Modern possibilities of topical corticosteroids

Author: Lyudmila Bolotnaya, MD, Professor of the Department of Dermatovenerology, Kharkov Medical Academy of Postgraduate Education (Kharkov)

One of the main components of the complex treatment of dermatoses has been and remains external therapy with its unique ability to directly influence the lesion. Since 1952, when Sulzberger M. and Witten V. first reported the successful experience of topical treatment of dermatosis with hydrocortisone acetate, glucocorticosteroids (GCS) have firmly taken their place in the arsenal of the most effective drugs for the treatment of inflammatory skin diseases of non-infectious nature - the so-called steroid-sensitive dermatoses (allergic contact dermatitis, atopic dermatitis, psoriasis, eczema, alopecia areata, etc.).

Over more than half a century of their use in clinical practice, topical corticosteroids have experienced ups and downs, but time has confirmed their safety when used correctly. Today, a dermatologist has several dozen topical glucocorticosteroids (more than 50) that have anti-inflammatory, antiallergic, vasoconstrictive and antiproliferative effects.

Market competition among pharmaceutical companies, which has intensified significantly in recent years in Ukraine, is causing the emergence of many generic drugs with different trade names, which can differ significantly from similar branded ones both in the strength of their anti-inflammatory effect and in the preservatives included in their composition. In these conditions, the choice of a corticosteroid drug sometimes becomes a difficult task for a dermatologist, so the doctor must have knowledge about the potential activity of GCS, their chemical structure, frequency of use , the presence of dosage forms and possible side effects. The solution to this problem can largely be facilitated by the use of a rational classification of topical corticosteroids, taking into account the strength of the local anti-inflammatory effect.

Classification of glucocorticosteroids

The standard test for the severity of anti-inflammatory activity is the vasoconstrictor effect of the drug, which directly correlates with its clinical effectiveness. According to the European classification, topical corticosteroids can be divided into 4 classes based on anti-inflammatory activity:

• weak (class I);
• medium (class II);
• strong (class III);
• very strong (class IV).

Various GCS substances are classified into four main classes conditionally, since the concentration of the active substance in the dosage form allows the same GCS to be classified into several classes.

Hydrocortisone acetate preparations, which belong to class I (see Table 1) and have the mildest effect, are currently almost never used in dermatological practice.

Table 1. Classification of glucocorticosteroids for external use by degree of activity

Much more often, topical drugs of the second generation are used (betamethasone valerate 0.025%, flucortolone, etc.), which have an average effect.

The third generation is represented by a significant number of topical corticosteroids, mainly halogenated (triamcinolone acetonide 0.1%, flucortolone acetonide 0.025%, fluocinonide 0.05%, betamethasone valerate 0.1%, etc.). The drugs have a moderate or strong anti-inflammatory effect, quickly relieve severe acute inflammatory phenomena, and are used in the treatment of chronic inflammatory skin diseases.

Class IV GCS drugs (clobetasol propionate, diflucortolone valerate) have very strong therapeutic activity and can be comparable in potency to systemic GCS. They should be used in the treatment of infiltrated foci of chronic dermatoses in limited areas of the skin, hypertrophic and keloid scars.

Quite often, practicing doctors, ignoring some features of the mechanism of action of fluorinated steroids, prescribe drugs of class III (Ftorokort, Sinaflan, Flucinar, Celestoderm), less often class IV (Dermovate, Delor), leading to the development of local side effects (skin atrophy, telangiectasia, perioral dermatitis , steroid acne, hypertrichosis, activation of viral, fungal or bacterial infection, slowdown of reparative processes, etc.). Fluorinated corticosteroids are not recommended for use for more than two weeks, applied to the skin of the face and folds for a long time in its pure form (without antiseptics), since fluoride preparations stimulate the activity and reproduction of Demodex folliculorum and the occurrence of perioral dermatitis.

The emergence in recent years of effective and safe non-halogenated corticosteroids for external use has significantly expanded the possibilities of rehabilitation of patients and changed the prognosis for many skin diseases. Natural corticosteroids and synthetic non-fluorinated analogues (for example, hydrocortisone 17-butyrate, mometasone furoate, methylprednisolone aceponate, prednicarbate) are considered the most preferable for use, since they successfully combine the positive properties of their predecessors: they have high activity, comparable to the potency of fluorinated corticosteroids, and minimal undesirable effect (balanced effect on gene expression and does not cause death of hypothalamic or thymic cells sensitive to them). Among the advantages of these corticosteroids are high lipophilicity and rapid penetration through the epidermis.

The spectrum of biological activity and the effectiveness of topical corticosteroids largely determine several of the most important processes, which include:

• receptor mechanisms of the influence of steroids on the protein synthetic apparatus of complementary cells;
• metabolism of steroids in the skin and other organs;
• transdermal penetration and interaction of steroids with transport proteins.

Anti-inflammatory effect

The anti-inflammatory effect of topical corticosteroids in the skin is achieved through various pathways, but the mechanism mediated by cytosolic glucocorticoid receptors is of greatest importance. The essence of the mechanism is that the hormone-receptor complex, penetrating into the nucleus of the target skin cell, increases the expression of genes encoding the synthesis of lipocortins, which inhibit the activity of lysosomal phospholipase A2. This leads to a decrease in the release of arachidonic acid from membrane phospholipids and the formation of inflammatory mediators from it - prostaglandins and leukotrienes. GCS suppress the synthesis of several cytokines, including interleukins 1, 2, 6, 10, and tumor necrosis factor α in various cell types by interacting with the nuclear receptor for GCS, which causes repression of cytokine gene transcription.

Another important mechanism of the pro-inflammatory effect of steroids is a decrease in the stability of mRNA cytokines and an increase in susceptibility to apoptosis. Topical corticosteroids have a pronounced antiallergic effect by inhibiting the migration of lymphocytes, granulocytes, Langerhans cells and inhibiting their function in areas of inflammation by suppressing the expression of adhesion molecules. The cessation of the synthesis of inflammatory mediators quickly leads to the restoration of impaired permeability of the vascular walls, their narrowing, and a decrease in exudation.

GCS increase the binding of histamine and serotonin in the skin, reduce the sensitivity of nerve endings to neuropeptides and biogenic amines. It is obvious that topical corticosteroids affect the early and late phases of the allergic reaction and have a powerful anti-inflammatory and membrane-stabilizing effect, thereby providing a therapeutic effect in the form of rapid relief of itching, reducing swelling, erythema, and infiltration.

On the other hand, GCS inhibit the synthesis of glycosaminoglycans, collagen and elastin, reduce the number of intraepidermal macrophages (Langerhans cells) in the epidermis, and mast cells in the dermis; if used irrationally, they contribute to the suppression of the function of the hypothalamus-pituitary-adrenal system, the development of Cushing's syndrome, and suppression of immune reactions. , that is, they can have adverse side effects both systemically and locally. Negative aspects are predictable and well controlled; the therapeutic effect of topical steroids, when properly selected and used, significantly exceeds the likely side effects.

The rate of penetration of GCS into the dermis

The effectiveness of GCS depends on its penetration into the skin, which occurs in three main ways: through the stratum corneum of the epidermis, hair follicles, and sebaceous and sweat glands. Transepidermal penetration is the main route of penetration of topical corticosteroids, which depends on the site of application of the drug, the age of the patient, the properties of the active components, the basis of the drug, the method of application, and the stage of the disease.

Place of application of the drug: the structure of the skin in different parts of the body differs significantly, and its permeability is correspondingly different. High sensitivity to GCS is typical for the groin and scrotum area, folds and other large folds. The facial area is also quite sensitive to the influence of topical corticosteroids, which is due to the insignificant thickness of the stratum corneum in this anatomical zone. The skin of the extremities, on the contrary, is less permeable. Therefore, for some diseases (palmoplantar psoriasis, verrucous lichen planus, nodular prurigo, etc.), only ointments of classes III and IV are effective.

Age of patients: topical corticosteroids have demonstrated high effectiveness in the external treatment of most inflammatory dermatoses of childhood - with the correct choice of drug, its rational use and an individual approach to the patient.

Active auxiliary components of drugs: glucocorticosteroids do not have antimicrobial, antimycotic and antiparasitic effects, therefore it is advisable to expand and enhance the therapeutic effect of external GCS by including in their composition auxiliary drugs that have antibacterial, fungicidal and keratolytic effects. For diseases with pronounced hyperkeratotic manifestations (some forms of psoriasis, chronic eczema, lichen planus), topical corticosteroids are successfully used in combination with keratolytics (salicylic acid, urea) in a certain concentration (Prednicarb, Diprosalic, Elokom S). For inflammatory dermatoses complicated by bacterial or fungal infection (atopic dermatitis, seborrheic dermatitis), combined drugs containing corticosteroids and an antibacterial and/or antimycotic component (Imacort, Pimafucort, Triderm, etc.) should be used in step-by-step treatment.

Basis of the drug: the rate of penetration of the drug depends on both the lipophilicity of the compound and the dosage form (ointment, cream, lotion). The more lipophilic the corticosteroid, the greater the concentration it accumulates in skin cells and the slower it enters the blood. The total resorption of corticosteroids through the skin in most anatomical regions ranges from 3–10%. If the resorption of steroids from the skin of the forearm is taken as 1, then this indicator in the eyelid area is 42, cheeks – 13, scalp – 3.5, palms – 0.83. The greatest degree of penetration of steroids is provided by an ointment base, the least by lotions and aerosols, and the average by creams and gels.

Stage of the disease: the choice of topical glucocorticosteroid depends on the stage and severity of the process, localization of lesions. For acute inflammation, aerosols or creams are recommended; for subacute and chronic inflammation, creams or ointments are recommended. Localization of the process on the scalp requires the use of the drug in the form of a lotion, aerosol, on the body - cream or ointment, in the folds - cream, lotion, on the mucous membranes - gel.

Method of application: when treating with topical glucocorticosteroids, several modes of application are used. In a continuous regimen, GCS is used on the affected areas 1–2 times a day to stabilize relapses of dermatoses. The tandem therapy regimen (intermittent) consists of the application of GCS several times a week, starting from application every other day with a gradual decrease in frequency to 1 time per week. Tandem therapy involves daily background use of emollients (Locobase Ripea, Excipial M, Xemoz, etc.), which allows you to maximize the relapse-free period and reduce the incidence of side effects of GCS. The use of a descending therapy method (starting treatment with strong topical corticosteroids and then switching to drugs with moderate therapeutic activity) allows for rapid regression of the acute phase of the disease and avoids steroid-resistant dermatosis. The use of a too weak drug at the beginning of therapy can lead to a worsening or persistence of the course of dermatosis, while the prescription of a highly active corticosteroid drug for a short course without a planned reduction in the volume of therapy can cause the development of withdrawal syndrome in the form of an exacerbation of the disease. In case of a widespread inflammatory process (large area of damage), in order to reduce the frequency of side effects, a mode of stepwise or streaked application of GCS to the affected areas of the skin is used, which consists of alternating application of GCS to different areas throughout the day or another period.

Question of dosage

It is important to use topical medications containing glucocorticosteroids in adequate quantities. To calculate the optimal amount of soft local form of corticosteroids (cream, ointment), the principle of “unit equal to the tip of the finger” (UTF) is used, which is quite simple for patients. It is believed that ~1 EPC is required to apply the drug to the hand or groin, 2 EPC to the face or foot, 3 EPC to the entire arm, 6 EPC to the entire leg and 14 EPC to the torso. The presence of various dosage forms of external steroids provides the possibility of choice, rationality and comfort in treating patients at any stage of the inflammatory process.

Summary

Topical corticosteroids, despite their high effectiveness, cannot become a panacea for the treatment of many chronic and common skin diseases. We are categorically against illiterate, “standardized” prescription of these drugs by doctors of various specialties or independent use by patients. Mindless use of these drugs without knowledge of the basic indications and rules for their use can do more harm to the patient than good. The use of topical corticosteroids in the treatment of dermatoses should be strictly regulated and carried out only by a dermatologist.

Analysis of the literature and our own experience suggest that the use of steroid drugs significantly increases the effectiveness of treatment of patients. The great demand for GCS is based on the fact that until now there is no therapeutic alternative to them in terms of the speed of onset and severity of the anti-inflammatory effect. Exhibiting high therapeutic activity at any stage of allergic inflammation, GCS quickly relieves objective and subjective symptoms of dermatoses, suppressing the main links in the early and late phases of allergic inflammation. As monotherapy, topical corticosteroids are successfully used to relieve exacerbations of limited and mild types of dermatoses. These drugs combine well with all types of systemic pharmacotherapy, as well as phototherapy. For widespread and severe dermatoses, topical steroids in the form of adjuvant therapeutic effects actively complement systemic and physiotherapeutic methods of treatment. By providing a rapid therapeutic response, external corticosteroids reduce the treatment time for dermatoses and lead to a significant improvement in the quality of life of patients. The demand for topical corticosteroids is largely due to their high aesthetic appeal (they are quickly absorbed by the skin, do not leave marks on clothes and underwear, do not have an unpleasant odor, and do not stain the skin). Taken together, these factors determine the high compliance of topical corticosteroids - the adherence of patients to the choice of these particular drugs for the treatment of acute and chronic dermatoses.

Source: Les Nouvelles Esthetiques Ukraine, No. 1 (71), 2012, pp. 70-74