Chapter 26 

PULMONARY PHARMACOLOGY
Charles W. Emala, Sr.

β2-ADRENOCEPTOR AGONISTS
The most widely used medications in pulmonary medicine are
Structure-Activity
those delivered via inhalation for small airway diseases such
Mechanism and Metabolism
as asthma, chronic obstructive pulmonary disease (COPD),
Clinical Pharmacology
and cystic fibrosis. Using the lung as a vehicle for drug deliv-
Drug Interactions
ery is well known to anesthesiologists who routinely deliver
Clinical Application
volatile anesthetics to the lungs for systemic distribution (see
ANTICHOLINERGICS
Chapter 3).
Structure-Activity
Three classes of medication are inhaled for therapeutic
Mechanism and Metabolism
treatment of chronic lung diseases including β2-adrenoceptor
Clinical Pharmacology
agonists, anticholinergic drugs (muscarinic receptor antago-
Clinical Application
nists), and glucocorticoid steroids. Although combinations
INHALED STEROIDS
of β2-adrenoceptor agonists and steroids are now the most
Structure-Activity
widely used therapies in bronchoconstrictive diseases, this
Mechanism and Metabolism
was not always so. In 1896, medical textbooks advocated the
Clinical Pharmacology
smoking of “asthma cigarettes” made from the dried leaf
Drug Interactions
or fruiting tops of the Datura stramonium plant, commonly
Clinical Application
known as jimson weed, devil’s trumpet, or thornapple. These
METHYLXANTHINES AND PHOSPHODIESTERASE INHIBITORS
plants contain tropane alkaloids such as atropine, hyoscya-
Structure-Activity
mine, and scopolamine that function as anticholinergics and
Mechanism and Metabolism
relieve reflex-induced bronchoconstriction. Modern use of
Clinical Pharmacology
anticholinergics has evolved with the introduction of inhaled
Drug Interactions
ipratropium bromide in the 1980s.
Clinical Application
Methylxanthines were first recognized as having therapeu-
LEUKOTRIENE RECEPTOR INHIBITORS AND 5-LIPOXYGENASE
tic effects for asthma when coffee was recommended as early
INHIBITORS
as the 1860s and again in Osler’s 1914 text.1,2 By the 1940s,
Structure-Activity
intravenous aminophylline was recognized as effective for
Mechanism
asthma even though today the mechanisms for this beneficial
Clinical Pharmacology
effect are not clearly established. The likely mechanisms
Drug Interactions
involve elevations of cyclic adenosine monophosphate (cAMP)
Clinical Application
in airway smooth muscle due to phosphodiesterase inhibition,
MONOCLONAL ANTIBODIES
antagonism of adenosine receptors, and/or systemic release of
Structure-Activity
catecholamines. Nonetheless, the low therapeutic benefit to
Mechanism and Metabolism
toxicity ratio led to its elimination from first-line asthma
Clinical Pharmacology
therapies.
Clinical Application
The β-adrenoceptor agonists (see Chapters 13 and 22)
ANESTHETIC AGENTS AS BRONCHODILATORS
have been the mainstay of asthma maintenance and rescue
MUCOLYTIC THERAPIES
therapy since the development of metered dose inhalers in the
Structure-Activity
1950s. However, in 1910, Melland described dramatic relief
Mechanism and Metabolism
of acute asthmatic symptoms by subcutaneous administration
Clinical Pharmacology
of epinephrine.3 Inhaled epinephrine and isoproterenol were
Clinical Application
the initial therapeutics directed at β2 adrenoceptors, but due
EMERGING DEVELOPMENTS
to increased asthma death rates, agents more selective for the
Smoking
β2 adrenoceptor were introduced in the 1960s.4,5
Novel Therapeutic Approaches
By the 1970s, it was recognized that systemic steroids dra-
matically improve asthma maintenance therapy. But the

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 Chapter 26  Pulmonary Pharmacology

devastating complications of long-term systemic steroid use

Table 26-1.  β2-Adrenoceptor Agonists and Anticholinergic
led to the search for alternative therapies in mild asthmatics Drugs Used for Treatment of Bronchospasm
and alternative routes of delivery of steroids for severe asth-
matics. With the development of inhaled steroids, combina- FORMULATION DELIVERY METHOD
tion inhalers that combine selective β2-adrenoceptor agonists
with steroids became the mainstay of asthma therapy and Short-acting Inhaled β2-adrenoceptor Agonists
Albuterol Generic Nebulization
ultimately culminated in the combination of long-acting β2- Proair HFA MDI
adrenoceptor agonists (LABAs) with steroids. However, by Proventil HFA MDI
the early 2000s it was recognized that LABAs alone are associ- Ventolin HFA MDI
ated with increased asthma deaths. In 2009 this led to a Levalbuterol Xopenex MDI and Nebulization
Metaproterenol Generic Nebulization
warning from the U.S. Food and Drug Administration (FDA)
Pirbuterol Maxair MDI
that LABAs should not be used alone in the treatment of
asthma, but should be used in combination with inhaled ste- Short-acting Inhaled β2-adrenoceptor Agonists-anticholinergic
Combinations
roids. Studies continue to examine whether LABAs added to Albuterol + ipratropium Generic Nebulization
inhaled steroids are indeed superior to inhaled steroids alone, bromide Duoneb Nebulization
and whether the continued use of LABAs is warranted given Combivent MDI
safety concerns.6 Long-acting Inhaled β2-adrenoceptor Agonists (LABA)
Formoterol Foradil Aerolizer DPI
Perforomist Nebulization
Salmeterol Serevent Diskus DPI
β2-ADRENOCEPTOR AGONISTS Arfomoterol Brovana Nebulization
LABA-corticosteroid Combinations
Structure-Activity Salmeterol/fluticasone Advair Diskus DPI
Advair HFA MDI
All short acting β2-adrenoceptor agonists (Table 26-1) are Formoterol/mometasone Dulera MDI
small molecules with a molecular structure very similar to the Formoterol/budesonide Symbicort MDI
endogenous nonselective agonist epinephrine (Figure 26-1).
Short-acting Oral β2-adrenoceptor Agonists
The LABAs salmeterol and formoterol have modified long Albuterol Generic Oral
side chains with additional aromatic moieties to increase lipo- VoSpire ER Oral
philicity, which prolongs their duration at the site of action. Metaproterenol Generic Oral
Terbutaline Generic Oral
Inhaled Anticholinergics
Mechanism and Metabolism Ipratropium bromide Generic Nebulization
Among the hundreds of types of G protein–coupled receptors Atrovent HFA MDI
Tiotropium bromide Spiriva DPI
(GPCRs), the biochemical understanding of β-adrenoceptor
ligand binding, G protein interactions, and mechanisms of DPI, Dry powder inhaler; HFA, hydrofluoroalkane propellant; MDI, metered
receptor phosphorylation, desensitization, and internalization dose inhaler.

have served as the prototypical model for GPCR function.

The effectiveness of β2-adrenoceptors in asthma and COPD
results from their combined effect at reducing inflammatory
cell activation and directly relaxing airway smooth muscle.
The potency of β2-adrenoceptors as bronchodilators is largely
due to the multiple signaling mechanisms activated within
airway smooth muscle cells that all favor smooth muscle relax-
ation. Classically, β2-adrenoceptors couple the Gs stimulatory
G protein that activates membrane-associated adenylyl cyclase
to synthesize the second messenger cAMP. cAMP activates a
number of targets, including protein kinase A, that ultimately
result in the opening of Ca2+-activated K+ channels and sub-
sequent plasma membrane hyperpolarization, decreased
intracellular entry of Ca2+, and a decrease in the sensitivity of
the contractile proteins to Ca2+.
The long-lasting effects of LABAs, such as salmeterol and
formoterol are thought to result from binding to two sites
within the β2-adrenoceptor: the classic ligand binding site and
an exo-site on the receptor to which the hydrophobic tail binds
irreversibly.7 A second mechanism proposed to contribute to
the prolonged duration of drug effect is high lipophilicity that
allows the LABAs to dissolve within the lipid bilayer of the
airway smooth muscle cell and serve as an agonist depot.8
The majority (80%-100%) of albuterol is excreted in the
urine; its primary metabolic route is sulfate conjugation by
sulfotransferase 1A3. Salmeterol is extensively metabolized to
α-hydroxysalmeterol (aliphatic oxidation) by CYP 3A4 with
25% eliminated in the urine and the majority in the feces.
The xinafoate moiety of salmeterol xinafoate has no pharma-
cologic activity and is highly protein bound (>99%) with an
elimination half-life of 11 days. Formoterol is metabolized by
glucuronidation and O-demethylation by CYP 2D6 and CYP
2C. About 60% of oral or intravenous formoterol is excreted
in the urine and the remainder in the feces.
Clinical Pharmacology
PHARMACOKINETICS, PHARMACODYNAMICS, AND
THERAPEUTIC EFFECTS
Inhaled β2-adrenoceptor agonists are rapidly absorbed
through the respiratory epithelium, reaching the airway
smooth muscle within a few minutes. The therapeutic effect
of inhaled β2 agonists depends on local tissue concentrations
that are not reflected in plasma drug concentrations.9 Regard-
less of the delivery device used, only about 10% of the inhaled
dose actually reaches the peripheral airways to mediate
bronchodilation.10 The mean time for a 15% increase in
forced expiratory volume in 1 second (FEV1) was 6 minutes
following two albuterol inhalations with a peak effect occur-
ring at 55 minutes and a mean duration of effect of 2.6 hours.11
A comparison of the racemic formulation to the levo (R-)

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Section III  CARDIOVASCULAR AND PULMONARY SYSTEMS

β-Agonists H
H N
O

H
H N H
H H N
O
O O
O
H H
H H N H
Epinephrine H N
O O
O O O O
H H H
Isoproterenol
O Metaproterenol
H O
H
O
H O
H
Albuterol
Levalbuterol
H N
H H
H N
O O H
O
H
N H
N H
O O
O O H H
O O
H O
Pirbuterol H H H
H H Terbutaline
N
H N
H
O

O
H
O
O Formoterol
H
Salmeterol

Anticholinergics

N+ H
N+ H
O S
S
H
O O O
H O
H
O O H

Tiotropium

Ipratropium
Figure 26-1  Structures of β-receptor agonists and anticholinergic drugs used as bronchodilators.

enantiomer of albuterol given by nebulization to healthy vol-
unteers demonstrated a shorter time to maximum plasma
concentrations for the R-enantiomer (0.2 hour for R-, 0.3
hour for RS-) but a longer half-life (1.5 hours for RS-, 3.4
hours for R-).12 Limited pharmacokinetic data are available
for salmeterol because plasma concentrations often cannot
be detected even 30 minutes after a therapeutic dose of
50 µg. Salmeterol-induced airway relaxation is slow in onset,
prolonged in duration, and resistant to washout. After inhala-
tion of 400 µg of salmeterol, plasma concentrations of 0.2 and
2 µg/L were achieved at 5 and 15 minutes in healthy volun-
teers.13 In a separate study, a second peak plasma concentra-
tion occurred 45 to 90 minutes after inhalation, likely
reflecting gastrointestinal absorption of swallowed drug.14
LABAs can require up to 30 minutes to first achieve broncho-
dilator effects with a duration of 12 hours.

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ADVERSE EFFECTS
The β agonists can produce dose-related cardiovascular effects
(arrhythmias, tachycardia), hypokalemia, and elevations of
blood glucose. Acute adverse effects are more common with
oral than inhaled β2 agonists, and most commonly include
tachycardia, nervousness, irritability, and tremor. Changes in
plasma concentrations of K+ and glucose are seen at doses far
exceeding those used clinically.15 Paradoxical bronchospasm
has been reported with β agonists. An initial concern regard-
ing an increased death rate in asthmatics using salmeterol was
raised in 1993 when 12 of 16,787 patients using salmeterol
died, but this outcome was attributed to the severity of the
patients’ illnesses at the time of study entry.16 The Salmeterol
Multicenter Asthma study Research Trial (SMART), con-
ducted at more than 6000 sites and enrolling more than
26,000 patients, was stopped after an interim data analysis
revealed a small but significant increase in respiratory-related
morbidity and mortality.16 A meta-analysis of 19 trials involv-
ing more than 33,000 patients also revealed an increased risk
of hospitalization for asthma exacerbations, life-threatening
asthma attack, or asthma-related death.17 Although the mech-
anism for these increased risks are unknown, speculations
include the lack of anti-inflammatory effect, downregulation
of β2 adrenoceptors, or incorrect use of these LABAs as rescue
inhalers. These findings led to a “black box” by the FDA
warning that LABAs should not be used as monotherapy and
should only be used in patients in whom asthma symptoms
are not adequately controlled by low- to medium-dose inhaled
steroids or whose disease severity warrants two maintenance
therapies. Subsequently the FDA initiated a clinical trial pro-
tocol in cooperation with academic experts and manufacturers
of LABAs that consists of five clinical trials, four in adults and
one in children. The trials will be multinational, randomized,
and double-blind, occurring from 2011 to 2017 and recruiting
11,700 adults.6
Drug Interactions
The β agonists can potentiate the hypokalemic effect of
non–potassium-sparing diuretics. Serum levels of digoxin
are reduced after the oral or intravenous administration of
albuterol. The vascular effects of β agonists can be exacer-
bated by patients currently or recently taking monoamine
oxidase inhibitors or tricyclic antidepressants. An increased
risk of cardiovascular side effects can occur when salmeterol
is used along with strong cytochrome P450 3A4 (CYP 3A4)
inhibitors.
Clinical Application
COMMON APPLICATIONS
The use of long-acting β2 agonists in combination with
inhaled steroids is an option for patients whose bronchospasm
is not adequately controlled using monotherapy with low to
medium doses of inhaled corticosteroids as recommended by
the Global Initiative for Asthma (GINA) and an expert report
from the U.S. National Institutes of Health.18,19 Conversely,
the use of inhaled LABAs without steroids is not approved by
the FDA due to an increased rate of asthma deaths with this
therapy. Short-acting β agonists are recommended as rescue
therapy for breakthrough episodes of bronchospasm and the
frequency of use of rescue therapy is often used as an indicator
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Chapter 26  Pulmonary Pharmacology
of the adequacy of asthma maintenance therapy. Inhaled
short-acting β agonists can be given to treat active wheezing
in the preoperative or intraoperative period. They can also be
administered prophylactically in patients at risk for broncho-
spasm, especially in those patients in whom intubation of the
trachea is planned.
RATIONALE FOR DRUG SELECTION AND ADMINISTRATION
The anesthesiologist most commonly administers short-
acting β2-adrenoceptor agonists (e.g., albuterol) by inhalation
via nebulization or metered dose inhalers either preopera-
tively or intraoperatively. Either modality can be connected
to the inspiratory circuit of the anesthesia machine, but effec-
tive drug delivery to the airway smooth muscle is variable.
This is affected by timing of drug administration relative to
inspiration and the volume of dead space (endotracheal tube
dimensions and anatomic dead space of the upper trachea/
bronchi). Many studies have addressed the efficacy of deliver-
ing inhaled β2-agonists in mechanically ventilated patients.
Nebulization is more effective than metered dose inhalers.20
A location 15 cm upstream from the endotracheal tube on the
inspiratory side of an anesthesia circuit was optimal in an in
vitro model.21 The mode of mechanical ventilation and the
humidity of the circuit are also important factors in delivery;
a dry circuit and spontaneous breaths under continuous posi-
tive airway pressure (CPAP) enhance delivery compared to
continuous mandatory volume, assist control, or pressure
control ventilator settings.22 It is also possible to administer
selective β2-adrenoceptor agonists parenterally (e.g., terbuta-
line). Emergency treatment of bronchospasm in the emer-
gency department utilizes inhaled short-acting β2 agonists and
systemic corticosteroids.23 Rescue therapy from intractable
bronchospasm can require intravenous epinephrine, but sys-
temic administration of these therapies is associated with sig-
nificant cardiovascular effects.
The propellants in most inhalers were chlorofluorocarbons
(CFCs) until an international agreement entitled “The Mon-
treal Protocol on Substances That Deplete the Ozone Layer”
led to the banning of this propellant and its replacement with
hydrofluoroalkanes (HFAs). Substantial new technology was
involved to make HFAs suitable for metered-dose inhalers.24
This provided the opportunity to improve the performance
of inhaled β2-agonist formulations and enhanced the ability
of inhaled steroids to reach smaller peripheral airways.25
Ultra-long acting β2-adrenoceptor agonists (olodaterol and
sibenadet) that achieve effective bronchodilation for 24 hours
are in development.26,27 Clinical trials continue to determine
whether the risk of LABAs are mitigated by the concurrent
use of inhaled corticosteroids.6
ANTICHOLINERGICS
Structure-Activity
Inhaled anticholinergic drugs (Table 26-1) are a mainstay in
the long-term management of COPD and are a component
of some asthma regimens.28 Ipratropium bromide (nebuliza-
tion or metered dose inhaler) and tiotropium bromide (dry
powder inhaler) (Figure 26-1) antagonize the effects of
acetylcholine released from airway parasympathetic nerves
on M3 muscarinic receptors on airway smooth muscle
(Figure 26-2).
461
Section III  CARDIOVASCULAR AND PULMONARY SYSTEMS

Arachidonic acid

Zileuton Inflammatory
cell
Leukotrienes Cytokines Histamine
Post-ganglionic
parasympathetic nerve
β2-Agonists Steroids
ACh
ACh
Leukotrienes Cytokines Histamine ACh
Ipratroprium
CysLT1 antagonists Tiotropium

β2-Adrenoreceptor CysLT1 receptor Histamine receptor M3 muscarinic receptor

γ γ γ γ
α α α α
β β β β
GTP GTP GTP GTP

↓ Phosphorylation of
myosin light chain ↑ [Ca2+]i Airway smooth
muscle cell

Relaxation Contraction
Figure 26-2  Sites of action of major classes of pulmonary drugs on inflammatory and airway smooth muscle cells. Inflammatory cells in the airway release
a wide variety of mediators that affect signal transduction of several types of cells in the airway (epithelium, smooth muscle, and nerves). 5-Lipoxygenase
inhibitors (e.g., zileuton) block the synthesis of leukotrienes while CysLT1 antagonists block the effect of leukotrienes on airway cells. Steroids nonspecifi-
cally block activation of many inflammatory cells in the airway responsible for cytokine production that alter signaling pathways of airway cells favoring
edema, mucus secretion, and airway smooth muscle contraction. β2-adrenoceptor agonists both directly relax airway smooth muscle and block activation of
inflammatory cells. Muscarinic receptor antagonists block M3 muscarinic receptors on airway smooth muscle as well as muscarinic receptors on epithelium
and nerves. The determinants of airway smooth muscle contraction are an increase in intracellular Ca2+ concentration ([Ca2+]i) as well as the sensitivity of
the contractile proteins to a given concentration of Ca2+ (dictated by phosphorylation of the myosin light chain [MLC20] and termed calcium
sensitization).

at 3 hours, and a duration of 24 hours. Only 7% of inhaled

Mechanism and Metabolism
Parasympathetic nerves traveling within the vagus nerve
release acetylcholine to act upon M2 and M3 muscarinic recep-
tors on airway smooth muscle. The nerve terminals also
express autoinhibitory M2 muscarinic receptors that respond
to released acetylcholine to inhibit further neurotransmitter
release. The M3 muscarinic receptor on airway smooth muscle
is a G protein–coupled receptor (Gq) that activates phospho-
lipase C to generate diacylglycerol and inositol phosphates
from membrane phospholipids. Diacylglycerol activates a
number of targets, primarily protein kinase C isoforms. Ino-
sitol phosphates elevate intracellular Ca2+ primarily via release
from the sarcoplasmic reticulum. This entire signaling cascade
is blocked upstream by ipratropium or tiotropium’s antago-
nism of cell surface airway smooth muscle muscarinic recep-
tors (see Figure 26-1).
Inhaled ipratropium is metabolized to eight metabolites
that have little to no anticholinergic activity, and are excreted
in approximately equal proportions in feces and urine.
Clinical Pharmacology
PHARMACOKINETICS, PHARMACODYNAMICS, AND
THERAPEUTIC EFFECTS
Inhaled ipratropium has an initial onset of 15 minutes with a
peak effect at 1 to 2 hours and a duration of 3 to 6 hours.
Tiotropium bromide has an onset of 30 minutes, a peak effect
ipratropium is bioavailable; the elimination half-life is 3.5
hours by all routes of administration.
Inhaled anticholinergics are indicated for the relief of
bronchoconstriction in COPD and asthma by blockade of
M3 muscarinic receptor on airway smooth muscle. They
can be used both prophylactically and as maintenance
therapy. Their slower onset of action compared to inhaled β2
agonists make them unacceptable as rescue therapy for acute
exacerbations.
ADVERSE EFFECTS
Anticholinergics inhibit mucosal secretions and thus dry
mouth is common (antisialagogue effect). As with β agonists,
paradoxical bronchospasm has been reported with ipratro-
pium. COPD patients using ipratropium bromide have an
increased risk of adverse cardiac events that occur less com-
monly with tiotropium.29-31 Inhaled anticholinergics increase
the risk of acute urinary retention over fourfold in men with
benign prostatic hypertrophy due to effects on parasympa-
thetic innervation to the detrusor muscles of the bladder.
Inhaled ipratropium can also worsen acute narrow angle glau-
coma due to its parasympathetic effects.
Clinical Application
Anticholinergics have been used to treat obstructive airway
disease since the early use of deadly nightshade genus

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 Chapter 26  Pulmonary Pharmacology

Parasympathetic efferents Protection by volatile

release acetylcholine, Table 26-2.  Inhaled and Systemic Steroids for Treatment
anesthetics, β2-agonists,
causing contraction of anticholinergics of Bronchospasm
airway smooth muscle
FORMULATION DELIVERY METHOD

Inhaled
Ciclesonide Alvesco HFA MDI
Mometasone Asmanes Twisthaler DPI
Budesonide Generic Nebulization
Pulmicort Flexhaler DPI
Pulmicort Respules Nebulization
AVPN Fluticasone Flovent Diskus DPI
Flovent HFA MDI
Beclomethasone Qvar HFA MDI
nTS Systemic
Methylprednisolone Generic Oral
Protection by Medrol Oral
central nervous Methylprednisolone Generic Parenteral
system depression Irritant Protection by sodium succinate Solu-Medrol Parenteral
by anesthetics afferent nerves local anesthetics Prednisolone Generic Oral
Figure 26-3  Sites of action of major classes of anesthetics on reflex-induced Orapred Oral
bronchoconstriction. Irritation of the upper airway by foreign bodies, includ- Pediapred Oral
ing endotracheal tubes or suction catheters initiates an afferent irritant Prelone Oral
reflex arc resulting in the release of acetylcholine from parasympathetic Veripred 20 Oral
nerves onto muscarinic receptors on airway smooth muscle resulting in Prednisone Generic Oral
bronchoconstriction. Anesthetics and other agents work at different levels Sterapred Oral
of this irritant reflex to block bronchoconstriction. Local anesthetics can Hydrocortisone Solu-Cortef Parenteral
attenuate the initial afferent stimulus while multiple classes of anesthetics sodium succinate
(general, intravenous, local) can attenuate the glutamatergic and GABAergic
relay at the nucleus of the solitary tract (nTS) to the airway vagal pregan- DPI, Dry powder inhaler; HFA, hydrofluoroalkane propellant; MDI, metered
dose inhaler.
glionic neurons (AVPN). Direct effects of volatile anesthetics, β2-adrenoceptor
agonists, or muscarinic receptor antagonists attenuate the effects of ace-
tylcholine on airway smooth muscle.

inhaled anticholinergic drug, aclidinium, demonstrates bron-

(Atropa) plants and asthma cigarettes.32 Although inhaled β2-
adrenoceptor agonists with steroids are often the initial
therapy for the bronchoconstrictive diseases asthma and
COPD, there is evidence of equivalence or even superiority
of inhaled anticholinergics in the treatment of COPD.33 In
the perioperative setting, the choice of anticholinergic is
mechanistically sound because bronchoconstriction following
airway irritation involves parasympathetic nerve release of
acetylcholine onto M3 muscarinic receptors on airway smooth
muscle.
Instrumentation of the upper airway with an endotracheal
tube or suction catheter is a potent stimulus for reflex-induced
bronchoconstriction (see Figure 26-3). This reflex originates
in the airway wall where irritant nerve fibers travel in the vagal
nerve complex to the nucleus of the solitary tract (nTS) which
synapses via GABAA and glutamate receptors on the airway-
related vagal preganglionic neurons (AVPNs).34 The efferent
outflow from this brainstem nucleus travels back down the
vagus to release acetylcholine onto M3 muscarinic receptors
on airway smooth muscle. The M3 muscarinic receptor via
Gq-coupling increases intracellular Ca2+, resulting in smooth
muscle contraction and airway narrowing. Thus anticholiner-
gic blockade of M3 muscarinic receptors are an ideal target to
attenuate reflex-induced bronchoconstriction.
Two inhaled antimuscarinics are available: the relatively
quick onset and short duration ipratropium bromide and the
longer duration tiotropium bromide.35 Ipratropium bromide
is available in either nebulized or metered dose inhaler for-
mulations making this an ideal preoperative or intraoperative
treatment for the anesthesiologist faced with a patient with
bronchoconstriction induced by airway irritation. A new
chodilation for a similar duration as tiotropium with preclini-
cal evidence of a reduced risk of anticholinergic heart rate
effects.36-38
INHALED STEROIDS
Structure-Activity
The specific structures of the inhaled corticosteroids on a
steroidal backbone are illustrated in Figure 26-4. Their for-
mulations and delivery methods are summarized in Table
26-2, along with formulations of systemic steroids that are
used in moderate to severe cases, particularly during initial
presentation and acute exacerbations. For a more detailed
discussion of systemic corticosteroid pharmacology, see
Chapter 31.
Mechanism and Metabolism
Corticosteroids interact with intracellular steroid receptors
that translocate to the nucleus and interact with transcription
factor complexes to regulate inflammatory protein synthesis.
The stimulation of gene transcription (transactivation) cor-
relates with negative side effects of corticosteroids, while
repression of transcription factors (e.g., NF-κB and AP-1) is
responsible for antiinflammatory effects.39 Although steroids
affect the inflammatory response of lymphocytes, eosinophils,
neutrophils, macrophages, monocytes, mast cells, and baso-
phils, particular attention has focused on the role of a subset
of interleukin (IL), producing T lymphocytes in asthma. CD+
Th2 cells that produce IL-4, IL-5, and IL-13 are particularly

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Section III  CARDIOVASCULAR AND PULMONARY SYSTEMS

F
O H
H O
O S
H
O O O
O O H H
F O O Cl
H
H O
H Cl
H O
H H H
O H
H
F O
Fluticasone Budesonide Mometasone

O H
O
H O
O H O
O
O O O
H
H O Cl
H
H H H
H
O O

Ciclesonide Beclomethasone
Figure 26-4  Structures of inhaled corticosteroids.

important in orchestrating the complex inflammatory events
in asthmatic lungs and are inhibited by inhaled steroids. Mast
cell and basophil numbers are increased in asthma, and
release of mediators (histamine, leukotrienes) in asthmatic
airways is enhanced. Although inhaled steroids also suppress
these cells, more specific therapy with oral leukotriene antag-
onists has allowed reduction in inhaled steroid use in some
patients.
Corticosteroids exhibit high first-pass metabolism by the
liver by CYP 3A4.
Clinical Pharmacology
PHARMACOKINETICS, PHARMACODYNAMICS, AND
THERAPEUTIC EFFECTS
Beclomethasone dipropionate is a prodrug that is rapidly acti-
vated by hydrolysis to the active monoester 17-beclomethasone
monopropionate, which has an affinity for the glucocorticoid
receptor that is 25 times that of the parent compound. Cicle-
sonide is an inactive prodrug that is converted to the active
metabolite desisobutyrylciclesonide in the lung. Forty percent
to 90% of an inhaled corticosteroid is swallowed and there-
fore available for systemic absorption (and potential systemic
side effects). Thus a low oral bioavailability of inhaled corti-
costeroids is desirable; it ranges from 1% for fluticasone pro-
pionate to 26% for 17-beclomethasone monopropionate.
In contrast to oral absorption, most of the drug deposited
in the lung will be absorbed systemically and is not subjected
to first-pass hepatic metabolism. Deposition and thus absorp-
tion from the lung is more a function of the efficiency of the
delivery device than the properties of the drug itself. Flutica-
sone has only 1% oral bioavailability due to first pass metabo-
lism but when delivered to the lung by dry powder or metered
dose inhalers total systemic bioavailability is 17% and 25%,
respectively.40 The transition from CFC- to HFA-powered
metered dose inhalers has resulted in unanticipated improve-
ment in the delivery of smaller particles deposited deeper in
the lung with less oropharyngeal deposition and thus less
systemic absorption. Most of the inhaled corticosteroids
(approximately 70%) are bound to plasma proteins, and
exhibit half-lives of 3 to 8 hours due to high extraction and
metabolism by the liver.
The efficacy of inhaled corticosteroids in asthma has been
shown in many studies usually with comparable benefits
to systemic steroids with fewer side effects. Asthma patients
discharged from the emergency department with 40-mg
oral prednisone daily versus 600 µg inhaled budesonide four
times a day exhibited similar rates of asthma relapse and
similar improvements in FEV1, asthma symptoms, and peak
expiratory flow.41 Personalized medicine may be able to
predict respondents to specific therapies, including inhaled
corticosteroids.42
ADVERSE EFFECTS
Many studies report no or minimal side effects on adrenal
function, bone density or subcapsular cataracts, while some
studies contend a dose-dependent effect of all inhaled steroids
on these parameters.43,44 A year-long study in adults receiving
inhaled fluticasone or beclomethasone and a 12-week study
in children receiving inhaled fluticasone showed no effect on
bone density.45,46
Drug Interactions
Numerous reports exist of clinically significant Cushing’s
syndrome and adrenal insufficiency in both children and
adults secondary to the combination of fluticasone propio-
nate or budesonide with a CYP 3A4 inhibitor (e.g.,

464
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ketoconazole, itraconazole, ritonavir).47 Most patients were
on high doses of inhaled corticosteroids. Plasma concentra-
tions of mometasone furoate and a metabolite of ciclesonide
increased with ketoconazole administration.
Clinical Application
Inhaled corticosteroids are commonly recommended as initial
therapy for asthma. The introduction of inhaled steroids in
the 1970s revolutionized therapy for bronchospastic diseases
by allowing the delivery of steroids directly to the airway
with a reduction in the systemic toxicity of chronic oral
steroid ingestion. Although the precise mechanisms of asthma
remain undefined, a significant component of asthma involves
a complex interplay between inflammatory and structural
cells of the airway on which steroids are efficacious. Inhaled
glucocorticoids are the most effective anti-inflammatory
medications for the treatment of asthma. Inhaled corticoste-
roids reduce the symptoms, frequency of exacerbations,
airway hyperresponsiveness, airway inflammation, and asthma
mortality.48-50 A review of clinical studies suggests that inhaled
fluticasone is more efficacious than inhaled budesonide as a
monotherapy, and that either a combination of fluticasone/
salmeterol or budesonide/formoterol was more effective than
corresponding monotherapies with inhaled corticosteroids or
inhaled long-acting β2 agonists.51 However, an ongoing con-
troversy regarding the uncertain risk/benefit of adding inhaled
long-acting β2 agonists to inhaled glucocorticoids for asthma
therapy led to an unprecedented series of clinical trials
coordinated between the FDA and drug manufacturers of
long-acting β2 agonists to be completed in 2017.6 Combina-
tion inhaled corticosteroids and long-acting β2 agonists are
also useful in COPD.52,53
METHYLXANTHINES AND PHOSPHODIESTERASE
INHIBITORS
Structure-Activity
Theophylline is a close structural analogue of caffeine on
a purine backbone. Aminophylline is two theophylline
molecules with a 1,2 ethanediamine moiety. Roflumilast is a
halide-modified benzamide molecule synthesized from
3-(cyclopropylmethoxy)-4-hydroxybenzaldehyde. The X-ray
crystal structure of roflumilast docked within the catalytic
sites of phosphodiesterase 4 has been determined, showing
with unprecedented mechanistic molecular detail the target
site of a medication newly added to clinical medicine.54
Mechanism and Metabolism
Methylxanthines have anti-inflammatory and bronchodilating
effects. Although these drugs are phosphodiesterase (PDE)
inhibitors in vitro, this is not likely to occur at the therapeutic
levels achieved.55 The methylxanthines release catecholamines
from the adrenal gland, which might contribute to their ben-
eficial activity in asthma, and also function as nonselective
antagonists of four known subtypes of adenosine receptors
(A1, A2a, A2b, and A3).56,57 Additional mechanisms that have
been proposed for the beneficial effects of methylxanthines
in bronchoconstrictive diseases include modulation of
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Chapter 26  Pulmonary Pharmacology
intracellular Ca2+ flux through ryanodine receptors, modula-
tion of histone deacetylase activity, and increased peroxisome-
proliferator-activated receptor γ expression.58
A new class of oral medication was introduced in 2011 for
severe COPD. Roflumilast, a type 4 PDE inhibitor, inhibits
degradation of cAMP in cells of the airway (airway smooth
muscle, epithelium, and inflammatory cells) and elsewhere
that express the type 4 PDE isoenzyme. Roflumilast and its
active metabolite N-oxide roflumilast are highly selective
inhibitors of PDE4 (which in turn is highly selective for
cAMP) and are inactive against PDE isoforms 1, 2, 3, 5, and
7. The selectivity of roflumilast is distinct from that of the
PDE inhibitors used in heart failure (milrinone, inamrinone,
and cilostazol) that target cAMP-selective PDE3 and from the
inhibitors used for erectile dysfunction (sildenafil and tadala-
fil) that target the cGMP-selective PDE5 isoforms. The
selectivity of roflumilast for type 4 phosphodiesterase is sug-
gested to produce fewer side effects than the nonselective
(PDE types 3, 4, and 5) inhibition by theophylline.
Theophylline is extensively (>70%) metabolized in the
liver by N-demethylation by CYP 1A2 primarily to
3-methylxanthine. Theophylline is also 8-hydroxylated to 1,3
dimethyluric acid, which is subsequently N-demethylated to
1-methyluric acid. In neonates it is directly 7-methylated to
caffeine. About 10% is excreted in the urine unchanged.
Many drug classes affect its metabolism and thus serum con-
centrations (see later).
Roflumilast is metabolized in liver by CYP 3A4 and 1A2
to roflumilast N-oxide (also a potent PDE4 inhibitor) and
then O-deacylated and glucuronidated for urinary excretion.
Clinical Pharmacology
PHARMACOKINETICS, PHARMACODYNAMICS, AND
THERAPEUTIC EFFECTS
Theophylline is 40% protein bound with a volume of distri-
bution of 0.5 L/kg. Oral theophylline is well absorbed from
the gastrointestinal tract, resulting in 90% to 100% bioavail-
ability, with peak serum levels occurring within 1 to 2 hours
of ingestion. Sustained release formulations are available due
to the relatively short half-life of 8 hours in healthy adults.
The elimination half-life varies widely: from 30 hours in pre-
mature neonates to 3.5 hours in children, 8 hours in non-
smoking adults, 5 hours in smoking adults, and 24 hours in
those with NYHA class III-IV congestive heart failure. The
intravenous dose required to achieve a therapeutic concentra-
tion of 10 to 20 µg/mL varies fourfold in an otherwise healthy
adult population. For rapid treatment of acute bronchospasm,
a loading dose followed by maintenance infusion is frequently
employed. In children, the rate of clearance of theophylline
is 40% greater than in adults.
Following oral administration of roflumilast, the time to
peak plasma concentrations is 1 hour, with nearly 99% being
protein bound. With daily dosing, steady-state levels are
achieved in 4 days with a mean plasma half-life of 17 hours.
The role of methylxanthines as anti-inflammatory and the
role of bronchodilators in asthma and COPD are well estab-
lished. However, methylxanthines are also respiratory stimu-
lants and have been evaluated in central apnea, obstructive
sleep apnea, and periodic breathing (Cheyne-Stokes respira-
tion).59 Clinical trials have shown a benefit in central sleep
apnea but not obstructive sleep apnea.60 In animal studies,
465
Section III  CARDIOVASCULAR AND PULMONARY SYSTEMS
roflumilast did not protect against leukotriene D4 or
serotonin-induced bronchoconstriction, and there is no evi-
dence that roflumilast is bronchodilatory in humans with
COPD. This suggests that its primary therapeutic benefit is
due to its anti-inflammatory effects via PDE4 inhibition in
airway inflammatory cells.
ADVERSE EFFECTS
Adverse reactions are uncommon at serum theophylline levels
below 20 µg/mL. Adverse reactions at serum concentrations
between 20 and 25 µg/mL include nausea, vomiting, diarrhea,
headache, and insomnia. Symptoms of overdosage at concen-
trations over 30 µg/mL include seizures, tachyarrhythmias,
congestive heart failure, tachypnea, hematemesis, and reflex
hyperexcitability. Methylxanthine use during anesthesia was
also problematic due to the release of catecholamines in com-
bination with volatile anesthetics that sensitized the myocar-
dium to their arrhythmogenic effects (e.g., halothane).61
Moreover, aminophylline does not add additional bronchodi-
latory effect to the bronchodilation achieved by maintenance
levels of volatile anesthetics.62
Drug Interactions
Many medications can increase the serum concentrations of
theophylline enhancing their potential for toxicity including
cimetidine, mexiletine, ticlopidine, propranolol, ciprofloxa-
cin, alcohol, allopurinol, disulfiram, erythromycin, and estro-
gens. Cigarette and marijuana smoking and medications
that induce liver metabolism (e.g., carbamazepine, phenytoin,
thiabendazole) reduce theophylline serum concentrations.
SPECIAL POPULATIONS
Theophylline should be used with caution in patients with
active peptic ulcer disease, seizure disorders, cardiac arrhyth-
mias, compromised cardiac function, angina, hypertension,
hyperthyroidism, or liver disease.
Clinical Application
Theophylline is among the most widely prescribed medica-
tion for the treatment of asthma worldwide, but is recom-
mended as second- or third-line therapy behind inhaled
corticosteroids and inhaled β-agonists due to theophylline’s
potential for systemic toxicity. By the 1980s, several studies
reported that inhaled β2-agonists were superior to aminophyl-
line or theophylline in acute asthmatic exacerbations.63 Ami-
nophylline and theophylline formulations are less commonly
used as maintenance therapy in the United States due to their
low therapeutic index.
LEUKOTRIENE RECEPTOR INHIBITORS AND
5-LIPOXYGENASE INHIBITORS
Structure-Activity
Leukotrienes are synthesized from arachidonic acid by
5-lipoxygnase. They are so named due to their source from
leukocytes and the presence of three conjugated double bonds
in their structure. The discovery that the slow reacting sub-
stance of anaphylaxis (SRS-A) was a mixture of leukotrienes
466
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Table 26-3.  Targeted Anti-inflammatory Therapies
for Bronchospasm
FORMULATION MODE OF ACTION
Leukotriene Receptor Antagonists
Zafirukast Accolate Leukotriene D4 and E4 receptor
antagonist
Montelukast Singulair Cysteinyl leukotriene receptor
antagonist
5-Lipoxygenase Inhibitor
Zileuton Zyflo Inhibits leukotriene synthesis
Cell Release Inhibitors
Omalizumab Xolair Inhibits IgE binding to mast cells
and basophils
released from mast cells and basophils sparked the search for
antagonists of leukotriene receptors. Independent medicinal
chemistry strategies were employed to identify both of the
antagonists in clinical use (Table 26-3). Montelukast was
discovered by modifying a quinoline with leukotriene struc-
tural elements. Zafirlukast was based on a compound incor-
porating components from both FPL 55712 and the natural
leukotrienes.64
Mechanism
The cysteinyl leukotrienes LTC4, LTD4, LTE4 and LTB4 are
products of plasma membrane phospholipids that increase
smooth muscle contraction, microvascular permeability, and
airway mucus secretion. These leukotrienes mediate their
airway effects primarily through the CysLT1 receptor subtype,
which is widely expressed on cells including mast cells, mono-
cytes, macrophages, eosinophils, basophils, neutrophils, T
and B lymphocytes, airway smooth muscle cells, microvascu-
lar endothelial cells, bronchial fibroblasts, and pluripotent
hemopoietic stem cells.65,66 The enzyme 5-lipoxygenase con-
verts arachidonic acid to LTA4, an upstream precursor to the
active cysteinyl leukotrienes. This enzyme is inhibited by the
only 5-lipoxygenase inhibitor approved for asthma, zileuton.
Montelukast and zafirlukast are antagonists of the CysLT1
receptor that directly block the effect of LTC4, LTD4, and
LTE4 on this receptor.
Clinical Pharmacology
PHARMACOKINETICS, PHARMACODYNAMICS, METABOLISM
The leukotriene receptor antagonists montelukast and zafir-
lukast are rapidly absorbed after oral administration and are
more than 99% bound to albumin. They achieve peak plasma
concentrations within 3 to 5 hours and undergo extensive
metabolism by cytochrome P450 subtypes in the liver. Zileu-
ton causes an increase in liver enzymes in 2% of patients and
should be avoided in patients with active liver disease or per-
sistent elevation of liver enzymes.
Drug Interactions
Certain anticonvulsants (phenytoin, carbamazepine, oxcar-
bazepine, phenobarbital) and rifamycin antibiotics can
decrease plasma concentrations of montelukast. Coadminis-
tration of zafirlukast with warfarin increases prothrombin

times by 35%. Coadministration of zafirlukast with oral the-
ophylline reduces zafirlukast plasma concentrations by 30%,
and coadministration of zafirlukast with aspirin decreases zaf-
irlukast concentrations. Zileuton is a weak inhibitor of CYP
1A2 and has been shown to increase theophylline and pro-
pranolol concentrations. It can increase prothrombin times in
patients coadministered warfarin.
Clinical Application
Leukotriene receptor antagonists and 5-lipoxygenase inhibi-
tors are commonly used as adjuvant therapy in asthma.67-69
The potential for toxicity from this therapy appears less than
that of inhaled steroids, and leukotriene receptor antagonists
can allow a reduction in the amount of steroid use. They are
effective as additional therapy for acute asthma. An investiga-
tional intravenous formulation of montelukast has an onset
within 10 minutes and improves airway obstruction for at least
2 hours.70
MONOCLONAL ANTIBODIES
Structure-Activity
Omalizumab is a recombinant human IgG1κ monoclonal anti-
body (150 kDa) that selectively binds to human IgE and is
effective as an adjuvant therapy in adults with moderate to
severe asthma. This antibody binds to the constant region of
circulating IgE molecules preventing their binding to the
high (FceRI) and low (FceRII) affinity IgE receptors on mast
cells, basophils, B lymphocytes, dendritic cells, and macro-
phages, impairing mediator release from these cells. One IgE
molecule has two antigenic binding sites for omalizumab
and omalizumab in turn has two antigen binding sites, thus
IgE/anti-IgE complexes are formed with molecular masses
of 500 to 1000 kDa.
Mechanism and Metabolism
As an anti-IgE antibody, omalizumab binds to circulating
IgE molecules interrupting the allergic cascade. It is effective
at treating patients with allergic asthma that exhibit a high
concentration of IgE molecules. Neutralizing IgE molecules
prevents the activation of degranulation of many IgE-
presenting cells including mast cells and basophils and thus
prevents release of histamine, leukotrienes, and cytokines
involved in the inflammatory component of reactive airway
disease.
The IgE/anti-IgE small immune complexes do not pre-
cipitate in the kidney and are easily cleared by the liver reticu-
loendothelial system (RES) and endothelial cells. Intact IgG
is also excreted in the bile with serum elimination half-life of
26 days.
Clinical Pharmacology
PHARMACOKINETICS, PHARMACODYNAMICS, AND
THERAPEUTIC EFFECTS
Omalizumab is administered subcutaneously every 2 to 4
weeks based on serum IgE levels and body weight. Absorp-
tion is slow after subcutaneous injection with peak serum
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Chapter 26  Pulmonary Pharmacology
con­centrations achieved at 7 to 8 days with 62% bioavail-
ability. Serum free IgE levels are reduced within 1 hour of the
initial dose of omalizumab. In addition to a reduction in
serum free IgE levels, omalizumab reduces expression of high
affinity IgE receptors on inflammatory cells and reduces cir-
culating numbers of eosinophils. The beneficial effects of
omalizumab in severe persistent asthmatics include improve-
ments in respiratory systems and quality of life, a reduction
in emergency room visits, and reduction in steroid use and
rescue asthma medications.71-73
ADVERSE EFFECTS
Anaphylaxis has been reported in 0.2% of patients receiving
omalizumab occurring as early as the first dose and as
late as 1 year after the initiation of therapy. Although con-
cerns were raised about a small increase in malignant neo-
plasms and a case of lymphoma in early studies with
omalizumab, subsequent review by independent oncologists
reported no causal relationship between omalizumab and
cancer development.73 Fever, arthralgia, and rash sometimes
accompanied by lymphadenopathy occur in some patients 1
to 5 days after omalizumab injections. Parasitic infections are
more common in patients receiving omalizumab than in
controls.74
Clinical Application
Omalizumab is used as adjuvant therapy in severe persistent
asthmatics older than 6 years who have elevated serum IgE
levels and who demonstrate positive skin tests or in vitro
reactivity to a seasonal aeroallergen when symptoms are not
adequately controlled with an inhaled corticosteroid.
ANESTHETIC AGENTS AS BRONCHODILATORS
Most volatile anesthetics are potent bronchodilators yet the
mechanism by which this occurs is unknown.75 With the
exception of desflurane, volatile anesthetics dose-dependently
bronchodilate airways and protect against reflex-induced
bronchoconstriction during intubation in both asthmatics and
patients with COPD.76-78 The mechanisms of direct airway
smooth muscle relaxation by inhaled anesthetics include
reduction in Ca2+ sensitivity of contractile proteins and inter-
ruption of G protein coupling of procontractile receptor ago-
nists (e.g., acetylcholine).79,80
The intravenous anesthetics vary in their ability to blunt
bronchoconstriction induced by intubation. Historically, ket-
amine was the induction drug of choice for asthmatics due
to its release of catecholamines with their effect on airway
smooth muscle β2-adrenoceptors. In the mid-1990s it was
recognized that propofol is very protective against broncho-
constriction during intubation in both asthmatics and patients
with COPD compared to thiobarbiturates or etomidate.81,82
A direct clinical comparison between propofol and ketamine
for bronchoprotective effects has not been done. The mecha-
nism of bronchoprotection afforded by intravenous anesthet-
ics is incompletely understood but might include direct
interaction of anesthetics with GABAA receptors expressed on
airway smooth muscle.83 Intravenous, epidural, and inhaled
local anesthetics have all been shown to inhibit histamine-
induced bronchoconstriction.84-86
467
Section III  CARDIOVASCULAR AND PULMONARY SYSTEMS

Table 26-4.  Mucolytics, Surfactants, and α1 Proteinase Clinical Application

Inhibitors
Inhaled acetylcysteine (by nebulization or direct tracheal
FORMULATION MODE OF ACTION instillation) is indicated in patients with viscous, increased
or inspissated secretions with chronic COPD, tuberculosis,
Mucolytics primary amyloidosis of the lung, or cystic fibrosis. Dornase
Acetylcysteine Mucomyst Reduced viscosity of mucus by
cleavage of disulfide bonds alfa is effective in lowering the viscosity of pulmonary secre-
Dornase alfa Pulmozyme Reduced viscosity of mucus by tions with high DNA content from injured and dead leuko-
cleavage of leukocyte DNA cytes such as in cystic fibrosis. Twice daily use of dornase alfa
Surfactant Substitutes reduces the incidence of pulmonary infections requiring par-
Poractant alfa Curosurf Reduced surface tension in
enteral antibiotics by 29%.
alveolus
Calfactant Infasurf
Beractant Survanta
α1 proteinase Aralast Inhibit neutrophil elastase in
inhibitors Glassia α1-proteinase inhibitor genetic EMERGING DEVELOPMENTS
Prolastin-C deficiency, protecting protein
Zemaira components of alveolar wall Smoking
Although the topic is not traditionally a part of pulmonary
pharmacology, perioperative smoking cessation therapy is an
emerging part of anesthesia practice.91 As part of a multidis-
MUCOLYTIC THERAPIES
ciplinary team, anesthesiologists are increasingly participating
in individualized efforts to promote smoking cessation in
Structure-Activity
perioperative patients.92 Often regarded as the single most
Inhaled mucolytics allow direct deposition of drugs to reduce preventable cause of premature death in industrialized societ-
mucus viscosity in pulmonary diseases, primarily cystic fibro- ies, smoking is also a major underlying factor in excess
sis (Table 26-4). Acetylcysteine by inhalation serves as a sulf- postoperative morbidity and mortality.93 Studies suggest
hydryl donor to cleave disulfide bounds in mucus resulting that a coordinated smoking cessation program instituted peri-
in lower viscosity. Acetylcysteine is also used orally as an operatively when patients are motivated about personal health
antidote for acetaminophen overdose. Dornase alfa is a can be effective in helping smokers to quit the habit.94,95 Some
recombinant human deoxyribonuclease I enzyme produced in advocate that anesthesiologists should play a lead role in this
cultured Chinese hamster ovary cells. The 37 kDa native process.96,97 This mandates that anesthesiologists must be
human enzyme cleaves DNA from injured and dead leuko- conversant with drug and nondrug therapies applied to assist
cytes reducing the overall viscosity of pulmonary secretions. patients in smoking cessation. The anesthesiologist, as a peri-
operative physician, has the opportunity to participate in
interventions that have long-term impacts on pulmonary
Mechanism and Metabolism
health. The stress of the perioperative period has been rec-
Respiratory mucins contain disulfide bonds that contribute to ognized as a “teachable moment,” a time in the patient’s life
the structure of mature mucins and are the target of sulfhydryl when he or she may be most receptive to advice regarding
donors such as acetylcysteine. Tenacious airway secretions of smoking cessation.98
cystic fibrosis arise in part from dying and dead leukocytes
responding to airway infection and inflammation. The DNA
Novel Therapeutic Approaches
of these dying cells contributes to the viscosity of secretions
and is the substrate for dornase alfa degradation. It has long been recognized that clinical asthma is a mixture
Acetylcysteine is rapidly deacetylated or oxidized in vivo of disease phenotypes such that a variety of mechanisms can
to form cysteine or diacetylcystine, respectively. lead to airway hyperresponsiveness.99 Future pharmacologic
therapy will undoubtedly make use of better phenotypic and
genotypic characterization in individual patients. This may
Clinical Pharmacology
allow more directed therapy particularly in the area of anti-
PHARMACOKINETICS, PHARMACODYNAMICS, AND inflammatory therapies where nonspecific steroid approaches
THERAPEUTIC AND ADVERSE EFFECTS might be replaced by targeting specific immunomodulatory
Inhalation of dornase alfa in cystic fibrosis patients results in mediators such as elevated IgE (e.g., omalizumab) or specific
measurable DNAse activity in sputum within 15 minutes. interleukins (e.g., IL-13).100,101
Inhalation of 10 mg of dornase alfa three times a day for 6 A nonpharmacologic therapy directed at airway smooth
days did not raise serum DNAse levels above endogenous muscle hyperresponsiveness is bronchial thermoplasty. The
levels.87 Inhaled acetylcysteine has been associated with sto- belief is that eliminating airway smooth muscle from mid-
matitis, bronchoconstriction, nausea, vomiting, fever, rhinor- sized airways by heat destruction will improve asthma symp-
rhea, and drowsiness. Bronchoconstriction responds to toms. This invasive procedure, which requires repeated
bronchodilators but gas exchange can initially worsen due to bronchoscopies, resulted in some short-term pulmonary com-
thin secretions traveling to more distal airways.88,89 Thus ace- plications but long-term improvements in the use of rescue
tylcysteine delivery through a bronchoscope or endotracheal medications, prebronchodilator FEV1, and quality of life mea-
tube should be followed by suctioning to prevent deteriora- surements.102 A blinded randomized trial reported an improve-
tion in gas exchange.90 ment in scores on an asthma quality of life questionnaire but

468
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no statistical change in several secondary effectiveness end-
points including FEV1 (before or after bronchodilator),
symptom-free days, or rescue medication use.103 Thus the
mechanism, efficacy, and future of this therapy currently are
unresolved.104,105
KEY POINTS
• Inhaled corticosteroids are the preferred initial therapy
for the management of asthma.
• The use of LABAs has been associated with increased
risk of asthma-related death.
• Anticholinergics block acetylcholine, released from
parasympathetic nerves, acting upon muscarinic
receptors on airway smooth muscle. Anticholinergics are
more often efficacious in chronic obstructive lung
disease than in asthma.
• Intubation or suctioning can induce reflex-induced
bronchoconstriction via a reflex arc that can be blocked
at different levels by local anesthetics, intravenous
anesthetics, or volatile anesthetics.
• Propofol is the preferred intravenous anesthetic for
induction in patients with asthma or chronic obstructive
lung disease.
• Volatile anesthetics, with the exception of desflurane,
are potent bronchodilators.
• Personalized therapy for asthma is evolving with the
introduction of monoclonal antibodies directed against
IgE or IL-13.
Key References
Brown RH, Mitzner W, Zerhouni E, et al. Direct in vivo visualiza-
tion of bronchodilation induced by inhalational anesthesia using
high-resolution computed tomography. Anesthesiology. 1993;78:
295-300. Direct visualization and quantification of airway bron-
chodilation during inhalation of volatile anesthetics. (Ref. 75)
Castro M, Musani AI, Mayse ML, et al. Bronchial thermoplasty:
a novel technique in the treatment of severe asthma. Ther Adv
Respir Dis. 2010;4:101-116. The first randomized and blinded
clinical trial of bronchial thermoplasty for control of asthma. (Ref.
103)
Chowdhury BA, Seymour SM, Levenson MS. Assessing the safety
of adding LABAs to inhaled corticosteroids for treating asthma.
N Engl J Med. 2011;364:2473-2475. Summarizes the ongoing
controversy and planned clinical trials to assess the safety of using
long-acting β2-adrenoceptor agonists as combined therapy with
inhaled corticosteroids. (Ref. 6)
Chu EK, Drazen JM. Asthma: one hundred years of treatment and
onward. Am J Respir Crit Care Med. 2005;171:1202-1208. This
historical review summarizes the origins of pharmacologic
therapy for hyperreactive airway disease. (Ref. 32)
Haxhiu MA, Kc P, Moore CT, et al. Brain stem excitatory and
inhibitory signaling pathways regulating bronchoconstrictive
responses. J Appl Physiol. 2005;98:1961-1982. Defines the neural
signaling pathways that mediate reflex-induced bronchoconstric-
tion induced by airway irritation. (Ref. 34)
Lazarus SC. Clinical practice. Emergency treatment of asthma. N
Engl J Med. 2010;363:755-764. Current recommended therapy
for treating acute bronchospasm in the emergency department,
which is applicable to other acute care settings such as the operat-
ing room and intensive care unit. (Ref. 23)
Pizov R, Brown RH, Weiss YS, et al. Wheezing during induction
of general anesthesia in patients with and without asthma: a ran-
domized blinded trial. Anesthesiology. 1995;82:1111-1116. Estab-
lished propofol as the preferred intravenous anesthetic for
anesthetic induction in asthmatics. (Ref. 81)
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Chapter 26  Pulmonary Pharmacology
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2. Osler W, McCrae T. Bronchial Asthma. The Principles and Practice of
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3. Melland B. The treatment of spasmodic asthma by the hypodermic
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Chapter 26  Pulmonary Pharmacology
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