Drugs Used for the Management of AsthmaReferenceLeaning ObjectivesDefinition of Asthma (What is Asthma?)Definition of AsthmaAsthma TherapyPowerPoint PresentationPathogenesis of Asthma (Immunological Model)Slide 9HyperresponsivenessMechanisms of Bronchial HyperreactivityAsthmatic BronchospasmSlide 13Slide 14Basic Pharmacology of Agents for Treatment of AsthmaSlide 16Basic Pharmacology (Sympathomimetic Agents)Slide 18Slide 19Slide 20Slide 21Slide 22Basic Pharmacology (β-adrenoceptor Agonists)Basic Pharmacology (Corticosteroids)Slide 25Clinical Pharmacology (Corticosteroids)Slide 27Slide 28Basic Pharmacology (Methylxanthine Drugs)Slide 30Slide 31Slide 32Basic Pharmacology (Antimuscarinic Agents)Slide 34Basic Pharmacology (Cromolyn & Nedocromil)Basic Pharmacology (Leukotriene Inhibitors)Slide 37Basic Pharmacology (Other Drugs)Slide 39QuestionsDrugs Used for the Drugs Used for the Management of AsthmaManagement of AsthmaJason X.-J. Yuan, M.D., Ph.D.Jason X.-J. Yuan, M.D., Ph.D.Professor of Medicine and Professor of Medicine and PharmacologyPharmacologyUniversity of Illinois at ChicagoUniversity of Illinois at ChicagoInstitute for Personalized Respiratory MedicineDepartment of Medicine(Section of Pulmonary, Critical Care, Sleep and Allergy )Department of PharmacologyCenter for Cardiovascular ResearchKatzung BG, Masters SB, Trevor AJKatzung BG, Masters SB, Trevor AJBasic & Clinical Basic & Clinical Pharmacology 11ePharmacology 11eChapter 20Chapter 20: Drugs Used in Asthma : Drugs Used in Asthma (Homer A. Boushey and Bertram G. Katzung)(Homer A. Boushey and Bertram G. Katzung)ReferenceReferenceLeaning ObjectivesLeaning ObjectivesDefinition and basic pathology of asthmaDefinition and basic pathology of asthmaVarious cell types and mediators in the Various cell types and mediators in the pathogenesis of asthmapathogenesis of asthmaRationale for the use of Rationale for the use of ββ-agonist-agonist therapy therapy ((bronchodilationbronchodilation) and its side effects) and its side effectsTherapeutic actions of Therapeutic actions of cromolyncromolyn ( (inhibiting inhibiting mast cell degranulationmast cell degranulation), ), corticosteroidscorticosteroids ((anti-inflammationanti-inflammation), and ), and theophyllinetheophylline ((bronchodilation and anti-inflammationbronchodilation and anti-inflammation))Definition of Asthma Definition of Asthma (What is Asthma?)(What is Asthma?)PhysiologicallyPhysiologically characterized characterized aa)) by by increased responsiveness of the trachea increased responsiveness of the trachea and bronchi to various stimuli and and bronchi to various stimuli and bb)) by by widespread narrowing of the airwayswidespread narrowing of the airwaysPathologicallyPathologically featured by airway featured by airway smooth muscle contraction, mucosal smooth muscle contraction, mucosal thickening from edema and cellular thickening from edema and cellular infiltration, an inspissation in the airway infiltration, an inspissation in the airway lumen of abnormally thick, viscid plugs lumen of abnormally thick, viscid plugs of mucus of mucusDefinition of AsthmaDefinition of AsthmaAsthma is a chronic inflammatory Asthma is a chronic inflammatory disease of the airwaysdisease of the airwaysHyper-responsivenessHyper-responsivenessAirway contraction (bronchospasm)Airway contraction (bronchospasm)InflammationInflammationAirway/bronchial remodeling Airway/bronchial remodeling (thickening)(thickening)Asthma TherapyAsthma TherapyShort-term Relievers:Short-term Relievers:BronchodilatorsBronchodilators–ββ-adrenoceptor agonists (e.g., isoproterenol)-adrenoceptor agonists (e.g., isoproterenol)–Antimuscarinic agents (e.g., theophylline)Antimuscarinic agents (e.g., theophylline)Long-term Controllers:Long-term Controllers:Anti-inflammatory AgentsAnti-inflammatory Agents–Inhaled corticosteroidInhaled corticosteroid–Leukotriene antagonistsLeukotriene antagonists–Inhibitors of mast cell degranulation (e.g., Inhibitors of mast cell degranulation (e.g., cromolyn or nedocromil)cromolyn or nedocromil)Schematic Diagram of the Deposition of Inhaled Drugs Delivery by inhalation results in the greatest local effect on airway smooth muscle with the least systemic toxicity. Aerosol deposition depends on particle size, breathing pattern, airway geometry. Even with particles in the optimal size range of 2-5 μm, 80-90% of the total dose of aerosol is deposited in the mouth or pharynx. Metered-dose inhaler (MDI)Pathogenesis of Pathogenesis of AsthmaAsthma((Immunological ModelImmunological Model))1)1)IgE antibodies bound to mast cells in airway IgE antibodies bound to mast cells in airway mucosa mucosa 2)2)On reexposure to antigens, antigen-antibody On reexposure to antigens, antigen-antibody interaction on the surface of master cells interaction on the surface of master cells triggers release/synthesis of mediators (e.g., triggers release/synthesis of mediators (e.g., histamine, tryptase, leukotrienes, and PGs)histamine, tryptase, leukotrienes, and PGs)3)3)Mediators (also including cytokines, Mediators (also including cytokines, interleukins) cause bronchial contraction interleukins) cause bronchial contraction (smooth muscle), vascular leakage, cellular (smooth muscle), vascular leakage, cellular infiltration, mucus hyper-secretioninfiltration, mucus hyper-secretion4)4)Inflammatory responseInflammatory responseConceptual Model for the Immunopathogenesis of Asthma1234Allergen causes synthesis of IgE which binds to mast cells;Allergen activates T-cellsOn reexposure to allergens, antigen-antibody interactioncauses release of mediatorsBronchoconstriction, vascularleakage, cellular infiltrationCytokines activate eosinophils/neutrophils releasing ECP/MBPproteases, PAF, and causelate reaction12343HyperresponsivenessHyperresponsivenessBronchospasm can be elicited by:Bronchospasm can be elicited by:Allergens (hypersensitivity to)Allergens (hypersensitivity to)Non-antigenic stimuli (e.g., distilled water, Non-antigenic stimuli (e.g., distilled water, exercise, cold air, sulfur dioxide, and rapid exercise, cold air, sulfur dioxide, and rapid ventilation) (“ventilation) (“nonspecific bronchial nonspecific bronchial hyperreactivityhyperreactivity” )” )Bronchial hyperreactivity is quantitated by Bronchial hyperreactivity is quantitated by measuring the fall in FEVmeasuring the fall in FEV11 (forced expiratory (forced
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