Inhaled Adrenergics and Anticholinergics in Obstructive ... · Inhaled Adrenergics and...

Inhaled Adrenergics and Anticholinergics in ObstructiveLung Disease: Do They Enhance Mucociliary Clearance?

Ruben D Restrepo MD RRT

IntroductionInnervation of Airway Secretory Structures

Adrenergic InnervationCholinergic InnervationNon-Adrenergic and Non-Cholinergic Pathway

AdrenergicsShort-Acting � Agonists

TerbutalineAlbuterolLevalbuterolFenoterol

Long-Acting � AgonistsSalmeterolFormoterol

AnticholinergicsIpratropiumTiotropiumGlycopyrrolate

Effects of Common Adrenergics and Anticholinergics on Mucociliary ClearanceSummary

Pulmonary mucociliary clearance is an essential defense mechanism against bacteria and particu-late matter. Mucociliary dysfunction is an important feature of obstructive lung diseases such aschronic obstructive pulmonary disease, asthma, cystic fibrosis, and bronchiectasis. This dysfunctionin airway clearance is associated with accelerated loss of lung function in patients with obstructivelung disease. The involvement of the cholinergic and adrenergic neural pathways in the pathophys-iology of mucus hypersecretion suggests the potential therapeutic role of bronchodilators as mu-coactive agents. Although anticholinergics and adrenergic agonist bronchodilators have been rou-tinely used, alone or in combination, to enhance mucociliary clearance in patients with obstructivelung disease, the existing evidence does not consistently show clinical effectiveness. Key words:anticholinergic, adrenergic, airway clearance, bronchodilator, chronic obstructive pulmonary disease,

Ruben D Restrepo MD RRT is affiliated with the Department of Respi-ratory Care, University of Texas Health Science Center, San Antonio,Texas.

The author reports no conflicts of interest related to the content of thispaper.

Dr Restrepo presented a version of this paper at the 39th RESPIRATORY CARE

Journal Conference, “Airway Clearance: Physiology, Pharmacology,

Techniques, and Practice,” held April 21–23, 2007, in Cancun,Mexico.

Correspondence: Ruben D Restrepo MD RRT, Department of Respira-tory Care, University of Texas Health Science Center at San Antonio,7703 Floyd Curl Drive, Mail Code 6248, San Antonio TX 78229-3900.E-mail: [email protected].

RESPIRATORY CARE • SEPTEMBER 2007 VOL 52 NO 9 1159

mucociliary clearance, mucus, sputum, obstructive lung disease. [Respir Care 2007;52(9):1159–1173.© 2007 Daedalus Enterprises]

Introduction

Mucociliary clearance is an effective and essential bio-logical barrier against microorganisms and particulate mat-ter. This specialized apparatus consists of secretory cellsand ciliated cells that beat in a coordinated and metachro-nal fashion.1,2 Their propulsive force mobilizes the mucusblanket toward the larynx for elimination.3

In the presence of infection and inflammation, the air-way mucosa typically responds by increasing the amountof secreted mucus, due to goblet cell and submucosal glandhyperplasia and hypertrophy, a phenomenon also knownas secretory hyperresponsiveness.4 Additionally, inflam-mation causes loss of cells and ciliary function, destructionof the surfactant layer by airway phospholipases, and al-teration of the biophysical properties of the mucus.5

Dysfunction of the mucociliary clearance is a commonrespiratory disturbance in patients with obstructive lungdisease (OLD) such as chronic bronchitis, asthma, bron-chiectasis, and cystic fibrosis (CF). This dysfunction is animportant marker of accelerated loss of lung function inchronic obstructive pulmonary disease (COPD).6 Coughand adequate airflow are of critical importance when hy-persecretion is severe, prolonged, and associated with ex-tensive ciliary damage, because airflow may become theprimary means of airway secretion clearance. Since coughis most effective with high expiratory flow, bronchodila-tors may have a therapeutic role in airflow-dependent clear-ance.5

There is variability in the abnormalities of secretionsproduced by patients with obstructive lung disease. In CFthe composition of the secretions is similar to pus, withalmost no mucin or mucus,7–10 whereas secretions frompatients with asthma are more viscous than those frompatients with COPD, CF, or bronchiectasis.11–15 The ab-normal secretion and retention of mucus in asthma hasbeen confirmed by postmortem studies of patients withstatus asthmaticus that showed obstructed airways withgelatinous mucus plugs.16–20

Although �2 adrenergics are important in the manage-ment of symptomatic obstructive lung disease, it appearsthat only the long-acting � adrenergics provide sustainedimprovement of mucociliary clearance.21 Evaluation ofshort-acting � adrenergics for the improvement of muco-ciliary clearance in patients with OLD has shown that theireffect is generally less than that seen in normal airways.22

Since neural control of mucus secretion is believed to bepredominantly cholinergic,23 anticholinergics have the po-tential to inhibit the neurogenic mucus secretion pathway

by blocking the cholinergic muscarinic receptor sub-type M3. However, their clinical benefit as mucoactiveagents has been difficult to demonstrate.24–27

The effect of �2 adrenergics and anticholinergics in mod-ifying human-neutrophil-elastase-induced impairment ofmucociliary clearance common to OLD has been confirmedin animal studies.27–29 Human neutrophil elastase is a knownmucus secretagogue with cilia-inhibiting properties thatcan stimulate epithelial sodium channels, reducing the peri-ciliary fluid layer and thus contribute to mucus stasis.27–31

Human neutrophil elastase depresses mucociliary clear-ance, as measured by tracheal mucus velocity in animals.32

Several studies have shown that human neutrophil elastaseis an important inflammatory mediator in OLD and thatdisease severity is linked to the concentration of humanneutrophil elastase in the airways.33–38

Innervation of Airway Secretory Structures

The sympathetic (adrenergic), parasympathetic (cholin-ergic), and non-adrenergic non-cholinergic pathways arethe main neural pathways responsible for the modulationof airway diameter and the innervation of secretory cells.Figure 1 shows photomicrographs of normal airway epi-thelium and secretory cell innervation. Darkfield illumi-nation shows the presence of cholinergic muscarinic re-ceptors in the submucosal glands and non-adrenergic non-cholinergic tachynin receptors binding to epithelium andglands.

Adrenergic Innervation

Based on histological analyses, the sympathetic-adren-ergic innervation of human airway smooth muscle andsecretory structures is sparse or nonexistent and plays littleor no role in regulating airway caliber. Adrenergic controlappears to be restricted to the interaction of circulatingcatecholamines, such as adrenaline, with adrenoceptors onthe secretory cells to increase mucus production.39

Cholinergic Innervation

The cholinergic system is the dominant neural pathwayin the airways, primarily by stimulation of the musca-rinic M3 pathway. The muscarinic receptors are classifiedinto M1–M5 subtypes. The M1 receptors are widely dis-tributed throughout the parasympathic ganglia and exo-crine glands. The prejunctional muscarinic M2 autorecep-tors are found in the smooth muscle and the myocardium,

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1160 RESPIRATORY CARE • SEPTEMBER 2007 VOL 52 NO 9

and provide negative presynaptic feedback to reduce fur-ther release of acetylcholine.40–44 The M3 receptor sub-type in the airway smooth muscle mediates bronchocon-striction and secretion of mucus with a low concentrationof mucin.24,45–47 When coupled to G-proteins, M1, M3, andM5 muscarinic receptors have a stimulatory effect on thetarget tissue, whereas the M2 and M4 subtypes are inhib-itory.43

The increased release of acetylcholine from cholinergicnerve terminals in OLD is thought to be the result of anabnormal muscarinic receptor expression.48 Stimulation ofthe M2 receptors explains the increased acetylcholine re-lease and the potentiation of cholinergic-induced broncho-constriction and hypersecretion in patients with asthma.47

CD8� T lymphocytes induced by viral infection appear to

cause M2 receptor dysfunction and cholinergic activationin asthmatics.49–52 The ideal anticholinergic mucoactivedrug for OLD should then antagonize M1 and M3 receptorsbut have little affinity for the M2 receptor.

Non-Adrenergic and Non-Cholinergic Pathway

The non-adrenergic and non-cholinergic pathway ap-pears to be a potent mucus secretagogue system.53,54 Neu-rotransmitters of the non-adrenergic non-cholinergic path-way include peptides such as vasoactive intestinal peptide,the tachynins substance P and neurokinin A, and gasessuch as nitric oxide. Most gland secretion is stimulated byvasoactive intestinal peptide and tachykinins,55 whereasnitric oxide has no effect on mucus secretion in animals.38

Fig. 1. Photomicrographs of secretory cells, nerves, and receptors in the airways. A: Normal respiratory epithelium (Ep). L � lumen. G submucosalglands. B: Intra-epithelial nerve fiber (N) between 2 goblet cells that contain mucin granules (MG) in guinea-pig trachea. The arrow points to theintercellular junction. C: Muscarinic receptors in ferret trachea. Darkfield illumination of tracheal section incubated with the muscarinic receptorantagonist [3H]quinuclidinylbenzilate, which shows localization of binding sites to submucosal glands (G) and, to a lesser extent, epithelium.D: Tachykinin receptors in ferret trachea. Darkfield illumination of tracheal section incubated with [125I]-Bolton-Hunter-SP, which shows local-ization of substance P binding sites to epithelium (Ep) and glands (G). Photograph A courtesy of David E Martin, PhD, Cardiopulmonary CareSciences, Georgia State University, Atlanta, Georgia. (Photographs B, C, and D from Reference 24, with permission.)



Whereas vasoactive intestinal peptide innervation is de-creased in patients with severe asthma,56 the number ofvasoactive intestinal peptide nerves in COPD is increased.57

Unfortunately, the properties of vasoactive intestinal pep-tide nerves have no significant effect on secretion produc-tion of patients with chronic bronchitis.

Sensory non-adrenergic non-cholinergic C-fibers con-tain substance P, which is a tachykinin that causes bron-choconstriction and increases mucus secretion. Althoughthe non-adrenergic non-cholinergic excitatory C-fibershave been thought to have an important role in the airwayhyperresponsiveness in asthma, their presence in the hu-man airways is not as critically important as in rodentspecies.53,58

Though the non-adrenergic non-cholinergic pathwayseems to play a critical role in respiratory mucus produc-tion, the description of agents that modulate that system isbeyond the scope of this article. The reader is encouragedto search the reports provided in this section.

Adrenergics

The available data conflict regarding the benefits of �2

adrenergics on mucociliary clearance.59–64 The effects ofthe �2 adrenergics on the airways are mediated by stimu-lation of the �2 receptors, which increases cyclic adeno-sine monophosphate, which is a regulator of ciliary beatfrequency in human airway epithelia.3,65–70 Because of theireffect on ciliary beat frequency, �2 adrenergics have beenconsidered mucokinetic medications and cough clearancepromoters.71 �2 adrenergic agonists increase passive move-ment of water across the airway surface, via active trans-port of ions across the airway epithelium.72 They alsostimulate secretion production, primarily from their actionon mucus-secreting cells and submucosal glands.73–75 Theseactions combined increase the amount of mucus in the

airways.76,77 In fact, Daviskas et al found that the majorityof the patients with chronic asthma in their study hadmucociliary clearance abnormalities to the same degree asin patients with bronchiectasis and CF.78 Enhanced muco-ciliary clearance, measured by mucin secretion, with �2

adrenergics in animal models is significantly less than thatobserved after administration of � adrenergics and �1 ad-renergics.73,77,79 There is, however, little evidence to sug-gest that there are increased proportions of mucins in theairway secretions of patients with OLD, except in patientswith asthma.5

Short-Acting � Agonists

Though short-acting � adrenergics have mucociliary-enhancing effects in healthy individuals,80,81 their effectin subjects with depressed clearance is minimal(Fig. 2).21,59,64,82

Terbutaline

A study by Sutton et al on the effect of nebulized ter-butaline, as an adjunct to chest physiotherapy in patientswith stable bronchiectasis, found no significant differencein either sputum volume or radioaerosol mucus clearancebetween saline solution and terbutaline treatment admin-istered prior to chest physiotherapy.83 Similarly, Mortensenet al63,64 found a decreased mucus production with ter-butaline delivered via metered-dose inhaler in healthy sub-jects and patients with asthma or bronchiectasis or CF.

Two studies have evaluated the mucoactive propertiesof terbutaline in a group of patients with pseudohyperal-dosteronism. These patients have a dysfunction of the pul-monary epithelial sodium channel. Terbutaline stimulatedchloride ion secretion toward the lumen, in a dose-depen-dent manner, which suggests enhanced water secretion

Fig. 2. Percentage clearance at 1 hour in healthy subjects, patients with asthma, and patients with chronic bronchitis (CB) after treatmentwith placebo versus terbutaline (0.25 mg subcutaneously). (From Reference 22, with permission.)



onto the airway surface.84–86 Daviskas et al investigatedbaseline mucociliary clearance and the short-term effect ofterbutaline in 16 patients with chronic asthma with sputumproduction while on long-term treatment with salmeterolin combination with inhaled corticosteroids. Although ter-butaline improved mucociliary clearance in a few of the pa-tients, mucociliary clearance remained impaired in the ma-jority of patients, probably because of persisting inflammationand hypersecretion of abnormal mucus (Fig. 3).78

Albuterol

Sabater et al measured tracheal mucus velocity (a markerof mucociliary clearance) in sheep before and for 12 hoursafter treatment with salmeterol, albuterol, ipratropium, or pla-cebo, to determine the effects on normal mucociliary clear-ance. They found that only albuterol and salmeterol can stim-ulate normal mucociliary clearance and reverse human-neutrophil-elastase-induced mucociliary dysfunction, and thatsalmeterol has a longer duration of action in these models ofnormal and abnormal mucociliary clearance (Fig. 4). Humanneutrophil elastase contributes to mucus stasis because it de-creases the tracheal mucus velocity.

Jones and Reid87 found that isoproterenol and albuterolincrease the number of secretory cells in rats, particularlyin the most peripheral airways. This hyperplasia and/orhypertrophy of mucus-secreting cells may be counterpro-ductive in maintaining effective mucociliary clearance.

Fig. 3a. Mean percent clearance at 80 min in the central, region ingroup A (n � 6) and group B (n � 10) patients with asthma. (FromReference 78, with permission.)

Fig. 4. Salmeterol and albuterol increased tracheal mucus velocityduring the initial 6-hour period, compared to ipratropium and ve-hicle. From 6–12 hours, only salmeterol-treated sheep had tra-cheal mucus velocity at or above the initial value, but all the treat-ments were different from vehicle. Overall (0–12 h), the effects ofsalmeterol and albuterol were different from ipratropium and ve-hicle. The values are mean � SE for 6 sheep. * p � 0.05 versusvehicle. Area under the curve is of the percentage of initial trachealmucus velocity per hour. A negative value indicates that trachealmucus velocity fell below baseline (100%). (From Reference 24,with permission).

Fig. 3b. Mean percent clearance at 80 min in the intermediateregion in group A (n � 6) and group B (n � 10) patients withasthma. (From Reference 78, with permission.)

Fig. 3c. Mean percent clearance at 80 min in the peripheral regionin group A (n � 6) and group B (n � 10) patients with asthma.(From Reference 78, with permission.)



Though albuterol can be associated with bronchodila-tion in asthma, it has been suggested that larger-than-usualdoses are needed for maximal short-term effects on mu-cociliary clearance, which increases the risk of increasedviscous mucus secretion (Fig. 5).21

Guleria et al used cine-scintigraphy of inhaled radio-aerosol to evaluate the effect on mucociliary clearance ofa single inhalation of albuterol, ipratropium bromide, andbeclomethasone in 8 patients with OLD, on 4 separatedays. Quantitative indices for the 3 drugs were comparableto placebo, and there was no significant increase in mu-cociliary clearance on any of the days. There was no sig-nificant difference between any of the 3 drugs in short-term improvement of mucociliary clearance, as comparedto placebo.88,89 Devalia et al also found that, while albu-terol had a less potent, slower, and shorter duration ofaction than salmeterol on stimulation of ciliary beat fre-quency in cultured human bronchial epithelium, both ago-nists produced only slight (� 20%) increases in ciliarybeat frequency above baseline.68

In a recent study, Laube et al measured radioactivityfrom inhaled particles labeled with technetium-99m in the

central and peripheral regions of 7 transplanted lungs. Asingle administration of albuterol significantly improve mu-cociliary clearance, compared with the baseline values, inthose lung-transplant patients (Fig. 6).90

Levalbuterol

Frohock et al used digital videomicroscopy to evaluatethe differences in effect of racemic versus single-enanti-omer albuterol on mucociliary clearance of single ovineairway epithelial cells. R-albuterol was associated with adose-dependent stimulation of ciliary beat frequency sig-nificantly higher than that of the racemic S-albuterol.91

O’Riordan et al assessed the clinical importance of stan-dard doses of the S-enantiomer on airway secretions in 14stable long-term intubated patients by comparing a race-mic formulation of albuterol, an R-enantiomer formula-tion, and normal saline solution. Tracheal aspirates wereanalyzed for volume, sodium, chloride, bicarbonate, inter-leukin-8, interleukin-1�, soluble intercellular adhesionmolecule, and tumor necrosis factor alpha. Although allthe agents were associated with increased secretion vol-ume after the first dose, this effect was not apparent onsubsequent doses. There was no significant difference inthe concentrations of the electrolytes or the inflammatoryindexes.92

A recent randomized double-blind placebo-controlledtrial with 10 healthy adult subjects evaluated the effects ofinhaled nebulized levalbuterol (1.25 mg), albuterol(2.5 mg), or placebo, for 7 days, 3 times daily. Gammacamera images of the lungs were obtained after inhalationof radiolabeled aerosol. Cleary et al found that inhaledlevalbuterol does not increase mucociliary clearance orcough clearance, compared to albuterol or placebo.93

Fig. 5. Percentage clearance at 1 hour in healthy subjects aftertreatment with low-dose versus high-dose nebulized albuterol (seetext). Also shown are the mean airway resistance values beforeand after treatment with the low dose versus the high dose.* p � 0.05 for comparison with control or pretreatment values.(Adapted from Reference 21, with permission.)

Fig. 6. A: Deposition of an isotopic marker during the baseline visitat time zero (ie, immediately after aerosol inhalation) in a patientwho had undergone single-lung transplantation. B: Radioactivityremaining in the lung after 76 min. (From Reference 90, with per-mission.)



Fenoterol

In an in vivo canine preparation, Wong et al found a4-fold increase in ciliary beat frequency 30 min after ad-ministration of fenoterol.94 In a study of 26 subjects withchronic bronchitis, airways reversibility of � 15% afterfenoterol administration was associated with faster tra-cheobronchial clearance, more coughs, lower sputum vis-cosity and elasticity, and larger 24-hour sputum produc-tion than those airways with reversibility of � 15%.95 In asimilar study by Weich et al, mucociliary clearance wasmeasured with a scintillation camera after inhalation of atechnetium-99m labeled aerosol. The increase in percent-age clearance after fenoterol administration for the left andright whole lung was 35% and 36% per hour, respective-ly.96

Long-Acting � Agonists

Though some in vitro and in vivo studies suggest thatlong-acting � adrenergics significantly improve mucocili-ary clearance, compared to short-acting � adrenergics, oth-ers suggest only a modest improvement.

Salmeterol

Salmeterol is the most thoroughly investigated long-acting � adrenergic, in regard to measuring the effect of �2

adrenergic agonists on mucociliary clearance. It has beensuggested that lipophilicity of the adrenergic agent pro-portionally prolongs its duration of action.97–100 Salmet-erol is more lipophilic than the short-acting � adrenergics,formoterol, and arformoterol.21 In vitro and in vivo studiesshow that salmeterol stimulates a faster and stronger cili-ary beat frequency than does albuterol.68,74,75

A study by Piatti et al, with patients with COPD andpneumonia, confirmed the ability of salmeterol to enhance“only to a modest degree” ciliary beat frequency in bothnormal and COPD nasal epithelium.74 This minimal stim-ulatory effect of �2 adrenergics in chronic bronchitis wasconfirmed by Mossberg et al, in a study in which patientswith the least ventilatory impairment had the greatest en-hancement of clearance.59 However, there have been noreports on the in vivo effect of salmeterol pretreatment oneither the quantity or quality of airway secretions in chronicbronchitis.

Bennett et al101 compared the short-term effect of sal-meterol (42 �g) to placebo on mucociliary and cough-enhanced secretion clearance in 14 patients with mildchronic bronchitis. A radiolabeled aerosol (technetium-99m sulfur colloid) and gamma camera analysis was usedto measure mucociliary and cough clearance on 2 studydays: a placebo/control day, and a salmeterol treatmentday. There were no significant correlations between the

average clearances over any period, relative to placebo andeither baseline lung function or improvements in lung func-tion (eg, percent increase in forced expiratory flow in themiddle half of the forced vital capacity) associated withsalmeterol treatment. Although mean whole-lung clear-ance was higher with salmeterol than with placebo, onlyperipheral lung clearance was significantly enhanced bysalmeterol (Fig. 7). The distribution of � adrenergic aero-sol particles and their impact on mucociliary clearancemay be particularly important in patients with mild tomoderate airway obstruction.102 Bennett et al has suggestedthat the observed enhanced clearance with salmeterol maybe primarily from its effect on the mucociliary apparatus,as opposed to the cough mechanism.101

A crossover study by Hasani et al103 found no signifi-cant enhancement of mucociliary clearance in patients withasthma following 2 weeks of salmeterol versus placebo,and concluded that salmeterol’s mucociliary clearance ben-efit was a result of increased airway patency.

One more mechanism by which long-acting � adrener-gics might benefit mucociliary clearance is by reducingneutrophil adhesion and accumulation in airway epithe-lium in patients with asthma. The reduction in epithelialdamage is associated with a decrease in total number ofbacteria that adhere to the respiratory mucosa. Salmeterol

Fig. 7. Top: Whole right-lung particle retention versus time in all 14subjects during the 2 hours after deposition. Bottom: Peripheralright-lung particle retention versus time in all 14 subjects duringthe 2 hours after deposition. Treatment was delivered via metered-dose inhaler immediately after time 0. (From Reference 101, withpermission.)



has a longer inhibition of the secretagogue human neutro-phil elastase than does albuterol.24

Although over 80% of patients with CF receive bron-chodilators,104 it is controversial whether bronchodilatorsbenefit mucociliary clearance.105,106 Some patients withCF report recurrent wheezing after receiving bronchodila-tors.107–109

A review by Colombo et al on the use of long-acting� adrenergics in CF revealed that some of the mechanismsimplicated in the response of CF to bronchodilators in-clude direct smooth muscle relaxation, increased muco-ciliary clearance, improved peripheral deposition of neb-ulized antibiotics or mucolytics, direct effects oninflammatory cells and bacterial adherence, and a possibledirect effect on CF transmembrane conductance regulatorfunction.106,110 Particularly important to patients with CFis the study by Taouil et al, who found that �2 receptorshave the same localization in the apical region of airwayepithelial cells as does the CF transmembrane conductanceregulator.110 The CF transmembrane conductance regula-tor protein is a cyclic-adenosine-monophosphate-regulatedchloride channel.111 Stimulation of human airway mucosawith salmeterol produces a time-dependent increase in api-cal CF transmembrane conductance regulator protein ex-pression in human airway epithelial cells. The maximumresponse is typically reached after 24 hours of treatmentwith salmeterol.107

Mortensen et al suggested that �2 adrenergic agonistsdo not significantly improve airway clearance because theydo not stimulate cyclic-adenosine-monophosphate-depen-dent chloride secretion in the lung, which is affected byCF, and thus do not improve hydration of the airway sur-face.112

Formoterol

Melloni and Germouty113 evaluated inhaled formoterolin 10 patients with stable chronic bronchitis. After 6 daysof treatment, mucociliary clearance had significantly in-creased to 46% versus placebo. The improvement waslinked to better functioning of the mucociliary apparatus,not to bronchodilation, since the airway resistance wasonly slightly (nonsignificantly) reduced. Formoterol sig-nificantly reduces the absolute number of airway neutro-phils, compared with placebo. There is a significant cor-relation between the percentage of neutrophils and sputuminterleukin-8 and the improvement of lung function, asmeasured by FEV1 (forced expiratory volume in the firstsecond).114

Anticholinergics

Although inhaled anticholinergics are considered mu-coregulatory agents that inhibit mucus secretion by block-

ing cholinergic muscarinic M3 subtype receptors,71 there ishistorical evidence of mucociliary clearance impairmentafter administration of old anticholinergic drugs.115,116 TheM1 receptor is not involved with mucus output,117 but inconjunction with the M3 receptor, the M1 receptor maycontrol water secretion.118 Stimulation of the cholinergicmuscarinic M2 subtype receptor inhibits further release ofacetylcholine into the synaptic space, so the use of M2

receptor antagonists is associated with increased mucussecretion.24 Cholinergic control of mucus secretion mightbe augmented in asthma because of dysfunctional airwaymuscarinic M2 receptors,119 and airways with hypertrophicsubmucosal glands have a significantly lower response toatropine and higher than normal response to acetylcholinein vitro.120

Ipratropium

Large doses of the short-acting anticholinergic ipratro-pium bromide caused no significant changes in the volumeor viscoelastic properties of tracheal mucus in animal stud-ies.121 Current evidence on the effect of inhaled ipratro-pium on mucociliary clearance in normal subjects, adultpatients with asthma, and patients with chronic bronchitissuggests that sputum volume does not change.97,122–126 Ben-nett et al previously reported that ipratropium has a ten-dency to slow cough-associated mucus clearance in pa-tients with severe COPD. Using a radiolabeled (technetium-99m iron oxide) monodisperse aerosol and gamma cameraanalysis, Bennett et al127 investigated the effect of inhaledipratropium bromide (40 �g) on cough-enhanced clear-ance of mucus from the airways of 15 subjects with stable,moderate-to-severe COPD. Clearance was measured dur-ing 2.5-hour periods on 3 separate days: a control day, acough day with ipratropium, and a cough day with pla-cebo. Ipratropium diminished the effectiveness of cough inclearing the radiolabeled particles from the airways. Anal-ysis of the data from the 2 study days (placebo versusipratropium) also showed significantly faster cough clear-ance on the placebo study day. This effect of ipratropiumon cough clearance may be due to changes in the airflowdynamics induced by bronchodilation, altered rheology, ordepth of airway secretions.127,128

Miyata et al had reported that neither oxitropium noripratropium depressed the normal mucociliary clearance inanimals.129 Those results were confirmed in 2 separatestudies by Guleria et al, who found no appreciable effecton mucociliary clearance after inhalation of ipratropium inpatients with chronic stable asthma88 and COPD.89

Pavia et al reported a decrease in 6-hour sputum weightfrom patients with reversible airway obstruction.125 A sim-ilar reduction in the volume of airway mucus in patientswith chronic bronchitis was found by Tamaoki et al afterlong-term administration of a short-acting anticholinergic,



oxitropium bromide.23 Sabater et al found that ipratropiumdid not affect the response to inhaled human neutrophilelastase, whereas the human-neutrophil-elastase-induceddepression in tracheal mucus velocity was reversed withonly albuterol and salmeterol, not with ipratropium.26

Tiotropium

Although the long-acting anticholinergic tiotropiumbinds to all 3 muscarinic receptors, its prolonged pharma-cologic activity is the result of its slow dissociation fromthe M1 and M3 receptors.21,130–132 Hasani et al133 con-ducted a 3-week randomized double-blind placebo-con-trolled tiotropium study with 34 subjects (age range 40–75 years) with stable COPD. Aerosol deposition, definedas the proportion of particles deposited in the non-ciliatedairways and therefore not available for mucociliary clear-ance, was significantly greater with tiotropium (Fig. 8).

Based on a significant decrease in cough frequency,Hasani et al133 hypothesized that tiotropium produces ashift from cough to mucociliary action. Because effectivebronchodilation led to deeper penetration of the radioaero-sol, they concluded that the transit pathway for mucus waslengthened. These findings suggest that tiotropium doesnot adversely affect mucus transport, and may marginallyenhance mucociliary transport efficiency.133 In a recentreview, Keam et al134 found that aerosol particle penetra-tion was improved with tiotropium, without delaying mu-cus clearance from the lungs.

Glycopyrrolate

Glycopyrrolate is a quaternary ammonium derivativewith minimal mucosal absorption and minimal systemictoxicity when inhaled. Its oral absorption is less than 5%.Although poorly studied, there is a resurging interest in

glycopyrrolate’s potential role as a long-acting anticholin-ergic for treating stable and unstable OLD.135 A study byPahl et al on human primary monocytes found that glyco-pyrrolate acts synergistically with anti-inflammatory drugsin inhibiting inflammatory mediators commonly secretedin patients with asthma and COPD.136 Additionally, ad-ministration of nebulized racemic glycopyrrolate has beenassociated with longer bronchodilation and bronchopro-tection against methacholine-induced bronchospasm in pa-tients with asthma, when compared to ipratropium bro-mide or placebo.137–139 In combination with albuterol,nebulized glycopyrrolate significantly improves FEV1 inpatients with COPD exacerbations.140

Although glycopyrrolate injection is more frequentlyused preoperatively, to reduce cholinergic symptoms suchas sialorrhea, bronchorrhea, and excessive pharyngeal se-cretions,141 there has been little research on glycopyrro-late’s role in mucociliary clearance. “Death rattle” is aterm commonly used to describe the respiratory noise indying subjects due to sialorrhea and bronchorrhea.142 Hu-gel et al143 compared glycopyrrolate and hyoscine hydro-bromide in 72 dying subjects with respiratory noise due todeath rattle. Glycopyrrolate provided a greater and moreprolonged improvement of respiratory tract secretions.143

However, a similar study by Back et al found glycopyr-rolate less effective than subcutaneous administration ofhyoscine hydrobromide.144 In a mini-review, Lawrey eval-uated the effectiveness of hyoscine hydrobromide and gly-copyrrolate in drying respiratory secretions in terminallyill patients, and found no clear evidence to support thechoice of hyoscine hydrobromide over glycopyrrolate.145

Effects of Common Adrenergics and Anticholinergicson Mucociliary Clearance

Table 1 shows a chronological summary of human andanimal studies on the effects of the most common adren-ergics and anticholinergics on mucociliary clearance. Thereare several important limitations to summarizing the re-sults and making recommendations. First, the differencesin research design may explain the variability of findingsin these studies. There are several techniques to evaluatemucociliary clearance. Second, some studies measured mu-cociliary clearance by creating central regions of analysisfor the gamma scintigrams, whereas others created andmeasured peripheral radioaerosol deposition and particleclearance to assess regional differences. Third, a limitednumber of clinical studies have been adequately poweredto show significant differences. The small statistical dif-ferences reported are of questionable clinical relevance.And, finally, the possible effects of different dosing regi-mens relative to the time when mucociliary clearance mea-surements were made may have affected the comparisonsand clinical recommendations. Longer mucociliary clear-

Fig. 8. Change in tracheobronchial clearance at 6 hours after ra-dioaerosol inhalation, and in productive coughing (represented byradioactivity of expectorated sputum), together with their differ-ence (mucociliary). (From Reference 133, with permission.)



Table 1. Summary of Human and Animal Trials on the Effects of �2 Adrenergics and Anticholinergics on Mucociliary Clearance.

First Author Year Agent(s) n Subjects Results

Mossberg59 1976 Terbutaline 12 Asthma vs healthy subjects Significant increase in mucociliary clearance butsignificantly less than in healthy subjects.Significantly less response in subjects with impairedmucociliary clearance.

Sutton83 1988 Terbutaline 8 Bronchiectasis Significantly increased sputum productionMortensen63 1991 Terbutaline 10 Asthma vs healthy subjects Significant increase in mucociliary clearance in healthy

subjectsMortensen112 1993 Terbutaline 10 Cystic fibrosis No significant increase in mucociliary clearanceMortensen64 1994 Terbutaline 62 Healthy subjects Significant increase in mucociliary clearanceDaviskas78 2005 Terbutaline 16 Asthma Little or no stimulation of mucociliary clearanceJones87 1979 Albuterol Rat epithelium Significant increase in number of secretory cellsDevalia68 1992 Albuterol

SalmeterolHuman bronchial epithelial cells Albuterol produced a transient but significant increase

in ciliary beat frequency. Salmeterol produced asignificantly rapid and prolonged increase in ciliarybeat frequency.

Frohock91 2002 AlbuterolLevalbuterol

Ovine tracheal epithelium R-albuterol is more efficacious than racemic albuterolin stimulating ciliary beat frequency

Guleria88 2003 AlbuterolIpratropiumBeclomethasone

8 Chronic airway disease No significant difference in mucociliary clearance vsplacebo

Guleria89 2003 AlbuterolIpratropiumBeclomethasone

8 Asthma No significant difference in mucociliary clearance vsplacebo

Sabater26 2005 AlbuterolSalmeterolIpratropium

6 Sheep Significant increase in tracheal mucus velocity andreversion of human-neutrophil-elastase-induceddepression of tracheal mucus velocity withsalmeterol and albuterol. Ipratropium had no effect.

O’Riordan92 2006 AlbuterolLevalbuterol

14 Long-term ventilated patients No significant differences in volume, electrolyteconcentration, or inflammatory indexes of sputum

Cleary93 2007 AlbuterolLevalbuterol

10 Healthy subjects No significant differences in mucociliary clearance vsplacebo

Laube90 2007 Albuterol 7 Lung transplant Significant improvement in mucociliary clearanceWong94 1988 Fenoterol 9 Healthy beagles Significant increase in ciliary beat frequencyWeich96 1988 Fenoterol 12 Chronic bronchitis Significant increase in mucociliary clearanceMoretti95 1997 Fenoterol 26 Chronic bronchitis Patients with FEV1 changes � 15% had significant

increase in mucociliary clearance, more coughs, andlarger 24-h sputum production

Hasani103 2003 Salmeterol 11 Asthma No significant increase in mucociliary clearancePiatti74 2005 Salmeterol 10 COPD Significant dose-dependent increase in ciliary beat

8 Community-acquired pneumonia frequency in all groups. No rheological changes.8 Healthy subjects

Bennett101 2006 Salmeterol 14 Chronic bronchitis No significant overall increase in mucociliary clearancevs placebo. Significant increase in lung peripheryclearance.

Melloni113 1992 Formoterol 10 Chronic bronchitis Significant increase in mucociliary clearanceFrancis122 1977 Ipratropium 12 Healthy subjects No significant difference in mucociliary clearance vs

placeboPavia125 1979 Ipratropium 12 Reversible airway obstruction No significant difference in mucociliary clearance vs

placeboMiyata129 1989 Ipratropium

OxitropiumAtropine

14 Pigeons and rabbits No depression of mucociliary clearance withipratropium and oxitropium

Bennett127 1993 Ipratropium 15 COPD Significant decrease in cough clearance vs placeboTamaoki23 1994 Oxitropium 17 Chronic bronchitis Significant decrease in sputum productionHasani133 2004 Tiotropium 34 COPD No depression of mucociliary clearance

FEV1 � forced expiratory volume in the first secondCOPD � chronic obstructive pulmonary disease.



ance observation times may be needed to evaluate theshort-term, medium-term, and long-term cumulative effectof bronchodilators.

Inhaled �2 adrenergics appear to stimulate mucociliaryclearance in normal airways.21,86,91,121 Because the muco-ciliary enhancing effect of these agents in patients withdepressed clearance is much less than in healthy individ-uals,2,20,64,65 routine administration of �2 adrenergics topatients with mucociliary dysfunction or patients under-going mechanical intubation, to change the volume andcomposition of airway secretions, is not supported by cur-rent evidence.92 Although short-acting � adrenergics maycause significant bronchodilation in some patients withairway obstruction, higher-than-usual doses may be re-quired to obtain maximal benefits on mucociliary clear-ance,21,78 which increases the risk of adverse effects, suchas increased mucus secretion.146 High doses or continuous�2 adrenergics quickly saturate receptors, and a patient ina severe asthma attack could literally drown in secre-tions.17–20 Patients who receive �2 adrenergics for acutesevere asthma should be closely monitored for mucus ob-struction.

Zach et al suggested that �2 adrenergic agonists maydecrease cough clearance of secretions by decreasing air-way tone and thus causing dynamic collapse of the air-ways or nonhomogeneous emptying of lung regions. Be-tween 15% and 26% of patients with CF report asthma-like symptoms, primarily recurrent wheezing, afterreceiving bronchodilators.108,109

�2 adrenergics may be considered in patients with dem-onstrated airway reversibility to enhance mucociliary clear-ance. However, a decreased response in mucociliary clear-ance to a second dose of albuterol suggests that prolongedmaintenance with long-acting � adrenergics may be moreeffective than the periodic increases in mucociliary clear-ance obtained with subsequent doses of short-acting � ad-renergics in these patients.24

�2 adrenergics can reverse the depression in trachealmucus velocity induced by human neutrophil elastase andmay be more beneficial than anticholinergics in improvingmucociliary clearance in respiratory diseases associatedwith high levels of elastase. Human neutrophil elastaselevel correlates well with airway disease severity.35–37

A clinical aspect of �2 adrenoceptor pharmacology inrecent years has been the recognition of genetic receptorpolymorphism that could change the physical propertiesand composition of the sputum matrix.147,148 The potentialrole of this polymorphism on the pharmacologic propertiesof the �2 adrenergics may have important therapeutic im-plications for patients with OLD. This requires furtherevaluation.

Anticholinergics are mucoregulatory agents that can re-duce mucus secretion by affecting the neural pathway.4

The available evidence shows no improvement in muco-

ciliary clearance, in either healthy subjects or pa-tients.97,125,126 Opposite to the �2 adrenergic agents, anti-cholinergics do not modify the human-neutrophil-elastase-induced depression in tracheal mucus velocity24 and doinhibit cough clearance. Cough might be of critical impor-tance to enhance mucociliary clearance in some patientswith severe COPD.127 Although tiotropium is associatedwith a minimal enhancement in mucociliary clearance,133

more studies are required to draw conclusions on tiotro-pium’s effects on cough and mucociliary clearance. Basedon existing evidence, routine administration of anticholin-ergics is not recommended to improve mucociliary clear-ance.

The effect on mucociliary clearance of �2 adrenergicsand anticholinergics combined with inhaled corticosteroidsand other mucoactive agents has not been extensively stud-ied. It is clear that a better understanding of the patho-physiology of mucus hypersecretion in obstructive airwaydisease is the key to identifying therapeutic targets in therespiratory tract and the development of mucoactive agents.

Summary

Bronchodilators are important in the management ofOLD. The benefit of �2 adrenergic and anticholinergicbronchodilators has typically been measured by lung func-tion improvement. Their effects on mucociliary clearanceneed to be further evaluated in a much larger group ofpatients. Excessive respiratory secretions may be an im-portant dysfunction of the mucociliary transport system inpatients with OLD, and excessive secretions considerablyincrease the risk of respiratory infections and exacerba-tions. A better understanding of the role of bronchodilatorsin mucociliary clearance is critical to establish a new ther-apeutic profile to optimize airway clearance. It appearsthat no single mucoactive agent is appropriate or enoughfor all patients with OLD. Combination therapy may pro-vide synergism to improve mucociliary clearance, but thisrequires further evaluation.

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Discussion

Rogers: The studies comparing thedifferences in mucociliary clearancebetween short- and long-acting�-agonists that you showed,1-3 sal-butamol versus salmeterol, must bedifficult to do in terms of the proto-col. For example, salbutamol willhave a quick onset of action and arelatively quick offset of action com-pared with salmeterol, which has aslower onset of action and, of course,a much slower offset. How are thosestudies conducted so that they arecomparing like for like, for exam-ple, in terms of concentration andtime course?

1. Daviskas E, Anderson SD, Shaw J, Eberl S,Seale JP, Yang IA, Young IH. Mucociliaryclearance in patients with chronic asthma:effects of beta agonists. Respirology 2005;10(4):426-435.

2. Devalia JL, Sapsford RJ, Rusznak C, Toum-bis MJ, Davies RJ. The effects of salmeteroland salbutamol on ciliary beat frequency ofcultured human bronchial epithelial cells, invitro. Pulm Pharmacol 1992;5(4):257–263.

3. Sabater JR, Lee TA, Abraham WM. Com-parative effects of salmeterol, albuterol, andipratropium on normal and impaired muco-

ciliary function in sheep. Chest 2005;128(5):3743-3749.

Restrepo: That is a very good ques-tion. They actually quoted a limitationfor long-acting � agonists, and that isthe inability to study even longer mu-cociliary clearance effect, or chronicbeneficial effect on mucociliary clear-ance of human subjects because thereis not an easy way to keep these pa-tients for longer periods of time inthis type of study.

In animals,1,2 it has been a little bitdifferent because studies could be sus-tained for days. One of the protocolsthat they actually have for long-actingagonists is to be able to measure sus-tained effects in the treatment of COPDpatients. So, if the patients were al-ready maintained on salmeterol, forexample, they were just brought backafter a few days to study.3 Again, it’smuch more feasible in animal subjectsthan in clinical studies. You can seethat it’s actually correlated with thenumber of subjects that had been stud-ied clinically.

1. Sabater JR, Lee TA, Abraham WM. Com-parative effects of salmeterol, albuterol, and

ipratropium on normal and impaired muco-ciliary function in sheep. Chest 2005;128:3743-3749.

2. Jones R, Reid L. �-agonists and secretorycell number and intracellular glycoprotein inairway epithelium. Am J Pathol 1979;95:407-22.

3. Moretti M, Lopez-Vidriero MT, Pavia D,Clarke SW. Relationship between bronchialreversibility and tracheobronchial clearancein patients with chronic bronchitis. Thorax1997;52(2):176-180.

Rogers: Just a quick follow-up. Iwas interested in the study that com-pared salbutamol to salmeterol wherepropranolol blocked the salbuterol re-sponse, but not the salmeterol re-sponse.1 Is that because once you setup the intracellular signal transductioncascade with salmeterol, the propran-olol is not going to hit that, whereasit’s more likely to hit it with the sal-butamol, which is short-acting. Is thathow the blocking mechanism works?

1. Devalia JL, Sapsford RJ, Rusznak C,Toumbis MJ, Davies RJ. The effects ofsalmeterol and salbutamol on ciliary beatfrequency of cultured human bronchial ep-ithelial cells in-vitro. Pulm Pharmacol1992;5(4):257–263.



Restrepo: I don’t have a goodanswer for that. I don’t know ifBruce . . .

Rubin: I don’t know. I saw that andwas wondering if, in fact, the verylong duration that the salmeterol re-mains on the receptor might actuallyallow the propranolol, which has afairly short on-and-off as well, to bewashed out, and so you are getting ablunting, but because of the relativelylong action and the long signaling youthen begin to pick up some of the �agonists action later on in the course.But I don’t think that’s actually beenstudied.

Homnick: In cystic fibrosis, it’s sortof been a knee-jerk for us to start �agonists prior to using airway clear-ance. I think that this emphasizes theimportance of individualizing � ago-nist use or bronchodilator use in CFpatients. Some will have more airwayobstruction following the � agonists,so that the use of spirometry beforeand after, before you decide to usethem on a chronic basis, I think isimportant. It looks to me like the li-pophilic � agonists are those that havethe most potential for increasing mu-cociliary clearance. Is that correct?

Restrepo: Yes, that is correct. Theshort-acting � agonists are more hy-drophilic, and the salmeterol more li-pophilic than the formoterol. The greatmajority of studies include the longacting � agonist salmeterol versus theformoterol. It will be interesting to seewhat kind of effects we will see withthe arformoterol (Brovana). The li-pophilic property has a lot to do withthe action of these agents due to theability to spread across the epitheliumversus the cleavage of the hydrophilicagents and their short term effect.

MacIntyre: You mentioned arfor-moterol. Is there any effect on theseL- and R-isomers on these mucus ac-tivities you’ve been talking about?

Restrepo: I couldn’t find any dataon it.

Rubin: Not on the arformoterol, butthere was a study done by TomO’Riordan’s group looking at leval-buterol versus albuterol.1 Assessingthe effects of racemic and single-en-antiomer albuterol on airway secre-tions in long-term intubated patients.And both of them were identical inonset of action, inflammation, and mu-cus secretion. This is similar to otherhuman studies comparing albuterol tolevalbuterol.

1. O’Riordan TG, Mao W, Palmer LB, ChenJJ. Assessing the effects of racemic and sin-gle-enantiomer albuterol on airway secre-tions in long-term intubated patients. Chest2006;129(1):124-132.

MacIntyre: This may be way outon the fringe, but all this discussionabout these mutations on the � recep-tor, do those have effects with mucussecretion as well as with bronchialsmooth muscle relaxation?

Restrepo: That’s been mentioned inprobably 2 discussions. Those differ-ent phenotypes of the �2 receptors haveto be looked at—that, along with thedifferent changes in the rheology ofthe mucus. But I don’t think it hasbeen addressed.

Myers: I want to go back to BruceRubin’s comments. There actually area couple of studies out there, cellularstudies that look at the S-isomer fromalbuterol.1,2 They potentially showedthat it does increase mucin or mucusproduction, also impacts ciliary beatfrequency, and actually makes it verydysfunctional. A lot of the studieslooked at racemic mixtures of albu-terol. And it would be interesting tosee some of those reproduced with asingle-isomer albuterol, to see if thiscellular mechanism truly does impactthe airway clearance mechanism in thehuman model.

1. Slattery D, Wong SW, Colin AA. Levalbu-terol hydrochloride. Pediatr Pulmonol 2002;33(2):151-157.

2. Chang MMJ, Zhao YH, Chen Y, Hack J,Snider ME, Peck K, Wu R. S)-albuterol, butnot other �2-agonist isomers, has stimula-tory effects on mucin secretion and changesin gene expression on airway epithelium (ab-stract). Am J Respir Crit Care Med 2001;163:A590.

Rogers: I think what they found withthe separate isomers was that the ac-tive isomer worked and the nonactiveisomer didn’t. In fact, it made thingsworse, as you so rightly say. Theyfound that it was due to an irritanteffect of the drug formulation. But,without the protective effect of the ac-tive isomer, the bronchodilation effectwas lost. Thus, in the racemic mixturethere is a combination of an irritant,bronchoconstrictor effect that is offsetby the protective bronchodilator ef-fect of the active isomer. In contrast,with the single, inactive isomer, thereis just the irritant effect without theprotective effect. Is that true?

Myers: That is correct, when yougive it as a dual-isomer mixture, the Roffsets the S, but you have to remem-ber that the metabolism clearance ofthe R-isomer really clears the lungs inabout 2-4 hours, where the S-isomer(in other studies1-3) has been shownto hang around as long as 10-12 hours.So, potentially, you do have the sin-gle-isomer, the S-albuterol, which the-oretically is the nonproductive part ofthe isomer that’s hanging around6-fold longer.

1. Gumbhir-Shah K, Kellerman DJ, DeGrawS, Koch P, Jusko WJ. Pharmacokinetics andpharmacodynamics of cumulative singledoses of inhaled salbutamol enantiomers inasthmatic subjects. Pulm Pharmacol Ther1999;12(6):353-362.

2. Schmekel B, Rydberg I, Norlander B,Sjosward KN, Ahlner J, Andersson RG. Ste-reoselective pharmacokinetics of S-salbuta-mol after administration of the racemate inhealthy volunteers. Eur Respir J 1999;13(6):1230-1235.

3. Gumbhir-Shah K, Kellerman DJ, DeGrawS, Koch P, Jusko WJ. Pharmacokinetic andpharmacodynamic characteristics and safetyof inhaled albuterol enantiomers in healthy



volunteers. J Clin Pharmacol 1998;38(12):1096-1106.

Schechter: I want to make a tech-nical comment about statistical test-ing, if people will bear with me, be-cause I think it’s important in thecontext of all the studies that youshowed. When a study concludes thatthere’s no discernible difference be-tween treatment groups, really what’sgoing on is it’s failing to prove thatthere’s a difference. It’s different, andmuch more difficult, to prove thatthere’s equivalence, and especiallywhen you’re looking at studies thatwere designed to look for a differ-ence.

Also, while some of the studies weresomewhat larger, you referenced stud-ies with 4, with 8, with 10 subjects,and so failure to find a difference be-tween groups might be due primarilyto a lack of statistical power. Even inthe studies with a larger number ofsubjects, if there’s a wide range ofvariation in measurements, the n value

might not be enough. With all the smallstudies that have been looking at thistopic, it looks like it’s a ripe area fora meta-analysis, where you could po-tentially combine the results of thesedifferent studies, and potentially drawsome more clear-cut conclusions.

Restrepo: I completely agree. Ithink one of the major limitations ishow to translate findings of poorlypowered studies into practice, as wellas how you translate the fact that well-powered studies could have resultedin good clinical response but no sta-tistically significant differences. Inother words it would be very nice torun a meta-analysis just to see whatyou end up with. Because at this point,it is a very limited number of subjects,which again creates a limitation onstudies of medications we use on aregular basis. This is actually relativelypoor evidence to extrapolate.

Hess: I have some clinical questions.Should I ever use � agonists to im-

prove airway clearance? Should I everuse anticholinergics in patients whohave a bronchorrhea? Should I thinkabout using anticholinergics in a pa-tient with sialorrhea, like a patient withALS?

Restrepo: My answer would bethat, based on the evidence that Ipresented today, the beneficial ef-fect of � agonists is limited whenyou have baseline impairment of themucociliary clearance. In terms ofthe anticholinergics, the potential in-hibition of cough will be importantto remember on those patients whodepend so much on the cough mech-anism for mucociliary clearance (notso much on bronchodilation). By pro-viding bronchodilation, the anticho-linergics compensate their effect oncough. Evidence for both broncho-dilators is poor; therefore, their rou-tine recommedation is still very ques-tionable.



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