1GlucocorticoidsGlucocorticoidsMineralocorticoidsMineralocorticoidsPharmacologic Uses of Synthetic Pharmacologic Uses of Synthetic GlucocorticoidsGlucocorticoids• Replacement Therapy• Anti-Inflammatory• Immunosuppresion• Treatment of Allergic Disorders• Large doses for cerebral injury (anti-oxidant)2Figure 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, corticotrophin-releasing factor.Circadian Rhythm of Plasma Cortisol3Figure 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.mineralocorticoidGlucocorticoidGlucocorticoidReceptorReceptor!!GRGR!!= 777 = 777 aaaa; found in cytoplasm of most cells ; found in cytoplasm of most cells associated with associated with HSPsHSPs(e.g. HSP90)(e.g. HSP90)Upon activation by Upon activation by cortisolcortisol, , translocatestranslocatesas a as a dimerdimer(w/o (w/o HSPsHSPs) ) to nucleusto nucleusCan also activate rapid signaling events in cytosol (nonCan also activate rapid signaling events in cytosol (non--genomic)genomic)!!GRGR""##Similar ligand and DNA binding regionsSimilar ligand and DNA binding regionsLacking part of C terminusLacking part of C terminus4GR!Corticoid/Cortisol – Mineralocorticoid relationship5A. 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. Transrepressionmechanism. 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). Figure 28-6 Molecular mechanism of action of glucocorticoids6PharmacokineticsPharmacokinetics!!Well absorbed orallyWell absorbed orally!!Highly bound to plasma proteins Highly bound to plasma proteins --CSBGCSBG!!Metabolized by liver; excreted by kidneyMetabolized by liver; excreted by kidney!!Plasma halfPlasma half--life shorter than biological halflife shorter than biological half--lifelife!!Substantial lag time before onset of actionSubstantial lag time before onset of action!!Persistence of effect after disappearance from Persistence of effect after disappearance from plasmaplasmaPhysiological Effects of Glucocorticoids!!Direct receptorDirect receptor--mediated effectsmediated effects!!Indirect effects Indirect effects ––homeostatic responseshomeostatic responsesto other endogenous signalsto other endogenous signalse.ge.g. increase blood glucose . increase blood glucose ––increase in increase in insulin insulin ––insulin effectsinsulin effects7General Actions of Endogenous General Actions of Endogenous GlucocorticoidsGlucocorticoids!!Effects intermediate metabolismEffects intermediate metabolism!!Regulation of the stress responseRegulation of the stress response!!Effects on central nervous system functionEffects on central nervous system function!!ImmunoregulationImmunoregulation!!REQUIRED for LIFEREQUIRED for LIFE8Hydrocortisone Prednisone BetamethasoneThe Drugs2.036-54300+012.5Paramethasone0.7536-54110-210025.0Dexamethasone0.7536-54300+025.0BetamethasoneLong acting418-36200+05.0Triamcinolone418-3678-1880.55.0Methylprednisolone518-36115-2120.84.0Prenisolone518-36160.84.0PrednisoneIntermediate----short12510Fludrocortisone**258-1280-1180.80.8Hydrocortisone208-12301.01.0CortisoneShort actingApproximate equivalent dose(mg)Biological half-life (hrs)Plasma half-life (min)Sodium retaining potencyAnti-inflammatory potency** MineralocorticoidCorticosteroid Drugs** Sometimes listed as long acting9Corticosteroids for Adrenal InsufficiencyCorticosteroids for Adrenal InsufficiencyCongenital Congenital AdrenogenitalAdrenogenitalSyndromeSyndrome!!2121""--hydroxylase insufficiencyhydroxylase insufficiency!!Shunting into production of sex steroidsShunting into production of sex steroids!!MasculinizationMasculinizationof the external genitaliaof the external genitalia!!Treat by replacing Treat by replacing glucocorticoidsglucocorticoidsand and mineralocorticoidsmineralocorticoidsGeneral (anti) immune and General (anti) immune and inflammatory effectsinflammatory effects!!AntiAnti--inflammatory, immunosuppressantinflammatory, immunosuppressant!!Influence leukocyte movement, antigen Influence leukocyte movement, antigen processing, processing, eosinophilseosinophils, and lymphatic tissues., and lymphatic tissues.!!Inhibit mediators of inflammatory responseInhibit mediators of inflammatory response!!Cytokines, prostaglandinsCytokines, prostaglandins!!Inhibit accumulation of Inhibit accumulation of neutrophilsneutrophilsand and monocytesmonocytesat site of inflammation at site of inflammation ––inhibit inhibit phagocytosisphagocytosis, antigen processing and , antigen processing and bacteriocidalbacteriocidaleffects.effects.101112GlucocorticoidsGlucocorticoids--UsesUses!!ArthritisArthritis!!Allergic reactionsAllergic reactions!!AsthmaAsthma!!Autoimmune diseasesAutoimmune diseases!!Collagen diseasesCollagen diseases!!Collagen vascular Collagen vascular diseases diseases ––polymyalgiapolymyalgiarheumaticarheumatica, temporal , temporal arteritisarteritis!!NephroticNephroticsyndromesyndrome!!Prevention of graph Prevention of graph rejection (transplant)rejection (transplant)!!Dermatological
View Full Document
Unlocking...