Management of Asthma Jason X.-J. Yuan, M.D., Ph.D. Professor of Medicine and Pharmacology University of Illinois at Chicago Institute for Personalized Respiratory Medicine Department of Medicine (Section of Pulmonary, Critical Care, Sleep and Allergy ) Department of Pharmacology Center for Cardiovascular Research Katzung BG, Masters SB, Trevor AJ Basic & Clinical Pharmacology 11e Chapter 20: Drugs Used in Asthma (Homer A. Boushey and Bertram G. Katzung) Reference 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) 2 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) 3 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 m, 80-90% of the total dose of aerosol is deposited in the mouth or pharynx. Metered-dose inhaler (MDI) 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 1 2 3 4 Allergen causes synthesis of IgE which binds to mast cells; Allergen activates T-cells On reexposure to allergens, antigen-antibody interaction causes release of mediators Bronchoconstriction, vascular leakage, cellular infiltration Cytokines activate eosinophils/ neutrophils releasing ECP/MBP proteases, PAF, and cause late reaction 1 2 3 4 3 4 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 FEV 1 (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 M 3 receptors on the smooth muscle) Airway smooth muscle cells Airway epithelial cells 5 Mechanisms of Inhaled Irritant-mediated Bronchial Constriction 1 CNS Inhaled irritants can cause bronchoconstriction by: (1) Triggering release of chemical mediators from response cells (e.g., mast cells, eosinophils, neutrophils) (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 2 1 ACh 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 (anti- histamine, 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 agonists Used as short-term relievers or bronchodilators Inhaled corticosteroids Used as long-term controllers or anti- inflammatory agents 6 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 Bronchoconstriction cAMP Theophylline Theophylline Muscarinic antagonists -agonists Acetylcholine Adenosine Bronchial tone + _ Activate or increase Inhibit or decrease AC, adenylyl cyclase 7 Basic Pharmacology (Sympathomimetic Agents) Mechanisms of Action Activation of -adrenergic receptor 1 and 2 receptors G protein-coupled receptor Stimulation of adenylyl cyclase (AC) Ten known ACs (AC1-AC10) AC1, AC3 and AC8 are activated by Ca 2+ /CaM AC5 and AC6 are inhibited by Ca 2+ /CaM Increase in the formation of cAMP Relaxation of airway smooth muscle Molecular Action of 2 - agonists to Induce Airway Smooth Muscle Relaxation Basic Pharmacology (Sympathomimetic Agents) Non-selective -Adrenoceptor Agonists ( 1 and 2 ) Epinephrine Injected subcutaneously or inhaled as a microaerosol, rapid action (15 min) Ingredient in non-prescription inhalants Ephedrine Oral intake, long-lasting action, obvious central effects (used less frequently now) Isoproterenol Inhaled as a microaerosol, rapid action (5 min) 8 Basic Pharmacology (Sympathomimetic Agents) Selective 2 -Adrenoceptor Agonists (most widely used -agonists for the treatment of asthma) Terbutaline, Metaproterenol, Albuterol, Pirbuterol, Levalbuterol, Bitolterol Inhalation from a metered-dose inhaler Bronchodilation is maximal by 30 min and persists for 3-4 hrs Salmeterol, Formoterol Long-acting 2 agonists (12 hrs or more) High lipid solubility (into smooth muscle cells) Interact with inhaled corticosteroids to improve asthma control Basic Pharmacology (-adrenoceptor Agonists) Administration Inhalation (by aerosol) Available orally and for injection Side Effects Muscle tremor Tachycardia and palpitations Increased free fatty acid, glucose, lactate V/Q mismatch due to pulmonary vasodilation Basic Pharmacology (Corticosteroids) Mechanism of Action Anti-inflammatory effect mediated by inhibiting production of inflammatory cytokines Inhibition of the lymphocytic, eosinophic airway mucosal inflammation of asthmatic airways Reduce bronchial reactivity Reduce the frequency of asthma exacerbations if taken regularly No relaxant effect on airway smooth muscle Potentiate the effect of -agonists 9 Basic Pharmacology (Corticosteroids) Administration Inhaled (aerosol treatment is the most effective way to decrease the systemic adverse effects, e.g., lipid-soluble beclomethasone, budesonide, flunisolide, fluticasone, triamcinolone) Oral and parenteral (e.g., intravenous infusion) use is reserved for patients who require urgent treatment (nonresponders to bronchodilators) Clinical Pharmacology (Corticosteroids) Side Effects Dysphonia Oropharyngeal candidiasis (an opportunistic mucosal infection caused by the fungus ) Both can be reduced by mouth rinsing with water after inhalation vocal cords Effect of Corticosteroids on Inflammatory and Structural Cells in the Airway 1) Anti-inflammation 2) Reducing bronchial reactivity 10 Cellular Mechanism of anti- inflammatory Action of Corticosteroids in Asthma GR, glucocorticoid receptor Basic Pharmacology (Methylxanthine Drugs) Major methylxanthines Theophylline 1,3-dimethylxanthine Aminophylline (a theophylline-ethylenediamine complex) Dyphylline (a synthetic analog of theophylline) Theobromine 3,7-dimethylxanthine Caffeine 1,3,7-trimethylxanthine Inexpensive and can be taken orally Basic Pharmacology (Methylxanthine Drugs) Mechanisms of Action Bronchodilation Inhibition of phosphodiesterases (PDEs; e.g. PDE4), which results in an increased level of cAMP (and cGMP) causing airway smooth muscle relaxation Inhibition of adenosine receptor on the surface membrane (adenosine causes airway smooth muscle contraction and provokes histamine release from master cells) Anti-inflammation Inhibition of antigen-induced release of histamine from lung tissue 11 Theophylline Affects Multiple Cell Types in the Airway Mechanisms of Theophylline- mediated Bronchodilation Bronchodilation Bronchoconstriction cAMP Theophylline Theophylline Muscarinic antagonists -agonists Acetylcholine Adenosine Bronchial tone + _ Activate or increase Inhibit or decrease cGMP AC GC PDE4 PDE5 Theophylline AMP/GMP ATP/GTP PDE, phosphodiesterase Basic Pharmacology (Antimuscarinic Agents) Mechanism of Action Inhibits the effect of acetylcholine (ACh) at muscarinic (M) receptors Block airway smooth muscle contraction Decrease mucus secretion by blocking vagal activity Major Antimuscarinic Agents Atropine Ipratropium bromide (a selective quaternary ammonium derivative of atropine) Tiotropium (for COPD) 12 Antimuscarinic Agent- mediated Bronchodilation 1 CNS Atropine and Ipratropium blocks bronchoconstriction induced by vagal activity ACh Basic Pharmacology (Cromolyn & Nedocromil) Mechanism of Action Blockade of chloride channels and calcium channels in mast cells (and airway smooth muscle cells), and inhibition of cellular activation Inhibition of mast cell degranulation (inhibiting inflammatory response to allergens, exercise, cold air. Inhibition of eosinophils/neutrophils to release inflammatory mediators Inhibition of bronchial responsiveness (with long-term treatment) No bronchodilator or antihistamine activity Basic Pharmacology (Leukotriene Inhibitors) Mechanism of Action Leukotriene causes bronchoconstriction, increased bronchial reactivity, mucosal edema, and mucus hypersecretion Inhibition of 5-lipoxygenase on arachidonic acid leads to decreased synthesis of leukotriene (zileuton) Blockade of leukotriene D 4 receptors leads to decreased action of leukotriene (zafirlukast, montelukast) Both inhibitors (used orally) decrease airway responses to allergens and exercise 13 Effects of Leukotrienes on the Airways and Their Inhibition by Anti-leukotriene Drugs LTC4 Receptor Blockers LT Synthesis Inhibitors Basic Pharmacology (Other Drugs) Anti-IgE Monoclonal Antibodies Omalizumab (anti-IgE Mab) Calcium channel blockers Nifedipine, verapamil Nitric Oxide Donors Sodium nitroprusside (SNP) Possible Future Therapies Monoclonal antibody against to cytokines (e.g., IL-4/-5/-8), antagonists of cell adhesion molecules, protease inhibitors, etc. 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) 14 Questions Jason Yuan 312-355-5911 (office phone) jxyuan@uic.edu (email) COMRB 3131