Hydrocortisone (Hydrocortisone, Cortef, Laticort, Oxycort).

Dexamethasone (Ambene, Dexa-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, various types of 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 for 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 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.
  • Other:
    • 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, infectious diseases such as 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.

Glucocorticoids- This is a type of hormone produced as a result of the work of the adrenal cortex. One of the hormones is cortisone, which during the work of the liver is converted into another hormone - hydrocortisone (cortisol). Cortisol is the most well-known and important hormone for the human body. Medicines based on these hormones have been used since the 40s of the last century.

Types of synthetic hormones

Today, in addition to natural glucocorticoids, there are a number of drugs based on synthetic hormones, which are divided into two types:

• fluorinated (dexamethasone, betamethasone, etc.);
• non-fluorinated (prednisone, prednisolone).

They are characterized by higher effectiveness when consuming a smaller dose. In addition, fluorinated glucocorticoids have the lowest rate of side effects.

Use of glucocorticoid drugs

Preparations containing glucocorticoids are used for a fairly large number of serious diseases, because have different effects on the body.

Frequent indicators for prescribing drugs in this group are:

• rheumatoid arthritis;
• leukemia;
• mononucleosis;
• skin diseases (dermatitis, eczema);
• anemia;
• pneumonia;
• allergic diseases;
• pancreatitis;
• hepatitis.

The mechanism of action is not fully understood, but the effect of glucocorticoids can be anti-inflammatory, immunoregulatory, anti-allergic, and anti-shock. The drugs are available in various forms:

• sprays;
• pills;
• lotions;
• ointments;
• liquids for injections and inhalations.

List of glucocorticoid drugs

The list of such means is quite extensive. The most famous and effective are:

• Cortisone – involved in replacement therapy;
• Prednisolone is 4 times more effective than hydrocortisone;
• Prednisone – not recommended for liver problems;
• Methylprednisolone - suitable for the treatment of patients with obesity, mental disorders, ulcers;
• Triamcinolone - has a more prolonged effect than prednisolone, with pronounced side effects on the muscles and skin;
• Dexamethasone is an effective drug for short-term use;
• Betamethasone is the drug closest in effectiveness to dexamethosone.

Side effects of glucocorticoids

Having a number of positive medicinal properties, glucocorticoids also have no less impressive side effects. That is why they are often prescribed in short courses or used in particularly difficult cases. Drugs of the glucocorticoid group can cause the following undesirable reactions.

Glucocorticoids are steroid hormones synthesized by the adrenal cortex. Natural glucocorticoids and their synthetic analogues are used in medicine for adrenal insufficiency. In addition, for some diseases, the anti-inflammatory, immunosuppressive, antiallergic, antishock and other properties of these drugs are used.

The beginning of the use of glucocorticoids as medicines dates back to the 40s. XX century. Back in the late 30s. last century, it was shown that hormonal compounds of a steroid nature are formed in the adrenal cortex. In 1937, the mineralocorticoid deoxycorticosterone was isolated from the adrenal cortex, and in the 40s. - glucocorticoids cortisone and hydrocortisone. The wide range of pharmacological effects of hydrocortisone and cortisone predetermined the possibility of their use as drugs. Soon their synthesis was carried out.

The main and most active glucocorticoid produced in the human body is hydrocortisone (cortisol), others, less active, are represented by cortisone, corticosterone, 11-deoxycortisol, 11-dehydrocorticosterone.

The production of adrenal hormones is under the control of the central nervous system and is closely related to the function of the pituitary gland. Adrenocorticotropic hormone of the pituitary gland (ACTH, corticotropin) is a physiological stimulator of the adrenal cortex. Corticotropin enhances the formation and release of glucocorticoids. The latter, in turn, affect the pituitary gland, inhibiting the production of corticotropin and thus reducing further stimulation of the adrenal glands (based on the principle of negative feedback). Long-term administration of glucocorticoids (cortisone and its analogues) into the body can lead to inhibition and atrophy of the adrenal cortex, as well as inhibition of the formation of not only ACTH, but also gonadotropic and thyroid-stimulating hormones of the pituitary gland.

Cortisone and hydrocortisone have found practical application as drugs from natural glucocorticoids. Cortisone, however, is more likely than other glucocorticoids to cause side effects and, due to the advent of more effective and safe drugs, currently has limited use. In medical practice, natural hydrocortisone or its esters (hydrocortisone acetate and hydrocortisone hemisuccinate) are used.

A number of synthetic glucocorticoids have been synthesized, including non-fluorinated (prednisone, prednisolone, methylprednisolone) and fluorinated (dexamethasone, betamethasone, triamcinolone, flumethasone, etc.) glucocorticoids. These compounds, as a rule, are more active than natural glucocorticoids and act in lower doses. The action of synthetic steroids is similar to the action of natural corticosteroids, but they have a different ratio of glucocorticoid and mineralocorticoid activity. Fluorinated derivatives have a more favorable relationship between glucocorticoid/anti-inflammatory and mineralocorticoid activity. Thus, the anti-inflammatory activity of dexamethasone (compared to that of hydrocortisone) is 30 times higher, betamethasone - 25-40 times, triamcinolone - 5 times, while the effect on water-salt metabolism is minimal. Fluorinated derivatives are not only highly effective, but also have low absorption when applied topically, i.e. less likely to develop systemic side effects.

The mechanism of action of glucocorticoids at the molecular level is not fully understood. It is believed that the effect of glucocorticoids on target cells is carried out mainly at the level of regulation of gene transcription. It is mediated by the interaction of glucocorticoids with specific glucocorticoid intracellular receptors (alpha isoform). These nuclear receptors are capable of binding to DNA and belong to a family of ligand-sensitive transcriptional regulators. Glucocorticoid receptors are found in almost all cells. In different cells, however, the number of receptors varies, and they can also differ in molecular weight, affinity for the hormone and other physicochemical characteristics. In the absence of a hormone, intracellular receptors, which are cytosolic proteins, are inactive and are part of heterocomplexes, which also include heat shock proteins (heat shock proteins, Hsp90 and Hsp70), immunophilin with a molecular weight of 56000, etc. Heat shock proteins help maintain the optimal conformation of the hormone-binding receptor domain and ensure high affinity of the receptor for the hormone.

After penetration through the membrane into the cell, glucocorticoids bind to receptors, which leads to activation of the complex. In this case, the oligomeric protein complex dissociates—heat shock proteins (Hsp90 and Hsp70) and immunophilin are detached. As a result, the receptor protein, which is part of the complex as a monomer, acquires the ability to dimerize. Following this, the resulting “glucocorticoid + receptor” complexes are transported into the nucleus, where they interact with DNA sections located in the promoter fragment of the steroid-responsive gene - the so-called. glucocorticoid response element (GRE) and regulate (activate or suppress) the process of transcription of certain genes (genomic effect). This leads to stimulation or suppression of m-RNA formation and changes in the synthesis of various regulatory proteins and enzymes that mediate cellular effects.

Recent studies show that GC receptors interact, in addition to GRE, with various transcription factors, such as transcription activator protein (AP-1), nuclear factor kappa B (NF-kB), etc. It has been shown that nuclear factors AP-1 and NF-kB are regulators of several genes involved in the immune response and inflammation, including genes for cytokines, adhesion molecules, proteinases, etc.

In addition, another mechanism of action of glucocorticoids was recently discovered, associated with the effect on the transcriptional activation of the cytoplasmic inhibitor of NF-kB, IkBa.

However, a number of effects of glucocorticoids (for example, rapid inhibition of ACTH secretion by glucocorticoids) develop very quickly and cannot be explained by gene expression (the so-called extragenomic effects of glucocorticoids). Such properties may be mediated by non-transcriptional mechanisms, or by interaction with glucocorticoid receptors found in some cells on the plasma membrane. It is also believed that the effects of glucocorticoids can be realized at different levels depending on the dose. For example, at low concentrations of glucocorticoids (>10 -12 mol/l), genomic effects appear (they require more than 30 minutes to develop), and at high concentrations, extragenomic effects appear.

Glucocorticoids cause many effects because... affect most cells in the body.

They have anti-inflammatory, desensitizing, anti-allergic and immunosuppressive effects, anti-shock and anti-toxic properties.

The anti-inflammatory effect of glucocorticoids is due to many factors, the leading of which is the suppression of phospholipase A 2 activity. In this case, glucocorticoids act indirectly: they increase the expression of genes encoding the synthesis of lipocortins (annexins), induce the production of these proteins, one of which - lipomodulin - inhibits the activity of phospholipase A 2. Inhibition of this enzyme leads to suppression of the liberation of arachidonic acid and inhibition of the formation of a number of inflammatory mediators - prostaglandins, leukotrienes, thromboxane, platelet activating factor, etc. In addition, glucocorticoids reduce the expression of the gene encoding the synthesis of COX-2, additionally blocking the formation of proinflammatory prostaglandins.

In addition, glucocorticoids improve microcirculation in the area of ​​inflammation, cause vasoconstriction of capillaries, and reduce fluid exudation. Glucocorticoids stabilize cell membranes, incl. membranes of lysosomes, preventing the release of lysosomal enzymes and thereby reducing their concentration at the site of inflammation.

Thus, glucocorticoids influence the alterative and exudative phases of inflammation and prevent the spread of the inflammatory process.

Limiting the migration of monocytes to the site of inflammation and inhibiting the proliferation of fibroblasts determine the antiproliferative effect. Glucocorticoids suppress the formation of mucopolysaccharides, thereby limiting the binding of water and plasma proteins at the site of rheumatic inflammation. They inhibit collagenase activity, preventing the destruction of cartilage and bones in rheumatoid arthritis.

The antiallergic effect develops as a result of a decrease in the synthesis and secretion of allergy mediators, inhibition of the release of histamine and other biologically active substances from sensitized mast cells and basophils, a decrease in the number of circulating basophils, suppression of the proliferation of lymphoid and connective tissue, a decrease in the number of T- and B-lymphocytes, mast cells , reducing the sensitivity of effector cells to allergy mediators, suppressing antibody formation, changing the body’s immune response.

A characteristic feature of glucocorticoids is their immunosuppressive activity. Unlike cytostatics, the immunosuppressive properties of glucocorticoids are not associated with a mitostatic effect, but are the result of suppression of various stages of the immune reaction: inhibition of migration of bone marrow stem cells and B-lymphocytes, suppression of the activity of T- and B-lymphocytes, as well as inhibition of the release of cytokines (IL -1, IL-2, interferon-gamma) from leukocytes and macrophages. In addition, glucocorticoids reduce the formation and increase the breakdown of components of the complement system, block Fc receptors of immunoglobulins, and suppress the functions of leukocytes and macrophages.

The antishock and antitoxic effect of glucocorticoids is associated with an increase in blood pressure (due to an increase in the amount of circulating catecholamines, restoration of the sensitivity of adrenergic receptors to catecholamines and vasoconstriction), activation of liver enzymes involved in the metabolism of endo- and xenobiotics.

Glucocorticoids have a pronounced effect on all types of metabolism: carbohydrate, protein, fat and mineral. From the side of carbohydrate metabolism, this is manifested by the fact that they stimulate gluconeogenesis in the liver, increase the blood glucose level (glucosuria is possible), and promote the accumulation of glycogen in the liver. The effect on protein metabolism is expressed in inhibition of synthesis and acceleration of protein catabolism, especially in the skin, muscle and bone tissue. This is manifested by muscle weakness, atrophy of the skin and muscles, and delayed wound healing. These drugs cause a redistribution of fat: they increase lipolysis in the tissues of the extremities, promote the accumulation of fat mainly in the face (moon face), shoulder girdle, and abdomen.

Glucocorticoids have mineralocorticoid activity: they retain sodium and water in the body by increasing reabsorption in the renal tubules, and stimulate the excretion of potassium. These effects are more typical for natural glucocorticoids (cortisone, hydrocortisone), and to a lesser extent for semisynthetic ones (prednisone, prednisolone, methylprednisolone). Fludrocortisone has predominant mineralocorticoid activity. Fluorinated glucocorticoids (triamcinolone, dexamethasone, betamethasone) have virtually no mineralocorticoid activity.

Glucocorticoids reduce the absorption of calcium in the intestine, promote its release from the bones and increase the excretion of calcium by the kidneys, which may result in the development of hypocalcemia, hypercalciuria, and glucocorticoid osteoporosis.

After taking even one dose of glucocorticoids, changes in the blood are noted: a decrease in the number of lymphocytes, monocytes, eosinophils, basophils in the peripheral blood with the simultaneous development of neutrophilic leukocytosis, an increase in the content of erythrocytes.

With long-term use, glucocorticoids suppress the function of the hypothalamus-pituitary-adrenal system.

Glucocorticoids differ in activity, pharmacokinetic parameters (degree of absorption, T1/2, etc.), methods of administration.

Systemic glucocorticoids can be divided into several groups.

By origin they are divided into:

Natural (hydrocortisone, cortisone);

Synthetic (prednisolone, methylprednisolone, prednisone, triamcinolone, dexamethasone, betamethasone).

According to the duration of action, glucocorticoids for systemic use can be divided into three groups (in parentheses - biological (from tissue) half-life (T 1/2 biol.):

Short-acting glucocorticoids (T 1/2 biol. - 8-12 hours): hydrocortisone, cortisone;

Glucocorticoids with an average duration of action (T 1/2 biol. - 18-36 hours): prednisolone, prednisone, methylprednisolone;

Long-acting glucocorticoids (T 1/2 biol. - 36-54 hours): triamcinolone, dexamethasone, betamethasone.

The duration of action of glucocorticoids depends on the route/site of administration, the solubility of the dosage form (mazipredone is a water-soluble form of prednisolone), and the administered dose. After oral or intravenous administration, the duration of action depends on T 1/2 biol., with intramuscular administration - on the solubility of the dosage form and T 1/2 biol., after local injections - on the solubility of the dosage form and the specific route/site introduction.

When taken orally, glucocorticoids are quickly and almost completely absorbed from the gastrointestinal tract. Cmax in the blood is observed after 0.5-1.5 hours. Glucocorticoids bind in the blood to transcortin (corticosteroid-binding alpha 1 -globulin) and albumin, and natural glucocorticoids bind to proteins by 90-97%, synthetic ones by 40-60%. . Glucocorticoids penetrate well through histohematic barriers, incl. through the BBB, pass through the placenta. Fluorinated derivatives (including dexamethasone, betamethasone, triamcinolone) pass through histohematological barriers worse. Glucocorticoids undergo biotransformation in the liver with the formation of inactive metabolites (glucuronides or sulfates), which are excreted primarily by the kidneys. Natural drugs are metabolized faster than synthetic drugs and have a shorter half-life.

Modern glucocorticoids are a group of drugs that are widely used in clinical practice, incl. in rheumatology, pulmonology, endocrinology, dermatology, ophthalmology, otorhinolaryngology.

The main indications for the use of glucocorticoids are collagenosis, rheumatism, rheumatoid arthritis, bronchial asthma, acute lymphoblastic and myeloblastic leukemia, infectious mononucleosis, eczema and other skin diseases, and various allergic diseases. For the treatment of atopic and autoimmune diseases, glucocorticoids are the basic pathogenetic agents. Glucocorticoids are also used for hemolytic anemia, glomerulonephritis, acute pancreatitis, viral hepatitis and respiratory diseases (COPD in the acute phase, acute respiratory distress syndrome, etc.). Due to the anti-shock effect, glucocorticoids are prescribed for the prevention and treatment of shock (post-traumatic, surgical, toxic, anaphylactic, burn, cardiogenic, etc.).

The immunosuppressive effect of glucocorticoids allows them to be used in organ and tissue transplantation to suppress the rejection reaction, as well as in various autoimmune diseases.

The main principle of glucocorticoid therapy is to achieve maximum therapeutic effect with minimal doses. The dosage regimen is selected strictly individually, depending more on the nature of the disease, the patient’s condition and response to treatment than on age or body weight.

When prescribing glucocorticoids, it is necessary to take into account their equivalent doses: in terms of the anti-inflammatory effect, 5 mg of prednisolone corresponds to 25 mg of cortisone, 20 mg of hydrocortisone, 4 mg of methylprednisolone, 4 mg of triamcinolone, 0.75 mg of dexamethasone, 0.75 mg of betamethasone.

There are 3 types of glucocorticoid therapy: replacement, suppressive, pharmacodynamic.

Replacement therapy glucocorticoids are necessary for adrenal insufficiency. With this type of therapy, physiological doses of glucocorticoids are used; in stressful situations (for example, surgery, trauma, acute illness) the doses are increased by 2-5 times. When prescribing, the daily circadian rhythm of endogenous secretion of glucocorticoids should be taken into account: at 6-8 a.m., most (or all) of the dose is prescribed. In chronic adrenal insufficiency (Addison's disease), glucocorticoids can be used throughout life.

Suppressive therapy glucocorticoids are used for adrenogenital syndrome - congenital dysfunction of the adrenal cortex in children. In this case, glucocorticoids are used in pharmacological (supraphysiological) doses, which leads to suppression of ACTH secretion by the pituitary gland and a subsequent decrease in the increased secretion of androgens by the adrenal glands. The majority (2/3) of the dose is given at night to prevent peak ACTH release, using the negative feedback principle.

Pharmacodynamic therapy used most often, incl. in the treatment of inflammatory and allergic diseases.

Several types of pharmacodynamic therapy can be distinguished: intensive, limiting, long-term.

Intensive pharmacodynamic therapy: used for acute, life-threatening conditions, glucocorticoids are administered intravenously, starting with large doses (5 mg/kg - day); after the patient recovers from the acute condition (1-2 days), glucocorticoids are canceled immediately, simultaneously.

Limiting pharmacodynamic therapy: prescribed for subacute and chronic processes, incl. inflammatory (systemic lupus erythematosus, systemic scleroderma, polymyalgia rheumatica, severe bronchial asthma, hemolytic anemia, acute leukemia, etc.). The duration of therapy is, as a rule, several months; glucocorticoids are used in doses exceeding physiological ones (2-5 mg/kg/day), taking into account the circadian rhythm.

To reduce the inhibitory effect of glucocorticoids on the hypothalamic-pituitary-adrenal system, different schemes for intermittent administration of glucocorticoids have been proposed:

- alternating therapy- use short/medium-acting glucocorticoids (prednisolone, methylprednisolone), once, in the morning (about 8 hours), every 48 hours;

- intermittent circuit- glucocorticoids are prescribed in short courses (3-4 days) with 4-day breaks between courses;

-pulse therapy- rapid intravenous administration of a large dose of the drug (at least 1 g) - for emergency therapy. The drug of choice for pulse therapy is methylprednisolone (it reaches inflamed tissues better than others and is less likely to cause side effects).

Long-term pharmacodynamic therapy: used in the treatment of chronic diseases. Glucocorticoids are prescribed orally, doses exceed physiological ones (2.5-10 mg/day), therapy is prescribed for several years, the withdrawal of glucocorticoids with this type of therapy is carried out very slowly.

Dexamethasone and betamethasone are not used for long-term therapy, since with the strongest and longest-lasting anti-inflammatory effect compared to other glucocorticoids, they also cause the most pronounced side effects, incl. inhibitory effect on lymphoid tissue and corticotropic function of the pituitary gland.

During treatment, it is possible to switch from one type of therapy to another.

Glucocorticoids are used orally, parenterally, intra- and periarticularly, inhalation, intranasally, retro- and parabulbarly, in the form of eye and ear drops, externally in the form of ointments, creams, lotions, etc.

For example, in rheumatic diseases, glucocorticoids are used for systemic, local or local (intra-articular, periarticular, external) therapy. For broncho-obstructive diseases, inhaled glucocorticoids are especially important.

Glucocorticoids are effective therapeutic agents in many cases. It is necessary, however, to take into account that they can cause a number of side effects, including the Itsenko-Cushing symptom complex (retention of sodium and water in the body with the possible appearance of edema, loss of potassium, increased blood pressure), hyperglycemia up to diabetes mellitus (steroid diabetes), slowing down tissue regeneration processes, exacerbation of gastric and duodenal ulcers, ulceration of the digestive tract, perforation of an unrecognized ulcer, hemorrhagic pancreatitis, decreased body resistance to infections, hypercoagulation with the risk of thrombosis, the appearance of acne, moon-shaped face, obesity, menstrual irregularities, etc. When taking glucocorticoids, increased calcium excretion and osteoporosis are observed (with long-term use of glucocorticoids in doses of more than 7.5 mg/day - equivalent to prednisolone - the development of osteoporosis of long tubular bones is possible). Prevention of steroid osteoporosis is carried out with calcium and vitamin D preparations from the moment of starting glucocorticoids. The most pronounced changes in the musculoskeletal system are observed in the first 6 months of treatment. One of the dangerous complications is aseptic bone necrosis, therefore it is necessary to warn patients about the possibility of its development and when “new” pain appears, especially in the shoulder, hip and knee joints, it is necessary to exclude aseptic bone necrosis. Glucocorticoids cause changes in the blood: lymphopenia, monocytopenia, eosinopenia, a decrease in the number of basophils in the peripheral blood, the development of neutrophilic leukocytosis, an increase in the content of erythrocytes. Nervous and mental disorders are also possible: insomnia, agitation (with the development in some cases of psychosis), epileptiform convulsions, euphoria.

With long-term use of glucocorticoids, one should take into account the possible inhibition of the function of the adrenal cortex (atrophy is possible) with suppression of hormone biosynthesis. Administration of corticotropin simultaneously with glucocorticoids prevents adrenal atrophy.

The frequency and severity of side effects caused by glucocorticoids can be expressed to varying degrees. Side effects, as a rule, are a manifestation of the actual glucocorticoid action of these drugs, but to a degree exceeding the physiological norm. With the correct dose selection, compliance with the necessary precautions, and constant monitoring of the progress of treatment, the incidence of side effects can be significantly reduced.

To prevent undesirable effects associated with the use of glucocorticoids, it is necessary, especially with long-term treatment, to carefully monitor the dynamics of growth and development in children, periodically conduct an ophthalmological examination (to detect glaucoma, cataracts, etc.), regularly monitor the function of the hypothalamic-pituitary-adrenal systems, glucose levels in the blood and urine (especially in patients with diabetes), monitor blood pressure, ECG, electrolyte composition of the blood, monitor the state of the gastrointestinal tract, musculoskeletal system, monitor the development of infectious complications, etc.

Most complications during treatment with glucocorticoids are treatable and disappear after discontinuation of the drug. Irreversible side effects of glucocorticoids include growth retardation in children (occurs when treated with glucocorticoids for more than 1.5 years), subcapsular cataracts (develops in the presence of a family predisposition), and steroid diabetes.

Abrupt withdrawal of glucocorticoids can cause an exacerbation of the process - withdrawal syndrome, especially when long-term therapy is stopped. In this regard, treatment should end with a gradual dose reduction. The severity of the withdrawal syndrome depends on the degree of preservation of the function of the adrenal cortex. In mild cases, withdrawal syndrome is manifested by increased body temperature, myalgia, arthralgia, and malaise. In severe cases, especially under severe stress, Addisonian crisis may develop (accompanied by vomiting, collapse, convulsions).

Due to side effects, glucocorticoids are used only if there are clear indications and under close medical supervision. Contraindications for the use of glucocorticoids are relative. In emergency situations, the only contraindication for short-term systemic use of glucocorticoids is hypersensitivity. In other cases, when planning long-term therapy, contraindications should be taken into account.

The therapeutic and toxic effects of glucocorticoids are reduced by inducers of microsomal liver enzymes, and enhanced by estrogens and oral contraceptives. Digitalis glycosides, diuretics (causing potassium deficiency), amphotericin B, carbonic anhydrase inhibitors increase the likelihood of arrhythmias and hypokalemia. Alcohol and NSAIDs increase the risk of erosive and ulcerative lesions or bleeding in the gastrointestinal tract. Immunosuppressants increase the likelihood of developing infections. Glucocorticoids weaken the hypoglycemic activity of antidiabetic agents and insulin, the natriuretic and diuretic activity of diuretics, the anticoagulant and fibrinolytic activity of coumarin and indanedione derivatives, heparin, streptokinase and urokinase, the activity of vaccines (due to a decrease in the production of antibodies), and reduce the concentration of salicylates and mexiletine in the blood. When using prednisolone and paracetamol, the risk of hepatotoxicity increases.

Five drugs are known to suppress the secretion of corticosteroids by the adrenal cortex (inhibitors of the synthesis and action of corticosteroids): mitotane, metyrapone, aminoglutethimide, ketoconazole, trilostane. Aminoglutethimide, metyrapone and ketoconazole suppress the synthesis of steroid hormones due to inhibition of hydroxylases (cytochrome P450 isoenzymes) involved in biosynthesis. All three drugs have specificity, because act on different hydroxylases. These drugs can cause acute adrenal insufficiency, so they should be used in strictly defined doses and with careful monitoring of the patient's hypothalamic-pituitary-adrenal axis.

Aminoglutethimide inhibits 20,22-desmolase, which catalyzes the initial (limiting) stage of steroidogenesis - the conversion of cholesterol to pregnenolone. As a result, the production of all steroid hormones is disrupted. In addition, aminoglutethimide inhibits 11-beta-hydroxylase as well as aromatase. Aminoglutethimide is used for Cushing's syndrome, caused by unregulated excess cortisol secretion by adrenal tumors or ectopic ACTH production. The ability of aminoglutethimide to inhibit aromatase is used in the treatment of hormone-dependent tumors such as prostate cancer and breast cancer.

Ketoconazole is used primarily as an antifungal agent. However, at higher doses it inhibits several cytochrome P450 enzymes involved in steroidogenesis, including. 17-alpha-hydroxylase, as well as 20,22-desmolase and thus blocks steroidogenesis in all tissues. According to some data, ketoconazole is the most effective inhibitor of steroidogenesis in Cushing's disease. However, the feasibility of using ketoconazole in case of excess production of steroid hormones requires further study.

Aminoglutethimide, ketoconazole, and metyrapone are used to diagnose and treat adrenal hyperplasia.

TO glucocorticoid receptor antagonists includes mifepristone. Mifepristone is a progesterone receptor antagonist; in large doses, it blocks glucocorticoid receptors, prevents inhibition of the hypothalamic-pituitary-adrenal system (via a negative feedback mechanism) and leads to a secondary increase in the secretion of ACTH and cortisol.

One of the most important areas of clinical use of glucocorticoids is the pathology of various parts of the respiratory tract.

Indications for use systemic glucocorticoids for respiratory diseases are bronchial asthma, COPD in the acute phase, severe pneumonia, interstitial lung diseases, acute respiratory distress syndrome.

After systemic glucocorticoids (oral and injectable forms) were synthesized in the late 40s of the 20th century, they were immediately used to treat severe bronchial asthma. Despite the good therapeutic effect, the use of glucocorticoids in bronchial asthma was limited by the development of complications - steroid vasculitis, systemic osteoporosis, diabetes mellitus (steroid diabetes). Local forms of glucocorticoids began to be used in clinical practice only some time later - in the 70s. XX century. The publication of the successful use of the first topical glucocorticoid - beclomethasone (beclomethasone dipropionate) - for the treatment of allergic rhinitis dates back to 1971. In 1972, a report appeared on the use of a topical form of beclomethasone for the treatment of bronchial asthma.

Inhaled glucocorticoids are basic drugs in the treatment of all pathogenetic variants of persistent bronchial asthma, used for moderate and severe COPD (with spirographically confirmed response to treatment).

Inhaled glucocorticoids include beclomethasone, budesonide, fluticasone, mometasone, and triamcinolone. Inhaled glucocorticoids differ from systemic glucocorticoids in their pharmacological properties: high affinity for GK receptors (act in minimal doses), strong local anti-inflammatory effect, low systemic bioavailability (oral, pulmonary), rapid inactivation, short T1/2 from the blood. Inhaled glucocorticoids inhibit all phases of inflammation in the bronchi and reduce their increased reactivity. Their ability to reduce bronchial secretion (reduce the volume of tracheobronchial secretion) and potentiate the effect of beta 2 adrenergic agonists is very important. The use of inhaled forms of glucocorticoids can reduce the need for tablet glucocorticoids. An important characteristic of inhaled glucocorticoids is the therapeutic index - the ratio of local anti-inflammatory activity and systemic action. Of the inhaled glucocorticoids, budesonide has the most favorable therapeutic index.

One of the factors determining the effectiveness and safety of inhaled glucocorticoids is the system for their delivery to the respiratory tract. Currently, metered-dose and powder inhalers (turbuhaler, etc.), and nebulizers are used for this purpose.

With the correct choice of inhalation system and technique, systemic side effects of inhaled glucocorticoids are insignificant due to the low bioavailability and rapid metabolic activation of these drugs in the liver. It should be borne in mind that all existing inhaled glucocorticoids are absorbed in the lungs to one degree or another. Local side effects of inhaled glucocorticoids, especially with long-term use, include the occurrence of oropharyngeal candidiasis (in 5-25% of patients), less often - esophageal candidiasis, dysphonia (in 30-58% of patients), cough.

It has been shown that inhaled glucocorticoids and long-acting beta-agonists (salmeterol, formoterol) have a synergistic effect. This is due to stimulation of the biosynthesis of beta 2 adrenergic receptors and an increase in their sensitivity to agonists under the influence of glucocorticoids. In this regard, in the treatment of bronchial asthma, combination drugs intended for long-term therapy, but not for stopping attacks, are effective - for example, the fixed combination of salmeterol/fluticasone or formoterol/budesonide.

Inhalations of glucocorticoids are contraindicated in case of fungal infections of the respiratory tract, tuberculosis, and pregnancy.

Currently for intranasal Applications in clinical practice include beclomethasone dipropionate, budesonide, fluticasone, mometasone furoate. In addition, dosage forms in the form of nasal aerosols exist for flunisolide and triamcinolone, but they are not currently used in Russia.

Nasal forms of glucocorticoids are effective in the treatment of non-infectious inflammatory processes in the nasal cavity, rhinitis, incl. medicinal, occupational, seasonal (intermittent) and year-round (persistent) allergic rhinitis, to prevent the recurrence of polyps in the nasal cavity after their removal. Topical glucocorticoids are characterized by a relatively late onset of action (12-24 hours), a slow development of the effect - manifests itself by the 3rd day, reaches a maximum on the 5-7th day, sometimes after several weeks. Mometasone begins to act most quickly (12 hours).

Modern intranasal glucocorticoids are well tolerated; when used in recommended doses, systemic effects (part of the dose is absorbed from the nasal mucosa and enters the systemic circulation) are minimal. Among local side effects, 2-10% of patients at the beginning of treatment experience nosebleeds, dryness and burning in the nose, sneezing and itching. It is possible that these side effects are due to the irritant effect of the propellant. Isolated cases of perforation of the nasal septum have been described when using intranasal glucocorticoids.

Intranasal use of glucocorticoids is contraindicated in case of hemorrhagic diathesis, as well as a history of repeated nosebleeds.

Thus, glucocorticoids (systemic, inhaled, nasal) are widely used in pulmonology and otorhinolaryngology. This is due to the ability of glucocorticoids to relieve the main symptoms of diseases of the ENT and respiratory organs, and if the process persists, to significantly prolong the interictal period. The obvious advantage of using topical dosage forms of glucocorticoids is the ability to minimize systemic side effects, thereby increasing the effectiveness and safety of therapy.

In 1952, Sulzberger and Witten first reported the successful use of 2.5% hydrocortisone ointment for the topical treatment of cutaneous dermatosis. Natural hydrocortisone is historically the first glucocorticoid used in dermatological practice, and subsequently became the standard for comparing the strength of different glucocorticoids. Hydrocortisone, however, is not effective enough, especially in severe dermatoses, due to its relatively weak binding to steroid receptors of skin cells and slow penetration through the epidermis.

Later, glucocorticoids found widespread use in dermatology for the treatment of various skin diseases of a non-infectious nature: atopic dermatitis, psoriasis, eczema, lichen planus and other dermatoses. They have a local anti-inflammatory, anti-allergic effect, eliminate itching (use for itching is justified only if it is caused by an inflammatory process).

Topical glucocorticoids differ from each other in their chemical structure, as well as in the strength of their local anti-inflammatory effect.

The creation of halogenated compounds (incorporation of halogens - fluorine or chlorine into the molecule) made it possible to increase the anti-inflammatory effect and reduce systemic side effects when applied topically due to lower absorption of drugs. The lowest absorption when applied to the skin is characterized by compounds containing two fluorine atoms in their structure - flumethasone, fluocinolone acetonide, etc.

According to the European classification (Niedner, Schopf, 1993), according to the potential activity of local steroids, 4 classes are distinguished:

Weak (class I) - hydrocortisone 0.1-1%, prednisolone 0.5%, fluocinolone acetonide 0.0025%;

Medium strength (class II) - alklometasone 0.05%, betamethasone valerate 0.025%, triamcinolone acetonide 0.02%, 0.05%, fluocinolone acetonide 0.00625%, etc.;

Strong (class III) - betamethasone valerate 0.1%, betamethasone dipropionate 0.025%, 0.05%, hydrocortisone butyrate 0.1%, methylprednisolone aceponate 0.1%, mometasone furoate 0.1%, triamcinolone acetonide 0.025%, 0 .1%, fluticasone 0.05%, fluocinolone acetonide 0.025%, etc.

Very strong (class III) - clobetasol propionate 0.05%, etc.

Along with an increase in therapeutic effect when using fluorinated glucocorticoids, the incidence of side effects also increases. The most common local side effects when using strong glucocorticoids are skin atrophy, telangiectasia, steroid acne, stretch marks, and skin infections. The likelihood of developing both local and systemic side effects increases when glucocorticoids are applied to large surfaces and prolonged use. Due to the development of side effects, the use of fluorinated glucocorticoids is limited when long-term use is necessary, as well as in pediatric practice.

In recent years, by modifying the steroid molecule, new generation local glucocorticoids have been obtained that do not contain fluorine atoms, but are characterized by high efficiency and a good safety profile (for example, mometasone in the form of furoate, a synthetic steroid that began to be produced in 1987 in the USA, methylprednisolone aceponate, which has been used in practice since 1994).

The therapeutic effect of topical glucocorticoids also depends on the dosage form used. Glucocorticoids for topical use in dermatology are available in the form of ointments, creams, gels, emulsions, lotions, etc. The ability to penetrate the skin (penetration depth) decreases in the following order: fatty ointment > ointment > cream > lotion (emulsion). With chronic dry skin, the penetration of glucocorticoids into the epidermis and dermis is difficult, therefore, for dermatoses accompanied by increased dryness and flaking of the skin, lichenification, it is more advisable to use ointments, because moisturizing the stratum corneum of the epidermis with an ointment base increases the penetration of drugs into the skin several times. In acute processes with pronounced weeping, it is more advisable to prescribe lotions and emulsions.

Since topical glucocorticoids reduce the resistance of the skin and mucous membranes, which can lead to the development of superinfection, in case of secondary infection it is advisable to combine a glucocorticoid with an antibiotic in one dosage form, for example Diprogent cream and ointment (betamethasone + gentamicin), Oxycort aerosols (hydrocortisone + oxytetracycline) and Polcortolone TS (triamcinolone + tetracycline), etc., or with an antibacterial and antifungal agent, for example Akriderm GK (betamethasone + clotrimazole + gentamicin).

Topical glucocorticoids are used in the treatment of complications of chronic venous insufficiency (CVI), such as trophic skin disorders, varicose eczema, hemosiderosis, contact dermatitis, etc. Their use is due to the suppression of inflammatory and toxic-allergic reactions in soft tissues that occur in severe forms of CVI. In some cases, local glucocorticoids are used to suppress vascular reactions that occur during phlebosclerosing treatment. Most often, ointments and gels containing hydrocortisone, prednisolone, betamethasone, triamcinolone, fluocinolone acetonide, mometasone furoate, etc. are used for this purpose.

The use of glucocorticoids in ophthalmology based on their local anti-inflammatory, antiallergic, antipruritic effect. Indications for the prescription of glucocorticoids are inflammatory diseases of the eye of non-infectious etiology, incl. after injuries and operations - iritis, iridocyclitis, scleritis, keratitis, uveitis, etc. For this purpose, the following are used: hydrocortisone, betamethasone, desonide, triamcinolone, etc. It is most preferable to use local forms (eye drops or suspension, ointments), in severe cases - subconjunctival injections. When systemically (parenterally, orally) using glucocorticoids in ophthalmology, one should remember the high probability (75%) of developing steroid cataracts with daily use of prednisolone at a dose of more than 15 mg for several months (as well as equivalent doses of other drugs), and the risk increases with increasing the duration of treatment.

Glucocorticoids are contraindicated in acute infectious eye diseases. If necessary, for example, for bacterial infections, combined drugs containing antibiotics are used, such as eye/ear drops Garazon (betamethasone + gentamicin) or Sofradex (dexamethasone + framycetin + gramicidin), etc. Combination drugs containing HA and antibiotics are widely used in ophthalmic and otorhinolaryngological practice. In ophthalmology - for the treatment of inflammatory and allergic eye diseases in the presence of a concomitant or suspected bacterial infection, for example, with certain types of conjunctivitis, in the postoperative period. In otorhinolaryngology - with external otitis; rhinitis complicated by secondary infection, etc. It should be borne in mind that the same bottle of the drug is not recommended for the treatment of otitis, rhinitis and eye diseases in order to avoid the spread of infection.

Drugs

Drugs - 2564 ; Trade names - 209 ; Active ingredients - 27

Active substance	Trade names
Information is absent

MEDICINES WITH GLUCOCORTICOID AND MINERALOCORTICOID HORMONE ACTIVITY, STEROID HORMONE SYNTHESIS INHIBITORS.

The doctor must first ask himself the question to what extent the disease for which corticosteroids are supposed to be used is more dangerous for the patient than the Cushing's syndrome that develops during their treatment

J.M. Liddle, 1961

The adrenal glands are paired endocrine organs that are located at the upper pole of the kidneys. The adrenal glands are divided into cortex and medulla. The medulla produces adrenaline, norepinephrine and adrenomedullin - hormones that control blood pressure levels in humans.

The adrenal cortex produces hormones with a steroid structure. Adrenal hormonal steroids can be divided into 3 groups:

Hormones that control interstitial metabolism (glucocorticosteroid hormones) - the main ones are cortisol and corticosterone (hydrocortisone);

Hormones that control sodium and potassium metabolism (mineralocorticoid hormones). The main representative of this group is aldosterone;

Hormones that control reproductive function (sex steroids) are progesterone and dihydroepiandrosterone. The main source of this group of hormones is not the adrenal glands, but the gonads. In men, the main androgen is produced in the testicles - testosterone, and in women in the ovaries - estrogens (estrone, estradiol and estriol) and gestagens (progesterone).

Glucocorticosteroid drugs

Synthesis and secretion of glucocorticoid hormones. The synthesis of corticosteroids is under the control of the pituitary gland and hypothalamus. The hypothalamus secretes corticoliberin in a pulsating manner, and the secretion stimuli are food intake and the beginning of daylight hours. Under the influence of corticoliberin, the hypothalamus produces ACTH, which activates receptors on the surface of cells of the adrenal cortex. Under the influence of ACTH, 3 key proteins involved in the synthesis of glucocorticosteroids are activated:

Cholesterol esterase is an enzyme that releases cholesterol from esters in intracellular stores.

StAR protein is a shuttle that transports cholesterol to mitochondria, where the first stage of steroid hormone synthesis (pregnenolone formation) occurs.

P 450 SCC is an enzyme that cleaves the side chain of cholesterol during the synthesis of pregnenolone.

After the formation of pregnenolone, the synthesis of steroid hormones occurs along 3 relatively independent pathways (see Fig. 1):

With the help of 17-β-hydroxylase, pregnenolone is converted into 17-hydroxypregnenolone, from which glucocorticosteroids (cortisol) are formed under the influence of 21β- and 11β-hydroxylases. This is the main pathway for the synthesis of glucorticosteroids.

Part of the 17-hydroxypregnenolone, which was formed at the previous stage, is subjected to repeated action by 17--hydroxylase and is converted into the main androgen of the adrenal glands - dihydroepiandrosterone. This is the main pathway for the synthesis of sex steroids in the adrenal glands. In the gonads, dihydroepiandrosterone is subsequently exposed to 17-ketoreductase and testosterone is formed. In the testicles of men, synthesis stops at this stage. In women, with the help of the enzyme aromatase, which is located in the ovaries, adipose tissue, and breast tissue, testosterone is converted into estrogens.

Under the influence of 3-hydroxy- 5  4 isomerase, pregnenolone is converted to progesterone. Which is subsequently converted into aldosterone under the influence of 21- and 11-hydroxylases. This is the main pathway for the synthesis of mineralocorticoids. Some of the aldosterone can be converted into the weak glucocorticoid corticosterone, so this is also an additional pathway for the synthesis of glucocorticoids.

Glucocorticoids, which the adrenal glands release into the blood in the form of 8-10 peaks (with the maximum 2 peaks occurring at 5-8 o’clock in the morning), use a negative feedback mechanism to reduce the synthesis and secretion of corticotropin-releasing hormone and ACTH.

Classification of drugs with glucocorticosteroid hormone activity.

Products with the activity of natural hormones: hydrocortisone.

Synthetic glucocorticoids: prednisolone, methylprednisolone, dexamethasone, triamcinolone.

Synthetic glucocorticoids for topical use: flumethasone, beclomethasone, budesonide.

Figure 1. Scheme of steroid hormone biosynthesis. In the adrenal glands, biosynthesis occurs along 3 pathways: 5  4 -isomerase pathway (synthesis of mineralocorticoids), 17 -hydroxylase pathway (synthesis of glucocorticoids), double 17 -hydroxylase pathway (synthesis of sex steroids). In the testes there is a 17-ketoreductase stage of testosterone synthesis, and in the ovaries there is an aromatase conversion of androgens to estrogens.

Mechanism of action. Glucocorticosteroids enter target cells and penetrate through their membrane into the cytoplasm, where they bind to specific receptors. At rest, glucorticoid receptors are associated with heat shock protein (hsp90) in an inactive complex. Under the influence of the glucocorticoid hormone, the receptor is freed from the protein, attaches the hormone, after which the hormone-receptor complexes are combined in pairs and the resulting pairs enter the cell nucleus, where they bind to receptor nucleotide sequences on the surface of DNA. Such a receptor sequence is a palindrome GGTACAxxxTGTTCT. Activation of DNA receptors leads to changes in the transcription processes of a number of genes.

Physiological effects of glucocorticoid hormones. This group of effects occurs even with physiological concentrations of hormones in the body.

Effect on carbohydrate metabolism. Glucocorticoids cause an increase in blood glucose concentrations in several ways:

reduce the uptake of glucose by tissues by inhibiting the work of glucose transporters GLUT-1 and GLUT-4;

stimulate the processes of gluconeogenesis from amino acids and glycerol (strengthen the synthesis of key enzymes of gluconeogenesis - phosphoenolpyruvate carboxykinase, fructose-2,6-biphosphatase, glucose-6-phosphatase);

stimulate glycogen synthesis due to the formation of additional glycogen synthetase molecules.

Effect on lipid metabolism. Hyperglycemia, which is caused by glucocorticosteroids, leads to an increase in insulin secretion and therefore adipose tissue is simultaneously affected by 2 hormones - glucocorticoid and insulin. Adipose tissue on the extremities is more sensitive to glucocorticoids, so here corticosteroids inhibit glucose uptake and enhance lipolysis (fat breakdown). As a result, the fat content in the limbs decreases.

On the torso, adipose tissue is more sensitive to the action of insulin and therefore lipogenesis (fat synthesis) increases in its cells. As a result, under the influence of glucocorticosteroids, a redistribution of fat in the body occurs: a person deposits fat on the chest, abdomen, buttocks, the face becomes rounded, and “bull withers” appear on the back of the neck. At the same time, the limbs of such people are practically devoid of fat.

Effect on amino acid metabolism. Glucocorticosteroids stimulate the synthesis of RNA and protein in the liver, increase the breakdown of proteins in muscle tissue, skin, connective, adipose and lymphoid tissue (lymph nodes, thymus, spleen). That. Glucocorticoids are characterized by a catabolic effect.

Mineralocorticoid activity. Glucocorticosteroid hormones are capable of activating mineralocorticoid receptors (although to a lesser extent than mineralocorticoid hormones). As a result, genes for the synthesis of permease protein are activated in the collecting ducts of the nephron, which forms channels for the reabsorption of sodium ions. As a result of sodium reabsorption, fluid is retained in the body, the volume of circulating blood increases and the secretion of potassium ions into the urine increases.

Pharmacological effects of glucocorticoids. This group of effects occurs only at supraphysiological concentrations of the hormone in the body.

Anti-inflammatory effect. Glucocorticoids suppress all phases of both acute and chronic inflammatory processes. The exact mechanism of the anti-inflammatory effect has not yet been established. Several processes are believed to play a role in its implementation:

Figure 2. Scheme of biosynthesis of eicosanoids from arachidonic acid. COX- I, II- cyclooxygenasesIAndIItypes, 5-LOG– 5-lipoxygenase,Pg– prostaglandins,LT– leukotrienes, 5- and 12-HPETE– 5- and 12-hydroperoxyeicosatetraenoic acids, GCS – glucocorticosteroids, NSAIDs – non-steroidal anti-inflammatory drugs. The diagram shows the receptors for prostaglandins:

E.P.– relaxation of smooth muscles, increased secretion of water in the intestines, inhibition of secretionHCl, natriuresis, decreased ADH release, pyrogenesis.

D.P.– platelet aggregation.

FP– contraction of smooth muscles, increased secretion of water in the intestines, release of FSH, LH, prolactin, inflammation.

IP– relaxation of smooth muscles, decreased platelet aggregation, natriuresis, decreased renin secretion.

TP– contraction of smooth muscles and increased platelet aggregation.

At the site of inflammation, the activity of phospholipase A 2 and cyclooxygenase-II (COX-II) type, which are involved in the synthesis of inflammatory mediators - prostaglandins and leukotrienes, increases. Corticosteroids inhibit the genes responsible for the synthesis of COX-II. In addition, under the influence of glucocorticoids, genes responsible for the synthesis of a special protein, lipocortin, are activated. This protein is capable of binding phospholipase A 2 into inactive complexes. Therefore, with the introduction of glucocorticosteroids, the activity of phospholipase A 2 and cyclooxygenase type II decreases, and the synthesis of proinflammatory cytokines decreases (see Fig. 2).

At the site of inflammation, cell adhesion molecules are formed in large quantities - special proteins that are synthesized by endothelial cells and are necessary to attract leukocytes and macrophages to the site of inflammation. Glucocorticosteroids reduce the synthesis of cell adhesion molecules, the migration of leukocytes and macrophages to the site of inflammation stops.

At the site of inflammation, mitogenic factors (TNF) are formed, which stimulate the proliferation of fibroblasts (the main cells of connective tissue) and the processes of scarring of the inflamed tissue. This process can be very dangerous, because... During the scarring process, normal cells in the tissue may die (for example, in rheumatic joint inflammation, the scarring process leads to the destruction of the cartilage and bone of the joint and the cessation of movement in the joint). Glucocorticoids inhibit TNF genes and reduce fibrosis processes at the site of inflammation.

Immunosuppressive effect. Glucocorticosteroids have a multifaceted inhibitory effect on the immune system associated with the suppression of a number of cytokines:

Impact on the immune system	Effect caused
Inhibition of synthesis genes:	There is no activation of T helper cells T-helpers do not transmit a signal to working lymphocytes B lymphocytes do not mature into plasma cells for antibody synthesis Maturation of T lymphocytes and NK cells does not occur, and the effect of IL-2 is weakened.
B-lymphocyte apoptosis	Suppression of humoral immunity (impaired antibody synthesis), decreased resistance to bacterial infections.
Apoptosis of T lymphocytes, macrophages and natural killer cells	Inhibition of cellular immunity: antiviral immunity, delayed-type allergic reactions, transplant rejection reactions.
Suppression of β-interferon synthesis	Violation of antiviral immunity.
Suppression of antigen production in damaged tissues	Reduction of autoimmune processes.
Inhibition of synthesis and increased breakdown of components of the compliment system	Violation of the processes of lysis of foreign cells (membrane attack complex is not formed)

1. Effect on the cardiovascular system. Glucocorticoids increase blood pressure and stabilize it at this elevated level. The effect is associated, on the one hand, with an increase in blood volume against the background of fluid retention due to mineralocorticoid activity, and on the other hand, with an increase in the sensitivity of the myocardium and blood vessels to catecholamines.

   Effect on hematopoiesis. Glucocorticoids inhibit the synthesis of hematopoietic factors - IL-4 and granulocyte-macrophage colony-stimulating factor (GM-CSF), which are necessary for the process of division of bone marrow stem cells. Therefore, against the background of the administration of glucocorticoids in the blood, the level of lymphocytes, monocytes, basophils, and eosinophils decreases. At the same time, the formation of neutrophils in the bone marrow and their concentration in the blood increases. After a single administration of glucocorticoids, this effect reaches its maximum value by the 6th hour and decreases by the end of the day.

   Effect on the respiratory system. In the last month of pregnancy in the fetus, glucocorticoids activate the genes responsible for the synthesis of surfactant, a surface-active substance that coats the alveoli of the lungs and is necessary both for their opening at the time of the first breath and for subsequently protecting the lung tissue from collapse.

Use of glucocorticoids. There are three types of glucocorticoid therapy.

Compensatory therapy - carried out for chronic adrenal insufficiency (Addison's disease) and acute adrenal insufficiency, for example in shock (Waterhouse-Fridreksen syndrome). As a rule, it is recommended to use glucocorticoids with mineralocorticoid activity for replacement therapy.

Suppressor (suppressive) therapy. Used in the following conditions:

To suppress androgen production in girls with adrenogenital syndrome. In adrenogenital syndrome, there is a congenital defect in the enzyme 21-hydroxylase, which provides the last stages of the synthesis of glucocorticosteroids. Therefore, in the body of girls with this syndrome, the level of glucocorticoids is low and, according to the negative feedback mechanism, this deficiency stimulates the cells of the hypothalamic-pituitary zone and the level of corticoliberin and ACTH increases. If the activity of the 21-hydroxylase enzyme were normal, this would cause an increase in the synthesis of glucocorticoids, but in this case the synthesis process stops at an earlier stage - at the level of progesterone and 17-hydroxypregnenolone, which are converted to dihydroepiandrosterone along the androgenic pathway (see Fig. 1). That. an excess of androgens occurs in the body of children with adrenogenital syndrome. In girls, this is manifested by virilization (hirsutism, male-type voice mutation, male physique, clitoral hypertrophy and underdevelopment of the uterus). The administration of small doses of glucocorticoids in such patients leads to the fact that, through a feedback mechanism, the release of ACTH is suppressed and the excess production of androgens by the adrenal glands stops.

To suppress graft rejection in patients with organ transplants. Glucocorticosteroids suppress cellular immune reactions that are caused by antigens of a foreign organ.

Corticosteroids are included in almost all modern chemotherapy regimens for malignant blood tumors and breast cancer. In this case, their use serves as the basis for synchronizing therapy. Tumor tissue cells are at different stages of maturation and division and therefore have different sensitivity to chemotherapy. The use of glucocorticosteroids stops the development of the cell at the moment when it passes through the G 2 phase of the life cycle (premitotic). Therefore, when glucocorticoids are prescribed, all cells are gradually synchronized - they freeze in the G 2 phase. Once synchronization is achieved, glucocorticosteroids are discontinued, and all tumor cells simultaneously enter mitosis and become highly sensitive to chemotherapy.

Pharmacodynamic (pathogenetic) therapy. Exists in two forms:

Intensive glucocorticoid therapy. Glucocorticoids are administered in high doses (5 mg/kg per day for prednisolone), usually intramuscularly or intravenously. If there is no effect, the dose is increased by 25-50% every 4 hours. After stabilization of the condition, treatment is stopped immediately after 1-2 days. This type of therapy is used for:

anaphylactic shock (steroids interrupt the allergic reaction and stabilize blood pressure);

traumatic shock (steroids stabilize blood pressure);

status asthmaticus (a condition in which asthma attacks follow each other without periods of improvement);

toxic pulmonary edema caused by asphyxiating substances (in this case, steroids are used by inhalation - within 15 minutes the patient needs to inhale 200-400 standard doses of the steroid, i.e. 1-2 aerosol cans).

Limiting (long-term) therapy. It lasts for several months, years or even life. In this case, doses of cortisteroids are selected individually, but, as a rule, they do not exceed 5-10 mg/kg per day for prednisolone. This therapy aims to suppress chronic inflammatory or autoimmune processes. It is used for:

connective tissue diseases (systemic lupus erythematosus, rheumatoid arthritis, systemic scleroderma, dermatomyositis, periarteritis nodosa, etc.);

gastrointestinal diseases (nonspecific ulcerative colitis, Crohn's disease, hepatitis);

respiratory tract diseases (severe bronchial asthma);

kidney diseases (chronic glomerulonephritis, nephrotic syndrome);

blood diseases (thrombocytopenic purpura or Werlhof's disease);

autoimmune diseases of the thyroid gland (autoimmune thyroiditis, subacute thyroiditis);

allergic diseases (angioedema, hay fever, atopic dermatitis, Stevens-Jones syndrome, Lyell's syndrome), psoriasis, eczema;

inflammatory diseases of the choroid (uveitis).

The effect of glucocorticoids on the hematopoietic system is sometimes used in the treatment of agranulocytosis, a condition in which there are no neutrophils in the blood (at the same time, immunity is sharply reduced, necrotizing tonsillitis, colitis, and pneumonia occur). Typically, agranulocytosis is caused by exposure to ionizing radiation (radiation sickness) or toxic factors (toxic agranulocytosis).

In women with miscarriage, the administration of glucocorticoids is used to induce the synthesis of surfactant in the fetus and prepare the lungs of the unborn child for independent breathing. If the birth occurs prematurely and the baby is more than 2 weeks premature, then there is no surfactant in his lungs and the lung tissue cannot expand at the moment of the first breath (newborn distress syndrome occurs). Subsequently, inflammation occurs in such collapsed lung tissue (atelectatic pneumonia) and the alveoli die, being replaced by cartilaginous membranes (pulmonary hyalinosis). The administration of corticosteroids before birth allows you to start the process of surfactant synthesis ahead of time and prepare the fetal lung tissue for independent breathing.

Glucocorticosteroid dosage regimen. As a rule, when treating a particular disease, the dose of steroids is indicated in terms of prednisolone. If it is necessary to prescribe another steroid, use a scale of equivalent doses (see table). Currently, three basic schemes for administering glucocorticosteroids are used.

Continuous injection. Glucocorticoids are used daily, with the daily dose administered in 2 doses: ⅔ dose in the morning at 7-8 o'clock and ⅓ dose at 14-15 o'clock in the afternoon. With this administration regimen, the natural circadian rhythm of glucocorticoid secretion is simulated and they are less likely to cause atrophy of the adrenal cortex.

Alternative therapy. The patient receives a double daily dose of glucocorticoids in the morning every other day. This treatment regimen is used only after the course of the disease has become stable. This type of therapy extremely rarely causes undesirable effects, because Between doses of the medicine, a sufficient period of rest is maintained to restore impaired functions.

Pulse therapy. In this regimen, the patient is administered intravenously 1000 mg of methylprednisolone once a week for 30-60 minutes. In the following days, the patient either does not receive steroids at all or is prescribed minimal doses. This mode of administration is used in severe cases of the disease that are refractory to traditional therapy.

Undesirable effects of steroid therapy. With short-term use (less than 1 week) of even moderately large doses, serious adverse effects usually do not develop. Long-term treatment with glucocorticoids is accompanied by the occurrence of undesirable effects in 50-80% of patients. All undesirable effects of steroid therapy can be combined into several groups:

Endocrine and metabolic disorders:

Exogenous Itsenko-Cushing syndrome (hypercortisolism). It is characterized by an increase in body weight, a special appearance (moon-shaped face, “bull withers”, hirsutism, acne, purplish-red stretch marks on the skin), arterial hypertension, neutrophilia in the blood of such patients, and a sharply reduced level of eosinophils and lymphocytes.

Atrophy of the adrenal cortex and inhibition of the hypothalamic-pituitary-adrenal system. When taking steroids in physiological doses (2.5-5.0 mg/day for prednisolone), the risk of developing adrenal atrophy is minimal, but if higher doses are used, then after 1-2 weeks suppression of the adrenal cortex is observed. Moreover, it should be remembered that if the course lasted 2-3 weeks, then it takes from 6 to 12 months to fully restore the function of the cortex.

Withdrawal syndrome is characterized by a sharp deterioration in the course of the disease upon sudden cessation of steroid use, signs of adrenal insufficiency: weakness, fatigue, loss of appetite, muscle and joint pain, fever. In severe cases, an adrenal crisis is possible - vomiting, convulsions, collapse.

“Steroid diabetes” – characterized by a typical picture of diabetes mellitus, caused by an increase in blood glycemia, the counter-insular effect of steroids.

Hyperlipidemia, progression of atherosclerotic vascular lesions.

Changes in the musculoskeletal system: osteoporosis, pathological bone fractures - this effect is associated with inhibition of calcitonin synthesis and increased production of parathyroid hormone, acceleration of calcium metabolism in patients taking glucocorticoids.

Changes in the skin: thinning and atrophy of the skin is observed. This effect most often occurs when hormones are injected intramuscularly into the shoulder.

Gastrointestinal tract: The emergence of “mute”, i.e. asymptomatic ulcers of the duodenum and stomach. The asymptomatic nature of ulcers is due to the effect of steroids, which suppress the inflammatory process and pain that occurs when an ulcer forms.

Cardiovascular system: edema and hypokalemia, which are caused by the mineralocorticoid component of the action of steroids. In severe cases, arterial hypertension may occur.

CNS: general agitation, psychotic reactions (delusions, hallucinations) when administered in large doses. Possible increased intracranial pressure with nausea and headache (brain pseudotumor syndrome).

Visual organs: glaucoma, posterior capsular cataract.

Immunity and regeneration: taking glucocorticoids leads to impaired wound healing, weakening of antibacterial and antiviral immunity: the patient experiences disseminated bacterial and viral infections, the clinical picture of which is erased, because steroids eliminate typical inflammation, pain, and hypertemia. Quite often, taking steroids and the resulting immunodeficiency lead to the development of candidiasis of the mucous membranes and skin, and the occurrence of tuberculosis.

Teratogenic effect.

It should be remembered that all glucocorticoids do not differ in effectiveness, but the differences lie in the activity, duration of action of the drugs, the characteristics of their pharmacokinetics and the frequency of undesirable effects (see also Table 1).

Glucocorticoids for systemic use.

Hydrocortisone (Hydrocortisone). Natural glucocorticoid hormone. In glucocorticoid activity it is inferior to prednisolone, but in mineralocorticoid activity it is 3 times superior.

F K: Available in the form of 2 esters: 1) hydrocortisone succinate - is an easily soluble powder that can be used for intramuscular and intravenous administration; 2) hydrocortisone acetate – a fine-crystalline suspension, which can only be administered intramuscularly or into the joint cavity.

In the blood, hydrocortisone is 90% bound to blood proteins (80% to transcortin and 10% to albumin). Only 10% of the free fraction of hydrocortisone is biologically active. Hydrocortisone can penetrate well into all organs and tissues, incl. and through the placenta. However, the placenta contains the enzyme 11-dehydrogenase, which converts more than 67% of hydrocortisone to inactive 11-keto-hydrocortisone. Therefore, this drug can be used for health reasons in pregnant women, because its effect on the fetus will be minimized.

Application and dosage regimen. Currently, hydrocortisone is used quite rarely, mainly for replacement therapy of acute adrenal insufficiency (intravenously at a dose of 100-500 mg/day, usually no more than 48-72 hours), and also locally:

• retrobulbar for inflammatory eye diseases, 5-20 mg once a week;

  cutaneously in the form of ointments, creams, lotions for skin allergic diseases, psoriasis, eczema 2-3 times a day, applied to the affected areas without rubbing it, the duration of treatment is no more than 2-3 weeks;

  rectally in the form of microenemas for nonspecific ulcerative colitis, Crohn's disease, 5-50 mg per enema daily or every other day;

  intra-articularly for rheumatoid arthritis and other systemic collagenoses, 5-25 mg into the cavity of a “dry” joint (i.e. in the absence of exudate in the joint cavity) once every 1-3 weeks for a total course of up to 6 injections.

FV: 0.5 1 and 2.5% eye ointment, 2.5 and 3.0 g; 0.1% cream 15.0 g and 0.1 lotion 20 ml;

suspension of hydrocortisone acetate 2.5% in ampoules of 1 and 2 ml;

hydrocortisone succinate powder 500 mg in bottles.

Prednisolone (Prednisolone). A synthetic glucocorticoid, which is considered as a reference agent in this group. Combines high glucocorticoid activity and moderate mineralocorticoid activity.

F K: phosphate and hemisuccinate esters of prednisolone are readily soluble salts that can be administered either intramuscularly or intravenously; Prednisolone acetate ester is a microcrystalline suspension, so it can only be administered intramuscularly.

After administration, prednisolone is 90% bound to blood proteins (50% with transcortin and 40% with albumin). Penetrates well into all organs and tissues; like hydrocortisone, 51% of prednisolone is destroyed by 11-dehydrogenase of the placenta to 11-keto-prednisolone. Therefore, it is relatively safe for the fetus and can be used for health reasons in pregnant women.

Application and dosage regimen. Prednisolone is used for all types of glucocorticoid therapy. When administered orally, doses are 15-100 mg/day (in the case of treatment of hemoblastosis - 40-60 mg/m2 body surface per day). When administered into the joint cavity, it is prescribed in doses of 5-50 mg once a week. Intravenous administration is used for severe systemic allergic reactions or status asthmaticus, and the dose can reach 400-1200 mg (it is currently believed that for status asthmaticus there is no maximum dose of prednisolone, the only criterion for the dose is relief of the status). Local applications of prednisolone for skin and eye diseases are carried out 2-3 times a day (the medicine is applied to the lesion without rubbing it).

FV: tablets of 5, 10 and 20 mg; ointment 0.5% -10.0; prednisolone phosphate solution 30 mg/ml (3%) ampoules of 1 ml; prednisolone hemisuccinate powder in ampoules of 10, 25, 50 and 250 mg; suspension of prednisolone acetate in ampoules of 10, 20, 25 and 50 mg; drops in bottles 0.5% -10 ml.

M ethylprednisolone(Methylprednisolone, Medrol). Compared to prednisolone, it has a 20% greater glucocorticoid effect and is practically devoid of mineralocorticoid activity. Unlike prednisolone and other corticosteroids, it extremely rarely causes undesirable effects on the cardiovascular system, gastrointestinal tract and central nervous system, therefore methylprednisolone is recommended for high-dose glucocorticoid therapy and pulse therapy.

Application and dosage regimen. Orally methylprednisolone is used at a dose of 4-96 mg/day; the depot form can be administered intramuscularly at 40-120 mg once a week (1-4 injections per course). When performing pulse therapy, 1000 mg of methylprednisolone is dissolved in 100 ml of saline and administered for 30-60 minutes once a week.

Methylprednisolone is sometimes used to prevent vomiting during treatment with cytotoxic drugs in cancer patients. In this case, methylprednisolone is prescribed at a dose of 250 mg 20 minutes before taking the chemotherapy drug and again at the same dose 6 hours after taking it.

FV: tablets of 4 and 16 mg; powder in bottles of 250, 500, 1000 and 2000 mg; methylprednisolone acetate suspension, 40 mg bottles.

Dexamethasone(Dexamethasone, Dexasone). Fluorinated synthetic glucocorticosteroid. One of the most powerful glucocorticoid compounds - 7 times stronger than prednisolone in glucocorticoid activity, lacking mineralocorticoid activity.

IN Causes strong and long-term depression of the hypothalamic-pituitary-adrenal system, severe disturbances of carbohydrate and fat metabolism, it can often cause psychotic reactions. Dexamethasone has a strong dehydrating effect on tissue, especially brain tissue. In this regard, it is recommended to include it in treatment regimens for cerebral edema.

FC: Unlike non-fluorinated glucocorticoids, after absorption it is only 60% bound to blood proteins (mainly albumin, not transcortin). The proportion of biologically active free fraction is about 40%.

Dexamethasone (like other fluorinated steroids) is resistant to the action of 11-dehydrogenase of the placenta and only 2% of the substance entering the placenta is converted into inactive 11-keto-dexamethasone, therefore dexamethasone penetrates well into fetal tissue and effectively stimulates the processes of surfactant synthesis and lung maturation.

Application and dosage regimen. Orally, 2-15 mg/day is prescribed in 1 or 2 doses, 4-20 mg/day is administered intravenously or intramuscularly, 2-8 mg is administered into the joint cavity every 3 days to 3 weeks.

For cerebral edema, dexamethasone is administered intravenously at a dose of 10 mg, then the administration is repeated every 6 hours at a dose of 4 mg intramuscularly until symptoms resolve. Treatment is continued for at least 2-4 days after stabilization of the condition, followed by gradual withdrawal of dexamethasone over 5-7 days.

To prevent vomiting in patients receiving cytostatic therapy, dexamethasone is administered 10 mg 20 minutes before taking the cytostatic and 6 hours after its administration.

To stimulate the synthesis of surfactant in the fetus during miscarriage, dexamethasone is prescribed to a pregnant woman at a dose of 5 mg 3 times a day (the optimal course is 5 days).

FV: tablets of 0.5 and 1.5 mg; dexamethasone phosphate solution 0.4% in ampoules of 1 and 2 ml.

Triamcinolone(Triamcinilone, Polcortolon). It is a fluorinated synthetic glucocorticoid. Its activity is comparable to methylprednisolone. When using it, undesirable effects on the skin (striae, hemorrhages, hirsutism) and muscles (“triamcinolone” myopathy) often occur.

P The pharmacokinetic parameters are similar to dexamethasone, however, it binds extremely weakly to plasma protein: 40% of the drug is bound to plasma albumin, and 60% is a free biologically active fraction. During the metabolism of triamcinolone, 3 metabolites are formed, and 2 of them have pharmacological activity.

Dosage regimen: taken orally at a dose of 4-48 mg/day in 2 doses, 40-80 mg is administered intramuscularly and into the joint cavity once a month (in the form of a depot preparation of Kenalog), applied topically in the form of an ointment that is applied to affected area 2-3 times a day.

VWF: tablets of 2, 4 and 8 mg, suspension of triacinolone cetonide 10 and 40 mg/ml (1 and 4%) in ampoules of 1 ml ( Kenalog), ointment 0.1% -15.0.

Table 1. Comparative characteristics of agents with glucocorticoid activity.

Means	activity		 HELL	gastrointestinal ulcers	psychosis	equiv. dose	bioavailable, per os	t ½ , days fabrics
hydrocortisone
prednisolone
methylprednisolone
dexamethasone
triamcinolone
flumethasone
beclomethasone
budesonide

Note: * - when applied topically in comparison with hydrocortisone.

Glucocorticoids for local use.

Beclomethasone(Beclometasone, Becotide). Used for inhalation use in the treatment of allergic diseases of the respiratory tract: hay fever, bronchial asthma. Currently, the use of inhaled corticosteroids is considered one of the most effective methods of preventing attacks in the treatment of bronchial asthma, which has a number of advantages compared to oral administration (see Table 2)

F K: After administration of the steroid into the respiratory tract, the maximum concentration of beclomethasone in the receptor area is achieved within 5 minutes. When administered by inhalation, only 10-20% of the drug reaches the lower respiratory tract, and 80-90% of the dose taken is deposited in the oral cavity and then swallowed. Therefore, to reduce the likelihood of corticosteroids entering the gastrointestinal tract, it is recommended to rinse your mouth after inhalation.

Dosage regimen. Beclomethasone is taken 200-1600 mcg/day in 2-3 doses. Doses above 1000 mcg/day should be used under strict medical supervision.

NE: When inhaled corticosteroids are administered at a dose of less than 1000 mcg/day, systemic undesirable effects do not develop. For inhalation administration, local undesirable effects associated with the effects of corticosteroids on the mucous membranes of the respiratory tract, oral cavity, pharynx and esophagus are most typical:

Candidiasis of the oral cavity, esophagus, respiratory tract;

Dry mouth, destruction of tooth enamel;

FV: aerosols inhaler 200 doses (1 dose = 50 mcg), isihaler 200 doses (1 dose = 200 mcg), diskhaler (1 dose = 100 and 200 mcg); nasal spray 200 doses (1 dose = 50 mcg).

Table 2. Comparative characteristics of inhalation and oral

routes of administration of corticosteroids.

Budesonide (Budesonide, Pulmicort). It has an increased affinity for glucocorticoid receptors (15 times greater than prednisolone) and therefore has a pronounced effect even in minimal doses.

F K: After inhalation administration, the maximum concentration in the receptor area is achieved after 0.5-1.0 hours. Budesonide has low systemic bioavailability - that part of its dose that enters the gastrointestinal tract is quickly metabolized by the liver by almost 90% and has a systemic effect of only 1- 2% of the administered dose.

Used inhalation in the treatment of allergic diseases of the respiratory tract and topically for atopic dermatitis, psoriasis, eczema, discoid lupus.

NE: similar to the effects of beclomethasone, but occur much less frequently.

FV: aerosols turbuhaler 100 and 200 doses (1 dose = 100 and 200 mcg), inhaler 200 doses (1 dose = 50 mcg mitte and 200 mcg forte); ointment and cream 0.025% -15.0.

Table 3. Classification of corticosteroids for external use.

Generic name of the steroid	Trade name of the drug
I. Very strong clobetasol propionate 0.05% chalcinonide 0.1%	dermovate chalciderm
II. Strong betamethasone valerate 0.1% budesonide 0.0375% triamcinolone acetonide 0.1% flumethasone pivalate 0.02% fluticasone propionate 0.05% mometasone furoate 0.1%	celestoderm-B apulein polcortolone, fluorocort Lorinden cutivate elocom
III. Medium strength perdnisolone 0.25 and 0.5% fluocortolone 0.025%	deperzolon ultralan
IV. Weak hydrocortisone acetate 0.1; 0.25; 1 and 5%	hydrocortisone

Flumethasone(Flumetasone, Lorinden). Steroid for external use. It has a powerful anti-inflammatory and anti-allergic effect. It is practically not absorbed from the surface of the skin, therefore it does not have a systemic effect.

P Application and dosage regimen. Flumethasone is used in the treatment of allergic skin diseases, eczema, neurodermatitis, discoid lupus and psoriasis. The cream and ointment are applied in a thin layer to the affected areas 3-5 times a day without rubbing into the skin. It is recommended to carry out the procedure with gloves. After the process has stabilized, the ointment can be applied 1-2 times a day.

NE: Typically these are skin manifestations in the form of skin atrophy, stretch marks, acne, perioral dermatitis (more often affects women), hirsutism and frontal alopecia. In severe cases, the development of erased forms of streptococcal and fungal skin infections is possible.

FV: lotion and ointment 0.02% -15 ml.

Glucocorticosteroids (GCS) are hormonal drugs that are similar in structure and function to glucocorticosteroid (also called glucocorticoid) hormones that are normally produced in the adrenal cortex of the human body.

Their release is influenced by the hypothalamus and pituitary gland due to corticotropic hormone and adrenocorticotropic hormone, respectively. Peak secretion is observed in the morning (between 5-8 hours).

Classification

GCS are classified depending on their origin, method of application, strength and duration of effect. List of drug names:

Principle of classification	Varieties
Origin	natural - cortisone and hydrocortisone (cortisol); synthetic - prednisolone, methylprednisolone, etc.
Duration of action	medium duration of action - prednisolone, methylprednisolone, prednisone, etc.; long-acting - dexamethasone, triamcinolone, betamethasone, etc.
Power of action	very strong - clobetasol, betamethasone dipropionate, chalcinonide; strong - dexamethasone, triamcinolone, flumethasone, fluocinolone, fluticasone, halobetasol, hydrocortisone butyrate, betamethasone valerate and benzoate, budesonide, mometasone; medium strength - prednisolone, fluocortolone; weak - hydrocortisone acetate
Mode of application	systemic - prednisolone, methylprednisolone, betamethasone, hydrocortisone, dexamethasone, etc.; inhalation - beclomethasone, budesonide, flunisolide, fluticasone (Avamys), triamcinolone, mometasone, etc.; local (dermatological) - fluocinolone, flumethasone (Sinaflan, Flucinar, Lorinden), etc.

There are many combined preparations of GCS for external use (ointments, creams, gels, etc.) with antibiotics (gentamicin, neomycin, tetracycline), antiseptics, antifungals, etc.

Mechanism of action and effects

Corticosteroids are steroid hormones in origin; their mechanism of action differs from protein hormones. GCS arrive at target cells and penetrate their cytoplasm through the cell membrane, where they bind to receptors and exert their specific effect.

These hormonal drugs affect the function of most cells in the body and are of great practical importance. Their main effects are the following:

1. 1. Participate in the regulation of normal metabolism:
   1. They affect carbohydrate metabolism (increase the concentration of glucose in the blood in various ways).
   2. 2. Affect protein metabolism (stimulate the formation of RNA and protein in the liver, enhance the breakdown of proteins in muscles and other tissues).
   3. 3. Affect fat metabolism (2 opposite processes occur in different areas - the growth and breakdown of adipose tissue).
2. They have mineralocorticoid activity. Capable of stimulating receptors for mineralocorticoids (although to a lesser extent than mineralocorticoid hormones), which results in the reabsorption of sodium in the body. This ultimately provokes fluid retention, increased blood volume and increased excretion of potassium ions into the urine.
3. The body's resistance to stress increases. The increase in blood glucose levels under the influence of glucocorticoids provides the energy needed to protect against stress caused by injury, infection, disease, etc.
4. They have an immunosuppressive effect (reduce the number of different classes of leukocytes).
5. They have a powerful anti-inflammatory effect, which is explained by a decrease in the level and distribution of the function of T- and B-lymphocytes and a violation of the formation of inflammatory mediators. They stabilize lysosome membranes and reduce the release of histamine by basophils. As a result, all three stages of inflammation are inhibited.
6. Participate in the regulation of the endocrine system: they slow down the secretion of ACTH and thyrotropin, increase the production of somatotropic hormone.
7. Affects the respiratory system. In the fetus in the last month of pregnancy, GCS contribute to the formation of surfactant, which covers the alveoli of the lungs from the inside and is necessary both for their opening at the time of the first breath and for protecting their tissue from collapse in the future.
8. Affects the cardiovascular system. GCS increase blood pressure and stabilize it at this elevated level. The effect is associated, on the one hand, with an increase in blood volume against the background of fluid retention due to mineralocorticoid activity, and on the other hand, with increased sensitivity of the heart muscle and blood vessels to endogenous catecholamines (adrenaline and norepinephrine).
9. Affect the process of hematopoiesis. GCS inhibit the formation of hematopoietic factors necessary for the division of red bone marrow stem cells. Against this background, the level of basophils, eosinophils and monocytes in the blood decreases. The formation of neutrophils increases.

Hydrocortisone - dosage forms and instructions for use

Application

Indications for the use of GCS are extremely diverse and have long changed, going beyond the scope of replacement therapy for hypofunction of the adrenal cortex.

Due to numerous and dangerous adverse reactions for most diseases, they are used as second-line drugs, that is, in cases where nothing else can be prescribed.

Glucocorticoids are used to treat the following diseases:

• with an allergic component (bronchial asthma, dermatitis, etc.);
• inflammatory (bursitis, arthritis, etc.);
• vascular edema of the brain (with tumors, bacterial meningitis and brain abscess);
• infectious (hepatitis, mycosis fungoides, etc.);
• autoimmune (rheumatoid arthritis, autoimmune hemolytic anemia, systemic lupus erythematosus, myasthenia gravis, multiple sclerosis, glomerulonephritis, ulcerative colitis and many others);
• tumor (leukemia, especially lymphocytic leukemia, myeloma);
• during tissue transplantation, as they suppress rejection of the transplanted organ;
• ocular (neuritis of the optic nerve, conjunctivitis, uveitis, etc.);
• for the purpose of preventing respiratory distress syndrome in premature infants.

Side effects and contraindications

Side effects are proportional to the dose and duration of treatment. According to the law of the “vulnerable organ,” they occur when there is already an existing lesion. For example, infectious complications due to the use of GCS appear in cases of weakened immunity, ulceration in the stomach and duodenum - in patients with peptic ulcer disease, osteoporosis - in women in menopause, etc.

All undesirable effects of GCS therapy can be combined into the following several groups:

1. 1. Endocrine and metabolic disorders:
   1. Hyperlipidemia, progression of atherosclerotic vascular lesions.
   2. 2. “Steroid diabetes” - characterized by typical symptoms of diabetes mellitus, caused by the action of GCS opposite to insulin.
   3. 3. “Withdrawal” syndrome - a sharp deterioration in the course of the disease with a sudden cessation of the use of GCS, signs of adrenal insufficiency (increased fatigue, weakness, joint and muscle pain, increased body temperature, loss of appetite). In severe cases, adrenal crisis is possible.
   4. 4. Atrophy of the adrenal cortex and inhibition of the hypothalamic-pituitary-adrenal system. As a result, the formation of all hormones in this area (mineralkorticoids, endogenous corticosteroids, sex hormones) is reduced. When using corticosteroids in physiological doses (2.5-5.0 mg/day for prednisolone), the risk of developing adrenal atrophy is minimal, but if higher doses are used, then after 1-2 weeks, suppression of their cortex is observed.
   5. 5. Exogenous Itsenko-Cushing syndrome. It is characterized by an increase in body weight, a special appearance (“bull withers” or “buffalo hump”, moon-shaped face, hypertrichosis, acne, purplish-red stretch marks on the skin), insomnia, arterial hypertension (AH), increased appetite. In such patients, the level of neutrophils in the blood increases and the number of lymphocytes and eosinophils is sharply reduced.
2. Musculoskeletal system: irreversible osteoporosis, avascular necrosis or pathological bone fractures. These manifestations are associated with an increase in parathyroid hormone production and inhibition of calcitonin synthesis (as a result, calcium is washed out of the bones), and acceleration of calcium metabolism.
3. Condition of the skin: thinning and atrophy are noted. This effect occurs most often when GCS is administered intramuscularly (into the shoulder).
4. Digestive tract: the occurrence of “silent”, that is, asymptomatic ulcers of the duodenum and stomach. The absence of ulcerative defects is due to the influence of corticosteroids, which suppress the inflammatory process and pain that occurs during the formation of ulcers.
5. Cardiovascular system: hypokalemia and edema caused by the mineralocorticoid component of the action of GCS. In severe cases, hypertension may develop.
6. Central nervous system: general agitation, psychotic reactions (hallucinations, delusions) when administered in large dosages. Possible increased intracranial pressure with headache and nausea (“pseudotumor of the brain” syndrome).
7. Visual organs: posterior capsular cataract, glaucoma.
8. Immunity and regeneration: taking GCS leads to impaired wound healing (due to decreased collagen formation), weakening of antiviral and antibacterial immunity. The patient experiences common viral and bacterial infections, the clinical manifestations of which are erased (since GCS eliminates typical inflammation, fever, pain). Frequent use of corticosteroids and the immunodeficiency caused by them lead to candidiasis of the skin and mucous membranes, tuberculosis.
9. Teratogenic effect: affect the process of fetal formation, which ultimately leads to the occurrence of various congenital malformations.

Patient with Itsenko-Cushing syndrome.

Patients with Cushing's syndrome have features of fat deposition. Adipose tissue on the extremities is more sensitive to GCS, so these hormones enhance its breakdown there. This results in a decrease in subcutaneous fat. On the body it is more sensitive to the action of insulin, so its formation increases. As a result, under the influence of GCS, a redistribution of fat in the body is observed: it is deposited on the abdomen, chest, buttocks, on the back of the neck, and face.

Corticosteroids have no absolute contraindications. If possible, you should not use these hormonal drugs in the following conditions:

• severe heart failure;
• peptic ulcer of the stomach and duodenum;
• severe hypertension;
• osteoporosis;
• diabetes;
• epilepsy;
• mental disorders.