Bronchial asthma is a chronic episodic
bronchospastic disorder characterized by an early-phase response
beginning immediately following exposure to a trigger stimulus and
a late-phase response which begins 6 to 8 hours later. In the classic
immunologic model, the early phase is initiated by the stimulus
(often an allergen) binding to IgE bound to mast cells in the airway
mucosa (Figure 35–2). Subsequent release of eicosanoids
and other mediators result in the initial bronchospasm and influx
of additional inflammatory cells. Bronchospasm decreases the airway
diameter and limits expiratory airflow. The hallmark of the late-phase
response is airway inflammation with interstitial airway edema,
invasion of white blood cells, epithelial injury with decreased
mucociliary function, and sustained bronchoconstriction. This combination
of factors during the late-phase response also decreases airway
diameter and limits expiratory airflow. Both the early and late
phases are associated with increased airway responsiveness to subsequent
allergen challenges. Examples of allergen triggers that initiate
the immunologic response include house dust mites and cockroach detritus,
animal dander, pollens, and molds. Nonallergen triggers that provoke
asthmatic responses include viral respiratory tract infections,
inhaled irritants (e.g., smoke), strong emotions, exercise, and
Manifestations of IgE-initiated bronchial asthma. In
the early-phase response, bronchospasm predominates resulting in
decreased expiratory airflow. In the late-phase response, airway
inflammation, edema, increased mucus production, and impaired mucociliary
function decrease expiratory airflow. Both early- and late-phase
responses are also associated with increased airway responsiveness
to subsequent allergic triggers. (Reproduced, with permission, from
Porth CM: Pathophysiology: Concept of
Altered Health States, 7th ed. Philadelphia: Lippincott Williams
& Wilkins, 2005:696.)
Chronic obstructive airway disease (or chronic obstructive pulmonary
disease, COPD) includes chronic bronchitis, emphysema, and bronchiectasis.
Common characteristics of COPD include chronic and repeated airway
obstruction and inflammation. The most common cause of COPD is smoking.
Emphysema is a loss of elasticity of the parenchyma (alveoli and
interstitial tissue) and breakdown of the alveolar walls. The former
inhibits expiratory airflow and the latter results in a loss of
surface area available for gas diffusion. In contrast, chronic bronchitis
is caused by inflammation that results in submucosal hyperplasia
and edema, along with excessive mucous secretion. Airway narrowing
and mucous plugs inhibit expiratory airflow. Bronchiectasis is a
form of COPD that results from cycles of bacterial infection and
subsequent inflammation. This process destroys the elastic support
of the airways and forms mucous plugs that decrease expiratory airflow.
Cystic fibrosis is a genetic disorder that affects many organs.
In the pulmonary system, it results in production of abnormally
viscous mucus and blockage of airways with inhibition of expiratory
airflow and repeated bacterial infections.
Strategies for Obstructive Lung Diseases
The drug classes used in the treatment of asthma and other obstructive
airway disorders are presented in Figure 35–3. Therapeutic
interventions may be divided into two categories: “short-term relievers” and “long-term
controllers.” The former drugs relieve acute bronchospasm
associated with obstructive airway diseases, and the latter drugs
minimize the associated inflammation or prevent subsequent acute
Drug classes useful in obstructive airway disorders include
bronchodilators (smooth muscle relaxants) and anti-inflammatory
drugs. Bronchodilators include β2-selective
agonists, muscarinic antagonists, and methylxanthines. Anti-inflammatory
drugs include mast cell release inhibitors, corticosteroids, and
an anti-IgE antibody. Leukotriene antagonists have both bronchodilator
and anti-inflammatory mechanisms of action.
Acute bronchospasm can usually be treated promptly and effectively
with bronchodilators. Beta2 (β2)–selective
agonists, muscarinic antagonists, and theophylline and its derivatives
are available for this indication. Late response inflammation and
bronchial hyperreactivity can be treated with corticosteroids, cromolyn
or nedocromil, and leukotriene antagonists. These drugs inhibit
release of mediators from mast cells and other inflammatory cells
or block their effects. The leukotriene antagonists may have inhibitory
effects on both bronchoconstriction and inflammation. Anti-IgE antibodies
also appear promising for chronic therapy in some cases. A review
of these drug classes and their clinical use in asthma is presented
in Figure 35–4. Many of these drug classes are used clinically
for other obstructive airway disorders.
Summary of treatment strategies in asthma. (Reproduced,
with permission, from Cockcroft DW: The bronchial late response
in the pathogenesis of asthma and its modulation by therapy. Ann Allergy 1985;55:857.)
agonists are the most important drugs used to reverse asthmatic
bronchoconstriction. Epinephrine and isoproterenol are still used occasionally
even though they are not selective for β2 receptors. Albuterol, terbutaline, and metaproterenolare the most important
short-acting β2 agonists in the United
States. Salmeterol and formoterolare
long-acting β2 agonists. Beta-receptor
agonists are given almost exclusively by inhalation, usually from
pressurized aerosol canisters, but occasionally by nebulizer. The
inhalational route decreases the systemic dose (and adverse effects),
while delivering an effective dose locally to the airway smooth muscle.
The older drugs have durations of action of 6 hours or less; salmeterol
and formoterol act for 12 hours or more.
The classification of β receptors,
mechanisms of action of drugs stimulating these receptors, and general
physiologic effects of β receptor stimulation are
discussed in Chapters 4 and 6. Activation of β receptors
stimulates adenylyl cyclase, and increases intracellular cyclic
adenosine monophosphate (cAMP) in smooth muscle cells. This causes
a decrease in smooth muscle tone and a powerful bronchodilator response
Bronchodilation is promoted by cyclic adenosine monophosphate
(cAMP). Intracellular levels of cAMP can be increased by β-adrenoceptor
agonists, which increase the rate of cAMP synthesis by adenylyl
cyclase (AC); or by phosphodiesterase (PDE) inhibitors such as theophylline,
which slow the rate of cAMP degradation. Bronchoconstriction can
also be inhibited by muscarinic antagonists and possibly by adenosine
These drugs are used extensively
in asthma. Shorter-acting β2 agonists
(albuterol, metaproterenol, terbutaline) should be used only for
acute episodes of bronchospasm (not for prophylaxis). The long-acting
agents (salmeterol, formoterol) should be used for prophylaxis,
not for acute episodes, because they are effective in improving
asthmatic control when taken regularly but have a slow onset of
action. In almost all patients, the shorter-acting β agonists
are the most effective bronchodilators available and therefore the
drugs of choice for acute asthma. Some patients with chronic COPD
also benefit, although the incidence of adverse effects is increased
in this condition.
Skeletal muscle tremor is a common
adverse β2 effect of these drugs. The β2 selectivity
of these drugs is not complete. At high dosage, these agents have
significant β1 cardiac effects. Even when
they are given by inhalation, tachycardia is common. When the agents are
used excessively, arrhythmias may occur. Loss of responsiveness
(tolerance, tachyphylaxis) can occur with excessive use of short-acting β2 agonists.
Patients with COPD often have concurrent cardiac disease and may
have arrhythmias even at normal dosage.
The methylxanthines are purine
derivatives. Three major methylxanthines are found in plants and provide
the stimulant effects of three common beverages: caffeine (in coffee), theophylline (in tea), and theobromine (in
cocoa). Theophylline is the only member of this group important
in the treatment of asthma.
Theophylline and several analogs are orally active and available
as a base and as various salts. The drug is available in both prompt-release
and slow-release forms, and is eliminated by P450 drug-metabolizing
enzymes in the liver. Clearance varies with age (highest in young
adolescents), smoking status (higher in smokers), and concurrent
use of other drugs that inhibit or induce hepatic enzymes.
The methylxanthines inhibit phosphodiesterase
(PDE), the enzyme that degrades cAMP to adenosine monophosphate
(AMP) (Figure 35–5), and thus increase cAMP levels. This
anti-PDE effect, however, requires high concentrations of the drug.
Methylxanthines also block adenosine receptors in the CNS and elsewhere,
but a relationship between this action and the bronchodilating effect
has not been clearly established. Finally, the possibility exists
that bronchodilation is caused by an unrecognized action.
In asthma, bronchodilation is the most important therapeutic
action. Increased diaphragm contraction strength has also been demonstrated
in some patients. Other effects of therapeutic doses include CNS
stimulation, cardiac stimulation, vasodilation, a slight increase
in blood pressure (probably caused by release of norepinephrine
from adrenergic nerve endings), and increased GI motility.
The major clinical indication
for the use of methylxanthines is asthma, but none of these drugs
are as safe or effective as the β2 agonists.
Slow-release theophylline (for control of nocturnal asthma) is the
most important methylxanthine in clinical use. Another methylxanthine
derivative, pentoxifylline, is promoted
as a remedy for intermittent claudication; this effect is said to
result from decreased blood viscosity. Nonmedical use of methylxanthines
in coffee, tea, and cocoa is far greater, in total quantities consumed,
than their medical uses.
These drugs have a narrow therapeutic
window. Therapeutic plasma concentrations range from 5 to 20 mg/L,
whereas adverse effects begin to occur in some patients when plasma
concentrations reach 15 to 20 mg/L. Common adverse effects
include GI distress, tremor, and insomnia. Severe nausea and vomiting,
hypotension, cardiac arrhythmias, and convulsions may result from
overdosage. Very large overdoses (e.g., in suicide attempts) are
potentially lethal because of arrhythmias and convulsions. Beta-receptor antagonists are useful antidotes for severe cardiovascular toxicity
Atropine and other naturally occurring
belladonna alkaloids were used for many years in the treatment of
asthma but have been replaced by ipratropium, a
quaternary antimuscarinic agent. Ipratropium is delivered to the
airways by pressurized aerosol and has little systemic action. Tiotropium is a newer, longer-acting
When given as an aerosol, ipratropium
competitively blocks muscarinic receptors in the airways and effectively
prevents bronchoconstriction mediated by vagal discharge (Figure
35–5). If given systemically (not an approved use), the
drug is indistinguishable from other short-acting muscarinic blockers.
Ipratropium reverses bronchoconstriction in some asthma patients
(especially children) and in many patients with COPD. The drug has
no effect on the inflammatory aspects of asthma.
Ipratropium is only useful in
one-third to two-thirds of asthmatic patients; β2 agonists
are effective in almost all. Therefore, β2 agonists
are usually preferred for acute bronchospasm. However, in patients
with COPD, which is often associated with acute episodes of bronchospasm,
antimuscarinic agents may be more effective and less toxic than β2 agonists.
Because ipratropium is delivered
directly to the airway and minimally absorbed, there are few systemic
effects. When given in excessive dosage, minor atropine-like toxic
effects may occur (Chapter 5). In contrast to β2 agonists,
ipratropium does not cause tremors or arrhythmias.
For an expanded discussion of
the mechanisms of action, clinical uses, and adverse effects of
corticosteroids (glucocorticoids), see Chapter 23. All of the corticosteroids
are potentially beneficial in severe asthma. However, because of
their toxicity, systemic (oral) corticosteroids are used chronically
only if other drug delivery options are unsuccessful. In contrast,
local aerosol administration of surface-active corticosteroids (e.g., beclomethasone, budesonide, dexamethasone,
flunisolide, fluticasone, mometasone) is relatively safe. Inhaled
corticosteroids have become common first-line therapy for individuals with
moderate to severe asthma. Important intravenous corticosteroids
for status asthmaticus (acute severe bronchospasm unresponsive to
usual bronchodilator medications) include prednisolone (the active metabolite of prednisone) and hydrocortisone.
Corticosteroids inhibit phospholipase
A2 and reduce eicosanoid synthesis. Excessive activity
of phospholipase A2 is thought to be particularly important
in asthma because the leukotrienes that result from eicosanoid synthesis
are extremely potent bronchoconstrictors, and also participate in
the late inflammatory response (Figure 35–6). Corticosteroids
reduce the release of arachidonic acid by phospholipase A2 and
inhibit the expression of type 2 cyclooxygenase (COX-2, Chapter 34), the inducible form of cyclooxygenase. Corticosteroids may also
increase the responsiveness of β2 adrenoceptors
in the airway. Corticosteroids bind intracellular receptors and
activate glucocorticoid response elements in the nucleus, resulting
in synthesis of substances that prevent the full expression of inflammation
and allergy (Chapter 23).
Flow diagram of the eicosanoid cascade and the mechanisms
of action of different anti-inflammatory drugs. Corticosteroids
inhibit the release of arachidonic acid, the substrate for lipoxygenase and
cyclooxygenase. Other leukotriene pathway antagonists either inhibit
the lipoxygenase enzyme directly, or inhibit the receptors for lipoxygenase
products (leukotrienes B, C, or D).
Inhaled corticosteroids are now
considered appropriate (even for children) in most cases of moderate
asthma that are not fully responsive to aerosol β2 agonists.
Early use of corticosteroids may prevent the severe, progressive
inflammatory changes characteristic of long-standing asthma. This
is a shift from earlier beliefs that steroids should be used only
in severe refractory asthma. In such cases of severe asthma, patients
are usually hospitalized and stabilized on daily systemic prednisone
and then switched to inhaled or alternate-day oral therapy before
discharge. In status asthmaticus, parenteral steroids are lifesaving
and apparently act more promptly than in ordinary asthma. Their
mechanism of action in this condition is not fully understood.
Local aerosol administration can
occasionally result in a very small degree of adrenal suppression,
but this is rarely significant. More commonly, changes in oropharyngeal
flora result in candidiasis. This adverse effect can be minimized
by gargling with water following drug administration. If oral (systemic)
therapy is required, adrenal suppression can be reduced by using alternate-day
therapy (i.e., giving the drug in slightly higher dosage every other
day rather than smaller doses every day). The major systemic toxicities
of these drugs (Chapter 23) are much more likely to occur if systemic
treatment is required for more than 2 weeks, as in severe refractory
asthma. Regular use of inhaled steroids causes mild growth retardation
in children, but these children eventually reach predicted adult
These drugs interfere with leukotriene synthesis or their receptor
interactions. They reduce the frequency of exacerbations but are
not as effective as corticosteroids in severe asthma and are not useful
in acute episodes.
Zileuton is an orally active drug
that selectively inhibits 5-lipoxygenase, a key enzyme in the conversion of
arachidonic acid to leukotrienes. The drug is effective in preventing
both exercise- and antigen-induced bronchospasm. Zileuton is also
effective against “aspirin allergy,” the bronchospasm
that results from ingestion of aspirin by individuals who apparently
divert all eicosanoid production to leukotrienes when the cyclooxygenase
pathway is blocked (Figure 35–6). The toxicity of zileuton includes
occasional elevation of liver enzymes. Therefore, this drug is less
popular than the leukotriene receptor blockers.
Zafirlukast and montelukastare antagonists at the
LTD4 leukotriene receptor (Figure 35–6). The LTE4 receptor
is also blocked. These drugs are orally active and are used for
prophylaxis. They have been shown to be effective in preventing
exercise-, antigen-, and aspirin-induced bronchospastic attacks.
They are not recommended for acute episodes of asthma. Toxicity
is generally low, but rare reports of Churg-Strauss syndrome (allergic
granulomatous angiitis) have appeared. Evidence of a causal association
Omalizumab is a humanized murinemonoclonal antibody to human IgE. The antibody binds to the IgE
antibody on sensitized mast cells and prevents mast cell activation
and subsequent release of inflammatory mediators by asthma triggers.
This very expensive therapy is approved for prophylaxis in asthma
and it must be administered parenterally.
Cromolyn (disodium cromoglycate) and nedocromil are unusual chemicals.
They are extremely insoluble, so that even massive doses given orally
or by aerosol result in minimal systemic blood levels. Because they
are not absorbed from the site of administration, cromolyn and nedocromil have
only local effects. When administered orally, cromolyn has some
efficacy in preventing food allergy. Similar actions have been demonstrated
after local application in the conjunctivae and the nasopharyngeal
tract. When used in the nasopharyngeal tract (for hay fever) or
in the bronchi (for asthma), these drugs are delivered by aerosol.
The mechanism of action of these drugs is poorly understood but
appears to involve a decrease in the release of mediators (such
as leukotrienes and histamine) from mast cells. Although these drugs
have no bronchodilator action, they can prevent bronchoconstriction
caused by a challenge with antigen to which the patient is allergic.
Cromolyn and nedocromil are capable of preventing both early and
late responses to challenge.
Asthma (especially in children) is the most important use for
cromolyn and nedocromil and requires inhalation of the drugs. Nasal
and eye drop formulations of cromolyn are available for hay fever,
and an oral formulation is used for food allergy.
These drugs may cause cough and airway irritation when given
by aerosol. Rare instances of drug allergy have been reported.