Glucocorticoids 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. • • • Adrenal medulla - physiology •A-cells – adrenaline - 80 % catecholamines secreted to the blood. Adrenalin secretion based on n •Nerve impulse →physical and psychological stress (crisis situation) →alarm reaction → adaptation stage → ↑ glucosis, lactate, free fatty acids concentration, → exhaustion stage. • •N-cells – noradrenaline – causes contraction of blood vessels (except heart vessels), thereby ↑ blood pressure. • • Glucocorticoids - regulation hypothalamus hypophysis Suprarenal gland CRH corticoliberine ACTH corticotropine cortisol pyrogens ↓ BP ↓ glycaemia ADH histamine pain stress + - - + + + + + + + + + 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 Glucocorticoid •Mechanism of action in cellular level Receptor Specific Receptor-hormon komplex Change of proteosynthesis •Mechanism of action in cellular level Specific Protein může působit již uvnitř buňky. 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 (cortizol) • • • • 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 • •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 • •Vazotropic - 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 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 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….) 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 • Anti-inflammatory effect •Decreased histamine release from basophils • •Inhibition of the formation of inflammatory mediators and allergic reactions (cytokines, complement components, kallikrein ...) • Anti- proliferative effect •Block cell cycle • •Induction of differentiation • •GCs - lymphocyte disintegration (acute and chronic lymphocytic leukemia, lymphomas, myelomas) • • 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 GCs effects, anti-inflammatory, immunosupressive and other effects •Strong anti-inflammatory and immunosuppressive action •INHIBITION OF ACUTE AND CHRONIC DISEASE, INFLUENCE OF ALL TYPES OF INFLAMMATORY REACTIONS •Inhibition of healing repair processes, prevention of graft rejection •Mineralocorticoid effects: sodium retention, potassium depletion •Blood and lymphatic system: ↓ lymphocytes, ↓ eosinophils in circulation, ↑ platelets, erythrocytes and HB •Kidneys: glucocorticoids maintain the ability of the kidneys to secrete water, retain glomerular filtration, tubular resorption, prevent the transfer of water to cells and maintain extracellular fluid volume •Heart and vessels: allow for increased sensitivity to the vasoactive effect of catecholamines and ATII, increased myocardial contractility and vascular tone •CNS: mood regulation, strong insomnia •GIT: increased secretion of HCL and pepsin, increased absorption of lipids from the intestine, decreased absorption of Ca •Bone metabolism: osteoporosis (metabolism of Ca, P, collagen synthesis and degradation, osteoblasts / clasts) •Pulmonary surfactant: cortisol - an endocrine stimulant for pulmonary surfactant formation Systemically administered GCs •1-4 times efficient than cortisol •prednisolone, prednisone •hydrokortisone • • •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) ad 1. poločas cca 8-12h. ad 2. poločas cca 12-36h ad3 poločas cca 36-72h 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 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 Glucocorticoids – adverse events Before therapy start: - potential infection elimination - fasting glycaemia - diabetes compensation - preventive application of D vitamine - anti-ulcer treatment During the therapy: - DM monitoring compensation - monitoring of mental state - myopathy and osteporosis prevention (K, Ca, rehab., exercise) - thromboembolic prevention - consultation the centre for growth hormone treatment in pediatric medicine Glucocorticoids – adverse events Prevention - Application of the lowest effective dose - If possible local applications - Combination with other drugs - Circadian therapy / alternating therapy - Minimizing the use of depot medication (circadian rhythm disruption, local trophic changes after application) Glucocorticoids – adverse events prevention Immunosuppression - ↑ susceptibility to infections, activation of latent infections - Slow wound healing - Even with local administration Supression of endogenous glucocorticoid production - Acute inadequacy when suddenly discontinuing higher doses - Prevention = complete therapy by gradual dose reduction Osteoporosis - Risk only for chronic therapy - Densitometric examination Mineralocorticoid effect - Water retention and Na + - ↑ TK, loss of K + Glucocorticoids – adverse events 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 KVS - HT, atherosclerosis, cardiomyopathy, ↑ coagulopathy, arrhythmia Glucocorticoids – adverse events 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 Glucocorticoids – interactions Prednisone reduces the plasma levels of salicylates and oral anticoagulants. The effect of prednisone is reduced by barbiturates, phenytoin, rifampicin. Therapeutic indications •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 •Renal Disease •Immunalternative disease in neurology •Substitution therapy for secondary adrenocortical insufficiency •Congenital adrenal hyperplasia Corticoids in clinical practice 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 • • • Skin diseases Eczema dyshidroticum, after therapy GCs and rheumatic fever •Rheumatic fever - a consequence of URT infection by hemolytic streptococcus •Hospitalization, bed rest - we can not reliably rule out heart disease - we use GCs corticosteroids instead of salicylates (prevention of heart muscle and valves damage) •The initial dose of Prednisone 60 mg - with gradual reduction, we can withstand treatment for at least 4 weeks. •Penicillin antibiotics to eradicate infection • •URT – upper respiratory tract rheumatic fever - definition of rheumatic fever by Medical dictionary: Thrombophlebitis •Movement, pressure bandage, legs elevation •Anti-inflammatory therapy (NSA), antibiotics at infection etiology, vascular treatment (troxerutin), anticoagulants •In case of migrating thrombophlebitis, corticosteroids are indicated in the failure of the above treatment of 20 - 40 mg daily Výsledek obrázku pro thrombophlebitis Fast progressive glomerulonephritis •Destruction of most glomeruli caused by: • - antibodies against neutrophil cytoplasm, • - antibodies against basal glomerulus membrane, • immunocomplexes •Not treated → kidney failure •Immunocomplex glomerulonephritis therapy: • Prednisone 1mg /kg, dose decrease very slow, not • earlier than 3 months, to achieve a dose of 20 mg/ • day in combination with Cyclophosphamide Výsledek obrázku pro glomerulonephritis Glucocorticoids in the treatment of rheumatoid arthritis •GK in supraphysiological doses are the most potent anti-inflammatory drug in the RA (except for biological treatment) • Long-term administration - problem •Treatment examples: •A) HD Prednisone 60 mg / day or day or day • HD Methylprednisolone 48mg / day or daily • For 1 - 2 months followed by a gradual decrease depending on the clinical condition •We want remission of the disease, great side effects •B) LD Prednison - less than 7.5 mg / day • LD Methylprednisolone - less than 6 mg / day •C) An alternative type of treatment - from the original 5 mg of prednisone daily, we switch to 10 mg daily • We already have control over the disease, we want control over the symptoms, sine side effects •D) Combination treatment type - methotrexate, sulfasalazine, cyclosporine, cyclophosphamide 6-12 weeks according to • Clinical condition •Concomitant treatment of long-term medication GK: densitometry, vitamin D, calcium ulcer, potassium-sparing diuretic, as needed Výsledek obrázku pro rheumatoid arthritis Pulse therapy of glucocorticoids in the treatment of rheumatoid arthritis •High doses of corticoids i. v. every second day •250 - 1000 mg of methylprednisolone (Solu-Medrol) in infusion •In cases of very active RA •In life threatening visceral RA manifestations (lung fibrosis) •Disease activity decrease will be exposed in lab tests (FW, CRP) •Indication: only on bed •Efficacy assessment: if pulse treatment leads to disease regression •(clinical condition improvement) for 6 - 8 weeks = effective •If the effect lasts only a few days, repeating pulse treatment is irrelevant. Výsledek obrázku pro solumedrol GCs Intra-articular therapy GK in AR •Principles of intra-articular administration of corticosteroids 1.Strict aseptic conditions of application 2.Exclusion of infection on the skin and around the entrance, acute or chronic overall infectious disease 3.Good knowledge of application technique only in the joint with synovialitis (warm joint, effusion). 4.Maximum 2 - 3 times a year 5.Medication: Methylprednisolone acetate Depo-Medrol, or betamethasone Diprophos • Intra-articular-Peripheral-Joint-Injection-1 GCs in SLE •SLE – multiorgan disease – Abs against cell nucleus structures •SLE – disability of the heart, vessels, lungs, blood elements, kidneys, CNS… •GCs - the most important drugs in the treatment of SLE •Rapid suppression of inflammatory and fulminant forms •Indications: • - mild forms 5 - 10 mg Prednisone daily • - severe forms with visceral affection of 20 - 60 mg Prednisone/day • - very serious forms - pulse GCs therapy •Therapeutic combinations: azathioprine, cyclophosphamide, methotrexate, cyclosporin • • • Výsledek obrázku pro systémový lupus erythematodes 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 Výsledek obrázku pro symbicort Acute rejection in transplant organs •Sudden deterioration of graft function on immune basis •It occurs in the first three months •Diagnosis of rejection - biopsy and histology result •Therapy: • Pulse treatment of corticosteroids 250 - 500 mg of methylprednisolone 3 - 5 days leading to a graft stabilisation in majority of patients • In case of corticoresistance - antithymocytic globulin Výsledek obrázku pro organ transplant Non-specific intestinal inflammation •Etiopathogenesis is unclear •Autoimmune disease direct to own intestine cells •Crohn's disease, proctocolitis (colitis ulcerosa) •Therapy is focused on influencing: • - mediators of inflammatory processes • - suppression of immunological changes •Corticosteroids: „Attack“ treatment in high disease activity •Application: tablets, suppositories, klyzma, parenteral application •Topical administration of KK: budesonide (Entocort klyzma/infusion), gastro-resistant capsules (advantage - minimal absorption from the digestive tract, minimal administration) •Highly active Crohn's Morbus: 1 - 1.5 mg / kg i.v. inf. Výsledek obrázku pro crohn disease