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Glucocorticoids Guochang Hu, MD, PhD Department of Pharmacology University of Illinois College of Medicine

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Presentation on theme: "Glucocorticoids Guochang Hu, MD, PhD Department of Pharmacology University of Illinois College of Medicine"— Presentation transcript:

1 Glucocorticoids Guochang Hu, MD, PhD Department of Pharmacology University of Illinois College of Medicine

2 Knowledge Objectives 1. Synthesis, regulation and mechanisms of action 2. Physiological effects 3. Pharmacological effects 4. Glucocorticoid drugs 5. Clinical uses 6. Side effects

3 Adrenal Medulla Adrenal Medulla Adrenal Cortex Adrenal Cortex Zona Glomerulosa Zona Glomerulosa Zona Faciculata Zona Faciculata Zona Reticularis Zona Reticularis Cortex Medulla Sites of Steroid Synthesis – Adrenal gland

4 Mineralocorticoid Glucocorticoid Sex steroids Sites of corticosteroid Synthesis – Cortex of Adrenal gland

5 Diurnal Variation of Glucocorticoids % Change 12 Midnight 12 Noon 12 Midnight 8-10 am 2 am Note: Related to sleep-Wake Cycle LKS

6 Hypothalamic-Pituitary-Adrenal (HPA) Axis Feedback CRH – Corticotropin releasing hormone ACTH – Adreno-corticotropic hormone ACTH binds receptors on surface of cells in zona fasciculata of adrenal cortex – cAMP second messenger increases production of glucocorticoid from cholesterol Cortico-centers -Amygdala – anterior brain - circadian rhythm - circadian rhythm - Reticular Formation – -Stressful stimuli Glucocorticoid

7 The long negative feedback loop is more important than the short loop. Exogenous glucocorticoid negatively regulates synthesis and secretion of endogenous glucocorticoid CRH ACTH Regulation of synthesis and secretion of adrenal corticosteroids 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)

8 Metyrapone inhibits both glucocorticoid and mineralocorticoid synthesis. Aminoglutethimide and trilostane blocks synthesis of all three types of adrenal steroid. Mineralocorticoid Biosynthesis of corticosteroids and adrenal androgens Cholesterol

9 Mechanism of Action Enters target cells by simple diffusion Enters target cells by simple diffusion Binds to cytosolic receptors Binds to cytosolic receptors The steroid receptor complex translocates into the nucleus The steroid receptor complex translocates into the nucleus Regulates the synthesis of specific proteins Regulates the synthesis of specific proteins

10 Steroid Receptor Activation S: steroid CBG: corticosteroid- binding globulin HSP: heat shock protein GRE: glucocorticoid response element

11 Glucocorticoid Receptor (GR) Expressed in a almost every cell (cytosol) in the body and regulates genes controlling the development, metabolism, and immune response. Expressed in a almost every cell (cytosol) in the body and regulates genes controlling the development, metabolism, and immune response. Associated with HSPs (e.g. HSP90) Associated with HSPs (e.g. HSP90) Upon activation by cortisol, GR translocates as a dimer (w/o HSPs) to nucleus (w/o HSPs) to nucleus Can also activate rapid signaling events in cytosol (non-genomic)

12 Target Tissues of Glucocorticoids Liver Liver Skeletal Muscle Skeletal Muscle Adipose Tissue Adipose Tissue Bone Bone Brain Brain Skin Skin Retina Retina Kidneys Kidneys Heart Heart Lymphoids Lymphoids Smooth Muscle Smooth Muscle Lung Lung Stomach Stomach Intestines Intestines Fibroblast Fibroblast Testes Testes = Most Important

13 Physiological Effects Direct receptor-mediated effects Direct receptor-mediated effects Indirect effects – homeostatic Indirect effects – homeostatic responses to other endogenous signals responses to other endogenous signals e.g. – increase blood glucose – increase in insulin

14 Physiological Effects 1. Metabolic Effects: Catabolic, glucose 2. Antiinflammatory and Immunosuppressive Effects Immunosuppressive Effects 3. Other Effects

15 Metabolic effects Glucose Glucose Influence carbohydrate and fat metabolism to ensure adequate delivery of glucose to the brain Influence carbohydrate and fat metabolism to ensure adequate delivery of glucose to the brain Increase gluconeogenesis, decrease peripheral use of glucose Increase gluconeogenesis, decrease peripheral use of glucose Fat Fat Increase in free fatty acids (increased lipolysis) Increase in free fatty acids (increased lipolysis) Redistribution of fat from the extremities to the trunk and face (buffalo hump) Redistribution of fat from the extremities to the trunk and face (buffalo hump) Protein Protein Favors protein breakdown and helps mobilize amino acids to the liver for gluconeogenesis Favors protein breakdown and helps mobilize amino acids to the liver for gluconeogenesis

16 Anti-inflammatory and immunosuppressant activity Anti-inflammatory and immunosuppressant activity Increase in circulating levels of neutrophils by interfering with adhesion Increase in circulating levels of neutrophils by interfering with adhesion Decrease in eosinophils, lymphocytes, and monocytes Decrease in eosinophils, lymphocytes, and monocytes Decrease leukocyte migration, and phagocytic activity Decrease leukocyte migration, and phagocytic activity Decrease production of phospholipase A, prostaglandins, thromboxanes and leukotrienes Decrease production of phospholipase A 2, prostaglandins, thromboxanes and leukotrienes

17 Other Effects 1. Electolytes: Decrease absorption of Ca 2+ from the intestine and increase renal excretion of Ca 2+ Increased Na + and H 2 O reabsorption, increased K + excretion. 2. Cardiovascular effects: Facilitates the effects of catecholamine, Maintenance of BP 3. Respiratory: Facilitates action of catecholamines (relax airway smooth muscle) Fetal lung maturation, increased surfactant secretion 4. Muscle: Maintain normal skeletal muscle 5. CNS Effects: mood, sleep patterns, and EEG

18 Pharmacokinetic Features Well absorbed orally Well absorbed orally Highly bound to plasma proteins (90%) - CBG Highly bound to plasma proteins (90%) - CBG Metabolized by liver (P450 3A4 enzymes); excreted by kidney (75%) Metabolized by liver (P450 3A4 enzymes); excreted by kidney (75%) Plasma half-life shorter than biological half- life Plasma half-life shorter than biological half- life Substantial lag time before onset of action Substantial lag time before onset of action Persistence of effect after disappearance from plasma Persistence of effect after disappearance from plasma

19 Pharmacological Effects (1) Osteoporosis of Bone Osteoporosis of Bone Skin Thinning and Wasting Skin Thinning and Wasting Connective Tissue Breakdown Connective Tissue Breakdown Blood Changes Blood Changes Neutrophils & Thrombocytes & RBC’s Neutrophils & Thrombocytes & RBC’s Lymphocytes & Eosinophils & Basophils Lymphocytes & Eosinophils & Basophils CNS Effects: Mood Stability, Psychoses, CNS Effects: Mood Stability, Psychoses, Excitability Excitability H 2 O Retention H 2 O Retention

20 Pharmacological Effects (2) Suppressed Immune Response-- Antiinflammatory Reaction Suppressed Immune Response-- Antiinflammatory Reaction Destruction of Eosinophils Destruction of Eosinophils Stabilization of Lysosomal Membranes Stabilization of Lysosomal Membranes Inhibition of Arachidonic Metabolism Inhibition of Arachidonic Metabolism Lipocortin (annexin) production Lipocortin (annexin) production Phospholipase A 2 Phospholipase A 2 Prostaglandins & Prostacyclins & Leucotrienes Vasoconstriction and loss of Edema Prostaglandins & Prostacyclins & Leucotrienes Vasoconstriction and loss of Edema

21 A. Transactivation mechanism: up-regulate the expression of anti- inflammatory proteins (lipocortin I). B. Transrepression mechanism: down-regulate the expression of proinflammatory proteins (NF-кB, Fos, IL-1, TNF- α) Molecular mechanism of Anti-inflammatory effect Transcriptional machinery (TM) transcription factors (TF).

22 Mechanism of Anti-Inflammatory Effect Suppress T-cell activation and cytokine production Suppress T-cell activation and cytokine production Suppress mast cell degranulation Suppress mast cell degranulation Decrease capillary permeability indirectly by inhibiting mast cells and basophils Decrease capillary permeability indirectly by inhibiting mast cells and basophils Reduce the expression of cyclooxygenase II and prostaglandin synthesis Reduce the expression of cyclooxygenase II and prostaglandin synthesis Reduce prostaglandin, leukotriene and platelet activating factor levels by altering phospholipase A 2 activity Reduce prostaglandin, leukotriene and platelet activating factor levels by altering phospholipase A 2 activity

23 Mechanism of Action of Anti-Inflammatory Steroids

24 Effects on cytokines and Inflammatory Mediators of

25 Glucocorticoid Drugs

26 Endogenous Glucocorticoids

27 Synthetic Glucocorticoids

28 Comparison of Corticosteroids 1.Stronger potency 2.Lower dose 3.Longer duration Differences between glucocorticoid drugs are potency, duration of action of the base, and pharmacokinetic behavior of the salts. Synthetic Drugs

29 Clinical Uses of Glucocorticoids Replacement Therapy Anti-Inflammatory Immuno-suppression Treatment of Allergic Disorders

30 Low adrenal activity Low adrenal activity Hypoglycemia, hypotension, weakness, anorexia, irritability Hypoglycemia, hypotension, weakness, anorexia, irritability Hyperpigmentation, Hyperpigmentation, hyperkalemia, hyponatremia hyperkalemia, hyponatremia Glucocorticoid Insufficiency (Addison’s Disease)

31 Anti-inflammatory and anti-allergic effects

32 Immuno-suppression

33 Glucocorticoids – Uses for diseases Arthritis Arthritis Allergic reactions Allergic reactions Asthma Asthma Autoimmune diseases Autoimmune diseases Collagen disease Collagen disease Collagen vascular diseases – polymyalgia rheumatica, temporal arteritis Collagen vascular diseases – polymyalgia rheumatica, temporal arteritis Nephrotic syndrome Nephrotic syndrome Prevention of graft rejection (transplant) Dermatological disorders Respiratory distress syndrome

34 Side Effects Adrenocortical insufficiency: Suppression of HPA Adrenocortical insufficiency: Suppression of HPA Adrenocortical excess (Cushing’s disease): “Moon face”, “buffalo hump” Adrenocortical excess (Cushing’s disease): “Moon face”, “buffalo hump” Diabetes Mellitus Diabetes Mellitus CNS effects: psychological and behavioral changes; aggravation of pre-existing psychiatric disorders CNS effects: psychological and behavioral changes; aggravation of pre-existing psychiatric disorders Impaired wound healing Impaired wound healing Musculoskeletal effects: osteoporosis (brittle bones), muscle weakness and atrophy Musculoskeletal effects: osteoporosis (brittle bones), muscle weakness and atrophy Cardiovascular effects: fluid retention, edema, hypertension Cardiovascular effects: fluid retention, edema, hypertension

35 Cushing’s Syndrome

36 Hyper- Adrenalism Hyper- Adrenalism Primarily the Glucocorticoids Primarily the Glucocorticoids

37 Side effects – – impaired release of GH and decreased activity of insulin-like growth factor-1 (IGF-1) in growing bone

38 Side effects

39 1.“Cold turkey” if glucocorticoid therapy of less than 2 weeks duration 2.Taper off if Glucocorticoid therapy of greater than 2 weeks duration. 3.Rate of taper should be proportional to duration of prior therapy. 4.The longer the original therapy, the slower the rate of dose reduction. Withdrawal syndrome: hypotension, hypoglycemia, myalgia and fatigue, joint pain, muscle stiffness, muscle tenderness, or fever. Withdrawal


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