Anticholinergics in Chronic Asthma: A Promising Future?

A recent publication has refocused interest on the use of anticholinergics as a controller treatment in asthma. ¹ The short-acting anticholinergic, ipratropium bromide, has been recommended for years as adjunctive therapy to inhaled short-acting β2 agonists in the emergency department management of severe acute asthma in both children and adults. ² However, ipratropium bromide has not gained marketing approval for use as a bronchodilator in persistent asthma or acute asthma. The study by the NIH-sponsored Asthma Clinical Research Network was a 3-way crossover that compared the addition of tiotropium bromide to doubling the dose of the inhaled corticosteroid in a superiority analysis and the addition of salmeterol in a noninferiority analysis. ¹ The addition of tiotropium bromide was superior to doubling the dose of the inhaled corticosteroid and noninferior to the addition of salmeterol. Although a new finding, this was not particularly surprising as the primary outcome was improvement in lung function as measured by improvement in peak expiratory flows and we have had 16 years of literature demonstrating improvement in lung function when adding long-acting bronchodilators, although long-acting β2 agonists (LABAs), to patients incompletely controlled on ICSs.^2,3 However, they also demonstrated greater improvement for tiotropium bromide in other measures from the impairment domain (symptom scores, asthma control days, and Asthma Control Questionnaire), indicating stabilization of persistent disease. So, should tiotropium bromide be considered an alternative long-acting bronchodilator to LABAs for the treatment of persistent asthma uncontrolled on inhaled corticosteroids alone?

Anticholinergic bronchodilators have a long history in the treatment of asthma, including the use of jimsonweed (Datura stramonium) cigarettes long before the discovery and use of adrenaline in the 1920s. ⁴ The anticholinergics competitively block acetylcholine at the muscarinic receptors in the airways. ⁴ Infants are born with fully functional airway smooth muscle that responds similarly to both β₂ agonists and cholinergic stimulation as adult bronchial tissue.^5,6 Unlike the β₂-adrenergic receptors the distribution of muscarinic receptors in the lung diminishes as the airways become more peripheral as does the cholinergic innervation. ⁶ The airway is innervated by parasympathetic, sympathetic, and nonadrenergic inhibitory nerves. ⁵ Parasympathetic innervation of the smooth muscle consists of efferent motor fibers in the vagus nerves and sensory afferent fibers in the vagus and other nerves. ⁶ The normal resting tone of human airway smooth muscle is maintained by vagal efferent activity. Maximum bronchoconstriction mediated by vagal stimulation occurs in the small bronchi and is absent in the small bronchioles. The nonmyelinated C fibers of the afferent system lie immediately beneath the tight junctions between epithelial cells lining the airway lumen. ⁷ These endings probably represent the irritant receptors of the airways. Stimulation of these irritant receptors by mechanical stimulation, chemical and particulate irritants, and pharmacologic agents such as histamine produces reflex bronchoconstriction. ⁷ Thus, the anticholinergics would be expected to produce bronchodilation in asthma.

The first anticholinergic used clinically (ie, active ingredient extracted from D. stramonium) was atropine, but atropine is a tertiary ammonium compound that is readily absorbed across membranes, including the central nervous system, so is of limited clinical utility due to adverse effects, including hallucinations. ⁴ Quaternary ammonium compounds such as ipratropium bromide, atropine methonitrate, oxitropium bromide, and glycopyrrolate bromide were developed. Quaternary ammonium compounds are very poorly absorbed across membranes causing minimal to no systemic effects when applied topically. ⁴ These compounds competitively inhibit the effect acetylcholine at all of the muscarinic receptors: ganglionic, M₁; postganglionic nerve, M₂; and smooth muscle, M₃. ⁴ Some have suggested that the nonselectivity may be disadvantageous in asthma because blocking of M₂ receptors interferes with the feedback inhibition of acetylcholine release from cholinergic nerves, thus enhancing bronchospasm further.^4,6 Inhibition of M₂ receptors has been linked to the bronchospasm associated with viral infections. ⁸

Unlike β₂ agonists that are physiologic or functional antagonists of bronchospasm, the anticholinergics will only reverse bronchospasm that is cholinergically mediated; thus, they produce a lower maximal response than the β₂ agonists in asthma but similar response in chronic obstructive pulmonary disease (COPD) where the reversible obstruction is primarily cholinergically mediated.^6,7 They have a slower onset than the short-acting β₂ agonists with the peak effect at 30–60 min compared to 10–15 min. However, they have still proven efficacious in severe acute asthma when added to short-acting β₂ agonists.^9,10 The short-acting anticholinergic ipratropium bromide provides additive efficacy with short-acting β₂ agonists in severe acute asthma exacerbations but only improves lung function another 10%–20% (reversing the cholinergic component) over frequent administration of high-dose short-acting β₂ agonists.^9,10 The addition of frequent dosing of inhaled ipratropium bromide has resulted in a significant reduction in hospitalizations in children and adults presenting to the emergency department with severe obstruction.^9,10 Once the child is hospitalized, the addition of ipratropium bromide to other therapy does not improve outcomes and is not recommended. ¹

The duration of action of the older short-acting anticholinergics is only slightly longer than the short-acting β₂ agonists about 6 h compared to 4–6 h and this may partly explain the lack of efficacy for chronic persistent asthma. Two systematic reviews with meta-analyses report that chronic administration of the short-acting anticholinergics does not alter outcomes in persistent asthma in children or adults even if administered 4 times daily.^11,12 In addition, combining the short-acting anticholinergic to short-acting β₂ agonists did not provide greater improvement in outcomes of lung function and symptoms than the β₂ agonists alone.^11,12 Neither of these systematic reviews included studies of tiotropium bromide as none had been completed. Thus, the anticholinergics only have approved labeling in COPD in adults. However, ipratropium bromide has been used effectively as an acute reliever in clinical trials of patients with mild to moderate persistent asthma, so it may be useful in patients who cannot tolerate β₂ agonists.^13,14

Tiotropium bromide has a longer duration of action, ≥24 h, due to its greater lipophilicity than the short-acting anticholinergics such as ipratropium bromide.^4,6 This is similar to the difference between LABAs and short-acting β₂ agonists. The increased lipophilicity facilitates retention in the lung tissues when administered by inhalation. In addition to the lipophilicity, tiotropium bromide has significantly longer dissociation half-lives with the muscarinic receptors than the short-acting anticholinergics and the dissociation half-life with the M₂ receptor is 10-fold faster than for the M₃ receptor providing greater selectivity for bronchodilation. ⁴ Tolerance has not been shown with long-term trials with tiotropium bromide in COPD. The prolonged duration of tiotropium bromide probably accounts for the slightly greater prebronchodilator forced expiratory volume in 1 s (0.11 L, P = 0.003) reported in the Asthma Clinical Research Network study. This was only a difference of 5% of the mean baseline values in this study. This study was also of insufficient duration (14 weeks) to assess effect on severe asthma exacerbations—an outcome that the addition of LABAs improves over doubling the dose of inhaled corticosteroids.^2,3

Should we now recommend the addition of tiotropium bromide to patients not completely controlled on inhaled corticosteroids alone? Currently, tiotropium bromide does not have marketing approval in asthma and a single well-controlled trial does not satisfy the criteria of 2 well-controlled clinical trials established by the U.S. Food and Drug Administration for approval. Long-term safety in asthma has not been assessed, and currently there is not even an Investigational New Drug Application at the U.S. Food and Drug Administration for studies in children. Although there are a number of ongoing clinical trials of tiotropium bromide in asthma, evidence is insufficient at this point to say anything other than that it represents a potentially promising addition to the asthma armamentarium.