1. Treatments for Asthma Ghazaleh Ebrahimnejadalamaki, Gea Panić, Natali Surkic, Romina Isip [1] PHM142 Fall 2015 Coordinator: Dr. Jeffrey Henderson Instructor: Dr. David Hampson

2. What is asthma? Bronchospasm: hyperreactivity of airways occurs due to smooth muscle contraction and relates to disease severity [2]. a chronic inflammatory disease of the airway characterized by reversible bronchospasm [2]. [3]

3. Autonomic Nervous System - Innervation of Lungs Parasympathetic constricts airways (bronchoconstriction) Sympathetic relaxes airways (bronchodilation) [2],[4],[5]

4. Parasympathetic: constricts airways (bronchoconstriction) Cholinergic receptors → Muscarinic Receptor M3 → stimulated by Acetylcholine [2],[4],[5]

5. Sympathetic: relaxes airways (bronchodilation) Adrenergic Receptors → B2 adrenergic receptor → stimulated by Epinephrine (E) E [2],[4],[5]

6. Asthma

7. Asthma Treatment Chronic inflammation Acute Inflammation Bronchoconstriction Oedema Secretions Cough Inflammatory Cell recruitment Epithelial damage [6]

8. Reliever Medications [7] used for quick relief of symptoms (ex. asthma attack) or prevention of exercise induced asthma bronchodilators only help with dilating the bronchi/bronchioles but do not reduce inflammation use should be limited medications include salbutamol and terbutaline (short-acting inhaled beta2- agonists)

9. Beta2-Agonist Mechanism [8]

10. Chronic Asthma Treatments Inhaled Corticosteroids [9] First line treatment to prevent asthma symptoms Act to inhibit recruitment of inflammatory cells and release of inflammatory mediators Advair, Flovent, Symbicort Leukotriene Modifiers [10] Used in combination with corticosteroids, most effective in treating mast cell disorders Prevent the action of leukotrienes in the body Montelukast, Zafirlukast, Pranlukast Immunomodulators [11] Used in combination with corticosteroids Block the activity of IgE before it can lead to an asthma attack Omalizumab

11. Corticosteroids [9]

12. Leukotriene Modifiers [10]

13. Immunomodulators/Biologics [11] Reduce the number of asthma attacks in people with moderate to severe allergic asthma when symptoms are not controlled by inhaled corticosteroids Block the activity of IgE (overproduced in allergic reactions) before asthma attack occurs Binding to IgE prevents it from binding to basophils and mast cells Decreases the number of basophils and prevents mast cells from releasing substances which would increase the severity of the allergic reaction

14. Future Directions? Large interest in developing biologics for the treatment of asthma such as Xolair (anti-IgE) Allows for a more personalized therapy management o depends on patient’s asthma clinical phenotype and endotype o use of biomarkers alongside treatment to better predict therapeutic outcome [12] Targets inflammatory mediators that can block amplification of pathways that lead to disease progression and exacerbation of symptoms [13] Examples: Anti-interleukin agents (anti-ILs) and Chemoattractant Receptor- homologous molecules expressed on T-helper type 2 lymphocyte (CRT H 2) antagonists [14]

15. Upcoming Treatments for Asthma [14] Current biologics undergoing clinical trials are: Anti-IL : Benralizumab (anti-IL-5), Dupilumab (anti-IL-4), Lebrikizumab (anti-IL-13) all are in phase 3 o decrease airway inflammation and inhibit eosinophil activation CRTH2 antagonists: OC000459 (phase 2) o inhibit activation of lymphocytes, eosinophils, and basophils which decreases asthma allergic response

16. Summary 1)Autonomic innervation: a)Parasympathetic: Muscarinic (M3) Receptor stimulated by Acetylcholine → bronchoconstriction b)Sympathetic: B2-adrenergic Receptor stimulated by Epinephrine → bronchodilation 2)Beta2-Agonists stimulate Beta2 Adrenergic receptors to increase cAMP levels and activate PKA through a G-protein, leading to smooth muscle relaxation 3)Corticosteroids reverse histone acetylation of the activated inflammatory genes 4)Leukotriene modifiers prevent the action of leukotrienes 5)Biologics block the activity of IgE before it can lead to an asthma attack 6)New therapies under clinical trials for asthma treatment: Anti-Interleukin agents, and CRTH2 antagonist: both act to decrease specific inflammatory response pathways

17. References 1. Untitled illustration of patient using puffer. Retrieved October 25, 2015, from http://www.ahealthy.us/wp-content/uploads/2010/12/ahealthy-us- asthama.jpg.http://www.ahealthy.us/wp-content/uploads/2010/12/ahealthy-us- asthama.jpg 2. Boushey, H. (2012). Drugs used in asthma. In Basic and clinical pharmacology (12th ed., pp. 339-358). McGraw-Hill Companies: Lange Medical Publications. 3. Untitled illustration of normal and asthmatic bronchiole. Retrieved October 25, 2015, from https://science-with- stevens.wikispaces.com/file/view/Gas+Exchange+Student+Notes.pdf.https://science-with- stevens.wikispaces.com/file/view/Gas+Exchange+Student+Notes.pdf 4. Sherwood, L. (2012). The peripheral nervous system: Efferent division. In Fundamentals of human physiology (4th ed., pp. 185-193). Belmont, CA: Brooks/Cole Cengage Learning. 5. Hong-Shuo, D. (2015, October 1). Autonomic Nervous System. Lecture presented at PHM145H1 Lecture in PB-B150, Toronto. 6. Boushey, H. (2012). Drugs used in asthma. In Basic and clinical pharmacology (12th ed., pp. 339-358). McGraw-Hill Companies: Lange Medical Publications. 7. McCormack, D. (n.d.). Asthma in Adults. Retrieved October 23, 2015, from http://www.e-therapeutics.ca.myaccess.library.utoronto.ca/search.http://www.e-therapeutics.ca.myaccess.library.utoronto.ca/search 8. Ohar, J., & Donohue, J. (n.d.). Mono- and Combination Therapy of Long-acting Bronchodilators and Inhaled Corticosteroids in Advanced COPD. Retrieved October 23, 2015, from http://www.medscape.com/viewarticle/723028_2.http://www.medscape.com/viewarticle/723028_2

18. References 9. Barnes, PJ., & Adcock, IM. How do Corticosteroids work in Asthma? Retrieved October 25, 2015 from http://www.the- aps.org/mm/publications/journals/pim/barnes-pdf.pdfhttp://www.the- aps.org/mm/publications/journals/pim/barnes-pdf.pdf 10. Al-Saadi, M. The clinical utility of montelukast in paediatric respiratory disease. Retrieved October 25, 2015 from http://www.pjms.com.pk/issues/octdec207/article/reviewarticle1.html http://www.pjms.com.pk/issues/octdec207/article/reviewarticle1.html 11. Dimov, VV., & Casale, TB. Immunomodulators for Asthma. Retrieved October 25, 2015 from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2946700/ http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2946700/ 12. Iii, W. C. A., & Szefler, S. J. (n.d.). New and future strategies to improve asthma control in children. Journal of Allergy and Clinical Immunology, 136(4), 848–859. 13. Darveaux, J., & Busse, W. W. (2016). Grand Rounds Review Biologics in Asthma — The Next Step Toward Personalized Treatment. The Journal of Allergy and Clinical Immunology in Practice, 3(2), 152–160. 14. Mcivor, R. A. (2015). Emerging therapeutic options for the treatment of patients with symptomatic asthma. Annals of Allergy, Asthma & Immunology, 115(4), 265–271.e5.