Anticholinergic therapies Presented by Athit Wutthisanwatthana, MD. March6, 2020

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

35. Short-Acting Anticholinergic
Agents in Obstructive Lung
Diseases

36. 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

37. 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

38. • 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)

39. 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

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
• Acute asthma: Anticholinergic +
β2-agonist
• Improvement in lung function and
in rates of hospitalization
Children and adolescent

41. 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

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

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

44. 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

45. 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

46. 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

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. 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)

49. 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

50. 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

51. • 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

52. 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

53. 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)

54. * 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

55. 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

56. 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