Usage of glucocorticoids in bronchial asthma
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Usage of glucocorticoids in bronchial asthma






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  • Glucocorticoids: Simple, derivatives of cholesterol Regulate nearly every organ system in the body Maintain homeostasis; e.g. dampen immunoresponses, regulate glucose metabolism Most prescribed class of drugs world wide (treatment of varioue inflammatory diseases)

Usage of glucocorticoids in bronchial asthma Usage of glucocorticoids in bronchial asthma Presentation Transcript

  • DRUG THERAPY OF ASTHMA Glucocorticoids & Anti-Inflammatory Agents
        • To understand the mechanism of action of the anti-inflammatory agents used in treating asthma.
        • To understand the basic physiology of glucocorticoids and the mechanism of action of the glucocorticoid receptor.
        • To understand the basis for the anti-inflammatory actions of glucocorticoids
        • To understand the basic mechanisms and pharmacology of glucocorticoid therapy for asthma
  • IMPORTANT CONCEPT 1: Asthma is an inflammatory disease and thus effective treatments for the chronic management of asthma should be directed to reduce the inflammatory response
    • Reduce inflammation and immune responses
    • In clinical practice since 1948
    • $10,000,000,000./year market size in US
  • Steroid Hormones: Derived from Cholesterol Lipid Soluble: Able to cross plasma membrane by passive diffusion
          •  Regulation of carbohydrate, protein and lipid metabolism
          •  Maintenance of fluid and electrolyte balance
          • Preservation of normal function of the cardiovascular system, the immune system, the kidney, skeletal muscle, the endocrine system and the nervous system
          • Preservation of organismal homeostasis
  • GR GR
  • CELL TYPE FACTOR COMMENTS Macrophages Prostaglandins, Inhibition of COX-2, Monocytes Leukotrienes Phospholipase A2 IL-1, IL-6. TNF  Inhib. Transcript., Release Endothelial Cells ICAM-1. ELAM-1 Inhib. Transcript., Release IL-1, Prostagl., Leuko. As above Basophils Histamine, Leukotriene Inhib. IgE Release Lymphocytes IL-1, IL-2, IL-3, etc As above Effects of Glucocorticoids on Components of Inflammatory/Immune Responses
  • IMPORTANT CONCEPT 2: The anti-inflammatory and immunosuppressive actions of glucocorticoids play an important role in preventing potential damaging effects of an unopposed inflammatory response and can be exploited therapeutically
  • Glucocorticoids: Side Effects
  • IMPORTANT CONCEPT 3: The beneficial effects of systemic glucocorticoids to limit inflammation is counter-balanced by its many adverse side effects
  • Glucocorticoid Receptor Regulation of Transcription
  • Glucocorticoid Response Unit of the PEPCK Gene CEBP/ß TBP -27 -90 -325 COUP GR GR -380 HNF3 HNF4 -410 -445 +1 Accessory DNA-binding Factors Required!! ( Can impart tissue-specificity) NOTE: Phosphoenolpyruvate carboxykinase (PEPCK) gene is glucocorticoid regulated in liver only
  • IMPORTANT CONCEPT 4: Tissue- and cell type-specific effects of glucocorticoids are likely to be driven by many factors that influence the gene regulatory activity of the glucocorticoid receptor
  • +1 GRE Transcriptional Activation Transcriptional Repression I ( Direct DNA-binding ) H H +1 nGRE GR H +1 cGRE GR H Transcriptional Repression II ( Co-occupancy ) +1 GR H NF  B Transcriptional Repression III ( Tethering ) AP1 Basic Mechanisms of Transcriptional Activation/Repression by the Glucocorticoid Receptor GR GR
  • Glucocorticoid Side Effects: Molecular Mechanisms
  • IMPORTANT CONCEPT 5: The broad anti-inflammatory actions of glucocorticoids are due primarily to transcriptional repression of many pro-inflammatory genes in multiple cell types by the glucocorticoid receptor.
  • From Glass and Rosenfeld
  • IMPORTANT CONCEPT 6: The glucocorticoid receptor regulates gene transcription (either positively or negatively) through the gene-selective recruitment of histone modifying enzymes
  • Glucocorticoid Analogs
  • Relative Potencies of Glucocorticoids Compound Anti-Inflammatory Na+ -Retaining Duration Potency Potency of Action Cortisol 1 1 S Cortisone 0.8 0.8 S Prednisolone 4 0.8 I Triamcinolone 5 0 I Betamethasone 25 0 L Dexamethasone 25 0 L
            • S, short (i.e., 8–12 hour biological half-life); I, intermediate (i.e., 12–36 hour biological half-life); L, long (i.e., 36–72 hour biological half-life)
  • IMPORTANT CONCEPT 7: Structural modifications of the natural glucocorticoid cortisol generate hormones with enhanced half-life and more potent and efficacious glucocorticoid activity
  • Lung Topical effect ~2-10% Liver First pass Metabolism (inactivation) GI Tract Mouth Deposition ~90% swallowed Lung Pulmonary absorption BLOOD STREAM Drug systemic effect + inactive metabolite Schematic representation of the disposition of inhaled drugs
  • IMPORTANT CONCEPT 8: The aerosol delivery of glucocorticoids to the lungs limits systemic exposure to the hormone and greatly reduces side effects
  • New Approaches for Glucocorticoid Treatment of Asthma
    • Fluticasone propionate (FLONASE)
  • New Approaches for Glucocorticoid Treatment of Asthma fluticasone propionate (FP) FP-17ß-carboxylic acid derivative cytochrome P450 3A4 (Liver) 1/2000 affinity for GR than FP!!
  • IMPORTANT CONCEPT 9: New generation synthetic glucocorticoids with more rapid metabolism in the liver overcome potential side effects due to ingested hormone upon aerosol delivery
  • Dissociated Glucocorticoids: Dissociating Transactivation from Transrepression Activity of the Glucocorticoid Receptor
  • IMPORTANT CONCEPT 10: New generation synthetic glucocorticoids that maintain gene repression but limit gene activation by the glucocorticoid receptor (i.e. dissociated glucocorticoids) may hold promise as anti-inflammatory drugs with reduced side effects
  • Mechanisms of Glucocorticoid Resistance in Asthma
  • Increased GRß Expression in Airway T cells of Patients with Glucocorticoid-Insensitive Asthma From: Hamid QA et al., (1999) Am J Respir Crit Care Med 159 , pp. 1600-1604 Bronchoalveolar lavage (BAL) cells and peripheral blood mononuclear cells (PBMC)
  • Effects of Stress on GR mRNA Expression in Normal Versus Asthmatic Children GR mRNA analyzed in total RNA samples from lymphocytes Acute stress in midst of ongoing chronic stress associated with reduced GR mRNA expression
    • Efficiency of GR transcriptional regulation related to GR expression
    • Stressful experiences may exacerbate asthma symptoms in children
    From: Miller GE & Chen E (2006) Proc Natl Acad Sci USA 103 , 5496-5501.
  • IMPORTANT CONCEPT 11: Disruptions in GR expression and signal transduction can contribute to corticosteroid-resistant asthma and underlie the worsening effects of stressful events on asthma symptoms.
  • Leukotriene Synthesis Pathway
  • Leukotriene Synthesis Pathway
  • Role of Leukotrienes in the Pathogenesis of Asthma
  • Leukotriene-Modifying Drugs for the Treatment of Asthma ZYFLO : 5-Lox Inhibitor SINGULAIR : Leukotriene-receptor antagonist
  • Cromolyn Sodium
    • EFFECTS:
    • Prevent both early and late asthmatic responses to inhaled allergens such as pollen
    • Reduce airway reactivity resulting from exposure to a range of inhaled irritants such as sulfur dioxide and cold air
    MECHANISM: Inhibit specific chloride channels in mast cells and sensory neurons
  • Mechanism of Action of Omalizumab (XOLAIR) Omalizumab
  • Novel Therapy: Nasal Delivery of an Anti-inflammatory Peptide Omalizumab Intranasal delivery of the cytoplasmic domain of CTLA-4 using a novel protein transduction domain prevents allergic inflammation Je-Min Choi et al. (2006) Nature Medicine Vol. 12, pp 574-579
  • Novel Therapy: Nasal Delivery of an Anti-inflammatory Peptide Omalizumab
    • CTLA-4 is an activation-induced surface molecule on T cells and is essential for the negative regulation of T-cell activation
    • The cytoplasmic domain of CTLA-4 is known to interact with the phosphatases SHP-1 or SHP-2, resulting in dephosphorylation of CD3-TCR chains, ERK and JNK, thereby inhibiting T-cell activation
  • Novel Therapy: Nasal Delivery of an Anti-inflammatory Peptide Omalizumab STRATEGY: USE PROTEIN TRANSDUCTION DOMAIN!!
    • Initially identified in Drosophila Antenaepedia protein and HIV Tat protein (1994)
    • Rich in basic residues
    • Efficiently enter cells even when linked to heterologous proteins, even when injected systemically
  • Novel Therapy: Nasal Delivery of an Anti-inflammatory Peptide Omalizumab Goblet cell staining Ovalbumin-induced asthma in mice PTD-linked peptide
  • IMPORTANT CONCEPT 12: Anti-inflammatory drugs that act on selective targets may be effective for the treatment of asthma and are likely to have fewer side effects than glucocorticoids