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Is there a rationale and role for long-acting anticholinergic bronchodilators in asthma?

Price D, Fromer L, Kaplan A, van der Molen T, Román-Rodríguez M - NPJ Prim Care Respir Med (2014)

Bottom Line: Patients with asthma have increased bronchial smooth muscle tone and mucus hypersecretion, possibly as a result of elevated cholinergic activity, which anticholinergic compounds are known to reduce.Further, anticholinergic compounds may also have anti-inflammatory properties.Thus, evidence suggests that long-acting anticholinergic bronchodilators might offer benefits for the maintenance of asthma control, such as in patients failing to gain control on ICS and a LABA, or those with frequent exacerbations.

View Article: PubMed Central - PubMed

Affiliation: 1] Centre of Academic Primary Care, University of Aberdeen, Aberdeen, UK [2] Research in Real Life Ltd, Cambridge, UK.

ABSTRACT
Despite current guidelines and the range of available treatments, over a half of patients with asthma continue to suffer from poor symptomatic control and remain at risk of future worsening. Although a number of non-pharmacological measures are crucial for good clinical management of asthma, new therapeutic controller medications will have a role in the future management of the disease. Several long-acting anticholinergic bronchodilators are under investigation or are available for the treatment of respiratory diseases, including tiotropium bromide, aclidinium bromide, glycopyrronium bromide, glycopyrrolate and umeclidinium bromide, although none is yet licensed for the treatment of asthma. A recent Phase III investigation demonstrated that the once-daily long-acting anticholinergic bronchodilator tiotropium bromide improves lung function and reduces the risk of exacerbation in patients with symptomatic asthma, despite the use of inhaled corticosteroids (ICS) and long-acting β2-agonists (LABAs). This has prompted the question of what the rationale is for long-acting anticholinergic bronchodilators in asthma. Bronchial smooth muscle contraction is the primary cause of reversible airway narrowing in asthma, and the baseline level of contraction is predominantly set by the level of 'cholinergic tone'. Patients with asthma have increased bronchial smooth muscle tone and mucus hypersecretion, possibly as a result of elevated cholinergic activity, which anticholinergic compounds are known to reduce. Further, anticholinergic compounds may also have anti-inflammatory properties. Thus, evidence suggests that long-acting anticholinergic bronchodilators might offer benefits for the maintenance of asthma control, such as in patients failing to gain control on ICS and a LABA, or those with frequent exacerbations.

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Autonomic regulation of airway smooth muscle tone.29,32,49,50 M1, M2, M3, muscarinic acetylcholine receptors 1, 2 and 3. + and − symbols represent signals increasing and decreasing airway smooth muscle tone, respectively. Note that non-adrenergic non-cholinergic autonomic pathways have been omitted for simplicity. Adapted from the study by Cazzola, et al.,32 with permission from the American Society for Pharmacology and Experimental Therapeutics.
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fig2: Autonomic regulation of airway smooth muscle tone.29,32,49,50 M1, M2, M3, muscarinic acetylcholine receptors 1, 2 and 3. + and − symbols represent signals increasing and decreasing airway smooth muscle tone, respectively. Note that non-adrenergic non-cholinergic autonomic pathways have been omitted for simplicity. Adapted from the study by Cazzola, et al.,32 with permission from the American Society for Pharmacology and Experimental Therapeutics.

Mentions: The symptoms of asthma, and of acute exacerbations, are attributed to airway narrowing that occurs as a consequence of chronic inflammation and associated hyper-responsiveness.2 Local influx of inflammatory cells and high levels of inflammatory mediators result in airway oedema, airway thickening, mucus hypersecretion and bronchial smooth muscle contraction (Table 1).2 Although multiple pathophysiological mechanisms are thought to contribute to the characteristic narrowing of airways and the hyper-responsiveness found in asthma (Table 1),2 bronchial smooth muscle contraction represents the primary cause of reversible airway obstruction in asthma.29,30 The degree of basal airway smooth muscle contraction (airway smooth muscle ‘tone’) is under autonomic nervous regulation (Figure 2), although the mechanisms are not fully understood. During normal ventilation, adrenergic sympathetic nerves and parasympathetic cholinergic and non-cholinergic nerves are all active,29,31,32 but cholinergic activity is thought to be the predominant driver of bronchoconstriction (Figure 2, Box 2).31 Acute treatment with the anticholinergic compounds atropine and ipratropium is known to reduce basal airway smooth muscle tone.33,34


Is there a rationale and role for long-acting anticholinergic bronchodilators in asthma?

Price D, Fromer L, Kaplan A, van der Molen T, Román-Rodríguez M - NPJ Prim Care Respir Med (2014)

Autonomic regulation of airway smooth muscle tone.29,32,49,50 M1, M2, M3, muscarinic acetylcholine receptors 1, 2 and 3. + and − symbols represent signals increasing and decreasing airway smooth muscle tone, respectively. Note that non-adrenergic non-cholinergic autonomic pathways have been omitted for simplicity. Adapted from the study by Cazzola, et al.,32 with permission from the American Society for Pharmacology and Experimental Therapeutics.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4373380&req=5

fig2: Autonomic regulation of airway smooth muscle tone.29,32,49,50 M1, M2, M3, muscarinic acetylcholine receptors 1, 2 and 3. + and − symbols represent signals increasing and decreasing airway smooth muscle tone, respectively. Note that non-adrenergic non-cholinergic autonomic pathways have been omitted for simplicity. Adapted from the study by Cazzola, et al.,32 with permission from the American Society for Pharmacology and Experimental Therapeutics.
Mentions: The symptoms of asthma, and of acute exacerbations, are attributed to airway narrowing that occurs as a consequence of chronic inflammation and associated hyper-responsiveness.2 Local influx of inflammatory cells and high levels of inflammatory mediators result in airway oedema, airway thickening, mucus hypersecretion and bronchial smooth muscle contraction (Table 1).2 Although multiple pathophysiological mechanisms are thought to contribute to the characteristic narrowing of airways and the hyper-responsiveness found in asthma (Table 1),2 bronchial smooth muscle contraction represents the primary cause of reversible airway obstruction in asthma.29,30 The degree of basal airway smooth muscle contraction (airway smooth muscle ‘tone’) is under autonomic nervous regulation (Figure 2), although the mechanisms are not fully understood. During normal ventilation, adrenergic sympathetic nerves and parasympathetic cholinergic and non-cholinergic nerves are all active,29,31,32 but cholinergic activity is thought to be the predominant driver of bronchoconstriction (Figure 2, Box 2).31 Acute treatment with the anticholinergic compounds atropine and ipratropium is known to reduce basal airway smooth muscle tone.33,34

Bottom Line: Patients with asthma have increased bronchial smooth muscle tone and mucus hypersecretion, possibly as a result of elevated cholinergic activity, which anticholinergic compounds are known to reduce.Further, anticholinergic compounds may also have anti-inflammatory properties.Thus, evidence suggests that long-acting anticholinergic bronchodilators might offer benefits for the maintenance of asthma control, such as in patients failing to gain control on ICS and a LABA, or those with frequent exacerbations.

View Article: PubMed Central - PubMed

Affiliation: 1] Centre of Academic Primary Care, University of Aberdeen, Aberdeen, UK [2] Research in Real Life Ltd, Cambridge, UK.

ABSTRACT
Despite current guidelines and the range of available treatments, over a half of patients with asthma continue to suffer from poor symptomatic control and remain at risk of future worsening. Although a number of non-pharmacological measures are crucial for good clinical management of asthma, new therapeutic controller medications will have a role in the future management of the disease. Several long-acting anticholinergic bronchodilators are under investigation or are available for the treatment of respiratory diseases, including tiotropium bromide, aclidinium bromide, glycopyrronium bromide, glycopyrrolate and umeclidinium bromide, although none is yet licensed for the treatment of asthma. A recent Phase III investigation demonstrated that the once-daily long-acting anticholinergic bronchodilator tiotropium bromide improves lung function and reduces the risk of exacerbation in patients with symptomatic asthma, despite the use of inhaled corticosteroids (ICS) and long-acting β2-agonists (LABAs). This has prompted the question of what the rationale is for long-acting anticholinergic bronchodilators in asthma. Bronchial smooth muscle contraction is the primary cause of reversible airway narrowing in asthma, and the baseline level of contraction is predominantly set by the level of 'cholinergic tone'. Patients with asthma have increased bronchial smooth muscle tone and mucus hypersecretion, possibly as a result of elevated cholinergic activity, which anticholinergic compounds are known to reduce. Further, anticholinergic compounds may also have anti-inflammatory properties. Thus, evidence suggests that long-acting anticholinergic bronchodilators might offer benefits for the maintenance of asthma control, such as in patients failing to gain control on ICS and a LABA, or those with frequent exacerbations.

Show MeSH
Related in: MedlinePlus