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UIC PCOL 425 - Corticosteroids 012709

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Outline1. Synthesis, regulation and mechanisms of action 2. Physiological effects3. Glucocorticoid drugs4. Pharmacological effects5. Clinical uses6. Side effectsGlucocorticoidsGlucocorticoidsAdrenal MedullaAdrenal MedullaAdrenal CortexAdrenal CortexZonaZonaGlomerulosaGlomerulosaZonaZonaFasiculataFasiculataZonaZonaReticularisReticularisCortexMedullaSites of Steroid Synthesis – Adrenal glandMineralocorticoidGlucocorticoidSex steroidsSites of Steroid Synthesis –Cortex of Adrenal glandDiurnal Variation of Diurnal Variation of GlucocorticoidsGlucocorticoids0-100+100% Change12 Midnight12Noon12 Midnight8-10 am2 amNote: Related to sleep-Wake CycleLKSHypothalamicHypothalamic--PituitaryPituitary--Adrenal (HPA) Adrenal (HPA) Axis FeedbackAxis FeedbackCRH CRH ––CorticotropinCorticotropinreleasing hormone releasing hormone ACTH ACTH ––AdrenoAdreno--corticotropiccorticotropichormone hormone ACTH binds receptors on surface ACTH binds receptors on surface of cells in of cells in zonazonafasciculatafasciculataof of adrenal cortex adrenal cortex ––cAMPcAMPsecond second messenger increases messenger increases production of production of glucocorticoidglucocorticoidfrom from cholesterolcholesterolCorticoCortico--centerscenters--AmygdalaAmygdala––anterior brain anterior brain --circadian rhythmcircadian rhythm--Reticular Formation Reticular Formation ––--Stressful stimuliStressful stimuliGlucocorticoidThe long negative feedback loop is more important than the short loop. Exogenous glucocorticoid negatively regulates synthesis and secretion of endogenous glucocorticoidCRHACTHRegulation of synthesis and secretion of adrenal corticosteroidsDaily administration of corticosteroidat physiological concentrations for atleast 2 weeks suppresses the HPA resulting in decreased production of endogenous hormones. Recovery maytake up to 9-12 months.ACTH has only a minimal effect on mineralocorticoid production. ADH, antidiuretic hormone (vasopressin)Metyrapone inhibits glucocorticoid synthesis, aminoglutethimide inhibits both glucocorticoidand sex hormone synthesis, and trilostane blocks synthesis of all three types of adrenal steroid.MineralocorticoidBiosynthesis of corticosteroids and adrenal androgensMechanism of ActionMechanism of ActionEnters target cells by simple diffusionEnters target cells by simple diffusionBinds to cytosolic receptorsBinds to cytosolic receptorsThe steroid receptor complex The steroid receptor complex translocatestranslocatesinto the nucleusinto the nucleusRegulates the synthesis of specific Regulates the synthesis of specific proteinsproteinsGlucocorticoidGlucocorticoidReceptorReceptorGRGRαα= 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 nucleus) to nucleusCan also activate rapid signaling events in cytosolCan also activate rapid signaling events in cytosol(non(non--genomic)genomic)GRGRββ??Similar ligand and DNA binding regionsSimilar ligand and DNA binding regionsLacking part of C terminusLacking part of C terminusSteroid Receptor ActivationSteroid Receptor ActivationS: steroidHSP: heat shock proteinCBG: corticosteroid-binding globulinGRE: glucocorticoidresponse elementPhysiological Effects Direct receptorDirect receptor--mediated effectsmediated effectsIndirect effects Indirect effects ––homeostatic homeostatic responses to other endogenous responses to other endogenous signalssignalse.ge.g. . ––increase blood glucoseincrease blood glucose––increase in insulinincrease in insulin––insulin effectsinsulin effectsTarget Tissues of Target Tissues of GlucocorticoidsGlucocorticoidsBrainBrainLiverLiverRetinaRetinaTestesTestesFibroblastsFibroblastsKidneysKidneysSkeletal MuscleSkeletal MuscleSkinSkinHeartHeartLymphoidsLymphoidsSmooth MuscleSmooth MuscleLungLungBoneBoneStomachStomachIntestinesIntestinesAdipose TissueAdipose Tissue= Most ImportantPhysiologic effectsPhysiologic effectsInfluence carbohydrate and fat metabolism to Influence carbohydrate and fat metabolism to ensure adequate delivery of ensure adequate delivery of glucoseglucoseto the brainto the brainIncrease Increase gluconeogenesisgluconeogenesis, decrease peripheral , decrease peripheral use of glucose and increase in free fatty acids use of glucose and increase in free fatty acids (increased (increased lipolysislipolysis))Decrease absorption of Decrease absorption of calciumcalciumfrom the from the intestine and increase renal excretion of calciumintestine and increase renal excretion of calciumPhysiologic effectsPhysiologic effectsRedistribution of fat Redistribution of fat from the extremities to the from the extremities to the trunk and face (buffalo hump)trunk and face (buffalo hump)Favors Favors protein breakdown protein breakdown and helps mobilize and helps mobilize amino acids to the liver for amino acids to the liver for gluconeogenesisgluconeogenesisAntiAnti--inflammatory and immunosuppressant inflammatory and immunosuppressant activityactivityIncrease in circulating levels of Increase in circulating levels of neutrophilsneutrophilsby by interfering with adhesioninterfering with adhesionDecrease in Decrease in eosinophilseosinophils, lymphocytes, and , lymphocytes, and monocytesmonocytesPhysiologic effectsPhysiologic effectsDecrease local edema, fibrin deposition, Decrease local edema, fibrin deposition, capillary dilatation, leukocyte migration, and capillary dilatation, leukocyte migration, and phagocyticphagocyticactivity activity Indirectly inhibits Indirectly inhibits phospholipasephospholipaseAA2(mediates (mediates arachidonicarachidonicacid release)acid release)End result is decreased production of End result is decreased production of prostaglandins, prostaglandins, thromboxanesthromboxanesand and leukotrienesleukotrienesMay also alter mood, sleep patterns, and EEG May also alter mood, sleep patterns, and EEG activityactivityPhysiological Effects (Summary)Physiological Effects (Summary)Glucocorticoid DrugsEndogenous Endogenous GlucocorticoidsGlucocorticoidsSynthetic Synthetic


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UIC PCOL 425 - Corticosteroids 012709

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