Bronchodilators: Beta2-Agonists and

Anticholinergics
Nicola A. Hanania and Mario Cazzola

Clinical Pearls
l

Bronchodilators play a pivotal role in the acute and maintenance management of asthma.
Beta2-agonists are the most effective bronchodilators in
asthma and are well tolerated when given by inhalation.
Inhaled short-acting beta2-agonists should be limited to rescue and emergency management of asthma symptoms.
Inhaled long-acting beta2-agonists are currently recommended as add-on therapy to inhaled corticosteroids for
maintenance therapy in patients with persistent asthma not
controlled with inhaled corticosteroids alone. They should
never be used as rescue medication or as monotherapy.
The use of short-acting anticholinergic bronchodilators is
currently limited to management of acute severe asthma
when used in conjunction with short-acting beta2-agonists.
The role of long-acting anticholinergic bronchodilators in
the management of asthma requires further evaluation.
Several novel once-daily inhaled bronchodilators are currently under development.

ronchial asthma is a chronic inflammatory disease characterB

ized by the presence of airway hyperresponsiveness and airflow obstruction. Airflow obstruction in patients with asthma
is usually widespread, but is variable and is often reversible
either spontaneously or with treatment. Bronchodilators play
a pivotal role in the acute and maintenance management of
asthma. The most common groups of bronchodilators currently in clinical use are the beta-agonists and the anticholinergic agents. The inhaled administration of bronchodilators is
generally safe and is preferred over their systemic administration. Current national and international asthma guidelines
recommend limiting the use of inhaled short-acting betaagonists (SABAs) for rescue and emergency management and
the maintenance daily use of long-acting agents as add-on therapy to inhaled corticosteroids for patients with chronic persistent asthma who are not controlled with inhaled corticosteroids
alone (Table 27-1). This chapter focuses on the pharmacology,
clinical use, and safety of currently available bronchodilators
in the management of acute and chronic asthma.

BETA2-Agonists
Historical Perspective
Beta2-agonists play a pivotal role in the acute and chronic
management of asthma. Beta-agonists have been used for
thousands of years but progress in drug development has

C h a p t e r

27

resulted in safer, longer acting and more beta2 receptors pecific agents. In traditional Chinese medicine, the botanical ma huang has been used for more than 2000 years for
the short-term treatment of respiratory symptoms due to
the efficacy of the sympathomimetic agent, ephedrine.
Beginning at the turn of the century, the nonselective alphaand beta-receptor agonist, epinephrine, was introduced and
was administered by the subcutaneous route for the treatment of acute asthma. Subsequently, an aerosolized formulation of this drug was introduced and delivered to the
lungs using a squeeze-bulb. In the 1940s, isoproterenol was
the first beta-agonist to be used in treating airway disease
and became the standard of care bronchodilator, although
its use was complicated by adverse effects due to activation
of the beta1-receptors in nontarget sites. Metaproterenol,
a noncatechol resorcinol derivative of isoproterenol was
developed in the early 1960s. However, the modern era of
selective SABAs did not begin until the simultaneous discovery of albuterol and terbutaline, which remain the SABAs
of choice until the present time. The next advance in the
development of beta2-agonists was the development of longacting agents, salmeterol and formoterol, which made their
use more appealing for maintenance treatment of asthma.
More recently and following suggestion of potential adverse
effects associated with one of the two chiral forms of albuterol (S-albuterol), the pure enantiomer, levalbuterol, was
developed and is currently in clinical use. At present, several
once-a-day ultralong-acting beta2-agonists are in different
stages of clinical development.
Pharmacology of Beta2-Agonists
Beta2-agonists act by binding to the beta2-adrenergic receptor
(b2AR), which is a member of the seven transmembrane
domains, G-proteincoupled family of receptors. Although
b2ARs are present in high density in airway smooth muscle

Table 27-1
Rational Use of Beta-agonists in Asthma Management

Short-acting beta2-agonists

Drugs of choice for acute bronchospasm

Rapid onset (e.g., albuterol)
Prevention of exercise-induced bronchospasm
Regularly scheduled use not recommended
Marker of disease control

Long-acting beta2-agonists

Used for maintenance control

Moderate-persistent, severe-persistent asthma
Patients receiving inhaled corticosteroids

241

S e c t i o n v n treatment
Table 27-2
Benefits of Inhaled Beta-agonists in the
Management of Asthma
l Relief

of bronchoconstriction due to smooth-muscle relaxation

protection against all nonspecific constrictor stimuli, such as cold
air, methacholine, and exercise
l Reduced vascular permeability and edema
l Increased mucociliary clearance due to increased ciliary beat frequency
l May reduce inflammation due to inhibition of mediator release from
inflammatory cells and priming of glucocorticoid receptors
l Marked

cells, they are also present in submucosal glands, vascular endothelium, ciliated epithelium, mast cells, circulating
inflammatory cells such as eosinophils and lymphocytes, Clara
cells, type II pneumocytes, and cholinergic ganglia. Upon agonist binding to receptor, adenylyl cyclase is activated via the
signal-transducing Gs protein, which results in a rise in cellular cyclic AMP (cAMP) levels and activation of protein kinase
A (PKA). The precise PKA phosphorylation targets mediating
bronchial smooth muscle relaxation are not fully understood
but likely include myosin light-chain kinase and Ca2+-dependent K+ (Kca) channels. One feature possessed by most Gproteincoupled receptors, including b2AR, is a mechanism
by which the signal is turned off following receptor activation. This process, termed desensitization, is discussed later.
Although the major action of beta2-agonists on airways is relaxation of airway smooth muscles, they also exert several effects
mediated through the activation of beta2-receptors expressed
on resident airway cells such as epithelial cells and mast cells
and circulating inflammatory cells such as eosinophils and
neutrophils (Table 27-2).
Numerous beta2-agonists of differing pharmacological properties are available for clinical use (Table 27-3). Beta2-agonists are
classified by their onset and duration of action, receptor selectivity, affinity, potency, and efficacy. Affinity refers to the attraction between the agonist and its receptor, potency refers to the
dependency of receptor activation on drug concentration, and
efficacy refers to the ability of the agonist to activate its receptor
without regard to its concentration and is detailed below.
Onset and Duration of Action
The onset of action of inhaled beta2-agonists is primarily determined by their lipophilicity. Relatively hydrophilic drugs such

Table 27-3
Commonly Used BETA2-agonists in Asthma Management

Receptor Selectivity

To minimize side effects, it is essential that a beta-agonist

activates its target receptor without activating other receptors.
Endogenous catecholamines activate alpha1-, alpha2-, beta1-,
beta2-, and beta3-adrenoceptors to varying degrees, but synthetic
agonists are capable of exquisite specificity. Currently used
synthetic beta2-agonists are moderately to highly selective agonists at the beta2-receptor. For example, the most widely used
beta2-agonist, albuterol, has a beta2:beta1 selectivity 650:1.
It is unlikely that greater selectivity is of clinical significance
because the heart contains abundant beta2-adrenoceptors
capable of regulating its chronotropic and inotropic properties,
so increased selectivity does not avert cardiac stimulation.
Stereoselectivity

Catecholamines and related beta2-agonists contain a chiral

(asymmetric) center at the hydroxyl carbon of the side chain.
As a result, they can exist as either of two stereoisomers, typically designated R and S. Only the R stereoisomer is active at
the 2AR, but most currently available beta2-agonists are equal
(racemic) mixtures of both stereoisomers. Such formulations
are based on the assumption that S stereoisomers have no activity, but this assumption may be incorrect as there is some evidence that the S stereoisomers of albuterol for example may
potentiate the response to bronchoconstrictors in vivo and in
vitro, possibly by inducing a calcium rise in airway smooth muscle cells. Levalbuterol, the R-isomer of albuterol, is the only
isomeric beta2-agonist currently available, beta for clinical use in
asthma. Arformoterol, the RR-isomer of formoterol was recently
approved by the U.S. Food and Drug Administration (FDA) for
clinical use in chronic obstructive pulmonary disease (COPD).
Potency

Onset of Action

Short-acting

Long-acting

Rapid

Fenoterol*
Pirbuterol
Procaterol*
Albuterol
Terbutaline
Levalbuterol

Formoterol

This refers to the concentration-dependency of a drugs

effect, with a highly potent drug being effective at low concentrations. Drug potency depends both on the affinity of the
drug for its receptor and on the efficacy of the drug-receptor
interaction. Potency is an important parameter in drug development, but relatively unimportant in clinical practice because
regulatory agencies ensure that marketed drugs achieve clinically effective concentrations.

Salmeterol

Efficacy

Duration of Action

Slow
*Not approved for use in the United States.

242

as albuterol have a very rapid onset of action as they activate

the receptor in the aqueous phase, whereas lipophilic drugs
such as salmeterol have a slower onset. It is worth mentioning that while formoterol has an intermediate lipophilicity,
it is still able to activate the receptor in the aqueous phase
and thus also has a rapid onset of action similar to albuterol.
The duration of action is similarly determined by lipophilicity, as well as by resistance to metabolism. For instance, salmeterol and formoterol have a longer duration of action than
albuterol, and because of their lipophilicity may have a depot
effect in the cell membrane. The slow onset and prolonged
action of salmeterol both appear to be primarily due to its
extreme lipophilicity, with some contribution from quasispecific interaction of the tail with hydrophobic regions of
the beta2-adrenoceptor (see Table 27-2).

This refers to the ability of a drug to exert an effect in a target

tissue. The measured effect can be clinical (bronchodilation),

C h a p t e r 27 n Bronchodilators: Beta2-Agonists and Anticholinergics

physiologic (smooth muscle relaxation), or biochemical (rise

in cAMP). Agonists of different efficacy can be compared by
measuring their maximal effects. However, efficacy is highly
dependent on tissue factors such as receptor density and the
degree of functional antagonism by a constrictor agonist such
as acetylcholine; therefore, the measured efficacy of an agonist in different tissues or in the same tissue under different
conditions may vary. Intrinsic efficacy refers to the ability of
a drug to interact with a receptor such that its signal transduction pathway is activated independent of tissue factors. It
serves as a measure of the relative agonism of a drug, that is,
a partial agonist is less efficient than a full agonist in causing a
downstream cellular response once bound to its receptor. For
example, the long-acting beta2-agonist (LABA) formoterol has
a higher intrinsic efficacy than albuterol, which has a higher
intrinsic efficacy than salmeterol. Methods are now available to
calculate the intrinsic efficacy of a drug. Efficacy is an important parameter of drug action because it plays a key role in
the activation of target and nontarget receptors. For example,
beta2-adrenoceptors are present in high density in airway
smooth muscle, and a partial beta2-agonist of low intrinsic
efficacy that activates only a small fraction of airway receptors may nonetheless cause full bronchodilation; in contrast,
beta2-adrenoceptors are present in low density in nontarget
tissues such as skeletal muscle and the same partial agonist
may not cause sufficient activation to lead to tremor. This
phenomenon accounts for the attractive side-effect profile of
partial agonists such as albuterol. On the other hand, a partial
agonist of low intrinsic efficacy may not provide sufficient
therapeutic effect in some situations such as severe disease or
during an acute exacerbation.
Regulation of b2 AR Function

Receptor desensitization refers to the decreased responsiveness

that occurs with repeated or chronic exposure to agonist and
is a general feature of most signaling membrane receptors.
Mechanistically, desensitization can be divided into receptor
uncoupling from downstream signal transduction elements by
phosphorylation and reversible binding of the protein arrestin;
receptor internalization by endocytosis; and receptor downregulation (i.e., reduction in total receptor number) by a combination of increased degradation and reduced synthesis. Of
importance, desensitization of the beta2-adrenoceptor in airway smooth muscle is self-limited such that responsiveness is
only partially impaired; this differs from the profound desensitization that can occur in other biologic systems. Some aspects
of beta2-adrenoceptor desensitization depend on agonist occupancy (homologous desensitization), whereas other aspects
do not (heterologous desensitization). Homologous desensitization is sensitive to agonist efficacy such that agonists of
higher intrinsic efficacy may induce more desensitization.
Genetic Variations of the b2AR

Variations of the 2AR gene (ADRB2) may also have important

effects on receptor function and regulation. Of the ADRB2
single nucleotide polymorphisms (SNPs) discovered to date,
three result in amino acid substitutions at positions 16, 27,
and 164 of the receptor and alter receptor function. An additional SNP results in an amino acid change (cysteine [Cys] to
arginine [Arg]) at position 19 of the receptors 5 upstream
peptide (BUP) and affects receptor expression. Cellular studies

of human airway smooth muscle cells and hamster fibroblasts

indicate that 2AR polymorphisms at amino acids 16 (arginine
[Arg] to glycine [Gly]) and 27 (glutamine [Gln] to glutamic
acid [Glu]) in the amino terminus may affect agonist-induced
receptor down-regulation. Gly16 has been shown in vitro to
promote increased receptor down-regulation while Glu27 is
believed to confer resistance to down-regulation. However, a
recent study of human airway smooth muscle cells suggests
that Glu27 actually may be associated with increased acute
and chronic receptor desensitization. Although 2AR polymorphisms do not cause asthma per se, they may be disease
modifying. For example, Gly16 has been noted to associate
with a nocturnal asthma phenotype and to be more prevalent in moderate asthmatic individuals than mild asthmatic
individuals. Further, healthy and asthmatic children homozygous for Gly16 are less responsive to a single dose of inhaled
albuterol as compared with children homozygous for Arg16.
Alternatively, Glu27 homozygotes exhibit marked reductions
in airway reactivity to methacholine while Gln27 is associated
with increased levels of immunoglobulin E (IgE). The role of
2AR polymorphisms on the response to regularly administered albuterol in individuals with asthma recently has been
evaluated. Surprisingly, in subjects who were Arg/Arg at
position 16, an SNP more prevalent in blacks than in whites,
the regular use of albuterol induced an approximately 30L/min
loss in morning PEF while no tachyphylaxis was seen in Gly/
Gly individuals . A study currently under way will investigate
whether similar relationship can be seen with the long-term
use of LABAs such as salmeterol.
Route of Administration

Aerosol delivery of beta2-agonists maximizes drug concentration in the target tissue (i.e., airway smooth muscle) with
minimal systemic delivery to adrenoceptors in nontarget tissues such as the heart or skeletal muscle. For this reason, the
inhaled route is preferred for delivery of beta2-agonists in
the treatment of asthma in all circumstances, except when
a patient cannot operate the delivery device or possibly in
some cases of severe asthma. Progress in aerosol technology
has resulted in the availability of a wide variety of nebulizers,
spacers, metered-dose inhalers, and dry powder inhalers capable of delivering drugs to the airway with varying efficiency.
Clinical Use of Beta2-Agonists
beta2-Agonists in the Maintenance Management
of Asthma

Medical therapy on a regular schedule is appropriate for all

patients with persistent asthma as defined by the National
Asthma Education and Prevention Program (NAEPP) Expert
Panel (Fig. 27-1) and the international Global Initiative on Asthma
(GINA) guidelines (Fig. 27-2). An anti-inflammatory drug, usually an inhaled corticosteroid, should be the first-line maintenance therapy. A long-acting inhaled beta2-agonist can be added
to an inhaled steroid when adequate symptomatic and physiologic control is not achieved with the inhaled steroid alone.
Two long-acting, highly selective inhaled beta2-agonists are
available worldwide: salmeterol and formoterol. Both are also
marketed in the United States for their concomitant twicedaily administration in conjunction with an inhaled corticosteroid. Formoterol and salmeterol are often viewed as

243

S e c t i o n v n treatment
Severe
persistent
Moderate
persistent
Step 3

Mild
persistent

Preferred:
Low-dose ICS

Preferred:
Medium-dose
ICS
or
Low-dose ICS
+ LABA

Alternative:
Cromolyn,
Nedocromil,
LTRA,
or
Theophylline

Alternative:
Low-dose ICS
and either
LTRA,
Theophylline
or Zileuton

Step 2
Intermittent

Step 1
Preferred:
SABA prn

Step 4

Step 5

Step 6

Preferred:
Medium-dose
ICS + LABA

Preferred:
High-dose
ICS + LABA

Alternative:
Medium-dose
ICS
and either
LTRA,
Theophylline
or Zileuton

and

Preferred:
High-dose
ICS + LABA
+ oral
corticosteroid

volume in 1 second) for this duration. For this reason, formoterol is sometimes given in higher doses in some countries.
Another major difference between formoterol and salmeterol
is in their intrinsic efficacies. In vitro, formoterol is almost a
full agonist, whereas salmeterol has a very low efficacy for
relaxing airway smooth muscle. The intrinsic efficacy of salmeterol is difficult to precisely measure because it partitions
into membranes, but its maximal efficacy in relaxing airway
smooth muscle has been measured at one third to one half

Treatment action
Maintain and find lowest controlling step
Consider stepping up to gain control

Exacerbation

Increase

Controlled
Partly controlled
Uncontrolled

Step up until controlled

Treat as exacerbation

Treatment steps

Reduce
Step 1

Consider
Omalizumab
for patients
who have
allergies

Reduce

interchangeable, but as mentioned above, differences in their

onset of action, duration of action, and intrinsic efficacy merit
consideration. The onset of bronchodilation with formoterol
is 2 to 3 minutes, whereas with salmeterol it is approximately
10 minutes and does not peak for hours. The activity of a
single 42-g dose of salmeterol decays only slightly after 12
hours, whereas the activity of a single 12-g dose of formoterol decays substantially by 12 hours and in some studies
does not sustain a 15% increase in FEV1 (forced expiratory

Level of control

and

Consider
Omalizumab
for patients
who have
allergies

Figure 27-1 Management approach

of asthma severity. Position of shortacting (SABAs) and long-acting beta2-agonists
(LABAs). (Adapted from National Asthma
Education and Prevention Program:
Expert Panel Report 3: Guidelines for the
Diagnosis and Management of Asthma
[Pub No. 08-5346]. Bethesda, MD,
National Institutes of Health, National
Heart, Lung, and Blood Institute,
October 2007.)

Step 2

Step 3

Increase
Step 4

Step 5

Asthma education
Environmental control
As needed rapidacting beta2-agonist

Controller
options

As needed short-acting beta2-agonist

Select one

Select one

Add one or more

Add one or both

Low-dose inhaled
ICS*

Low-dose ICS plus

long-acting beta2-agonist

Medium- or high-dose
ICS plus long-acting
beta2-agonist

Oral glucocorticosteroid
(lowest dose)

Leukotriene
modifier

Medium- or
high-dose ICS

Leukotriene
modifier

Anti-IgE
treatment

Low-dose ICS plus

leukotriene modifier

Sustained release
theophylline

Low-dose ICS plus

sustained release
theophylline
*ICS, inhaled glucocorticosteroids
, receptor antagonist or synthesis inhibitors
Figure 27-2 Management of asthma based on control. Rationale use of short- and long-acting beta-agonists.

244

C h a p t e r 27 n Bronchodilators: Beta2-Agonists and Anticholinergics

that of albuterol, so its intrinsic efficacy must be even less.

To put this in perspective, the intrinsic efficacy of albuterol is
only 5% that of a full agonist such as epinephrine or isoproterenol. The low efficacy of salmeterol in relaxing airway smooth
muscle is mirrored by its low induction of desensitization in
vitro. Large controlled, randomized clinical trials with mild
to moderate asthmatic individuals show that the maximal
bronchodilation achieved with regular administration of salmeterol is comparable to that achieved with albuterol. Side
effects from both salmeterol and formoterol are very low at
the doses used for maintenance therapy of asthma, and we
are not aware of any convincing evidence that side effects
from salmeterol are lower than formoterol at equally effective
doses. Greater desensitization of bronchodilator effect with
formoterol is suggested by the decline in peak expiratory flow
that occurred after the first few days of regular treatment
with formoterol but not salmeterol, and by the more dramatic shift in beta2-agonist dose-response curves following
regular treatment with formoterol. It is not known whether
there is any clinical significance to the subtle bronchodilator subsensitivity caused by LABAs because the improvement
they induce in lung function is sustained during long-term
trials and is not associated with increases in the frequency or
severity of exacerbations. Because of its slow onset of action,
low intrinsic efficacy, and risks from accumulation, salmeterol
should not be used for rescue therapy. On the other hand,
because of its rapid onset of action and high intrinsic efficacy,
formoterol has been used effectively as a rescue therapy in
some countries. The twice-daily use of either salmeterol or
formoterol results in improved lung function, reduced symptoms, fewer exacerbations, and improvement in health status.
These agents also protect against exercise-induced asthma for
up to 12 hours, and eliminate asthma-related nighttime awakening in most patients.
While the main effect of the existing LABAs is smooth
muscle relaxation, the nonbronchodilator activities of beta2agonists may enhance their efficacy in the management
of asthma (Table 27-4). In preclinical studies, the antiinflammatory effects of beta2-agonists are demonstrated
through their stabilizing effect on mast cells and their inhibition of mediator release from eosinophils, macrophages,
T-lymphocytes, and neutrophils. In addition, beta2-agonists
may inhibit plasma exudation in the airway, the release of
neuropeptides from sensory nerves, and mediator release
from epithelial cells and may have an effect on mucociliary
function. These preclinical observations are not as clearly
demonstrated in clinical trials, which may be explained by
their induction of rapid desensitization of beta2-adrenergic
receptors on airway inflammatory cells.
Therefore, based on current studies in humans, neither
salmeterol nor formoterol is clinically effective in reducing airway inflammation when used as stand-alone medication. However, the beneficial effects of inhaled LABAs
have been revealed in multiple studies when regularly
used in conjunction with an inhaled corticosteroid; salmeterol and formoterol effectively relieve asthma symptoms and improve physiology without decreasing asthma
control or increasing mortality. In this situation, the clinical and functional efficacies of adding a long-acting inhaled
beta2-agonist are greater than doubling the dose of inhaled
steroid.

Table 27-4
Potential Nonbronchodilator Activities of b2-Agonists
Target Site

Effect

Airway smooth muscles

Bronchoprotectiondecrease response to
nonspecific stimuli (methacholine) and
allergens.
Increase mucociliary clearance.
Inhibit eosinophil and lymphocyte activation
in response to allergen exposure. Reduce
serum eosinophilic cationic protein levels.
May decrease number of mast cells,
eosinophils, lymphocytes, and neutrophils
in the bronchial mucosa.* Enhance the
effects of inhaled corticosteroids on several
inflammatory cells.
Decrease vascular permeability and airway
wall edema, decrease angiogenesis when
combined with inhaled corticosteroids.

Airway mucosa
Airway inflammatory cells*

Airway vessels

*Data are controversial.

BETA2-Agonists in the Rescue Management of

Asthma

It is generally agreed that the short-acting inhaled beta2agonists are by far the most effective drugs for rescue therapy
in asthma. Several short-acting inhaled beta2-agonists are available for use as rescue medication. Albuterol, pirbuterol, terbutaline, and levalbuterol are highly selective beta2-agonists with
onset of action less than 5 minutes and peak action between 60
and 90 minutes. Differences in potency are compensated by differences in dosing such that all available products are essentially
equipotent on a per puff basis. Older agents, such as isoetharine and metaproterenol, have shorter durations of action and
less beta2-selectivity and will not be further considered here.
Along with high receptor selectivity, the excellent side-effect
profile of the rescue beta2-agonists appears to be due in part
to their partial agonism. Among these agents, albuterol is the
most widely used and the best studied; its intrinsic efficacy has
been measured at 5% that of a full agonist such as epinephrine
or isoproterenol. As described under pharmacology, a weak
partial agonist induces little activation of nontarget tissues due
to low density of beta2-adrenoceptors in these tissues, and clini
cal studies confirm that the strong agonist fenoterol induces
more side effects at comparable target effect than albuterol.
The metered-dose inhaler (MDI) is currently the most popular device to deliver these medications, although they can also
be delivered using a dry powder device or nebulizer. Although
the use of MDI for delivery is more cost-effective in terms of
simplicity, targeting medication to the lung, cost, maintenance,
personnel time-investment, and risk of contamination when
compared to a nebulizer, the use of this device is techniquedependent and its misuse may be associated with inconsistency
of the delivered dose of medication. Patients who cannot use
an MDI correctly, such as the elderly and young children, may
benefit from the use of alternative devices such as breath-actuated devices (e.g., Autohaler), dry powder inhalers, or nebulizers. Historically, MDI technology has used chlorofluorocarbons
(CFCs) as propellants, but CFCs will eventually be phased out
because of their environmental hazards. Several MDIs for albuterol with hydrofluoroalkane (HFA134a), a nonchlorinated
propellant, are currently available.

245

S e c t i o n v n treatment

The frequency of rescue beta2-agonist use is a clinically useful indicator of disease activity, and increasing use has been
associated with increased risk of death. This is most likely
more a reflection of severe and unstable asthma than a direct
toxicity of the drug. In general, the use of more than one
canister a month indicates overreliance on rescue drugs and
suggests inadequate asthma control. It is recommended that
patients who require rescue medication more than two times/
week during the day and/or more than two times/month at
night take a step-up in therapy such as an increase in the dosage of inhaled corticosteroid or an addition of another medication (e.g., a LABA or a leukotriene modifier).
BETA2-Agonists in the Acute Management of Asthma

Although systemic corticosteroids play an essential role in

the therapy of acute severe exacerbations of asthma, these
agents act slowly and induce bronchodilation only indirectly.
Beta2-agonists, on the other hand, act rapidly and are the most
effective bronchodilators available; their use is a cornerstone
of the initial management of acute asthma exacerbations. The
severity of acute asthma ranges from mild exacerbations that
readily respond to initial therapy in the emergency department to severe, life-threatening exacerbations requiring intubation and admission to the intensive care unit. Therefore, a
single agent, a standard dose, and a particular route of delivery
are not appropriate for all settings. In most cases, an inhaled
rescue drug such as albuterol, given more frequently and in
higher doses than for simple rescue, will suffice. However,
in a patient with impending respiratory failure despite the
administration of high doses of a rescue medication, an agonist of higher intrinsic efficacy (full agonist) has theoretical
advantages. Beta2-adrenoceptors are functionally antagonized
by inflammatory mediators that are present during an acute
exacerbation, and they may be desensitized by prior use of
beta2-agonists for maintenance and rescue therapy. In this setting, the submaximal efficacy of a partial agonist may become
apparent, and a full agonist with a rapid onset of action should
be considered. In addition, drug delivery by the inhaled route
may be inadequate because of airway obstruction, and parenteral delivery may offer greater benefit. For most patients
in the emergency setting, inhaled administration of beta2agonists is superior and safer than systemic administration.
The drug is given at higher doses and more frequently than
in the rescue setting to overcome strong constrictive stimulation by inflammatory and neural mediators. In addition, the
higher dosing may be necessitated by reduced peripheral airway caliber resulting in poor delivery of beta2-agonists. Most
commonly, the drug is delivered by continuous or back-toback nebulization. Continuous nebulization may be superior
to intermittent nebulization and nebulization with a low dose
of albuterol (2.5mg/hour) offers excellent benefit with minimal side effects. In severe asthma, approximately one third of
patients have a poor response to a standard dose of nebulized
albuterol. In this situation, several options are available. First,
a higher inhaled dose of the same medication may be given.
Second, a beta2-agonist may be given by the parenteral route in
addition to the inhaled route. Third, a beta2-agonist of higher
intrinsic efficacy may be given. In a multicenter, randomized,
double-blind, parallel-group study, patients receiving inhaled
fenoterol had significantly more maximal improvement in airflow than those receiving inhaled albuterol. However, therapy

246

with fenoterol was associated with more systemic adverse

effects. Similarly, a recent study demonstrated that isoproterenol administration was associated with superior physiologic and
symptomatic response than albuterol in patients with acute
severe asthma.
For patients requiring intubation, inhaled bronchodilators
have traditionally been administered via nebulization. However,
an MDI used with an inline spacer is as efficacious and offers
some advantages. In some settings, the nebulizer must be placed
in line with the ventilator circuit; in this case, the machine-delivered tidal volume must be reduced to account for the volume
added by the nebulizer. Furthermore, contamination of nebulizers can lead to aerosolization of bacteria and thus to respiratory tract infections. Last, the fraction of beta2-agonist aerosol
deposited in the lungs of mechanically ventilated patients is
higher with an MDI with holding chamber compared with a
nebulizer.
Safety of Beta2-Agonists in Asthma
Adverse effects from the highly selective inhaled beta2-agonists
are largely due to activation of beta2-adrenoceptors in nontarget tissues. These side effects are not usually a problem
when the agents are administered by inhalation, but become
more frequent with oral and systemic administrations. Most
commonly, cardiac stimulation may lead to tachycardia,
increased oxygen demand, and occasional arrhythmias, while
skeletal muscle stimulation may lead to tremor and hypokalemia. Adverse effects, such as allergic reactions or paradoxical
bronchospasm, can also occur but are very rare. Some tolerance has been reported to the bronchoprotective effects of
SABAs and LABAs. However, although the reduction in the
protective effect of these agents has been demonstrated, this
is not progressive and most of the initially observed protective effect is preserved. Modest but nonprogressive tolerance has also been seen in the bronchodilator effects of some
beta2-agonists. However, the improvements in lung function
induced by LABAs are sustained over long periods and the
clinical significance of the tolerance they induce to bronchodilation is unknown.
The regular use of SABAs has been associated with
increased asthma mortality. Although, as mentioned earlier,
this may be more a reflection of severe and unstable asthma
rather than adverse effect from the medication, it is of
interest that the two reported asthma mortality epidemics reported in some countries several years ago were
observed with the use of the full agonists, isoproterenol and
fenoterol. More recently, some studies demonstrated that
the regular use of short-acting beta-agonists may be associated with poor asthma control in certain individuals with
homozygous arginine genotype at position 16 of their Bin
b2AR (one sixth of whites and one fifth of blacks in the
United States). Whether the above association is present with the use of long-acting agents remains to be determined. However, a recent study suggested an association
between the use of LABAs with an increase in asthmarelated deaths and life-threatening experiences. The SMART
trial (Salmeterol Multicenter Asthma Research Trial) was
designed to randomize 60,000 asthma patients to either
salmeterol twice daily or placebo. However, following an
interim analysis in 26,355 subjects, the study was terminated

C h a p t e r 27 n Bronchodilators: Beta2-Agonists and Anticholinergics

because of the findings in blacks and difficulties in enrollment.

The occurrence of the primary outcome, respiratory-related
deaths or life-threatening experiences was low and not
significantly different for salmeterol versus placebo (50 versus
36). However, there was a small but significant increase in
respiratory-related deaths and asthma-related deaths, and
in combined asthma-related deaths or life-threatening experiences in subjects receiving salmeterol. This imbalance
occurred largely in the black subpopulation. It is important
to note that this subpopulation had more severe asthma at
baseline and less than half of subjects were receiving concomitant inhaled corticosteroids. As a consequence of SMART
trial results, the FDA issued a public advisory to highlight
recommendations about the use of LABAs for asthma. This
advisory emphasized the need to use these agents only as addon therapy in patients who fail to achieve asthma control with
the use of moderate doses of inhaled corticosteroids.

and vasodilation. Three muscarinic receptor subtypes are

expressed in the lung (Fig. 27-3). M1 receptors are localized
to parasympathetic ganglia in the bronchial plexus that continues into the smaller airways. M2 receptors are autoreceptors found on the parasympathetic nerve endings and inhibit
the release of acetylcholine, while M3 receptors on airway
smooth-muscle cells mediate bronchoconstriction. Since acetylcholine causes not only airway smooth-muscle contraction
but also proliferation, it could mediate some aspects of airway
remodeling in asthma. In addition, cholinergic receptors are
found outside the neuromuscular system, with muscarinic
receptors on lymphocytes and neutrophils, and on a variety
of other airway cells. Cholinergic neurotransmission may
be enhanced by inflammatory mediators; cholinergic nerves
are the dominant neural pathway for bronchoconstriction in
humans. In particular, it has been suggested that serum IgE
may be one of the factors that determine the airway tone,
possibly via cholinergic mechanisms, because it has been

Anticholinergic (Antimuscarinic)
Agents
Historical Perspective
Anticholinergic medications have been used for hundreds of
years for the treatment of bronchospasm. A very common
treatment for wheezing in ancient India was the inhalation
of Datura stramonium (Jimson weed), due to the anticholinergic properties of atropine. Asthma cigarettes were
once a popular method of administering this medication to
the lungs. However, because of its systemic effects, atropine
was later on replaced by the N-quaternary compounds that
do not penetrate the blood-brain barrier. Ipratropium bromide,
one of these compounds, has now been used for many years
as a bronchodilator of choice in COPD; however, it possesses
inferior bronchodilator properties to beta2-agonists in asthma.
Tiotropium bromide, a longer acting anticholinergic, was
recently approved for use in COPD but its exact role in
asthma remains to be fully explored.
Pharmacology of Anticholinergic Agents
The efferent cholinergic pathway represents a key mechanism
in the control of airway smooth muscle tone as well as a number of other physiological and pathophysiological reactions.
For many years, the general belief has been that anticholinergics appear to be less effective in asthmatic patients, probably
because airway narrowing in asthma is mainly due to the direct
effects of inflammatory mediators on airway smooth muscle and
not due to increase in cholinergic tone as is the case in COPD.
However, although asthma is considered to be an inflammatory
disease of the airways, neural mechanisms remain very important. Furthermore, it must be highlighted that an anticholinergic
effect on the bronchi in asthma is possible even in the absence of
a true bronchodilator effect. In fact, it has been documented that
anticholinergic agents can reduce airway hyperresponsiveness.
Interestingly, there is a complex relationship between
inflammation and neural control of the airways. Acetylcholine
release from parasympathetic nerves activates muscarinic
receptors on airway smooth muscle, submucosal glands, and
blood vessels to cause bronchoconstriction, mucus production,

Parasympathetic
nerves
Ganglion

ACh

ACh

M1

M1

M2

M2

M2

M2

ACh

ACh

ACh

ACh

M3

M2

M1

M3

Airway smooth
muscle
Submucosal
glands

Figure 27-3 Muscarinic receptors in the lung. Vagal parasympathetic

nerves from the brain terminate at peripheral ganglia in the lungs. Acetylcholine
(ACh) released acts via M1 muscarinic receptors on postganglionic,
nonmyelinated efferent nerves that innervate the submucosal glands and
airway smooth muscle. Presynaptic M2 muscarinic receptors are inhibitory
autoreceptors on the postganglionic nerves. ACh released onto the airway
smooth muscle causes bronchoconstriction via the M3 muscarinic receptors and
mucus secretion via the M1 and M3 muscarinic receptors (Adapted from Lee AM,
Jacoby DB, Fryer AD: Selective muscarinic receptor antagonists for airway diseases.
Curr Opin Pharmacol 2001;1:224.)

247

S e c t i o n v n treatment

observed that higher serum IgE levels were correlated with

lower values of FEV1. Furthermore, anticholinergic agents
caused more pronounced bronchodilation than beta2-agonists
in subjects with high IgE levels. This finding contrasts with
the documentation that atopic status appears to have a significant negative effect on the degree of responsiveness to
inhaled anticholinergic drugs.
Mucus secretion in airways also plays an important role
in asthma, and muscarinic agonists can induce mucus secretion from airway tissue. M3 receptors are involved in mediating cholinergic stimulation of mucus secretion. Ciliary beat
frequency is also stimulated by acetylcholine and muscarinic
agonists and reduced by muscarinic antagonists.
Clinical Use of Anticholinergic Agents
in Asthma
Anticholinergics in the Maintenance
Management of Asthma

As mentioned earlier, the possibility of treating asthma with

an anticholinergic agent was suggested many years ago. In
1896, Stewart and Gibson proposed that one of the primary
treatments for an asthmatic paroxysm was the use of belladonna alkaloids. However, by 1975, belladonna alkaloids were
not considered a significant enough part of asthma treatment
to be included in the 14th edition of Cecils A Textbook of
Medicine. Nonetheless, the treatment of asthma with ipratropium bromide was introduced in the 1980s, but some studies
documented that patients with chronic bronchitis responded
better in general to ipratropium bromide, whereas asthmatic
subjects responded better to beta2-agonists. Attempts to
identify subgroups of asthmatic individuals who respond better to anticholinergic agents have not been very successful.
In general, in patients younger than 40, beta2-agonists remain
the bronchodilator of choice in asthma. With advancing age, and
the apparent decline of beta-adrenergic responsiveness, the
initial comparatively small response to ipratropium becomes
relatively more important and may predominate. In older
patients, the use of anticholinergic agents or continued therapy with both groups of drugs may be preferable.
When given in advance of bronchospastic stimuli, anticholinergic agents provide variable degrees of bronchoprotection.
They also have prophylactic effects against the bronchospasm
induced in asthmatic patients by beta-blocking agents. Further
more, a recent genotype-stratified study revealed that patients
with certain b2AR polymorphisms (Arg/Arg genotype at the
position 16) might benefit from discontinuation of the use of
albuterol as rescue medication and may benefit from the use
of as-needed ipratropium bromide instead. Anticholinergic
agents may also be useful in patients with chronic asthma who
develop fixed airway obstruction. Although chronic asthma
is a loosely defined disease, it may be equated approximately
with nonallergic or intrinsic asthma arising in adult life. It
has been demonstrated that intrinsic asthmatic individuals and
those with longer duration of asthma respond better to anticholinergic agents. However, a Cochrane analysis of randomized controlled trials in which anticholinergic drugs were given
for chronic asthma in children older than 2, documented that,
although there were some small beneficial findings in favor of
anticholinergic therapy, there are insufficient data to support
the use of anticholinergic drugs in the maintenance treatment

248

of chronic asthma in children. Another Cochrane analysis,

which examined the effectiveness of anticholinergic agents versus placebo and in comparison with beta2-agonists or as adjunctive therapy to beta2-agonists in the management of chronic
asthma in adults, concluded that there is no justification for
routinely introducing anticholinergics as part of add-on treatment for patients whose asthma is not well controlled on standard therapies. This does not exclude the possibility that there
may be a subgroup of patients who derive some benefit and a
trial of treatment in individual patients may still be justified.
Nocturnal asthma is considered another likely option for
the anticholinergic agents. In fact, it is due, at least in part,
to an increase in cholinergic tone during sleep. In one study,
vagal blockade with intravenous atropine caused significant
bronchodilatation and significantly increased the pulse rate
at 4 am and 4 pm; moreover, nocturnal asthma was almost
totally reversed. In another study, morning dipping, assessed
by the fall in peak flow overnight, was significantly reduced
in the periods when either oxitropium or theophylline was
taken, whereas no difference was noticed during the placebo
administration. The same finding was demonstrated with the
use of ipratropium bromide in 12 patients with morning dipping. Maintenance treatment with ipratropium bromide 40
g
three times daily in 31 children with asthma reduced the provocative dose of histamine, causing a 20% fall in FEV1, despite
an 8- to 12-hour gap between the last dose of ipratropium and
histamine challenge. It did not, however, diminish the diurnal
variation in airway caliber or in bronchodilator responsiveness.
These intriguing observations indicate that parasympathetic
activity may contribute, but not fully explain, nocturnal airflow obstruction. Therefore, the exact role of anticholinergic
agents in nocturnal asthma remains uncertain.
The role of long-term anticholinergics such as tiotropium
bromide has yet to be established in patients with asthma and
any future trials might draw on the messages derived from this
review. It must be highlighted that tiotropium bromide inhibits allergen-induced airway remodeling in a guinea pig model
of ongoing asthma. This finding could have important implications for the use of long-acting anticholinergic agents in the
treatment of allergic asthma, by protecting against the development of chronic airway hyperresponsiveness and decline of lung
function in addition to their acute bronchodilating effects.
Anticholinergics in the Acute Management
of Asthma

The rationale for the use of anticholinergic therapy in

acute asthma has been the presumption of increased airway vagal tone in these patients. However, the role of anticholinergics has been less well defined than beta2-agonists
even in this situation. The overall pooled effect size of trials comparing ipratropium bromide with a beta2-agonist in
acute severe asthma shows that a nebulized beta2-agonist
produces significantly more bronchodilation than ipratropium. A meta-analysis published in 1993 concluded that
anticholinergics should not be used alone to treat acute
asthmatic exacerbations. In general, large doses of an anticholinergic agent are required in acute severe asthma, presumably because of increased vagal discharge. In fact, a
cumulative dose-response study carried out in patients
with acute severe asthma demonstrated that only 0.5mg
ipratropium bromide given by nebulizer produced maximal

C h a p t e r 27 n Bronchodilators: Beta2-Agonists and Anticholinergics

improvement in peak expiratory flow rates. However, a recent

review undertaken to incorporate the more recent evidence
available about the effectiveness of treatment with a combination of beta2-agonists and anticholinergics compared with
beta2-agonists alone in the treatment of acute asthma suggested that the addition of multiple doses of inhaled ipratropium bromide to beta2-agonists is indicated as the standard
treatment in children, adolescents, and adults with moderate
to severe exacerbations of asthma in the emergency setting.
The combined used of these two classes of bronchodilators
has been reported to have independent and additive action
and reported to attain greater peak and sustained bronchodilatation. This can be accounted for by their different mechanism of action, times of peak effect, and duration of action.
Nonetheless, there is substantial evidence that ipratropium bromide is of limited usefulness in episodes of mild
to moderate acute asthma. A Cochrane systematic review of
acute asthma in children looked at 13 trials of ipratropium
bromide. A single dose of ipratropium bromide was of no
additional benefit in children with mild to moderate asthma.
Multiple doses of ipratropium bromide, while safe, only had
sufficient evidence to support its use in school-aged children
with acute severe asthma. Another evidence-based review
found that whereas multiple doses of ipratropium bromide
are indicated in the emergency management of children and
adults with severe asthma, there was no apparent benefit of
adding single doses of ipratropium bromide to those with
mild to moderate asthma. Given that most presentations to
the emergency department are mild to moderate in severity,
many patients may therefore receive an expensive therapy
with little evidence for its efficacy.
Safety of Anticholinergic Agents in Asthma
While atropine produces numerous systemic side effects
related to the inhibition of physiological functions of the
parasympathetic system, quaternary anticholinergic agents
such as ipratropium bromide are poorly absorbed from the
mucosa and thus the risk of adverse effects is insignificant. In
normal clinical use, the only adverse effects encountered by
these agents include dryness of the mouth, which may occur
in 5% of patients. However, these agents need to be used
with caution in patients with increased intraocular pressure
and those with prostatic hypertrophy.

group on the carbostyril aromatic ring, is a pure (R,R)-isomer that has a high potency for the beta2-adrenoceptor and a
long duration of action after removal of the drug using both
guinea pig tracheal muscle relaxation and bovine trapezium
muscle binding experiments. Preliminary clinical trials indicated duration of effect exceeding 24 hours after inhalation
of only 3g. In a study that evaluated the effects of single
doses of carmoterol in mild asthmatic individuals, carmoterol
had an exceptional duration of action in man, with significant
improvement in FEV1 sustained for 30 hours, twice that of
salmeterol or formoterol. Carmoterol restored FEV1 levels to
the normal range within 20 minutes of inhalation.
Indacaterol (QAB-149)

Indacaterol (QAB-149) is another once-daily beta2-agonist

that demonstrates a fast onset and long duration of action in
vitro and in vivo in the experimental setting. Phase II clinical trials in patients with mild-to-moderate asthma have
shown that this ultra-LABA at 200- and 400-g doses is statistically superior (P < .05) to placebo at all time points
from 5 minutes to 26 hours post dose, except for 26 hours
post dose for the 200-g dose, but also at a 25-g dose it
has elicited response in mild asthma patients compared to
placebo. Improvement in efficacy responses was generally
dose dependent and was accompanied by a positive safety
profile up to a 2000-g dose. The efficacy of indacaterol in
patients with asthma has further been investigated in longerterm trials in which the 24-hour bronchodilator efficacy of
indacaterol observed on the first day was maintained for the
duration of the studies, suggesting that regular use of indacaterol is not associated with the development of tolerance,
or tachyphylaxis.
Other Ultra-Labas

The compound GSK-159797 (TD-3327) is an ultra-LABA

for the potential once-daily treatment for asthma and COPD,
but its structure has not yet been disclosed. It achieved the
target increase in FEV1 throughout the 24-hour evaluation
period in studies of patients with mild asthma with improvements in efficacy responses that were dose dependent. GSK159797 was well tolerated, with no increase in heart rate.
Also GSK-597901, another ultra-LABA, proved encouraging
in early phase II studies, although fewer details have been
disclosed. GSK-159802, GSK-642444, and GSK-678007 are
three other ultra-LABAs in development.

Novel Bronchodilators
Novel Beta2-Agonists
After the discovery of formoterol and salmeterol, new candidates for LABAs have emerged. In particular, once-daily
beta2-agonists, the so-called ultra-LABAs, are in development
for treating asthma in an attempt to simplify its management.
Once-daily dosing would allow better compliance and management of patients if desensitization does not occur.
Two compounds, carmoterol and indacaterol, are in
advanced phase of clinical development.
Carmoterol (CHF-4226, TA-2005)

Carmoterol, a noncatechol beta2-agonist with a p-methoxyphenyl group on the amine side chain and a 8-hydroxyl

Novel Long-Acting Anticholinergic

Agents (LAMAs)
Several new anticholinergic agents , currently in development
mainly for the treatment of COPD, could be considered as
potential alternatives or be integrated in the treatment of
chronic asthma. NVA237 (AD 237) is a once-daily, longacting muscarinic antagonist (LAMA) with a fast onset of action.
This drug has been identified as glycopyrrolate, a quaternary
ammonium anticholinergic compound that has been shown
to cause bronchodilatation for at least 12 hours in patients
with asthma and has been successfully employed in the treatment of exercise-induced asthma and acute exacerbations of
asthma in the past. Recently it has been documented that
protection against methacholine-induced bronchospasm after

249

S e c t i o n v n treatment

administering glycopyrrolate was maintained to 30 hours, the

last time point measured. In addition, glycopyrrolate caused
bronchodilation that was fast in onset and sustained at up to
30 hours. Both bronchodilatation and bronchoprotection were
significantly longer with glycopyrrolate than after ipratropium
bromide, and bronchoprotection was significant at all time
points from 2 to 30 hours compared to placebo. LAS-34273
and LAS-35201 are two new LAMAs under development by
Almirall, and TD-5742 is a new LAMA under development
by Theravance, all with presumably very long duration of
effect. Darifenacin is a selective M3 receptor antagonist but
has shown 10-fold and 6-fold less potency in binding to the
trachea and salivary gland, respectively, compared with atropine.

Salivary gland responses were inhibited at doses 6 to 10

times higher than those required to inhibit gut and bladder
responses. Zamifenacin and darifenacin, which are developed
to treat overactive bladder, have the highest affinity for M3
muscarinic receptors of all the current anti-muscarinic antagonists and these new drugs may be clinically useful for antagonizing M3 muscarinic receptors on submandibular glands.
Increased mucus secretion is seen in exacerbations of asthma
and this contributes to airway narrowing; these drugs may
decrease mucus secretion in the airways. LAMAs are likely
to have additive effects when combined with ultra-LABAs,
thus making once-daily combination bronchodilator inhalers
a likely development in the future.

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