Glucocorticoids

In clinical practice, natural glucocorticoids are used - cortisone and hydrocortisone and their synthetic and semi-synthetic derivatives. Depending on the presence or absence of fluorine or chlorine ions in the structure of the drug, glucocorticoids are divided into non-halogenated (prednisone, prednisolone, methylprednisolone) and halogenated compounds (triamcinolone, dexamethasone and betamethasone).

Natural glucocorticoids have mineralocorticoid activity, although weaker than true mineralocorticoids. Non-halogenated semi-synthetic glucocorticoids also have mineralocorticoid effects, the severity of which, in turn, is inferior to the effects of natural glucocorticoids. Halogenated drugs have virtually no mineralocorticoid activity.

Targeted changes in the structure of natural glucocorticoids have led to an increase in glucocorticoid activity and a decrease in mineralocorticoid activity. Currently, halogenated metazones (beclomethasone, dexamethasone, mometasone) have the strongest glucocorticoid activity. The combination of GCS with various esters (succinates and phosphates) makes the drug solubility and the ability to administer them parenterally. The depot effect is achieved using a suspension of crystals insoluble in water. These glucocorticoids have reduced absorption and are convenient for local use.

In anesthesiology and resuscitation practice, water-soluble glucocorticoids are used for intravenous administration.

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Glucocorticoids: place in therapy

For pharmacodynamic therapy (as opposed to replacement therapy), it is preferable to use drugs with low mineralocorticoid activity. Glucocorticoids used in clinical practice have certain differences in the strength of the main therapeutic effects, pharmacokinetics and spectrum of side effects, which must be taken into account when prescribing.

Glucocorticoids are used in anesthesiology and resuscitation practice in the following conditions: hypotension during massive bleeding and its recurrence; hypotension during acute cardiovascular failure;

• traumatic, hemorrhagic
• infectious toxic shock;
• allergic or anaphylactic reaction (Quincke's edema, acute urticaria, asthmatic status, acute toxic-allergic reactions, etc.);
• allergic reactions to narcotic analgesics or other pharmacological drugs;
• acute adrenal insufficiency.

For emergency treatment of conditions such as shock, allergic reactions, intoxication, glucocorticoids are administered intravenously. The administration can be single or repeated over several days.

The main indication for the use of glucocorticoids during anesthesia and in the early postoperative period is a decrease in SBP below 80 mm Hg, which can be observed in many pathological conditions. Intravenous administration of GCS during the induction of anesthesia and its maintenance allows for rapid stabilization of hemodynamics against the background of complex treatment within 10 minutes from the moment of administration of the initial dose.

Usually during surgery glucocorticoids are used in a wide range of doses: from 20 to 100 mg when converted to prednisolone doses. At the same time, the effectiveness of their use in complex therapy can reach 96%. Only in a small number of cases are drugs ineffective. Most often, the absence of a hemodynamic effect is noted in patients with a decrease in blood pressure in response to the introduction of a local anesthetic (for example, trimecaine). No effect has been noted in single doses of glucocorticoids in patients with severe intoxication if its source remains, as well as in rare cases of initial resistance of the body to drugs.

In severe circulatory disorders, the therapeutic effect of glucocorticoids is realized through increased tissue perfusion, increased venous outflow, normalization of peripheral resistance and SV, stabilization of cellular and lysosomal membranes and other effects. Despite the traditional use of glucocorticoids in various types of shock, their effectiveness in these conditions remains unproven. This is due to the complexity of taking into account the entire variety of factors that underlie the development of a shock state and affect the effectiveness of therapy. The use of glucocorticoids in these conditions should be carried out in combination with the entire pharmacological symptomatic arsenal for the correction of complications.

Glucocorticoids are widely used in the treatment of allergic reactions that occur during anesthetic support of surgical interventions. In severe manifestations of allergy, intravenous administration of adequate doses of glucocorticoids has a suppressive effect. The onset of action of glucocorticoids in allergic diseases is delayed. For example, the main biological effects of hydrocortisone develop only 2-8 hours after its administration. Therefore, patients with severe allergic reactions need immediate administration of epinephrine to avoid bronchospasm.

Glucocorticoids have a pronounced effect in adrenal insufficiency that developed before and during surgical interventions. Hydrocortisone, cortisone and prednisolone are used for replacement therapy.

Short-term administration of long-acting GCS is used to prevent respiratory distress syndrome in premature infants, reducing the risk of death and complications from this condition by 40-50%.

Mechanism of action and pharmacological effects

Glucocorticoids are hormonal agents whose main action is realized at the level of nuclear structures of the cell and consists in regulating the expression of certain genes. Glucocorticoids interact with specific protein receptors of target cells in the cytoplasm of the cell (cytosolic receptors). The resulting hormone-receptor complex moves to the nucleus, where it binds to co-activating molecules and the sensitive element of genes. As a result, gene transcription processes are activated in cells (genomic effect) and, as a consequence, the rate of formation of proteins with an anti-inflammatory effect increases: lipocortin-1 (annexin-1), IL-10, IL-1 receptor antagonist, inhibitor of the nuclear factor CARR, neutral endopeptidase and some others. The effect of steroid hormones does not appear immediately, but after a certain time (several hours), which is necessary for gene expression and subsequent synthesis of a specific protein. However, many of the effects of glucocorticoids occur rapidly enough that they can only be explained by stimulation of gene transcription and are likely to be due to extragenomic effects of glucocorticoids.

The extragenomic effect of glucocorticoids consists of interaction with transcription factors and inhibitory proteins. The latter are regulators of several genes involved in the immune response and inflammation, including cytokine genes (IL-1-6, -8, -11, -13, -16-18, tumor necrosis factor-a (TNF-a), granulocyte-macrophage colony-stimulating factor, eotaxin, macrophage inflammatory protein, monocyte chemotactic protein, etc.), as well as their receptors, adhesion molecules, proteinases, etc. The result of this interaction is inhibition of transcription of proinflammatory and immunomodulatory genes.

Anti-inflammatory, anti-allergic and immunosuppressive action. Glucocorticoids suppress the production of many factors that are critical for the initiation and development of the inflammatory response and thereby suppress excessive reactions of the body. The action of GCS is aimed at the main participants in the inflammatory response: inflammation mediators, vascular and cellular components of inflammation. Glucocorticoids reduce the production of prostanoids and leukotrienes, suppressing the induction of lipocortin biosynthesis, which inhibits phospholipase A2, as well as the expression of the COX-2 gene. Due to the effect on the production of pro- and anti-inflammatory mediators, glucocorticoids stabilize lysosomal membranes, reduce capillary permeability, which explains their pronounced effect on the exudative phase of inflammation. Stabilization of lysosomal membranes limits the release of various proteolytic enzymes beyond the lysosomes and prevents destructive processes in tissues. The accumulation of leukocytes in the inflammation zone is reduced, the activity of macrophages and fibroblasts is reduced. By inhibiting the proliferation of fibroblasts and their activity in relation to collagen synthesis and sclerotic processes in general, glucocorticoids are able to suppress the proliferative phase of inflammation. Inhibition of basophil maturation under the action of glucocorticoids leads to a decrease in the synthesis of immediate allergy mediators. Thus, glucocorticoids are able to suppress both early and late manifestations of the inflammatory reaction and inhibit proliferation reactions in chronic inflammation.

The anti-inflammatory effect of glucocorticoids is non-specific and develops in response to any damaging stimuli: physical, chemical, bacterial or pathological immune, such as hypersensitivity or autoimmune reactions. The non-specific nature of the anti-inflammatory effect of GCS makes it suitable for influencing numerous pathological processes. Although the action of GCS does not affect the causes underlying the inflammatory disease and never cures it, suppression of clinical manifestations of inflammation is of great clinical importance.

It is impossible to draw a clear line between the mechanisms that provide the anti-inflammatory and immunosuppressive effects of GCS, since many factors, including cytokines, play an important role in the development of both pathological processes.

Disruption of the production of regulatory and effector cytokines, as well as expression of molecules that ensure interaction of immunocompetent cells, leads to deregulation of the immune response and, as a consequence, to its incompleteness or complete blockade. By inhibiting the production of cytokines that regulate various phases of the immune response, glucocorticoids equally effectively block the immune response at any stage of its development.

Glucocorticoids are of great clinical importance in the treatment of diseases that result from undesirable immunological reactions. These diseases include both conditions that are predominantly the result of humoral immunity (such as urticaria) and conditions that are mediated by cellular immune mechanisms (such as transplant rejection). Suppression of antibody production occurs only with very high doses of glucocorticoids. This effect is observed only after a week of therapy.

The second mechanism explaining the immunosuppressive action of glucocorticoids is the increased production of endonucleases in cells. Activation of endonucleases is the central event of the late stages of apoptosis, or physiological programmed cell death. Accordingly, the direct consequence of the action of GCS is the death of a large number of cells, in particular, leukocytes. Glucocorticoid-induced apoptosis affects lymphocytes, monocytes, basophils, eosinophils and mast cells. Clinically, the apoptogenic effect of GCS is manifested as the corresponding types of cytopenias. The effect of glucocorticoids on neutrophils is opposite, i.e. under the influence of these drugs, neutrophil apoptosis is suppressed, and the duration of their circulation increases, which is one of the causes of neutrophilia. However, glucocorticoids cause a sharp decrease in the functional activity of neutrophils. For example, under the influence of GCS, neutrophils lose the ability to leave the bloodstream (inhibition of migration) and penetrate into foci of inflammation.

Due to direct interaction with DNA, steroids induce or inhibit the synthesis of enzymes that participate in the regulation of metabolism, which is the main cause of adverse reactions to GCS. Most adverse metabolic effects do not appear immediately, but only with long-term GCS therapy.

Carbohydrate metabolism

One of the important effects of GCS is their stimulating effect on gluconeogenesis. Glucocorticoids cause an increase in the formation of glycogen and glucose production in the liver, inhibit the action of insulin and reduce the permeability of membranes for glucose in peripheral tissues. As a result, hyperglycemia and glucosuria may develop.

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Protein metabolism

Glucocorticoids reduce protein synthesis and increase its breakdown, which is manifested by a negative nitrogen balance. This effect is especially pronounced in muscle tissue, skin and bone tissue. Manifestations of a negative nitrogen balance are weight loss, muscle weakness, skin and muscle atrophy, striae, hemorrhages. A decrease in protein synthesis is one of the reasons for the delay in regenerative processes. In children, tissue formation is disrupted, including bone tissue, and growth slows down.

Lipid metabolism

Glucocorticoids cause redistribution of fat. The effect on fat metabolism is manifested by a local lipolytic effect in the limbs, while lipogenesis is induced in the trunk. As a result, with systematic use of drugs, significant amounts of fat accumulate in the face, dorsal part of the body, shoulders with a decrease in adipose tissue of the limbs. Glucocorticoids increase the synthesis of fatty acids and triglycerides, causing hypercholesterolemia.

Water-salt metabolism

Long-term administration of GCS leads to the implementation of their mineralocorticoid activity. There is an increase in the reabsorption of sodium ions from the distal sections of the renal tubules and an increase in the tubular secretion of potassium ions. The retention of sodium ions in the body causes a gradual increase in the BCC and an increase in blood pressure. The mineralocorticoid effects of GCS are more inherent in natural GCS - cortisone and hydrocortisone and to a lesser extent in semi-synthetic GCS.

Glucocorticoids tend to cause a negative calcium balance in the body, reducing calcium absorption from the gastrointestinal tract and increasing its excretion by the kidneys, which can cause hypocalcemia and hypercalciuria. With long-term administration, calcium metabolism disorders coupled with the breakdown of the protein matrix lead to the development of osteoporosis.

Formed elements of blood

Glucocorticoids reduce the number of eosinophils, monocytes and lymphocytes in the blood. At the same time, the content of erythrocytes, reticulocytes, neutrophils and thrombocytes increases. Most of these changes are observed after taking even one dose of GCS with the maximum effect after 4-6 hours. The initial state is restored after 24 hours. With long-term treatment with GCS, changes in the blood picture persist for 1-4 weeks.

According to the feedback principle, glucocorticoids exert a depressing effect on the hypothalamic-pituitary-adrenal system (HPAS), as a result of which ACTH production decreases. The resulting adrenal cortex insufficiency may manifest itself with abrupt discontinuation of glucocorticoids. The risk of developing adrenal insufficiency increases significantly with regular glucocorticoid use for more than 2 weeks.

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Anti-stress effect

Glucocorticoids are adaptive hormones that increase the body's resistance to stress. Under severe stress, cortisol production increases significantly (at least 10-fold). There is evidence of a connection between the immune system and the HPA axis. These interactions may represent at least one of the mechanisms of the anti-stress effect of glucocorticoids. It has been shown that the HPA axis function is regulated by many cytokines (IL-1, -2, -6, tumor necrosis factor TNF-a). All of them have a stimulating effect. Many have a wide range of effects. For example, IL-1 stimulates the release of corticotropin-releasing hormone by hypothalamic neurons, directly affects the pituitary gland (increases the release of ACTH) and the adrenal glands (increases the release of glucocorticoids). At the same time, glucocorticoids are capable of inhibiting many links of the immune system, such as the production of cytokines. Thus, the HPA axis and the immune system have bidirectional communication during stress and these interactions are likely to be important in maintaining homeostasis and protecting the body from the potentially life-threatening consequences of an extensive inflammatory response.

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Permissive action

Glucocorticoids can influence the action of other hormones, significantly potentiating their effects. This effect of glucocorticoids on the effects of other regulatory hormones is called permissive and reflects changes in protein synthesis caused by GCS, which change the response of tissues to certain stimuli.

Thus, small doses of glucocorticoids cause significant potentiation of the lipolytic action of catecholamines. Glucocorticoids also increase the sensitivity of adrenoreceptors to catecholamines and enhance the pressor effect of angiotensin II. It is believed that due to this, glucocorticoids have a tonic effect on the cardiovascular system. As a result, vascular tone is normalized, myocardial contractility increases, and capillary permeability decreases. On the contrary, insufficient production of natural GCS is characterized by low SV, arteriolar dilation, and a weak response to adrenaline.

It has been shown that glucocorticoids enhance the bronchodilating effect of catecholamines, restoring the sensitivity of beta-adrenergic receptors to them, which is associated with an increase in the biosynthesis of adrenergic receptors in the vascular wall.

Pharmacokinetics

Glucocorticoids are small lipophilic molecules that easily pass through cellular barriers by simple diffusion. When taken orally, glucocorticoids are well absorbed from the upper jejunum. Cmax in the blood is created in 0.5-1.5 hours. The rate of development of effects and the duration of action of GCS depend on the dosage form, solubility and rate of metabolism of the drug.

Glucocorticoids are produced in many dosage forms. The features of injection forms are determined by the properties of both the glucocorticoid itself and the ester bound to it. Succinates, hemisuccinates, and phosphates are water-soluble and have a rapid but relatively short-term effect. They can be administered intramuscularly and intravenously. Acetates and acetonides are finely crystalline suspensions, they are insoluble in water and are absorbed slowly, over several hours. Water-insoluble esters are intended for administration into the joint cavity and joint bags. Their effect reaches its maximum after 4-8 days and lasts up to 4 weeks.

In the blood, glucocorticoids form complexes with plasma proteins - albumins and transcortin. If natural glucocorticoids bind to transcortin by 90%, and to albumins - by 10%, then synthetic glucocorticoids, with the exception of prednisolone, bind mainly to albumin (about 60%), and about 40% circulate in a free form. Free glucocorticoids are deposited by erythrocytes and leukocytes by 25-35%.

Only non-protein-bound glucocorticoids are biologically active. They easily pass through mucous membranes and histohematic barriers, including the blood-brain and placental barriers, and are quickly eliminated from plasma.

Glucocorticoid metabolism occurs primarily in the liver, partly in the kidneys and other tissues. In the liver, glucocorticoids are hydroxylated and conjugated with glucuronide or sulfate. Natural steroids cortisone and prednisone acquire pharmacological activity only after metabolization in the liver to form hydrocortisone and prednisolone, respectively.

Metabolism of synthetic GCS in the liver by reduction and conjugation occurs more slowly compared to natural steroids. Introduction of halogen ions of fluorine or chlorine into the structure of GCS slows down the metabolism of drugs and extends their T1/2. Due to this, the effect of fluorinated GCS lasts longer, but at the same time they suppress the function of the adrenal cortex more.

Glucocorticoids are excreted from the body by the kidneys through glomerular filtration in the form of inactive metabolites. Most of the GCS (85%) is reabsorbed in the tubules, and only about 15% is excreted from the body. In case of renal failure, the dose is not adjusted.

Contraindications

Relative contraindications are conditions that are part of the spectrum of side effects of GCS therapy itself. There are no absolute contraindications if the expected benefit from glucocorticoid treatment outweighs the increased risk of complications. This applies primarily to emergency situations and short-term use of glucocorticoids. Relative contraindications are taken into account only when planning long-term therapy. They include:

• decompensated diabetes mellitus;
• productive symptoms in mental illnesses; and gastric ulcer and duodenal ulcer in the acute phase; o severe osteoporosis;
• severe arterial hypertension; and severe heart failure;
• active form of tuberculosis, syphilis; and systemic mycoses and fungal skin lesions;
• acute viral infections;
• severe bacterial diseases; and primary glaucoma;
• pregnancy.

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Tolerability and side effects

In general, glucocorticoids are well tolerated. The likelihood of side effects depends largely on the duration of treatment and the prescribed dose. They are more likely with long-term (more than 2 weeks) administration of glucocorticoids, especially in high doses. However, even very high doses of GCS when prescribed for 1-5 days do not cause the development of undesirable effects. This is due to the fact that a significant part of the side effects of glucocorticoids is a consequence of metabolic disorders and requires more time to develop. Substitution therapy is also considered safe, since very low doses of glucocorticoids are used for treatment, which do not suppress the function of the adrenal glands and the development of other undesirable effects associated with excess exogenous glucocorticoids.

Abrupt discontinuation of short-term (7-10 days) glucocorticoid therapy is not accompanied by the development of acute adrenal insufficiency, although some suppression of cortisone synthesis still occurs. Longer glucocorticoid therapy (over 10-14 days) requires gradual withdrawal of the drug.

According to the timing and frequency of development, side effects of glucocorticoids can be divided into:

• characteristic of the initial stages of treatment and essentially inevitable:
  • insomnia;
  • emotional lability;
  • increased appetite and/or weight gain;
• late and developing gradually (probably due to cumulation):
  • osteoporosis;
  • cataract;
  • growth retardation;
  • fatty liver disease;
• rare and unpredictable:
  • psychosis;
  • benign intracranial hypertension;
  • glaucoma;
  • epidural lipomatosis;
  • pancreatitis.
  • According to the development conditions, the following can be distinguished:
• typical in patients with risk factors or toxic effects of other drugs:
  • arterial hypertension;
  • hyperglycemia (up to the development of diabetes mellitus);
  • ulceration in the stomach and duodenum;
  • acne;
• expected with high doses and developing over a long period of time:
  • "Cushingoid" appearance;
  • suppression of the hypothalamic-pituitary-adrenal axis;
  • susceptibility to infectious diseases;
  • osteonecrosis;
  • myopathy;
  • poor wound healing.

When taken daily for a long time, synthetic glucocorticoid analogues with a long T1/2 cause side effects more often than drugs with a short or medium T1/2. Abrupt discontinuation of treatment after long-term therapy may lead to acute adrenal insufficiency due to suppression of the ability of the adrenal cortex to synthesize corticosteroids. Complete restoration of adrenal function may require from 2 months to 1.5 years.

There are isolated reports in the literature on the possibility of developing allergic reactions to the administration of glucocorticoids. These reactions may be caused by components of the dosage forms of steroid drugs or possible interactions with other pharmacological drugs.

Interaction

Glucocorticoids can interact with many drugs. In the vast majority of cases, these interactions are clinically significant only during long-term glucocorticoid therapy.

Cautions

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

Glucocorticoids penetrate the placenta well. Natural and non-fluorinated preparations are generally safe for the fetus and do not lead to the intrauterine development of Cushing's syndrome and suppression of the HPA axis.

Fluorinated glucocorticoids may cause adverse reactions, including deformities, when taken over a long period of time. A woman in labor who has taken glucocorticoids for the past 1.5-2 years should additionally receive hydrocortisone hemisuccinate 100 mg every 6 hours to prevent acute adrenal insufficiency.

When breastfeeding, low doses of glucocorticoids equivalent to 5 mg of prednisolone are not dangerous for the child, since glucocorticoids poorly penetrate into breast milk. Higher doses of drugs and their long-term use can cause growth retardation and HPA axis suppression.

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