inhalation is intended for long-term regular use. The drug is not used to relieve the bouts of bronchial asthma, the therapeutic effect is manifested only a few days after the start of treatment. Patients who had previously assigned systemic corticosteroid therapy should continue it for another 1 week after the start of the use of a becotide, then you can try to gradually lower its dose.

The usual therapeutic dose of the becotide is 400 μg per day, it should be divided into 2-4 one-time doses (2-4 inhalation). In case of severe bronchial asthma, it is possible to increase the daose dose to 1000-1500 μg and even 2000 μg. This dose is effective and does not cause systemic side effects, does not oppress the adrenal cortex. If necessary, apply large doses of the becotide. It is advisable to use Beko-TID-250 (1-2 inhale 2-3 times a day).

The supporting dose of the drug is 200-400 μg per day at twofold use (in the morning and evening). Reducing the dose to supporting is produced gradually (1 inhalation every 3-7 days).

In the treatment with a becotide (beclomet), it is possible to precipitate the drug on the oral mucosa, which contributes to the development of candidomicosis and pharyngitis. For the prevention of candidiasis oral inhalation bekotid made using a special dispenser spacer which is put on the inhaler, whereby the drug particles are deposited in the oral cavity, are retained in a cell-spacer. After the inhalation of the becotide, it is advisable to rinse your mouth. When applying a spcessor dispenser, the amount of the drug reaching the lungs increases.

Bekotide inhalation can be partially replaced by the dose of glucocorticoids taken inward, and reduce cortico addiction (400 μg of the becotide is equivalent to 6 mg of prednisolone).

Bekodisk- In one dose, it contains 100 and 200 μg of a becotide, in the form of dry substance is inhaled in a daily dose of 800-1200 μg (i.e. 1-2 inhale 4 times a day) with a special inhaler.

Beclometazone dipropionate is produced in the form of a drug becllort.in 2 forms: Mita and Forte. Beclockort is used in the same doses as a becotide. Becklokort-forte, 1 dose of which contains 250 μg of the beclometazone dipropionate, has a longer action than a beclloritetress, it should be used for 1-2 inhalation 2-3 times a day.

Becmetazone dipropionate is also available in the form of a drug aldeqing.It is shown for the treatment of patients who have bronchial asthma combined with vasomotor allergic rhinitis, polypose of the nose. In the packaging of the drug, there is a replaceable nozzle for the nasal inhalation of the pebetazone, as well as the nozzle for inhalation through the mouth of the aldzin, are used by 1 inhalation (50 μg) in each nasal stroke 4 times a day or through an oral nozzle inhaled through the mouth (1-2 inhale 4 times in day)

Fad.- Combined dosage aerosol containing glucocorticoid and p 2 -adrenomimetics (Ventoline) is inhaled by 1-2 inhale 3-4 times a day

Inhalation glucocorticoids of the 2nd generation

Inhalation glucocorticoids of the 2nd generation have a more significant affinity for glucocorticoid receptors in the bronchopulmonal system, it is believed that the drugs of this generation are more effective than a becotide, and more durable

Budesonide(Mountain) - Aerosol (200 doses of 160 μg) - the drug of extended in capsules, operates about 12 hours, is inhaled 2 times with 200 μg, with a serious flow of bronchial asthma, a daily dose increases to 1600 μg

Flunisolide(IngaCort) is produced in the form of an aerosol for inhalations. One dose of aerosol contains 250 μg of flunisolide. The initial dose of the drug is 2 inhales in the morning and in the evening, which corresponds to 1000 μg of flunisolide, if necessary, a dose can be increased to 4 inhalations 2 times a day (2000 μg per day)

After the fluidisolide inhalation, only 39% of the administered dose enters the overall bloodstream with more than 90% of the drug, which has been resorption in the lungs, turns into liver into almost inactive metabolite - 6p hydroxyifunisolide its activity 100 times lower than the source activity of the original preparation

In contrast to the beclometazone dipropionate, the fluidides is initially biologically active, not subjected to metabolism in the lungs, at a dose of 2000 μg per day does not affect the hypothalamic-pituitary-adrenal axis and does not have systemic side effects, a planer with a flunisolide is equipped with a specially designed spacer, which contributes to a more effective and deeper entering of the drug in the bronchi, it reduces the deposition in the mouth and, consequently, the rate of complications from the mouth, pharynx (candidiasis, hoarseness, bitterness in the mouth, cough)

Flucuzone propionate(Flixomide) - produced in the form of a dosage aerosol with a content in 1 dose 25, 50, 125 or 250 μg of the drug, inhalations are used in a dose from 100 to 1000 μg 2 times a day, depending on the severity of the patient's condition supporting dose - 100-500 μg 2 3 times a day practically does not give systemic side effects, is the most efficient and safe inhalation glucocorticoid

Fluticasone has a high local activity, its affinity to glucocorticoid receptors is 18 times higher than this dexamethasone and 3 times - budesonide

In the inhalation of fluctaisone, 70-80% of the drug is swallowed, but it is absorbed by no more than 1% at the first passage through the liver, almost complete biotransformation of the drug with the formation of an inactive metabolite - 17-carboxylic derivative

All three drugs (Becklomethazone dipropionate, floutionate, flunisolide, fluctaisone propionate) reduce the number of bronchial asthma seizures in day and night, the need for sympathomimetics and the frequency of relapses However, the positive effects are more pronounced and faster when using the fluctaisone, while there are practically no danger of the development of system side Action glucocorticoids

With the lung and medium-free forms of bronchial asthma, any inhaled glucocorticoids in doses of 400-800 μg / day can be used with a more severe course of the disease that requires high doses of inhalation glucocorticoids (1500-2000 μg / day and (yulya); fluctuation propionate

Side effects of inhalation glucocorticoid therapy

1 Development of pharyngitis, dfony due to atrophy of the muscles of the larynx, the Candidomicosis of the oral mucosa for the prevention of this side action due to the sedimentation of the glucocorticoid particles on the oral mucosa during inhalation, the mouth should be ringed after inhalation, and use the spacer (see above)

2 System Side Effects The development of systemic side effects is due to partial suction of the inhaled glucocorticoids of the mucous membrane of the bronchopulmonal system, the gastrointestinal tract (part of the drug is swallowed by patients) and the flow of it in the bloodstream

The absorption of the inhaled glucocorticoid through the bronchopulmonal system depends on the degree of inflammation of the bronchi, the intensity of glucocorticoid metabolism in respiratory tract and the amount of drug entering the respiratory tract during inhalation

Systemic side effects occur when using large doses of inhaled glucocorticoids (more than 2000 μg of a becotide per day) and may manifest themselves with the development of coschingoid syndrome, inhibition of the pituitary and adrenal system, a decrease in the intensity of the processes of costh formation, the development of osteoporosis. Ordinary therapeutic doses of inhaled glucocorticoids of system side effects do not cause

Flunisolide (Ingokort) and fluucasone dipropionate very rarely show systemic side effects compared to a becotide

Thus, the use of inhalation forms of glucocorticoids is a modern and active method of treating bronchial asthma, which allows to reduce the need for oral glucocorticoids, as well as p-adreminimetics (Woolcock)

It is advisable to combine the inhalation of glucocorticoid and bronchologists according to the scheme first inhalation sympathomimetics (Berotek, Salbutamola), and after 15-20 min - inhalation of glucocorticoid combined use of inhalation glucocorticoid with another inhalation anti-inflammatory agent (intortal, tillage) allow many patients to reduce the healing dose of glucocorticoid drug

The use of glucocorticoids inside or parenterally (systemic glucocorticoid therapy)

Systemic glucocorticoid therapy is carried out only by strict indications

· Very serious flow of bronchial asthma in the absence of effect from all other methods of treatment,

Cortically addicted bronchial asthma (i.e., when the patient is already treated for glucocorticoids, and at the moment it is impossible to cancel);

Astmatic status (glucocorticoids are applied parenterally);

Coma with bronchial asthma (glucocorticoids are applied parenterally);

Systemic glucocorticoid therapy has the following mechanisms of action:

Stabilizes fat cells, prevents their degranulation and exit of allergy and inflammation mediators;

Block the formation of IgE (reacts);

Suppress the late asthmatic reaction, due to the suppression of the cellular inflammatory reaction due to the redistribution of lymphocytes and monocytes, the oppression of the ability of neutrophils to migration from the vascular bed, the redistribution of eosinophils. Late asthmatic reaction begins 3-4 hours after exposure to allergen, its maximum is observed after 12 hours, it lasts more than 12 hours; It reflects the mechanisms of progressive asthma. The hyperreactivity of the bronchi, which remains long
(for weeks and months), is associated with a late asthmatic reaction;

Stabilize lysosomal membranes and reduce the yield of lysosomal enzymes damaging the bronchopulmonal system;

Suppress the vasodilatory effect of histamine;

Increase the number and sensitivity of the P-adrenoreceptors of the bronchi to the bronchorated effects of adrenomimetics;

Reduce the swelling of the mucous membrane of the bronchi; increasing the activity of endogenous catecholamines;

After penetration into the cell, glucocorticoids are associated with specific cytoplasmic receptors, forming a complex of hormone receptor, interacting in the core with chromatin. As a result, the synthesis of proteins encouraged the effects of glucocorticoids is activated. The whole process takes about 6 hours, so glucocorticoids do not stop the attacks of suffocation in the exacerbation of bronchial asthma, they act no earlier than 6 hours after their introduction

3 glucocorticoid groups are used:

Prednisolone group: prednisone (tablets of 0.005 g; 1 ml ampoules with a content of 30 mg of the drug); methylprednisolone (methipred, urbazon - tablets of 0.004 g);

Triamcinolone group: Triamcinolone, Kenakort, PolcorTolon, Berlikort (tablets of 0 004 g);

Dexamethasone Group: Dexamethasone, Dexon, DEXAZAZ (Tablets

0 0005 g; ampoules for intravenous and intramuscular administration by

1 and 2 ml of 0.4%-solvent with a preparation content of 4 and 8 mg, respectively).

For the treatment of patients with bronchial asthma, preparations of a group of prednisolone and triamcinolone are most acceptable.

With a very serious flow of bronchial asthmaand in the absence of the effect of the rest of the treatment methods, it is recommended to use drugs short action (prednisone, prednisone, methylprednisolone).

Treatment technique in M. E. Gershwin (1984):

When aggravating starting with high doses (for example, 40-80 mg of prednisolone daily);

After decreasing symptoms - slowly reduce the dose (within 5-7 days) to supporting, for example, by 50% each day;

For chronic (long) treatment apply a daily dose
prednisone below 10 mg;

Take the drug in the first half of the day;

At the beginning of the treatment, the daily dose is divided into 2-3 receptions;

If more than 7.5 mg of prednisone is required per day, take an attempt to intermittent therapy (for example, 15 mg of prednisolone in a day instead of daily reception of 7.5 mg);

To reduce the daily oral dose of prednisolone, a portion of the drug taken into the drug is inhabited, based on the fact that 6 mg of prednisone is equal to 400 mg of a becotide.

V. I. Trofimov (1996) recommends starting the therapy with tableted glucocorticoids from a daily dose of 20-40 mg of prednisolone or 16-32 mg of methipred, triamcinolone. 2 / S-3/4 daily dose of the patient must take in the morning after breakfast, the rest is after lunch (until 15.00) in accordance with the circadian rhythms of products of glucocorticoids and sensitivity to them tissues and organism cells. After a significant improvement in the state of the patient (the absence of stroke attacks for 7-10 days), it is possible to reduce the dose of glucocorticoids on "/ 2 tablets in 3 days, and when a dose of 10 mg / day of prednisolone or an equivalent dose of another drug - on" / 4 tablets for 3 days before complete cancellation or preservation of the maintenance dose (usually "/ g" 2 tablets). If the patient received glucocorticoids for a long time (more than 6 months), the dose reduction should be produced more slowly: on "/ V" a tablets for 7-14 or more days.

If you need long-term use of glucocorticoids to monitor the asthma of severe flow, it is advisable to use an alternating method of reception (double daily dose day 1 time per day in the morning), which reduces the risk of oppressions and the development of system side effects. The short period of the half-life of oral glucocorticoids of the prednisolone group and triamcinolone allows you to apply an alternating scheme. It should be emphasized that the alternating method of receiving glucocorticoids is usually acceptable when with the help of their daily intake, it was already possible to achieve an improvement in the flow of asthma and reduce the daily dose of prednisolone to 5-7.5 mg / day; However, if a deterioration is made, it is necessary to return to the daily reception of the drug. With very severe asthma, an alternating scheme is ineffective, it is necessary to apply glucocorticoids daily and even 2 times a day.

According to the joint report of the National Institute of Heart, Lungs and Blood (USA) and WHO "Bronchial Asthma Global Strategy" - a short course of treatment with oral glucocorticoids (5-7 days) can be used as "maximum therapy" to achieve the control of the flow of asthma in the patient. This course can be applied or at the beginning of the treatment of a patient with an uncontrolled asthma or during the period when the patient notes a gradual deterioration of its state side effects with short courses (less than 10 days), as a rule, are not observed, the glucocorticoids can be canceled immediately after short courses

In the presence of contraindications to the reception of glucocorticoid preparations inside (erosive gastritis, peptic ulcer of the stomach and duodenum) can be applied kenalog-40.(The preparation of triamcinolone extended) is intramuscularly at a dose of 1-2 ml (40-80 mg) 1 time in 4 weeks.

The number of injections on the course of treatment and intervals between injections are determined individually, however, unfortunately, with prolonged treatment, the duration of the effect decreases and the need for more frequent administrations is arising. Some patients suffering from a cortic-dependent bronchial asthma version, instead of systematic oral administration of glucocorticoids, intramuscular administration of Kenalog is used 1 time in 3-4 weeks

With pronounced exacerbations, severe attacks of bronchial asthma, threatening the development of an asthmatic state, often have to use large doses of glucocorticoids intravenously through short time intervals It is believed that the optimal concentration of glucocorticoid plasma is achieved when the hydrocortisone of the hemisuccinate is administered in a dose of 4-8 mg / kg or prednisone at a dose 1-2 mg / kg at intervals of 4-6 hours. More efficiently intravenous drip administration of glucocorticoids, which can be produced 1-4 times a day depending on the state of the patient. Typically, the course of treatment with intravenous drip injections of glucocorticoids until the optimal effect is 3-7 days, after which glucocorticoids are canceled, gradually reducing the dose on the "d of the initial daily dose, adding inhalation glucocorticoids.

With glucocortic-dependent bronchial asthma, it is impossible to cancel completely glucocorticoids, a daily dose of prednisone 5-10 mg is sufficiently active.

Side effectssystemic treatment with glucocorticoids:

Obesity, mainly in the chest, abdomen, the cervical spine, the appearance of a moon-shaped hyperemic person;

Psychosis, emotional lability;

Thinning, dry skin, crimson-purple stria;

Acne, girsutism;

Amyotrophy;

Osteoporosis, incl. spine (spinal fractures possible);

Hypersecretion and increase in the acidity of gastric juice, development
ulcers of the stomach and duodenal intestine;

Hyperglycemia (steroid diabetes);

Arterial hypertension;

Sodium delay, swelling;

Rear subcapsular cataract;

Activation of the tuberculosis process;

Inhibition of adrenal functions.

Sudden cancellation of glucocorticoids after their long-term use, especially in large doses, leads to a rapid appearance cancellation syndromewhich manifests itself:

Deterioration of the flow of bronchial asthma, the resumption of attacks
suffocation, possible development of asthmatic status;

A significant drop in blood pressure;

Harsh weakness;

Nausea, vomiting;

Artralgia, Malgia;

Poles in the stomach;

Headache.

To reduce the development of adverse phenomena of glucocorticoid therapy and to reduce cortico dependence, it is recommended:

Try to do smaller doses of the drug;

Combine treatment with intalam inhalations;

Prescribe short-range preparations (prednisolone, urbazon, polchankolone) and not to use long-term glucocorticoids (Kenalog, dexazone, etc.);

Prescribe glucocorticoid in the first half of the day, the greatest part of the daily dose to be given in the morning so that the concentration of the drug in the blood coincides with the highest emission of endogenous cortisol;

Supportive dose of the drug (1.5-2 tablets) is advisable to give an intermittent way (i.e., a double-supported dose is taken once in the morning, but in a day). With this reception, the possibility of oppressing the adrenal glands and the development of side effects is reduced;

· To reduce cortic addiction at the time of reducing the dose of prednisolone and transition to supporting doses etimisole.0.1 g 3 times a day (under the control of blood pressure), glycyircles0.05 g 2-3 times a day inside. These means stimulate adrenal glands. To reduce cortico dependence, you can also apply tincture of the dioxy of Caucasian30 drops 3 times a day;

Apply RDT with a combination with needleflexotherapy;

· To prevent or reduce the side phenomena of oral glucocorticoid therapy, it is advisable to replace inhalations of glucocorticoids;


· Apply plasmapheresis, hemosorption.

One of the most severe complications of systemic glucocorticoid therapy is osteoporosis. For its prevention and treatment, preparations containing hormone C-cells of the thyroid gland Calcitonin - calcitrin, Miakalzic.Calcitrin is appointed by 1 unit subcutaneously or intramuscularly every day during a month with breaks every 7th day (course 25 injections) or 3 units every other day (course 15 injections). Miakalzik (calcitonin salmon) is introduced subcutaneously or intramuscularly by 50 units (course 4 weeks). You can also use a miakalcic in the form of a spray intranasally for 50 units every other day within 2 months with a subsequent two-month break. Calcitonin treatment should be carried out in combination with the reception of calcium gluconate inside 3-4 g / day. Calcitonin preparations contribute to the flow of calcium into bone tissue, reduce osteoporosis phenomena, have an anti-inflammatory effect, reduce the degranulation of fat cells and cortico addiction.

Treatment of glucocorticoids of pregnant women suffering from bronchial asthma

Most pulmonologists consider contraindicated systemic oral glucocorticoid therapy in the first trimester of pregnancy due to the high risk of developing ugliness in the fetus. Inhalation glucocorticoids can be used to treat bronchial asthma (at a dose of not more than 1000 μg per day) during the entire period of pregnancy, because Their systemic side effects are insignificant, and the risk of fetal death due to hypoxia at the attacks of asthma is great.

Small doses of glucocorticoids, if necessary, can be prescribed inwards in P-W trimesters in combination with inhalation glucocorticoids. With a severe attack of asthma and asthmatic status, intravenous administration of glucocorticoids is shown.

Cytostatic treatment (immunosuppressants)

Cytostatic treatment is currently applied rarely.

The mechanism of action of cytostatics is to oppress the products of reactors and the anti-inflammatory effect. Unlike glucocorticoids, they do not oppress adrenal glands.

Indications

Severe form of atopic bronchial asthma
treatment with ordinary means, incl. glucocorticoids;

Cortically-dependent corortio-resistant bronchial asthma - in order to reduce cortico addiction;

Autimmune bronchial asthma.

The method of treatment with cytostatics is set out in the section "Treatment of autoimmune bronchial asthma".

Immunomodulatory therapy

Immunomodulatory therapynormalizes the work of the immune system. It is prescribed with a protracted flow of bronchial asthma, resistant to therapy with ordinary means, especially with a combination of atopic form with infection in the bronchopulmonal system.

Inhalation glucocorticosteroids (ICCC) are the first line means, which are used for the long-term treatment of patients with bronchial asthma (BA). They effectively block the inflammatory process in the respiratory tract, and the clinical manifestation of the positive effect of ICCC is considered to reduce the severity of the symptoms of the disease and, accordingly, a decrease in the need for oral glucocorticosteroids (GKS), β 2 short-acting, reducing the level of inflammatory mediators in the liquid of bronchoalveolar lavage, Improved lung function indicators, reduced variability in their fluctuations. Unlike systemic GKS, ICCCs have high selectivity, pronounced anti-inflammatory and minimal mineralocorticoid activity. With the inhalation path of the introduction of drugs in the lungs, approximately 10-30% of the nominal dose is postponed. The percentage of deposit depends on the ICCC molecule, as well as the drug delivery system in the respiratory tract (dosage aerosols or dry powder), and when using a dry powder, the proportion of pulmonary deposits is doubled compared to the use of dosage aerosols, including the use of spacers. Most of the ICCC dose is swallowed, absorbed from the gastrointestinal tract and is rapidly metabolized in the liver, which provides a high therapeutic ICCC index compared to systemic GKS

The drugs for local inhalation use include Fluisolone (IngaCort), triamcinolone Acetonide (TAA) (ARASCORT), Becotomezazone Dipropionate (BDP) (Bekotide, Becklomet) and Preparations of Modern Generation: Budesonide (Pulmikort, BenaCort), Flikotid (FL) ), Mometazone Furoate (MF) and cyclezonide. For inhalation applications, drugs are produced in the form of aerosols, dry powder with appropriate devices for their use, as well as solutions or suspensions for use using nebulizers

Due to the fact that there are many ICCC inhalation devices, as well as due to the insufficient ability of patients, the inhalers need to be taken into account that the amount of ISX, delivered to the respiratory tract in the form of aerosols or dry powder, is determined not only by the nominal dose of GKS, but also characteristic Devices for delivery of the drug - the type of inhaler, as well as the technique of inhalation of the patient.

Despite the fact that ICCC has a local impact on the respiratory tract, there are contradictory information about the manifestation of unwanted systemic effects (NE) of ICCC, from their absence and pronounced manifestations representing the risk for patients, especially for children. To such NE, it is necessary to include the suppression of the function of the adrenal cortex, the impact on the metabolism of bone tissue, bruises and skin thinning, the formation of cataracts.

The manifestations of the systemic effects are mainly determined by the pharmacokinetics of the drug and depend on the total amount of GKS entering the systemic blood flow (systemic bioavailability, F) and the magnitude of the GKS clearance. Based on this, it can be assumed that the severity of the manifestations of certain NEs depends not only on the dosage, but also, to a greater extent, from the pharmacokinetic properties of drugs.

Therefore, the main factor determining the effectiveness and safety of ICCC is the selectivity of the drug with respect to the respiratory tract - the presence of high local anti-inflammatory activity and low systemic activity (Table 1).

In clinical practice, ICCC differs among themselves by the magnitude of the therapeutic index, which is the relationship between the severity of clinical (desirable) effects and systemic (undesirable) effects, therefore, with a high therapeutic index, there is a better effect / risk ratio.

Bioavailability

IGCCs are quickly absorbed in the gastrointestinal tract and respiratory tract. The dimensions of the inhaled particles can be influenced on the GKS absorption, as particles of less than 0.3 mmc are laid in alveoli and absorbed into pulmonary blood flow.

When inhaling aerosols from dosage inhalers through a spacer with a large volume (0.75 L - 0.8 liters), the percentage of drug delivery to the peripheral respiratory tract (5.2%) increases. When using dosage inhalers with aerosols or dry powder GCS through the diskaler, the turbochaler and other devices only 10-20% of the inhaled dose is postponed in the respiratory tract, while up to 90% of the dose is postponed in the rotoglotage region and swallows. Further, this part of ICCC, absorbing from the gastrointestinal tract, falls into the hepatic blood flow, where most of the drug (up to 80% or more) is inactivated. The systemic bloodstream IS is carried out mainly in the form of inactive metabolites, with the exception of the active metabolite of the BDP - Beklomethasone 17-Monopropionate (17-BMP) (approximately 26%), and only a small part (from 23% of TAA to less than 1% FP) - as unchanged drug. Therefore, the systemic oral bioavailability (FORA1) at ICCC is very low, it is almost equal to zero.

However, it should be noted that part of the ICCC dose [approximately 20% nominally accepted, and in the case of the BDP (17-BMP) - up to 36%], entering the respiratory tract and quickly absorbing, enters systemic blood flow. Moreover, this part of the dose may cause extrapileous system NEs, especially when prescribing high doses of ICCC, and here the type of inhaler used with ICCCs used, because when inhaling the dry powderonide, the pulmonary deposition of the drug increases 2 times and more compared With inhalation from dosage aerosols.

Thus, the high percentage of the deposits of the drug in intimilk respiratory tracts normally gives the best therapeutic index for those IGCs that have low systemic bioavailability with an oral route of administration. This applies, for example, to the BDP, which has a systemic bioavailability due to intestinal absorption, unlike budesonide, which has systemic bioavailability mainly due to pulmonary absorption.

For ICCC with zero bioavailability after oral dose (flucta), the nature of the device and the technique of inhalation determine only the effectiveness of treatment, but do not affect the therapeutic index.

Therefore, when assessing systemic bioavailability, it is necessary to take into account the overall bioavailability, that is, not only low oral (almost zero in fluctaisone and 6-13% at budesonide), but also inhalation bioavailability, the average values \u200b\u200bof which range from 20 (FP) to 39% ( Flunicolid) ().

For ICCC with a high fraction of inhalation bioavailability (budesonide, FP, BDP), systemic bioavailability may increase in the presence of inflammatory processes in the mucous membrane of the bronchial tree. It was established in a comparative study of systemic effects in terms of the level of cortisol in the blood plasma after a single appointment of budesonide and the BDP at a dose of 2 mg at 22 hours in healthy smoking and non-smoking persons. It should be noted that after the inhalation of Budesonide, the level of cortisol in smokers was 28% lower than in non-smoking.

This made it possible to conclude that in the presence of inflammatory processes in the airlessness of the respiratory tract during asthma and chronic obstructive bronchitis, the systemic bioavailability of those IGCs, which have pulmonary absorption (in this study it is budesonide, but not the BDP, which has intestinal absorption).

Of great interest calls for Mometazon Furoate (MF), new ICCC with very high anti-inflammatory activity, which does not have bioavailability. There are several versions explaining this phenomenon. According to the first of them, 1 MF from the lungs does not immediately enter the systemic bloodstream, like budesonide, longly delayed in the respiratory tract due to the formation of lipophilic conjugates with fatty acids. This is explained by the fact that the MF has a high-vicious Furoate group in the position of C17 of the drug molecules, in connection with which it enters into systemic bloodstream slowly and in quantities insufficient to determine. According to the second version, the MF is rapidly metabolized in the liver. The third version reads: Agglomerates Lactose-MF cause low bioavailability due to a decrease in solubility. According to the fourth version, the MF is rapidly metabolized in the lungs and therefore inhalation does not reach the system circulation. Finally, the assumption that the MF does not go into the lungs, does not find confirmation, since there are data on the high efficiency of MF at a dose of 400 μg in patients with asthma. Therefore, the first three versions can to some extent to explain the fact of the absence of the abuse of MF, but this issue requires further study.

Thus, the systemic bioavailability of ICCC is the sum of inhalation and oral bioavailability. In the flonovolide and beclomethazone dipropionate, the systemic bioavailability is approximately 60 and 62%, respectively, which slightly exceeds the amount of oral and inhalation bioavailability of other ICCCs.

Recently, a new ISCC drug was proposed - cyclicesonide, the oral bioavailability of which is almost equal to zero. This is explained by the fact that the cyclezonide is a prodrug, its atticness in relation to GKS receptors is almost 8.5 times lower than that of dexamethasone. However, falling into the lungs, the drug molecule is exposed to enzymes (Esterase) and enters its active form (the atticness of the active form of the drug is 12 times higher than that of dexamethasone). In this regard, the cyclezonide is deprived of a number of undesirable adverse reactions associated with ICCC in systemic blood flow.

Communication with blood plasma proteins

IGCCs have a rather high bond with blood plasma proteins (); Budesoncond and fluctaisone, this relationship is slightly higher (88 and 90%) compared to flonminolide and triamcinolone - 80 and 71%, respectively. Usually, the level of the free fraction of the drug in the blood plasma is of great importance for the manifestation of the pharmacological activity of drugs. Modern more active IGCs - budesonide and FP is 12 and 10%, respectively, which is somewhat lower than that of the flonolide and TAA - 20 and 29%. These data may indicate that in the manifestation of the activity of budesonide and FP, in addition to the level of free fraction of drugs, other pharmacokinetic properties of drugs play a major role.

Volume of distribution

The distribution volume (VD) of ICCC indicates the degree of extrapiletous tissue distribution of the drug. Large VD suggests that a more significant part of the drug is distributed in peripheral tissues. However, a large VD cannot be an indicator of high systemic pharmacological activity of ICCC, since the latter depends on the number of free fraction of the drug capable of communicating with the GKR. At the equilibrium concentration level, the largest VD, many times greater than this indicator in other ICCCs, was revealed in FP (12.1 l / kg) (); In this case, this may indicate the high lipophilicity of FP.

Lipophilicity

The pharmacokinetic properties of ICCC at the level of tissues are predominantly determined by their lipophilicity, which is a key component for manifestation of selectivity and time delay in the tissues. Lipophilicity increases the concentration of ISKS in the respiratory tract, slows down their release from the tissues, increases the affinity and lengthens the connection with the GKR, although the face of the optimal Lipophilicity of ICCCs has not yet been determined.

The greatest degree of lipophilicity is manifested in the FP, further in the BDP, Budesonide, and Taa and Fluisolide are water-soluble drugs. High-breeding preparations - FP, budesonide and BSP - are absorbed faster from the respiratory tract and are delayed longer in the tissues of the respiratory tract compared with non-evalation GKS - hydrocortisone and dexamethasone appointed inhalation. This fact may be explained by the relatively unsatisfactory anti-asthma activity and the selectivity of the latter. The high selectivity of budesonide shows the fact that its concentration in the respiratory tract after 1.5 hours after inhalation of 1.6 mg of the drug is 8 times higher than in the blood plasma, and this ratio is preserved for 1.5-4 hours after Inhalation. Another study revealed a large distribution of FP in the lungs, since after 6.5 hours after taking 1 mg of the drug, a high concentration of FP in lung tissue and low in plasma was found in relation to from 70: 1 to 165: 1.

Therefore, it is logical to assume that more lipophilic ICCCs can be deposited on the mucous membranes of the respiratory tract in the form of "microdepo" of drugs, which allows you to extend their local anti-inflammatory effect, since it takes more than 5-8 hours to dissolve the BDP crystals and FP in bronchial mucus, whereas for Budesonide and a flonolide that have quick solubility, this indicator is 6 minutes and less than 2 minutes, respectively. It has been shown that the water-soluble crystals that ensures the solubility of the GKS in the bronchial mucus is an important property in the manifestation of the local activity of ICCC.

Another key component for the manifestation of anti-inflammatory ACC activity is the ability of drugs to linger in the tissues of the respiratory tract. In in vitro studies conducted on pulmonary tissue preparations, it was shown that the ICCC ability to delay in tissues is quite closely correlated with lipophilicity. In FP and Beklomethasone, it is higher than that of budesonide, fluessolide and hydrocortisone. At the same time, in the in vivo studies, it was shown that on the tracheal mucosa ratsononide and FP delayed longer compared to the BDP, and Budesonide was delayed longer than the FP. In the first 2 hours after intubation by Budesonide, FP, BDP and hydrocortisone, the release of a radioactive label (Ra-label) from the trachea at Budesonide was slowed down and amounted to 40% against 80% in FP and BDP and 100% at the hydrocortisone. In the next 6 hours, a further increase in the release of budesonide was observed by 25% and the BDP by 15%, while the FP had a further increase in the release of the Ra label was not

These data are contrary to the generally accepted opinion on the presence of correlation between the ISCC lipophility and their ability to tissue communication, since less lipophilic budesonide is delayed longer than the FP and BDP. This fact should be explained by the fact that under the action of acetyl coenzyme A and adenosine trifosphate, the bondesonide hydroxyl group at the carbon atom in position 21 (C-21) is replaced by the ester of fatty acids, that is, the bordersonide is esterification with the formation of budesonide conjugates with fatty acids. This process proceeds intracellular in the tissues of lungs and respiratory tract and in hepatic microscoms, where fatty acid esters (oleats, palmitates, etc.) are identified. Budesonide conjugation in the respiratory tract and lungs occurs quickly, since after 20 minutes after the use of the drug 70-80% Ra-tag was determined in the form of conjugates and 20-30% - in the form of intact budsonide, where, after 24 hours, only 3 was determined after 24 hours, 2% of the initial conjugate conjugates, and in the same proportion, they were detected in the trachea and in the lungs, which indicates the absence of uncertain metabolites. Budesonide conjugates have a very low affinity for the GCR and therefore do not possess pharmacological activity.

The intracellular conjugation of budesonide with fatty acids can occur in many types of cells, budesonide can accumulate in inactive, but reversible form. Budesonide lipophilic conjugates are formed in the lungs in the same proportions as in the trachea, which indicates the absence of unidentified metabolites. Budesonide conjugates are not defined in plasma and in peripheral tissues.

The conjugated budesonide is hydrolyzed by intracellular lipases, gradually releasing the pharmacologically active budesonide, which can lengthen the saturation of the receptor and prolong the glucocorticoid activity of the preparation.

If the budesonide is approximately 6-8 times less lipophile than FP, and, accordingly, 40 times less lipophile compared to the BDP, the lipophilicity of budesonide conjugates with fatty acids in tens of times exceeds the lipophilicity of intact budsonide (Table 3) than and The duration of its stay in the tissues of the respiratory tract is explained.

Studies have shown that the oxerification of bold acid budesonide leads to the prolongation of its anti-inflammatory activity. In the pulsating appointment of Budesonide, the lengthening of the GKS effect was noted, unlike the FP. At the same time, in the study in vitro, with a constant presence of FP, it was 6 times more efficient to budesonide. It may be explained by the fact that the FP is easier and faster extracted from cells than the more conjugated budesonide, as a result of which the concentration of FP is approximately 50 times and, accordingly, its activity) is reduced.

Thus, after the inhalation of budesonide in the respiratory tract and the lungs, the "depot" of an inactive drug in the form of reversible conjugates with fatty acids is formed, which can lengthen its anti-inflammatory activity. This is undoubtedly of great importance for the treatment of patients ba. As for the BDP, more lipophilic than the FP (Table 4), the time of its delay in the tissues of the respiratory tract in shorter than that of the FP, and coincides with this indicator in dexamethasone, which is apparently the result of the BDP hydrolysis to 17- BMP and beclometazone, the lipophilicity of the last and dexamethasone are the same. Moreover, in the In Vitro study, the duration of the stay of the Ra label in the trachee after the inhalation of the BDP was greater than after its perfusion, which is associated with a very slow dissolution of the BDP crystals, postponed in respiratory lumets during inhalation.

The prolonged pharmacological and therapeutic effect of ICCC is explained by the HCS bond with a receptor and the formation of the GKS + GKR complex. At first, Budesonide binds to the GKR slower than the FP, but faster than dexamethasone, but after 4 hours, the difference in the total number of communication with the GCR between budesonide and the FP was not detected, while at dexamethasone, it was only 1/3 of the associated fraction of the FP and budesonide.

The dissociation of the receptor from the GKS + GKR complex was different from Budesonide and the FP, budesonide compared to FP dissociated faster from the complex. The duration of the Budesonide + receptor in vitro is 5-6 hours, this indicator is lower compared to FP (10 h) and 17-BMP (8 h), but higher compared to dexamethasone. It follows from this that the differences in the local tissue bond of Budesonide, FP, the BDP are not determined at the receptor level, and the predominant effect on the difference in indicators is distinguished into the degree of non-specific bonding of GKS with cellular and subcellular membranes.

As shown above (), the greatest affinity for the GCR has an FP (approximately 20 times higher than that of dexamethasone, 1.5 times higher than in 17-BMP, and 2 times higher than that of budesonide). The GKS molecule configuration of the GCS molecule can affect the GKS receptor affinity. For example, at Budesonide, its right and leaving isomers (22R and 22S) have not only different affinities for the GCR, but also different anti-inflammatory activity (Table 4).

The affinity of 22R to the GCR is more than 2 times the affinity of 22s, and budesonide (22r22S) occupies an intermediate position in this graduation, its affinity for the receptor is 7.8, and the power suppression force is 9.3 (dexamethasone parameters are taken for 1.0 ) (Table 4).

Metabolism

BDP quickly, for 10 minutes, is metabolized in the liver to form one active metabolite - 17-BMP and two inactive - beclometazone 21-monopropyonate (21-BMH) and Becmetazone.

In the lungs due to the low solubility of the BDP, which is the determining factor in the degree of education 17-BMP from the BDP, the formation of an active metabolite can be slowed down. The metabolism of 17-BMP in the liver occurs 2-3 times more slowly than, for example, budesonide metabolism, which can be a limiting factor in the transition of the BDP in 17-BMP.

TAA is metabolized with the formation of 3 inactive metabolites: 6β-trioxipaliamolone acetonide, 21-carboxytryamicinolone acetonide and 21-carboxy-6β-hydroxycinolone acetonide.

Flunicolide forms the main metabolite - 6β-hydroxyifluondurbolide, the pharmacological activity of which is 3 times higher than the activity of the hydrocortisone and has T1 / 2 equal to 4 hours.

FP quickly and completely is inactivated in the liver to form one partially active (1% activity of FP) metabolite - 17β-carboxyl acid.

Budesonide is quickly and fully metabolized in the liver with the participation of cytochrome P450 3A (CYP3A) with the formation of 2 main metabolites: 6β-hydroxybudendide (forms both isomers) and 16β-hydroxyprednisolone (forms only 22r). Both metabolites possess weak pharmacological activity.

Furoate Mometazone (pharmacokinetic parameters of the drug were studied in 6 volunteers after inhalation of 1000 μg - 5 inhalations of dry powder with a radiometer): 11% plasma radiometers was determined after 2.5 hours, this indicator increased to 29% after 48 hours. The excretion of the joy radiometers was 74% and with urine 8%, the total amount reached 88% after 168 hours.

Ketoconazole and cimetidine can increase the level of budesonide in the plasma after an orally accepted dose as a result of the CYP3A blockade.

Clearance and half-life

ICCCs have quick clearance (CL), its value roughly coincides with the size of hepatic blood flow, and this is one of the reasons for the minimum manifestations of system NE. On the other hand, fast clearance provides ICCC high therapeutic index. Clearance ICCC fluctuates from 0.7 l / min (TAA) to 0.9-1.4 l / min (FP and budesonide, in the latter case, the dependence on the adopted dose). Systemic clearance for 22R is 1.4 l / min and for 22s - 1.0 l / min. The fastest clearance, which exceeds the speed of hepatic blood flow, was found at the BDP (150 l / h, and according to other data - 3.8 l / min, or 230 l / h) (), which gives reason to assume the presence of extrahepatic Metabolisms of the BDP, in this The case in the lungs leading to the formation of an active metabolite 17-BMP. Clearance 17-BMP equals 120 l / h.

The half-life (T1 / 2) period from the blood plasma depends on the volume of the distribution and magnitude of the systemic clearance and indicates a change in the concentration of the drug over time. Ichax T1 / 2 from blood plasma varies widely - from 10 min (BDP) to 8-14 h (FP) (). T1 / 2 Other ICCC is rather short - from 1.5 to 2.8 h (Taa, Flunicolid and Budesonide) and 2.7 hours in 17-BMP. In fluctaisone T1 / 2, after intravenous administration is 7-8 hours, while after inhalation from the peripheral chamber, this indicator is 10 hours. There are other data, for example, if T1 / 2 from blood plasma after intravenous administration was 2.7 (1.4-5.4) h, then T1 / 2 from the peripheral chamber, calculated on the three-phase model, was an average of 14 , 4 h (12.5-16.7 h), which is associated with relatively fast absorption of the drug from the lungs - T1 / 2 2 (1.6-2.5) h compared with its slow systemal elimination. The latter can lead to the accumulation of the drug during its long-term application, which was shown after the seven-day destination of the FP through the diskaler at a dose of 1000 μg 2 times a day 12 healthy volunteers, in which the concentration of FP in the blood plasma increased by 1.7 times compared with the concentration after One-time dose of 1000 μg. The accumulation was accompanied by an increase in the suppression of the level of cortisol in the blood plasma (95% against 47%).

Conclusion

The bioavailability of the inhalation GKS depends on the drug molecule, from the drug delivery system in the respiratory tract, from the technique of inhalation, etc. When local appointment of ICCC, there is a significantly better capture of respiratory drugs, they are longer held in the tissues of the respiratory tract, the high selectivity of drugs is ensured, especially fluctuity Propionate and budesonide, the best relationship / risk and high therapeutic index of drugs. Intracellular esterification of budesonide with fatty acids in the tissues of the respiratory tract leads to a local delay and the formation of "depot" inactive, but slowly regenerating free budesonide. Moreover, the large intracellular supply of the conjugated budesonide and the gradual release of free budesonide from the conjugated form can lengthen the saturation of the receptor and the anti-inflammatory activity of budesonide, despite its smaller activity, compared to the fluctaisone propionate and beclometazone monopropyonate, affinity to the GKS receptor. To date, there are isolated information on pharmacokinetic studies a very promising and highly efficient drug of Furoate Mometazone, in which, in the absence of bioavailability, with inhalation administration, high anti-inflammatory activity in patients with asthma are found.

Long-term exposure and slow-saturation receptor provide the elongation of the anti-inflammatory activity of budesonide and fluctaisone in the respiratory tract, which can serve as a base for one-time drugs.

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Inhalation corticosteroids are recommended with a prophylactic goal in patients with a bronchial asthma persistent flow, starting with a light severity. Inhalation steroids practically do not have systemic effects compared to systemic steroids, however, high doses of inhaled steroids should be used with caution in patients who are included in the risk group for the development of glaucoma and cataracts.

In the measured doses of inhalation corticosteroids I and II generations do not cause suppression of adrenal cortex, and also do not affect the metabolism of bone tissue, but when prescribing their children it is recommended to control the growth of the child. Preparations III generation can be prescribed to children from age 1 year precisely because they have a minimal coefficient of systemic bioavailability. In order to achieve a sustainable effect, the inhalation forms of corticosteroids should be used regularly. Reducing the symptoms of asthma is usually achieved by the 3-7th day of therapy. If it is necessary to simultaneously appoint | 1g agonists and inhalation steroids for better penetration of the latter in the air pathways)

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