GLUCOCORTICOIDS Department of Pharmacology MF MU Adobe Systems Suprarenal glands - anatomy http://www.zdravi4u.cz/pages/Image/telo-organy/nadledvinky.gif Soubor:Pineal clip image004.gif [USEMAP] Adobe Systems Adrenal cortex - physiology http://player.slideplayer.cz/11/3374824/data/images/img3.jpg Zona glomerulosa Zona fasciculata Zona reticularis • ̶Zona glomerulosa – mineralocorticoids production - aldosteron 10 – 15% of tissue, controlled by ATII a K+. • ̶Zona fasciculata 75% of tissue, controlled by ACTH, „stock“ of cholesterol, its releasing and transformation to cortizol = main human glucocorticoid. • ̶Zona reticularis 10 – 15 % of tissue – androgens, gestagens, cortisol production. ̶ ̶ • Adobe Systems Steroid hormones biosynthesis - biochemistry Cholesterol Pregnenolone Progesterone 17α-OH - pregnenolone 17α-OH - progesterone DHEA 11- deoxycorticosterone 11 - deoxycortisol androstendion other 17 - ketosteroids corticosterone aldosterone Hydrocortisone = cortizol cortizon estrone estradiol testosterone dihydrotestosterone Precurzors Intermediate products Mineralocorticoids Glucocorticoids Estrogens Androgens 17 ketosteroids 20,22 desmolase 3β - dehydrogenase 21-β hydroxylase 17α hydroxylase 17α hydroxylase 11-β hydroxylase TRILOSTAN METYRAPON Adobe Systems Glucocorticoids - regulation hypothalamus hypophysis suprarenal gland CRH corticoliberine ACTH corticotropine cortisol pyrogens ↓ BP ↓ glycaemia ADH histamine pain stress + - - + + + + + + + + + [USEMAP] Adobe Systems Slide24 [USEMAP] Adobe Systems http://drchelson.com/wp-content/uploads/2014/09/Untitled.png Endogenous and exogenous cortisol secretion Resting – 20 – 25 mg/24 hours Stress: 10 times higher Maximum: 6 – 8 hours a.m. Exogenous corticoids usage – endogenous secretion downturn [USEMAP] Glucocorticoid Mechanism of action in cellular level Receptor Specific Receptor-hormon komplex Change of proteosynthesis Mechanism of action in cellular level Specific [USEMAP] Adobe Systems Glucocorticoids ̶ influence sugar, fat and protein metabolism ̶ have anti-inflammatory and anti-allergic effect ̶ have immunosuppressive effect (in many branches – in next slides) ̶ have antiproliferative effect ̶ ̶hydrocortisone (cortisol) ̶ ̶ ̶ [USEMAP] reduced glucose uptake and reduced glucose utilisation in the cell Proteolysis, tissue proteins = aminoacids decomposition of tissue proteins ↑ gluconeogenesis catabolism (glucose formation from non sugar residues) ↑ glycaemia Connective tissue muscle atrophy fibroblasts growth stopping ↑ of insulin secretion ↓osteoblasts, ↑osteoclasts ↓collagen synthesis ↓Ca resorption from intestine, kidneys (osteoporosis) ↑ storage of glycogen in the liver lipogenesis support, lipolysis inhibition fat deposition, redistribution, ↑glycerol, aminoacids in blood GCs and sugar, fat and protein metabolism Fats: ↑ lipolysis, facilitation of lipid absorption, fat redistribution [USEMAP] CNS: Euphoria / psychotic disorder after high doses / depression GIT: Increasing formation of HCl and pepsin in the stomach BLOOD: ↑ Tro, Ery, circul. ↓lymfocytes, ↓eosinofils LUNGS: ↑ formation of pulmonary surfactant HCl – hydrochloric acid Other effects Permissive effect to: - Development of organs of the fetus - Development and maturation of intestinal enzymes - Increases the synthesis of surfactant in the lungs of the fetus - Suppresses bone growth - Ions - Decreased calcemia - Increased potassium loss - Sodium and chloride retention GCs and congenital developmental defects GK and ions •Negative feedback on the hypothalamus and the anterior lobe of the pituitary gland reduced release of endogenous glucocorticoids •Vasotropic - GCs - vasoconstriction, decrease of permeability of vessels, suppression of edema •At cell level: in place of acute inflammation: decrease in migration and leucocyte activity in place of chronic inflammation: decrease proliferation of blood vessels and fibrosis In place of lymphoid tissue: decrease B and T lymphocyte expansion •Towards the mediators of inflammation and immunological reaction: Decrease of cytokine production and activity, decreased synthesis of PGs Regulatory effects Adobe Systems Anti-inflammatory – cascade inhibition of AA glucocorticoids Phospholipase A2 A2 Membrane phospholipids Arachidonic acid lipoxygenase cyclooxygenase LEUKOTRIENS PROSTAGLANDINS PROSTACYCLINS THROMBOXANS inflammation Fagycytosis mobilisation Blood vessel permeability change Inflammation A-A NSAID Inh. 5-LOX - antileukotriens lipocortins eikosanoids [USEMAP] Adobe Systems Anti-inflammatory effect ̶AA cascade inhibition ̶Migration and leucocyte function disruption ̶Antibody production reduction All types of inflammation regardless of origin! (aseptic, viral, bacterial, parasitic….) Lymfocyty T/B = cca 70:30% T – CD4 „helper” (dirig. Interleukiny, IL=poslové (2:1) – celulár. imun.) T – CD8 „supresor” (cytotox.) T – CD0 „natural killer” B – Ly plasmocyty, Ig humorální imunita Adobe Systems Immunosupressive effect • •Inhibition of antigen recognition • Inhibition of the effector phase of the immune response (cell lysis) ̶! CAUTION: ̶Inhibition CELL MEDIATED immunity ̶ANTIBODY immunity is affected significantly less and in GSc higher doses • Adobe Systems Anti-inflammatory effect ̶Decreased histamine release from basophils ̶ ̶Inhibition of the formation of inflammatory mediators and allergic reactions (cytokines, complement components, kallikrein ...) • Adobe Systems Anti- proliferative effect •Block cell cycle • •Induction of differentiation • •GCs - lymphocyte disintegration (acute and chronic lymphocytic leukemia, lymphomas, myelomas) • • [USEMAP] Adobe Systems Effect and equipotent doses of CSs Substance Equip.dose Anti infl. effect Mineral. effect Cortisol 20 mg 1 1 Cortisone 25 mg 0,8 0,8 Prednisone 5 mg 4 0,8 Prednisolone 5 mg 4 0 Methylpredn. 4 mg 5 0 Triamcinolone 4 mg 5-10 0 Dexamethasone 0,75 mg 25 0 Bethametasone 0,6 mg 25 0 Fludrocortisone - 10 125 [USEMAP] Adobe Systems Systemically administered GCs ̶1-4 times efficient than cortisol ̶prednisolone, prednisone ̶hydrocortisone • • ̶5-15times efficient than cortisol ̶methylprednisolone (Solu-Medrol) ̶triamcinolone ̶paramethasone ̶fluprednisolone ̶ ̶approx 30times efficient than cortisol ̶bethametasone ̶dexamethasone • Short term acting Medium term acting Long term acting (stronger axis supression) [USEMAP] Adobe Systems Glucocorticoids therapeutical regimen types Short term application of high doses A) single (2-4 g methylprednisolone) Polytraumatas, septic, toxic shock Hydrocortisone 30 mg / kg B) repeated (methylprednisolone, hydrocortisone, dexamethasone) Anaphyl. shock, status asthmaticus, hypoglycemic coma ... Duration up to 48 hours Exceptionally up to 7 days [USEMAP] Adobe Systems C) Pulse therapy Short-term infusions for several days Originally in transplant rejection Today predominantly in immune-mediated diseases resistant to standard therapy D) Prolonged therapy In most branches Primarily for anti-inflammatory and immunosuppressive effects Dosage and length depends on the current status of the patient Strength differences, duration and frequency of adverse effects No hydrocortisone with respect to mineralocorticoid activity Glucocorticoids therapeutical regimen types Adobe Systems Supression of endogenous glucocorticoid production -Acute inadequacy when suddenly discontinuing higher doses - - Prevention = complete therapy by gradual dose reduction [USEMAP] Adobe Systems Hyperglycemia, steroidal diabetes Muscle weakness, myopathy, atrophy Psychotropic effects Insomnia, motor agitation, vertigo, euphoria, depression Psychic habit GIT Exacerbation of gastric ulcer Intestinal perforation, acute pancreatitis CVS - HT, atherosclerosis, cardiomyopathy, ↑ coagulopathy, arrhythmia Glucocorticoids – adverse events [USEMAP] Adobe Systems Eye Induction of glaucoma (↑ intraocular pressure) Corneal ulceration in keratitis herpetica Endocrine Growth inhibition in children (therapy longer than 6 months) Amenorrhea, potency and libido decrease Skin atrophy Intradermal bleeding Acne, hirsutism Glucocorticoids – adverse events [USEMAP] Adobe Systems Glucocorticoids – interactions Prednisone reduces the plasma levels of salicylates and oral anticoagulants. The effect of prednisone is reduced by barbiturates, phenytoin, rifampicin. [USEMAP] Adobe Systems Routes of administration ̶p.o. ̶i.v. ̶i.m. ̶s.c. ̶inhalatory ̶ ̶ointment/cream ̶eye/nose drops ̶intraarticularly [USEMAP] Adobe Systems •PHYSIOLOGICAL (low) DOSES ̶insufficiency: kortisol + fludrocortison (mineralokortikoid) ̶I: Addison’s disease ̶ Výsledok vyhľadávania obrázkov pre dopyt addison disease Therapeutic indications [USEMAP] Adobe Systems Therapeutic indications Higher doses ̶Diseases of connective tissue, rheumatological diseases and collagenoses (RA, SLE, SS, DM…) ̶Severe forms of allergic reactions ̶Non-infectious inflammatory diseases of the eye ̶Severe skin disorders ̶Haematological diseases ̶Malignant diseases ̶Conditions after organ transplantation ̶Inflammatory gastrointestinal disease ̶Non-inflammatory respiratory disorders ̶Immunalternative disease in neurology [USEMAP] Corticoids in clinical practice [USEMAP] Adobe Systems Rheumatoid arthritis http://www.kcvl.cz/IMGs/RA1.jpg •Glucocorticoids are used during periods of acute symptoms disease. • to bridge the period until the onset of effect DMD (MTX). • •Recent studies, however, show that small doses of glucocorticoids have • modifying effect and slowdown the X-ray progression of the disease. • •Prednisone at doses up to 10 mg daily or every other day. Only •Exceptionally, it is necessary to take higher doses, and it is only •In the case of very active disease, extra-articular symptoms, it´s better to start therapy with GK pulse therapy. • •Biological treatment is currently the most effective RA treatment and, in a number of cases, it can decisively slow down or stop the progression of the disease: • Chimeric monoclonal antibody against TNF-alpha infliximab, • Fully human monoclonal antibody against TNF-alpha-adalimumab • Soluble receptor for TNF-alpha etanercept • Monoclonal chimeric anti-CD20 molecule – rituximab • CTLA4 molecule linked to a modified Fc portion of human IgG1 - abatacept • Skin diseases Eczema dyshidroticum, before therapy Hand-foot syndrom Man 35 years old 2 – 3 years of hands eczema, after 1 year added hands eczema Status of treatment with local corticosteroids for 2 years Extreme impact on quality of life! Prednison 50 mg / daily – 1 month Proton pump inhibitors Effect after 1 week of systemic therapy, but: Severe AE: -Sleep disturbances -Depression -Hypertension (repeatedly 160/110) withadrawal Next strategy? Immunosupressants? Skin diseases Eczema dyshidroticum, after therapy Adobe Systems Inhalation GCs in asthma treatment ̶The most effective preventative antiasthmatics ̶Improve pulmonary function, reduce bronchial hyperreactivity, reduce exacerbations, improve quality of life ̶Beclomethasone dipropionate, budesonide, fluticasone propionate ̶Inhaled corticosteroids have a better safety profile than oral ̶Fixed combination - fluticasone + salmeterol (Seretide Discus) • - budesonide + formoterol (Symbicort Turbuhaler) Výsledek obrázku pro seretide [USEMAP]