Anticholinergic therapies

1. Anticholinergic Therapies A Wutthisanwatthana

2. Outline • Autonomic nervous system • Cholinergic nervous system • Pharmacology of anticholinergic agent • Short-acting anticholinergic agents in obstructive lung disease • Long-acting anticholinergic agents for treating chronic obstructive pulmonary disease • Tiotropium for treating asthma • Anticholinergic agents for treating rhinitis

3. Introduction • Cholinergic mechanisms affect several key elements central to obstructive lung disease • Airway/bronchial hyperresponsiveness • Muscarinic receptors present on neurons and structural and immunological elements important in asthma and COPD pathogenesis

4. Airway Hyperresponsiveness • Stimuli causing bronchoconstriction by a direct effect on airway smooth muscle or indirectly by interacting with neural pathways or mast cells • Found in asthma, COPD, allergic rhinitis, bronchiectasis, cystic fibrosis, normal individual • Methacholine challenge in asthma • 27% negative in physician-diagnosed1 • 60% had symptoms characteristic of asthma • 39% reported ED visits • 77% sensitivity, 96% specificity if ICS use2 Ian DP, Ruth HG, PranabashisHaldar. Diagnosis and Management of Asthma in Adults. In: Stephen G. Spiro, Gerard A. Silvestri and Alvar Agustí. Clinical Respiratory Medicine. Philadelphia; Elsevier Saunders; 2012. 501-20 1McGrath KW, Fahy JV. Negative methacholine challenge tests in subjects who report physician-diagnosed asthma. Clin Exp Allergy. 2011 Jan;41(1):46-51 2Sumino K, Sugar EA, Irvin CG, Kaminsky DA, Shade D, Wei CY. Methacholine challenge test: diagnostic characteristics in asthmatic patients receiving controller medications. J Allergy Clin Immunol. 2012 Jul;130(1):69-75

5. McGrath KW, Fahy JV. Negative methacholine challenge tests in subjects who report physician-diagnosed asthma. Clin Exp Allergy. 2011 Jan;41(1):46-51 Positive Negative

6. Autonomic Nervous System

7. The autonomic nervous system and the adrenal medulla. In: John EH. Guyton and Hall textbook of medical physiology. Saunders; 2015 Sympathetic chain Prevertibral ganglia 75%

8. Richard EK. Autonomic ganglia. https://cvpharmacology.com/autonomic_ganglia • All preganglionic neurons are cholinergic • All or almost all of the postganglionic neurons of the parasympathetic system are also cholinergic • Most of the postganglionic sympathetic neurons are adrenergic

9. The autonomic nervous system and the adrenal medulla. In: John EH. Guyton and Hall textbook of medical physiology. Saunders; 2015

10. The autonomic nervous system and the adrenal medulla. In: John EH. Guyton and Hall textbook of medical physiology. Saunders; 2015

11. Cholinergic Nervous System as a Target for Anticholinergic Agents

12. • Lung innervation altered in asthma and COPD • Adrenergic (sympathetic) • Cholinergic (parasympathetic) • Nonadrenergic/noncholinergic: NO, VIP • Differences between asthma and COPD in the relative magnitude • Asthma: β-adrenergic hyporesponsiveness (bronchospasm), ɑ-adrenergic hyporesponsiveness, cholinergic hyperresponsiveness (bronchospasm)

13. Innervation of the lungs and tracheobronhial tree. Pediagenosis. https://www.pediagenosis.com/2019/11/innervation-of-lungs-and.html • Medulla  vagus nerve  cardiac plexus  lower trachea and bronchi • Postganglionic cell bodies located in parallel chains along smooth muscle of the trachea and bronchi  smooth muscle and glands Parasympathetic Nerves Supplying Lung Airways

14. Taylor P, Brown JH. Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition. 1999 • Acetylcholine released by preganglionic, postganglionic parasympathetic nerve, epithelial cell • Nicotinic receptors: Neurotransmission through parasympathetic ganglia • Can be modulate by postganglionic muscarinic receptor • Muscarinic receptor • Highest density in the proximal airways and hilum • Concentrated in smooth muscle, proximate to submucosal glands of the airway

15. Muscarinic Receptor Subtypes in the Lung • M1-M5, inhibited by atropine • M1, M2, M3 principal receptors in the airways • M1, M3, M5 stimulatory effect • M2 inhibitory or stimulatory • M4 inhibitory • Different airway structures and different downstream effects

16. Muscarinic Receptor Subtypes in the Lung Antagonist Effect M1 Atropine Stimulatory M2 Inhibitory or stimulatory M3 Stimulatory M4 Inhibitory M5 Stimulatory

17. Ganglia, mast cells Ganglia, nerve, smooth muscle Smooth muscle, gland, epithelium, Eo, M∅ Neutrophils Neutrophils Stephen PP, Mark SD. Anticholinergic therapies. In: : Adkinson NF, Jr, Bocher BS, Burks AW, Busse WW, Holgate ST, Lemanske RF, et al. Middleton’s allergy principles and practice. Philadelphia; Elsevier Saunders; 2020. 1547-60

18. M1 Receptors • Postganglionic*  promote ganglionic transmission primarily mediated by nicotinic receptors • Smooth muscle  bronchoconstriction • Epithelial cells and submucosal glands  stimulate electrolyte and water secretion that contribute with mucin to produce mucus

19. M2 Receptors • Most highly expressed muscarinic receptors on airway smooth muscle • Less clinically important then M3 • Prejunctional  inhibit acetylcholine release • Postjunctional  Limit β-adrenoceptor–mediated relaxation, smooth muscle contraction

20. M3 Receptors • Present on smooth muscle epithelium, glands, macrophages, eosinophils, and possibly neutrophils • Smooth muscle  bronchoconstriction • Glands  mucin production

21. Muscarinic Receptor Effects on Airway Smooth Muscle Tone • Resting bronchomotor tone occurs because of tonic vagal nerve release of acetylcholine adjacent to airway smooth muscle • M2: M3 = 4:1 • M3 receptor have a greater role in bronchial smooth muscle contraction • Absence of vagal and methacholine-induced bronchoconstriction in M3-knockout but not M2-knockout mice • Antagonism of M3 receptors is considered the most important mechanism for a bronchodilator effect from anticholinergic agent

22. Muscarinic Receptor Effects on Mucus Hypersecretion • Mucus production in the central airways in under cholinergic control • Source • Goblet cells in response to muscarinic receptor stimulation • Airway submucosal glands (primary) • M1: M3 expression = 1: 2 • M3  mucin secretion • M1 and M3  electrolyte and water secretion

23. Muscarinic Receptor Effects on Inflammation • Lymphocyte proliferation and activation • Cytokine release • Eosinophilic chemotactic activity • Bronchial epithelial cells release of eosinophil, monocyte, and neutrophil chemotactic activity and GM-CSF Lymphocytes M1 Mast cells M1 Eosinophils M3, M4 Macrophage M3 Neutrophils M4, M5, ±M3

24. Muscarinic Receptor Regulation of Airway Remodeling • Cholinergic mechanisms may play a significant role in airway smooth muscle remodeling, mucous gland hypertrophy • Proliferation of primary cultured human lung fibroblasts promoted through muscarinic receptor • Increase the mitogenic response of myocytes to platelet-derived growth factor

25. Dysregulation of Muscarinic Receptors in Asthma • ⓵increase M3 ⓶dysfunction of M2  increased acetylcholine release and increased cholinergic hyperreactivity • Viral infections can induce CD8+ T lymphocytes that cause M2 receptor dysfunction and result in enhanced cholinergic activation in the airway • Eosinophilic major basic protein is an allosteric inhibitor of M2 receptors  loss of autoinhibition of acetylcholine release and the potential for enhancement of vagally mediated bronchoconstriction

26. Pharmacology of Anticholinergic Agents

27. Anticholinergic Agents • Competitive inhibitors of muscarinic receptors • Decreases intracellular levels of cyclic guanosine monophosphate • Decrease of tonic cholinergic activity • Bronchodilation • Optimal pharmacologic profile • Antagonism of M1 and M3 receptors • Minimal affinity for M2 receptors

28. Atropine • A standard treatment for asthma before the introduction of adrenergic agents and methylxanthine • Systematically absorbed • Significant anticholinergic adverse effects • ↓pulmonary ciliary clearance • Urinary retention • ↑intraocular pressure

29. Ipratropium Bromide and Tiotropium Bromide • Little absorption through respiratory mucosa • Do not penetrate the blood-brain barrier • Do not significantly alter mucociliary clearance or respiratory secretions

30. Ipratropium Bromide • Nonselective antagonist of M1, M2, and M3 receptors • Net bronchodilatory effect • T1/2 = 1.6 h • Metabolized by ester hydrolysis

31. Tiotropium Bromide • 6-20x affinity for muscarinic receptors than ipratropium • More selective binding to M2 and M3 > M1 receptors • Dissociation  functionally selective antagonist • M3 < M2 10x • M1 and M3 100x less than ipratropium • T1/2 of tioprium-M3 receptor complex = 35 h  once daily dosing

32. Other Long-Acting Anticholinergic Agents and Muscarinic Antagonists • Glycopyrrolate • Aclidimium • Rapidly metabolized in plasma • Umeclinidium • Functionally selective antagonist of M3 receptors • Prolong duration of action

33. Stephen PP, Mark SD. Anticholinergic therapies. In: : Adkinson NF, Jr, Bocher BS, Burks AW, Busse WW, Holgate ST, Lemanske RF, et al. Middleton’s allergy principles and practice. Philadelphia; Elsevier Saunders; 2020. 1547-60

34. Short-Acting Anticholinergic Agents in Obstructive Lung Diseases

35. Short-Acting Anticholinergic Agents in Chronic Obstructive Pulmonary Disease • Stable COPD • ↑FEV1 ≥short-acting β-agonist • Ipratropium + SABA produce greater peak ↑FEV1 • No tachyphylaxis • Longer duration of bronchodilation

36. Appleton S, Jones T, Poole P, Pilotto L, Adams R, Lasserson TJ, et al. Ipratropium bromide versus short acting beta-2 agonists for stable chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2006 Apr 19;(2):CD001387 • 11 studies • ≥4 wks duration • Ipratropium, ipratropium + SABA, SABA • ↑Lung function: Combination, ipratropium > SABA • ↓oral corticosteroid: Ipratropium, combination • ↑ Quality of life: Ipratropium

37. • COPD exacerbations • ↑FEV1 at 90 min and 24 h no difference Singh D, Agusti A, Anzueto A, Barnes PJ, Bourbeau J, Celli BR, et al. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease: the GOLD science committee report 2019. Eur Respir J. 2019 May 18;53(5)

38. Short-Acting Anticholinergic Agents in Asthma • Anticholinergic alone vs placebo • Daytime dyspnea -0.09 (-0.14 - -0.04) • Peak expiratory flow 14.38 L/min (7.69-21.08) • Anticholinergic + β2-agonist • No improvement in symptoms or lung function over β2-agonist alone • Effective reliever in trials studying the pharmacogenetics of short- and long-acting β-adrenergic agonist Westby M, Benson M, Gibson P. Anticholinergic agents for chronic asthma in adults. Cochrane Database Syst Rev. 2004;(3):CD003269

39. Rodrigo GJ, Castro-Rodriguez JA. Anticholinergics in the treatment of children and adults with acute asthma: a systematic review with meta-analysis. Thorax. 2005 Sep;60(9):740-6 • Acute asthma: Anticholinergic + β2-agonist • Improvement in lung function and in rates of hospitalization Children and adolescent

40. Rodrigo GJ, Castro-Rodriguez JA. Anticholinergics in the treatment of children and adults with acute asthma: a systematic review with meta-analysis. Thorax. 2005 Sep;60(9):740-6 Adult

41. © Global Initiative for Asthma, www.ginasthma.org Management of asthma exacerbations in primary care (adults, adolescents, children 6–11 years)

42. © Global Initiative for Asthma, www.ginasthma.org Management of asthma exacerbations in acute care facility, e.g. emergency department

43. Long-Acting Anticholinergic Agents for Treating Chronic Obstructive Pulmonary Disease: Monotherapy • Aclinidium, glycopyrrolate, tiotropium, umeclindinium approved for COPD • ↑pulmonary function and symptoms • ↑ St George’s Respiratory Questionnaire score (50 items - impact on overall health, daily life, and perceived well-being) • ↑ Transitional dyspnea index score (changes from this baseline of dyspnea) • Tiotropium • Ameliorate annual decline in the FEV1 in GOLD stage 1, 2 • Longer time to first acute exacerbation Ismaila AS, Huisman EL, Punekar YS, Karabis A. Comparative efficacy of long-acting muscarinic antagonist monotherapies in COPD: a systematic review and network meta-analysis. Int J Chron Obstruct Pulmon Dis. 2015 Nov 16;10:2495-517

44. Dual Bronchodilators Glycopyrrolate + formoterol (Bevespi Aerosphere) Glycopyrrolate + indacaterol (Utibron Neohaler) Tiotropium + olodaterol (Stiolto Respimat) Umeclidinium + vilanterol (Anoro Ellipta) • Approved for long-term maintenance treatment • Better bronchodilation than individual components • ↑FEV1 • ↑St George’s Respiratory Questionnaire score • Reduced COPD exacerbations Ran P, Zhou Y, Guan WJ. Tiotropium in Early-Stage COPD. N Engl J Med. 2017 Dec 7;377(23):2293-2294

45. Triple Therapies • Fluticasone furoate + umeclidinium + vilanterol (Trelegy Ellipta) • Maintenance treatment • Reduce exacerbations • Superior to fluticasone furoate + umeclidinium or umeclidinium + vilanterol • Improving health-related quality of life • Preventing moderate to severe exacerbation in moderate COPD • Budesonide + formoterol + glycopyrrolate • ↑FEV1 • ↓exacerbation

46. Singh D, Agusti A, Anzueto A, Barnes PJ, Bourbeau J, Celli BR, et al. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease: the GOLD science committee report 2019. Eur Respir J. 2019 May 18;53(5)

47. Singh D, Agusti A, Anzueto A, Barnes PJ, Bourbeau J, Celli BR, et al. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease: the GOLD science committee report 2019. Eur Respir J. 2019 May 18;53(5)

48. Tiotropium for Treating Asthma • The Tiotropium Bromide as an Alternative to Increased Inhaled Glucocorticoid in Patients Inadequately Controlled on a Lower Dose of Inhaled Corticosteroids (TALC) trial • 210 participant • Double-blind, randomized triple-dummy • Intervention: Adding ⓵tiotropium ⓶salmeterol ⓷doubling dose of ICS • In asthma inadequately controlled on low-dose ICS Peters SP, Kunselman SJ, Icitovic N, Moore WC, Pascual R, Ameredes BT. Tiotropium bromide step-up therapy for adults with uncontrolled asthma. N Engl J Med. 2010 Oct 28;363(18):1715-26

49. Peters SP, Kunselman SJ, Icitovic N, Moore WC, Pascual R, Ameredes BT. Tiotropium bromide step-up therapy for adults with uncontrolled asthma. N Engl J Med. 2010 Oct 28;363(18):1715-26

50. • Predictor for positive response • Acute response to a short-acting bronchodilator • Decreased FEV1/FVE ratio • Higher cholinergic tone • Ethnicity, sex, atopy, IgE level, sputum eosinophil count, fraction of exhaled nitric oxide, asthma duration, and body mass index were not Peters SP, Bleecker ER, Kunselman SJ, Icitovic N, Moore WC, Pascual R, et al. Predictors of response to tiotropium versus salmeterol in asthmatic adults. J Allergy Clin Immunol. 2013 Nov;132(5):1068-1074

51. Metanalysis on Tiotropium Add on No. of studies No. of patient Age ICS Med-high dose ICS ICS+salmeterol ICS+LABA Rodrigo GJ1 13 4,966 12-75 ↑PEF, FEV1, asthma control ↓rate of exacerbation (NNT 36) Noninferior to salmeterol ↑pulmonary function, asthma control ↓rate of exacerbation (NNT 17) Rodrigo GJ2 3 895 12-17 ↑peak FEV1, trough FEV1 ↓ACQ-7 worsening episode ↓number of patients with at least one exacerbation Rodrigo GJ3 3 903 6-11 ↑peak FEV1, trough FEV1 ↑rate of ACQ-7 responder ↓number of patients with at least one exacerbation 1Rodrigo GJ, Castro-Rodríguez JA. What is the role of tiotropium in asthma?: a systematic review with meta-analysis. Chest. 2015 Feb;147(2):388-396 2Rodrigo GJ, Castro-Rodríguez JA. Tiotropium for the treatment of adolescents with moderate to severe symptomatic asthma: a systematic review with meta-analysis. Ann Allergy Asthma Immunol. 2015 Sep;115(3):211-6 3Rodrigo GJ, Neffen H. Efficacy and safety of tiotropium in school-age children with moderate-to-severe symptomatic asthma: A systematic review. Pediatr Allergy Immunol. 2017 Sep;28(6):573-578

52. Other controller options Leukotriene receptor antagonist (LTRA), or low dose ICS taken whenever SABA taken* Low dose ICS+LTRA High dose ICS- LABA, or add- on tiotropium, or add-on LTRA Add-on anti-IL5, or add-on low dose OCS, but consider side-effects Low dose ICS taken whenever SABA taken*; or daily low dose ICS RELIEVER * Off-label; separate ICS and SABA inhalers; only one study in children PREFERRED CONTROLLER to prevent exacerbations and control symptoms STEP 1 STEP 2 Daily low dose inhaled corticosteroid (ICS) (see table of ICS dose ranges for children) STEP 3 Low dose ICS-LABA, or medium dose ICS Box 3-5B Children 6-11 years Personalized asthma management: Assess, Adjust, Review response Asthma medication options: Adjust treatment up and down for individual child’s needs STEP 5 Refer for phenotypic assessment ± add-on therapy, e.g. anti-IgE STEP 4 Medium dose ICS-LABA Refer for expert advice Symptoms Exacerbations Side-effects Lung function Child and parent satisfaction Confirmation of diagnosis if necessary Symptom control & modifiable risk factors (including lung function) Comorbidities Inhaler technique & adherence Child and parent goals Treatment of modifiable risk factors & comorbidities Non-pharmacological strategies Education & skills training Asthma medications As-needed short-acting β2 -agonist (SABA)

53. * Off-label; data only with budesonide-formoterol (bud-form) † Off-label; separate or combination ICS and SABA inhalers STEP 2 Daily low dose inhaled corticosteroid (ICS), or as-needed low dose ICS-formoterol * STEP 3 Low dose ICS-LABA STEP 4 Medium dose ICS-LABA Leukotriene receptor antagonist (LTRA), or low dose ICS taken whenever SABA taken † As-needed low dose ICS-formoterol * As-needed short-acting β2 -agonist (SABA) Medium dose ICS, or low dose ICS+LTRA # High dose ICS, add-on tiotropium, or add-on LTRA # Add low dose OCS, but consider side-effects As-needed low dose ICS-formoterol ‡ STEP 5 High dose ICS-LABA Refer for phenotypic assessment ± add-on therapy, e.g.tiotropium, anti-IgE, anti-IL5/5R, anti-IL4R Symptoms Exacerbations Side-effects Lung function Patient satisfaction Confirmation of diagnosis if necessary Symptom control & modifiable risk factors (including lung function) Comorbidities Inhaler technique & adherence Patient goals Treatment of modifiable risk factors & comorbidities Non-pharmacological strategies Education & skills training Asthma medications 1© Global Initiative for Asthma, www.ginasthma.org STEP 1 As-needed low dose ICS-formoterol * Low dose ICS taken whenever SABA is taken† ‡ Low-dose ICS-form is the reliever for patients prescribed bud-form or BDP-form maintenance and reliever therapy # Consider adding HDM SLIT for sensitized patients with allergic rhinitis and FEV >70% predicted PREFERRED CONTROLLER to prevent exacerbations and control symptoms Other controller options Other reliever option PREFERRED RELIEVER Box 3-5A Adults & adolescents 12+ years Personalized asthma management: Assess, Adjust, Review response Asthma medication options: Adjust treatment up and down for individual patient needs

54. Anticholinergic Agents for Treating Rhinitis • M1 and M3 muscarinic receptor subtypes regulate mucin glycoprotein secretion from human nasal mucosa • Nasal ipratropium bromide reduces rhinorrhea caused • SAR, PAR • Nonallergic rhinitis (gustatory, cold induced, vasomotor) • Viral respiratory infections • Concomitant use of ipratropium bromide and intranasal corticosteroids has an additive effect in controlling rhinorrhea • Rapid onset Wallace DV, Dykewicz MS, Bernstein DI, Blessing-Moore J, Cox L, Khan DA. The diagnosis and management of rhinitis: an updated practice parameter. J Allergy Clin Immunol. 2008 Aug;122(2 Suppl):S1-84

55. Anticholinergic Agents for Treating Rhinitis • No adverse effect on physiologic nasal functions (sense of smell, ciliary beat frequency, mucociliary clearance) • Low incidence of epistaxis, nasal dryness

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