1Kishore K Wary, PhDAssistant ProfessorCenter for Lung and Vascular BiologyDepartment of PharmacologyUniversity of Illinois, Chicago, IL 60126Drugs useful in asthmaLearning objectives• Know working definitions of asthma and basic pathology of the disease.• Understand role of cell types and mediators in pathogenesis of asthma. • Know autonomic innervation of the lung as it relates to asthma.• Know rationale for use of !-agonists and their side effects.2• Know therapeutic actions of cromolyn and rationale for its use.• Know rationale for use of corticosteroids for treatment of asthma, and the frequently used steroid analogs.• Understand therapeutic actions and precautions in use of theophylline and its analogs for treatment of asthma.Objectives ContinuedDrug List Subclass Prototype Analogs•sympathomimetics epinephrine metaproterenolalbuterolterbutaline salmeterol •mast cellstabilizers cromolyn sodium nedocromil Na•corticosteroids prednisone beclomethasone triamcinolone•xanthines caffeine theophylline enprophylline aminophylline3Asthma: “narrowing of airways, which changes in severity either spontaneously or in response to challenge and is characterized by increased responsiveness of airways to provocative stimuli". Basic abnormality of asthma is increased excitability of smooth muscle or BHR (bronchial hyperresponsiveness). However, asthma cannot be defined by BHR alone because: • BHR in response to bronchial constrictors is found in some subjects without symptoms of asthma• asthma can be induced by allergens in subjects who do not show BHR to provocative bronchial constrictorsDefinition of AsthmaWorking definitionsAsthmaPresence of intermittent symptoms such as chest tightness, wheeze, and cough, together with demonstrable BHR. AtopyProduction of IgE antibodies in response to aeroallergens (type I response). BHR (Bronchial Hyper-Responsiveness) 20% decrease in FEV1 (Forced Expiratory Volume in 1 second) in response to a provoking stimulus that causes less than a 5% decrease in normal subjects (at the same dose); or 20% increase in FEV1 in response to an inhaled bronchodilating drug. (In asthmatics, the FEV1 response to histamine or methacholine is 10! to 100!fold greater than normal subjects.)4Classifications of AsthmaExtrinsicasthma occurring in atopic patient; can result in acuteattacks; e.g. pollen asthma, exercise-induced asthma. Intrinsicno evidence of atopy; often begins in adults; can be chronic in nature Occupationaloccurs with exposure to provoking agents at the workplace; symptoms usually lessen on withdrawal from stimulusCells of Airway in Asthma1. Bronchial smooth muscle• abnormal hypertrophy • contractile response is supra-normal; relaxation is abnormal2. Mediator- releasing cells• Mast cellsa. found in entire length of airway epitheliumb. cell numbers increased c. in allergic asthma, mediators released at lower doses of provocative stimulus• Basophilsa. involved in late phase of allergic reactionsb. in asthmatics, circulating basophils are hyperresponsive to histamine secretagogues53. Mononuclear cells• Macrophagesa. scavengers in airways and alveoli; process antigens for presentation to lymphocytesb. stimulate mediator release from mast cells• Lymphocytesa. B-lymphocytes secrete IgE b. T-helper cells make mast cell secretagogues (e.g. IL-3, eosinophil-activating and chemotactic factors)64. Vascular endothelial cells• airway edema results from protein and fluid leakage from microvasculature• endothelial cells contract in response to histamine, leukotrienes, and substance P5. Eosinophils• infiltrate airways in asthma in response to mast cell-derived chemotactic factors• release tissue-damaging proteins involved in the epithelial shedding; Major Basic Protein (MBP)6. Airway epithelial cells• produce mediators; 5-HETE, LTB4, PGE2• shed in asthma as result of leukocyte adherence and transmigration• epithelial shedding and increased epithelial permeability involved in development of bronchial hyper-responsiveness; if devoid of epithelium show increased responsiveness to bronchoconstrictors77. Mucous-secreting cells (Goblet cells, mucous glands)• mucous plugging is common• mucous secretion stimulated by cholinergic agonists and mast cell mediators8. Role of mediators in asthma• histaminea. bronchoconstrictorb. vasodilatorc. can be released without BHR; thus, it is unlikely that histamine causes BHR • eosinophil chemotactic factor (ECF)a. involved in development of BHR through damage to airway epithelium by eosinophil-derived MBP b. released after allergic and exercise challenge• "newly generated factors"a. prostaglandins and leukotrienesb. LTs important in asthma8Summary of Mechanisms Underlying AsthmaSmooth musclecontractionimmediate symptoms• episodic wheezingMCTBEO AllergenIL-5IL-4IgE productionHistamine, LTs, PGs, PAFPAF, LTs Basicproteinsinflammationchronic symptons• chronic wheezing• bronchial hyperresponsiveness1. Intrinsic Asthma (lower pathway)• T!lymphocytes are activated directly by allergens, then secrete lymphokines• lymphokines activate eosinophils, which secrete mediators and damaging proteins• mediators potentiate inflammation and damage epithelium, enhancing BHR• important in chronic form of asthma92. Extrinsic Asthma (upper pathway)• allergens (or other stimuli) directly activate mast cells and eosinophils through surface-bound IgE• released mediators elicits bronchoconstriction and leads to chronic symptoms • involved in severe acute attacksMCTBEO AllergenIL-5IL-4IgE productionHistamine, LTs, PGs, PAFPAF, LTs BasicproteinsAutonomic Nervous System in Asthma101. Beta-adrenergic system• No direct sympathetic nerve supply to bronchial smooth muscle in humans• !2-adrenoceptors are found along the bronchial tree in smooth muscle; agonists cause relaxation of muscle cells and bronchodilation• Asthmatics rely on circulating catecholamines for !2-receptor stimulation (lower levels at night are associated with asthma)• !2-adrenoceptors are altered asthmatics; i.e., long-term use of !-agonists doesn’t desensitize !2-receptors as in normal or atopic subjects2. "#adrenergic system• Role in asthma poorly understood• In asthmatics, stimulation may cause bronchoconstriction• Agonists