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Similaire à Usage of glucocorticoids in bronchial asthma
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Usage of glucocorticoids in bronchial asthma
- 1. DRUG THERAPY OF ASTHMA Glucocorticoids & Anti-Inflammatory Agents www.freelivedoctor.com
- 4. 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 www.freelivedoctor.com
- 6. Steroid Hormones: Derived from Cholesterol Lipid Soluble: Able to cross plasma membrane by passive diffusion www.freelivedoctor.com
- 9. 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 www.freelivedoctor.com
- 10. 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 www.freelivedoctor.com
- 11. Glucocorticoids: Side Effects www.freelivedoctor.com
- 12. IMPORTANT CONCEPT 3: The beneficial effects of systemic glucocorticoids to limit inflammation is counter-balanced by its many adverse side effects www.freelivedoctor.com
- 13. NUCLEAR RECEPTOR SUPERFAMILY www.freelivedoctor.com
- 15. Glucocorticoid Receptor Regulation of Transcription www.freelivedoctor.com
- 16. 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 www.freelivedoctor.com
- 17. 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 www.freelivedoctor.com
- 18. +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 www.freelivedoctor.com GR GR
- 19. Glucocorticoid Side Effects: Molecular Mechanisms www.freelivedoctor.com
- 20. 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. www.freelivedoctor.com
- 21. From Glass and Rosenfeld www.freelivedoctor.com
- 24. IMPORTANT CONCEPT 6: The glucocorticoid receptor regulates gene transcription (either positively or negatively) through the gene-selective recruitment of histone modifying enzymes www.freelivedoctor.com
- 27. IMPORTANT CONCEPT 7: Structural modifications of the natural glucocorticoid cortisol generate hormones with enhanced half-life and more potent and efficacious glucocorticoid activity www.freelivedoctor.com
- 28. 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 www.freelivedoctor.com
- 29. IMPORTANT CONCEPT 8: The aerosol delivery of glucocorticoids to the lungs limits systemic exposure to the hormone and greatly reduces side effects www.freelivedoctor.com
- 31. 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!! www.freelivedoctor.com
- 32. 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 www.freelivedoctor.com
- 33. Dissociated Glucocorticoids: Dissociating Transactivation from Transrepression Activity of the Glucocorticoid Receptor www.freelivedoctor.com
- 34. 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 www.freelivedoctor.com
- 35. Mechanisms of Glucocorticoid Resistance in Asthma www.freelivedoctor.com
- 36. 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) www.freelivedoctor.com
- 38. 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. www.freelivedoctor.com
- 40. Leukotriene Synthesis Pathway www.freelivedoctor.com
- 41. Leukotriene Synthesis Pathway www.freelivedoctor.com
- 42. Role of Leukotrienes in the Pathogenesis of Asthma www.freelivedoctor.com
- 43. Leukotriene-Modifying Drugs for the Treatment of Asthma ZYFLO : 5-Lox Inhibitor SINGULAIR : Leukotriene-receptor antagonist www.freelivedoctor.com
- 45. Mechanism of Action of Omalizumab (XOLAIR) Omalizumab www.freelivedoctor.com
- 46. 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 www.freelivedoctor.com
- 49. Novel Therapy: Nasal Delivery of an Anti-inflammatory Peptide Omalizumab Goblet cell staining Ovalbumin-induced asthma in mice PTD-linked peptide www.freelivedoctor.com
- 50. 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 www.freelivedoctor.com
Notes de l'éditeur
- 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)