Glucocorticoids 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 (cortisol binding globulin) and albumin • Intensively metabolised • Metabolites excerted in 72 h • Synthetic ones have longer thalf • (prednison – prednisolon) Effects (terapeutic): • anti-inflammatory • antialergic and immunosupresive • antiproliferative • Substitution (therapeutic) 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 Sacharides: ↓ Glu uptake and utilisation ↑ gluconeogenesis (from AA, FA) ↑ glycemia BUT ! in general – fat redistribution and deposition, ↑glycerol, FA in blood Proteins: ↑ catabolism, atrophy Glucocorticoids Influences Intermediary Metabolism Fat: permisive action on lipolytic hromones fat redistribution (Cushing sy.) •↓ fction of fibroblasts, osteoblasts, ↑ osteoclasts activity, (= osteoporosis) • defective collagen metabolism, impaired fibrous tissues synthesis Glucocorticoids Influences Intermediary Metabolism Cortisol must be present for an effect to occur, although cortisol does not produce the effect by itself. Permissive Action Permissive effects on different tissues - inhibit fibroblasts (connective tissue loss) - negative calcium balance (osteoporosis) - negative nitrogen balance (catabolism) - CNS: euphoria, behavioral changes, psychosis - GI: increase stomach acid and pepsin production - cardiovascular effects (increase in heart rate) - uptake of fat by fat cells - gluconeogenesis - insulin release and glycogen deposition Permissive Action 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 Antiinflammatory and imunosupresive effect • Impairment of migration and functions of leucocytes • AA cascade inhibition, ↓production of prostaglandins, IgG, influx and activity of neutrofils and macrophages • Inhibition of transcription of genes of adhesion factors Antiinflammatory and immunosuppressant effect • ↓ release of HIS from basophiles • ↓ blood vessels proliferation… • ↓ function of fibroblasts • ↓ activity of osteoblasts • ↑ osteoclasts (= osteoporosis) Inhibit all types of inflammation regardless of localisation or ethiology ! Antiinflammatory and imunosupresive effect Acute effects of cortisol - It stabilizes the lysosomal membranes (proteolytic enzymes) - It inhibits the production of inflammatory proteins (IL, TNF, etc.) - It decreases the permeability of capillaries - It depresses the phagocytosis - It prevents capillary dilation Antiinflammatory and imunosupresive effect Chronic effects of cortisol -It decreases the collagen synthesis -It decreases the activity of fibroblasts Anti-immune and Antiallergic Effects of Glucocorticoids Anti-immune responses of cortisol - suppresses the B lymphocytes - suppresses synthesis of interleukin-1 and interleukin-2 - stimulates synthesis of lipocortins that inhibit the generation of proinflammatory eicosanoids Antiallergic effects of cortisol - decreases the histamine release - decreases the number of eosinophils - decreases the permeability of capillaries - prevents capillary dilation Regulatory effects negative feedback to hypothalamus and adenohypophysis (anterior pituitary) - decr. secretion of endogenous glucocorticoids vascular decr. in vascular permeability, decr. oedema, decr. NO production on cellular level: in acute inflammation: ↓ Leu migration and activity in chronic inflammation: vascular proliferation, fibrotic changes in lymphoid tissue: ↓ B and T lymphocytes 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... Indications Physiological doses substitution – adrenocortical insuficiency, congenital adrenal hyperplasia, Addison dissease (hydrocortisone, fludrocortisone) Pharmacological doses Antiinflammatory and imunosupressive effects asthma (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 Review of glucocorticoids Drug GC MC Usage, duration of effect (ant-inflamm.) Hydrocortisone 1 1 Substitution, 8 - 12 h (cortisol) Cortisone 0,8 0,8 Prodrug Prednisolone 4 0,8 antiinflammatory, imunosupresive Prednisone 4 0,8 Prodrug Methylprednisolone 5 minor antiinflammatory, imunosupresive 12-26 h Triamcinolone 5 0 12 - 26 h Dexamethasone 30 minor antiinflammatory, imunosupresive treatment, esp. where fluids retention is unfavourable Betamethasone 30 minor - „ Beclomethasone + - local antiinflammatory imunosupresive treatment Budesonide + - - „ - 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 Glucocorticoids for systemic use • Approx. 1-5 times more eff. than cortisole – methylprednisolone, prednisolone – prednisone, hydrocortisone • Approx. 5-15 times more eff. than cortisole – triamcinolone – paramethasone – fluprednisolone • Approx. 30 times more eff. than cortisole – betamethasone – dexamethasone short acting intermediate long - acting (more powerfull axis suression) Topically administered glucocorticoids – hydrocortisone – dexamethasone – prednisolone – triamcinolone – flumethasone – prednikarbat – bethametason valerate – fluocinolone – betamethason adipate – budesonid – halcinomide – clobetasole Weak action Very strong acting 1) Very High doses (2 - 4 g methylprednisolone) polyutrauma, septic, toxic shock 30 mg / kg methylprednisolone in short infusion 2) Few –day administration of high dose anaphylaxis, status asthmaticus, hypoglycemic coma, acute hypercalcemia, brain oedema, thyreotoxic crisis, snakebite... more than 500 mg i.v. / 24 h Glucocorticoid therapy 3) pulse therapy 1 g metylprednisolone (infusion) 3 - 5x – different intervals Needs hospitalization resistent RA, lupus erythemoatodes, myasthenia gravis... 4) prolonged glucocorticoid treatment in most cases, antiinflammatory, imunosupressive effects antiallergy effects 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