Glucocorticoids Mineralocorticoids Pharmacologic Uses of Synthetic Glucocorticoids Replacement Therapy Anti Inflammatory Immunosuppresion Treatment of Allergic Disorders Large doses for cerebral injury anti oxidant 1 Figure 28 4 Regulation of synthesis and secretion of adrenal corticosteroids The long negative feedback loop is more important than the short loop dashed lines Adrenocorticotrophic hormone ACTH corticotrophin has only a minimal effect on mineralocorticoid production ADH antidiuretic hormone vasopressin CRF corticotrophinreleasing factor Circadian Rhythm of Plasma Cortisol 2 mineralocorticoid Figure 28 5 Biosynthesis of corticosteroids and adrenal androgens Glucocorticoids are produced by cells of the zona fasciculata and their synthesis is stimulated by ACTH aldosterone is produced by cells of the zona glomerulosa and its synthesis is stimulated by angiotensin II Metyrapone inhibits glucocorticoid synthesis aminoglutethimide inhibits both glucocorticoid and sex hormone synthesis and trilostane blocks synthesis of all three types of adrenal steroid Glucocorticoid Receptor GR 777 aa found in cytoplasm of most cells associated with HSPs e g HSP90 Upon activation by cortisol cortisol translocates as a dimer w o HSPs HSPs to nucleus Can also activate rapid signaling events in cytosol non nongenomic GR Similar ligand and DNA binding regions Lacking part of C terminus 3 GR Corticoid Cortisol Mineralocorticoid relationship 4 Figure 28 6 Molecular mechanism of action of glucocorticoids A Transactivation mechanism transcriptional machinery TM is presumed to be operating at a low level The liganded glucocorticoid receptor GR dimer binds to one or more positive glucocorticoid response elements GREs within the promoter sequence shaded zone and up regulates transcription B Transrepression mechanism The transcriptional machinery is constitutively driven by transcription factors TF In binding to the negative GRE nGRE the receptor complex displaces these factors and expression falls C Fos Jun mechanism Transcription is driven at a high level by Fos Jun transcription factors binding to their AP 1 regulatory site This effect is reduced in the presence of the GR D Nuclear factor B mechanism The transcription factors P65 and P50 bind to the NF B site promoting gene expression This is prevented by the presence of the GR which binds the transcription factors preventing their action this may occur in the cytoplasm also 5 Pharmacokinetics Well absorbed orally Highly bound to plasma proteins CSBG Metabolized by liver excreted by kidney Plasma half life shorter than biological half life Substantial lag time before onset of action Persistence of effect after disappearance from plasma Physiological Effects of Glucocorticoids Direct receptor mediated effects Indirect effects homeostatic responses to other endogenous signals e g increase blood glucose increase in insulin insulin effects 6 General Actions of Endogenous Glucocorticoids Effects intermediate metabolism Regulation of the stress response Effects on central nervous system function Immunoregulation REQUIRED for LIFE 7 The Drugs Hydrocortisone Prednisone Betamethasone Corticosteroid Drugs Antiinflammatory potency Sodium retaining potency Plasma half life min Biological halflife hrs Approximate equivalent dose Cortisone 1 0 1 0 30 8 12 20 Hydrocortisone 0 8 0 8 80 118 8 12 25 Fludrocortisone 10 125 short Prednisone 4 0 0 8 16 18 36 5 Prenisolone 4 0 0 8 115 212 18 36 5 Methylprednisolone 5 0 0 5 78 188 18 36 4 Triamcinolone 5 0 0 200 18 36 4 Betamethasone 25 0 0 300 36 54 0 75 Dexamethasone 25 0 0 110 210 36 54 0 75 Paramethasone 12 5 0 300 36 54 2 0 mg Short acting Intermediate Long acting Mineralocorticoid Sometimes listed as long acting 8 Corticosteroids for Adrenal Insufficiency Congenital Adrenogenital Syndrome 21 hydroxylase insufficiency Shunting into production of sex steroids Masculinization of the external genitalia Treat by replacing glucocorticoids and mineralocorticoids General anti immune and inflammatory effects Anti inflammatory immunosuppressant Influence leukocyte movement antigen processing eosinophils and lymphatic tissues Inhibit mediators of inflammatory response Cytokines prostaglandins Inhibit accumulation of neutrophils and monocytes at site of inflammation inhibit phagocytosis antigen processing and bacteriocidal effects 9 10 11 Glucocorticoids Uses Arthritis Allergic reactions Asthma Autoimmune diseases Collagen diseases Prevention of graph rejection transplant Dermatological disorders Respiratory distress syndrome Collagen vascular diseases polymyalgia rheumatica rheumatica temporal arteritis Nephrotic syndrome 12 Cushing s Syndrome Metyrapone inhibits glucocorticoid synthesis aminoglutethimide inhibits both glucocorticoid and sex hormone synthesis and trilostane blocks all 3 13 14 15
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