IGCC - the main group of drugs for the treatment of bronchial asthma. Below is the classification of inhalation glucocorticosteroids, depending on the chemical structure:

Non-alogenated: Budesonide (bulvikort, Benacort), Cycisconeid (Alvesko)

Chlorinated: Becklomethasone Dipropionate (Bekotide, Becklong, Kletenyl, Beclason Eco, Beklason Eco Light Breathing), Mometazone Furoate (Asmonek)

Fluorinated: Flunicolid (IngaCort) Trynzenolone Acetonidamasport, Flicazon Propionate (Flixotide)

Glucocorticosteroids for systemic use

Glucocorticosteroids for systemic applications or system-prednisolone glucocorticosteroids (SGS) can be used by intravenously in small doses during asthma exacerbations, orally short-circuits or a long time. Much less often uses intravenous administration of large doses of SGS (pulse therapy).

Antlaicotrial preparations

Currently, the following leukotriene antagonists are known: Zafirlukast (acolat) Montelukast (singular) Prange

Preparations of this group quickly eliminate the basal tone of the respiratory tract created by leukotrienes due to chronic activation of the 5-lipoxygenase enzyme system. Due to this, this group of preparations received a wide application with aspirin bronchial asthma, in the pathogenesis of which there is an enhanced activation of a 5-lipoxygenase system and an increased sensitivity of receptors to leukotrienes. Leukotriene antagonists are particularly effective in this form of asthma, whose therapy often causes difficulties.

Zafirlukast helps a reliable improvement compared with placebo indicators of FEV1, PSV and elimination of symptoms when adding to ICCC.

The use of montelukast in combination with ISX and prolonged β2 agonists, especially if there are allergic rhinitisallows you to quickly improve the disease control, reduce the dose of ICCC

β2-adrenomimetics of long-term action

Long-term β2-adreminomimetics are currently referred to: FINTEROL (OXIS, Foradil) Salmeterol (SEREVENT) Indcatorol

methylxantins of long-term action - Theophylline (Teoopek, Teotard)

Saving attacks

β2-adrenomimetics short action

The range of β2-adrenomimetics of short action is presented next drugs: Fenoterol (Berothek) Salbutamol (Ventoline)

terbutalin (Brikanil)

Anticholinergic drugs

- iPratropium Bromide (Atrovant)

Methylxantins of short action

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Systemic GKS.

Ticket 29.

9. Gastroesophaginal reflux disease. Definition. Classification. Friendly and esophageal manifestations. Diagnostics.

GERB (gastroesophageal reflux disease) is one of the most common chronic diseases of the upper department. digestive systemarising due to gastrointestinal reflux. Reflux is a retrograde cast of the contents of the stomach and duodenal intestine in the esophagus. Gastric juice, enzymes damage its mucous membrane, and sometimes overlying organs (trachea, bronchi, pharynx, larynx).

The most common causes of GERB: reducing the tone of the lower esophageal sphincter; increase in pressure in the abdominal cavity (during pregnancy, obesity, ascite); diaphragmal hernia; overeating or hood food consumption, as a result of which a large amount of air is swallow; ulcerative disease of the stomach and duodenum; Eating foods that require more time to digest, and as a result, delaying in the stomach.

There are two variants of the flow of GERD: non-erosive reflux disease and erosive esophagitis.

Non-erosive reflux disease - a disease caused by frequent episodes of throwing gastric content in the esophagus, but during gastroscopy (FGDS) there are no changes in the mucous membrane of the esophagus. That is, the patient has only symptoms in the form of heartburn for 3 months, but no significant changes in the wall of the esophagus have not yet happened.

Erosyphanis - at the same time there is also a cast of gastric content in the esophagus, but here already with FGDS there is erosive or ulcerative damage to the mucous membrane of the esophagus, defects are detected by the mucosa defects, it can be imagined as abrasions.

In turn, erosive esophagitis is divided into the following stages:

Stage A: One or more damage to the mucous membrane of the esophagus, not exceeding 5 mm and exciting no more than one milcinous fold.

Stage B: One or more damage to the mucous membrane of the esophagus exceeding 5 mm and exciting no more than one fold.

Stage C: one or more damage to the mucous membrane of the esophagus, exciting more than one fold, but not more than 75% of the circumference of the esophagus.

Stage D: Damage to the mucous membrane of the esophagus, exciting more than 75% of the circumference of the esophagus.

Symptoms GERB

Heartburn is a feeling of burning beast, appearing in 1-1.5 hours after meals or at night. The burning sensation can rise to the opposite region, to give in the neck and in the inter-opaque area. Discomfort may increase after exercise, overeating, receiving carbonated drinks, strong coffee. Ubuilt - the phenomenon caused by the receipt of the contents of the stomach through the lower esophageal sphincter directly into the esophagus, and then into the oral cavity. As a result of belching in the mouth, an acidic taste appears. The belching is most often appearing in a horizontal position, slopes of the body. The pain and feeling of difficulty in swallowing food. These symptoms appear more often in the development of complications of the disease (narrowing or tumor of the esophagus) and are due to the presence of permanent inflammation in the damaged mucous membrane of the esophagus. Esophageal vomiting - a sign of GERD, also emerging in the development of complications. Massows are not rebounded food eaten shortly before the start of the attack of vomiting. ICOT - a sign of the disease, the development of which is due to irritation of the diaphragmal nerve, causing frequent reduction of the diaphragm.

The GERD is characterized by the strengthening of the above-described esophageal symptoms in the horizontal position of the body, with tilts forward and physical exertion. These manifestations can decrease with alkaline mineral water or milk. In some patients, surveying symptoms of the disease are observed. Patients may disturb their chest pain, which can be regarded as signs of heart disease (acute coronary syndrome). If the contents of the stomach in the larynx, especially at night, the patients begins to bother with a dry cough, a throat, witnessing voice. A cast of gastric contents in the trachea and bronchi may occur, with the result that the development of obstructive bronchitis and aspiration pneumonia is possible. Signs of gastroesophageal reflux can be observed and absolutely healthy peopleIn this case, the reflux does not cause the development of pathological changes in the mucous membrane of the esophagus and other organs.

Diagnostics GERB

To clarify the diagnosis, the following studies are carried out: Daily Introduction PN-Monitoring is the main research method confirming the HARB patient. During this study, the number and duration of refluxs during the day, as well as the duration of time during which the pH level drops below 4. The test with the proton pump inhibitor. The patient for 2 weeks is assigned to the drug from the group of proton pump inhibitors (omens, nonxium) in a standard dose. The effectiveness of therapy is a confirmation of the disease. In addition to these diagnostic methods, other studies may be assigned to the patient. They are usually necessary to assess the state of the esophagus and other organs of the digestive system, identifying concomitant diseases, as well as to eliminate diseases, with a similar clinical picture: FEGDS (fibroezophagastroduodenoscopy) with ureazny test; Chromendoscopy of the esophagus; X-ray studies of the esophagus and stomach using contrast; ECG and daily monitoring of ECG; Frameworking study of the abdominal organs.

Treatment of GERB

First of all, the patient needs to change the lifestyle, namely refuse such a bad habit as smoking, and from use alcoholic beverages. These factors contribute to the emergence of reflux. People suffering from obesity, it is necessary to normalize body weight with a specially selected diet and a complex of exercise. Compliance with diet and power mode. Food should be taken by small portions 5-6 times a day, prevent overeating. After eating, it is recommended to avoid physical exertion and horizontal position of the body within a few hours. From the diet should eliminate strong coffee and tea, carbonated drinks, chocolate, citrus, sharp dishes and spices, as well as products contributing to gas formation (bean, cabbage, fresh black bread). Drug therapy is aimed at relieving symptoms of the disease and prevention of complications. The patients are prescribed proton pump inhibitors (omens, nonxium), Blockers H2-histamine receptors (Ranitidine, Famotidin). With a bile reflux, ursodoxichetic acid preparations (URSOFALK) and prokinetics (trime) are prescribed. Occasionally, antacids (almagel, phosphhalugel, gavisson) can be used to get rid of heartburn.

According to sightseeing data, according to doctors estimates, it is believed that approximately 7% of Americans suffer from bronchial asthma ,, disease affects people of all races and ethnic groups around the world, from infancy to old age, with a small predominance among boys A, after puberty, among women . The tragic increase in the prevalence of atopy and asthma, has occurred over the past few decades in Western countries, and later in developing, it is assumed that around 300 million people suffer from Asthma.

In the 1970s and 1980s, in the United States, the number of heavy exacerbations of asthma has sharply increased (which reflects the growth of attendance of emergency departments and hospitalizations about asthma) and the mortality rate associated with asthma. Still, despite the constantly high prevalence of the disease, the most recent available data indicate improved indicators, and a decrease in the number of annual hospitalizations about asthma attacks, and associated with asthma deaths. One of the possible explanations of these favorable trends is the wider distribution of the preventive use of inhaled corticosteroids and the introduction over the past 10 - 15 years of new, very effective drugs and improved anti-asthma protocols.

The obstruction of the respiratory tract with asthma and the subsequent symptoms in the form of cough, shortness of breath, constraints in the chest, and wheezing are caused by several factors: the spasm of smooth muscles of the respiratory tract and inflammation of the bronchi. Spasm can be severe and lead to life-threatening narrowing and closing respiratory tract, even in the absence of the mucous membrane. This can contribute to both an abnormal smooth muscle reduction and an increase in the smooth muscle mass. Inflammation of the respiratory tract with asthma includes mucous, submucous and interstitial swelling; Cellular infiltration, especially eosinophils (and in some cases, neutrophils) and activated T-helper lymphocytes, as well as mastocytes, which (in contrast to mastocytes with other eosinophilic diseases of the respiratory tract) infiltrate smooth muscle beams; an increase in the secretion in the respiratory tract, including the secreted sputum, the rated epithelium, and inturaminal eosinophils; stagnation in capillaries; hyperplasia smooth muscles; and sedimentation of excess collagen, especially directly under the epithelium market membrane,

Traditionally, drugs used to treat asthma were classified by categories according to their prevailing effect - the relaxation of smooth muscles of respiratory tract (bronchodylators) and suppressing inflammation of the respiratory tract (anti-inflammatory drugs). More new drugs (for example, leukotriene modifiers) and combination of drugs (for example, inhalation corticosteroids combined with B-agonists of prolonged action) have a double effect, in contrast to such traditional dichotomy. Now, asthma drugs are classified according to their roles in holistic control over asthma (short and prolonged action), this model is especially useful when discussing with the patients of their drugs from asthma.

All patients with asthma should have an affordable brief-acting bright-actor for use as needed. It is generally accepted that when rapidly active bright-taiters are needed to facilitate symptoms more than 2 times a week (or more than two times a month with night awakens caused by asthma symptoms), controlling drugs should be appointed. .

Short action preparations.

b-agonists of short action used inhalation are the most effective therapy to quickly stop the obstruction of the respiratory tract and facilitating asthmatic manifestations. The most widely used short-acting drugs, B2-selective adrenomimetics: albuterol (usually known as outside the United States), LevAllbuterol, and Pibbuterol). Metaproterenol supplied in Dai (dosage aerosol inhaler (eng. Metered-Dose Inhaler (MDI)) was recently removed from production.

Table. one. B - short-acting adrenomimetics.

All high-speed B-agonists begin to act in 5 minutes or less, with a peak effect after 30 - 60 minutes, the duration of the action 4 to 6 hours. With regular use of broutine (four or more every day), the potential efficiency (measured by an increase in the maximum exhaled flow) does not decrease, but the duration of action is somewhat reduced ,. Since the regular reception schedule four times a day does not improve the results, in comparison with the reception as needed (and in patients with a certain genotypic version of B-receptors, may have a harmful effect), the short-acting inagonists are recommended for use only if necessary to facilitate symptoms (or before the expected impact of well-known asthmogenic factors). The practice of introducing short-acting B-agonists before using inhalation corticosteroids to improve the delivery of the corticosteroid to lower respiratory tracts was discarded as an insolvent. Similarly, there is no need for a patient to wait more than 10 - 15 seconds between inhalations, when the dose is needed in two or more inhalation

In patients with moderate and severe obstruction of the respiratory tract, on the log-of-linear curve of the "dose-response" dependence, you can demonstrate, the need for large doses, for brief-action B-agonists (up to 4000 μg Albuterola from Dai). It is often faced with dose-dependent side effects of sympathomimetics, such as tremor, anxiety, heartbeat, and tachycardia (without hypertension), a slight decrease in the level of potassium and magnesium in serum can also be detected. However, under the usual dose (two inhalations at a time), unpleasant side effects are rare. But their effectiveness can be reduced, in cases where patients simultaneously receive betta blockers. .

The decision, which of the B-agonists of the short action is based largely at the cost and preference of the patient and the doctor. Pourbuterol is available in an activated inhale dosed aerosol inhaler (DAI-AV) - a device created to optimize the delivery of the drug, by injection only at the initialization of the inhalation. Levalbuterol, purified albuterol D-rotating isomer, was created to eliminate side Effectswhich, according to some data, are characterized only by S-torque isomers. However, when using LevAllbuterol in DEA, the profile is the effectiveness and side effects, indistinguishable from such a molecular mixture in albuterol. Now Albuterol has become available in Dai, and does not contain chlorofluorocarbon (CFCS), and CFC-containing albuterol inhalers were removed from production on December 31, 2008. Like CFC, alternative propylene, hydrofluoroalko (HFA), inert in the respiratory tract of man, but in The difference from CFC does not contribute to the depletion of the stratospheric ozone layer. HFA inhalers are equivalent to CFC-containing inhalers, and can be used with spacers in patients with poor inhalation technique. They provide brightness comparable to albuterol in a nebulizer, if the required number of breaths is regulated, and the technique of inhalation is quite good.

b-agonists of short action for oral administration in tablets or in liquid form are undesirable, despite their seeming convenience (especially for young children). They begin to act later, are more weak, and more often than inhalation forms cause side effects. Similarly, anticholinergic broutine, such as the IPratropium not recommended (and not approved by the Office for Food Control and Drugs) to quickly relieve asthma symptoms. They are later (after 20 - 30 minutes) begin to act and cause weaker broutine than inhalation B - bronchitators Anticholinergic broutine must be used only in rare cases in patients with intolerance to all b - mimetics, or for the treatment of severe asthmatic attack, or asthmatic attacks caused by Betta blockers.

A new approach to the treatment of asthma, not yet accepted in the United States, offers to combine B - agonists with inhalation corticosteroids in one bottle, to relieve symptoms as needed. The use of such a combination led to more favorable consequences in patients with moderate asthma, compared with the use of albuterol monotherapy as needed. Similarly, a prolonged B-agonist with a rapid start of action () is used in combination with inhalation corticosteroid in one inhaler for supporting and emergency therapy at the same time, the safety of this approach in a wide and heterogeneous group of the population is waiting for its evidence.

Long-term control.

Achieving good long-term control over asthma (infrequent asthmatic symptoms, an unlimited level of activity, a normal or almost normal function of the lungs, and rare asthmatic seizures requiring emergency care) requires a multifaceted approach: restriction of environmental factors that can cause bronchokonstriction, and acute or chronic respiratory inflammation; monitoring changes in the activity of the disease; In some cases, immunotherapy; and medicia treatment. The use of controlling drugs should be expanded until there is no good control over asthma, including a reduction in the number of asthma attacks that require systematic corticosteroids to one per year maximum. Inhalation corticosteroids make up the class of the most efficient drugs that allow patients to achieve a good level of control over Asthma.

Inhalation corticosteroids.

Corticosteroids were effective in the treatment of asthma, since they are effective in many other inflammatory diseases due to a diverse anti-inflammatory action, including the multiple effect on transcription (both amplification and weakening) of many genes. In the biopsyats of the respiratory tract of asthmatics, which had long therapy in inhalation corticosteroids, histological deviations typical of asthma were less pronounced. Changes include a decrease in the number of mastocytes, eosinophils, T-lymphocytes, and dendritic cells in the mucous membrane and submissible layers; reduction of hyperslasia of glassoid cells and damage to epithelial cells; Reducing vascularization.

Along with the suppression of the inflammation of the respiratory tract, nonspecific bronchial hyperreactivity is usually reduced. Positive clinical results include a decrease in asthmatic symptoms, an increase in the function of the lungs, improving asthma - specific quality of life, and a reduction in asthmatic seizures, including heavy, leading to hospitalization or death. Along with optimistic predictions, reliable evidence indicating the ability to prevent, with the long-term use of inhalation corticosteroids, a progressive decrease in the function of the lungs observed in some patients with asthma is mostly lacking ,. Inhalation steroids are suppressed, but do not heal asthmatic inflammation: in the phase of stabilization of the disease, aircraft inflammation markers (for example, the concentration of exhaled nitrogen oxide and eosinophils in sputum), and bronchial hyperreactivity return to the initial level in approximately 2 weeks after the use of inhalation corticosteroids It was discontinued. .

Not all patients help inhalation corticosteroids equally. For example, smokers are less likely to receive the same anti-masted effect as non-smoking. Neutrophilic inflammation of the respiratory tract is less likely to respond to treatment as well as eosinophilic inflammation. Genetic differences in people with asthma can also cause immunity to corticosteroids.

Most of the inhalation corticosteroids are currently available, after swallowing and systemic suction in the gastrointestinal treatise, exposed to extensive primary metabolic inactivation in the liver before reacing the systemic blood flow. In addition, due to the fact that less than 20% of the received dose remains in the respiratory tract, only a small amount can be absorbed through the mucous membrane of the respiratory tract. Using changes in the hypothalamic-pituitary-adrenal function as a test, the system effect can be noted when the inhalation corticosteroid is introduced in such doses as 88 μg of the floutoosone per day. However, in fact, no clinically important, long-term adverse system effects are not observed among adults that make low and medium doses of these drugs. With large doses (usually\u003e 1000 μg of the beclometazone or its equivalent per day), the risk of skin lesions, cataracts, increasing intraocular pressure, and acceleration of bone loss increases. Children have a slowdown in growth. The expected growth retardation is on average for approximately 1 cm in the first year after appointing the child inhalation corticosteroids ,,, but these research in children in pre-following and school age indicate that even when these children continue to receive inhaled corticosteroids for a long time, they ultimately achieve their Normal alleged growth ,.

Pulp and gang-in-house side effects of inhalation corticosteroids include the ulceration of the larynx, cough with the inhalation of drugs, a weak or hoarse voice, and candidiasis. The rinsing of the mouth after each use of the drug and the use of the Spacer with Dai is methods that help minimize the risk of developing candidiasis in the oral cavity. (The use of the Spacer with Dai also reduces the amount of the drug that can suck in the rotoglot.) Cough can usually be overcome by changing the corticosteroid or inhalation system. Distonia, generally an unstable symptom, as believed, arises due to the sandy and thickening of the mucous membrane or, possibly, Mopathic 57. This usually takes place with a temporary cessation of treatment or after changing the generation of an aerosol and a delivery sample (for example, switching from a dry powder inhaler to dia with a spacer).

When for the treatment of asthma in the mid-1970s, the inhalation corticosteroid was first introduced, it was appointed four times a day, and each inhaling the drug from Dai sold in the United States contained only 42 μg of the hormone. Since then, other corticosteroids have become available, including more powerful, having a large dose for inhalation, and appointed one - twice a day, which contributed to improved efficiency and convenience).

Table. 2. Inhalation corticosteroids.

Each of the inhaled corticosteroids has its own characteristics. For the most part, the choice is based on the convenience of reception (one - twice a day) and the delivery method (Dai, a dry powder inhaler, or a nebulizer solution), starting dose and flexibility in the dose control, the cost of the drug, and the existing side effects. However, only minor differences were found in the therapeutic action.

The use of inhalation corticosteroids in large doses turned out to be effective in the treatment of severe persistent asthma. However, the "dose - response" curve (based on the exhalation flow), for inhaled corticosteroids is relatively common, while the system absorption curve of the dose, it turned out to be more linear. As a result, strategies were more acceptable, under which it is possible to achieve control over asthma, without using large doses of inhaled corticosteroids, and reducing their doses in patients with a well-managed asthma (the so-called "lowering" therapy) can often be achieved without reducing control over Asthma.

Inhalation B-adreminimeters of prolonged action.

Inhalation B-adrethomimetics of prolonged action, Salmetterol and Formoterol (s), largely replaced earlier bronchylators of long-term action - oral, slowly released albuterol and theophylline. B-adreminimetics of prolonged action - powerful broutine (with a brief-acting effect of B-agonists), retain activity more than 12 hours, and due to their high B-2 adrenaselectivity, have a small number of side effects (mostly soft sympathomimetic effects, Such as single myoclonies and tachycardia). . They do not interact with food and other drugs, unlike theophylline, which complicates its use, and toxicity in the overdose of the drug is extremely rare, in contrast to those in theophylline.

Table. 3.Inhalation B-adreminimeters of prolonged action.

As in the B-agonists with a short action, the regular use of B-adrethns of prolonged action - manifests itself only in moderate tachofilaxia and the maximum armored effect with longer preservation of the activity of these drugs. On the contrary, the bronchoprotective effect when using B-adrenomimetics of prolonged action (that is, the prevention of bronchokonstriction caused by physical activity) is rapidly decreased with regular use, opposite pharmacological effectwho was not fully explained. With a rare exception, the rapid relief of the attacks provided by B-adrenomimetics with a short action is not inhibited from b-adrethnomimetics of long-term use with regular use. Variations of the structure B - adrenergic receptors caused by genetic polymorphism, which are distributed in the American population (15-20%), can reduce the effectiveness of B-agonists of long-term action in some patients.

The fact that B-adreminimetics of prolonged action can ensure improvement of the functions of the lungs, can force clinicians to use them as long-term treatment without sharing inhalation corticosteroid with anti-inflammatory effect. However, this strategy leads to the persistence of inflammation of the respiratory tract and the unacceptably high frequency of asthmatic seizures. Inhalation B-adrenomimetics of prolonged action should not be used without appropriate anti-inflammatory therapy for the treatment of asthma.

As an additional or combined therapy with inhalation corticosteroids, prolonged b-adrenomimetics turned out to be effective to reduce day and especially night symptoms, improving the functions of the lungs, reducing the risk of attacks, and reduce the necessary dose of inhalation corticosteroids. Comparison of the use of inhaled corticosteroids in combination with B-adrenomimetics of prolonged action and the use of higher doses of alone inhalation corticosteroids shows that combination therapy gives more favorable results (against a lower dose of corticosteroids). , Pharmacological data brought the theoretical basis for a favorable interaction between these two classes of drugs: laboratory studies have shown that corticosteroids improve B - receptor - mediated transmission of signals in the lungs, and B-agonists increase the transcription of genes under the influence of corticosteroids. Combined therapy (B-adreminimeters of prolonged action, combined with corticosteroid in one inhaler) () guarantees the joint use of the anti-inflammatory drug and optimizes compliance due to greater convenience. Its main inconvenience is that by regulating the dose of inhalation corticosteroids, without changing the dose of b - mimetics (for example, an increase in the dose of corticosteroid during an asthmatic attack) requires a change of device or the presence of a separate inhalation corticosteroid.

The vital benefit that many patients with moderate or severe persistent asthma felt when using B-adrenomimetics of prolonged action together with an inhalation corticosteroid, should be opposed to the results of multicenter use of Salmetterol with asthma (Salmeterol Multicenter Asthma Research Trial - Smart), according to the results of which adding B-adrenomimetics of prolonged action to "ordinary therapy" can cause an increase in the risk of fatal or almost fatal asthmatic seizures, compared with "ordinary therapy". In most cases, inhalation, inhalation corticosteroids were not used at Smart, and among patients receiving b-adrethomymeters of prolonged action and inhalation corticosteroids, no increase in asthma mortality has never been reported. However, the mechanism, thanks to which Salmetterol caused an increase in the number of deaths associated with asthma, both among the black and white studied, remains unclear, and therefore everywhere in the annotations and on the boxes of all drugs containing Salmetterol or Formoterol contains a warning. In addition, national and international expert groups recommended the use of B-adreminometrics of prolonged action only in patients whose inhaled corticosteroids themselves either do not allow to achieve good control over asthma or for initial therapyif not expected she will give a good result. Future guidelines in the treatment of asthma should adopt the appropriate conclusion on recent observations that the reception of B-adrethns of prolonged action in combination with an inhalation corticosteroid once a day, provides good control in patients with a mild persistent asthma.

Both B-adrenomimetics of prolonged action are characterized by properties, both in practical and theoretical terms, the beginning of formoterol in 5 minutes, as well as the B-agonists of a short action, while Salmeterol has a higher action (15 to 20 minutes). Therefore, in some countries, except for the United States, a formoterol combination is an inhalation corticosteroid in one inhaler is recommended for rapidly relieve the attack and, for regular use, with long-term control. Formoterol is a complete agonist B - adrenoreceptors, while Salmetterol is a partial agonist (and a partial antagonist). The significance of this pharmacological difference, especially with respect to the risk of fatal asthmatic seizures, is doubtful.

Lakeotrine modifiers.

Cisteinyl leukotriene receptor antagonists:, and Prankast (the latter, not available in the United States)), the effect of leukotriene C4, D4, and E4 in Cisteinyl receptors leukotriene type 1 is blocked. Bronching occurs within a few hours after the first dose, and the maximum effect is manifested during the first few days after the start of use ,. The level of circulating in blood eosinophils in the treatment of leukotriene receptor antagonists is reduced ,. . However, when using indirect respiratory inflammation indicators (for example, the amount of eosinophils in the sputum and the level of exhaled nitrogen oxide) to determine the results, the effect of antagonists of leukotriene receptor for inflammation of the respiratory tract, compared to placebo, turned out to be variable ,,,.

Table. four.Lakeotrine modifiers.

The leukotriene receptor antagonists can be taken in tablets once (in the case of montelukast) or twice (in the case of Zathirlukast) per day. Montelukast is available in chewing tablets and oral granules (for mixing in food) for small children. The recommendation to take Montelukast once a day in the evening was based on the choice of time for its use in the original tests presented by the FDA during the application for approval of the drug. However, no data indicate greater benefits when receiving in the evening, compared to reception at any other day of the day.

Zileuton is inhibits the products of cysteinyl leukotrienes (and leukotriene B4, powerful peeled peerals for neutrophils), as it is an anthyhonist of 5-lipoxygenase. The opinion is now widespread that it is necessary to take it twice a day. No clinical trials were carried out directly comparing the effectiveness of the zileuton compared to the leukotriene receptor antagonists or the effectiveness of their sharing. Some clinicians find zileuton more preferable than leukotriene receptor antagonists with a asthmatic triade (asthma, aspirin intolerance, and nasal polyposis), and to control asthma and in terms of reducing the nasal polyps.

Zileuton causes reversible toxic hepatitis in 2 - 4% of cases. The liver function should be monitored monthly during the first 3 months of therapy, every 3 months before the end of the first year, and periodically after that. Reports on the appearance of Charga Strauss syndrome (eosinophilic vasculitis and granulomatosis complicating the course of asthma) in patients recently launched leukotriene receptor antagonists (often with a concomitant decrease in oral corticosteroids), may reflect the exacerbation of the previously existing charm-stroke syndrome, although the possibility of causal communication It remains controversial. In general, leukotriene receptor antagonists considered actually free from side effects, and one (montelukast) was even approved for use during asthma in children under the year. In recent postmarketing messages, several cases are described when Montelukast caused depression and suicidal inclinations in children. But there was no confirmation to be confirmed, and when viewing all available placebo-controlled clinical trial data, the FDA did not find an increase in the risk of suicidal inclinations or suicide in any of the leukotriene modifiers. The possibility of changes in mood and behavior under the action of these drugs is studied.

Due to the awareness of their safety and convenience, the leukotriene receptor antagonists were largely replaced with cromoglycats (Cromoline and shortcut) as non-advertid-sized drugs, especially in young children who are often difficult to treat aerosol. Cromoline requires four one-time applications daily by means of diol or nebulizer, providing sufficiently limited long-term control over asthma and, unlike leukotriene receptor antagonists, there was no additional benefit from its use in combination with inhalation corticosteroids.

Short-term, double-blind, placebo controlled studies revealed an improvement in the function of the lungs, improvement, in questionnaire surveys associated with asthma quality of life, and a decrease in asthmatic seizures in patients receiving leukotriene modifiers. ,,,, people with obesity, smokers, and with high sensitivity to aspirin, may be particularly profitable for treatment with leukotriene modifiers. In the future, the identification of certain individual characteristics of genes encoding the enzymes of the metabolic pathway leukotriene may be clinically useful for predicting the effectiveness of treatment in a particular patient. Currently, a therapeutic test is often used; If there is an improvement in symptoms and objective data, it is usually observed during the first month after the start of therapy.

In general, inhalation corticosteroids provide better control over asthma than leukotriene modifiers ,,,,,. As a result, inhalation corticosteroids are recommended as preparations of the first choice in the treatment of patients with persistent asthma, including children of all ages. Leukotriene receptor antagonists are an alternative to treatment easy persistent asthma. Patients of any age that have no good control over asthma from using leukotriene modifiers are shown to transition to inhalation corticosteroids. In patients with heavier asthma, the addition of leukotriene receptor antagonist to a low dose of inhalation corticosteroid can improve control over asthma, but other therapeutic combinations (namely, inhalation corticosteroids plus b - long-term agonists) are more efficient,

Anti-IgE therapy.

Anti-IgE monoclonal antibodies, omalizumab, are the first biological immunoregulating agents available for the treatment of asthma. They associate that part of the IGE to which the high affinity of the receptors (FC R1) are on the surface of obese cells and basophils. When intravenous administration, omalizumab reduces the level of the circulating IgE by 95%, and the level of free IgE can lead to 10 IU per milliliter or less, the target idea is a clinically significant inhibition of allergic reactions in the respiratory tract. Its use also leads to a decrease in the expression of receptors (FC R1) on the surface of mastocytes and other immunoregulating cells (basophiles, monocytes, and dendritic cells). In contrast to hyposensitizing immunotherapy, the treatment of omalizumab is not limited to an action on some particular allergen or group of allergens.

Oralizumab is appointed subcutaneously every 2 or 4 weeks, depending on the dose. The dose is calculated depending on the patient's weight and IgE level in the blood. Local allergic reactions (by type of urticaria) are rare, and systemic allergic reactions (that is, anaphylaxis) are possible in 1 - 2 patients out of 1000. Most, but not all, systemic reactions are noted within 2 hours after the introduction of the first multiple doses. Patients are asked to remain under medical supervision within 2 hours after each of their first three injections and within 30 minutes after each subsequent injection and over the next 24 hours, wearing a pre-filled adrenaline - containing the autoinrhector for the specification, if necessary.

Oralizumab is shown for the treatment of moderate and severe persistent asthma, if inhaled corticosteroids, long-acting B-agonists and leukeotry modifiers did not provide adequate control, or cannot be used due to unbearable side effects. Currently, the appreciated dosing range for Omalizumab is limited by using patients with IgE levels in the blood from 30 to 700 IU per milliliter; Registered increase in sensitivity to permanent aero allergenu (for example, dust, dandruff animals, mold, cockroaches) is an additional selection criterion.

Olizumab was approved for use in adults and children over 12 years old. For patients in this age range, the drug, as it turned out, does not change the disease, in the sense that it does not prevent remote changes in the lung function and does not lead to the remission of the disease (which means suspension without repetition of asthma symptoms). The treatment of OmaMizumab, as it turned out, reduced the frequency of asthmatic seizures, even among patients already taking many other drugs. In patients taking only inhaled corticosteroid, the addition of omalizumab, compared with placebo, made it possible to significantly reduce the dose of corticosteroid, while maintaining or some improvement in the pulmonary function and reduce the need for rescue broutine.

One of the greatest drawbacks, for the widespread use of Oralizumab, this cost is from about $ 10,000 to $ 30,000 annually only for one drug. Pharmacogenetic markers, predicting the favorable effect of the drug, would be very desirable, given the greater value of the therapeutic test of 4 to 6 months. Observations so far show that traditional clinical data at the starting point cannot reliably predict which patients will have an answer to anti-IgE therapy.

Conclusion.

If a bronchial asthma manifests itself infrequent, short-term and light symptoms, Episodic use of a quick-acting armored armor to remove the spasm of the smooth muscles of the respiratory tract, is a completely acceptable approach. However, when symptoms become more frequent and more severe, the emphasis is on preventing symptoms (and asthmatic attacks)). To suppress the inflammation of the respiratory tract, inhalation corticosteroids are prescribed, used once or twice a day, and reducing the frequency of the episodes of bronchokonstriction and the risk of asthmatic seizures. In low and medium doses, inhalation corticosteroids are safe with long-term use, even young children. Alternative to corticosteroids with light asthma - leukotriene receptor antagonists who are aimed at blocking the inflammatory mediator-specific asthma. Anti-hypospose, and possibly anti-penetration vaccines are shown in patients, against the background of regular anti-asthma therapy. .

Picture 1.A stupid approach to asthma therapy.

This simplified step approach to the treatment of asthma was developed based on the central role of inhalation corticosteroids. For each of the preceded dose of the inhalation corticosteroid can be adjusted to the need to achieve good ASTMA control, on the background of minimizing long-term risks associated with large doses. Laba means a long-term B-agonist (Long-Acting B-Agonist), LTM - leukotriene modifier, LTRA - leukotriene receptor antagonist, and SABA - short-acting B-agonists (short-acting b-agonist).

When the symptoms persist, despite the treatment, compliance and good inhalation technique, the use of long-acting B-agonists in combination with inhalation corticosteroids, showed itself the most effective next step, as it affects both aspects of the narrowing of the respiratory tract during asthma: bronchokonstriction and respiratory inflammation. A new opportunity for patients with refractory allergic asthma - therapy by monoclonal anti-IgE antibodies.

Asthma control can often be achieved with an increase in the dose of inhalation corticosteroids. However, with large doses and long-term exposure, the potential risk of side effects increases. Thus, as soon as the control over Asthma was achieved for a period of 3 to 6 months, efforts should be taken to reduce the dose of inhalation corticosteroids to medium or low. The use of long-acting B-agonists, leukotriene modifiers, and anti-IgE therapy can facilitate a decrease in the dose of inhaled corticosteroids, against the background of proper control over Asthma.

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For more information: Drugs affecting bronchial permeability

For the treatment of bronchial asthma, drug therapy preparations, affecting the mechanism of the disease, through which patients control asthma, and symptomatic drugs that affect only smooth musculatubronchial trees are removing the attack.

To preparations symptomatic therapyrelated Breakdaters:

β 2 -adrenomimetics

xanthines

To preparations base therapyinclude

• inhalation glucocorticosteroids

  antagonists leukotriene receptors

  monoclonal antibodies

If not to take basic therapy, eventually the need for inhalation of broutine (symptomatic means) will increase over time. In this case, in the event of insufficiency of the dose of basic drugs, the growth of the need for bronchodulators is a sign of an uncontrolled course of the disease.

Kromonons

Cromons include sodium cromoglycat (Intal) Intocromeyl sodium (Torály). These means are shown as basic therapy of bronchial asthma intermittent and easy flow. Cromons are inferior in their effectiveness of ICCC. Since there are testimony for the appointment of ICCC already with a light degree of bronchial asthma, Cromons gradually oscillate more convenient to the use of ICCC. The transition to Kromons with ICCC is also not justified under the condition of complete control over the symptoms of minimal igx doses.

Glucocorticosteroids

In asthma, inhalation glucocorticosteroids are used, which are not characterized by most side effects of system steroids. With ineffectiveness of inhalation corticosteroids, glucocorticosteroids are added for systemic applications.

Inhalation glucocorticosteroids (IGCC)

IGCC - the main group of drugs for the treatment of bronchial asthma. Below is the classification of inhalation glucocorticosteroids, depending on the chemical structure:

Non-alointed

• budesonide (bulvikort, Benacort, Benenitis Stheri-sky)

  cyclesonide (alvasko)

Chlorinated

• becklomethasone Dipropionate (Bekotide, Becklong, Kletenyl, Beclason Eco, Beclason Eco Light Breathing)

  mometazone Furoate (Asmanares)

Fluorinated

• flunicolid (IngaCort)

  trynzenolone acetonide

  aSMOCT

  flicazon Propionate (Flixotide)

The anti-inflammatory effect of ICCC is associated with the suppression of inflammation cells, a decrease in products, the intervention in the metabolizumrachidonic acid ofe, a decrease in the permeability of the microcirculatory vessels, to prevent the direct migration and activation of inflammation cells, an increase in the sensitivity of B-receptors of smooth muscles. IGCCs also increase the synthesis of the anti-inflammatory lipocortin-1 protein, by inhibiting interlakin-5-bypasshapoptosisosinophils, thereby reducing their amount lead to the stabilization of cell membranes. Unlike systemic glucocorticosteroids, igxlipophils, have short selective semi-uniforms, are quickly inactivated, they have a local (topical) effect, due to which they have minimal systemic manifestations. The most important property is lipophilicity, thanks to which ICCC accumulates in the respiratory tract, slow down their release from tissues and increase their affinity for glucocorticoid receptor. EMCI light bioavailability depends on the percentage of drug entering into light (which is determined by the type of inhaler used and the correctness of the inhalation technique), the presence or absence of a carrier (the best indicators have inhalers that do not contain freon) and from the absorption of the drug in the respiratory tract.

Until recently, the concept of a stepped approach was dominant, which means higher doses of ISCCs at earliest forms of the disease.

The basis of therapy for long-term control of the inflammatory process is the ICCC, which are used in the persistent bronchial asthma of any severity and to this day remain the means of the first line of bronchial asthma therapy. According to the concept of a stepped approach: "The higher the severity of the flow of Ba, the greater doses of inhalation steroids should be applied." In a number of research, it has been shown that patients who have begun treatment of ICCCs no later than 2 years from the onset of the disease are noted significant advantages in improving control over the symptoms of asthma, compared to those who started such therapy after 5 years or more.

There are fixed combinations of ISX and prolonged β 2 -adrenomimetics, combining a means of basic therapy and a symptomatic agent. According to the GINA global strategy, fixed combinations are the most effective means of basic therapy of bronchial asthma, since they allow you to remove the attack and at the same time are therapeutic agent. Two such fixed combinations are in popularity of popularity:

salmetterol + Fluticazone (Seryoteide 25/50, 25/125 and 25/250 μg / dose, Serylate Multidisc 50/100, 50/250 and 50/500 μg / dose, Tevaacomb 25/50, 25/125 and 25/250 μg /dose)

formoterol + Budesonide (symbiracort turbuchaler 4.5 / 80 and 4.50 μg / dose, in the composition of the drug Sertide enters salmeterol at a dose of 25 μg / dose in a dosed aerosol inhaler and 50 μg / dose in the Multidisc apparatus. Maximum The permissible daily dose of salmeterol is 100 μg, that is, the maximum multiplicity of the application of the sewage is 2 breaths 2 times for the dosage inhaler and 1 breath 2 times to fix "Multidisc". This gives a symbicant advantage if you need to increase the ISX dose. Simbicort contains Formoterol The maximum permissible daily dosascoach is 24 μg, makes it possible to be inhaled by a symbicant to 8 times a day. In the SMART study, the risk associated with the use of Salmeterol compared to placebo was revealed. In addition, the indisputable advantage of Formoterol is that it begins to act immediately After inhalation, and not after 2 hours, like Salmetterol.

Citation:Suithernikova O.A. Inhalation glucocorticosteroids are the most efficient and safe anti-inflammatory drugs for the treatment of asthma // RMG. 1997. №17. P. 5.

The review form provides an analysis of inhalation corticosteroids - the most effective anti-inflammatory drugs for the treatment of bronchial asthma.

Therapeutic measures and possible local complications are shown depending on the dosage, combinations of drugs and the methods of their introduction.

The Paper Analyzes Inhaled Glycocorticosteroids, The Most Effective AntiInflammatory Drugs In The Treatment Of Therapeutical Action and Possible Local Complications Resulting from The Dosage, Combinations of Drugs and Routees of their Administration.

O. A. Suithernikova
Research Institute of Pulmonology Ministry of Health of the Russian Federation, Moscow
O. A. Sutochnikova.
Research Institute of Pulmonology, Ministry of Health Of The Russian Federation, Moscow

Introduction

Bronchial asthma (BA) is currently one of the most common human diseases. Epidemiological studies of the last twenty-five years indicate that the incidence of asthma has reached a level of 5% among the adult population, and among children - 10%, representing a serious social, epidemiological and medical problem, attracting close attention of medical societies. International consensus (1995) formulated the working definition of BA, based on pathological changes and functional disorders as consequences of inflammation of the respiratory tract.
The main purpose of treating the BA is to improve the quality of life of the patient by preventing exacerbations, ensuring the normal function of the lungs, maintaining the normal level of physical activity, excluding side effects medicinesApplied in the treatment (National Heart, Lung & Blood Institute, National Institutes of Health. International Consensus Report on Diagnosis and Management of Asthma // EUR Respir J. - 1992). Based on the leading role of inflammation in the pathogenesis Ba, the treatment involves the use of anti-inflammatory funds, the most effective of which are corticosteroids that reduce the vascular permeability, preventing the emissions of the bronchial wall, which reduces the yield of effector cells of inflammation into the bronchoalveolar space and blocking mediators of inflammation from effector cells (A. P. Chucenin, 1994; Bergner, 1994; Fuller et al., 1984).
Back in the late 40s, the doctors began to use system corticosteroids (Carryer et al., 1950; Gelfand ML, 1951), which played a significant role in the therapy of this disease. The mechanism of the action of corticosteroids is due to their ability to bind to specific glucocorticoid receptors in cytoplasm cells. However, the long-term intake of systemic corticosteroids leads to the occurrence of unwanted systemic effects: Itsenko - Cushing syndrome, steroid diabetes and osteoporosis, arterial hypertension, gastric and intestine ulcers, frequent occurrence of opportunistic infection, myopathy, which limits their clinical use.
Pharmacokinetics of inhalation corticosteroids

In the blood of corticosteroids circulate in the free and associated state. Corticosteroids with albumin plasma and transcertine are associated. Only free corticosteroids are biologically active. On the number of free corticosteroids, i.e. Metabolically active hormones that come into cells affect 3 factors:

• the degree of binding to plasma protein;
• the speed of their metabolism;
• the ability of corticosteroids to contact specific intracellular receptors (Muller et al., 1991; Ellul-Micallef, 1992).

System Corticosteroids have a long half-life due to the period of their biological action. Only 60% of systemic corticosteroids binds to plasma protein, and 40% circulates freely. In addition, with a deficiency of protein or the use of high dose of systemic corticosteroids, the biologically active part of the blood corticosteroids is rising. This contributes to the development of the systemic side manifestations listed above (Shimbach et al., 1988). Disassemble the positive anti-asthma effect and unwanted systemic manifestations of tableted steroids is difficult, and Ba is the disease of the respiratory tract, in this regard, it was suggested that the possibility of local corticosteroids was expressed.

Anti-inflammatory effect of inhalation corticosteroids

In the late 1960s, aerosols of water-soluble hydrocortisone and prednisone were created. However, attempts to treat asthma with these drugs were ineffective (Brokbank et al., 1956; Langlands et al., 1960) due to the fact that they have a low anti-asthmatic and high system action that can be compared with the effect of tableted corticosteroids. In the early 1970s, a group of fat-soluble corticosteroids for local use by aerosol, which, unlike water-soluble, had high local anti-inflammatory activity, were characterized by a low systemic action or its absence within the therapeutic concentration. The clinical efficacy of such a form of drugs was shown in a number of experimental studies (Clark, 1972; Morrow-Brown et al., 1972). The most significant in the local anti-inflammatory effect of inhalation corticosteroids is (BORSON et al., 1991; Cox et al., 1991; Venge et al., 1992):

• inhibition of synthesis or reduced IgE-dependent release of inflammation mediators from leukocytes;
• reducing the survival of eosinophils and the formation of colonies of granulocytes and macrophages;
• increasing the activity of neutral endopeptidase - enzyme that destroys inflammation mediators;
• suppression of monocytes mediated by monocytes, eosinophilic cationic proteins of cytotoxicity and a decrease in their content in the bronchoalveolar space;
• reducing the permeability of the epithelium of the respiratory tract and plasma exudation through the endothelial epithelial barrier;
• reduction of bronchial hyperreactivity;
• braking of M-cholinergic stimulation by reducing the number and effectiveness of CGMF.

The anti-inflammatory effect of inhalation corticosteroids is associated with the impact on biological membranes and a decrease in permeability of capillaries. Inhalation corticosteroids stabilize lysosomal membranes, which leads to a limitation of the release of various proteolytic enzymes beyond the limits of lysosomes and prevents destructive processes in the wall of the bronchial tree. They oppress the proliferation of fibroblasts and reduce the synthesis of collagen, which reduces the pace of development of the sclerotic process in the Bronchi wall (Burke et al., 1992; Jeffery et al., 1992), inhibit the formation of antibodies and immune complexes, reduce the sensitivity of effector tissues to allergic reactions, contribute to Bronchial cyliogenesis and restoration of damaged bronchi epithelium (Laitinen et al., 1991a, b) reduce nonspecific bronchial hyperreactivity (Juniper et al., 1991; Sterk, 1994).
Inhalation administration of corticosteroids quickly creates a high concentration of the drug directly in the tracheoobronchial tree and avoids the development of systemic side manifestations (Agertoft et al., 1993). Such use of drugs in patients with dependence on system corticosteroids reduces the need for constant reception. It has been established that inhalation corticosteroids do not have side effect on Mukiciliar clearance (Dechatean et al., 1986). Long-term treatment with inhalation corticosteroids in medium and intermediate doses (up to 1.6 mg / day) not only does not lead to morphologically visible damage to the epithelium and connective tissue of the bronchial wall, which is confirmed in light and electron microscopic levels, but also contributes to bronchial cylinegenesis and restoration Damaged epithelium (Laursen et al., 1988; Lundgren et al., 1977; 1988). In experimental studies, when analyzing bronchobiops in patients receiving inhaled corticosteroids, it was found that the ratio of glassoid and eyelant cells increases to a level similar to that, which is observed in healthy volunteers (Laitinen, 1994), and when analyzing the cytogram of the bronchoalveolar fluid, there is no disappearance of specific inflammatory cells. - Eosinophil (Janson-Bjerklie, 1993).

Systemic effect corticosteroids

Glucocorticoids affect the hypothalamic-pituitary and adrenal system. When exposed to the hypothalamus, the products and release of the corticotropin-rilizing factor are reduced, the products and release of the hypophysome of the adrenocorticotropic hormone (ACTH) are reduced and, as a result, reduced cortisol products with adrenal glands (Taylor et al., 1988).
A long period of treatment with systemic corticosteroids, as a rule, suppresses the function of the hypothalamic-pituitary-adrenal system. Significant individual differences in the pituitary response to the corticotropin-rilizing factor were revealed, while the dose of the prednisone received after prednisolone did not explain these differences (Schurmeyer et al., 1985). The value of persistent adrenocortical hypofunction in patients with dependence on system corticosteroids should not be underestimated (Yu. S. Lyandyshev et al., 1994), since the sharp heavy episodes of asthma, which developed on a background, can end in death.
Of great interest is the degree of hypothalamic-pituitary-adrenal suppression when using inhalation corticosteroids (BROIDE 1995; Jennings and Sovut., 1990; 1991). Inhalation corticosteroids have a moderately pronounced systemic effects due to the part of the drug that is absorbed in bronchi, is swallowed and absorbed in the intestine (Bisgard, et al., 1991; Prahl, 1991). This is due to the fact that inhalation corticosteroids have a short half-life, quickly biotransflowed in the liver after systemic absorption, which significantly reduces their biological action. When using high doses of inhalation corticosteroids (1.6 - 1.8 mg / day) or combinations with systemic corticosteroids, there is a risk of developing systemic side effects (SELROOS et al., 1991). The effects of inhalation corticosteroids on the hypothalamic-pituitary-adrenal system in patients who were not previously taken, significantly less than in patients who used inhaled corticosteroids earlier (Toogood et al., 1992). The frequency and degree of severity of the suppression increase when using high doses of inhalation corticosteroids in patients receiving simultaneously systemic and inhalation corticosteroid therapy, and when replacing long-term therapy with systemic corticosteroids on inhalation in high doses (Brown et al., 1991; Wong et al., 1992) . The existing suppression of the hypothalamic-pituitary-adrenal system can be restored, but this process can be delayed up to three years and more. Systemic side manifestations of inhalation corticosteroids include partial eosinopenia (Chaplin et al., 1980; Evans et al., 1991; 1993). The question of the development of osteoporosis, a slowdown in the growth and formation of cataracts in the treatment of inhalation corticosteroids (Nadasaka, 1994; Wolters et al., 1992) continues to be discusted. However, the possibility of the occurrence of these complications is associated using these drugs in high doses (1.2 - 2.4 mg / day) for a long period (Ali et al., 1991; Kewley, 1980; Toogood et al., 1988; 1991; 1992). On the other hand, the slowdown in some children, patients of B and receiving inhaled corticosteroids, is more often due to violations in the pubertal period, but does not depend on the influence of steroid inhalation therapy (Balfour-Lynn, 1988; NASSIF et al., 1981; Wolters and Sovt ., 1991). It is recognized that large doses of inhalation corticosteroids are able to penetrate the placental barrier, providing a teratogenic and fetotoxic effect. However, the clinical use of low and secondary therapeutic doses of these drugs with pregnant women suffering from bronchial asthma is not affected by increasing the frequency of congenital anomalies in newborns (Fitzsimons et al., 1986).
In immunocompetent patients, the frequency, severity and duration of viral or bacterial infections do not increase against the background of therapy in inhalation corticosteroids (Frank et al., 1985). At the same time, due to the risk of opportunistic infection in immunocomplete patients, inhalation corticosteroids should be used with great caution. With a combination of Ba, treated with inhalation preparations, with active tuberculosis, additional anti-tuberculosis therapy, as a rule, is not required (Horton et al., 1977; Schatz et al., 1976).

Local side manifestations of inhalation corticosteroids

Local complications of inhalation corticosteroid therapy include candidiasis and dysphony (Tooogood et al., 1980). It was shown that these complications depend on the daily dose of the drug (Toogood et al., 1977; 1980). The growth of yeast-like mushrooms of the genus Candida in the oral cavity and the sip is the result of an overwhelming effect of inhalation corticosteroids on protective functions of neutrophils, macrophages and T-lymphocytes on the surface of their mucous membrane (Toogood et al., 1984). The dysphony when using inhalations of corticosteroids is associated with dyskinesia muscles controlling the voltage of voice ligaments (Williams et al., 1983). Non-specific irritation of voice ligaments with propellant - freon contained in a dosage aerosol inhaler as a gas-displacer may also cause a dysphony. The most common, severe dispony is observed in patients who, by the nature of activity, have a load on voice ligaments - priests, dispatchers, teachers, coaches, etc. (Toogood et al., 1980).

Modern inhalation corticosteroids

Currently, the main drugs of the group of inhalation corticosteroids include the following: Becklomethazone dipropionate, Betamethazone Valerat, Budesonide, triamxinolone acetonide, flonolide and fluticasone propionate, having widespread use in world pulmonary practice and having high efficiency (Harding, 1990; Svendsen, 1990; Toogood and Sow., 1992). However, they differ in the ratio of local anti-inflammatory activity and systemic action, as evidenced by such an indicator as a therapeutic index. Of all the inhalation corticosteroids, budesonide has the most favorable therapeutic index (Dahl et al., 1994; Johansson et al., 1982; Phillips, 1990), which is associated with its high affinity for glucocorticoid receptors and accelerated metabolism after systemic absorption in the lungs and intestines ( Anderson et al., 1984; Brattsand et al. 1982; Chaplin et al., 1980; CLISSOLD et al., 1984; Phillips 1990; Ryrfeldt et al., 1982).
For inhalation corticosteroids (aerosol form), it is established that 10% of the drug falls into the lungs, and 70% remains in the oral cavity and large bronchops (I. M. Kakhanovsky et al., 1995; Dahl et al., 1994). Patients have different sensitivity to inhalation corticosteroids (N. R. Paleev et al., 1994; Bogaska, 1994). It is known that children the metabolism of drugs flow faster than adults (Jennings et al., 1991; Pedersen et al., 1987; Vaz et al., 1982). The pharmacokinetics of the main drugs of the group of inhalation corticosteroids are presented in the table.

Dosage questions and combinations of drugs

Inhalation and systemic corticosteroids show the total effect, if used together (toogood et al., 1978; WYA et al., 1978), but systematic corticosteroidal activity of combination treatment (inhalation + systemic corticosteroids) is several times lower than that of prednisone used in The daily dose required to achieve equitable control over the symptoms of asthma.
It has been established that the severity of asthma correlates with the degree of sensitivity to inhalation corticosteroids (Toogood et al., 1985). Low doses of inhalation preparations are effective and reliable in patients with light asthma, with a short period of the disease and in most patients with moderately severe chronic asthma (LEE et al., 1991; Reed, 1991). Increased dose is necessary to quickly achieve control over the symptoms of asthma (Boe, 1994; Toogood, 1977; 1983). Continue treatment, if necessary, high doses of inhalation corticosteroids should be normalized or improved external respiratory functions (Selroos et al., 1994; Van Essen-Zandvliet, 1994), which makes it possible to part patients to stop taking system corticosteroids or reduce their dose (tarlo et al., 1988). With the clinical need to combine the use of inhalation and systemic corticosteroids, the dose of each drug should be chosen as minimally effective to achieve the maximum symptomatic effect (Selroos, 1994; Toogood, 1990; Toogood et al., 1978). In patients with severe asthma, having a dependence on system corticosteroids, as well as part of patients with moderately severe chronic asthma in the absence of an effect from the use of low or medium doses. inhalation drugs It is necessary to use their high doses - up to 1.6 - 1.8 mg / day. In such patients, their combination with systemic corticosteroids is justified. However, when taking high doses of inhalation corticosteroids, the risk of oro-fabulinal complications increases and reducing the level of the morning cortisol in plasma (Toogood et al., 1977). To select the optimal dosage and mode of receiving inhalation drugs, use the indicators of the function of external respiration, daily monitoring of picofloumetria. For long-term maintenance of the remission of the disease, the dose of inhalation corticosteroids ranges from 0.2 to 1.8 mg per day. Due to the fact that when using low doses there are no systematic effects, the preventive purpose of such doses at an early stage of Ba is justified, which allows to delay the progression of the disease (Haahtela et al., 1994; Van Essen-Zandvliet, 1994). In patients with light asthma, the reduction in the hyperreactivity of the bronchi and the stabilization of the disease is achieved over 3 months of reception of inhalation corticosteroids (I. M. Kakhanovsky et al., 1995).
Patients with asthma of the moderate severity of the treated beclomethazone dipropionate and budesonide, on average, 9 months of treatment are required to achieve a reliable reduction in the performance of the respiratory tract hyperreactivity (Woolcoch et al., 1988). In rare observations, such a decrease was achieved only after 15 months of treatment. With a sharp abolition of inhalation corticosteroids in patients with asthma, the average severity of the flow, which were treated with low doses of inhalation preparations, in 50% of observations there are relapse of the disease in 10 days and 100% in 50 days (TooGood et al., 1990). On the other hand, the long and regular use of inhalation corticosteroids increases the period of remission of the disease up to 10 years or more (Boe et al., 1989).

Methods for the introduction of inhalation corticosteroids

The disadvantage of inhalation corticosteroids is the method of administering the drug, requiring special training of the patient. The effectiveness of the inhalation is associated with the delay of its active particles in the respiratory tract. However, such a retention of the drug in an adequate dose is often difficult due to the violation of the technique of inhalation. Many patients use an aerosol inhaler incorrectly, and poor inhalation technique is the main factor in its extremely low efficiency (Crompton, 1982). Spacers and them similar nozzles for aerosol inhalers eliminate the problem of synchronization of inhalation and release of the dose, reduce the delay in the drug in the larynx, increase the delivery to the lungs (NEWMAN et al., 1984), reduce the frequency and severity of the ororoparingeal candidiasis (Toogood et al., 1981; 1984 ), hypothalamic-pituitary-adrenal suppression (prachl et al., 1987), increase anti-inflammatory efficiency. The use of the spacer is recommended in the case of clinical need to appoint antibiotics or additional systemic corticosteroids (MOREN, 1978). However, to completely exclude local side manifestations in the form of a chopping candidiasis, dysphony, sporadic cough until it is possible. To eliminate them, gentle voice regime is recommended, a reduction in the daily dose of corticosteroids (MOREN, 1978).
A longer respiratory delay after inhalation can reduce the deposition of the drug during the exhalation in the Rothoglik (NEWMAN et al., 1982). Rinsing the oral cavity and throat immediately after the inhalation of the drug reduce to a minimum local absorption. The observations showed that the 12-hour interval between the inhalations of the corticosteroid is sufficient to temporarily restore the normal protective function of neutrophils, macrophages and T-lymphocytes on the surface of the oral mucosa. In studies with Becklomethasone, dipropionate and budesonide showed that the division of the daily dose for two receptions warns the development of the colonium genush the genus of the genus Candida and eliminates the thrush (Toogood et al., 1984). Paroxysmal cough or bronchospasm, which can be caused by the inhalation of aerosol, in patients associated with the irritating effect of propellants and the delay of particles of the drug in the respiratory tract, incorrect inhalation technology, exacerbation of the concomitant respiratory tract infection or the recently transferred exacerbation of the underlying disease, after which the increased hypereactivity of the respiratory tract persists . At the same time, most of the dose is thrown into a reflex cough and an erroneous opinion about the ineffectiveness of the drug (CHIM, 1987) occurs. However, the complete solution to this problem requires more efficient measures to eliminate primary reasons: the relief of the concomitant infectious process, a decrease in the hyperreactivity of bronchi, improving mukiciliary clearance. In the aggregate, this will allow an inhaled drug to get into the peripheral respiratory tract, and not to settle in the trachea and large bronchops, where the particle deposition causes a reflex cough and bronchospasm.
Given the listed side manifestations and some problems in the use of aerosol corticosteroids, inhaled corticosteroids were developed as a dry powder. For the inhalation of this form of the drug, special devices are designed: Rotokhaler, turbochâcher, spinchaler, dischecher. These devices have advantages compared with an aerosol inhaler (Selroos et al., 1993a; Thorsoon et al., 1993), as they are activated by breathing due to the maximum breath rate, which eliminates the problem of coordination inhale with the release of the dose of the drug, in the absence of a toxic effect of propellant . Inhalers with medicinal substance in the form of dry powder are environmentally safe because they do not contain chlorofluorocarboons. In addition, inhalation corticosteroids in the form of dry powder have a more pronounced local anti-inflammatory effect and have advantages on clinical efficacy (De Graaft et al., 1992; Lundback, 1993).

Conclusion

Inhalation corticosteroids are currently the most effective anti-inflammatory drugs for the treatment of Ba. Studies have shown their effectiveness that manifested itself in improving the function of external respiration, reducing the hypersensitivity of the bronchi, reducing the symptoms of the disease, reducing the frequency and severity of exacerbations and improving the quality of life of patients.
The main rule of corticosteroid therapy is the use of drugs in a minimum effective dose for a short period of time required to achieve a maximum symptomatic effect. For the treatment of high flow asthma, it is necessary to prescribe high doses of inhalation corticosteroids for a long period of time, which will reduce the need for patients in tableted corticosteroids. Such therapy has a significantly less systemic side effect. The dose of drugs should be selected individually, since the optimal dose varies from individual patients and can change over time in the same patient. To select the optimal dosage and mode of reception of inhalation corticosteroids, use the indicators of the function of external respiration, daily monitoring of picofloumetria. The dose of corticosteroids should always be reduced gradually. The constant monitoring of patients receiving corticosteroids is important to identify adverse reactions and ensure the regularity of treatment. The development of local side manifestations of inhaled corticosteroids can often be prevented, if you use a spacer, rinse your mouth after inhalation. Proper inhalation technology is 50% of success in the treatment of bronchial asthma patients, which requires development and implementation in the daily practice of methods for the proper use of inhalation devices to achieve maximum efficiency of inhalation drugs. It must be remembered that the aggravation of asthma may indicate the ineffectiveness of anti-inflammatory therapy of chronically occurring disease and requires revision of the supporting therapy and dosages of the drugs used.

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Full list of references used in the editorial office

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 gastrointestinal tract and quickly metabolized in the liver, which provides high therapeutic ICCC index compared with 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 IGCCs differ among themselves by the magnitude of the therapeutic index, which is a 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% ( Fluisolide) ().

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 it was proposed new drug IGCC - cyclezonide, 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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