Glucocorticoids Department of Pharmacology MU Histology of the adrenal cortex Three concentric zones comprise 80-90% 􀂄 Zona glomerulosa Zona fasiculata Zona reticularis Zona glomerulosa (outer zone) producing mineralcorticoids (aldosterone) O OH O OH O Zona fasiculata (middle zone) producing glucocorticoids (cortisol) O OH OH O OH Zona reticularis (inner zone) producing sex steroids (dehydroepiandrosterone (DHEA) : androgens) O OH OH O hypotalamus hypophysis adrenal CRH corticoliberin ACTH corticotropin cortisol stress ADH histamin pyrogens painhypoglycemia ↓ BP + + + + + + + + + - - Cushing's syndrome iatrogenic bronchial carcinoma + + + - - Mechanism of glucocorticoid action on cellular level After entering the cell they bind to specific receptors in cytoplasm causing change of conformation = activation of receptors Complexes of corticoid + receptor are transported to cell nucleus and bind to DNA elements. The result is increased transcription of genes either inducing or inhibiting synthesis of other proteins • GLC receptors are present in all tissues!!! • Proteins called lipocortins are able to suppress phospholipase A Endogenous secretion: Quiescent : 25 - 30 mg /24 In stress: 10-fold Not stored – rate of synth. = rate of release Maximal: 6-8 A.M. Pharmacokinetics • Bound to CBG and albumin • Intensively metabolised • Metabolites excerted in 72 h • Synthetic ones have longer thalf • (prednison – prednisolon) 1. Influences on intermediary metabolism 2. Permissive Action and circulatory effects 3. Effects on Water Metabolism 4. Effects on the bones and muscles 5. Anti-inflammatory, anti-immune effects 6. Effects on the Central Nervous System 7. Developmental effects Physiological effects of Glucocorticoids Effects (terapeutic): • anti-inflammatory • antialergic and immunosupresive • antiproliferative • Substitution (therapeutic) Glucocorticoids Phospholipase A2 Membrane phospholipids Arachidonic acid lipooxygenase cyclooxygenase LEUCOTRIENS PROSTAGLANDINES PROSTACYKLINES TROMBOXANES inflammation Mobilization of fagocytosis Changes in vessels permeability Inflammation A-A NSAID Inh. 5-LOX Indications Physiological doses substitution – adrenocortical insuficiency, congenital adrenal hyperplasia, Addison dissease (hydrocortisone, fludrocortisone) Pharmacological doses Antiinflammatory and imunosupressive effects astma (inhaltions) topic application, in allergy (conjuctivitis, rhinitis) hypersensitivity in general anaphylaxis autoimune diseases (revmatoid arthritis, Crohn disease …) prevent non-acceptance in transplantations Indications Oncology Acute Lymphoblastic Leucaemia, hodgkin disease tumors of brain (antioedematose effect - dexamethasone) antiemetics Others height sickness, nephrotic sy., sclerosis multiplex, subacute thyreoitidis Adverse effects (after pharmaclogical intervence!) 1) ↓ Immune responses recurrent infects, ulcer dissease, mycotic infects… 2) Decrease in endogenous corticoid production (supresion of axis hypothalamus –pituitary – adrenal glands) --- acute insuficiency in sudden glucocorticoid withdrawal 3) Osteoporosis 4) Mineralocorticoid action – water retention, salts ↑blood pressure, Na, Cl ↓ K+, NO production Adverse effects (after pharmaclogical intervence!) 5) Steroid diabetes mellitus 6) Muscle atrophy 7) Psychotrophic effect: euphoria/ depression/psychosis 8) ↑ gastric secretion of HCl 9) Cartillage impairment, striae, reduced wound healing 9) others: increased clottin, ↑trombocytes, erys glaucoma, increased intracranial pressure Iatrogenic Cushing sy. Sudden weight gain Central obesity Hypertension Proximal muscle weakness Diabetes mellitus Decreased libido or impotence Depression or psychosis Osteopoenia or osteoporosis Easy bruising Hyperlipidemia Menstrual disorders Violaceous striae wider than 1 cm Recurrent infections Acne Hirsutism... Glucocorticoids: Glucocorticoid effect Mineralocorticoid effect Cortisol 1 1 Cortisone 0,8 0,8 Prednisone 4 0,8 Prednisolone 4 0 Triamcinolon 5-10 0 Betametazon 25 0 Dexametazon 25 0 Topically administered glucocorticoids – hydrocortisone – dexamethasone – prednisolone – triamcinolone – flumethasone – prednikarbat – bethametason valerate – fluocinolone – betamethason adipate – budesonid – halcinomide – clobetasole Weak action Very strong acting CAVE ! To prevent axis supression (hypothalamus- ant. pituitary – adrenal glands) • Administration up to 10 days • 6 - 8 A.M. • Preparations with lower blocking effect (non-fluorinated derrivatives) • Pulse therapy Adverse effects prevention • lowest effective dose should be administered • topic administration if possible (inh., rect., intraarticular, s.c.) with low bioavailability • total dose can be decreased by combination with imunosupresives • dosing schedule should reflect circadian rhythm – if possible (not in life threating situations) • avoid sustained release preparations • stepwise decreasing of doses approx. 2.5 mg eq. prednisolone /3 days Contraindications • hypertension • heart insufficiency /CHF • Cushing. sy • peptic ulcer • diabetes • glaucoma • psychoses • viral/bacterial infection • vaccination with attenuated vaccine