Glucocorticoids: myths and truth

Some are afraid of them, others cannot imagine life without them. All this is about glucocorticosteroids. Glucocorticosteroids (GCS) are steroid hormones that are produced in the adrenal cortex.

The production and level of these hormones is controlled by a system that includes brain structures: the hypothalamus, pituitary gland and the adrenal glands themselves. The main one is the hypothalamus, it is sensitive to the amount of hydrocortisone in the blood plasma and stress. If the level of hydrocortisone in the blood is low or stress occurs (stress, injury, infection), the hypothalamus produces a special substance that activates the pituitary gland. The pituitary gland, in turn, releases adrenocorticotropic hormone into the blood. It already acts on the adrenal glands and stimulates them to produce glucocorticosteroid hormones. When the level of these substances in the blood rises to the desired concentration, the hypothalamus stops stimulating this chain. Also, the work of the pituitary gland and adrenal glands can be stimulated by pro-inflammatory cytokines. The presence of a large number of GCS inhibits their production. This is how, in a simplified form, the interaction and regulation of the synthesis of glucocorticosteroids in the body occurs. The adrenal glands actively produce hormones in the morning from 6-8 hours, and in the evening and at night their activity is minimal.

At the cellular level, glucocorticosteroids enter the cell and increase the rate of production of proteins with anti-inflammatory effects. The effect does not appear immediately, but after several hours, since the synthesis of these substances takes time.

Action in the body

Anti-inflammatory

Hormones of the adrenal cortex have an anti-inflammatory effect, as they influence many parts of this process. They inhibit the synthesis of substances that contribute to the development of the inflammatory reaction and, on the contrary, stimulate the formation of anti-inflammatory elements. Reduce capillary permeability, which reduces the formation of edema. Reduces the formation of scar tissue in the area of ​​inflammation. Reduce the severity of immediate allergic reactions.

The effect of GCS is so broad that it can be used for any type of inflammation. For example, for allergies, injuries, infections. Yes, this will not remove the cause of the problem, but it can curb the symptoms, which are sometimes destructive to the body.

Immune suppression

It is impossible to clearly define the line when the anti-inflammatory effect turns into immune suppression. Interference with immune mechanisms leads to dysregulated immunity. Some processes are inhibited, others are completely blocked. It proves useful in autoimmune diseases, organ and tissue transplantation.

Metabolism

Glucocorticosteroids can accelerate and slow down the formation of enzymes that play a role in metabolism.

Carbohydrate metabolism. Promotes the deposition of glycogen in the liver. Tissues become less sensitive to glucose, causing blood sugar levels to rise. The action of insulin is inhibited.

Protein metabolism. They increase protein breakdown and reduce its production. It predominates in the skin, bones, and muscles. This can manifest itself as weight loss, muscle weakness, thinning of the skin, stretch marks, and hemorrhages. A decrease in protein synthesis becomes one of the reasons for the slowdown in regenerative processes. Children's growth slows down.

Lipid metabolism . There is a redistribution of fat deposits. The amount of fat on the arms and legs decreases, but on the body (back, shoulders) and face, on the contrary, it accumulates. The blood lipid profile may be disrupted and hypercholesterolemia may occur.

Water-salt exchange. In the kidneys, the retention of sodium ions causes a gradual increase in circulating blood volume and an increase in blood pressure. Potassium deficiency occurs.

In the kidneys, the retention of sodium ions causes a gradual increase in circulating blood volume and an increase in blood pressure.

Calcium. GCS reduce the absorption of calcium from the gastrointestinal tract and increase its excretion by the kidneys, which can cause hypocalcemia and hypercalciuria. With long-term administration of GCS, disturbances in calcium metabolism, together with the breakdown of the protein component in bone tissue, lead to the development of osteoporosis.

Blood

The use of GCS reduces the number of eosinophils, monocytes and lymphocytes in the blood. The content of red blood cells, reticulocytes, neutrophils and platelets increases. Even a single injection works this way, with the effect achieved after 4-6 hours. Restoration of the original state occurs after 24 hours. With prolonged use, changes in the blood can remain for up to 1-4 weeks.

Suppression of the hypothalamic-pituitary-adrenal system

Since taking GCS inhibits the production of its own hormones, insufficiency of adrenal cortex function may develop. And it will manifest itself when the drug is abruptly discontinued. The risk arises after 2 weeks of use.

Anti-stress effect

When talking about stress, we mean damage to the body (trauma, infection) that can upset its balance. GCS increase the body's resistance to stress. Under severe stress, cortisol levels can increase more than 10-fold. This is necessary so that the excessive inflammatory reaction does not lead to fatal consequences and is under control. The cytokines themselves, which are produced during inflammation, stimulate the production of hormones by the adrenal glands, which limit the degree of inflammation. So many interconnected regulatory pathways help the body maintain balance and survive in difficult conditions.

Effect on other hormones

Glucocorticosteroids can affect the body by enhancing the effects of other hormones. Thus, the effect of small doses of GCS promotes the breakdown of fat and has a tonic effect on the cardiovascular system. As a result, vascular tone is normalized, myocardial contractility increases and capillary permeability decreases. On the contrary, a lack of natural corticosteroids is characterized by low cardiac output, dilation of arterioles and a weak response to adrenaline.

APPLICATION IN DERMATOLOGY

Glucocorticoids are used externally in the form of ointments, creams, gels, and lotions for a number of skin diseases. They have a local anti-inflammatory, anti-allergic effect, eliminate swelling, hyperemia, and itching. When using glucocorticoids externally, it is very important, depending on the location and nature of the lesion, to choose the optimal dosage form, each of which has some features (Table 13).

Table 13.

Features of the action of dosage forms for external use.

Classification

Glucocorticoid preparations for external use are traditionally divided into several groups, depending on the strength of the local anti-inflammatory effect. Moreover, there are some, not of fundamental importance, differences between the classifications considered in different literary sources. According to the above classification (Table 14), drugs are divided into 4 groups.

Table 14.

Classification of glucocorticoids for external use.

The most powerful effect is exerted by fluorinated glucocorticoids (“very strong” and “strong” drugs), which are poorly absorbed from the surface of the skin and have a predominantly local effect. Their disadvantage is the more frequent development of local adverse reactions compared to other drugs (see below).

Drugs belonging to groups III and IV (prednisolone, hydrocortisone acetate and others) are characterized by a greater ability to be absorbed from the area of ​​application, therefore their local effect is weaker, and the likelihood of developing systemic adverse reactions is higher.

The strength of the drug also depends on the type of dosage form (ointment > cream > lotion) and concentration.

One of the modern principles of systematization of glucocorticoid drugs for external use is their division into four generations, differing in their characteristics of action. To the first generation

includes hydrocortisone acetate, which has the mildest effect.
The second
is prednisolone, which has a moderate effect.

Third generation

is represented by a wide range of fluorinated glucocorticoids, which have a “strong” or “very strong” local effect.
The fourth group
includes “strong” glucocorticoids that do not contain a fluorine atom in their structure - hydrocortisone-17-butyrate, mometasone furoate, as well as a drug of moderate activity - prednicarbate.

The fourth generation drugs created in recent years are considered the most preferable, since they successfully combine the positive properties of their predecessors: they have high activity comparable to the potency of fluorinated glucocorticoids, and minimal undesirable local effects characteristic of hydrocortisone acetate.

Mometasone furoate ( elokom

- cream, ointment, lotion) refers to fourth generation glucocorticoids. It is superior to hydrocortisone, dexamethasone and betamethasone in its ability to block the formation of cytokines (interleukin-1 and interleukin-6), which play an important role in skin inflammation, in particular in psoriasis. Controlled clinical studies have shown higher efficacy of mometasone in psoriasis and atopic dermatitis compared to hydrocortisone and betamethasone. The drug is well tolerated and does not cause skin atrophy. Mometasone has a prolonged effect, so it is applied once a day. Thanks to its improved tolerability, it is suitable for use in children and the elderly.

Hydrocortisone 17-butyrate ( laticort, locoid

), unlike hydrocortisone acetate, is poorly absorbed from the area of ​​application, so the likelihood of systemic action is extremely low. At the same time, like fluorinated glucocorticoids, it has a powerful local effect, but, unlike the latter, it rarely causes local adverse reactions and may have wider use.

Prednicarbate ( dermatope

) is a glucocorticoid with a moderate degree of activity and is characterized by a mild, gentle local effect. It practically does not cause systemic adverse reactions. Local effects are very rare. Can be used on large surfaces and applied to areas of the skin with the most increased sensitivity (face, groin area). Controlled clinical studies have shown high efficacy and good tolerability of prednicarbate in children from 2 months to 16 years and the elderly, therefore the drug is recommended primarily for use in these age groups.

Indications

Psoriasis, eczema, neurodermatitis, contact dermatitis, solar dermatitis, seborrheic dermatitis, atonic dermatitis, lichen planus, discoid lupus erythematosus, erythroderma.

Rules of application

1. Before using glucocorticoid drugs, it is necessary to establish an accurate diagnosis.
2. It is recommended to start treatment with the use of a drug with weak activity (Table 14), if there is no effect within 2-3 weeks, switch to a stronger one, and after achieving the effect, use a weak glucocorticoid again.
3. Drugs with very strong activity (clobetasol propionate, chalcinonide) should be used only for lichenoid eczema and discoid lupus erythematosus.
4. The drug is applied to clean skin (after a bath or shower) 2 times a day, in a thin layer, do not rub or massage. It is recommended to carry out the procedure with gloves. Mometasone furoate and fluticasone propionate, which have a prolonged effect, are applied once a day, which is convenient for diseases that require long-term use of glucocorticoids (eczema, psoriasis).
5. After applying the drug to enhance the therapeutic effect (usually for psoriasis), you can use occlusive dressings for a short time, no more than 2 days.
6. The process of releasing the active substance from an ointment is usually slower than from a cream, so for chronic processes it is preferable to use an ointment.
7. When the lesion is localized on the scalp, it is recommended to use a gel or lotion.
8. If an infection is suspected, combined topical glucocorticoids containing antimicrobial components should be used (see below).

Adverse reactions

1. From the skin:

• atrophy (more often on the face - “corticosteroid face”, therefore, if possible, strong ointments should not be used on the face, with the exception of hydrocortisone 17-butyrate); striae; depigmentation; skin irritation; telangiectasia;
• acne;
• Tinea incognito
  is an atypical clinical picture of dermatomycosis when using glucocorticoids (both locally and systemically);
• perioral dermatitis (more often in young women; tetracycline can be used for treatment for 4-6 weeks);
• hirsutism or frontal alopecia in women.

• Accession or dissemination of infection.
• Systemic action
  (with long-term use, application to large areas of the body, more often in children and when using occlusive dressings).
• Withdrawal syndrome
  (usually requires resumption of the use of local glucocorticoids).

Contraindications

• Acne, including acne rosacea
  .
• Perioral dermatitis.
• Scabies.
• Tuberculosis.
• Syphilis.
• Viral and helminthic skin lesions.
• Bacterial and fungal skin infections that have not previously been treated with other drugs.
• Skin reactions after vaccination.
• During pregnancy, it is not recommended to use for a long time and on large areas of the body.

Features of use in children

In children, with local use of glucocorticoids, there is a higher susceptibility to their systemic action

than in adults (including suppression of the function of the hypothalamic-pituitary-adrenal system, the development of Cushing's syndrome, growth and development delay), since the ratio of surface area to body weight in children is greater.

Therefore, glucocorticoid preparations should be used in limited areas, especially in newborns, if possible, for a short course. In children under 1 year of age, only ointments with hydrocortisone (no more than 1%) or the fourth generation glucocorticoid prednicarbate should be used; for children under 5 years of age, ointments of medium strength and hydrocortisone 17-butyrate should be used.

Combination drugs

Combination ointments and creams are produced, which, along with glucocorticoids, include other components (Table 15). They may include antibiotics (neomycin and others), drugs that combine antifungal and antibacterial activity (miconazole, triclosan and others), antifungal and antitrichomoniacal action (natamycin), antiseptics, salicylic acid, local anesthetics, vitamin-like compounds, antihistamines.

Some features of the composition of the drug may be indicated by the presence of an additional letter in its trade name. For example, flucinar N

includes the antibiotic neomycin,
sinalar K
- the antifungal agent clioquinol,
lorinden A
- salicylic acid.
In other cases, combination drugs have special trade names (localen, triderm)
.

Preparations containing antimicrobial components are recommended for use in case of a bacterial or fungal infection, suspicion of it and a high probability of its development (weeping processes, intertriginous lesions, anogenital and senile itching). It should be borne in mind that neomycin, when applied externally, can be absorbed and have oto- and nephrotoxic effects, therefore dosage forms containing it should not be used for a long time and on large surfaces.

Salicylic acid has a kerato- and squamolytic effect, promotes the penetration of glucocorticoids through excessively keratinized epidermis, restores the protective cover of the skin, and has a weak antiseptic effect. Therefore, drugs that contain it are advisable to use for diseases accompanied by increased keratinization of the epidermis, desquamation, hyperkeratosis, callus, for example, with lichenoid eczema, chronic cases of psoriasis, ichthyosis and others.

Table 15.

Combined preparations of glucocorticoids for external use.

APPLICATION IN OPHTHALMOLOGY AND ENTRYNOLARYNGOLOGY

The use of glucocorticoids in ophthalmology is based on their local anti-inflammatory, antiallergic, and antipruritic effects. They prevent the expansion of capillaries, reduce their permeability, inhibit the migration of leukocytes, the release of kinins, reduce the deposition of fibrin, collagen, and the formation of scar tissue. When used, pain, burning, lacrimation and photophobia are reduced.

Indications

are various inflammatory diseases of eye tissue of non-infectious etiology, including after injuries and operations (iritis, iridocyclitis, scleritis, keratitis, uveitis, severe forms of conjunctivitis and others).

The most preferred are special preparations of glucocorticoids for topical use - solutions, suspensions, ointments (Table 16). They have a more pronounced local anti-inflammatory effect than glucocorticoids used orally or parenterally in such situations. The most effective “ophthalmic” drugs are fluorometholone and prednisolone acetate.

In particularly severe cases, glucocorticoids can be administered subconjunctivally. For this, dexamethasone and betamethasone phosphate are used, and injections of the second are less painful. There is evidence of the possibility of subconjunctival administration of betamethasone phosphate/dipropionate (diprospan)

.

Glucocorticoids are contraindicated

for acute infectious eye diseases. If necessary, combination drugs containing antibiotics are used.

Table 16.

Glucocorticoids for local use in ophthalmology. Applied Therapeutics, 1995 [8]

Adverse reactions

Despite the fact that glucocorticoids, when applied topically, in contrast to systemic administration, do not enhance, but rather inhibit the formation of chamber humor, they can also cause an increase in intraocular pressure (dexamethasone to the greatest extent, fluorometholone to the least) and lead to the development of glaucoma . Exophthalmos may be present. Sometimes a serious complication is posterior subcapsular cataract. In diseases accompanied by thinning of the cornea, perforation is possible.

Combination drugs

In ophthalmological and otorhinolaryngological practice, a number of combination drugs are used, which, in addition to glucocorticoids, include antibiotics (Table 17). They combine anti-inflammatory and bactericidal effects, and more preferable are drugs that include the glucocorticoid betamethasone, which has less effect on intraocular pressure (Garazon)

.

In ophthalmology

These drugs are used for inflammatory and allergic eye diseases, if a bacterial infection is present or suspected (staphylococcal blepharoconjunctivitis, fluctenular and microbial-allergic keratoconjunctivitis, keratitis, episcleritis, dacryocystitis, iridocyclitis, eye injuries and others).

In otorhinolaryngology

indications for the use of combined drugs are acute and chronic external otitis; eczema of the external auditory canal; seborrheic dermatitis; contact dermatitis complicated by secondary infection; allergic and vasomotor rhinitis, complicated by secondary infection.

Precautionary measures.

It is not recommended to use the same bottle of the drug to treat otitis, rhinitis and eye diseases to avoid the spread of infection.
It is not advisable to use these drugs for the treatment of otitis media, which requires systemic (oral, parenteral) use of antibiotics. The drug maxitrol
, containing two ototoxic antibiotics (neomycin and polymyxin B), can only be used in short courses.

Table 17.

Combined preparations of glucocorticoids for use in ophthalmology and otorhinolaryngology.

Types of drugs

This group of hormones can be divided into groups according to the rate of excretion from the body:

• from 8 to 12 hours, short-acting: hydrocortisone, cortisone;
• from 18 to 36 hours, average duration: prednisolone, methylprednisolone, triamcinolone;
• from 36 to 54 hours, long-acting: dexamethasone, betamethasone.

Hormones also differ in the severity of glucocorticoid and mineralcorticoid properties and in the strength of their effect on the hypothalamic-pituitary-adrenal regulatory system.

Systemic glucocorticosteroids

Glucocorticosteroids (“steroids” or “hormones”) are among the most powerful drugs used to treat inflammatory bowel disease. In case of severe exacerbations of ulcerative colitis and Crohn's disease, it is often impossible to do without their use. However, like most other IBD medications, steroids can cause numerous and quite serious side effects. The use of steroids in the treatment of IBD is always a temporary and necessary measure. Current guidelines unanimously recommend against using hormones frequently or for too long.

What are steroids?

Glucocorticosteroids are secreted daily in the body by the adrenal glands. For example, the hormone cortisol (also known as hydrocortisone) is released into the blood upon awakening and during stress and stimulates the functioning of the cardiovascular system: it increases heart rate and increases blood pressure. It has long been noted that adrenal hormones also have the ability to reduce immunity. Hydrocortisone (i.e., “natural” cortisol) was one of the first steroids used to treat ulcerative colitis and Crohn’s disease. Since their discovery, chemically modified steroids have also been synthesized.

How do they work?

Glucocorticosteroids penetrate the cell, bind to special receptors (transporter proteins) and enter the cell nucleus. There, the steroid blocks the reading of information from DNA in the area in which information about molecules that cause inflammation is “encoded.” As a result, the cell stops secreting interleukins, tumor necrosis factor, leukotrienes, that is, substances (“cytokines”) that cause inflammation - migration of immune cells into the intestine, vasodilation and damage to inflamed tissue. Thanks to this anti-inflammatory effect, glucocorticosteroids are successfully used to treat all kinds of inflammatory reactions: joint diseases (for example, rheumatoid arthritis), allergic phenomena (for example, severe allergies - anaphylaxis), as well as to quickly eliminate inflammation in the intestine.

Why are glucocorticosteroids dangerous?

Any glucocorticosteroid, in addition to the anti-inflammatory effect we need, also has side effects to one degree or another. This:

• fluid retention in the body, which can lead to tissue swelling
• redistribution of fat from the arms and legs to the body: with long-term use of steroids, a person develops a “moon-shaped” appearance (the face becomes puffy)
• poor tissue healing: for this reason, operations that have to be done while taking steroids are more often accompanied by complications
• increased levels of glucose (sugar) in the blood: this is often something to remember in older patients
• decreased bone density (osteoporosis): this can lead to pathological (non-traumatic) bone fractures
• increased blood pressure
• an increase in the risk of blood clots (blood clots), however, inflammatory bowel diseases themselves during an exacerbation increase this risk
• stomach damage: hormones reduce the production of mucus in the stomach, which protects the stomach wall from its own acid
• clouding of the lens (cataract) and increased intraocular pressure (glaucoma)
• mental and neurological disorders: from anxiety and insomnia to psychosis

We also have to remember about the possible suppression of the function of our own adrenal glands. The body, “seeing” that there is a substance in the blood that resembles its own hormone cortisol, stops stimulating the adrenal glands. With long-term use, adrenal insufficiency leads to a decrease in blood pressure, temperature fluctuations and fainting. For the same reason, steroids are never stopped abruptly: the dose of the drug is reduced gradually.

How long can you take glucocorticosteroids?

International guidelines recommend prescribing systemic steroids for no more than 12 weeks. Taking hormones for more than 3 months, a person runs the risk of experiencing many more side effects than with a short course of treatment. But the most important thing: although hormones almost always help initially, after a while their effect decreases .

If a person with IBD experiences a new exacerbation as the dose of steroids is reduced or soon after they are stopped, doctors talk about hormonal dependence. Usually, in such a situation, they try to make sure that the resumption of symptoms is associated precisely with inflammation of the intestine, and not with some superimposed problems, for example, with a Clostridium difficile infection. If endoscopic examination, stool testing for calprotectin, or other methods clearly indicate the return of IBD, medications are prescribed to overcome steroid dependence.

How to reduce the harm from steroids

The main rule when prescribing hormones is to prescribe them as rarely as possible. Partly for this purpose - to prevent new exacerbations and new courses of hormonal therapy - almost any person with IBD is prescribed lifelong maintenance treatment with non-hormonal drugs. If steroids still had to be prescribed due to the severity of the exacerbation, you can follow simple rules to promptly identify or prevent side effects. Only a doctor can give exact recommendations on the dose of hormones and measures to prevent side effects.

Application

Glucocorticosteroids are used by doctors only if necessary.

These drugs are used in anesthesiology and resuscitation practice. Intravenous administration of corticosteroids during anesthesia maintains hemodynamic parameters. In severe circulatory disorders, drugs help increase tissue perfusion and venous outflow, normalize peripheral resistance and cardiac output, and stabilize cellular and lysosomal membranes.

In severe allergic reactions, intravenous administration of adequate doses of GCS has a therapeutic effect, but the onset of action of GCS is delayed. Thus, the main effects of hydrocortisone develop only 2-8 hours after its administration.

Glucocorticosteroids have a pronounced effect in adrenal insufficiency that develops before and during surgery. Hydrocortisone, cortisone and prednisolone are used for replacement therapy.

The administration of long-acting corticosteroids is practiced to prevent respiratory distress syndrome in premature infants, which reduces the risk of complications and death by 40-50%.

Forms of drugs

Various forms of hormonal drugs are available. This is done not only for ease of use, but also allows you to get the desired effect. Tablet forms are used to treat systemic diseases and allergies.

Inhalation forms are used in the treatment of diseases of the respiratory system (Symbicort, Pulmicort, Seretide). Because their use is usually long-term, they are formulated to have minimal systemic effects.

For the treatment of autoimmune inflammatory diseases of the joints, drugs are produced for intra-articular administration (Diprospan, Kenolog). They are released slowly and the effect of 1 injection on a joint can be quite long.

Ointments (Sinaflan), gels are used in dermatology to treat skin diseases and allergies.

Undesirable effects

Undesirable effects are related to the duration of treatment and dose. More often with prolonged use of more than 2 weeks and high doses. However, high doses of hormones for 1-5 days usually do not cause the development of adverse events. Replacement therapy is considered safe, since very low doses of GCS are used.

Undesirable effects:

1. At the initial stages of admission:

• poor sleep;
• emotional excitability;
• excess appetite, weight gain.

2. When taking GCS and other drugs or diseases in combination:

• hypertonic disease;
• increased sugar levels and risk of diabetes;
• ulcers of the digestive system;
• acne.

3. Possible when used for a long time with large doses:

• Cushingoid;
• suppression of the adrenal glands;
• weakening of protection against infectious diseases;
• osteonecrosis;
• myopathy;
• poor healing from injuries.

4. Late and gradually developing (associated with accumulation):

• osteoporosis;
• cataract;
• atherosclerosis;
• growth retardation in children;
• fatty liver degeneration.

Abrupt cessation of short-term (within 7-10 days) GCS therapy is not accompanied by the development of acute adrenal insufficiency, although some suppression of cortisol synthesis still occurs. Longer therapy with GCS (longer than 10-14 days) requires gradual withdrawal of drugs.

Taking synthetic drugs with a long duration of action causes undesirable effects. Abruptly stopping hormones can lead to acute adrenal insufficiency. Restoring adrenal function can take from several months to a year and a half.

Contraindications

Glucocorticosteroids should not be used without a doctor's recommendation.

There are no absolute contraindications if the benefit is greater than the risk. Especially in emergency situations and short-term use. For long-term treatment, relative contraindications may be:

• decompensated diabetes mellitus;
• symptoms of mental illness;
• exacerbation of peptic ulcer of the stomach and duodenum;
• severe osteoporosis;
• severe hypertension;
• severe heart failure;
• active form of tuberculosis;
• systemic mycoses and fungal skin infections;
• acute viral infections;
• severe bacterial diseases;
• primary glaucoma;
• pregnancy.

Today we cannot do without glucocorticosteroids in medicine. Since their effects are very diverse, the doctor must choose the drug that is suitable specifically for your case.

GLUCOCORTICOID DRUGS

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