Institute for Personalized Respiratory Medicine Department of Medicine Section of Pulmonary Critical Care Sleep and Allergy Department of Pharmacology Center for Cardiovascular Research Drugs Used for the Management of Asthma Jason X J Yuan M D Ph D Professor of Medicine and Pharmacology Reference Katzung BG Masters SB Trevor AJ Basic Clinical Pharmacology 11e Chapter 20 Drugs Used in Asthma Homer A Boushey and Bertram G Katzung Leaning Objectives Definition and basic pathology of asthma Various cell types and mediators in the pathogenesis of asthma Rationale for the use of agonist therapy bronchodilation and its side effects Therapeutic actions of cromolyn inhibiting mast cell degranulation corticosteroids anti inflammation and theophylline bronchodilation and anti inflammation Definition of Asthma What is Asthma Physiologically characterized a by increased responsiveness of the trachea and bronchi to various stimuli and b by widespread narrowing of the airways Pathologically featured by airway smooth muscle contraction mucosal thickening from edema and cellular infiltration an inspissation in the airway lumen of abnormally thick viscid plugs of mucus Definition of Asthma Asthma is a chronic inflammatory disease of the airways Hyper responsiveness Airway contraction bronchospasm Inflammation Airway bronchial remodeling thickening Asthma Therapy Short term Relievers Bronchodilators adrenoceptor agonists e g isoproterenol Antimuscarinic agents e g theophylline Long term Controllers Anti inflammatory Agents Inhaled corticosteroid Leukotriene antagonists Inhibitors of mast cell degranulation e g cromolyn or nedocromil Schematic Diagram of the Deposition of Inhaled Drugs Metered dose inhaler MDI 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 m 80 90 of the Pathogenesis of Asthma Immunological Model 1 IgE antibodies bound to mast cells in airway mucosa 2 On reexposure to antigens antigen antibody interaction on the surface of master cells triggers release synthesis of mediators e g histamine tryptase leukotrienes and PGs 3 Mediators also including cytokines interleukins cause bronchial contraction smooth muscle vascular leakage cellular infiltration mucus hyper secretion 4 Inflammatory response Conceptual Model for the Immunopathogenesis of Asthma 4 Cytokines activate eosinophils neutrophils releasing ECP MBP proteases PAF and cause late reaction 3 3 Bronchoconstriction vascular leakage cellular infiltration 3 2 2 4 On reexposure to allergens antigen antibody interaction causes release of mediators 1 1 Allergen causes synthesis of IgE which binds to mast cells Allergen activates T cells Hyperresponsiveness Bronchospasm can be elicited by Allergens hypersensitivity to Non antigenic stimuli e g distilled water exercise cold air sulfur dioxide and rapid ventilation nonspecific bronchial hyperreactivity Bronchial hyperreactivity is quantitated by measuring the fall in FEV1 forced expiratory volume in 1 s provoked by inhaling aerosolized histamine or methacholine serially increasing concentration Mechanisms of Bronchial Hyperreactivity 1 Inflammation of airway mucosa 2 Increased ozone exposure allergen inhalation viral infection causing airway inflammation 3 Increased inflammatory cells eosinophils neutrophils lymphocytes and macrophages and increased products from these cells causing airway smooth muscle contraction 4 Sensitization of sensory nerves afferent and efferent vagal nerves in the airways 5 Cellular mechanisms in airway smooth muscle cells and epithelial cells Asthmatic Bronchospasm Caused by a combination of Increased release synthesis of contractile mediators mainly from master cells and inflammatory cells Enhanced responsiveness of airway smooth muscle to these mediators Afferent and efferent vagal nerves e g cholinergic motor fibers innervate M3 receptors on the smooth muscle Airway smooth muscle cells Airway epithelial cells Mechanisms of Inhaled Irritant mediated Bronchial Constriction CNS Inhaled irritants can cause bronchoconstriction by 1 Triggering release of chemical mediators from response cells e g mast cells eosinophils neutrophils 1 2 1 ACh 2 Stimulating afferent receptors to initiate reflex bronchoconstriction via acetylcholine ACh or to release tachykinins e g substance P that directly stimulate smooth muscle contraction Asthmatic Bronchospasm Treated by drugs that Reduce the amount of IgE bound to mast cells anti IgE antibody Prevent mast cell degranulation cromolyn agonists calcium channel blockers Block the action of released mediators antihistamine leukotriene receptor blockers Inhibit the effect of acetylcholine ACh released from vagal motor nerves muscarinic antagonists Directly relax airway smooth muscle theophylline agonists Basic Pharmacology of Agents for Treatment of Asthma The drugs mostly used for management of asthma are Adrenoceptor Used as short term relievers or bronchodilators Inhaled agonists corticosteroids Used as long term controllers or anti inflammatory agents Basic Pharmacology of Agents for Treatment of Asthma Symathomimetic Agents adrenoceptor agonists Epinephrine isoproterenol salmeterol formoterol Corticosteroids Beclomethasone flunisolide fluticasone triamcinolone Methylxanthine Drugs Theophylline theobromine caffeine Antimuscarinic Agents Ipratropium atropine Cromolyn and Nedocromil inhibitors of mast cell degranulation Leukotriene Inhibitors Zileuton montelukast zafirlukast Other Drugs in the Treatment of Asthma Anti IgE monoclonal antibodies omalizumab calcium channel blockers nifedipine verapamil Nitric oxide donors sodium nitroprusside Basic Pharmacology Sympathomimetic Agents Adrenergic Receptors adrenoceptors receptors 1 2 receptors 1 heart muscle causing increased heart rate contractility kidney causing renin release 2 airway smooth muscle causing bronchodilation GI smooth muscle cardiac muscle skeletal muscle vascular smooth muscle 3 adipose tissue causing lipolysis increasing fatty acids in the blood Bronchodilation is Promoted by Increased cAMP Bronchodilation agonists AC adenylyl cyclase cAMP Bronchial tone Acetylcholine Muscarinic antagonists Theophylline Adenosine Theophylline Bronchoconstriction Activate or increase Inhibit or decrease Basic Pharmacology Sympathomimetic Agents Mechanisms of Action Activation of
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