Glucocorticoids

1. Glucocorticoids Guochang Hu, MD, PhD Department of Pharmacology University of Illinois College of Medicine gchu@uic.edu

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. Sites of Steroid Synthesis – Adrenal gland • Adrenal Medulla • Adrenal Cortex • ZonaGlomerulosa • ZonaFaciculata • ZonaReticularis Cortex Medulla

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

5. Diurnal Variation of Glucocorticoids % Change +100 Note: Related to sleep-Wake Cycle 8-10 am 0 -100 2 am 12 Midnight 12 Noon 12 Midnight LKS

6. Hypothalamic-Pituitary-Adrenal (HPA) Axis Feedback Cortico-centers • Amygdala – anterior brain - circadian rhythm • Reticular Formation – • Stressful stimuli 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 Glucocorticoid

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

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

9. 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

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. • Associated with HSPs (e.g. HSP90) Upon activation by cortisol, GR translocates as a dimer (w/o HSPs) to nucleus Can also activate rapid signaling events in cytosol (non-genomic)

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

13. Physiological Effects Direct receptor-mediated effects Indirect effects – homeostatic 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 3. Other Effects

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

16. Anti-inflammatory and immunosuppressant activity Increase in circulating levels of neutrophils by interfering with adhesion Decrease in eosinophils, lymphocytes, and monocytes Decrease leukocyte migration, and phagocytic activity Decrease production of phospholipase A2, prostaglandins, thromboxanes and leukotrienes

17. Other Effects 1. Electolytes: Decrease absorption of Ca2+from the intestine and increase renal excretion of Ca2+ Increased Na+ and H2O 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 • Highly bound to plasma proteins (90%) - CBG • Metabolized by liver (P450 3A4 enzymes); excreted by kidney (75%) • Plasma half-life shorter than biological half-life • Substantial lag time before onset of action • Persistence of effect after disappearance from plasma

19. Pharmacological Effects (1) • Osteoporosis of Bone • Skin Thinning and Wasting • Connective Tissue Breakdown • Blood Changes • Neutrophils & Thrombocytes & RBC’s • Lymphocytes & Eosinophils & Basophils • CNS Effects: Mood Stability, Psychoses, • Excitability • H2O Retention

20. Pharmacological Effects (2) Suppressed Immune Response--Antiinflammatory Reaction Destruction of Eosinophils Stabilization of Lysosomal Membranes Inhibition of Arachidonic Metabolism Lipocortin (annexin) production Phospholipase A2 Prostaglandins & Prostacyclins & Leucotrienes Vasoconstriction and loss of Edema

21. Molecular mechanism of Anti-inflammatory effect 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) transcription factors (TF). Transcriptional machinery (TM)

22. Mechanism of Anti-Inflammatory Effect Suppress T-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

23. Mechanism of Action of Anti-Inflammatory Steroids

24. of Effects on cytokines and Inflammatory Mediators

25. Glucocorticoid Drugs

26. Endogenous Glucocorticoids

27. Synthetic Glucocorticoids

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

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

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

31. Anti-inflammatory and anti-allergic effects

32. Immuno-suppression

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

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

35. Cushing’s Syndrome

36. Cushing’s Syndrome • Hyper-Adrenalism • 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. Withdrawal • “Cold turkey” if glucocorticoid therapy of less than 2 weeks duration • Taper off if Glucocorticoid therapy of greater than 2 weeks duration. • Rate of taper should be proportional to duration of prior therapy. • 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.