Glucocorticoids Guochang Hu MD PhD Department of Pharmacology University of Illinois College of Medicine Outline 1 Synthesis regulation and mechanisms of action 2 Physiological effects 3 Glucocorticoid drugs 4 Pharmacological effects 5 Clinical uses 6 Side effects Sites of Steroid Synthesis Adrenal gland Adrenal Medulla Adrenal Cortex Zona Glomerulosa Zona Faciculata Cortex Zona Reticularis Medulla Sites of Steroid Synthesis Cortex of Adrenal gland Mineralocorticoid Glucocorticoid Sex steroids Diurnal Variation of Glucocorticoids Change 100 8 10 am Note Related to sleep Wake Cycle 0 100 LKS 2 am 12 Midnight 12 Noon 12 Midnight Hypothalamic Pituitary Adrenal HPA Axis Feedback CorticoCortico centers Amygdala anterior brain circadian rhythm Reticular Formation Stressful stimuli Glucocorticoid CRH Corticotropin releasing hormone ACTH AdrenoAdreno corticotropic hormone ACTH binds receptors on surface of cells in zona fasciculata of adrenal cortex cAMP second messenger increases production of glucocorticoid from cholesterol Regulation of synthesis and secretion of adrenal corticosteroids CRH The long negative feedback loop is more important than the short loop Exogenous glucocorticoid negatively regulates synthesis and secretion of endogenous glucocorticoid ACTH Daily administration of corticosteroid at physiological concentrations for at least 2 weeks suppresses the HPA resulting in decreased production of endogenous hormones Recovery may take up to 9 12 months ACTH has only a minimal effect on mineralocorticoid production ADH antidiuretic hormone vasopressin Biosynthesis of corticosteroids and adrenal androgens Mineralocorticoid Metyrapone inhibits glucocorticoid synthesis aminoglutethimide inhibits both glucocorticoid and sex hormone synthesis and trilostane blocks synthesis of all three types of adrenal steroid Mechanism of Action Enters target cells by simple diffusion Binds to cytosolic receptors The steroid receptor complex translocates into the nucleus Regulates the synthesis of specific proteins 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 non genomic GR Similar ligand and DNA binding regions Lacking part of C terminus Steroid Receptor Activation S steroid HSP heat shock protein CBG corticosteroidbinding globulin GRE glucocorticoid response element Physiological Effects Direct receptor mediated effects Indirect effects homeostatic responses to other endogenous signals e g increase blood glucose increase in insulin insulin effects Target Tissues of Glucocorticoids Brain Liver Retina Testes Fibroblasts Kidneys Skeletal Muscle Skin Heart Lymphoids Smooth Muscle Lung Bone Stomach Intestines Adipose Tissue Most Important Physiologic effects Influence carbohydrate and fat metabolism to ensure adequate delivery of glucose to the brain Increase gluconeogenesis decrease peripheral use of glucose and increase in free fatty acids increased lipolysis Decrease absorption of calcium from the intestine and increase renal excretion of calcium Physiologic effects Redistribution of fat from the extremities to the trunk and face buffalo hump Favors protein breakdown and helps mobilize amino acids to the liver for gluconeogenesis Anti inflammatory and immunosuppressant activity Increase in circulating levels of neutrophils by interfering with adhesion Decrease in eosinophils lymphocytes and monocytes Physiologic effects Decrease local edema fibrin deposition capillary dilatation leukocyte migration and phagocytic activity Indirectly inhibits phospholipase A2 mediates arachidonic acid release End result is decreased production of prostaglandins thromboxanes and leukotrienes May also alter mood sleep patterns and EEG activity Physiological Effects Summary Glucocorticoid Drugs Endogenous Glucocorticoids Synthetic Glucocorticoids Comparison of Corticosteroids 1 Stronger potency 2 Lower dose 3 Longer duration Pharmacokinetic Features Well absorbed orally Highly bound to plasma proteins CSBG Metabolized by liver P450 3A4 enzymes excreted by kidney 75 Plasma half life shorter than biological halflife Substantial lag time before onset of action Persistence of effect after disappearance from plasma Pharmacological Effects 1 Osteoporosis of Bone Skin Thinning and Wasting Connective Tissue Breakdown Blood Changes Neutrophils Thrombocytes RBC RBC s Lymphocytes Eosinophils Basophils CNS Effects Mood Stability Psychoses Excitability H2O Retention Pharmacological Effects 2 Suppressed Immune Response Antiinflammatory Reaction Destruction of Eosinophils Stabilization of Lysosomal Membranes Inhibition of Arachidonic Metabolism Lipocortin annexin annexin production Phospholipase A2 Prostaglandins Prostacyclins Leucotrienes Vasoconstriction and loss of Edema Mechanism of Action of Anti Inflammatory Steroids Mechanism of Anti Inflammatory Effect Suppress TT cell activation and cytokine production Suppress mast cell degranulation Decrease capillary permeability indirectly by inhibiting mast cells and basophils Reduce the expression of cyclooxygenase II and prostaglandin synthesis Reduce prostaglandin leukotriene and platelet activating factor levels by altering phospholipase A2 activity Molecular mechanism of Anti inflammatory effect A Transactivation mechanism B Transrepression mechanism C Fos Jun mechanism D Nuclear factor B mechanism Transcriptional machinery TM transcription factors TF Effects on cytokines and Inflammatory Mediators of Clinical Uses of Glucocorticoids Replacement Therapy Anti Inflammatory Immuno suppression Treatment of Allergic Disorders Glucocorticoid Insufficiency Addison s Disease Low adrenal activity Hypoglycemia hypotension weakness anorexia irritability Hyperpigmentation Hyperpigmentation hyperkalemia hyperkalemia hyponatremia Anti inflammatory and anti allergic effects Immuno suppression Glucocorticoids Uses for diseases Arthritis Allergic reactions Asthma Autoimmune diseases Collagen disease Collagen vascular diseases polymyalgia rheumatica rheumatica temporal arteritis Prevention of graft rejection transplant Dermatological disorders Respiratory distress syndrome Nephrotic syndrome Adverse Effects Adrenocortical insufficiency Suppression of HPA Adrenocortical excess Cushing Cushing s disease Moon face face buffalo hump hump Diabetes Mellitus CNS effects psychological and behavioral changes
View Full Document
Unlocking...