Glucocorticoids
Glucocorticoids (also glucocorticoids , abbreviated GK ) belong to the corticosteroids , a class of steroid hormones from the adrenal cortex . The name refers to their function in glucose metabolism , where they promote the conversion of protein into glucose and glycogen .
The naturally occurring glucocorticoids are descendants of the corpus luteum hormone ( progesterone ); They include cortisol and corticosterone as well as cortisone .
In addition, there are artificial corticoids derived from glucocorticoids with a glucocorticoid effect, such as those used in medicine, such as prednisolone or dexamethasone . These are also called glucocorticoids and are usually injected (cortisone syringes), administered in tablet form or applied locally using a cortisone cream ( topical application ).
The glucocorticoids have a variety of physiological and therapeutic effects. They influence the metabolism , the water and electrolyte balance , the cardiovascular system and the nervous system . They also have an anti-inflammatory and immunosuppressive effect ( reducing the body's immune reactions ).
physiology
biosynthesis
As with all steroids , the biosynthesis of the corticoids starts with cholesterol , which is either ingested with food or (in much larger quantities) is formed from mevalonate . The intermediate product is pregnenolone , which is converted into cortisol in several possible ways , and this subsequently into cortisone . There is a distinct daily rhythm with a minimum at midnight and a maximum between 6 and 8 a.m.
Dismantling
Like other corticoids, the glucocorticoids are inactivated in the liver and excreted mainly in the bile , 10% also in the urine, in the form of inactive conjugates .
Effects
Natural concentrations of glucocorticoids promote gluconeogenesis (the formation of new carbohydrates from amino acids and carbohydrate precursors). Protein and lipid deposits are broken down and used to generate energy. This causes increased concentrations of glucose , amino acids and fatty acids in the blood as well as their breakdown products. Chronic overproduction of the hormones creates a condition known as Cushing's syndrome .
Glucocorticoids have an intensifying effect on the glucagon- induced expression of the gluconeogenesis enzymes. The complicated mechanisms can only be explained here using one of the enzymes, phosphoenolpyruvate carboxykinase (PEPCK), as an example: PEPCK catalyzes the formation of phosphoenolpyruvate from oxaloacetate , using one GTP . PEPCK is a key enzyme in gluconeogenesis, which occurs when you are hungry and when your blood sugar is low. More PEPCK is created through increased transcription from the PCK1 gene, which codes for this enzyme PEPCK. The process of this signal transduction :
- The hormone glucagon binds to its glucagon receptor on the cell membrane. As a result, the GDP-binding α-subunit separates from the β- and γ-subunits of the heterotrimeric membrane-bound G s protein and dissociates to the receptor, where GDP is exchanged for GTP. The activated α-subunit in turn activates the adenylate cyclase to convert several molecules of ATP into cAMP . A high cAMP level activates protein kinase A , which in turn phosphorylates the cAMP-responsive element binding protein ( CREB ). CREB is to CRE, a regulatory region of the PCK1 - promoter bound. As a result, this will PCK1 - gene expressed.
- The glucocorticoid binds to its nuclear receptor, which is bound to the heat shock protein 90 (Hsp90) and is inactive in the cytosol . When the ligand binds , Hsp90 dissociates. The glucocorticoid receptor homodimerizes to its active state and translocates as a receptor-ligand complex into the cell nucleus, where the complex binds to a palindromic sequence as a transcription factor . This glucocorticoid- responsive element represents a further regulatory area in the PCK1 promoter. The effect of CRE / CREB-P is thus potentiated.
In a much higher dose, as can only be achieved after the use of medication, further effects occur: Protein synthesis is inhibited, antibody production in the immune system is reduced and inflammatory processes are suppressed. Even higher doses, which can only be achieved with the administration of highly effective artificial glucocorticoids such as dexamethasone , counteract circulatory shock in life-threatening diseases and injuries.
Pathologies
The enzyme 11 β- hydroxysteroid dehydrogenase 1 catalyzes the inactivation of cortisol through dehydration to cortisone . Mutations in the coding therefor HSD11B1 - gene are responsible for the so-called AME syndrome , a form of hyperandrogenism and rare genetic disease.
Therapeutic use
Glucocorticoid preparations have anti-inflammatory effects and are therefore analgesic, often pain relievers.
They are used in therapy, for example, for allergic rhinitis or bronchial asthma . Highly effective variants are used in acute emergencies ( anaphylaxis , sepsis , shock ) or acute severe pain ( herniated disc , disc protrusion , rotator cuff rupture ). Other preparations can be used topically, for example on the skin or in the nose. Numerous topical glucocorticoids such as budesonide or fluticasone propionate are available today .
Effects: On the bronchial mucous membrane anti-inflammatory and decongestant - the hyperreactivity of the bronchial mucous membrane is reduced - as well as on the bronchial muscles antispasmodic. Both effects appear no earlier than 30 minutes after taking the drug.
If there is a risk of premature birth , glucocorticoids are used to promote lung maturation .
Side effects
Depending on the strength class and localization, side effects can occur with (topical) corticosteroids applied to the skin with long-term application (weeks to months) or with systemic (i.e. non-local) application : water storage in the tissue ( edema ) and thus weight gain, weakening of the immune system, promote the formation and amplification of an existing diabetes mellitus , promotion and reinforcement of an existing bone loss ( osteoporosis ) in inhalation administration hoarseness . They also increase intraocular pressure and can induce glaucoma .
Glucocorticoids reduce the conversion of vitamin D3 from the inactive storage form (25OH-cholecalciferol) to the active one (1,25OH-cholecalciferol). Nevertheless, when taking systemic corticoids, it is preferable to take inactive vitamin D over active, as it cannot lead to overdoses. Only in the case of renal insufficiency is the administration of "active" vitamin D (calcitriol) under control of the serum calcium level indicated due to a largely lacking conversion from the inactive (25OH-cholecalciferol) to the active (1,25OH cholecalciferol) form. Short-term shock therapy for acute illnesses has few side effects. Evidence has also been found that glucocorticoids increase the risk of thrombosis.
Criticism of the application
Andreas Imhoff , Medical Director of the Department and Polyclinic for Sports Orthopedics at the Klinikum rechts der Isar at the Technical University of Munich, explicitly sees the importance of administering glucocorticoids in the form of cortisone injections for selective use in diseases such as rheumatoid arthritis or as a one-off emergency medication.
Imhoff, however, is critical of the fact that general practitioners often inject cortisone too early and too often. The patient does not even know what side effects cortisone can have - according to the motto: The main thing is that it helps first. From Imhoff's point of view, cortisone injections would be attractive due to the cost policy of the health insurance companies. Time-consuming consultations or referrals to physiotherapy, the importance of which cannot be overestimated, are badly rewarded. For economic reasons, the doctors are practically forced to provide additional services, which leads to "dangerous excessive spraying".
The side effects are considerable, such as the dissolving of skin and fatty tissue and cartilage being destroyed.
Potency
25 mg of cortisol roughly corresponds to the daily production of the adrenal cortex in humans. Based on this, the potency and the equivalent dose of various glucocorticoids from clinical practice result as shown in the following table.
| Generic name | Biological half-life | Potency | Equivalent dose (mg) |
|---|---|---|---|
| Cortisol / hydrocortisone | very short | 1 | 25-30 |
| Cortisone acetate | very short | 0.8 | 35-37.5 |
| Cloprednol | ? | 2 | 2.5-5 |
| Prednisone | short | 4th | 5-7.5 |
| Prednisolone | short | 4th | 5-7.5 |
| Deflazacort | ? | 4th | 6-9 |
| Methylprednisolone | short | 5 | 4-6 |
| Fluocortolone | medium | 5 | 5 |
| Triamcinolone | medium | 5 | 4-6 |
| Betamethasone | long | 25th | 1.2 |
| Dexamethasone | long | 30th | 0.75-1 |
| Mometason | long note 1 | ? | ? |
| Clobetasol | long note 2 | 10 | ? |
Topical application
If glucocorticoids are not applied systemically, but only at certain points, mostly on the skin (i.e. topically), the individual active ingredients show quite different relative efficacies than with parenteral application. A strong anti-inflammatory / anti- proliferative effect is as desirable here as possible in order to make various skin symptoms such as eczema disappear without atrophying (breaking down) the skin itself too far. In addition, with strong active ingredients, prolonged use and a large application area or a greatly reduced barrier function of the skin, noticeable systemic (mostly undesirable) effects of the corticoids can occur.
In order to improve the dermal action profile, “intelligent” steroids are being developed, which are metabolized more quickly . Their main effect should only come into play superficially, as they are rapidly broken down in deeper layers or in the circulation. This faster metabolism is achieved through special derivatizations on the corticoid molecule: Examples are prednicarbate, mometasone furoate, hydrocortisone butyrate, aceponate, and methylprednisolone aceponate. Such derivatives can also modify biological effectiveness, both topically and systemically.
Topically applied active ingredients are divided according to the potency (according to Niedner) of the substances:
- Class 1 - weakly effective
- Hydrocortisone (acetate), prednisolone, fluocortin butyl ester, triamcinolone acetonide, dexamethasone, clocortolone pivalate (hexanoate).
- Class 2 - moderately effective
- Clobetasone butyrate, Hydocortisonaceponat, dexamethasone (-sulfobenzoat) Alclomethasondipropionat, flumetasone pivalate, triamcinolone acetonide, Fluoprednidenacetat, Fluorandrenolon, hydrocortisone butyrate, Hydrocortisonbuteprat, betamethasone benzoate, fluocortolone, prednicarbate .
- Class 3 - highly effective
- Mometasone furoate , methylprednisolone aceponate, betamethasone valerate, fluticasone propionate, halomethasone, betamethasone dipropionate, fluocortolone (hexanoate), fluocinolone acetonide, diflorasone diacetate, desoximethasone, fluocinidone valerine, amortcinone.
- Class 4 - very effective
- Diflucortolone valerate, clobetasol propionate .
Applications
With topical-dermal application, the active ingredients are incorporated into solutions, ointments , creams or fatty ointments , depending on the initial condition of the skin . For the treatment of infected skin lesions are combination products with antibacterial or antifungal agents available. If the skin area is very scaly , urea or salicylic acid (3 percent) can be added to dissolve the scales . This also favors the resorption of the glucocorticoids. To increase the effectiveness, an occlusal bandage can soften the upper layers of the skin.
Local inflammatory reactions that are not accessible to external corticosteroid application can be treated locally with a depot syringe. Corresponding crystal suspensions with the corticoids betamethasone, dexamethasone, triamcinolone and prednisolone are available for this.
See also
literature
- Hans J. Hatz: Glucocorticoids . Stuttgart 1998, ISBN 3-8047-1486-2 .
- Lois Jovanovic, Genell J. Subak-Sharpe: Hormones. The medical manual for women. (Original edition: Hormones. The Woman's Answerbook. Atheneum, New York 1987) From the American by Margaret Auer, Kabel, Hamburg 1989, ISBN 3-8225-0100-X , pp. 27–31, 306–310 and 374.
Individual evidence
- ↑ UniProt P28845
- ↑ MU Dardenne: The glaucoma-inducing effect of glucocorticoids: General aspects. In: W. Böke (Ed.): Corticosteroids in ophthalmology. Symposium of the German Ophthalmological Society from 28. – 30. September 1972 in Kiel. Springer, ISBN 978-3-642-87229-7 , pp. 281-286.
- ^ Sigrun A. Johannesdottir: Use of Glucocorticoids and Risk of Venous Thromboembolism - A Nationwide Population-Based Case-Control Study. In: JAMA Internal Medicine. S. 1, doi: 10.1001 / jamainternmed.2013.122 .
- ↑ a b c pain through monotony , article about Imhoff and his treatment principles in Hallo München, May 25, 2018.
- ↑ a b Boateng doctor warns of “a lot of spraying” , article from July 22, 2017 about Andreas Imhoff, tz , Munich.
- ↑ Andreas Imhoff is the top specialist in the field of shoulder and knee in the Focus list of doctors, with top marks since 2010.
- ↑ See: Dexamethasone is in the list of indispensable drugs of the WHO as an analgesic, in the therapy of allergies and anaphylaxis and as an immunosuppressant.
- ↑ In addition to cortisone, a cortisone syringe contains a local anesthetic.
- ^ Hanns Kaiser, Hans K. Kley, Tilo Andus: Cortisontherapie: Corticoide in clinic and practice. Georg Thieme Verlag, 2002, ISBN 3-13-357211-3 , p. 184, (books.google.de)
- ↑ Christoph Henzen: Therapy with glucocorticoids: Risks and side effects. In: Switzerland Med Forum. Volume 19, No. 7, May 7, 2003, pp. 442-446, (medicalforum.ch , PDF).
- ^ A b Hanns Kaiser, Hans K. Kley, Tilo Andus: Local (= topical) corticoid application. In: Cortisontherapie: Corticoids in clinic and practice. Georg Thieme Verlag, 2002, ISBN 3-13-357211-3 , pp. 172-179.
