Download Inhaled Adrenergics and Anticholinergics in Obstructive Lung Disease

Inhaled Adrenergics and Anticholinergics in Obstructive
Lung Disease: Do They Enhance Mucociliary Clearance?
Ruben D Restrepo MD RRT
Introduction
Innervation of Airway Secretory Structures
Adrenergic Innervation
Cholinergic Innervation
Non-Adrenergic and Non-Cholinergic Pathway
Adrenergics
Short-Acting ␤ Agonists
Terbutaline
Albuterol
Levalbuterol
Fenoterol
Long-Acting ␤ Agonists
Salmeterol
Formoterol
Anticholinergics
Ipratropium
Tiotropium
Glycopyrrolate
Effects of Common Adrenergics and Anticholinergics on Mucociliary Clearance
Summary
Pulmonary mucociliary clearance is an essential defense mechanism against bacteria and particulate matter. Mucociliary dysfunction is an important feature of obstructive lung diseases such as
chronic obstructive pulmonary disease, asthma, cystic fibrosis, and bronchiectasis. This dysfunction
in airway clearance is associated with accelerated loss of lung function in patients with obstructive
lung disease. The involvement of the cholinergic and adrenergic neural pathways in the pathophysiology of mucus hypersecretion suggests the potential therapeutic role of bronchodilators as mucoactive agents. Although anticholinergics and adrenergic agonist bronchodilators have been routinely used, alone or in combination, to enhance mucociliary clearance in patients with obstructive
lung 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 Respiratory Care, University of Texas Health Science Center, San Antonio,
Texas.
The author reports no conflicts of interest related to the content of this
paper.
Dr Restrepo presented a version of this paper at the 39th RESPIRATORY CARE
Journal Conference, “Airway Clearance: Physiology, Pharmacology,
RESPIRATORY CARE • SEPTEMBER 2007 VOL 52 NO 9
Techniques, and Practice,” held April 21–23, 2007, in Cancún,
Mexico.
Correspondence: Ruben D Restrepo MD RRT, Department of Respiratory 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].
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mucociliary clearance, mucus, sputum, obstructive lung disease. [Respir Care 2007;52(9):1159–1173.
© 2007 Daedalus Enterprises]
Introduction
by blocking the cholinergic muscarinic receptor subtype M3. However, their clinical benefit as mucoactive
agents has been difficult to demonstrate.24 –27
The effect of ␤2 adrenergics and anticholinergics in modifying human-neutrophil-elastase-induced impairment of
mucociliary clearance common to OLD has been confirmed
in animal studies.27–29 Human neutrophil elastase is a known
mucus secretagogue with cilia-inhibiting properties that
can stimulate epithelial sodium channels, reducing the periciliary fluid layer and thus contribute to mucus stasis.27–31
Human neutrophil elastase depresses mucociliary clearance, as measured by tracheal mucus velocity in animals.32
Several studies have shown that human neutrophil elastase
is an important inflammatory mediator in OLD and that
disease severity is linked to the concentration of human
neutrophil elastase in the airways.33–38
Mucociliary clearance is an effective and essential biological barrier against microorganisms and particulate matter. This specialized apparatus consists of secretory cells
and ciliated cells that beat in a coordinated and metachronal fashion.1,2 Their propulsive force mobilizes the mucus
blanket toward the larynx for elimination.3
In the presence of infection and inflammation, the airway mucosa typically responds by increasing the amount
of secreted mucus, due to goblet cell and submucosal gland
hyperplasia and hypertrophy, a phenomenon also known
as secretory hyperresponsiveness.4 Additionally, inflammation causes loss of cells and ciliary function, destruction
of the surfactant layer by airway phospholipases, and alteration of the biophysical properties of the mucus.5
Dysfunction of the mucociliary clearance is a common
respiratory disturbance in patients with obstructive lung
disease (OLD) such as chronic bronchitis, asthma, bronchiectasis, and cystic fibrosis (CF). This dysfunction is an
important marker of accelerated loss of lung function in
chronic obstructive pulmonary disease (COPD).6 Cough
and adequate airflow are of critical importance when hypersecretion is severe, prolonged, and associated with extensive ciliary damage, because airflow may become the
primary means of airway secretion clearance. Since cough
is most effective with high expiratory flow, bronchodilators may have a therapeutic role in airflow-dependent clearance.5
There is variability in the abnormalities of secretions
produced by patients with obstructive lung disease. In CF
the composition of the secretions is similar to pus, with
almost no mucin or mucus,7–10 whereas secretions from
patients with asthma are more viscous than those from
patients with COPD, CF, or bronchiectasis.11–15 The abnormal secretion and retention of mucus in asthma has
been confirmed by postmortem studies of patients with
status asthmaticus that showed obstructed airways with
gelatinous mucus plugs.16 –20
Although ␤2 adrenergics are important in the management of symptomatic obstructive lung disease, it appears
that only the long-acting ␤ adrenergics provide sustained
improvement of mucociliary clearance.21 Evaluation of
short-acting ␤ adrenergics for the improvement of mucociliary clearance in patients with OLD has shown that their
effect is generally less than that seen in normal airways.22
Since neural control of mucus secretion is believed to be
predominantly cholinergic,23 anticholinergics have the potential to inhibit the neurogenic mucus secretion pathway
The cholinergic system is the dominant neural pathway
in the airways, primarily by stimulation of the muscarinic M3 pathway. The muscarinic receptors are classified
into M1–M5 subtypes. The M1 receptors are widely distributed throughout the parasympathic ganglia and exocrine glands. The prejunctional muscarinic M2 autoreceptors are found in the smooth muscle and the myocardium,
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Innervation of Airway Secretory Structures
The sympathetic (adrenergic), parasympathetic (cholinergic), and non-adrenergic non-cholinergic pathways are
the main neural pathways responsible for the modulation
of airway diameter and the innervation of secretory cells.
Figure 1 shows photomicrographs of normal airway epithelium and secretory cell innervation. Darkfield illumination shows the presence of cholinergic muscarinic receptors in the submucosal glands and non-adrenergic noncholinergic tachynin receptors binding to epithelium and
glands.
Adrenergic Innervation
Based on histological analyses, the sympathetic-adrenergic innervation of human airway smooth muscle and
secretory structures is sparse or nonexistent and plays little
or no role in regulating airway caliber. Adrenergic control
appears to be restricted to the interaction of circulating
catecholamines, such as adrenaline, with adrenoceptors on
the secretory cells to increase mucus production.39
Cholinergic Innervation
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Fig. 1. Photomicrographs of secretory cells, nerves, and receptors in the airways. A: Normal respiratory epithelium (Ep). L ⫽ lumen. G submucosal
glands. B: Intra-epithelial nerve fiber (N) between 2 goblet cells that contain mucin granules (MG) in guinea-pig trachea. The arrow points to the
intercellular junction. C: Muscarinic receptors in ferret trachea. Darkfield illumination of tracheal section incubated with the muscarinic receptor
antagonist [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 localization of substance P binding sites to epithelium (Ep) and glands (G). Photograph A courtesy of David E Martin, PhD, Cardiopulmonary Care
Sciences, Georgia State University, Atlanta, Georgia. (Photographs B, C, and D from Reference 24, with permission.)
and provide negative presynaptic feedback to reduce further release of acetylcholine.40 – 44 The M3 receptor subtype in the airway smooth muscle mediates bronchoconstriction and secretion of mucus with a low concentration
of mucin.24,45– 47 When coupled to G-proteins, M1, M3, and
M5 muscarinic receptors have a stimulatory effect on the
target tissue, whereas the M2 and M4 subtypes are inhibitory.43
The increased release of acetylcholine from cholinergic
nerve terminals in OLD is thought to be the result of an
abnormal muscarinic receptor expression.48 Stimulation of
the M2 receptors explains the increased acetylcholine release and the potentiation of cholinergic-induced bronchoconstriction and hypersecretion in patients with asthma.47
CD8⫹ T lymphocytes induced by viral infection appear to
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cause M2 receptor dysfunction and cholinergic activation
in asthmatics.49 –52 The ideal anticholinergic mucoactive
drug for OLD should then antagonize M1 and M3 receptors
but have little affinity for the M2 receptor.
Non-Adrenergic and Non-Cholinergic Pathway
The non-adrenergic and non-cholinergic pathway appears to be a potent mucus secretagogue system.53,54 Neurotransmitters of the non-adrenergic non-cholinergic pathway include peptides such as vasoactive intestinal peptide,
the tachynins substance P and neurokinin A, and gases
such as nitric oxide. Most gland secretion is stimulated by
vasoactive intestinal peptide and tachykinins,55 whereas
nitric oxide has no effect on mucus secretion in animals.38
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Fig. 2. Percentage clearance at 1 hour in healthy subjects, patients with asthma, and patients with chronic bronchitis (CB) after treatment
with placebo versus terbutaline (0.25 mg subcutaneously). (From Reference 22, with permission.)
Whereas vasoactive intestinal peptide innervation is decreased in patients with severe asthma,56 the number of
vasoactive intestinal peptide nerves in COPD is increased.57
Unfortunately, the properties of vasoactive intestinal peptide nerves have no significant effect on secretion production of patients with chronic bronchitis.
Sensory non-adrenergic non-cholinergic C-fibers contain substance P, which is a tachykinin that causes bronchoconstriction and increases mucus secretion. Although
the non-adrenergic non-cholinergic excitatory C-fibers
have been thought to have an important role in the airway
hyperresponsiveness in asthma, their presence in the human airways is not as critically important as in rodent
species.53,58
Though the non-adrenergic non-cholinergic pathway
seems to play a critical role in respiratory mucus production, the description of agents that modulate that system is
beyond the scope of this article. The reader is encouraged
to search the reports provided in this section.
airways.76,77 In fact, Daviskas et al found that the majority
of the patients with chronic asthma in their study had
mucociliary clearance abnormalities to the same degree as
in patients with bronchiectasis and CF.78 Enhanced mucociliary clearance, measured by mucin secretion, with ␤2
adrenergics in animal models is significantly less than that
observed after administration of ␣ adrenergics and ␤1 adrenergics.73,77,79 There is, however, little evidence to suggest that there are increased proportions of mucins in the
airway secretions of patients with OLD, except in patients
with asthma.5
Short-Acting ␤ Agonists
Though short-acting ␤ adrenergics have mucociliaryenhancing effects in healthy individuals,80,81 their effect
in subjects with depressed clearance is minimal
(Fig. 2).21,59,64,82
Terbutaline
Adrenergics
The available data conflict regarding the benefits of ␤2
adrenergics on mucociliary clearance.59 – 64 The effects of
the ␤2 adrenergics on the airways are mediated by stimulation of the ␤2 receptors, which increases cyclic adenosine monophosphate, which is a regulator of ciliary beat
frequency in human airway epithelia.3,65–70 Because of their
effect on ciliary beat frequency, ␤2 adrenergics have been
considered mucokinetic medications and cough clearance
promoters.71 ␤2 adrenergic agonists increase passive movement of water across the airway surface, via active transport of ions across the airway epithelium.72 They also
stimulate secretion production, primarily from their action
on mucus-secreting cells and submucosal glands.73–75 These
actions combined increase the amount of mucus in the
A study by Sutton et al on the effect of nebulized terbutaline, as an adjunct to chest physiotherapy in patients
with stable bronchiectasis, found no significant difference
in either sputum volume or radioaerosol mucus clearance
between saline solution and terbutaline treatment administered prior to chest physiotherapy.83 Similarly, Mortensen
et al63,64 found a decreased mucus production with terbutaline delivered via metered-dose inhaler in healthy subjects and patients with asthma or bronchiectasis or CF.
Two studies have evaluated the mucoactive properties
of terbutaline in a group of patients with pseudohyperaldosteronism. These patients have a dysfunction of the pulmonary epithelial sodium channel. Terbutaline stimulated
chloride ion secretion toward the lumen, in a dose-dependent manner, which suggests enhanced water secretion
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onto the airway surface.84 – 86 Daviskas et al investigated
baseline mucociliary clearance and the short-term effect of
terbutaline in 16 patients with chronic asthma with sputum
production while on long-term treatment with salmeterol
in combination with inhaled corticosteroids. Although terbutaline improved mucociliary clearance in a few of the patients, mucociliary clearance remained impaired in the majority of patients, probably because of persisting inflammation
and hypersecretion of abnormal mucus (Fig. 3).78
Albuterol
Fig. 3a. Mean percent clearance at 80 min in the central, region in
group A (n ⫽ 6) and group B (n ⫽ 10) patients with asthma. (From
Reference 78, with permission.)
Sabater et al measured tracheal mucus velocity (a marker
of mucociliary clearance) in sheep before and for 12 hours
after treatment with salmeterol, albuterol, ipratropium, or placebo, to determine the effects on normal mucociliary clearance. They found that only albuterol and salmeterol can stimulate normal mucociliary clearance and reverse humanneutrophil-elastase-induced mucociliary dysfunction, and that
salmeterol has a longer duration of action in these models of
normal and abnormal mucociliary clearance (Fig. 4). Human
neutrophil elastase contributes to mucus stasis because it decreases the tracheal mucus velocity.
Jones and Reid87 found that isoproterenol and albuterol
increase the number of secretory cells in rats, particularly
in the most peripheral airways. This hyperplasia and/or
hypertrophy of mucus-secreting cells may be counterproductive in maintaining effective mucociliary clearance.
Fig. 3b. Mean percent clearance at 80 min in the intermediate
region in group A (n ⫽ 6) and group B (n ⫽ 10) patients with
asthma. (From Reference 78, with permission.)
Fig. 3c. Mean percent clearance at 80 min in the peripheral region
in group A (n ⫽ 6) and group B (n ⫽ 10) patients with asthma.
(From Reference 78, with permission.)
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Fig. 4. Salmeterol and albuterol increased tracheal mucus velocity
during the initial 6-hour period, compared to ipratropium and vehicle. From 6 –12 hours, only salmeterol-treated sheep had tracheal mucus velocity at or above the initial value, but all the treatments were different from vehicle. Overall (0 –12 h), the effects of
salmeterol and albuterol were different from ipratropium and vehicle. The values are mean ⫾ SE for 6 sheep. * p ⬍ 0.05 versus
vehicle. Area under the curve is of the percentage of initial tracheal
mucus velocity per hour. A negative value indicates that tracheal
mucus velocity fell below baseline (100%). (From Reference 24,
with permission).
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Fig. 6. A: Deposition of an isotopic marker during the baseline visit
at time zero (ie, immediately after aerosol inhalation) in a patient
who had undergone single-lung transplantation. B: Radioactivity
remaining in the lung after 76 min. (From Reference 90, with permission.)
central and peripheral regions of 7 transplanted lungs. A
single administration of albuterol significantly improve mucociliary clearance, compared with the baseline values, in
those lung-transplant patients (Fig. 6).90
Fig. 5. Percentage clearance at 1 hour in healthy subjects after
treatment with low-dose versus high-dose nebulized albuterol (see
text). Also shown are the mean airway resistance values before
and 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.)
Levalbuterol
Though albuterol can be associated with bronchodilation in asthma, it has been suggested that larger-than-usual
doses are needed for maximal short-term effects on mucociliary clearance, which increases the risk of increased
viscous mucus secretion (Fig. 5).21
Guleria et al used cine-scintigraphy of inhaled radioaerosol to evaluate the effect on mucociliary clearance of
a single inhalation of albuterol, ipratropium bromide, and
beclomethasone in 8 patients with OLD, on 4 separate
days. Quantitative indices for the 3 drugs were comparable
to placebo, and there was no significant increase in mucociliary clearance on any of the days. There was no significant difference between any of the 3 drugs in shortterm improvement of mucociliary clearance, as compared
to placebo.88,89 Devalia et al also found that, while albuterol had a less potent, slower, and shorter duration of
action than salmeterol on stimulation of ciliary beat frequency in cultured human bronchial epithelium, both agonists produced only slight (⬍ 20%) increases in ciliary
beat frequency above baseline.68
In a recent study, Laube et al measured radioactivity
from inhaled particles labeled with technetium-99m in the
Frohock et al used digital videomicroscopy to evaluate
the differences in effect of racemic versus single-enantiomer albuterol on mucociliary clearance of single ovine
airway epithelial cells. R-albuterol was associated with a
dose-dependent stimulation of ciliary beat frequency significantly higher than that of the racemic S-albuterol.91
O’Riordan et al assessed the clinical importance of standard doses of the S-enantiomer on airway secretions in 14
stable long-term intubated patients by comparing a racemic formulation of albuterol, an R-enantiomer formulation, and normal saline solution. Tracheal aspirates were
analyzed for volume, sodium, chloride, bicarbonate, interleukin-8, interleukin-1␤, soluble intercellular adhesion
molecule, and tumor necrosis factor alpha. Although all
the agents were associated with increased secretion volume after the first dose, this effect was not apparent on
subsequent doses. There was no significant difference in
the concentrations of the electrolytes or the inflammatory
indexes.92
A recent randomized double-blind placebo-controlled
trial with 10 healthy adult subjects evaluated the effects of
inhaled nebulized levalbuterol (1.25 mg), albuterol
(2.5 mg), or placebo, for 7 days, 3 times daily. Gamma
camera images of the lungs were obtained after inhalation
of radiolabeled aerosol. Cleary et al found that inhaled
levalbuterol does not increase mucociliary clearance or
cough clearance, compared to albuterol or placebo.93
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Fenoterol
In an in vivo canine preparation, Wong et al found a
4-fold increase in ciliary beat frequency 30 min after administration of fenoterol.94 In a study of 26 subjects with
chronic bronchitis, airways reversibility of ⬎ 15% after
fenoterol administration was associated with faster tracheobronchial clearance, more coughs, lower sputum viscosity and elasticity, and larger 24-hour sputum production than those airways with reversibility of ⬍ 15%.95 In a
similar study by Weich et al, mucociliary clearance was
measured with a scintillation camera after inhalation of a
technetium-99m labeled aerosol. The increase in percentage clearance after fenoterol administration for the left and
right whole lung was 35% and 36% per hour, respectively.96
Long-Acting ␤ Agonists
Though some in vitro and in vivo studies suggest that
long-acting ␤ adrenergics significantly improve mucociliary clearance, compared to short-acting ␤ adrenergics, others suggest only a modest improvement.
Salmeterol
Fig. 7. Top: Whole right-lung particle retention versus time in all 14
subjects during the 2 hours after deposition. Bottom: Peripheral
right-lung particle retention versus time in all 14 subjects during
the 2 hours after deposition. Treatment was delivered via metereddose inhaler immediately after time 0. (From Reference 101, with
permission.)
Salmeterol is the most thoroughly investigated longacting ␤ adrenergic, in regard to measuring the effect of ␤2
adrenergic agonists on mucociliary clearance. It has been
suggested that lipophilicity of the adrenergic agent proportionally prolongs its duration of action.97–100 Salmeterol is more lipophilic than the short-acting ␤ adrenergics,
formoterol, and arformoterol.21 In vitro and in vivo studies
show that salmeterol stimulates a faster and stronger ciliary beat frequency than does albuterol.68,74,75
A study by Piatti et al, with patients with COPD and
pneumonia, confirmed the ability of salmeterol to enhance
“only to a modest degree” ciliary beat frequency in both
normal and COPD nasal epithelium.74 This minimal stimulatory effect of ␤2 adrenergics in chronic bronchitis was
confirmed by Mossberg et al, in a study in which patients
with the least ventilatory impairment had the greatest enhancement of clearance.59 However, there have been no
reports on the in vivo effect of salmeterol pretreatment on
either the quantity or quality of airway secretions in chronic
bronchitis.
Bennett et al101 compared the short-term effect of salmeterol (42 ␮g) to placebo on mucociliary and coughenhanced secretion clearance in 14 patients with mild
chronic bronchitis. A radiolabeled aerosol (technetium99m sulfur colloid) and gamma camera analysis was used
to measure mucociliary and cough clearance on 2 study
days: a placebo/control day, and a salmeterol treatment
day. There were no significant correlations between the
average clearances over any period, relative to placebo and
either baseline lung function or improvements in lung function (eg, percent increase in forced expiratory flow in the
middle half of the forced vital capacity) associated with
salmeterol treatment. Although mean whole-lung clearance was higher with salmeterol than with placebo, only
peripheral lung clearance was significantly enhanced by
salmeterol (Fig. 7). The distribution of ␤ adrenergic aerosol particles and their impact on mucociliary clearance
may be particularly important in patients with mild to
moderate airway obstruction.102 Bennett et al has suggested
that the observed enhanced clearance with salmeterol may
be primarily from its effect on the mucociliary apparatus,
as opposed to the cough mechanism.101
A crossover study by Hasani et al103 found no significant enhancement of mucociliary clearance in patients with
asthma following 2 weeks of salmeterol versus placebo,
and concluded that salmeterol’s mucociliary clearance benefit was a result of increased airway patency.
One more mechanism by which long-acting ␤ adrenergics might benefit mucociliary clearance is by reducing
neutrophil adhesion and accumulation in airway epithelium in patients with asthma. The reduction in epithelial
damage is associated with a decrease in total number of
bacteria that adhere to the respiratory mucosa. Salmeterol
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has a longer inhibition of the secretagogue human neutrophil elastase than does albuterol.24
Although over 80% of patients with CF receive bronchodilators,104 it is controversial whether bronchodilators
benefit mucociliary clearance.105,106 Some patients with
CF report recurrent wheezing after receiving bronchodilators.107–109
A review by Colombo et al on the use of long-acting
␤ adrenergics in CF revealed that some of the mechanisms
implicated in the response of CF to bronchodilators include direct smooth muscle relaxation, increased mucociliary clearance, improved peripheral deposition of nebulized antibiotics or mucolytics, direct effects on
inflammatory cells and bacterial adherence, and a possible
direct effect on CF transmembrane conductance regulator
function.106,110 Particularly important to patients with CF
is the study by Taouil et al, who found that ␤2 receptors
have the same localization in the apical region of airway
epithelial cells as does the CF transmembrane conductance
regulator.110 The CF transmembrane conductance regulator protein is a cyclic-adenosine-monophosphate-regulated
chloride channel.111 Stimulation of human airway mucosa
with salmeterol produces a time-dependent increase in apical CF transmembrane conductance regulator protein expression in human airway epithelial cells. The maximum
response is typically reached after 24 hours of treatment
with salmeterol.107
Mortensen et al suggested that ␤2 adrenergic agonists
do not significantly improve airway clearance because they
do not stimulate cyclic-adenosine-monophosphate-dependent chloride secretion in the lung, which is affected by
CF, and thus do not improve hydration of the airway surface.112
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ing cholinergic muscarinic M3 subtype receptors,71 there is
historical evidence of mucociliary clearance impairment
after administration of old anticholinergic drugs.115,116 The
M1 receptor is not involved with mucus output,117 but in
conjunction with the M3 receptor, the M1 receptor may
control water secretion.118 Stimulation of the cholinergic
muscarinic M2 subtype receptor inhibits further release of
acetylcholine into the synaptic space, so the use of M2
receptor antagonists is associated with increased mucus
secretion.24 Cholinergic control of mucus secretion might
be augmented in asthma because of dysfunctional airway
muscarinic M2 receptors,119 and airways with hypertrophic
submucosal glands have a significantly lower response to
atropine and higher than normal response to acetylcholine
in vitro.120
Ipratropium
Although inhaled anticholinergics are considered mucoregulatory agents that inhibit mucus secretion by block-
Large doses of the short-acting anticholinergic ipratropium bromide caused no significant changes in the volume
or viscoelastic properties of tracheal mucus in animal studies.121 Current evidence on the effect of inhaled ipratropium on mucociliary clearance in normal subjects, adult
patients with asthma, and patients with chronic bronchitis
suggests that sputum volume does not change.97,122–126 Bennett et al previously reported that ipratropium has a tendency to slow cough-associated mucus clearance in patients with severe COPD. Using a radiolabeled (technetium99m iron oxide) monodisperse aerosol and gamma camera
analysis, Bennett et al127 investigated the effect of inhaled
ipratropium bromide (40 ␮g) on cough-enhanced clearance of mucus from the airways of 15 subjects with stable,
moderate-to-severe COPD. Clearance was measured during 2.5-hour periods on 3 separate days: a control day, a
cough day with ipratropium, and a cough day with placebo. Ipratropium diminished the effectiveness of cough in
clearing the radiolabeled particles from the airways. Analysis of the data from the 2 study days (placebo versus
ipratropium) also showed significantly faster cough clearance on the placebo study day. This effect of ipratropium
on cough clearance may be due to changes in the airflow
dynamics induced by bronchodilation, altered rheology, or
depth of airway secretions.127,128
Miyata et al had reported that neither oxitropium nor
ipratropium depressed the normal mucociliary clearance in
animals.129 Those results were confirmed in 2 separate
studies by Guleria et al, who found no appreciable effect
on mucociliary clearance after inhalation of ipratropium in
patients with chronic stable asthma88 and COPD.89
Pavia et al reported a decrease in 6-hour sputum weight
from patients with reversible airway obstruction.125 A similar reduction in the volume of airway mucus in patients
with chronic bronchitis was found by Tamaoki et al after
long-term administration of a short-acting anticholinergic,
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Formoterol
Melloni and Germouty113 evaluated inhaled formoterol
in 10 patients with stable chronic bronchitis. After 6 days
of treatment, mucociliary clearance had significantly increased to 46% versus placebo. The improvement was
linked to better functioning of the mucociliary apparatus,
not to bronchodilation, since the airway resistance was
only slightly (nonsignificantly) reduced. Formoterol significantly reduces the absolute number of airway neutrophils, compared with placebo. There is a significant correlation between the percentage of neutrophils and sputum
interleukin-8 and the improvement of lung function, as
measured by FEV1 (forced expiratory volume in the first
second).114
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Fig. 8. Change in tracheobronchial clearance at 6 hours after radioaerosol inhalation, and in productive coughing (represented by
radioactivity of expectorated sputum), together with their difference (mucociliary). (From Reference 133, with permission.)
oxitropium bromide.23 Sabater et al found that ipratropium
did not affect the response to inhaled human neutrophil
elastase, whereas the human-neutrophil-elastase-induced
depression in tracheal mucus velocity was reversed with
only albuterol and salmeterol, not with ipratropium.26
Tiotropium
Although the long-acting anticholinergic tiotropium
binds to all 3 muscarinic receptors, its prolonged pharmacologic activity is the result of its slow dissociation from
the M1 and M3 receptors.21,130 –132 Hasani et al133 conducted a 3-week randomized double-blind placebo-controlled tiotropium study with 34 subjects (age range 40 –
75 years) with stable COPD. Aerosol deposition, defined
as the proportion of particles deposited in the non-ciliated
airways and therefore not available for mucociliary clearance, was significantly greater with tiotropium (Fig. 8).
Based on a significant decrease in cough frequency,
Hasani et al133 hypothesized that tiotropium produces a
shift from cough to mucociliary action. Because effective
bronchodilation led to deeper penetration of the radioaerosol, they concluded that the transit pathway for mucus was
lengthened. These findings suggest that tiotropium does
not adversely affect mucus transport, and may marginally
enhance mucociliary transport efficiency.133 In a recent
review, Keam et al134 found that aerosol particle penetration was improved with tiotropium, without delaying mucus clearance from the lungs.
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glycopyrrolate’s potential role as a long-acting anticholinergic for treating stable and unstable OLD.135 A study by
Pahl et al on human primary monocytes found that glycopyrrolate acts synergistically with anti-inflammatory drugs
in inhibiting inflammatory mediators commonly secreted
in patients with asthma and COPD.136 Additionally, administration of nebulized racemic glycopyrrolate has been
associated with longer bronchodilation and bronchoprotection against methacholine-induced bronchospasm in patients with asthma, when compared to ipratropium bromide or placebo.137–139 In combination with albuterol,
nebulized glycopyrrolate significantly improves FEV1 in
patients with COPD exacerbations.140
Although glycopyrrolate injection is more frequently
used preoperatively, to reduce cholinergic symptoms such
as sialorrhea, bronchorrhea, and excessive pharyngeal secretions,141 there has been little research on glycopyrrolate’s role in mucociliary clearance. “Death rattle” is a
term commonly used to describe the respiratory noise in
dying subjects due to sialorrhea and bronchorrhea.142 Hugel et al143 compared glycopyrrolate and hyoscine hydrobromide in 72 dying subjects with respiratory noise due to
death rattle. Glycopyrrolate provided a greater and more
prolonged improvement of respiratory tract secretions.143
However, a similar study by Back et al found glycopyrrolate less effective than subcutaneous administration of
hyoscine hydrobromide.144 In a mini-review, Lawrey evaluated the effectiveness of hyoscine hydrobromide and glycopyrrolate in drying respiratory secretions in terminally
ill patients, and found no clear evidence to support the
choice of hyoscine hydrobromide over glycopyrrolate.145
Effects of Common Adrenergics and Anticholinergics
on Mucociliary Clearance
Glycopyrrolate is a quaternary ammonium derivative
with minimal mucosal absorption and minimal systemic
toxicity when inhaled. Its oral absorption is less than 5%.
Although poorly studied, there is a resurging interest in
Table 1 shows a chronological summary of human and
animal studies on the effects of the most common adrenergics and anticholinergics on mucociliary clearance. There
are several important limitations to summarizing the results and making recommendations. First, the differences
in research design may explain the variability of findings
in these studies. There are several techniques to evaluate
mucociliary clearance. Second, some studies measured mucociliary clearance by creating central regions of analysis
for the gamma scintigrams, whereas others created and
measured peripheral radioaerosol deposition and particle
clearance to assess regional differences. Third, a limited
number of clinical studies have been adequately powered
to show significant differences. The small statistical differences reported are of questionable clinical relevance.
And, finally, the possible effects of different dosing regimens relative to the time when mucociliary clearance measurements were made may have affected the comparisons
and clinical recommendations. Longer mucociliary clear-
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Summary of Human and Animal Trials on the Effects of ␤2 Adrenergics and Anticholinergics on Mucociliary Clearance.
Table 1.
First Author
59
Year
Agent(s)
n
Subjects
Results
Mossberg
1976
Terbutaline
12
Asthma vs healthy subjects
Sutton83
Mortensen63
1988
1991
Terbutaline
Terbutaline
8
10
Bronchiectasis
Asthma vs healthy subjects
Mortensen112
Mortensen64
Daviskas78
Jones87
Devalia68
1993
1994
2005
1979
1992
Terbutaline
Terbutaline
Terbutaline
Albuterol
Albuterol
Salmeterol
10
62
16
Cystic fibrosis
Healthy subjects
Asthma
Rat epithelium
Human bronchial epithelial cells
Frohock91
2002
Guleria88
2003
Guleria89
2003
Sabater26
2005
Albuterol
Levalbuterol
Albuterol
Ipratropium
Beclomethasone
Albuterol
Ipratropium
Beclomethasone
Albuterol
Salmeterol
Ipratropium
O’Riordan92
2006
Cleary93
2007
Laube90
Wong94
Weich96
Moretti95
2007
1988
1988
1997
Albuterol
Levalbuterol
Albuterol
Levalbuterol
Albuterol
Fenoterol
Fenoterol
Fenoterol
Hasani103
Piatti74
2003
2005
Salmeterol
Salmeterol
Bennett101
2006
Melloni113
Francis122
Ovine tracheal epithelium
Significant increase in mucociliary clearance but
significantly less than in healthy subjects.
Significantly less response in subjects with impaired
mucociliary clearance.
Significantly increased sputum production
Significant increase in mucociliary clearance in healthy
subjects
No significant increase in mucociliary clearance
Significant increase in mucociliary clearance
Little or no stimulation of mucociliary clearance
Significant increase in number of secretory cells
Albuterol produced a transient but significant increase
in ciliary beat frequency. Salmeterol produced a
significantly rapid and prolonged increase in ciliary
beat frequency.
R-albuterol is more efficacious than racemic albuterol
in stimulating ciliary beat frequency
No significant difference in mucociliary clearance vs
placebo
8
Chronic airway disease
8
Asthma
No significant difference in mucociliary clearance vs
placebo
6
Sheep
Significant increase in tracheal mucus velocity and
reversion of human-neutrophil-elastase-induced
depression of tracheal mucus velocity with
salmeterol and albuterol. Ipratropium had no effect.
No significant differences in volume, electrolyte
concentration, or inflammatory indexes of sputum
No significant differences in mucociliary clearance vs
placebo
Significant improvement in mucociliary clearance
Significant increase in ciliary beat frequency
Significant increase in mucociliary clearance
Patients with FEV1 changes ⬎ 15% had significant
increase in mucociliary clearance, more coughs, and
larger 24-h sputum production
No significant increase in mucociliary clearance
Significant dose-dependent increase in ciliary beat
frequency in all groups. No rheological changes.
14
Long-term ventilated patients
10
Healthy subjects
7
9
12
26
Lung transplant
Healthy beagles
Chronic bronchitis
Chronic bronchitis
Salmeterol
11
10
8
8
14
Asthma
COPD
Community-acquired pneumonia
Healthy subjects
Chronic bronchitis
1992
1977
Formoterol
Ipratropium
10
12
Chronic bronchitis
Healthy subjects
Pavia125
1979
Ipratropium
12
Reversible airway obstruction
Miyata129
1989
14
Pigeons and rabbits
Bennett127
Tamaoki23
Hasani133
1993
1994
2004
Ipratropium
Oxitropium
Atropine
Ipratropium
Oxitropium
Tiotropium
15
17
34
COPD
Chronic bronchitis
COPD
No significant overall increase in mucociliary clearance
vs placebo. Significant increase in lung periphery
clearance.
Significant increase in mucociliary clearance
No significant difference in mucociliary clearance vs
placebo
No significant difference in mucociliary clearance vs
placebo
No depression of mucociliary clearance with
ipratropium and oxitropium
Significant decrease in cough clearance vs placebo
Significant decrease in sputum production
No depression of mucociliary clearance
FEV1 ⫽ forced expiratory volume in the first second
COPD ⫽ chronic obstructive pulmonary disease.
1168
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ance observation times may be needed to evaluate the
short-term, medium-term, and long-term cumulative effect
of bronchodilators.
Inhaled ␤2 adrenergics appear to stimulate mucociliary
clearance in normal airways.21,86,91,121 Because the mucociliary enhancing effect of these agents in patients with
depressed clearance is much less than in healthy individuals,2,20,64,65 routine administration of ␤2 adrenergics to
patients with mucociliary dysfunction or patients undergoing mechanical intubation, to change the volume and
composition of airway secretions, is not supported by current evidence.92 Although short-acting ␤ adrenergics may
cause significant bronchodilation in some patients with
airway obstruction, higher-than-usual doses may be required to obtain maximal benefits on mucociliary clearance,21,78 which increases the risk of adverse effects, such
as increased mucus secretion.146 High doses or continuous
␤2 adrenergics quickly saturate receptors, and a patient in
a severe asthma attack could literally drown in secretions.17–20 Patients who receive ␤2 adrenergics for acute
severe asthma should be closely monitored for mucus obstruction.
Zach et al suggested that ␤2 adrenergic agonists may
decrease cough clearance of secretions by decreasing airway tone and thus causing dynamic collapse of the airways or nonhomogeneous emptying of lung regions. Between 15% and 26% of patients with CF report asthmalike symptoms, primarily recurrent wheezing, after
receiving bronchodilators.108,109
␤2 adrenergics may be considered in patients with demonstrated airway reversibility to enhance mucociliary clearance. However, a decreased response in mucociliary clearance to a second dose of albuterol suggests that prolonged
maintenance with long-acting ␤ adrenergics may be more
effective than the periodic increases in mucociliary clearance obtained with subsequent doses of short-acting ␤ adrenergics in these patients.24
␤2 adrenergics can reverse the depression in tracheal
mucus velocity induced by human neutrophil elastase and
may be more beneficial than anticholinergics in improving
mucociliary clearance in respiratory diseases associated
with high levels of elastase. Human neutrophil elastase
level correlates well with airway disease severity.35–37
A clinical aspect of ␤2 adrenoceptor pharmacology in
recent years has been the recognition of genetic receptor
polymorphism that could change the physical properties
and composition of the sputum matrix.147,148 The potential
role of this polymorphism on the pharmacologic properties
of the ␤2 adrenergics may have important therapeutic implications for patients with OLD. This requires further
evaluation.
Anticholinergics are mucoregulatory agents that can reduce mucus secretion by affecting the neural pathway.4
The available evidence shows no improvement in muco-
ciliary clearance, in either healthy subjects or patients.97,125,126 Opposite to the ␤2 adrenergic agents, anticholinergics do not modify the human-neutrophil-elastaseinduced depression in tracheal mucus velocity24 and do
inhibit cough clearance. Cough might be of critical importance to enhance mucociliary clearance in some patients
with severe COPD.127 Although tiotropium is associated
with a minimal enhancement in mucociliary clearance,133
more studies are required to draw conclusions on tiotropium’s effects on cough and mucociliary clearance. Based
on existing evidence, routine administration of anticholinergics is not recommended to improve mucociliary clearance.
The effect on mucociliary clearance of ␤2 adrenergics
and anticholinergics combined with inhaled corticosteroids
and other mucoactive agents has not been extensively studied. It is clear that a better understanding of the pathophysiology of mucus hypersecretion in obstructive airway
disease is the key to identifying therapeutic targets in the
respiratory tract and the development of mucoactive agents.
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Summary
Bronchodilators are important in the management of
OLD. The benefit of ␤2 adrenergic and anticholinergic
bronchodilators has typically been measured by lung function improvement. Their effects on mucociliary clearance
need to be further evaluated in a much larger group of
patients. Excessive respiratory secretions may be an important dysfunction of the mucociliary transport system in
patients with OLD, and excessive secretions considerably
increase the risk of respiratory infections and exacerbations. A better understanding of the role of bronchodilators
in mucociliary clearance is critical to establish a new therapeutic profile to optimize airway clearance. It appears
that no single mucoactive agent is appropriate or enough
for all patients with OLD. Combination therapy may provide synergism to improve mucociliary clearance, but this
requires further evaluation.
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Discussion
Rogers: The studies comparing the
differences in mucociliary clearance
between short- and long-acting
␤-agonists that you showed,1-3 salbutamol versus salmeterol, must be
difficult to do in terms of the protocol. For example, salbutamol will
have a quick onset of action and a
relatively quick offset of action compared with salmeterol, which has a
slower onset of action and, of course,
a much slower offset. How are those
studies conducted so that they are
comparing like for like, for example, in terms of concentration and
time course?
1. Daviskas E, Anderson SD, Shaw J, Eberl S,
Seale JP, Yang IA, Young IH. Mucociliary
clearance in patients with chronic asthma:
effects of beta agonists. Respirology 2005;
10(4):426-435.
2. Devalia JL, Sapsford RJ, Rusznak C, Toumbis MJ, Davies RJ. The effects of salmeterol
and salbutamol on ciliary beat frequency of
cultured human bronchial epithelial cells, in
vitro. Pulm Pharmacol 1992;5(4):257–263.
3. Sabater JR, Lee TA, Abraham WM. Comparative effects of salmeterol, albuterol, and
ipratropium on normal and impaired muco-
141.
142.
143.
144.
145.
146.
147.
148.
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obstructive pulmonary disease. Ann Emerg Med 1995;25(4):
470–473.
Gomez A, Bellido I, Sanchez de la Cuesta F. Atropine and glycopyrronium show similar binding patterns to M2 (cardiac) and M3
(submandibular gland) muscarinic receptor subtypes in the rat. Br J
Anaesth 1995;74(5):549–552.
Kompanje EJ. ‘Death rattle’ after withdrawal of mechanical ventilation: practical and ethical considerations. Intensive Crit Care Nurs
2006;22(4):214–219.
Hugel H, Ellershaw J, Gambles M. Respiratory tract secretions in
the dying patient: a comparison between glycopyrronium and hyoscine hydrobromide. J Palliat Med 2006;9(2):279–284.
Back IN, Jenkins K, Blower A, Beckhelling J. A study comparing
hyoscine hydrobromide and glycopyrrolate in the treatment of death
rattle. Palliat Med 2001;15(4):329–336.
Lawrey H. Hyoscine vs glycopyrronium for drying respiratory secretions in dying patients. Br J Community Nurs 2005;10(9):421–
424.
Barnes PJ, Basbaum CB. Mapping of adrenergic receptors in the
trachea by autoradiography. Exp Lung Res 1983;5(3):183–192.
Culpitt SV, Rogers DF, Traves SL, Barnes PJ, Donnelly LE. Sputum
matrix metalloproteases: comparison between chronic obstructive pulmonary disease and asthma. Respir Med 2005;99(6):703–710.
Elbahlawan L, Binaei S, Christensen ML, Zhang Q, Quasney MW,
Dahmer MK. Beta2-adrenergic receptor polymorphisms in African
American children with status asthmaticus. Pediatr Crit Care Med
2006;7(1):15–18.
ciliary function in sheep. Chest 2005;128(5):
3743-3749.
Restrepo: That is a very good question. They actually quoted a limitation
for long-acting ␤ agonists, and that is
the inability to study even longer mucociliary clearance effect, or chronic
beneficial effect on mucociliary clearance of human subjects because there
is not an easy way to keep these patients for longer periods of time in
this type of study.
In animals,1,2 it has been a little bit
different because studies could be sustained for days. One of the protocols
that they actually have for long-acting
agonists is to be able to measure sustained effects in the treatment of COPD
patients. So, if the patients were already maintained on salmeterol, for
example, they were just brought back
after a few days to study.3 Again, it’s
much more feasible in animal subjects
than in clinical studies. You can see
that it’s actually correlated with the
number of subjects that had been studied clinically.
1. Sabater JR, Lee TA, Abraham WM. Comparative effects of salmeterol, albuterol, and
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ipratropium on normal and impaired mucociliary function in sheep. Chest 2005;128:
3743-3749.
2. Jones R, Reid L. ␤-agonists and secretory
cell number and intracellular glycoprotein in
airway epithelium. Am J Pathol 1979;95:
407-22.
3. Moretti M, Lopez-Vidriero MT, Pavia D,
Clarke SW. Relationship between bronchial
reversibility and tracheobronchial clearance
in patients with chronic bronchitis. Thorax
1997;52(2):176-180.
Rogers: Just a quick follow-up. I
was interested in the study that compared salbutamol to salmeterol where
propranolol blocked the salbuterol response, but not the salmeterol response.1 Is that because once you set
up the intracellular signal transduction
cascade with salmeterol, the propranolol is not going to hit that, whereas
it’s more likely to hit it with the salbutamol, which is short-acting. Is that
how the blocking mechanism works?
1. Devalia JL, Sapsford RJ, Rusznak C,
Toumbis MJ, Davies RJ. The effects of
salmeterol and salbutamol on ciliary beat
frequency of cultured human bronchial epithelial cells in-vitro. Pulm Pharmacol
1992;5(4):257–263.
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Restrepo: I don’t have a good
answer for that. I don’t know if
Bruce . . .
Rubin: I don’t know. I saw that and
was wondering if, in fact, the very
long duration that the salmeterol remains on the receptor might actually
allow the propranolol, which has a
fairly short on-and-off as well, to be
washed out, and so you are getting a
blunting, but because of the relatively
long action and the long signaling you
then begin to pick up some of the ␤
agonists action later on in the course.
But I don’t think that’s actually been
studied.
Homnick: In cystic fibrosis, it’s sort
of been a knee-jerk for us to start ␤
agonists prior to using airway clearance. I think that this emphasizes the
importance of individualizing ␤ agonist use or bronchodilator use in CF
patients. Some will have more airway
obstruction following the ␤ agonists,
so that the use of spirometry before
and after, before you decide to use
them on a chronic basis, I think is
important. It looks to me like the lipophilic ␤ agonists are those that have
the most potential for increasing mucociliary clearance. Is that correct?
Restrepo: Yes, that is correct. The
short-acting ␤ agonists are more hydrophilic, and the salmeterol more lipophilic than the formoterol. The great
majority of studies include the long
acting ␤ agonist salmeterol versus the
formoterol. It will be interesting to see
what kind of effects we will see with
the arformoterol (Brovana). The lipophilic property has a lot to do with
the action of these agents due to the
ability to spread across the epithelium
versus the cleavage of the hydrophilic
agents and their short term effect.
MacIntyre: You mentioned arformoterol. Is there any effect on these
L- and R-isomers on these mucus activities you’ve been talking about?
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Restrepo:
on it.
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I couldn’t find any data
Rubin: Not on the arformoterol, but
there was a study done by Tom
O’Riordan’s group looking at levalbuterol versus albuterol.1 Assessing
the effects of racemic and single-enantiomer albuterol on airway secretions in long-term intubated patients.
And both of them were identical in
onset of action, inflammation, and mucus secretion. This is similar to other
human studies comparing albuterol to
levalbuterol.
1. O’Riordan TG, Mao W, Palmer LB, Chen
JJ. Assessing the effects of racemic and single-enantiomer albuterol on airway secretions in long-term intubated patients. Chest
2006;129(1):124-132.
MacIntyre: This may be way out
on the fringe, but all this discussion
about these mutations on the ␤ receptor, do those have effects with mucus
secretion as well as with bronchial
smooth muscle relaxation?
Restrepo: That’s been mentioned in
probably 2 discussions. Those different phenotypes of the ␤2 receptors have
to be looked at—that, along with the
different changes in the rheology of
the mucus. But I don’t think it has
been addressed.
Myers: I want to go back to Bruce
Rubin’s comments. There actually are
a couple of studies out there, cellular
studies that look at the S-isomer from
albuterol.1,2 They potentially showed
that it does increase mucin or mucus
production, also impacts ciliary beat
frequency, and actually makes it very
dysfunctional. A lot of the studies
looked at racemic mixtures of albuterol. And it would be interesting to
see some of those reproduced with a
single-isomer albuterol, to see if this
cellular mechanism truly does impact
the airway clearance mechanism in the
human model.
1. Slattery D, Wong SW, Colin AA. Levalbuterol 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, but
not other ␤2-agonist isomers, has stimulatory effects on mucin secretion and changes
in gene expression on airway epithelium (abstract). Am J Respir Crit Care Med 2001;
163:A590.
Rogers: I think what they found with
the separate isomers was that the active isomer worked and the nonactive
isomer didn’t. In fact, it made things
worse, as you so rightly say. They
found that it was due to an irritant
effect of the drug formulation. But,
without the protective effect of the active isomer, the bronchodilation effect
was lost. Thus, in the racemic mixture
there is a combination of an irritant,
bronchoconstrictor effect that is offset
by the protective bronchodilator effect of the active isomer. In contrast,
with the single, inactive isomer, there
is just the irritant effect without the
protective effect. Is that true?
Myers: That is correct, when you
give it as a dual-isomer mixture, the R
offsets the S, but you have to remember that the metabolism clearance of
the R-isomer really clears the lungs in
about 2-4 hours, where the S-isomer
(in other studies1-3) has been shown
to hang around as long as 10-12 hours.
So, potentially, you do have the single-isomer, the S-albuterol, which theoretically is the nonproductive part of
the isomer that’s hanging around
6-fold longer.
1. Gumbhir-Shah K, Kellerman DJ, DeGraw
S, Koch P, Jusko WJ. Pharmacokinetics and
pharmacodynamics of cumulative single
doses of inhaled salbutamol enantiomers in
asthmatic subjects. Pulm Pharmacol Ther
1999;12(6):353-362.
2. Schmekel B, Rydberg I, Norlander B,
Sjöswärd KN, Ahlner J, Andersson RG. Stereoselective pharmacokinetics of S-salbutamol after administration of the racemate in
healthy volunteers. Eur Respir J 1999;13(6):
1230-1235.
3. Gumbhir-Shah K, Kellerman DJ, DeGraw
S, Koch P, Jusko WJ. Pharmacokinetic and
pharmacodynamic characteristics and safety
of inhaled albuterol enantiomers in healthy
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volunteers. J Clin Pharmacol 1998;38(12):
1096-1106.
Schechter: I want to make a technical comment about statistical testing, if people will bear with me, because I think it’s important in the
context of all the studies that you
showed. When a study concludes that
there’s no discernible difference between treatment groups, really what’s
going on is it’s failing to prove that
there’s a difference. It’s different, and
much more difficult, to prove that
there’s equivalence, and especially
when you’re looking at studies that
were designed to look for a difference.
Also, while some of the studies were
somewhat larger, you referenced studies with 4, with 8, with 10 subjects,
and so failure to find a difference between groups might be due primarily
to a lack of statistical power. Even in
the studies with a larger number of
subjects, if there’s a wide range of
variation in measurements, the n value
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might not be enough. With all the small
studies that have been looking at this
topic, it looks like it’s a ripe area for
a meta-analysis, where you could potentially combine the results of these
different studies, and potentially draw
some more clear-cut conclusions.
prove airway clearance? Should I ever
use anticholinergics in patients who
have a bronchorrhea? Should I think
about using anticholinergics in a patient with sialorrhea, like a patient with
ALS?
Restrepo: I completely agree. I
think one of the major limitations is
how to translate findings of poorly
powered studies into practice, as well
as how you translate the fact that wellpowered studies could have resulted
in good clinical response but no statistically significant differences. In
other words it would be very nice to
run a meta-analysis just to see what
you end up with. Because at this point,
it is a very limited number of subjects,
which again creates a limitation on
studies of medications we use on a
regular basis. This is actually relatively
poor evidence to extrapolate.
Restrepo: My answer would be
that, based on the evidence that I
presented today, the beneficial effect of ␤ agonists is limited when
you have baseline impairment of the
mucociliary clearance. In terms of
the anticholinergics, the potential inhibition of cough will be important
to remember on those patients who
depend so much on the cough mechanism for mucociliary clearance (not
so much on bronchodilation). By providing bronchodilation, the anticholinergics compensate their effect on
cough. Evidence for both bronchodilators is poor; therefore, their routine recommedation is still very questionable.
Hess: I have some clinical questions.
Should I ever use ␤ agonists to im-
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