Tiotropium in Asthma
•
12 likes•1,900 views
Tiotropium is a long-acting muscarinic antagonist (LAMA) that has been shown to improve asthma control when added to inhaled corticosteroids (ICS) and long-acting beta-agonists (LABAs) in adults with severe asthma. The document reviewed the pathophysiology of cholinergic bronchoconstriction in asthma and how tiotropium's M1/M3 receptor selectivity and long duration of action at these receptors provides 24-hour bronchodilation. Phase III clinical trials demonstrated that adding tiotropium to ICS/LABA resulted in improved symptom control, lung function, reduced severe exacerbations, and was well-tolerated with a safety profile comparable to
Recommended
More Related Content
What's hot
What's hot (20)
Viewers also liked
Viewers also liked (20)
Similar to Tiotropium in Asthma
Similar to Tiotropium in Asthma (20)
More from Ashraf ElAdawy
More from Ashraf ElAdawy (20)
Recently uploaded
Recently uploaded (20)
Tiotropium in Asthma
- 1. 1
- 5. 5
- 6. Despite all medicines and guidelines available, there is still a big unmet need in asthma (Over 50% of patients poorly controlled in EU1) 1. Adamek L. et al. Poster presented at ATS Denver 2011
- 13. Achieving control in asthmatic patients: still a critical issue?
- 18. Aim of Asthma Therapy CONTROL Daytime symptoms None ( 0-2 / week) Nocturnal symptoms / awakening None Limitations of activities None Need for rescue / “reliever” treatment None ( 0-2 / week) FEV1 or PEF Normal Exacerbation None
- 20. 1. In the past 4 weeks, how much of the time did your asthma keep you from getting as much done at work, school or at home? 2. During the past 4 weeks, how often have you had shortness of breath? 3. During the past 4 weeks, how often did your asthma symptoms (wheezing, coughing, shortness of breath, chest tightness or pain) wake you up at night, or earlier than usual in the morning? 4. During the past 4 weeks, how often have you used your rescue inhaler or nebulizer medication (such as salbutamol)? 5. How would you rate your asthma control during the past 4 weeks? Score Patient Total Score Copyright 2002, QualityMetric Incorporated. Asthma Control Test Is a Trademark of QualityMetric Incorporated. Asthma Control Test™ (ACT)
- 24. 24
- 26. The WHO definition of severe asthma. According to the WHO definition, severe asthma is defined as: ‘uncontrolled asthma which can result in risk of frequent severe exacerbations (or death) and/or adverse reactions to medications and/or chronic morbidity Bousquet J, J Allergy Clin Immunol 2010;126:926–938.
- 30. Difficult asthma Asthma that is poorly controlled, despite prescription of optimal asthma treatment Consider: 1. Poor adherence to treatment 2. Poor inhaler technique 3. Alternative diagnosis (?vocal cord dysfunction) 4. Persistent allergens exposure 5. Undertreated co-morbidities
- 31. Severe refractory asthma Patients with asthma in whom: Alternative diagnoses have been excluded Co-morbidities have been treated Trigger factors have been removed (if possible) Compliance with treatment has been checked But still have: Poor asthma control, or frequent (2) severe exacerbations per year Despite : The prescription of high-intensity treatment, or Can only maintain adequate control when taking systemic corticosteroids
- 33. 33 2014
- 40. When a diagnosis of asthma is confirmed and comorbidities addressed, severe asthma is defined as ‘‘asthma which requires treatment with high dose ICS plus a second controller (and/or systemic corticosteroids) to prevent it from becoming ‘uncontrolled’ or which remains ‘uncontrolled’ despite this therapy.’ These doses are likely to be on the relatively "flat" portion of the corticosteroid dose-response relationship, above which the potential for further therapeutic effect diminishes and the likelihood of systemic side- effects is significant ERS/ATS Guidelines 2014
- 41. Therapeutic Ratio of Inhaled Steroids
- 42. Despite current treatment options, in particular ICS/LABA, at least 40% of asthma patients still experience symptoms and could benefit from new treatment options Patients with severe refractory asthma represent small subset of asthmatic patients (5-10% of all patients), but: 1. The greatest burden on health care system 2. The population most in need for new treatment approaches
- 46. Step 2 Step 3 Step 4 Step 5Step 1 Asthma Education Enviromental Control As needed rapid acting 2 agonists As needed rapid acting 2 agonists Controller options Select one Select one Add one or more Add one or both Low-dose ICS Low-dose ICS + LABA Medium or high dose ICS+ LABA Oral steroid LTRA Medium or high dose ICS LTRA Anti-IgE Low-dose ICS + LTRA Theophylline Low-dose ICS + Theophylline INCREASEREDUCE TREATMENT STEPS GINA 2013 As needed rapid acting B2-agonist
- 50. Will anticholinergics fill the gap in asthma control ?
- 52. The neural supply to respiratory tract includes parasympathetic supply through vagus, which is more prominent, and sympathetic supply, which is less prominent. The sympathetic innervations to the respiratory tract are very limited. However, they respond very well to catecholamines and sympathomimetic drugs . The basic science
- 53. The basic science The smooth muscle that surrounds the airways is innervated by cholinergic, parasympathetic nerves which cause bronchoconstriction and mucus secretion. The acetylcholine released from these nerve fibres acts on muscarinic receptors to mediate these effects in response to activation of sensory nerves which are activated by irritants and inflammatory mediators in the airways Blocking muscarinic receptors with anti-muscarinic drugs can ameliorate these effects. This has proven to be a particularly effective therapeutic strategy in treating COPD, and to a lesser extent asthma
- 54. 54
- 56. The use of Short-acting anticholinergic agents, particularly ipratropium bromide in patients with asthma has been relegated primarily to the acute setting. The use of ipratropium results in fewer hospitalizations if given in combination with a SABA to patients experiencing exacerbations in the emergency department (EPR-3 2007). 56
- 57. Short-acting anticholinergics are generally considered less effective acute bronchodilators than SABAs, and their short duration of action makes them broadly unsuitable as controller medication
- 59. Muscarinic receptors exist on smooth muscle and submucosal glands. Acetylcholine (ACh) released from postganglionic nerve endings in the airways activate these receptors. Five muscarinic receptor subtypes have been identified, of which three subtypes—M1, M2, and M3—have been identified in human airways. These receptor subtypes serve different regulatory functions: –Post-synaptic muscarinic receptors (M1) receptors facilitate neurotransmission and enhance cholinergic reflex effects in the airways.
- 60. –The pre-synaptic M2 receptors on postganglionic cholinergic nerves have an auto inhibitory effect on acetylcholine release. –M3 receptors in airway smooth muscle mediate bronchoconstrictor and mucus secretory response to acetylcholine. Inhaled anticholinergics exhibit kinetic receptor subtype selectivity in that they dissociate more slowly from M3 than from M2 and M1 receptors. M3 subtype selectivity of an inhibitor has pharmacological advantages that may have useful therapeutic implications. Dissociation from M1 is slower than from M2
- 61. Pre-ganglionic nerve pre-synaptic Parasympathetic ganglion Post-ganglionic nerve ACh Airway smooth muscle Nicotinic transmission M1 receptors (facilitate) Pre-synaptic M2 receptors (inhibitory) Post-synaptic M3 receptors (facilitate) CholinergicCholinergic Transmission in the AirwaysTransmission in the Airways byby AcetylcholineAcetylcholine ((AChACh)) Neuromuscular junction
- 62. 62
- 63. M2 receptors act as autoreceptors on postganglionic nerve terminals and inhibit acetylcholine release. Therefore, blocking these receptors selectively would have the undesirable effect of increasing vagal excitation of smooth muscle and glands. Thus, it is preferable for antimuscarinic bronchodilators to have a relatively high affinity for M1 and M3 receptors and low affinity for the M2 receptor.
- 64. Ipratropium and oxitropium Currently available short-acting anticholinergics are non-selective antagonists of M1, M2 and M3 receptors, they block all muscarinic receptors In contrast, tiotropium has comparative selectivity for the M1/M3, receptors, Dissociates very slowly from M1 and M3 receptors but rapidly from M2 receptors 64
- 66. The interesting property of tiotropium is that it binds only briefly to M2 receptors, but dissociates from M3 receptors much more slowly (24 hours). Thus, by the time the body has eliminated free tiotropium, the remainder still bound to M3 receptors keep working without affecting M2 receptors. A long-acting anticholinergic which is M1- and M3- selective (tiotropium) may have an advantage over ipratropium, as M2-receptor blockade may limit bronchodilation
- 67. Long-Acting Muscarinic Agents (LAMAs) A New Frontier for Asthma Treatment
- 70. 70
- 71. 71
- 72. 72
- 78. Safety profile comparable to placebo 21% risk reduction for severe asthma exacerbation 68% more likely to improve asthma control up to 154 mL improvement in lung function Tiotropium Respimat® added on to at least ICS+LABA resulted in: PrimoTinAasthmaTM studiesPHASE IIIConclusions…
- 87. Tiotropium add-on therapy offers advantages to adults with severe asthma who are failing to gain control on ICS and LABA combinations. The benefit: risk ratio of ICS falls at high ICS doses, suggests that addition of long-acting anticholinergic bronchodilators to ICS plus a LABA is likely to be a useful option for patients with poorly controlled severe asthma, and an alternative to further increases in ICS dose. 87
- 91. © Global Initiative for Asthma GINA Global Strategy for Asthma Management and Prevention 2015 This slide set is restricted for academic and educational purposes only. Use of the slide set, or of individual slides, for commercial or promotional purposes requires approval from GINA.
- 92. Potential for tiotropium Step 5Step 4Step 3Step 2Step 1 Asthma education, environmental control As-needed rapid- acting β2-agonists As needed rapid-acting β2-agonist Controller options*** Select one Select one To Step 3 treatment, select one or more To Step 4 treatment, add either Low-dose ICS* Low-dose ICS plus LABA Medium- or high-dose ICS plus LABA Oral glucocorticosteroid (lowest dose) Leukotriene modifier** Medium- or high- dose ICS Low-dose ICS plus leukotriene modifier Leukotriene modifier Sustained-release theophylline Anti-IgE treatment Low-dose ICS plus sustained release theophylline GINA 2013
- 93. © Global Initiative for AsthmaGINA 2015, Box 3-5, Step 4 (7/8) *For children 6-11 years, theophylline is not recommended, and preferred Step 3 is medium dose ICS **For patients prescribed BDP/formoterol or BUD/formoterol maintenance and reliever therapy # Tiotropium by soft-mist inhaler is indicated as add-on treatment for patients with a history of exacerbations; it is not indicated in children <18 years. Other controller options RELIEVER STEP 1 STEP 2 STEP 3 STEP 4 STEP 5 Low dose ICS Consider low dose ICS Leukotriene receptor antagonists (LTRA) Low dose theophylline* Med/high dose ICS Low dose ICS+LTRA (or + theoph*) As-needed short-acting beta2-agonist (SABA) As-needed SABA or low dose ICS/formoterol** Low dose ICS/LABA* Med/high ICS/LABA Refer for add-on treatment e.g. anti-IgE PREFERRED CONTROLLER CHOICE Add tiotropium# High dose ICS + LTRA (or + theoph*) Add tiotropium# Add low dose OCS UPDATED! GINA 2015
- 94. GINA 2015 Add-on tiotropium (softmist inhaler) now included as a new ‘Other controller option’ for Steps 4 and 5 in adults and adolescents. # Tiotropium by soft-mist inhaler is an add-on treatment for patients with a history of exacerbations; it is not indicated in children <18 years.
- 98. متشکرم THANKS