What does Gks mean? Glucocorticosteroids: when prescribed, rules of administration. General information about GCS. What is it in medicine

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.

Research recent years showed 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 sub cell membranes(mitochondria and lysosomes);

decreased permeability 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 the regulation of activity of cardio-vascular 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 effects. side effects(PE) 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 initial stages 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 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, disorder menstrual cycle, 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. Truncal 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

Promotion blood pressure may be observed in patients taking GCS 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

Stomach ulcer or duodenum is an uncommon but serious PE. 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 secretion of hydrochloric acid, decreased mucus synthesis and inhibition of epithelial regeneration.

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

At long-term treatment GCS may develop posterior subcapsular cataracts and secondary open-angle glaucoma.

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. Pathophysiological mechanisms“steroid” glaucoma is 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 compression fracture spine are frequent 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. The head is most often affected than other bones femur. 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 viral infections, including the description of a 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, now infectious complications Hormone therapy is uncommon.

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, for the prevention of thromboembolism pulmonary artery Constant monitoring of the volume of circulating blood, correction of hypovolemia, and the prescription of anticoagulants and antithrombotic agents are necessary.

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,

you 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 disturbances are functional in nature, but later they may occur morphological changes adrenal cortex until 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

Greatest risk 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

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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,

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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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Glucocorticoid drugs (GCS) occupy a special place not only in allergology and pulmonology, but also in medicine in general. Irrational administration of GCS can lead to a large number of side effects and dramatically change the patient’s quality and lifestyle. In such cases, the risk of complications from the administration of GCS significantly exceeds the severity of the disease itself. On the other hand, fear of hormonal drugs, which arises not only among patients, but also among incompetent medical workers, is the second extreme of this problem, requiring advanced training of doctors and special work among patients who need glucocorticoid therapy. Thus, the main principle of GCS therapy is to achieve maximum effect using minimal doses; It must be remembered that the use of insufficient doses increases the duration of treatment and, accordingly, increases the likelihood of developing side effects.

Classification. GCS are classified into short-, intermediate- and long-acting drugs depending on the duration of ACTH suppression after taking a single dose (Table 2).

Table 2. Classification of GCS by duration of action

A drug		Equivalent dose	ness of GCS	Mineral corticoid activity
Short acting:
Cortisol (hydrocortisone)
Cortisone
Prednisone
Average duration of action
Prednisolone
Methylprednisolone
Triamcinolone
Long-lasting
Beclamethasone
Dexamethasone

For more than 40 years, glucocorticoid drugs with high activity when used topically have been widely used on the market. Created new class GCS for inhalation therapy must meet the following requirements: on the one hand, have a high affinity for glucocorticoid receptors and, on the other hand, extremely low bioavailability, the reduction of which can be achieved by reducing the lipophilicity of the GCS and, accordingly, the degree of absorption. Below is a classification of GCS according to method of use, indicating release forms, trade names and dose regimens (Table 3).

Table 3 . Classification of GCS by route of administration

A drug	Trade names		Release forms
GCS for oral use
Betamethasone	Celeston		Tab.0.005 No. 30
Dexamethasone	Dexazone Dexamed Fortecortin Dexamethasone		Tab.0.005 No. 20 Tab.0.005 No. 10 and No. 100 Tab.0.005 No. 20 and No. 100, tab. 0.0015 No. 20 and No. 100, elixir 100 ml in a bottle (5 ml = 500 mcg) Tab. 0.005 No. 100 Tab.0.005 No. 20, 0.0015 No. 50 and 0.004 No. 50 and 100 Tab.0.005 No. 20 and No. 1000
Methyl prednisolone	Metipred		Tab.0.004 No. 30 and No. 100, tab. 0.016 No. 50, tab. 0.032 No. 20 and tab. 0.100 No. 20 Tab.0.004 No. 30 and 100, tab.0.016 No. 30
Prednisolone	Prednisolone Decortin N Medopred Prednisol		Tab.0.005 No. 20, No. 30, No. 100, No. 1000 Tab.0.005 No.50 and No.100, tab.0.020 No.10, No.50, No.100, tab.0.05 No.10 and No.50 Tab.0.005 No. 20 and No. 100 Tab.0.005 No. 100
Prednisone	Apo-prednisone		Tab.0.005 and 0.05 No. 100 and No. 1000
Triamcinolone	Polcortolon Triamcinolone Berlicourt Kenacort		T ab.0.004 No. 20 Tab.0.002 and 0.004 No. 50, 100, 500 and 1000 Tab.0.004 No. 25 Tab.0.004 No. 100 Tab.0.004 No. 50 Tab.0.004 No. 100
GCS for injection
Betamethasone	Celeston		In 1 ml 0.004, No. 10 ampoules of 1 ml
Dexamethasone	Dexaven Dexabene Dexazone Dexamed Dexamethasone Fortecortin mono		In 1 ml 0.004, No. 10 ampoules of 1 and 2 ml 0.004 in 1 ml, 1 ml in a bottle In 1 ml 0.004, No. 3 ampoules of 1 ml and 2 ml In 1 ml 0.004, No. 25 ampoules of 1 ml In 2 ml 0.008, No. 10 ampoules of 2 ml In 1 ml 0.004, No. 5 ampoules of 1 ml In 1 ml 0.004, No. 10 ampoules of 1 ml In 1 ml 0.004, No. 100 ampoules of 1 ml In 1 ml 0.004, No. 3 ampoules of 1 ml and 2 ml, in 1 ml 0.008, No. 1 ampoule of 5 ml
Hydrocortisone	Hydrocortisone Solu-cortef Sopolcourt N		Suspension in bottles, in 1 bottle 5 ml (125 mg)* Lyophilized powder in bottles, 1 bottle 2 ml (100 mg) Solution for injection, 1 ml in ampoule (25 mg) and 2 ml (50 mg)
Prednisolone	Metipred Solu-Medrol		Suspension for injection, 1 ml in ampoule (40 mg) Lyophilized powder in bottles, 1 bottle 40, 125, 250, 500 or 1000 mg Dry substance with solvent in ampoules No. 1 or No. 3, 250 mg each, No. 1 1000 mg
Prednisolone	Medopred Prednisol Prednisolone hafslund nycomed Prednisolone Prednisolone acetate Prednisolone hemisuccinate Solyu-decortin N		In 1 ml 0.020, No. 10 ampoules of 2 ml In 1 ml 0.030, No. 3 ampoules of 1 ml In 1 ml 0.025, No. 3 ampoules of 1 ml In 1 ml 0.030, No. 3 ampoules of 1 ml In 1 ml 0.025, No. 10 or No. 100 ampoules of 1 ml In 5 ml 0.025, No. 10 lyophilized powder in ampoules of 5 ml In 1 ampoule 0.010, 0.025, 0.050 or 0.250, No. 1 or No. 3 ampoule
Triamcinolone	Triam-denk 40 for injection Triamcinolone		In 1 ml 0.010 or 0.040 in bottles In 1 ml 0.040, No. 100 suspension in ampoules In 1 ml 0.010 or 0.040, suspension in ampoules
Depot – form: Triamcinolone	Triamcinolone acetonide		In 1 ml 0.040, No. 5 in ampoules of 1 ml In 1 ml 0.010, 0.040 or 0.080, suspension in ampoules
Depot form: Methylprednisolone acetate	Depo-Medrol Methylpredni-zolone acetate		In 1 ml 0.040, bottles of 1, 2 or 5 ml In 1 ml 0.040, No. 10 ampoules, 1 ml of suspension per ampoule
Combination of depot form and fast-acting form
Betamethasone	Diprospan Flosteron		In 1 ml 0.002 dinitrate phosphate and 0.005 dipropionate, No. 1 or 5 ampoules of 1 ml The composition is similar to diprospan
GCS for inhalation
Beclamethasone	Aldecin Beklazon Beklomet-Easyhaler Bekodisk Beklocort Becklofort Plybekort		In 1 dose 50, 100 or 250 mcg, in an aerosol 200 doses 1 dose 200 mcg, Easyhaler 200 doses In 1 dose 100 mcg or 200 mcg, in a dischaler 120 doses In 1 dose 50 mcg, in an aerosol 200 doses In 1 dose 50 mcg (mita), in an aerosol 200 doses and 250 mcg (Forte), 200 doses in aerosol In 1 dose 250 mcg, in an aerosol 80 or 200 doses In 1 dose 50 mcg, in an aerosol 200 doses
Budesonide	Benacort Pulmicort Budesonide		In 1 dose 200 mcg, in the Cyclohaler inhaler 100 or 200 doses In 1 dose 50 mcg, in an aerosol 200 doses and in 1 dose 200 mcg, in an aerosol 100 doses Similar to pulmicort
Fluticasone	Flixotide		In 1 dose 125 or 250 mcg, in an aerosol 60 or 120 mcg; powder for inhalation in rotadisks: blisters 4 x 15, in 1 dose 50, 100, 250 or 500 mcg
Triacinolone	Azmacort		1 dose 100 mcg, aerosol 240 doses
GCS for intranasal use
Beclomethasone	Aldecin Baconase	The same (see above) aerosol with a nasal mouthpiece In 1 dose 50 mcg, aqueous aerosol for 200 doses for intranasal use 50 mcg in 1 dose, 50 doses in aerosol
Flunisolide	Sintaris	In 1 dose 25 mcg, in an aerosol 200 doses
Fluticasone	Flixonase	In 1 dose 50 mcg, in aqueous spray for intranasal use 120 doses
Mometasone	Nasonex	In 1 dose 50 mcg, in an aerosol 120 doses
GCS for local application in ophthalmology
	Prenatsid	Eye drops 10 ml in a bottle (1 ml = 2.5 mg), eye ointment 10.0 (1.0 = 2.5 mg)
Dexamethasone	Dexamethasone	Eye drops 10 and 15 ml in a bottle (1 ml = 1 mg), eye suspension 10 ml in a bottle (1 ml = 1 mg)
Hydrocortisone	Hydrocortisone	Eye ointment in tube 3.0 (1.0 = 0.005)
Prednisolone	Prednisolone	Ophthalmic suspension in a 10 ml bottle (1 ml = 0.005)
Combined drugs: With dexamethasone, framycetin and gramicidin With dexamethasone and neomycin	Sofradex Dexon
GCS for topical use in dentistry
Triamcinolone	Kenalog Orabase	Paste for topical use in dentistry (1.0 = 0.001)
GCS for local use in gynecology
Combined drugs: With prednisolone	Terzhinan	Vaginal tablets of 6 and 10 pieces, containing prednisolone 0.005, ternidazole 0.2, neomycin 0.1, nystatin 100,000 units
GCS for use in proctology
Combined drugs: With prednisolone With hydrocortisone	Aurobin Posterisan forte Proctosedyl	Ointment 20, in tubes (1.0 = prednisolone 0.002, lidocaine 0.02, d-panthetol 0.02, triclosan 0.001) Rectal suppositories No. 10, (1.0 = 0.005) Ointment 10.0 and 15.0 in a tube (1.0 = 5.58 mg), rectal capsules No. 20, 2.79 mg in 1 capsule
GKS for external use
Betamethasone	Betnovate Diprolene Celestoderm -B	Cream and ointment 15.0 each in tubes (1.0 = 0.001) Cream and ointment 15.0 and 30.0 in tubes (1.0 = 0.0005) Cream and ointment 15.0 and 30.0 in tubes (1.0 = 0.001)
Betamethasone + Gentamicin	Diprogent	Ointment and cream 15.0 and 30.0 in tubes (1.0 = 0.0005)
Betamethasone + Clotrimazole	Lotriderm	Ointment and cream 15.0 and 30.0 in tubes (1.0 = 0.0005, clotrimazole 0.01)
Betamethasone + Acetylsalicylic acid	Diprosalik	Ointment 15.0 and 30.0 in tubes (1.0 = 0.0005, salicylic acid 0.03); Lotion 30 ml in a bottle (1 ml = 0.0005, salicylic acid 0.02)
Budesonide		Ointment and cream 15.0 in tubes (1.0 = 0.00025)
Clobetasol	Dermovate	Cream and ointment 25.0 in tubes (1.0 = 0.0005)
Fluticasone	Cutivate	Ointment 15.0 in tubes (1.0 = 0.0005) and cream 15.0 in tubes (1.0 = 0.005)
Hydrocortisone	Laticort	Ointment 14.0 in tubes (1.0 = 0.01) Ointment, cream or lotion 15 ml (1.0 = 0.001) Ointment, cream or lipocrem 0.1% 30.0 each in tubes (1.0 = 0.001), lotion 0.1% 30 ml each (1ml = 0.001)
Hydrocortisone + natamycin + Neomycin	Pimafukort	Ointment and cream 15.0 in tubes (1.0 = 0.010), lotion 20 ml in a bottle (1.0 = 0.010)
Mazipredone	Deperzolon	Emulsion ointment 10.0 in tubes (1.0 = 0.0025)
Mazipredon + Miconazole	Mycozolon	Ointment 15.0 in tubes (1.0 = 0.0025, miconazole 0.02)
Methyl prednisolone	Advantan
Mometasone		Ointment, cream 15.0 in tubes and lotion 20 ml (1.0 = 0.001)
Prednicarbate	Dermatol	Ointment and cream 10.0 in tubes (1.0 = 0.0025)
Prednisolone + Clioquinol	Dermozolon	Ointment 5.0 in tubes (1.0 = 0.005 and clioquinol 0.03)
Triamcinolone	Triacort Fluorocort	Ointment 10.0 in tubes (1.0 = 0.00025 and 1.0 = 0.001) Ointment 15.0 in tubes (1.0 = 0.001)

Mechanism of action of GCS: Decryption of the implementation anti-inflammatory effect GCS is extremely complex. Currently, it is believed that the leading link in the action of GCS on the cell is their influence on the activity of the genetic apparatus. Various classes of GCS bind to varying degrees with specific receptors located on the cytoplasmic or cytosolic membrane. For example, cortisol (endogenous GCS, with pronounced mineralocorticoid activity) has a preferential binding to cytoplasmic membrane receptors, and dexamethasone (synthetic GCS, characterized by minimal mineralocorticoid activity) binds to a greater extent to cytosolic receptors. After active (in the case of cortisone) or passive (in the example of dexamethasone) penetration of GCS into the cell, a structural rearrangement occurs in the complex formed by GCS, receptor and carrier protein, allowing it to interact with certain sections of nuclear DNA. The latter causes an increase in RNA synthesis, which is the main stage in the implementation of the biological effects of GCS in the cells of target organs. The determining factor in the mechanism of the anti-inflammatory effect of GCS is their ability to stimulate the synthesis of some (lipomodulin) and inhibit the synthesis of other (collagen) proteins in cells. Lipomodulin blocks phospholipase A2 of cell membranes, responsible for the release of phospholipid-bound arachidonic acid. Accordingly, the formation of active anti-inflammatory lipids—prostaglandins, leukotrienes and thromboxanes—from arachidonic acid is stimulated. Inhibition of leukotriene B4 reduces the chemotaxis of leukocytes, and leukotrienes C4 and D4 reduces the contractile ability of smooth muscles, vascular permeability and mucus secretion in the respiratory tract. In addition, GCS suppress the formation of some cytokines involved in inflammatory reactions in bronchial asthma. Also, one of the components of the anti-inflammatory effect of GCS is the stabilization of lysosomal membranes, which reduces the permeability of the capillary endothelium, improves microcirculation and reduces the exudation of leukocytes and mast cells.

The antiallergic effect of GCS is multifactorial and includes: 1) the ability to reduce the number of circulating basophils, which leads to a decrease in the release of mediators of immediate allergic reactions; 2) direct inhibition of the synthesis and secretion of mediators of immediate allergic reactions due to an increase in intracellular cAMP and a decrease in cGMP; 3) reducing the interaction of allergy mediators with effector cells.

At present, the mechanisms of the antishock effect of glucocorticoids have not been fully deciphered. However, a sharp increase in the concentration of endogenous glucocorticoids in plasma during shocks of various etiologies has been proven, as well as a significant decrease in the body’s resistance to shockogenic factors when the hypothalamic-pituitary-adrenal system is suppressed. The practice-confirmed high effectiveness of GCS in shock is also obvious. It is believed that GCS restores the sensitivity of adrenergic receptors to catecholamines, which, on the one hand, mediates the bronchodilator effect of GCS and the maintenance of systemic hemodynamics, and on the other hand, the development of side effects: tachycardia, arterial hypertension, excitation of the central nervous system.

The effect of GCS on metabolism. Carbohydrate metabolism. Gluconeogenesis increases and glucose utilization in tissues decreases due to antagonism with insulin, which can result in hyperglycemia and glycosuria. Protein metabolism. Anabolic processes in the liver and catabolic processes in other tissues are stimulated, and the content of globulins in the blood plasma decreases. Lipid metabolism. Lipolysis is stimulated, the synthesis of higher fatty acids and triglycerides is enhanced, fat is redistributed with predominant deposition in the shoulder girdle, face, abdomen, and hypercholesterolemia is recorded. Water-electrolyte metabolism. Due to mineralocorticoid activity, sodium and water ions are retained in the body, and potassium excretion increases. The antagonism of GCS towards vitamin D causes the leaching of Ca 2+ from the bones and an increase in its renal excretion.

Other effects of GCS. GCS inhibit the growth of fibroblasts and collagen synthesis, cause a decrease in the reticuloendothelial clearance of cells with antibodies, and reduce the level of immunoglobulins without affecting the production of specific antibodies. In high concentrations, GCS stabilize lysosome membranes, increase hemoglobin and the number of erythrocytes in peripheral blood.

Pharmacokinetics. GCS for systemic use are poorly soluble in water, but well soluble in fats. Minor changes in the chemical structure can lead to significant changes in the extent of absorption and duration of action. In plasma, 90% of cortisol is reversibly bound to two types of proteins - globulin (glycoprotein) and albumin. Globulins have high affinity but low binding capacity, while albumins, on the contrary, have low affinity but high binding capacity. The metabolism of GCS occurs in several ways: the main one is in the liver, the other is in extrahepatic tissues and even in the kidneys. Microsomal liver enzymes metabolize GCS to inactive compounds, which are then excreted by the kidneys. Metabolism in the liver increases with hyperthyroidism and is induced by phenobarbital and ephedrine. Hypothyroidism, cirrhosis, concomitant treatment with erythromycin or oleandomycin leads to a decrease in the hepatic clearance of GCS. In patients with hepatic cell failure and low serum albumin, significantly more unbound prednisolone forms circulate in the plasma. There is no correlation between T1/2 and the duration of the physiological action of a particular GCS drug. Various activities of GCS are determined to varying degrees binding to plasma proteins. Thus, most of the cortisol is in a bound state, while 3% of methylprednisolone and less than 0.1% of dexamethasone. Fluorinated compounds (metazones) have the greatest activity. Beclomethasone contains chlorine as a halogen and is especially indicated for local endobronchial use. It was esterification that made it possible to obtain drugs with reduced absorption for local use in dermatology (fluocinolone pivalate). Succinates, or acetonides, are water-soluble and are used in the form of injections (prednisolone succinate, triamcinolone acetonide).

Performance criteria when used orally prednisone the same as for cromoglycate.

Safety criteria when used systemically glucocorticosteroids the following:

1) Absence of 1 infectious disease, including tuberculosis, due to suppression of the immune response;

2) Absence of osteoporosis, including in postmenopausal women, due to the risk of fractures;

3) Maintaining a sufficiently active lifestyle and the absence of osteomyelitis due to the threat of aseptic bone necrosis;

4) Control of the glycemic profile and exclusion of diabetes mellitus due to the possibility of complications in the form of ketoacidosis, hyperosmolar coma;

5) Consideration of mental status due to the possibility of developing “steroid” psychosis;

6) Monitoring blood pressure and water-electrolyte balance due to sodium and water retention;

7) No history of peptic ulcers, as well as the threat of gastrointestinal bleeding due to impaired rates of repair of the gastrointestinal mucosa;

8) Absence of glaucoma due to the possibility of provoking glaucomatous crises;

9) Absence of superficial wounds, fresh postoperative scars, burn injuries due to suppression of fibroplasia;

10) Absence of puberty due to cessation of growth and exclusion of pregnancy due to possible teratogenic effects.

Features of oral applicationsGKS .

Preference when choosing is given to fast-acting drugs with an average duration of action, having 100% bioavailability when used orally and to a lesser extent inhibiting the hypothalamic-pituitary-adrenal system. A short course (3-10 days) can be prescribed to achieve optimal effect at the beginning long course therapy for gradual deterioration of the patient’s condition or for rapid relief of a severe attack. To treat severe forms of bronchial asthma, long-term therapy with GCS may be required using one of the following regimens:

 Continuous regimen (most commonly used), with 2/3 of the daily dose given in the morning and 1/3 in the afternoon. Due to the danger of increasing the aggression of the acid-petic factor in conditions of a decrease in the rate of repair of the gastrointestinal mucosa, it is recommended to prescribe GCS after meals, in some cases under the guise of antisecretory drugs and agents that improve reparative processes in the gastrointestinal mucosa. However, combining administration with antacids is not advisable, since the latter reduce the absorption of GCS by 46-60%.

 An alternating regimen involves taking a double maintenance dose of the drug once in the morning every other day. This method can significantly reduce the risk of side effects while maintaining the effectiveness of the chosen dose.

 An intermittent regimen involves the use of GCS in short courses of 3-4 days with 4-day intervals between them.

If indicated, a trial two-week course of GCS is prescribed based on prednisolone from 20 to 100 mg (usually 40 mg). Further treatment with these drugs is carried out only if a repeated study after 3 weeks reveals a significant improvement in respiratory function: an increase in FEV 1 by at least 15% and an increase in FVC by 20%. Subsequently, the dose is reduced to the minimum effective, preference is given to an alternating dosage regimen. The minimum effective dose is selected by sequentially reducing the initial dose by 1 mg every 4-6 days with careful monitoring of the patient. The maintenance dose of prednisolone is usually 5-10 mg; a dose below 5 mg is ineffective in most cases. Systemic therapy with GCS leads to the development of side effects and complications in 16% of cases. After stopping the use of corticosteroids, the function of the adrenal cortex is restored gradually, over 16-20 weeks. Systemic corticosteroids are replaced if possible inhalation forms.

Performance criteria use inhaled corticosteroids the same as other means of basic therapy for patients with bronchial asthma.

Safety criteria when used inhaled corticosteroids the following:

1) Administration of the drug in the minimum effective dose, through spacers or turbohalers, with constant monitoring of the condition of the oral mucosa due to the possibility of developing oropharyngeal candidiasis; in rare cases - prophylactic use of antifungal agents;

2) Absence of professional restrictions associated with the threat of hoarseness (possibly due to local steroid myopathy of the laryngeal muscles, which disappears after discontinuation of the drug); a similar side effect is less often recorded for powder inhalation forms;

3) Lack of cough and irritation of the mucous membrane (mainly due to the additives included in the aerosol).

Conditions for use of inhaled corticosteroids and features of individual drugs.

A 400 mcg inhalation dose of beclomethasone (Becotide) is equivalent to approximately 5 mg of prednisolone taken orally. With an effective maintenance dose of prednisolone of 15 mg, patients can be completely transferred to treatment with inhaled corticosteroids. In this case, the dose of prednisolone begins to be reduced no earlier than a week after the addition of inhaled drugs. Inhibition of the function of the hypothalamic-pituitary-adrenal system occurs when beclomethasone is inhaled at a dose exceeding 1500 mcg/day. If the patient's condition worsens during a maintenance dose of inhaled corticosteroids, the dose must be increased. The maximum possible dose is 1500 mcg/kg; if in this case there is no therapeutic effect, it is necessary to add oral GCS.

Beklofort is a high-dose drug of beclamethasone (200 mcg in one dose).

Flunisolide (Ingacort), unlike beclomethasone, is already in a biologically active form from the moment of administration and therefore immediately manifests its effect in the target organ. In comparative studies on the effectiveness and tolerability of beclomethasone at a dose of 100 mcg 4 times a day and flunisolide at a dose of 500 mcg twice a day, the latter was significantly more effective. Flunisolide is equipped with a special spacer, which ensures a “deeper” penetration of the drug into the bronchi by inhaling most of the small particles. At the same time, there is a decrease in the frequency of oropharyngeal complications, a decrease in bitterness in the mouth and cough, irritation of the mucous membrane and hoarseness of the voice. In addition, the presence of a spacer makes it possible to use metered-dose aerosols in children, the elderly, and in patients with difficulty coordinating the process of inhalation and inhalation of the drug.

Triamcinolone acetonide (Azmacort) is most commonly used in the United States. A fairly wide range of doses used (from 600 mcg to 1600 mcg in 3-4 doses) allows the use of this drug in patients with the most severe asthma.

Budesonide is a long-acting drug and, compared to beclomethasone, is 1.6-3 times more active in anti-inflammatory activity. It is of interest that the drug is available in 2 dosage forms for inhalation use. The first is a traditional metered dose inhaler containing 50 and 200 mcg of budesonide in one puff. The second form is a turbohaler, a special inhalation device that provides the administration of the drug in powder form. The air flow created thanks to the original design of the turbohaler captures the smallest particles of the drug powder, which leads to a significant improvement in the penetration of budesonide into small-caliber bronchi.

Fluticasone propionate (flixotide) is an inhaled GCS with greater anti-inflammatory activity, pronounced affinity for glucocorticoid receptors, and less systemic side effects. The pharmacokinetic features of the drug are reflected in the high threshold dose - 1800-2000 mcg, only when exceeded, systemic adverse reactions can develop.

Thus, inhaled corticosteroids are one of the most effective means of treating patients with bronchial asthma. Their use leads to a reduction in symptoms and exacerbations of bronchial asthma, improvement in functional pulmonary parameters, a decrease in bronchial hyperreactivity, and a decrease in the need for bronchodilator drugs short acting, as well as improving the quality of life of patients with bronchial asthma.

Table 4. Estimated equivalent doses (mcg) inhalation

Ph.D. L.I. DYATCHINA

To date, a huge amount has been accumulated; experience in the use of glucocorticosteroids (GCS). The amazing clinical effect, powerful anti-inflammatory effect, and pronounced immunomodulatory activity of GCS allow their use in many diseases. Exposure to glucocorticosteroids; on organs and systems is necessary for the normal functioning of the entire organism as a whole.

REGULATION OF GLUCOCORTICOSTEROIDS RELEASE

The main endogenous GCS is cortisol, which is synthesized and secreted by the adrenal cortex in response to the stimulating effect of adrenocorticotropic hormone (ACTH). Normally, about 15-30 mg of cortisol is secreted daily. The hormone is released in pulses - 8-10 pulses/day. The level of cortisol secretion does not remain constant throughout the day (the maximum concentration in the blood is reached at 7-8 a.m., the minimum at midnight). Under stress (infection, surgery, hypoglycemia), the synthesis and secretion of GCS increases approximately 10 times (up to 250 mg/day).

Regulation of the release of GCS is controlled by the hypothalamic-pituitary mechanism. When the concentration of free cortisol decreases, the hypothalamus releases corticotropin, a releasing factor that stimulates the release of adrenocorticotropic hormone (corticotropin) in the anterior pituitary gland. Adrenocorticotropic hormone (ACTH), in turn, causes the release of GCS from the adrenal cortex.

MECHANISM OF ACTION OF GLUCOCORTICOSTEROIDS

The effect of glucocorticosteroid hormones on the cell is manifested through their effect on the genetic apparatus of the cell. The primary link in the action of glucocorticosteroids on the cell is their interaction with specific receptors of target organs.
GCS are lipid substances (cholesterol derivatives) and can dissolve in cell membranes. Penetration of the hormone into the cell is possible not only in bound form (with the help of a carrier protein), but also passively. 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 tissue sensitivity to GCS. In addition, GCS may have different tropism for GCR. Thus, the endogenous glucocorticosteroid cortisol preferentially binds to the GCR of the cytoplasmic membrane, while the synthetic GCS, dexamethasone, binds to a greater extent to the cytosolic GCR. The number of glucocorticosteroid receptors (GCR) can vary significantly and change during GCS therapy.
The next step is the movement of the hormone receptor complex (HRC) into the cell nucleus. Penetration of GRKs into the nucleus is possible after a restructuring of their structure (activation), leading to their ability to bind to the components of the nucleus.
Activated GRK binds to a specific region of DNA in the nucleus. The GRK-DNA complex helps increase RNA synthesis. 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. The possibility of interaction of steroids with non-histone chromatin proteins has been described, which leads to a change in their structure. The anti-inflammatory effect of steroids is mediated through specific GCRs, changes in GRC activity and the synthesis of RNA and proteins (nuclear pathway).

PHARMACODYNAMIC EFFECTS OF GLUCOCORTICOSTEROIDS

1. The anti-inflammatory effect of GCS manifests itself in the form of antiexudative and antiproliferative effects.
2. Immunosuppressive effect
3. Antiallergic effect
4. Impact on metabolic processes

The antiexudative effect of GCS o6 is conditional (Table No. 1):

• Membrane-stabilizing effect and, as a consequence, a decrease in the permeability of cellular and subcellular membranes (mitochondria and lysosomes);
• Reduced permeability of the vascular wall, in particular capillaries, and vasoconstriction at the site of inflammation. Vasoconstriction is a specific effect of GCS on the vascular bed at the site of inflammation. At the same time, their effect on other vessels can, on the contrary, cause vasodilation. The mechanism of this action of GCS is not fully understood; it is associated with suppression of the release of lipid mediators and activators of the kinin system, and a decrease in hyaluronidase activity;
• Suppression of the synthesis of certain cytokines involved in inflammatory reactions, as well as blockade of the synthesis of cytokine receptor proteins;
• Decreased production of interleukins (IL): IL-1, IL-3, IL-4, IL-5, IL-b and IL-8, tumor necrosis factor - alpha (TNF - α), granulocyte-macrophage-colony-stimulating factor (GM-CSF ), through suppression, transcription or reduction of the half-life of messenger RNA;
• Inhibition of the migration of mast cells and eosinophils to the site of inflammation. Glucocorticosteroids are known to reduce the number of eosinophils by suppressing the production of GM-CSF and IL-5;
• Suppression of mast cell degranulation and the release of biologically active amines (histamine, serotonin, kinins and prostaglandins) from mast cells;
• Reducing the intensity of energy generation processes in the inflammation site;
• Inhibition of neutrophil migration to the site of inflammation, disruption of their functional activity (chemotactic and phagocytic). GCS cause peripheral leukocytosis both after a single dose (for 4-6 hours) and with long-term treatment (on the 14th day) with a subsequent decrease in the level of leukocytes;
• Suppression of monocyte migration by slowing down the release of mature monocytes from the bone marrow and reducing their functional activity.

ANTI-INFLAMMATORY EFFECT OF GLUCOCORTICOSTEROIDS

Anti-exudative effect	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 effect	suppression of nucleic acid synthesis; impaired differentiation of fibrocytes from fibroblasts; decrease in the functional activity of fibrocytes

Currently, there is a hypothesis that in the mechanism of the anti-inflammatory action of GCS, their ability to induce the synthesis of some (lipomodulin) and suppress the synthesis of other (collagen) proteins in cells is important. The mediator of the anti-inflammatory effect of GCS is most likely lipomodulin (macrocortin, lipocortin), the synthesis of which occurs under the influence of small concentrations of these hormones in various types of cells. Lipomodulin blocks phospholipase A2 of cell membranes and thereby disrupts the release of phospholipid-bound arachidonic acid, which is then converted into prostaglandins, leukotrienes and thromboxane. The latter take an active part in the processes of inflammation. Inhibition of leukotriene B4 reduces the chemotaxis of leukocytes, and leukotrienes C4 and D4 (slowly reacting substance) reduces the contractile ability of smooth muscles, vascular permeability and mucus secretion in the airways.

The decrease in the production of cytokines, in particular IL-1, caused by GCS, also suppresses the activity of phospholipase A2 and, to a large extent, cyclooxygenase-2 (COX-2).
Currently, nitrogen monoxide (NO) is also considered as the most important initiator of the inflammatory response. Glucocorticosteroids reduce the production of nitric oxide by inhibiting the activity of the enzyme NO synthetase (NOS), as shown in an experiment on monocytes.
An increase in the expression of neutral endopeptidase is important in the implementation of the anti-inflammatory effect of glucocorticosteroids in neurogenic inflammation. Neutral endopeptidase plays a role in the breakdown of tachykinin, the latter being released from sensory nerve endings. Endopeptidases, as studies have shown, are also responsible for the degradation of bronchoconstrictor peptides such as bradykinin, tachykinin and endothelin-1.
The antiproliferative effect of GCS is associated with:

• with their suppression of nucleic acid synthesis;
• impaired differentiation of fibrocytes from fibroblasts;
• a decrease in their functional activity, which leads to inhibition of the processes of sclerosis at the site of inflammation.

INFLUENCE OF GLUCOCORTICOSTEROIDS ON THE IMMUNE RESPONSE

The effect of glucocorticosteroids on immune system mediated by the presence of specific glucocorticoid receptors on lymphoid cells. Under the influence of steroids, the number of lymphocytes in the peripheral blood decreases. This is largely due to the redistribution of lymphocytes from the blood to tissues, primarily to the bone marrow and spleen. In this case, GCS cause apoptosis of immature or activated T- and B-lymphocytes. There is a point of view that the immunosuppressive effect of glucocorticosteroids is realized by controlling the absolute number of lymphoid cells and their subpopulations.
Cytokines play an important role in immune reactions. The key cytokine is IL-2, which is involved in the induction of immune responses that occur after the interaction of a T cell with an antigen-presenting cell. GCS significantly reduce the production of IL-2, resulting in a decrease in IL-2-dependent phosphorylation of various proteins. This leads to suppression of T cell proliferation. In addition, glucocorticosteroids suppress T-cell activation by inhibiting the production of IL-3, IL-4, IL-6 and other cytokines. Since glucocorticosteroids suppress cytokines secreted by other cells, the function of T-helpers, T-suppressors, cytotoxic T-lymphocytes and, in general, immunological reactions decreases. At the same time, T-helpers are more sensitive to glucocorticosteroids than T-suppressors.
The inhibitory effect of GCS on B cells is weak. Moderate and low doses of corticosteroids do not cause any significant changes in the level of immunoglobulins in the blood. Reducing the content of immunoglobulins is achieved by prescribing high and very high doses of glucocorticosteroids (pulse therapy). Steroids inhibit the activity of the complement system and the formation of fixed immune complexes.
GCS have a pronounced effect on the activity of macrophages and monocytes. Considering that monocytes and macrophages play a significant role in the development of the inflammatory process and the involvement of other types of cells in it, it is obvious that the effect of GCS on their migration, secretion and functional activity can be decisive in the inflammatory reaction itself.
Other effects of GCS are associated with inhibition of phagocytosis, release of pyrogenic substances, decreased bactericidal activity of cells, inhibition of the secretion of collagenase, elastase and plasminogen activators, and impaired release of macrophage factors that cause mucus formation.
The main immunosuppressive effects of GCS are reflected in Table No. 2.

IMMUNOSUPPRESSIVE EFFECT OF GLUCOCORTICOSTEROIDS

Mechanisms underlying this effect

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, and possibly their accumulation 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.

In the immune inflammatory process, as well as in the development of the stress response, the hypothalamus-pituitary-adrenal cortex system plays a significant role. Many cytokines stimulate the functional hypothalamus-pituitary-adrenal system.

INFLUENCE OF GLUCOCORTICOSTEROIDS ON TISSUE METABOLISM

The effect of GCS on carbohydrate metabolism is to stimulate the processes of glyconeogenesis, i.e. synthesis of glycogen from products of protein and nitrogen metabolism. At the same time, the rate of glucose utilization by tissues is disrupted by reducing its penetration into the cell. As a result, some patients may experience transient hyperglycemia and glycosuria. Prolonged hyperglycemia leads to depletion of the pancreatic insular apparatus and the development of “steroid” diabetes mellitus.
The effect of GCS on protein metabolism manifested by increased protein breakdown in most organs and tissues and, above all, in muscle tissue. The consequence of this is an increase in the content of free amino acids and nitrogen metabolism products in the blood plasma. Subsequently, the products of protein and nitrogen metabolism are used in the processes of gluconeogenesis.
The breakdown of muscle tissue proteins causes weight loss, muscle atrophy, muscle weakness, and impaired growth of cartilage and bone tissue. Suppression of protein synthesis in the bone matrix of the vertebrae leads to a delay in the formation of the skeleton in children. Dystrophic processes occurring in other tissues are accompanied by the development of “steroid” ulcers, myocardial dystrophies, and skin atrophy (striae).
An increase in the processes of protein catabolism is observed when using medium therapeutic doses of GCS. The use of small doses of GCS, on the contrary, stimulates the synthesis of albumin in the liver from free amino acids in the blood plasma. This is especially important in patients with impaired protein-synthetic liver function.
The effect of GCS on fat metabolism is manifested in the form of their lipolytic and at the same time lipogenetic action. The lipolytic effect is observed in the subcutaneous fat of the arms and legs, the lipogenetic effect is manifested by the predominant deposition of fat in the anterior abdominal wall, interscapular area, on the face and neck. This process is most pronounced with long-term use of corticosteroids and leads to changes in appearance patients and is described in the literature as Cushingoid (moon-shaped face, pituitary-type obesity, impaired glucose tolerance, etc.). The effect of GCS is manifested by an increase in the content of cholesterol and lipoproteins in the blood serum. GCS accelerate the process of converting carbohydrates into fats, which also contributes to the development of obesity.
The effect of GCS on water-mineral metabolism is associated, on the one hand, with the suppression of the secretion of antidiuretic hormone, which is accompanied by an increase in the glomerular filtration rate, the release of sodium and water from the body. At the same time, in patients with severe heart failure, GCS can stimulate the synthesis of aldosterone, which leads to sodium and fluid retention and an increase in edema syndrome. The breakdown of protein in tissues is accompanied by an increase in potassium and calcium in the blood plasma. Gradually developing hypocaligistia contributes to the intensification of degenerative processes in tissues and, first of all, in the heart muscle, which can cause cardiac arrhythmias, cardialgia and lead to increased severity of heart failure. GCS inhibit the absorption of calcium in the intestine and increase its excretion in the urine. As a result, the release of calcium from bone tissue increases, which contributes to the formation of “steroidal” osteoporosis. Hypercalciuria and, at the same time, an increase in urea content in the urine, uric acid leads to the development of uric acid diathesis and exacerbation of gout in a number of patients taking corticosteroids for a long time. Calcium deficiency in bones can contribute to pathological bone fractures in children and the elderly.
The effect of GCS on tissue metabolic processes is presented in Table #3.

INFLUENCE OF GLUCOCORTICOSTEROIDS ON TISSUE METABOLISM PROCESSES

Types of exchange
for carbohydrate metabolism	stimulation of glyconeogenesis processes; impaired rate of glucose utilization by tissues; transient hyperglycemia and glycosuria depletion of the insular apparatus of the pancreas.
for protein metabolism	increased protein breakdown; an increase in the content of free amino acids and nitrogen metabolism products in the blood plasma; stimulation of glyconeogenesis processes; stimulation of the synthesis of albumin in the liver and free amino acids in plasma.
for fat metabolism	lipolytic effect in the subcutaneous fat of the hands; lipogenetic effect with predominant fat deposition in the anterior abdominal wall, interscapular region, face and neck; increased levels of cholesterol and lipoproteins in the blood plasma; accelerating the process of converting carbohydrates into fats.
for water-mineral metabolism	suppressing the secretion of antidiuretic hormone, increasing the glomerular filtration rate and stimulating the excretion of sodium and water from the body (with short courses); stimulation of aldosterone synthesis and sodium and fluid retention, increase in edema syndrome (with long-term use); an increase in the content of potassium and calcium in the blood plasma, hypokaligistia; increased calcium levels in blood plasma, hypercalciuria; the content of urea and uric acid in the blood increases, and uric acid diathesis.

It should be said about the influence of GCS on the functions of other organs and systems that are not responsible for the formation of the main pharmacological response.

• The administration of GCS leads to an increase in the production of hydrochloric acid and pepsin in the stomach.
• The effect of GCS on the endocrine organs is manifested in the inhibition of the secretion of ACTH and gonadotropin in the anterior lobe of the pituitary gland, a decrease in the function of the gonads with the development of secondary amenorrhea and infertility, and suppression of the secretion of thyroid hormones.
• GCS in the central nervous system can increase the excitability of cortical structures of the brain and reduce the seizure threshold. They have a euphoric effect in a number of patients, and under certain conditions cause the development of depression.
• GCS have an effect on peripheral blood (Table No. 4).

INFLUENCE OF GLUCOCORTICOSTEROIDS ON PERIPHERAL BLOOD

PHARMACOKINETICS OF GLUCOCORTICOSTEROIDS

When taken orally, GCS are absorbed predominantly into small intestine. Absorption occurs in the proximal (75%) and distal (25%) parts of the small intestine.
The adrenal cortex of a healthy adult, under the influence of corticotropin, produces 15-60 mg of cortisol and 1-4 mg of corticosterone daily. More than 95% of plasma cortisol forms complexes with plasma proteins, mainly with corticosteroid-binding alpha globulin (transcortin). The affinity of the hormone for transcortin is very high, however, the binding capacity of transcortin is low and when the plasma cortisol concentration increases above 20 mcg/100 ml, it is completely exhausted. In this case, the transfer of the drug is carried out by plasma albumins (from 40 to 90% of GCS in the blood plasma are in a state associated with albumins). At the same time, only the unbound (free) fraction of GCS is physiologically active, which exerts its pharmacological effect on target cells. Side effects in patients receiving corticosteroids are determined by the amount of free fraction of GCS. However, there is no correlation between the half-life and the duration of physiological action of a particular GCS drug.
GCS are classified into short-, intermediate- and long-acting drugs depending on the duration of ACTH suppression after a single dose. At the same time, the half-life of GCS is much shorter: from 30 minutes for cortisone and 60 minutes for prednisolone to 300 minutes for dexamethasone.
Interestingly, the maximum pharmacological activity of GCS occurs at a time when their peak concentrations in the blood are already behind them. Thus, according to pharmacokinetic studies, the peak concentration of prednisolone in plasma is achieved after 1–3 hours, the half-life is 2–3.5 hours, and the maximum biological effect develops in approximately 6 hours. This suggests that the effects of GCS depend to a greater extent on their induction of enzymatic activity inside the cell than on their direct action. The period of anti-inflammatory activity of GCS is approximately equal to the duration of their suppression of the hypothalamic-pituitary-adrenal axis - HPA (from 4 to 8 days).
Normally, cortisol levels begin to increase at 2 a.m. with a peak at 8 a.m. and return to basal levels by 12 p.m. Symptoms of RA (stiffness, inflammatory activity) usually decrease a few hours after waking up at the peak of cortisol synthesis. Until recently, it was believed that taking GCS in the morning inhibits the synthesis of ACTH and cortisol to a lesser extent than at night and evening time. Recently, evidence has emerged that a circadian increase in IL-6 levels may also be associated with an increase in RA activity in the morning. Daily fluctuations in IL-6 are observed normally and in patients with RA. Normally, the peak concentration of IL-6 occurs slightly earlier than ACTH and cortisol between 1 and 4 am. However, in RA, the peak of IL-6 is delayed and occurs between 2 and 7 am and the concentration of IL-6 is significantly higher than normal. Therefore, the administration of GCS (5-7.5 mg) at night (at about 2 am) is more preferable from the point of view of suppressing the secretion of IL-6 and is associated with a significantly more pronounced reduction in the duration of morning stiffness, joint pain, Lansbury index, Ritchie index.
In untreated patients with active RA, a weakening of basal and corticotropin-stimulated cortisol synthesis is also observed. Moreover, approximately 10% of RA patients show signs of adrenal insufficiency. Obviously, in these patients we can expect a higher effectiveness of low doses of GCS than in patients without a defect in the HPA axis.
The different activities of GCS are also determined by the different degrees of binding to plasma proteins. Thus, most of the natural cortisol is bound, while only 3% of methylprednisolone and less than 0.1% of dexamethasone are bound to corticosteroid binding globulin.
Microsomal liver enzymes metabolize GCS to inactive compounds, which are then excreted by the kidneys. Metabolites are excreted in the urine in the form of glucuronides, sulfates and unconjugated compounds. Conjugation reactions occur primarily in the liver and, to a lesser extent, in the kidneys. Metabolism in the liver increases with hyperthyroidism and is induced by phenobarbital and ephedrine. Hypothyroidism, cirrhosis, and concomitant treatment with erythromycin lead to a decrease in the hepatic clearance of GCS. In patients with hepatocellular insufficiency and low serum albumin levels in plasma, the concentration of the free fraction of prednisolone increases, which contributes to a more rapid development of side effects. During pregnancy, on the contrary, the proportion of its free fraction decreases.

CLASSIFICATION OF GLUCOCORTICOSTEROIDS

Depending on the duration of ACTH inhibition after a single dose, GCS are divided into: a) short-acting GCS - inhibit ACTH activity for up to 24-36 hours, b) medium-duration GCS - up to 48 hours and c) long-acting GCS - over 48 hours.
I. NATURAL– Cortisol, Cortisone (Hydrocortisone), Cortisone acetate – inhibit ACTH activity for up to 24-36 hours.
II. SEMI-SYNTHETIC

1. Short-acting drugs - Prednisolone, Prednisone, Methylprednisolone (Urbazon, Metipred) - inhibit the activity of AGTG for up to 24-36 hours.
2. Medium-acting drugs – Triamcinolone (Polcortolone) – inhibit ACTH for up to 48 hours.
3. Long-acting drugs - Betamethasone, dexamethasone - inhibit ACTH for more than 48 hours.

APPLICATION OF GLUCOCORTICOSTEROIDS

The classic area of ​​​​therapeutic use of GCS is such general pathological processes as inflammation, allergies, sclerosis and degeneration of connective tissue derivatives.
GCS are used as anti-inflammatory, antiallergic and immunosuppressive agents, as well as replacement therapy for adrenal insufficiency.
The following options for GC therapy are distinguished:

1. System:
   • average therapeutic doses
   • alternating therapy
   • pulse therapy
   • "mini-pulse" therapy
   • combined (primarily with cytotoxics)
2. Local (intra-articular, inhalation, rectal administration, etc.);
3. Local (ointments, drops, aerosol).

Systemic therapy with GCS is one of the most effective methods treatment of a number of diseases. The use of steroids can significantly improve the prognosis and increase the life expectancy of patients.
In the treatment of GCS, the following phases are conventionally distinguished:

• Induction: use short-acting corticosteroids (prednisolone or methylprednisolone) in a dose approximately corresponding to 1 mg/kg body weight per day at 8-hour intervals.
• Consolidation: involves switching to a single dose of the entire dose of GCS in the morning.
• Decrease: the rate of decline of GCS depends on the dose. It is possible to switch to alternative therapy.
• Maintenance treatment: use of the minimum effective dose of drugs.
• Prevention of complications of GCS therapy: begins with the induction phase.

When conducting systemic therapy with GCS, several factors must be taken into account: general principles pharmacotherapy, compliance with which can increase the effectiveness and safety of treatment, as well as reduce the frequency of unwanted side effects.
GK therapy should be started only if there are strict indications and as early as possible, without trying to use “softer” treatment methods first. In this case, hormonal therapy should be used together with conventional therapy, and not prescribed instead of it. Rational therapy involves the use of short-acting corticosteroids in the optimal dose and, if possible, for the period necessary to control the activity of the process.
GCS should be prescribed only under medical supervision of their use in order to early detect side effects and correct them. When prescribing hormone therapy, not only the doctor, but also the patient should be informed in detail about the possibilities and complications this method treatment.

• Prednisolone is considered the standard among GCS and the effectiveness of other drugs in this group is assessed in relation to it. Average therapeutic doses of GCS per prednisolone are 0.5-1 mg per kg of body weight.
• When prescribing GCS, the principle of equivalent doses should be observed in order to obtain the same anti-inflammatory effect. Equivalent doses: prednisolone – 5 mg: triamcinolone – 4 mg: methylprednisolone – 4 mg: dexamethasone – 0.5 mg: betamethasone – 0.75 mg: hydrocortisone – 25 mg. In this case, the calculation always goes to prednisolone. When transferring patients from parenteral administration of GCS to oral administration, it is necessary to reduce the daily dose by 5-6 times.
• In cases where long-term use of GCS is expected, patients should be transferred as quickly as possible to a single dose of the entire dose in the morning, and then to an alternating regimen of GCS therapy. At the beginning of treatment, the daily dose of the drug is usually divided into 3 doses (induction phase), then they switch to a single dose of the drug in the morning (consolidation phase).
• The choice of the initial dose of GCS, determination of the duration of therapy and the rate of dose reduction should be carried out not empirically, but taking into account standardized clinical and laboratory indicators of the activity of the process and the nature of the disease. When prescribing GCS therapy, you should pay attention to the following:
  • necessary daily dose should be selected individually, starting with the minimum average therapeutic doses usually recommended for this disease;
  • for chronic diseases, GCS should not be prescribed in large doses and for a long course, and when remission occurs, the use of GCS should be stopped;
  • in case of life-threatening conditions, large doses of corticosteroids should be prescribed immediately.
• During hormone therapy in the peripheral blood, there is a decrease in the number of eosinophils, lymphocytes, erythrocytes, a decrease in the level of hemoglobin, while the content of leukocytes increases due to neutrophils (up to 12,000). Such a hemogram can be mistakenly interpreted as a continuation of an exacerbation of the process. At the same time, these changes should be considered favorable and indicating a sufficient dosage of GCS.
• Rate of GCS dose reduction. After achieving a clinical effect, the dose of GCS should be reduced to a maintenance dose. To do this, the initial dose of GCS is gradually reduced to the minimum level at which the resulting positive effect is maintained. If the daily dose of the course of treatment is in the range of 15-40 mg/day in terms of prednisolone, then withdrawal should be carried out at a rate of 2.5-5 mg every 5-7 days until the physiological dose is reached. When GCS is prescribed in doses of 40 mg or more, the dose reduction can occur more quickly (5 mg and even in some cases 10 mg per week) to the level of 40 mg, and then as indicated above. In these cases, the rate of reduction in the dose of GCS is determined by the duration of their use. The shorter the duration of the course of treatment, the faster the withdrawal of GCS is possible. However, the lower the dose of GCS, the longer the periods between successive drug dose reductions should be. This tactic allows you to create conditions for restoring the functionality of the hypothalamic-pituitary-adrenal system already during drug withdrawal.
• In case of relapse of the disease, hormone therapy is resumed. The dose of GCS is increased to the one at which the patient experienced stabilization of the process. In the future, withdrawal should be carried out more carefully and gradually. Determining the duration of therapy and the rate of dose reduction should not be done empirically, but taking into account standardized clinical and laboratory indicators of the activity of the process and the nature of the disease. There are several laboratory criteria for determining the effectiveness of GCS therapy: stabilization of ESR within 7 days; decrease in C level - reactive protein, fibrinogen, etc.
• Cancellation of glucocorticosteroids. Problems associated with the withdrawal of glucocorticosteroids arise after a long course of therapy. In this case, more abrupt withdrawal of drugs threatens the development of two types of complications. Firstly, these are manifestations of adrenal insufficiency associated with suppression of the hypothalamic-pituitary-adrenal system. Secondly, this is a relapse of the inflammatory process underlying the disease itself.
  • Suppression of adrenal function depends on the dose of hormones taken and, to an even greater extent, on the duration of glucocorticoid therapy, as well as on the properties of the drug used and the underlying disease.
  • A dose of prednisolone in the range of 10-15 mg gives a full replacement effect and is considered physiological. In this regard, withdrawal of the drug to a physiological dose can be carried out quite quickly. Further reduction in the dose of GCS should occur at a much slower pace.
  • During treatment, it must be remembered that inhibition of the hypothalamic-pituitary-adrenal axis persists in patients who received even small doses of GCS (over 10 mg/day for three or more weeks) for a long time (up to 1 year) after discontinuation of the drug.
  • Rapid discontinuation of the drug (within 1-2 days) is carried out extremely rarely only in the case of acute steroid psychosis, or in case of generalization of herpesvirus infection.
  • In cases where it is not possible to completely avoid glucocorticosteroid therapy, patients should be transferred to maintenance doses of hormones, individual for each patient and corresponding, as a rule, to replacement doses of 5-15 mg of prednisolone per day. Hormones should be taken in the morning (from 6 to 9 am), taking into account the natural biorhythm of their release.
  • There is evidence that there is no significant inhibition of the hypothalamic-pituitary-adrenal axis if the dose of prednisolone does not exceed 10 mg per day. During treatment with GCS, the occurrence of adverse reactions significantly more common in patients receiving more than 10 mg of prednisolone per day. The risk of side effects is less when the total dose of prednisolone is reduced and the drug is taken at a certain time. At the same time, treatment with low doses of GCS can reduce the potential risk of osteoporosis due to inhibition of IL-6 synthesis.
  • In order to reduce the dose of GCS, it is recommended to combine them with NSAIDs and basic therapy. However, this increases the likelihood of developing ulcerative lesions of the gastrointestinal tract. To stimulate the production of your own hormones, in some cases it is possible to prescribe ACTH (corticotropin) against the background of gradual withdrawal of GCS.
  • When using GCS as replacement therapy for primary adrenal insufficiency (Addison's disease), simultaneous administration of a glucocorticosteroid and a mineralocorticosteroid is indicated. Cortisone acetate or hydrocortisone in combination with deoxycorticosterone acetate or fludrocortisone are recommended as corticosteroids.

In case of secondary adrenal insufficiency, due to the preserved basic secretion of aldosterone, in most cases it is possible to use one GCS. With adrenogenital syndrome, patients should receive maintenance doses of GCS throughout their lives. Hormone-dependent patients with the development of severe intercurrent diseases or the need for surgical interventions must necessarily receive GCS replacement therapy in doses 5-10 mg higher than those that patients take constantly.

MAIN INDICATIONS FOR PRESCRIPTION OF GLUCOCORTICOSTEROIDS

1. Rheumatic diseases:
   • rheumatism 2-3 degrees. process activity in the presence of rheumatic carditis, especially in combination with polyarthritis and polyserositis - average therapeutic doses of GCS;
   • systemic lupus erythematosus during an exacerbation (pulse therapy), in chronic forms - average therapeutic doses of GCS or as maintenance therapy;
   • systemic dermatomyositis during an exacerbation - pulse therapy with GCS or as maintenance therapy;
   • periarteritis nodosa during an exacerbation - pulse therapy with GCS or as maintenance therapy;
   • rheumatoid arthritis in combination with visceritis (febrile syndrome, carditis, nephritis, serositis); for rapidly progressing articular forms of rheumatoid arthritis and a high titer of rheumatoid factor - pulse therapy, then, often, maintenance therapy; ineffectiveness of previous NSAID therapy and basic therapy - average therapeutic doses of GCS, for monoarthritis - intra-articular administration of GCS;
   • juvenile rheumatoid arthritis.

The main indications for prescribing GCS for rheumatic diseases are shown in Table No. 5.

The use of GCS in rheumatic diseases
Diseases	Indications	A drug
RA Rheumatoid vasculitis	Ineffectiveness of NSAIDs or contraindications for prescribing NSAIDs (+ basic therapy)	Prev. 10 mg/day	– 2 mg/kg/day
	Arthritis, low disease activity. Kidney and central nervous system damage	Prev. 15 mg/day	Prev. 1 mg/kg/day + CP
PM/DM Sjögren's syndrome Polyarteritis nodosa Churg–Strauss syndrome Wegener's granulomatosis	Vasculitis Moderate activity High activity	Prev. 1 mg/kg/day Prev. 1 mg/kg/day Prev. 1 mg/kg/day + CP 1 mg/kg/day	2 mg/kg/day -2 mg/kg/day -2 mg/kg/day
SD Eosinophilia-myalgia syndrome	Myositis, pleurisy, vasculitis, pericarditis, arthritis	Prev. 15-60 mg/day Prev. 1 mg/kg/day
Relapsing polychondritis		Prev. 0.5 – 1.0 mg/kg/day
Side effects of the baseline therapy	Gold salts, penicillamine, sulfasalazine, etc.	Prev. 15 – 60 mg/day
Note: Prev. – prednisolone.

1. Systemic vasculitis - systemic therapy with GCS.
2. Carditis (infectious-allergic myocarditis, Abramov-Fiedler myocarditis, subacute septic endocarditis - immunological phase) - systemic therapy with GCS.
3. Diseases of the musculoskeletal system:
   • post-traumatic osteoarthritis - for short-term use in the acute period or for intra-articular administration of GCS;
   • ankylosing spondylitis (ankylosing spondylitis);
   • subacute gouty arthritis - for short-term use in the acute period or for intra-articular administration of GCS;
   • acute and subacute bursitis;
   • acute nonspecific tenosynovitis;
   • psoriatic arthritis.
4. Kidney diseases (chronic nephritis with nephrotic syndrome - the most indicated use of GCS for membranous and membranous-proliferative variants; for lupus nephritis) - systemic therapy with GCS.
5. Diseases of the gastrointestinal tract (nonspecific ulcerative colitis, Crohn's disease, SPRU) - systemic therapy with GCS.
6. Liver diseases (autoimmune hepatitis) - systemic therapy with GCS.
7. Diseases of the bronchopulmonary system (obstructive bronchitis, allergic bronchial asthma, sarcoidosis - systemic therapy and inhaled corticosteroids).
8. Hematological diseases: acquired (autoimmune) hemolytic anemia, thrombocytopenic purpura - systemic therapy with GCS.
9. Allergic conditions. Control of allergic conditions when conventional remedies are ineffective: seasonal or chronic allergic rhinitis, nasal polyps, bronchial asthma (including asthmatic condition), contact dermatitis, atopic dermatitis (neurodermatitis), hypersensitivity to drugs and serum sickness (anaphylactic shock, Quincke's edema, Lyell's syndrome, Steven-Johnson syndrome, drug or food agranulocytosis, thrombocytopenia, giant urticaria).
10. Eye diseases: severe acute and chronic allergic reactions and inflammatory processes in the eyes and adjacent structures, such as allergic conjunctivitis, keratitis, allergic marginal corneal ulcer, corneal herpes, iritis and iridocyclitis, chorioretinitis, anterior segment inflammation, diffuse posterior uveitis and choroiditis, retrobulbar neuritis, sympathetic ophthalmia.
11. Skin diseases: eczema (chronic dermatitis), in the treatment of keloids and localized hypertrophic infiltrating inflammation (injection of corticosteroids into the affected area), lichen planus, psoriasis, granuloma annulare, simple chronic lichen (neurodermatitis), discoid lupus erythematosus, necrobiosis lipoidica in diabetics, nested alopecia, psoriasis, erythema nodosum and others - local therapy GKS.
12. Tumor diseases: palliative treatment of leukemia and lymphoma in adults, acute childhood leukemia.
13. Endocrine disorders: primary or secondary adrenal insufficiency, acute failure adrenal glands, bilateral adrenectomy, congenital adrenal hyperplasia, acute thyroiditis and thyrotoxic crisis, hypercalcemia associated with cancer.
14. Shock conditions: hemodynamic, traumatic, endotoxic, cardiogenic (infarction).
15. Cerebral edema (increased intracranial pressure) – GCS are needed as an adjuvant to reduce or prevent cerebral edema associated with surgical or other brain trauma, stroke, primary or metastatic malignant brain tumors. The use of glucocorticosteroids should not be considered as a replacement for neurosurgical treatment.
16. Prevention of renal allograft rejection. The drug is used in combination with commonly used immunosuppressants.

Hydrocortisone (Hydrocortisone, Cortef, Laticort, Oxycort).

Dexamethasone (Ambene, Dex-Gentamicin, Maxidex, Maxitrol, Polidexa, Tobradex).

Methylprednisolone (Advantan, Metypred, Solu-Medrol).

Mometasone furoate (Momat, Nasonex, Elokom).

Prednisolone (Aurobin, Dermosolone, Prednisolone).

Triamcinolone acetonide (Kenalog, Polcortolone, Fluorocort).

Fluticasone propionate (Flixonase, Flixotide).

Flucortolone (Ultraproct).

• Mechanism of action

  Glucocorticosteroids penetrate into the cell cytoplasm by diffusion and interact with intracellular steroid receptors.

  Inactive glucocorticosteroid receptors are hetero-oligomeric complexes, which, in addition to the receptor itself, include heat shock proteins, different kinds RNA and other structures.

  The C-terminus of steroid receptors is associated with a large protein complex that includes two subunits of the hsp90 protein. After the glucocorticosteroid interacts with the receptor, hsp90 is cleaved off, and the resulting hormone-receptor complex moves into the nucleus, where it acts on certain sections of DNA.

  Hormone-receptor complexes also interact with various transcription factors or nuclear factors. Nuclear factors (eg, activated transcription factor protein) are natural regulators of several genes involved in the immune response and inflammation, including genes for cytokines, their receptors, adhesion molecules, and proteins.

  By stimulating steroid receptors, glucocorticosteroids induce the synthesis of a special class of proteins - lipocortins, including lipomodulin, which inhibits the activity of phospholipase A 2.

  The main effects of glucocorticosteroids.
  

  Glucocorticosteroids, due to their multilateral influence on metabolism, mediate the body’s adaptation to stressors from the external environment.

  Glucocorticosteroids have anti-inflammatory, desensitizing, immunosuppressive, antishock and antitoxic effects.

  The anti-inflammatory effect of glucocorticosteroids is due to the stabilization of cell membranes, suppression of the activity of phospholipase A 2 and hyaluronidase, inhibition of the release of arachidonic acid from phospholipids of cell membranes (with a decrease in the levels of its metabolic products - prostaglandins, thromboxane, leukotrienes), as well as inhibition of the processes of degranulation of mast cells (with the release of histamine , serotonin, bradykinin), synthesis of platelet activating factor and connective tissue proliferation.

  The immunosuppressive activity of glucocorticosteroids is the total result of suppression of various stages of immunogenesis: migration of stem cells and B-lymphocytes, interaction of T- and B-lymphocytes.

  The antishock and antitoxic effect of glucocorticosteroids is explained mainly by an increase in blood pressure (due to an increase in the concentration of catecholamines circulating in the blood, restoration of the sensitivity of adrenoreceptors to them, as well as vasoconstriction), a decrease in vascular permeability and activation of liver enzymes involved in the biotransformation of endo- and xenobiotics.

  Glucocorticosteroids activate hepatic gluconeogenesis and enhance protein catabolism, thereby stimulating the release of amino acids - substrates of gluconeogenesis from peripheral tissues. These processes lead to the development of hyperglycemia.

  Glucocorticosteroids enhance the lipolytic effect of catecholamines and growth hormone, and also reduce the consumption and utilization of glucose by adipose tissue. Excessive amounts of glucocorticosteroids lead to stimulation of lipolysis in some parts of the body (extremities) and lipogenesis in others (face and torso), as well as an increase in the level of free fatty acids in plasma.

  Glucocorticosteroids have an anabolic effect on protein metabolism in the liver and a catabolic effect on protein metabolism in muscles, adipose and lymphoid tissues, skin, and bones. They inhibit the growth and division of fibroblasts and the formation of collagen.

  In the hypothalamus-pituitary-adrenal system, glucocorticosteroids suppress the formation of corticotropin-releasing hormone and adrenocorticotropic hormone.

  The biological effects of glucocorticosteroids persist for a long time.

  
  By duration of action highlight:
  • Short-acting glucocorticosteroids (hydrocortisone).
  • Medium-acting glucocorticosteroids (methylprednisolone, prednisolone).
  • Long-acting glucocorticosteroids (betamethasone, dexamethasone, triamcinolone acetonide).

• Pharmacokinetics By method of administration distinguish:
  • Oral glucocorticosteroids.
  • Inhaled glucocorticosteroids.
  • Intranasal glucocorticosteroids.
  Oral glucocorticosteroids.
  

  When taken orally, glucocorticosteroids are well absorbed from the gastrointestinal tract and actively bind to plasma proteins (albumin, transcortin).

  The maximum concentration of drugs in the blood is reached after about 1.5 hours. Glucocorticosteroids undergo biotransformation in the liver, partially in the kidneys and in other tissues, mainly by conjugation with glucuronide or sulfate.

  About 70% of conjugated glucocorticosteroids are excreted in the urine, 20% in feces, and the remainder through the skin and other biological fluids.

  The half-life of oral glucocorticosteroids averages 2-4 hours.

  
  Some pharmacokinetic parameters of glucocorticosteroids

  A drug	Plasma half-life, h	Tissue half-life, h
  Hydrocortisone	0,5-1,5	8-12
  Cortisone	0,7-2	8-12
  Prednisolone	2-4	18-36
  Methylprednisolone	2-4	18-36
  Fludrocortisone	3,5	18-36
  Dexamethasone	5	36-54

  
  Inhaled glucocorticosteroids.
  

  Currently, beclomethasone dipropionate, budesonide, mometasone furoate, flunisolide, fluticasone propionate and triamcinolone acetonide are used in clinical practice.

  
  Pharmacokinetic parameters of inhaled glucocorticosteroids

  Drugs	Bioavailability, %	First pass effect through the liver, %	Half-life from blood plasma, h	Volume of distribution, l/kg	Local anti-inflammatory activity, units
  Beclomethasone dipropionate	25	70	0,5	-	0,64
  Budesonide	26-38	90	1,7-3,4 (2,8)	4,3	1
  Triamcinolone acetonide	22	80-90	1,4-2 (1,5)	1,2	0,27
  Fluticasone propionate	16-30	99	3,1	3,7	1
  Flunisolide	30-40		1,6	1,8	0,34

  
  Intranasal glucocorticosteroids.
  

  Currently, beclomethasone dipropionate, budesonide, mometasone furoate, triamcinolone acetonide, flunisolide, and fluticasone propionate are used in clinical practice for intranasal use.

  After intranasal administration of glucocorticosteroids, part of the dose that settles in the pharynx is swallowed and absorbed in the intestine, while part enters the blood from the mucous membrane of the respiratory tract.

  Glucocorticosteroids entering the gastrointestinal tract after intranasal administration are absorbed by 1-8% and are almost completely biotransformed to inactive metabolites during the first passage through the liver.

  That part of the glucocorticosteroids that is absorbed from the mucous membrane of the respiratory tract is hydrolyzed to inactive substances.

  Bioavailability of glucocorticosteroids after intranasal administration

  A drug	Bioavailability when absorbed from the gastrointestinal tract,%	Bioavailability when absorbed from the mucous membrane of the respiratory tract, %
  Beclomethasone dipropionate	20-25	44
  Budesonide	11	34
  Triamcinolone acetonide	10,6-23	No data
  Mometasone furoate
  Flunisolide	21	40-50
  Fluticasone propionate		0,5-2

• Place in therapy Indications for the use of oral glucocorticosteroids.
  • Replacement therapy primary adrenal insufficiency.
  • Replacement therapy for secondary chronic adrenal insufficiency.
  • Acute adrenal insufficiency.
  • Congenital dysfunction of the adrenal cortex.
  • Subacute thyroiditis.
  • Bronchial asthma.
  • Chronic obstructive pulmonary disease (in the acute phase).
  • Severe pneumonia.
  • Acute respiratory distress syndrome.
  • Interstitial lung diseases.
  • Nonspecific ulcerative colitis.
  • Crohn's disease.
  Indications for the use of intranasal glucocorticoids.
  • Seasonal (intermittent) allergic rhinitis.
  • Perennial (persistent) allergic rhinitis.
  • Nasal polyposis.
  • Non-allergic rhinitis with eosinophilia.
  • Idiopathic (vasomotor) rhinitis.

  Inhaled glucocorticosteroids used to treat bronchial asthma, chronic obstructive pulmonary disease.

• Contraindications Glucocorticosteroids are prescribed with caution in the following clinical situations:
  • Itsenko-Cushing's disease.
  • Diabetes.
  • Peptic ulcer of the stomach or duodenum.
  • Thromboembolism.
  • Arterial hypertension.
  • Severe renal failure.
  • Mental illnesses with productive symptoms.
  • Systemic mycoses.
  • Herpetic infection.
  • Tuberculosis (active form).
  • Syphilis.
  • Vaccination period.
  • Purulent infections.
  • Viral or fungal eye diseases.
  • Diseases of the cornea combined with epithelial defects.
  • Glaucoma.
  • Lactation period.
  Intranasal administration of glucocorticoids is contraindicated in the following cases:
  • Hypersensitivity.
  • Hemorrhagic diathesis.
  • History of repeated nosebleeds.

• Side effects Systemic side effects of glucocorticosteroids:
  • From the side of the central nervous system:
    • Increased nervous excitability.
    • Insomnia.
    • Euphoria.
    • Depression.
    • Psychoses.
  • From the cardiovascular system:
    • Myocardial dystrophy.
    • Increased blood pressure.
    • Deep vein thrombosis.
    • Thromboembolism.
  • From the digestive system:
    • Steroid ulcers of the stomach and intestines.
    • Bleeding from the gastrointestinal tract.
    • Pancreatitis.
    • Fatty liver degeneration.
  • From the senses:
    • Posterior subcapsular cataract.
    • Glaucoma.
  • From the endocrine system:
    • Depression of function and atrophy of the adrenal cortex.
    • Diabetes.
    • Obesity.
    • Cushing's syndrome.
  • From the outside skin:
    • Thinning of the skin.
    • Striae.
    • Alopecia.
  • From the musculoskeletal system:
    • Osteoporosis.
    • Fractures and aseptic necrosis of bones.
    • Growth retardation in children.
    • Myopathy.
    • Muscle wasting.
  • From the reproductive system:
    • Menstrual irregularities.
    • Sexual dysfunctions.
    • Delayed sexual development.
    • Hirsutism.
  • From the laboratory parameters:
    • Hypokalemia.
    • Hyperglycemia.
    • Hyperlipidemia.
    • Hypercholesterolemia.
    • Neutrophilic leukocytosis.
  • Others:
    • Sodium and water retention.
    • Edema.
    • Exacerbation of chronic infectious and inflammatory processes.
  Local side effects.
  Inhaled glucocorticosteroids:
  • Candidiasis of the oral cavity and pharynx.
  • Dysphonia.
  • Cough.
  Intranasal glucocorticosteroids:
  • Itchy nose.
  • Sneezing.
  • Dryness and burning of the nasal mucosa and pharynx.
  • Nosebleeds.
  • Perforation of the nasal septum.

• Precautionary measures

  In patients with hypothyroidism, liver cirrhosis, hypoalbuminemia, as well as in elderly and senile patients, the effect of glucocorticosteroids may be enhanced.

  When prescribing glucocorticosteroids during pregnancy, the expected therapeutic effect for the mother and the risk of negative effects on the fetus must be taken into account, since the use of these drugs can lead to impaired fetal growth, some developmental defects (cleft palate), atrophy of the adrenal cortex in the fetus (in the third trimester pregnancy).

  In children and adults taking glucocorticosteroids, such infectious diseases, like measles and chicken pox, can be severe.

  Live vaccines are contraindicated in patients taking immunosuppressive doses of glucocorticosteroids.

  Osteoporosis develops in 30-50% of patients who take systemic glucocorticosteroids (oral or injectable dosage forms) for a long time. As a rule, the spine, pelvic bones, ribs, hands, and feet are affected.

  Steroid ulcers during treatment with glucocorticosteroids can be mild or asymptomatic, manifesting with bleeding and perforation. Therefore, patients receiving oral glucocorticosteroids for a long time should periodically undergo fibroesophagogastroduodenoscopy and fecal occult blood testing.

  In various inflammatory or autoimmune diseases (rheumatoid arthritis, systemic lupus erythematosus and bowel diseases), cases of steroid resistance may occur.