home Auditorium 8 Glucocorticosteroids: when prescribed, rules of administration. Characteristics and list of glucocorticosteroid drugs: rules for the use of hormonal drugs for renal diseases GCS, which are drugs in medicine

Glucocorticosteroids: when prescribed, rules of administration. Characteristics and list of glucocorticosteroid drugs: rules for the use of hormonal drugs for renal diseases GCS, which are drugs in medicine

The history of the use of glucocorticosteroids (GCS) in clinical practice goes back a little more than half a century, although the “antirheumatic substance X” has been known since the 20s of the twentieth century. A detailed study of the clinical significance of adrenal hormones, begun by Edward Calvin Kendall and Tadeus Reichstein, was continued only after Philip Hench in the late 40s drew attention to the improvement of rheumatoid arthritis in jaundice and pregnancy. In 1950, all three were awarded the Nobel Prize for "...discoveries concerning the hormones of the adrenal cortex, their structure and biological effects."

Currently, GCS includes both natural hormones of the adrenal cortex with a predominantly glucocorticoid function - cortisone and hydrocortisone (cortisol), and their synthesized analogues - prednisone, prednisolone, methylprednisolone, etc., including halogenated (fluorinated) derivatives - triamcinolone, dexamethasone, betamethasone etc. A wide range of physiological and pharmacological effects of glucocorticoids (adaptogenic, anti-inflammatory, analgesic and antipyretic, nonspecific membrane-stabilizing and anti-edematous, antiallergic and immunosuppressive, hematological, hemodynamic and anti-shock, antitoxic, antiemetic, etc.) makes these drugs almost universal medicines , and today it is difficult to find a pathological condition in which they would not be indicated at one or another stage of development. Among the indications, first of all, we can highlight the so-called rheumatic diseases, kidney diseases, blood diseases, allergic diseases, transplantations, urgent conditions.

Depending on the purpose, there are three options for GCS therapy; Moreover, any of them can be either urgent or planned.

In contrast to planned therapy, the use of GCS in urgent situations is, as a rule, symptomatic, less often pathogenetic in nature and does not replace, but complements other treatment methods. As part of emergency therapy, GCS are used for acute adrenal insufficiency, thyrotoxic crisis, allergic diseases (serum sickness, anaphylactic shock, bronchial asthma, urticaria, Quincke's edema), liver diseases (hepatocellular failure), neurological diseases (tuberculous and bacterial meningitis, some forms of cerebral edema), various types of shock (except cardiogenic).

Due to the abundance of side effects, GCS therapy is aimed mainly at achieving maximum effect when prescribing minimal doses, the value of which is determined by the disease and does not depend on body weight and age; the dose is adjusted according to individual response. Two fundamentally different schemes for prescribing GCS have been adopted:

starting with the lowest possible dose, increase it if the effect is insufficient to the optimal one; in this case, there is a danger of increasing the duration of treatment, loss of effectiveness and development of side effects;
starting from the maximum daily doses, they are reduced after obtaining a clinical effect; in this case, a rapid effect is achieved, the duration of treatment and the total dose of GCS are reduced.

Depending on the daily dose (in terms of prednisolone) and the duration of use of GCS, it is customary to distinguish several types of therapy with different indications:

in situations that are directly life-threatening, intensive therapy is prescribed with ultra-high (up to 500-4000 mg intravenously) or medium/high (25-150 mg orally) doses (an oral dose of prednisolone is equivalent to approximately 1/6 intravenous) - such therapy can be carried out for several days and does not require gradual withdrawal;
in case of severe exacerbations or in the chronic course of severe diseases (leukemia, some collagenoses, hemolytic anemia, thrombocytopenia), limited therapy is carried out, limited to weeks when using high doses orally (80-200 mg) and weeks or months when using medium doses (25-60 mg); the maximum doses prescribed at the beginning are gradually reduced as the condition improves, followed by a transition to maintenance doses;
for a number of chronic diseases (bronchial asthma, rheumatoid arthritis), long-term therapy with low doses (up to 10 mg) is carried out, but doses less than 5 mg are most likely only replacement and provide a clinical effect only with atrophy of the adrenal cortex induced by long-term glucocorticoid therapy.

The result of GCS therapy depends not only on the dose, but also on the dosage regimen. The most promising are intermittent regimens of use, when the drug is not taken every day by increasing the daily dose. Intravenous pulse therapy with maximum doses seems to be the most effective, but it also turns out to be the most unsafe. The “mini-pulse” mode should be considered significantly safer, which, however, is inferior in effectiveness to pulse therapy. Prescribing a moderate/high dose, divided into several doses, is equally effective; but in terms of safety, this mode is inferior to “mini-pulse”. Next in effectiveness are the alternating regimen (every other day, double the daily dose followed by a gradual decrease) and the regimen of a daily single dose of moderate/high dose; the first of them is safer and according to this criterion is closer to a “mini-pulse”. The safest therapy is low doses, which, however, provides only a maintenance effect. For all daily regimens, GCS should be administered in the early morning hours (between 6 and 8 a.m.); if a one-time dose is not possible due to the size of the dose, 2/3 of the dose is prescribed at 8 o’clock and 1/3 in the afternoon (around noon). With any dosage regimen, once the planned effect is achieved, the dose is gradually reduced to a maintenance dose or the drug is discontinued altogether.

An important problem in GCS therapy is the choice of drug. The pharmacokinetic and pharmacodynamic properties of GCS, including their side effects, vary significantly among individual drugs (,). Taking the severity of the various effects of hydrocortisone as one, it is possible to obtain quantitative characteristics of the activity of individual drugs. When comparing GCS, the anti-inflammatory effect of these drugs is most often analyzed, according to which the equivalent oral dose is calculated, decreasing as the anti-inflammatory activity increases. Its increase, parallel to the increase in the duration of action of individual corticosteroids, is accompanied by a decrease in mineralocorticoid activity, which can generally be neglected in methylprednisolone (solu-medrol) and fluorinated compounds.

The ratio of therapeutic and side effects suggests that currently the drug of choice for long-term and lifelong therapy is methylprednisolone (solu-medrol). Currently, solu-medrol is widely used in the treatment of autoimmune diseases, in transplantation and intensive care. The variety of release forms allows the drug to be used in all age categories in optimal dosages.

The second most effective drug remains in most cases prednisolone. In many urgent situations, fluorinated compounds have certain advantages: dexamethasone (Dexazone, Dexona) and betamethasone (Celeston, Diprospan). However, in the case of emergency therapy, in which the anti-inflammatory effect does not play a leading role, a comparative assessment of the effectiveness and safety of various drugs is very difficult for at least two reasons:

The effectiveness and safety of different drugs can only be compared on the basis of their equivalent doses. Meanwhile, if there are relative activity characteristics for various side effects of individual GCS, of all the therapeutic effects only the anti-inflammatory effect is compared, according to which the equivalent dose is calculated;
There is no clear data on the ratio of doses for oral and parenteral use of specific drugs, even when it comes to the anti-inflammatory effect, not to mention other therapeutic or side properties.

In connection with the above difficulties, a conventional equivalent unit (CUE) was proposed, which is taken to be the minimum effective dose. It has been shown that the maximum daily effective doses of fluorinated corticosteroids (dexamethasone and betamethasone), expressed in UEE, are five times less than those of non-halogenated drugs. This ensures not only higher efficiency and safety of this group of drugs prescribed in certain situations, but also their pharmacoeconomic advantages.

No matter how carefully the choice of drug, dosage regimen and type of therapy is made, it is not possible to completely prevent the development of certain side effects when using GCS. The nature of adverse reactions may depend on a number of reasons ().

The likelihood and severity of suppression of the HPA axis with the development of first functional failure and later atrophy of the adrenal cortex are determined by the dose and duration of therapy. Discontinuation of glucocorticoid therapy is almost always associated with the risk of developing acute adrenal insufficiency.

A common side effect of GCS is infectious complications, which in this case occur atypically, which is associated with the anti-inflammatory, analgesic and antipyretic activity of these drugs. This makes timely diagnosis difficult and requires a number of preventive measures. Due to the tendency to generalization, protracted course, tissue decay and resistance to specific therapy, these complications become especially dangerous. Equally insidious are “steroid ulcers”, characterized by an asymptomatic course and a tendency to bleeding and perforation. Meanwhile, gastric discomfort, nausea, and other dyspeptic complaints while taking GCS are often not associated with damage to the mucous membrane. Exogenous Cushing's syndrome as a complication of GCS therapy does not always occur, however, individual disorders of metabolism, hormonal regulation and the activity of certain systems develop in almost all cases of glucocorticoid therapy.

It is with regret that we note that the statement of E.M. Tareev, who called GCS therapy difficult, complex and dangerous, is still true. As Tareev wrote, such therapy is much easier to start than to stop. However, a responsible approach to treatment can significantly improve its safety. This is achieved through strict consideration of contraindications (among which there are no absolute ones) and side effects of GCS (assessment of the “expected effect/estimated risk” ratio), as well as conducting “cover therapy” in risk groups (antibacterial drugs for chronic foci of infection, dose adjustment of hypoglycemic drugs or switching to insulin for diabetes, etc.). A special place in the long-term use of GCS is occupied by metabolic therapy, which is carried out in order to prevent and correct disturbances of electrolyte metabolism and catabolic processes primarily in the myocardium (dystrophy) and bone tissue (osteoporosis). However, the most reliable way to ensure the safety of GCS therapy remains compliance with the basic principle of clinical pharmacology and pharmacotherapy—prescribing treatment according to strict indications.

V. V. Gorodetsky, Candidate of Medical Sciences
A. V. Topolyansky, Candidate of Medical Sciences

Note!

Currently, GCS includes both natural hormones of the adrenal cortex with a predominantly glucocorticoid function, and their synthesized analogues, including halogenated (fluorinated) derivatives.
Depending on the purpose, there are three options for GCS therapy: replacement, blocking and pharmacodynamic; Moreover, any of them can be either urgent or planned.
Due to the abundance of side effects, GCS therapy is aimed at achieving maximum effect with minimal doses, the magnitude of which is determined by the disease and does not depend on body weight and age; Dose adjustment is carried out in accordance with individual response.
The result of GCS therapy depends not only on the dose, but also on the dosage regimen. The most promising are intermittent regimens of use, when the drug is not taken every day by increasing the daily dose.
No matter how carefully the choice of drug, dosage regimen and type of therapy is made, it is not possible to completely prevent the development of certain side effects when using GCS.

Surely you have heard about steroid hormones at least once. Our body continuously produces them to regulate vital processes. In this article we will look at glucocorticoids - steroid hormones that are produced in the adrenal cortex. Although we are most interested in their synthetic analogues - GCS. What is this in medicine? What are they used for and what harm do they cause? Let's get a look.

General information about GCS. What is this in medicine?

Our body synthesizes steroid hormones such as glucocorticoids. They are produced by the adrenal cortex, and their use is mainly associated with the treatment of adrenal insufficiency. Nowadays, not only natural glucocorticoids are used, but also their synthetic analogues - GCS. What is this in medicine? For humanity, these analogues mean a lot, as they have an anti-inflammatory, immunosuppressive, anti-shock, and anti-allergic effect on the body.

Glucocorticoids began to be used as medicines (hereinafter in the article - drugs) back in the 40s of the twentieth century. By the end of the 30s of the twentieth century, scientists discovered steroid hormonal compounds in the human adrenal cortex, and already in 1937 the mineralocorticoid deoxycorticosterone was isolated. In the early 40s, the glucocorticoids hydrocortisone and cortisone were also introduced. The pharmacological effects of cortisone and hydrocortisone were so varied that it was decided to use them as drugs. After some time, scientists synthesized them.

The most active glucocorticoid in the human body is cortisol (an analogue is hydrocortisone, the price of which is 100-150 rubles), and it is considered the main one. Less active ones can also be distinguished: corticosterone, cortisone, 11-deoxycortisol, 11-dehydrocorticosterone.

Of all the natural glucocorticoids, only hydrocortisone and cortisone have found use as drugs. However, the latter causes side effects more often than any other hormone, which is why its use in medicine is currently limited. Today, only hydrocortisone or its esters (hydrocortisone hemisuccinate and hydrocortisone acetate) are used among glucocorticoids.

As for glucocorticosteroids (synthetic glucocorticoids), a number of such drugs have been synthesized in our time, among which we can distinguish fluorinated (flumethasone, triamcinolone, betamethasone, dexamethasone, etc.) and non-fluorinated (methylprednisolone, prednisolone, prednisone) glucocorticoids.

Such agents are more active than their natural counterparts, and treatment requires smaller doses.

Mechanism of action of GCS

The effect of glucocorticosteroids at the molecular level has not been fully elucidated. Scientists believe that these drugs act on cells at the level of gene transcription regulation.

When glucocorticosteroids penetrate into the cell (through the membrane), they bind to receptors and activate the “glucocorticoid + receptor” complex, after which it penetrates the cell nucleus and interacts with DNA sections that are located in the promoter fragment of the steroid-responsive gene (they are also called glucocorticoid -responding elements). The glucocorticoid + receptor complex is capable of regulating (suppressing or, conversely, activating) the process of transcription of certain genes. This is what leads to suppression or stimulation of m-RNA formation, as well as changes in the synthesis of various regulatory enzymes and proteins that mediate cellular effects.

Various studies show that the glucocorticoid + receptor complex interacts with various transcription factors, such as nuclear factor kappa B (NF-kB) or transcription activator protein (AP-1), which regulate genes involved in the immune response and inflammation (adhesion molecules, cytokine genes, proteinases, etc.).

Main effects of GCS

The effects of glucocorticosteroids on the human body are numerous. These hormones have antitoxic, antishock, immunosuppressive, antiallergic, desensitizing and anti-inflammatory effects. Let's take a closer look at how GCS work.

Anti-inflammatory effect of GCS. It is caused by the suppression of the activity of phospholipase A 2. When this enzyme is inhibited in the human body, the liberation (release) of arachidonic acid is suppressed and the formation of certain inflammatory mediators (such as prostaglandins, leukotrienes, troboxane, etc.) is inhibited. Moreover, taking glucocorticosteroids leads to a decrease in fluid exudation, vasoconstriction (narrowing) of capillaries, and improvement of microcirculation at the site of inflammation.
Antiallergic effect of GCS. Occurs as a result of a decrease in the secretion and synthesis of allergy mediators, a decrease in circulating basophils, inhibition of the release of histamine from basophils and sensitized mast cells, a decrease in the number of B and T lymphocytes, a decrease in the sensitivity of cells to allergy mediators, changes in the body's immune response, as well as inhibition of antibody formation.
Immunosuppressive activity of GCS. What is this in medicine? This means that the drugs inhibit immunogenesis and suppress the production of antibodies. Glucocorticosteroids inhibit the migration of bone marrow stem cells, suppress the activity of B and T lymphocytes, and inhibit the release of cytokines from macrophages and leukocytes.
Antitoxic and antishock effect of GCS. This effect of hormones is due to an increase in blood pressure in humans, as well as activation of liver enzymes that are involved in the metabolism of xeno- and endobiotics.
Mineralocorticoid activity. Glucocorticosteroids have the ability to retain sodium and water in the human body and stimulate the excretion of potassium. In this regard, synthetic substitutes are not as good as natural hormones, but they still have the same effect on the body.

Pharmacokinetics

If during the use of GCS the patient suffers an infectious disease (chicken pox, measles, etc.), it can be very severe.

When treating GCS in patients with autoimmune or inflammatory diseases (rheumatoid arthritis, intestinal diseases, systemic lupus erythematosus, etc.), cases of steroid resistance may occur.

Patients receiving oral glucocorticosteroids for a long time should periodically undergo a stool test for occult blood and undergo fibroesophagogastroduodenoscopy, since steroid ulcers may not be a concern during treatment with GCS.

30-50% of patients treated with glucocorticosteroids for a long time develop osteoporosis. As a rule, it affects the feet, hands, pelvic bones, ribs, and spine.

Interaction with other drugs

All glucocorticosteroids (classification does not matter here) give a certain effect when in contact with other drugs, and this effect is not always positive for our body. Here's what you need to know before using corticosteroids with other drugs:

GCS and antacids - absorption of glucocorticosteroids decreases.
GCS and barbiturates, diphenin, hexamidine, diphenhydramine, carbamazepine, rifampicin - the biotransformation of glucocorticosteroids in the liver increases.
GCS and isoniazid, erythromycin - the biotransformation of glucocorticosteroids in the liver decreases.
GCS and salicylates, butadione, barbiturates, digitoxin, penicillin, chloramphenicol - all of these drugs increase elimination.
GCS and isoniazid are disorders of the human psyche.
GCS and reserpine - the appearance of a depressive state.
GCS and tricyclic antidepressants - intraocular pressure increases.
GCS and adrenomimetics - the effect of these drugs is enhanced.
GCS and theophylline - the anti-inflammatory effect of glucocorticosteroids is enhanced, cardiotoxic effects develop.
GCS and diuretics, amphotericin, mineralocorticoids - the risk of hypokalemia increases.
GCS and fibrinolytics, butadine, ibuprofen, hemorrhagic complications may follow.
GCS and indomethacin, salicylates - this combination can lead to ulcerative damage to the digestive tract.
GCS and paracetamol - the toxicity of this drug increases.
GCS and azathioprine - increases the risk of cataracts and myopathies.
GCS and mercaptopurine - the combination can lead to an increase in the concentration of uric acid in the blood.
GCS and hingamine - the undesirable effects of this drug increase (corneal opacification, myopathy, dermatitis).
GCS and methandrostenolone - the undesirable effects of glucocorticosteroids are enhanced.
GCS and iron supplements, androgens - increase the synthesis of erythropoietin, and against this background, an increase in erythropoiesis.
GCS and sugar-lowering drugs - an almost complete decrease in their effectiveness.

Conclusion

Glucocorticosteroids are drugs that modern medicine can hardly do without. They are used both to treat very severe stages of diseases, and simply to enhance the effect of a drug. However, like all medications, glucocorticosteroids also have side effects and contraindications. Don't forget about this. Above we have listed all the cases when you should not use glucocorticosteroids, and also provided a list of interactions of GCS with other drugs. The mechanism of action of GCS and all their effects were also described in detail here. Now everything you need to know about GCS is in one place - this article. However, under no circumstances begin treatment only after reading general information about GCS. These drugs, of course, can be purchased without a doctor’s prescription, but why would you need this? Before using any medications, you should first consult a specialist. Be healthy and do not self-medicate!

Receptors for steroids are located in the cytoplasm of cells. However, their density in different cells is not the same: from 10 to 100 steroid-sensitive receptors, which may cause different sensitivity tissues to GCS. In addition, GCS may have different tropism to GKR. Quantity glucocorticosteroid receptors (GCR) can vary significantly and change during GCS therapy.

Recent studies have shown that the effect of glucocorticosteroid hormones on the biosynthesis of messenger RNA (mRNA) is the main step in the implementation of the biological effects of GCS in the cells of target organs.

GCS can have both a specific stimulating effect and an inhibitory effect on the synthesis of various RNAs. Multidirectional effects can manifest themselves in the same organ and, perhaps, the final response of the cell to a hormonal signal depends on their ratio. GCS also affect the activity of RNA polymerase.

Pharmacodynamic effects of glucocorticosteroids

1. The anti-inflammatory effect of GCS manifests itself in the form of antiexudative and stabilization of cellular and subcellular membranes (mitochondria and lysosomes);

decreased permeability of the vascular wall, in particular capillaries;

vasoconstriction at the site of inflammation;

reducing the release of biologically active amines (histamine, serotonin, kinins and prostaglandins) from mast cells;

reduction in the intensity of energy formation processes in the focus of inflammation;

inhibition of migration of neutrophils and macrophages to the site of inflammation, disruption of their functional activity (chemotactic and phagocytic), peripheral leukocytosis;

suppression of monocyte migration, slowing down the release of mature monocytes from the bone marrow and reducing their functional activity;

inducing the synthesis of lipomodulin, which blocks phospholipase A of cell membranes, disrupts the release of phospholipid-bound arachidonic acid and the formation of pro-inflammatory prostaglandins, leukotrienes and thromboxane A2;

inhibition of the formation of leukotrienes (leukotriene B4 reduces the chemotaxis of leukocytes, and leukotrienes C4 and D4 (slowly reacting substance) reduce the contractile ability of smooth muscles, vascular permeability and mucus secretion in the airways);

suppression of the synthesis of some pro-inflammatory cytokines and blockade of the synthesis of cytokine receptor proteins in tissues.

antiproliferative effects. suppression of nucleic acid synthesis;

impaired differentiation of fibrocytes from fibroblasts;

decrease in the functional activity of fibrocytes

2. Immunosuppressive effect: a decrease in the number of lymphocytes in the peripheral blood (lymphopenia), due to the transition of circulating lymphocytes (mainly T cells) into lymphoid tissue, possibly accumulating them in the bone marrow;

increased apoptosis of immature or activated T- and B-lymphocytes;

suppression of T cell proliferation;

decreased function of T-helpers, T-suppressors, cytotoxic T-lymphocytes;

inhibition of the activity of the complement system;

inhibition of the formation of fixed immune complexes;

decrease in the level of immunoglobulins (high doses of glucocorticoids);

inhibition of delayed type hypersensitivity reactions (type IV allergic reactions), in particular the tuberculin test;

violation of cooperation between T - and B - lymphocytes;

disruption of the synthesis of immunoglobulins and antibodies, including autoantibodies;

decrease in the number of monocytes in the vascular bed.

Side effects of the glucocorticosteroid therapy system

E.O. Borisova

Glucocorticosteroids (GCS) have a complex and multifaceted effect on body functions. They interfere with carbohydrate, protein, fat, water-electrolyte metabolism, and play an important role in regulating the activity of the cardiovascular system, kidneys, skeletal muscles, nervous system and other organs and tissues. Therefore, it is not surprising that systemic therapy with GCS in pharmacological doses causes a variety of undesirable side effects (AE) from many organs and systems, which on average develop in 50% of patients.

Many side effects, like therapeutic ones, are dose-dependent and develop in the range of low and medium doses. PE of GCS therapy can be divided into 2 groups: those developing during the treatment process (manifestations of exogenous hypercorticism) and those resulting from rapid withdrawal of drugs after long-term therapy (withdrawal syndrome).

The first group includes such manifestations of exogenous hypercorticism as fluid retention and electrolyte disturbances, arterial hypertension, hyperglycemia and glucosuria, increased susceptibility to infections (including tuberculosis). peptic ulcers, osteoporosis, myopathy, mental disorders, posterior subcapsular cataracts, glaucoma, growth retardation in children, Cushingoid habitus (obesity with characteristic redistribution of fat

Elena Olegovna Borisova - Ph.D.

honey. Sciences, Associate Professor, Department of Clinical Pharmacology, Russian State Medical University.

tissue, stretch marks, ecchymosis, acne and hirsutism).

The symptoms of exogenous hypercorticism in their spectrum differ little from endogenous Cushing's syndrome - Cushing's disease (pituitary adenoma producing adrenocorticotropic hormone - ACTH). However, with endogenous Cushing's syndrome, benign increased intracranial pressure, glaucoma, posterior subcapsular cataract, pancreatitis and aseptic bone necrosis, which are characteristic of long-term use of large doses of corticosteroids, practically do not occur. At the same time, with Cushing’s disease, arterial hypertension is more often observed.

body weight, mental disorders, edema and impaired wound healing are equally characteristic of both forms of the syndrome. These differences are associated with the fact that in Cushing's disease there is an increase in the synthesis of ACTH, and in iatrogenic hypercorticism there is a suppression of the synthesis of this hormone (the secretion of androgens and mineralocorticoids does not increase).

At the beginning of treatment with GCS, adverse effects such as sleep disturbances, emotional lability, increased appetite and body weight often develop. With long-term use of large doses, many patients develop trophic skin changes: dryness and thinning of the skin, stretch marks, acne, increased capillary patterns on the palms. Frequent reaction

Characteristic for the initial stages of treatment; essentially inevitable:

Insomnia;

Emotional lability;

Increased appetite and/or weight gain.

Typical in patients with risk factors or toxic effects of other drugs:

Arterial hypertension;

Hyperglycemia (up to the development of diabetes mellitus);

Ulceration in the stomach

and duodenum;

Expectations when using high doses for a long time:

“Cushingoid” appearance;

Suppression of the hypothalamic-pituitary-adrenal axis;

Tendency to infectious diseases;

Osteonecrosis;

Myopathy;

Poor wound healing.

Late and developing gradually (probably due to dose accumulation):

Osteoporosis;

Cataract;

Atherosclerosis;

Growth retardation in children;

Fatty hepatosis.

Rare and unpredictable:

Benign intracranial hypertension (pseudotumor cerebri);

Glaucoma;

Epidural lipomatosis;

Pancreatitis.

Time and conditions for the development of HE during treatment with GCS.

zia, acne formation, menstrual irregularities, hirsutism and

Side effects of systemic GCS therapy develop in half of the patients.

virilization in women, impotence in men, stretch marks and purpura. Increase

tion for the treatment of GCS is leukocytosis. Hypokalemia may occur. These changes do not pose a health threat, but they are usually difficult to avoid.

The likelihood of PE from hormonal therapy is associated with many factors. They are more often caused by long-acting corticosteroids (triamcinolone, betamethasone and dexamethasone) than drugs with a shorter half-life (prednisolone, methylprednisolone, hydrocortisone). Most PEs are dose-dependent, so the administration of even short-acting drugs in large doses significantly increases the frequency of their development. The duration of therapy, along with the dose, is of decisive importance in the development of PE. Long-term therapy with GCS, even in small doses, can lead to the development of PE. The risk of AE associated with long-term administration or use of large doses of corticosteroids can be reduced by rational use of doses, gentle dosing regimens and careful monitoring of expected AEs. Many adverse effects depend not only on the dose and duration of treatment, but also on the individual characteristics of the patient, his genetic and constitutional predisposition. These PEs often develop in patients who already have corresponding diseases or are prone to developing them. Some PEs are quite rare, but their development can be difficult to predict (Figure).

Metabolic disorders

Hyperglycemia is associated with a decrease in tissue sensitivity to insulin and the contrainsular effect of GCS. Although treatment with GCS may complicate glycemic control in patients with existing diabetes mellitus and provoke hyperglycemia in patients predisposed to this, the appearance of glucosuria does not prevent continued use of GCS, nor is the presence of diabetes mellitus a contraindication for starting GCS therapy. When

glucosuria is usually limited to diet, and oral antidiabetic drugs or insulin are prescribed only if necessary. Steroid-induced diabetes most often develops with the use of dexamethasone and betamethasone.

The effect of GCS on fat metabolism is manifested by a sharp redistribution of fat from the extremities to the torso and face. Adipocytes of the limbs and trunk are thought to differ in their sensitivity to insulin and the lipolytic stimuli of other endogenous substances. Trunk adipocytes preferentially respond to increased insulin levels in response to GCS-induced hyperglycemia. Adipocytes of the limbs are less sensitive to insulin and, in the presence of GCS, respond mainly to lipolytic stimuli of other hormones. As a result of fat deposition on the back of the neck, supraclavicular areas and face and loss of adipose tissue in the extremities, the characteristic Cushingoid habit develops.

Disturbances in water-electrolyte metabolism are manifested by hypokalemia, hypocalcemia, sodium and water retention. Fluid retention and hypochloremic alkalosis are rarely detected in patients receiving synthetic GCS, and even less often when taking GCS with low mineralocorticoid activity. The risk of hypokalemia increases when taking diuretics.

Arterial hypertension

An increase in blood pressure can be observed in patients taking GCS for a long time or in large doses. The mechanism of the hypertensive action of GCS has not been sufficiently studied. It is probably due to the ability of GCS to increase the expression of adrenergic receptors in the vascular wall. Threatening hy-

hypertension is possible during pulse therapy. To treat it, calcium antagonists, potassium-sparing diuretics, and angiotensin II receptor antagonists can be used.

Ulcerogenic effect

Gastric or duodenal ulcers are uncommon but serious AEs. It is believed (although there is no clear data in the literature) that GCS therapy increases the risk of developing ulcers by almost 2 times; they are more often caused by prednisolone. However, in most cases this occurs with the combined use of non-steroidal anti-inflammatory drugs. The formation of ulcers can be manifested by pain in the epigastric region and dyspepsia, but often proceeds with little or asymptomatic symptoms, manifesting with bleeding or perforation. The mechanism of the ulcerogenic effect of GCS is to increase the secretion of hydrochloric acid, reduce mucus synthesis and inhibit the regeneration of the epithelium.

Patients receiving systemic corticosteroids must be examined to exclude steroid ulcers (fibrogastroscopy, fluoroscopy of the stomach). Prevention of ulcer formation in patients with a history of ulcers or those predisposed to this disease consists of prescribing antisecretory drugs.

Myopathy

Occasionally, in patients taking high doses of corticosteroids, myopathy is diagnosed, characterized by weakness and atrophy of the skeletal muscles of the shoulder girdle, legs and pelvic muscles. The mechanism of its development is associated with the negative effect of GCS on protein and mineral metabolism. Myopathy is not a specific AE of synthetic corticosteroids, since it can also be observed with endogenous Cushing’s syndrome. This complication is most often caused by fluorinated corticosteroids - triamcinolone (more often than others), dexamethasone and betamethasone.

Side effects are most often caused by long-acting corticosteroids: triamcinolone, betamethasone and dexamethasone.

Myopathy develops soon after the start of therapy and can be quite severe, limiting the movement of patients. The process can also spread to the respiratory muscles (intercostal muscles, diaphragm), contributing to the development of respiratory failure. The development of myopathy is considered an indication for discontinuation of GCS therapy. Recovery is slow and may be incomplete. Potassium supplements and anabolic steroids are used for treatment.

Mental disorders

Mild mental disturbances (nervousness, anxiety, mild euphoria, other mood changes, sleep disturbances) are often observed at the beginning of treatment with GCS. Their frequency can range from 4 to 36%. Severe steroid psychoses of the manic-depressive or schizophrenic type are rare. In this case, suicidal tendencies are possible. It has been shown that a predisposition to mental disorders does not increase the risk of developing these PEs, and, conversely, the absence of a history of mental disorders does not guarantee against the occurrence of psychoses during GCS therapy.

Eye diseases

With long-term treatment with GCS, the development of posterior subcapsular cataract and secondary open-angle glaucoma is possible.

Cataract is one of the late, but well-known complications of GCS therapy and can lead to a decrease in visual acuity. Its development may be facilitated by a certain predisposition of patients. Clouding of the lens is caused by both the use of high doses of corticosteroids and the duration of treatment. Children are especially susceptible to this complication, in whom ophthalmological disorders occur in 28-44% of cases. Cessation of therapy does not always lead to restoration of lens transparency; moreover, progression is possible

cataracts. Patients receiving long-term prednisolone at a dose of 10 mg per day or higher should undergo periodic examination by an ophthalmologist.

Glaucoma is a rare and unpredictable complication of long-term GCS therapy. The risk of this PE is highest if the patient has a family history of open-angle glaucoma. In patients with a family history, an increase in intraocular pressure occurs in almost 90% of cases, and in the absence of such a history - in no more than 5% of cases. The pathophysiological mechanisms of “steroid” glaucoma are not fully understood. Although the course of the disease can vary, in typical cases, intraocular pressure normalizes after cessation of GCS therapy.

Skeletal lesions

Osteoporosis and vertebral compression fracture are common severe complications of GCS therapy in patients of all ages. It is estimated that 30-50% of all patients requiring long-term treatment will eventually develop osteoporosis. (This problem is discussed in detail in the article by I.A. Baranova in this issue of the magazine. - Ed.)

Aseptic bone necrosis can complicate long-term therapy with GCS, but when high doses are prescribed, they can develop in a short time. The mechanism of development of this complication is unknown. More often than other bones, the head of the femur is affected. The first symptoms may be joint pain and stiffness. This complication is irreversible; the process often progresses and may require joint transplantation. It is necessary to warn patients about the possibility of such a complication. If any new pain appears in the joints (especially in the hip, shoulder or knee), avascular necrosis of the bone should be excluded.

Stunting

Prescribing even relatively small doses of GCS can lead to

linear growth retardation in children. This PE is most pronounced in boys. Although its exact mechanism is unknown, it is believed that it may be due to a decrease in sex hormone production and bone formation. There are reports in the literature that collagen synthesis and linear growth can be restored by administration of growth hormone, but further research is required to clarify these results. Growth retardation may persist even after discontinuation of GCS.

Decreased synthesis of sex hormones

Treatment with GCS is accompanied by a decrease in the concentration of estradiol, testosterone, luteinizing and follicle-stimulating hormones, which is associated with suppression of the synthesis of ACTH and gonadotropic hormone. Possible AEs include menstrual irregularities in women and impotence in men. In addition, a deficiency of sex hormones with anabolic activity creates the preconditions for the development of osteoporosis.

Infectious complications

The immunosuppressive effect of GCS (suppression of the activity of neutrophils and monocytes, cellular immunological reactions, lymphopenia) leads to increased susceptibility to infections and the risk of reactivation of latent diseases, such as chicken pox, herpes zoster, mycoses, pyelonephritis, osteomyelitis, tuberculosis. Patients with underlying immune disorders are especially susceptible to infectious complications. As a rule, due to the anti-inflammatory effect of GCS, infections are asymptomatic and tend to generalize and develop complications.

Most often, patients develop bacterial infections. They usually manifest themselves in the form of pneumonia or septicemia. The main pathogens are staphylo-

cocci and gram-negative bacteria of the intestinal group.

Patients with positive tuberculin reactions are at risk of developing severe tuberculosis, therefore, during long-term therapy with GCS, they should receive isoniazid for prophylactic purposes.

The use of GCS increases the risk of dissemination of viral infections, including the severe course of chickenpox. To prevent viral infections, specific immunoglobulins are used, which are prescribed in the first 48 hours after contact with a contagious patient.

In the presence of an infectious process, GCS therapy can be carried out only if absolutely necessary under the cover of adequate antibacterial or antifungal drugs. Thanks to such prevention, infectious complications of hormonal therapy are now rare.

Changes in blood

Thromboembolic complications are caused by the ability of GCS to suppress the formation of heparin by mast cells and, as a result, increase blood clotting. The formation of blood clots in deep veins is possible when high doses of GCS are prescribed to patients with hypovolemia and hypercoagulation. Therefore, in severe patients, primarily with nephrotic syndrome, the prevention of pulmonary embolism requires constant monitoring of the volume of circulating blood, correction of hypovolemia, and the prescription of anticoagulants and antithrombotic agents.

Neutrophilic leukocytosis is possible without a shift in the leukocyte formula to the left. It is believed that it is due to the stimulating effect of GCS on granulopoiesis.

Steroid vasculitis is most often caused by fluorinated corticosteroids (dexamethasone and triamcinolone). There is increased vascular permeability, hemorrhages on the forearms, mucous membranes of the stripes,

mouth, gastrointestinal tract, conjunctiva of the eyes.

Suppression of adrenal cortex function

A special and difficult to overcome adverse effect of GCS therapy is the suppression of adrenal cortex function, which is caused by suppression of ACTH secretion by the pituitary gland in response to the circulation of exogenous GCS in doses exceeding physiological ones. With any long-term treatment with high doses of corticosteroids, one has to take into account the possibility of reducing the reactivity of hypo-

thalamo-pituitary-adrenal (HPA) system, although the severity of suppression is subject to large individual fluctuations, which makes it difficult to determine the risk in a particular patient. At first, the disorders are functional in nature; later, morphological changes in the adrenal cortex may occur, up to its atrophy. Common risk factors for suppression of the HPA system include high doses of corticosteroids, long-term treatment, incorrect drug regimens, and the use of long-acting corticosteroids.

When taking corticosteroids in physiological doses (2.5-5 mg/day prednisolone for adults), inhibition of cortisol production does not occur. However, higher doses (5-7.5 mg or more), used for 1-2 weeks, are already able to cause functional inhibition of the adrenal cortex. With longer (for example, 4-5 months) therapy, the development of atrophy of the adrenal cortex should be expected in 40% of patients.

Obviously, the longer the treatment, the higher the likelihood of adrenal suppression. Treatment with even very high doses of GCS for a short period of time (1-3 days) may not have serious consequences, which allows abrupt cessation of treatment without undesirable consequences during

pulse therapy. Restoration of adrenal function, the suppression of which is observed in this case, occurs within about 4 weeks. Prescribing moderate doses for 7-14 days is also considered quite safe. Therefore, a short course of treatment with immediate withdrawal of GCS is often used, for example, during exacerbation of bronchial asthma. If therapy needs to be continued for longer than 2 weeks, then the abolition of GCS should be carried out gradually under the control of the patient’s condition. The higher the dose and the longer the course of treatment, the slower the withdrawal of the drug should be. In many patients, restoration of the function of the adrenal cortex occurs within a few months, while in others it takes a year or even more.

The greatest degree of inhibition of the HPA system is observed when taking fluorinated (long-acting) corticosteroids - triamcinolone, dexamethasone and betamethasone. Depot drugs (kenalog, diprospan) also cause a long-term suppressive effect.

Withdrawal syndrome

With rapid withdrawal of high doses of GCS, withdrawal syndrome may develop, which most often manifests itself as an exacerbation of the underlying disease. The severity of the withdrawal syndrome depends on how much the function of the adrenal cortex is preserved.

In mild cases, weakness, malaise, fatigue, loss of appetite, nausea, muscle pain and headaches, insomnia, and increased body temperature are possible.

In severe cases, with significant suppression of adrenal function, a clinical picture of acute adrenal insufficiency may develop, accompanied by vomiting, collapse, and convulsions. This condition threatens the patient’s life, especially under stress.

In rare cases, when GCS is discontinued, an increase in intracranial pressure with disc edema may occur.

When the duration of therapy is more than 2 weeks, GCS is discontinued gradually.

optic nerve, which is a symptom of benign pseudotumor cerebri.

GCS regimen

The greatest risk of PE with systemic use of GCS occurs when GCS is taken in equal doses throughout the day. A single dose of GCS in the morning reduces the number of PEs. This is explained by the fact that in the morning and first half of the day the sensitivity of the HPA system to

the inhibitory effects of exogenous corticosteroids are the least, and in the evening hours - the greatest. Taking 5 mg of prednisolone in the evening has a greater inhibitory effect on the HPA system than 20 mg in the morning. In most cases, the entire daily dose of GCS is prescribed in the morning (primarily long-acting drugs) or 2/3-3/4 of the daily dose in the morning, and the rest around noon. A uniform distribution of the daily dose makes sense in the early phases of the most aggressive diseases, and then one should strive to transfer the patient to a single morning dose of the entire daily dose within 1-2 weeks.

An alternating drug regimen helps reduce the inhibitory effect of pharmacological corticosteroids on the function of the adrenal cortex. It consists of taking a double daily dose of GCS every second day in the morning at a time, based on the assumption that the anti-inflammatory

The beneficial effect of GCS lasts longer than the suppressive effect on ACTH synthesis. A regimen with a 48-hour interval between doses of GCS allows you to maintain their anti-inflammatory effect and reduce the suppressive effect on the HPA system.

The most effective and safe in the alternating regimen were drugs with an average half-life (prednisolone and methylprednisolone). Fluorinated corticosteroids (triamcinolone, dexamethasone and betamethasone) circulate in the systemic circulation for a longer time and inhibit ACTH secretion to a greater extent, so they are not used for alternating therapy.

Although alternating use of GCS to a certain extent reduces the risk of suppressing adrenal function, in many cases, for example, with blood diseases, ulcerative colitis, malignant tumors, this regimen is not effective enough. It should also not be used at the initial stage of treatment, when the patient’s condition has not been stabilized, or during an exacerbation of the disease. Unfortunately, in many patients, alternative therapy is difficult due to deterioration in health on the intervening day between doses.

Conclusion

Although the development of insufficiency of the HPA system is more often associated with the prescription of high doses and

If we take long-term therapy with GCS, it is impossible to reliably predict its occurrence either by the dose of hormones taken, or by the duration of treatment, or by the level of endogenous plasma cortisol. Unfortunately, today we have to admit that it is impossible to completely avoid the development of adverse events during systemic therapy with GCS. Therefore, the doctor should warn the patient about the possible consequences of long-term systemic therapy with GCS. Particular caution should be given to the inadmissibility of stopping treatment on your own or quickly reducing the dose without appropriate medical advice.

Bibliography

1. Zmushko E.I., Belozerov E.S. Medication complications. St. Petersburg, 2001. P. 281.

2. Nasonov E.L. // Rus. honey. magazine 1999. T. 8. P. 377.

3. Korovina N.A. and others. Glucocorticosteroid drugs for internal diseases of childhood. M., 2002. P. 17.

4. Boumpas D.T. et al. //Ann. Int. Med. 1993. V. 119. P. 1198.

5. The Pharmacological Basis of Therapeutics / Ed. by Hardman J.G. et al. New York,

6. Piper J.M. et al. //Ann. Intern. Med. 1991. V. 114. P. 735.

7. Strachunsky L.S., Kozlov S.N. Gluco-corticoid drugs. Smolensk,

8. Nasonov E.L., Chichasova N.V. // Rus. honey. magazine 1999. T. 8. P. 371.

9. Boulet L. et al. //Canadian Med. Association J. 1999. V. 161. Suppl. 11. S. 1.

10. Bereznyakov I.G. // http://provisor. kharkov.ua/archive/1998/N10/glukokor/ htm

A single dose of GCS in the morning reduces the risk of side effects.

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For quotation: Princely N.P. Glucocorticosteroids in the treatment of bronchial asthma // Breast Cancer. 2002. No. 5. P. 245

Department of Pulmonology, Federal Institute of Internal Medicine, Russian State Medical University

IN Recent years have seen significant progress in treatment bronchial asthma (BA). Apparently, this is due to the definition of asthma as a chronic inflammatory disease of the respiratory tract, and as a result, with the widespread use of inhaled glucocorticosteroids (GCS) as basic anti-inflammatory drugs. However, despite the progress achieved, the level of control over the course of the disease cannot be considered satisfactory. For example, almost every third patient with asthma wakes up at least once a month at night due to symptoms of the disease. More than half of patients have limitations in physical activity, and more than a third are forced to miss school or be absent from work. More than 40% of patients are forced to seek emergency care due to exacerbation of the disease. The reasons for this situation are diverse, and not the least role in this is played by the doctor’s lack of awareness of the pathogenesis of asthma and, accordingly, the choice of incorrect treatment tactics.

Definition and classification of asthma

Bronchial asthma is a chronic disease of the airways in which many cells are involved: mast cells, eosinophils and T-lymphocytes. In susceptible individuals, this inflammation leads to repeated episodes of wheezing, shortness of breath, chest tightness and cough, especially at night and/or in the early morning. These symptoms are accompanied by widespread but variable bronchial obstruction that is at least partially reversible, either spontaneously or with treatment. Inflammation also causes the airways to increase their response to various stimuli (hyperresponsiveness).

The key provisions of the definition should be considered the following:

1. Asthma is a chronic persistent inflammatory disease of the respiratory tract, regardless of severity.

2. The inflammatory process leads to bronchial hyperreactivity, obstruction and the appearance of respiratory symptoms.

3. Airway obstruction is at least partially reversible.

4. Atopy - a genetic predisposition to the production of class E immunoglobulins (may not always be present).

Bronchial asthma can be classified based on etiology, severity and characteristics of the manifestation of bronchial obstruction.

However, at present, bronchial asthma should first of all be classified according to severity, since this is what reflects the severity of the inflammatory process in the respiratory tract and determines the tactics of anti-inflammatory therapy.

Severity determined by the following indicators:

Number of nighttime symptoms per week.
Number of daytime symptoms per day and per week.
Frequency of use of short-acting b 2 -agonists.
The severity of physical activity and sleep disorders.
Peak expiratory flow (PEF) values and its percentage with the proper or best value.
Daily fluctuations of PSV.
The volume of therapy provided.

There are 5 degrees of severity of asthma: mild intermittent; mild persistent; moderately severe persistent; severe persistent; severe persistent steroid-dependent (Table 1).

BA intermittent: asthma symptoms less than once a week; short exacerbations (from several hours to several days). Night symptoms 2 times a month or less often; absence of symptoms and normal lung function between exacerbations: peak expiratory flow (PEF) > 80% predicted and PEF fluctuations less than 20%.

Mild persistent asthma. Symptoms once a week or more often, but less than once a day. Exacerbations of the disease can interfere with activity and sleep. Nighttime symptoms occur more often than twice a month. PEF is more than 80% of the expected value; fluctuations in PSV 20-30%.

Moderate asthma. Daily symptoms. Exacerbations disrupt activity and sleep. Nighttime symptoms occur more than once a week. Daily use of short-acting b2-agonists. PSV 60-80% of due. PEF fluctuations are more than 30%.

Severe asthma: persistent symptoms, frequent exacerbations, frequent nighttime symptoms, physical activity limited by asthma symptoms. PEF is less than 60% of the expected value; fluctuations of more than 30%.

It should be noted that determining the severity of asthma using these indicators is possible only before starting treatment. If the patient is already receiving the necessary therapy, then its volume should also be taken into account. Thus, if a patient’s clinical picture is determined to have mild persistent asthma, but at the same time he receives drug treatment corresponding to severe persistent asthma, then this patient is diagnosed with severe asthma.

Severe steroid-dependent asthma: Regardless of the clinical picture, a patient receiving long-term treatment with systemic corticosteroids should be regarded as suffering from severe asthma.

Inhaled corticosteroids

Recommended stepwise approach to asthma therapy depending on the severity of its course (Table 1). All drugs for the treatment of asthma are divided into two main groups: for long-term control of the inflammatory process and for the relief of acute asthma symptoms. The basis of therapy for long-term control of the inflammatory process are inhaled glucocorticosteroids (ICS), which should be used from the second stage (mild persistent course) to the fifth (severe steroid-dependent course). Therefore, ICS are currently considered as first-line agents for the treatment of asthma. The higher the severity of asthma, the higher doses of ICS should be used. According to a number of studies, patients who began treatment with ICS no later than two years from the onset of the disease showed significant benefits in improving control over asthma symptoms compared with the group that began treatment with ICS after more than 5 years from the onset of the disease.

Mechanisms of action and pharmacokinetics

ICS are able to bind to specific receptors in the cytoplasm, activate them and form a complex with them, which then dimerizes and moves into the cell nucleus, where it binds to DNA and interacts with the transcription mechanisms of key enzymes, receptors and other complex proteins. This leads to the manifestation of pharmacological and therapeutic effects.

The anti-inflammatory effect of ICS is associated with their inhibitory effect on inflammatory cells and their mediators, including the production of cytokines, interference with the metabolism of arachidonic acid and the synthesis of leukotrienes and prostaglandins, and prevention of migration and activation of inflammatory cells. ICS increase the synthesis of anti-inflammatory proteins (lipocortin-1), increase apoptosis and reduce the number of eosinophils by inhibiting interleukin-5. Thus, ICS lead to the stabilization of cell membranes, reduce vascular permeability, improve the function of b-receptors both by synthesizing new ones and increasing their sensitivity, and stimulate epithelial cells.

ICS differ from systemic glucocorticosteroids in their pharmacological properties: lipophilicity, rapidity of inactivation, short half-life from blood plasma. It is important to consider that treatment with ICS is local (topical), which provides pronounced anti-inflammatory effects directly in the bronchial tree with minimal systemic manifestations. The amount of ICS delivered to the respiratory tract depends on the nominal dose of the drug, the type of inhaler, the presence or absence of propellant, and the inhalation technique. Up to 80% of patients experience difficulty using metered dose aerosols.

The most important characteristic for the manifestation of selectivity and retention time of the drug in tissues is lipophilicity. Due to their lipophilicity, ICS accumulate in the respiratory tract, slowing down their release from tissues and increasing their affinity for the glucocorticoid receptor. Highly lipophilic ICS are absorbed faster and better from the bronchial lumen and remain for a long time in the tissues of the respiratory tract. What distinguishes ICS from systemic drugs is their topical (local) effect. Therefore, it is useless to prescribe inhaled systemic corticosteroids (hydrocortisone, prednisolone and dexamethasone): these drugs, regardless of the method of administration, have only a systemic effect.

Numerous randomized placebo-controlled studies in patients with asthma have shown the effectiveness of all doses of ICS compared with placebo.

System bioavailability consists of oral and inhalation. From 20 to 40% of the inhaled dose of the drug enters the respiratory tract (this value varies significantly depending on the delivery vehicle and the patient’s inhalation technique). Pulmonary bioavailability depends on the percentage of the drug reaching the lungs, the presence or absence of a carrier (inhalers that do not contain freon have the best results) and on the absorption of the drug in the respiratory tract. 60-80% of the inhalation dose settles in the oropharynx and is swallowed, then undergoing complete or partial metabolism in the gastrointestinal tract and liver. Oral availability depends on absorption in the gastrointestinal tract and on the severity of the “first pass” effect through the liver, due to which inactive metabolites enter the systemic circulation (with the exception of beclomethasone 17-monopropionate, the active metabolite of beclomethasone dipropionate). Doses of ICS up to 1000 mcg/day (for fluticasone up to 500 mcg/day) have little systemic effect.

All ICS have fast system clearance, comparable to the magnitude of hepatic blood flow. This is one of the factors that reduces the systemic effect of ICS.

Characteristics of the most commonly used drugs

ICS include beclomethasone dipropionate, budesonide, fluticasone propionate, flunisolide, triamsinolone acetonide, mometasone furoate. They are available in the form of metered-dose aerosols, powder inhalers, and also as solutions for inhalation through a nebulizer (budesonide).

Beclomethasone dipropionate . It has been used in clinical practice for more than 20 years and remains one of the most effective and frequently used drugs. The use of the drug in pregnant women is permitted. Available as a metered-dose aerosol inhaler (Bekotide 50 mcg, Bekloforte 250 mcg, Aldecin 50 mcg, Beklocort 50 and 250 mcg, Beclomet 50 and 250 mcg/dose), a breath-activated metered-dose inhaler (Beclazon Easy Breathing 100 and 250 mcg/dose) , powder inhaler (Bekodisk 100 and 250 mcg/dose, Diskhaler inhaler; Easyhaler multi-dose inhaler, Beklomet 200 mcg/dose). For Bekotide and Bekloforte inhalers, special spacers are produced - “Volyumatic” (large-volume valve spacer for adults) and “Babyhaler” (small-volume 2-valve spacer with a silicone face mask for young children).

Budesonide . A modern, highly active drug. Used as a metered dose aerosol inhaler (Budesonide-mite 50 mcg/dose; Budesonide-forte 200 mcg/dose), powder inhaler (Pulmicort Turbuhaler 200 mcg/dose; Benacort Cyclohaler 200 mcg/dose) and nebulizer suspension (Pulmicort 0.5 and 0.25 mg/dose). Pulmicort Turbuhaler is the only dosage form of ICS that does not contain a carrier. A spacer is produced for the metered dose inhalers Budesonide Mite and Budesonide Forte. Budesonide is part of the combination drug Symbicort.

Budesonide has the most favorable therapeutic index, which is associated with its high affinity for glucocorticoid receptors and accelerated metabolism after systemic absorption in the lungs and intestines. Budesonide is the only ICS for which single-dose use has been proven. The factor that ensures the effectiveness of budesonide once a day is the retention of budesonide in the respiratory tract in the form of an intracellular depot due to reversible esterification (formation of fatty acid esters). When the concentration of free budesonide in the cell decreases, intracellular lipases are activated, and budesonide released from the esters again binds to the receptor. This mechanism is not typical for other corticosteroids and makes it possible to prolong the anti-inflammatory effect. A number of studies have shown that intracellular storage may be more important in terms of drug activity than receptor affinity.

Recent studies on the drug Pulmicort Turbuhaler have proven that it does not affect final growth with long-term use in children, bone mineralization, and does not cause angiopathy and cataracts. Pulmicort is also recommended for use in pregnant women: it has been found that its use does not cause an increase in the number of fetal abnormalities. Pulmicort Turbuhaler is the first and only ICS to which the FDA (drug control organization in the United States) has assigned category “B” in the rating of drugs prescribed during pregnancy. This category includes medications that are safe to take during pregnancy. The remaining ICS belong to category “C” (taking them during pregnancy is not recommended).

Fluticasone propionate . The most highly active drug to date. Has minimal oral bioavailability (<1%). Эквивалентные терапевтические дозы флютиказона почти в два раза меньше, чем у беклометазона и будесонида в аэрозольном ингаляторе и сопоставимы с дозами будесонида в Турбухалере (табл. 2). По данным ряда исследований, флютиказона пропионат больше угнетает надпочечники, но в эквивалентных дозах имеет сходную с другими ИГКС активность в отношении надпочечников.

Presented in the form of a metered-dose aerosol inhaler (Flixotide 50, 125 and 250 mcg/dose) and a powder inhaler (Flixotide Diskhaler - rotadiscs 50, 100, 250 and 500 mcg/dose; Flixotide Multidisc 250 mcg/dose). Special spacers are produced for aerosol inhalers - “Volyumatic” (large-volume valve spacer for adults) and “Babyhaler” (small-volume 2-valve spacer with a silicone face mask for young children). Fluticasone is part of the combination drug Seretide Multidisk.

Flunisolide . A drug with low glucocorticoid activity. It is represented on the domestic market by the Ingacort trademark (metered-dose inhaler 250 mcg/dose, with a spacer). Despite high therapeutic doses, it has virtually no systemic effects due to the fact that already during the first passage through the liver it is 95% converted into an inactive substance. Currently used quite rarely in clinical practice.

Triamsinolone acetonide . A drug with low hormonal activity. Metered dose inhaler 100 mcg/dose. The Azmacort brand is not represented on the Russian market.

Mometasone furoate . A drug with high glucocorticoid activity. It is presented on the Russian market only in the form of Nazonex nasal spray.

Clinical trials comparing the effectiveness of ICS in improving symptoms and respiratory function show that:

Budesonide and beclomethasone dipropionate in aerosol inhalers at the same doses practically do not differ in effectiveness.
Fluticasone propionate provides the same effect as twice the dose of beclomethasone or budesonide in a metered-dose aerosol.
Budesonide administered through Turbuhaler has the same effect as twice the dose of budesonide in a metered dose aerosol.

Undesirable effects

Modern ICS are drugs with a high therapeutic index and have a high safety profile even with long-term use. Systemic and local undesirable effects are distinguished. Systemic adverse effects may only become clinically significant when high doses are used. They depend on the drug's affinity for the receptor, lipophilicity, volume of distribution, half-life, bioavailability and other factors. The risk of systemic adverse effects for all currently available ICS correlates with the desired effects in the respiratory tract. The use of ICS in moderate therapeutic doses reduces the risk of systemic effects.

The main side effects of ICS are related to their route of administration and include oral candidiasis, hoarseness, mucosal irritation and cough. To avoid these phenomena, proper inhalation technique and individual selection of ICS are necessary.

Combination drugs

Despite the fact that ICS are the basis of BA therapy, they do not always allow complete control of the inflammatory process in the bronchial tree and, accordingly, the manifestations of BA. In this regard, there was a need to prescribe short-acting b 2 -agonists on an as-needed or regular basis. Thus, there is an urgent need for a new class of drugs, free from the disadvantages that are inherent in short-acting b 2 -agonists, and with a proven long-term protective and anti-inflammatory effect on the respiratory tract.

Long-acting b2-agonists have been created and are currently widely used, which are represented on the pharmaceutical market by two drugs: formoterol fumarate and salmeterol xinafoate. Modern guidelines for the treatment of asthma recommend the addition of long-acting b2-agonists in case of insufficient control of asthma with monotherapy with inhaled corticosteroids (starting from the second stage). A number of studies have shown that the combination of inhaled corticosteroids with a long-acting b 2 -agonist is more effective than doubling the dose of inhaled corticosteroids, and leads to a more significant improvement in lung function and better control of asthma symptoms. A reduction in the number of exacerbations and a significant improvement in quality of life in patients receiving combination therapy have also been shown. Thus, the emergence of combination drugs containing inhaled corticosteroids and a long-acting b 2 agonist is a reflection of the evolution of views on asthma therapy.

The main advantage of combination therapy is the increased effectiveness of treatment when using lower doses of ICS. In addition, combining two drugs in one inhaler makes it easier for the patient to follow doctor's orders and potentially improves compliance.

Seretide Multidisc . The constituent components are salmeterol xinafoate and fluticasone propionate. Provides a high level of control over asthma symptoms. Used only as basic therapy, can be prescribed starting from the second stage. The drug is presented in various dosages: 50/100, 50/250, 50/500 mcg salmeterol/fluticasone in 1 dose. Multidisc is a low-resistance inhalation device, which allows it to be used in patients with reduced inspiratory flow.

Symbicort Turbuhaler . The constituent components are budesonide and formoterol fumarate. It is presented on the Russian market in a dosage of 160/4.5 mcg in 1 dose (doses of drugs are indicated as the output dose). An important feature of Symbicort is the ability to use it both for basic therapy (to control the inflammatory process) and for immediate relief of asthma symptoms. This is primarily due to the properties of formoterol (quick onset of action) and the ability of budesonide to actively act within 24 hours on the mucous membrane of the bronchial tree.

Symbicort allows individual flexible dosing (1-4 inhalation doses per day). Symbicort can be used starting from stage 2, but it is especially indicated for patients with unstable asthma, which is characterized by sudden severe attacks of difficulty breathing.

System GCS

Systemic corticosteroids are used mainly to relieve exacerbation of asthma. Oral corticosteroids are the most effective. Intravenous corticosteroids are prescribed for exacerbation of asthma, if intravenous access is more desirable, or for impaired absorption from the gastrointestinal tract, using high doses (up to 1 g of prednisolone, methylprednisolone and hydrocortisone). Corticosteroids lead to clinically significant improvement 4 hours after their administration.

During exacerbation of BA, a short course of oral corticosteroids (7-14 days) is indicated, starting with high doses (30-60 mg of prednisolone). Recent publications recommend the following short course of systemic corticosteroids for non-life-threatening exacerbations: 6 tablets of prednisolone in the morning (30 mg) for 10 days, followed by discontinuation of use. Although treatment regimens for systemic corticosteroids can be different, the fundamental principles are their administration in high doses to quickly achieve effect and subsequent rapid withdrawal. It should be remembered that as soon as the patient is ready to take inhaled corticosteroids, they should be prescribed to him in a stepwise manner.

Systemic glucocorticoids should be prescribed if:

Moderate or severe exacerbation.
The administration of short-acting inhaled b 2 -agonists at the beginning of treatment did not lead to improvement.
The exacerbation developed despite the fact that the patient was on long-term treatment with oral corticosteroids.
Oral corticosteroids were required to control previous exacerbations.
Courses of glucocorticoids were administered 3 or more times a year.
The patient is on mechanical ventilation.
Previously there were life-threatening exacerbations.

It is undesirable to use long-acting forms of systemic steroids to relieve exacerbations and provide maintenance therapy for asthma.

For long-term therapy in severe asthma, systemic corticosteroids (methylprednisolone, prednisolone, triamsinolone, betamethasone) should be prescribed in the lowest effective dose. With long-term treatment, an alternating prescription regimen and administration in the first half of the day (to reduce the effect on the circadian rhythms of cortisol secretion) cause the least amount of side effects. It should be emphasized that in all cases of prescribing systemic steroids, the patient should be prescribed high doses of inhaled corticosteroids. Among oral corticosteroids, preference is given to those that have minimal mineralocorticoid activity, a relatively short half-life and limited effect on striated muscles (prednisolone, methylprednisolone).

Steroid addiction

Patients who are forced to constantly take systemic corticosteroids should pay special attention. There are several options for the formation of steroid dependence in patients with asthma and other diseases accompanied by bronchial obstruction:

Lack of compliance (interaction) between doctor and patient.
Not prescribing inhaled corticosteroids to patients. Many doctors believe that there is no need to prescribe inhaled corticosteroids to patients receiving systemic steroids. If a patient with asthma receives systemic steroids, he should be regarded as a patient with severe asthma who has a direct indication for high doses of inhaled corticosteroids.
In patients with systemic diseases (including pulmonary vasculitis, for example, Charge-Strauss syndrome), bronchial obstruction can be regarded as asthma. Withdrawal of systemic steroids in these patients may be accompanied by severe manifestations of systemic disease.
In 5% of cases, steroid resistance occurs, which is characterized by resistance of steroid receptors to steroid drugs. Currently, two subgroups are distinguished: patients with true steroid resistance (type II), who do not have side effects when taking high doses of systemic corticosteroids for a long time, and patients with acquired resistance (type I), who have side effects of systemic corticosteroids. In the latter subgroup, resistance can most likely be overcome by increasing the dose of GCS and prescribing drugs that have an additive effect.

It is necessary to develop diagnostic programs for patients who receive adequate therapy, are sensitive to corticosteroids, have high compliance, but despite all this, experience asthma symptoms. These patients are the most “incomprehensible” from the point of view of therapy and from the point of view of pathophysiology. They should undergo a careful differential diagnosis to exclude other diseases that mimic the clinical picture of asthma. Literature:

1. Bronchial asthma. Global strategy: a joint report of the National Heart, Lung, and Blood Institute and the World Health Organization. Pulmonology, 1996.

2. Bronchial asthma. Guide for doctors in Russia (formulary system). “Pulmonology”, supplement-99.

3. Leading directions in the diagnosis and treatment of bronchial asthma. Highlights of the EPR-2 Expert Group Report. National Institute of Health. National Heart, Lung and Blood Institute. NIH publication-97. Translation ed. Prof. Tsoi A.N., M, Grant, 1998.

4. Ilyina N.I. Inhaled glucocorticoids. Asthma.ru. Allergic and respiratory diseases. 0*2001 (pilot episode).

5. Ogorodova L.M. Systems for inhalation delivery of drugs into the respiratory tract. Pulmonology, 1999; No. 1, 84-87

6. Formulary system: treatment of bronchial asthma. Asthma. ru ,0. 2001, 6-9

7. Chuchalin A.G. Bronchial asthma. Moscow, 1997.

8. Tsoi A.N. Inhaled glucocorticoids: effectiveness and safety. RMJ 2001; 9: 182-185

9. Tsoi A.N. Comparative pharmacokinetics of inhaled glucocorticoids. Allergology 1999; 3:25-33

10. Agertoft L., Pedersen S. Effect of long-term treatment with inhaled budesonide on adult height in children with asthma. N Engl J Med 2000; 343:1064-9

11. Ankerst J., Persson G., Weibull E. A high dose of budesonide/formoterol in a single inhaler was well tolerated by asthmatic patients. Eur Respir J 2000; 16 (Suppl 31): 33s+poster

12. Barnes P.J. Inhaled glucocorticoids for asthma. N.Engl. Med. 1995; 332:868-75

13. Beclomethasone Dipropionate and Budesonide. The clinical evidence Reviewed. Respir Med 1998; 92 (Suppl B)

14. The British Guidelines on Asthma Management. Thorax, 1997; 52 (Suppl. 1) 1-20.

15. Burney PGJ. Current questions in the epidemiology of asthma, in Holgate ST, et al, Asthma: Physiology. Immunology, and Treatment. London, Academic Press, 1993, pp. 3-25.

16. Crisholm S et al. Once-daily budesonide in mild asthma. Respir Med 1998; 421-5

17. Kips JC, O/Connor BJ, Inman MD, Svensson K, Pauwels RA, O/Byrne PM. A long-term study of the antiinflammatory effect of low-dose budesonide plus formoterol versus high-dose budesonide in asthma. Am Respir Crit Care Med 2000; 161:996-1001

18. McFadden ER, Casale TB, Edwards TB et al. Administration of budesonide once daily by means of Turbuhaler to subjects with stable asthma. J Allergy Clin Immunol 1999; 104:46-52

19. Miller-Larsson A., Mattsson H., Hjertberg E., Dahlback M., Tunek A., Brattsand R. Reversible fatty acid conjugation of budesonide: novel mechanism for prolonged retention of topically applied steroid in airway tissue. Drug Metab Dispos 1998; 26: 623-30

20. Miller-Larsson A. et al. Prolonged airway activity and improved selectivity of budesonide possibly due to esterification. Am J Respir Crit Care Med 2000;162:1455-1461

21. Pauwels RA et al. Effect of inhaled formoterol and budesonide on exacerbations of asthma. N Engl J Med 1997; 337:1405-11

22. Pedersen S, O/Byrne P. A comparison of the efficacy and safety of inhaled corticosteroids in asthma. Allergy 1997; 52 (Suppl 39): 1-34.

23. Woolcock A. et al. Comparison of addition of salmeterol to inhaled steroids with doubling of the dose of inhaled steroids. Am J Respir Crit Care Med 1996, 153, 1481-8.