GLUCOCORTICOIDS Department of Pharmacology MF MU Suprarenal glands - anatomy http://www.zdravi4u.cz/pages/Image/telo-organy/nadledvinky.gif Soubor:Pineal clip image004.gif [USEMAP] 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. • • • [USEMAP] 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 [USEMAP] Glucocorticoids - regulation hypothalamus hypophysis suprarenal gland CRH corticoliberine ACTH corticotropine cortisol pyrogens ↓ BP ↓ glycaemia ADH histamine pain stress + - - + + + + + + + + + [USEMAP] Slide24 [USEMAP] 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 [USEMAP] Change of proteosynthesis Mechanism of action in cellular level Specific [USEMAP] 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) • • • [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 [USEMAP] 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 [USEMAP] •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 [USEMAP] Anti-inflammatory – cascade inhibition of AA glucocorticoids Phospholipase 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] 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….) [USEMAP] Anti-inflammatory effect •Decreased histamine release from basophils • •Inhibition of the formation of inflammatory mediators and allergic reactions (cytokines, complement components, kallikrein ...) • [USEMAP] 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 • [USEMAP] Anti- proliferative effect •Block cell cycle • •Induction of differentiation • •GCs - lymphocyte disintegration (acute and chronic lymphocytic leukemia, lymphomas, myelomas) • • [USEMAP] 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] 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] 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] 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 [USEMAP] Glucocorticoids – adverse events Before therapy start: - potential infection elimination - fasting glycaemia - diabetes compensation - preventive application of D vitamine - anti-ulcer treatment [USEMAP] 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 [USEMAP] 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 [USEMAP] 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 + - ↑ BP, loss of K + Glucocorticoids – adverse events [USEMAP] 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 [USEMAP] 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] Glucocorticoids – interactions Prednisone reduces the plasma levels of salicylates and oral anticoagulants. The effect of prednisone is reduced by barbiturates, phenytoin, rifampicin. [USEMAP] Routes of administration •p.o. •i.v. •i.m. •s.c. •inhalatory • •ointment/cream •eye/nose drops •intraarticularly [USEMAP] 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 [USEMAP] •PHYSIOLOGICAL (low) DOSES •insufficiency: cortisol + fludrocortison (mineralokortikoid) •I: Addison’s disease • Výsledok vyhľadávania obrázkov pre dopyt addison disease Therapeutic indications [USEMAP] Therapeutic indications Higher doses •Diseases of connective tissue, rheumatological diseases and collagenoses •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] 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 [USEMAP] Corticoids in clinical practice [USEMAP] Skin diseases Eczema dyshidroticum, before therapy Hand-foot syndrom Man 35 years old 2 – 3 years of hands eczema Status of treatment with local corticosteroids for 2 years Extreme impact on quality of life! [USEMAP] 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 [USEMAP] MINERALOCORTICOIDS [USEMAP] •The main endogenous mineralocorticoid is aldosterone. • •Its chief action is to increase Na+ reabsorption by the distal tubules in the kidney, with a concomitant increase in excretion of K+ and H+. • •An excessive secretion of mineralocorticoids: marked Na+ and water retention, with increased extracellular fluid volume and sometimes hypokalaemia, alkalosis and hypertension • •Decreased secretion: Addison’s disease, Na+ loss, marked decrease in extracellular fluid volume • [USEMAP] • •Mechanism of action • •Like other steroid hormones, aldosterone acts through specific intracellular receptors of the nuclear receptor family. • •Unlike the glucocorticoid receptor, which is present in most cells, the mineralocorticoid receptor is restricted to a few tissues (kidney and the transporting epithelia of the colon and bladder). • [USEMAP] • •Fludrocortisone is given orally to produce a mineralocorticoid effect. • •increases Na+ reabsorption in distal tubules • •increases K+ and H+ efflux into the tubules • •acts on intracellular receptors that modulate DNA transcription, causing synthesis of protein mediators • •is used together with a glucocorticoid in replacement therapy • [USEMAP] • •Clinical use of mineralocorticoids • •The main clinical use of mineralocorticoids is in replacement therapy of patients with Addison’s disease. • •The most commonly used drug is fludrocortisone (p.o.) to supplement the necessary glucocorticoid replacement. • [USEMAP]