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Treatment of Asthma

Learning Objectives

By the end of this self study module you should be able to:

1. Discuss the role of the immune system in the etiology of asthma.

2. Categorize asthma medications as either “rescue” or “control” medications.
3. Describe the role of cyclic AMP & PKA in the regulation of bronchiolar smooth muscle tone.
4. Describe the “stepwise” treatment algorithm for asthma management, and how the frequency of
use of rescue medications can be used to determine the need for a daily control medication.
5. Explain why oxygen should be given before bronchodilators in an asthmatic patient with a low O2
saturation.
6. Explain why long acting beta-2 agonists should not be used as monotherapy.
7. Explain the beneficial aspects of aerosol drug formulations vs. oral drug formulations.
8. Describe two potentially life-threatening side effects of theophylline.

Drugs:

● OXYGEN (by face mask or nasal cannula)

● BRONCHODILATORS:
❍Short Acting Beta2 Agonists (SABAs): albuterol, levalbuterol, metaproterenol, pirbuterol,
terbutaline
❍Long Acting Beta2 Agonists (LABAs): formoterol, salmeterol
❍Antimuscarinics: ipratropium, tiotropium
● ANTIINFLAMMATORY DRUGS:
❍Corticosteroids (ICS): beclomethasone, budesonide, fluticasone, prednisone,
prednisolone
● ANTI-IgE ANTIBODY: omalizumab
● LEUKOTRIENE PATHWAY INHIBITORS:
❍Receptor Antagonists: montelukast, zafirlukast
❍5-lipoxygentase inhibitor: zileuton
● RARELY USED:
❍cromolyn sodium (low-efficacy degranulation inhibitor)
❍theophylline (low efficacy bronchodilator, life-threatening toxicity, narrow TI)

Clinical Case

Johnny is a 6-year-old African American boy who is brought into the Emergency
Department by his mother after waking up at 4 AM with difficulty breathing. His mother
states that Johnny recently recovered from an upper respiratory flu, but he has been
wheezing and coughing for the past few days since his fever broke. She informs the nurse
that Johnny has been using an albuterol inhaler at least 4-5 times per week for the past 2

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months.

This is Johnny's second visit to the ED in the past 2 months. During his last visit his
symptoms also included watery eyes and a stuffy nose. Johnny has had six visits to the
Tulane ED for upper respiratory symptoms associated with wheezing over the past year.
After his previous two visits he was sent home with a prescription for an albuterol inhaler
& a macrolide & cephalosporin antibiotic combination.1) His mother states that his
breathing problems have been getting worse & more frequent, and that the antibiotics do
not seem to be working. His vaccinations are up to date.

In the ED Johnny is observed to have expiratory bilateral wheezing with an elevated

respiratory rate of 40/min. He is afebrile, and his EKG reveals a sinus tachycardia of
130/min. Pulse oximetry indicates that his SpO2 is 87%.

Questions:

1. How would you treat Johnny's current symptoms while he is in the Emergency
Department?
2. Based upon Johnny's past medical history, what type of other medication should Johnny
have been prescribed during his recent visits?
3. How should Johnny & his parent(s) be educated concerning the appropriate standard of
care for patients with his level of asthma severity?

Terms & Definitions

● Atophy: a syndrome caused by a genetic predisposition to develop allergic hypersensitivity

reactions to allergens. Patients with atophy develop excessive IgE reactions when exposed to
allergens. High IgE levels cause patients with atophy to have a positive skin-prick test to common
allergens. Atophy is the strongest identifiable risk factor for the development of asthma. Patients
with asthma also commonly suffer from other atopic diseases such as allergic rhinitis (hay fever)
and eczema (atopic dermatitis). In contrast, non-atopic individuals have a very low risk of
developing asthma (Barnes, 2015; Liu, 2016; Wikipedia: Atophy).

● FEV1 (Forced Expiratory Volume in 1 second): the volume of air that can be forcibly blown out in
one second after a full inspiration. Normal values vary with age and gender. Reduced in asthma.
Measured by spirometry (a type of pulmonary function test).

● FVC (Forced Vital Capacity): the maximum volume of air that can be forcibly blow out after full
inspiration. Normal values vary with age and gender. Reduced in asthma. Measured by spirometry
(a type of pulmonary function test).

● FEV1/FVC (or FEV1%): in healthy adults FEV1/FVC should be 70-85% (declining with age). In
obstructive lung diseases such as asthma & COPD FEV1 is reduced due to airway resistance to
expiratory flow. FVC may also be reduced, but not to the same extent. Hence the ratio of
FEV1/FVC is usually <80% in patients with asthma or COPD. In contrast, in patients with
restrictive diseases such as pulmonary fibrosis, the ratio of FEV1/FVC is either normal or increased
due to reduced lung compliance (Fanta, 2017).

● Wheezing: A wheeze is a continuous, whistling sound produced in the airway when some part of
the respiratory tree is narrowed or obstructed. Wheezing heard during the expiratory phase of
breathing usually signifies that the patient's peak expiratory flow rate is less than 50% of normal
(Shim & Williams, 1983).

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Pathophysiology

Asthma is a very complex disease that is still poorly understood. Classic “allergic” asthma is
mediated by IgE immune globulin that is produced in response to exposure to environmental
allergens from sources including dust mites, animal dander, pollen, mold and cockroaches (Galanter
et al, 2015). The predisposition to develop specific IgE antibodies against common environmental
antigens may be due to multiple factors including genetic inheritance, and/or promotion of an
asthmatic phenotype early in life due to a lack of infections early in life. Exposure to infections and
endotoxin early in life is known to promote a shift in the differentiation of T helper cell subtypes from
the type 2 (Th2) phenotype present at birth to a more protective type 1 (Th1) phenotype. This has
become known as the “hygiene hypothesis for asthma” (illustrated in Figure 1)(Busse, 2001;
Barnes, 2015).

Figure 1. The hygiene hypothesis. Adapted from Busse (2001).

Th1 cells predominantly produce cytokines (IL-2 & interferon-γ) that trigger immunity responses
against intracellular bacteria and protozoa. In contrast, Th2 cells produce cytokines (e.g. IL-4, IL-5, IL-
9, IL-13) that stimulate eosinophils to attack extracellular parasites (e.g. helminths). However, the
antigen-mediated eosinophilic response produced by an abnormally large population of
Th2 cells also facilitates the tissue damage observed in allergic diseases such as asthma
(Figure 2)(Barnes, 2001).

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Figure 2. Cellular mechanisms involved in the pathogenesis of asthma. A large variety of

inflammatory cells are both recruited and activated in the airways of the lung, where they release
many different cytokines and inflammatory mediators. These substances result in
bronchoconstriction, vasodilation, edema, mucus hypersecretion, and activation of sensory nerves.
Over time, structural changes develop including epithelial shedding, thickening of the basement
membrane (subepithelial fibrosis), angiogenesis, hyperplasia of mucus-secreting cells, and smooth
muscle hypertrophy & hyperplasia. Associated with the late-phase response to allergen exposure
there is a recruitment of multiple subtypes of immune cells, in particular eosinophils, neutrophils and
memory T-cells. In severe cases of asthma, the release of multiple inflammatory mediators
can cause cholinergic hyper-reactivity that increases both mucus secretion and
bronchoconstriction, effects that can be reduced by inhaled antimuscarinics (Wenzel et al, 1999;
Gibson et al, 2001; Liu, 2016). ECP: eosinophil cationic protein; LT: leukotrienes; MBP: major basic
protein; PAF: platelet activating factor; PG: prostaglandins; Adapted from Barnes (2011).

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Figure 3. Effect of acute asthma attack on the lung. The combination of muscle constriction,
increased wall thickness due to inflammation, and increased mucus results in a narrowed airway,
which limits air flow. Adapted from NHLBI & Wikipedia Commons.

Wheezing

● A wheeze is a continuous, whistling sound produced in the airway when some part of the
respiratory tree is narrowed or obstructed. Wheezing heard during the expiratory phase of breathing
usually signifies that the patient's peak expiratory flow rate is less than 50% of normal (Shim &
Williams, 1983). Wheezing can be heard here (Wikipedia Commons).

Classifying Asthma Severity

Drug therapy is the mainstay of asthma management for most patients (Fanta, 2016). The current
clinical guidelines published by the National Asthma Education and Prevention Program (NAEPP) in
2007 recommend a step-wise approach to therapy based upon the frequency & severity of asthma
symptoms, as summarized in Figure 4. In these guidelines, asthma severity is classified based upon:

● the frequency and severity of symptoms (interference with normal activities, night time awakenings)
● the frequency of need for using a bronchodilator (# per day or week)
● measurements of FVC and FEV1

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FEV1 and FVC can be easily measured in the clinic by spirometry. FEV1 and FVC values vary with sex
and age. Patients with a FEV1 value of 80-120% of their predicted average value (for their age &
gender) are considered “normal”. Patients with obstructive lung disease, such as asthma, will have a
reduced FEV1 or FEV1/FVC ratio, which are used in diagnosing the severity of asthma (Figure 4).

Figure 4. Classifying asthma severity and initiating treatment in youths > 12 years of age & adults.
EIB: Exercise-induced bronchoconstriction; FEV1: forced expiratory volume in one second; FVC:
forced vital capacity; SABA: Short Acting Beta-2 Agonist (e.g. albuterol). (Adapted from National
Heart, Blood, and Lung Institute Expert Panel Report 3 (EPR 3): Guidelines for the Diagnosis and
Management of Asthma. NIH Publication no. 08-4051, 2007.

Treatment Overview

Patients with “persistent” vs “intermittent” asthma require the inclusion of one or more
daily “control” medications in addition to the use of a “rescue” bronchodilator (e.g. a
Short Acting Beta-2 Agonist, or SABA) that is taken as needed (Figure 5). A common
variable used in decision-making is the patient's frequency of use of a rescue
bronchodilator. As indicated in Figure 4, if a patient is using a rescue bronchodilator more
than twice a week, then they are considered to have “persistent” asthma, and require the
inclusion of a “control” agent, most commonly in the form of adding daily therapy with an

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inhaled corticosteroid (ICS), in addition to use of an inhaled bronchodilator that is taken

as needed. Guidelines recommend that patients with more severe persistent asthma (as
judged by the criteria shown in Figure 4) require a change or “step up” in their daily
control medications, as recommended in Figure 5.

If asthma symptoms become more severe, therapy should be “stepped up” as summarized
in Figure 5.

Figure 5. The stepwise approach to treatment that is designed to meet individual patient needs for
adults. If an alternative treatment is used, and the response is inadequate, it is recommended that
the patient be switched to the preferred treatment, before stepping up. The role of allergy in asthma
is more common in children than adults. Initiation of immunotherapy or omalizumab should only be
conducted in a hospital or clinic prepared to identify and treat anaphylaxis, should it occur. SABA:
inhaled SHORT-acting β-2 agonist; prn: administer as needed; ICS: inhaled corticosteroid; LTRA:
leukotriene receptor antagonist; LABA: inhaled LONG-acting β-2 agonist. Adapted from the Expert
Panel Report 3: Guidelines for the Diagnosis & Management of Asthma (Natl Heart, Lung & Blood Inst,
2007). * Note: cromolyn sodium has very limited availability, and is now only available in a nebulizer
formulation.

Controlling Indoor Allergens

Indoor environmental exposure to allergens (e.g. dust mites, mold, rodent, cockroach and pet

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allergens) & pollutants (e.g. nitrogen dioxide from gas stoves & second-hand smoke) are major
contributors to asthma morbidity, especially in children. Environmental control strategies that
include eradication of the allergen source, the use of HEPA air purifiers, and allergen-proof mattress &
pillow covers can be as effective as asthma controller medications for reducing asthma
symptoms and flare-ups (Matsui et al, 2016).

The Major Drug Classes Used in Treating Asthma

Figure 6. The different classes of drugs used in the treatment of asthma. The drug categories most
commonly used in the initial treatment of intermittent asthma, persistent asthma & severe asthmatic
exacerbations (emergency department settings) are highlighted in bold. Other drug types that are
also used in the treatment of persistent asthma are also shown. ICS: inhaled corticosteroid; SABA:
inhaled short-acting β-2 agonist; LABA: inhaled long-acting β-2 agonist.

The Pharmacology of Asthma Medications

Oxygen in the Emergency Treatment of Asthma

Oxygen is the first-line treatment of acute severe asthma in order to control hypoxemia

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related to bronchoconstriction. A high concentration of oxygen should be given (e.g. by face

mask) to achieve an arterial oxygen saturation of >90% (Barnes, 2012). During severe asthma
attacks, portions of the lung are subjected to either over- or under-inflation due to changes in airway
resistance. These changes result in a ventilation/perfusion mismatch, which causes hypoxemia. To
prevent hypoxemia, oxygen saturation above 90% needs to be maintained.

Note that the administration of a β2 agonist can produce a vasodilator effect in the
pulmonary circulation. The resulting increase in blood flow to poorly ventilated areas of
the lung can increase the ventilation/perfusion mismatch and thereby worsen the
hypoxemia. A decrease in arterial oxygen saturation following the administration of a β2 agonist
alone (e.g. albuterol) is well recognized in acute asthma attacks, with a maximum reduction in
saturation occurring within 5-10 minutes, and while usually self-limiting, can last up to 20 minutes.
Because of this, oxygen is the first line treatment of acute asthma exacerbation in patients
with low pO2 levels (e.g. <90%); (although the use of β2 agonists is important to achieve
adequate bronchodilation, they should not be used as initial monotherapy before oxygen in these
situations) (Volovitz & Nussinovitch, 2002).

Beta-2 Agonists

Beta-2 adrenergic agonists are the most potent bronchodilators currently approved for treating
asthma & obstructive lung disease. Depending on their duration of action, they are used as either
“rescue” medications (short acting beta-2 agonists), or “control” medications (long acting beta-2
agonists).

At the cellular level, activation of beta-2 receptors produces bronchodilation through multiple
pathways, most of which involve stimulation of adenylyl cyclase and phosphorylation of target
proteins by protein kinase A (PKA). Experiments indicate that PKA is the predominant and most
physiologically relevant effector through which beta agonists cause bronchial smooth muscle
relaxation (Morgan et al, 2014) (Figure 7). Identified cellular targets through which PKA activation
produces a bronchodilator effect include:

● MLCK: Phosphorylation of myosin light chain kinase (MLCK) by cAMP-dependent protein kinase
(PKA) decreases the affinity of the kinase for Ca2+ and calmodulin, resulting in a decrease in MLCK
activity. Phosphorylated MLCK is ineffective in sustaining the interaction between actin & myosin,
and therefore the bronchial smooth muscle relaxes passively (Miller et al, 1983; Anderson, 2006;
Morgan et al, 2014).
●
PI/Cai2+: Experimental studies have shown that increased cAMP and PKA activation inhibits
methacholine- and histamine-induced phosphoinositide (PI) hydrolysis and its effect to cause Ca2+
mobilization (Hoiting et al, 1996; Billington et al, 2013).
● KCa Channel: Beta-2 receptor stimulation has been shown to stimulate calcium-activated potassium
(KCa) channels in airway smooth muscle by both PKA-induced phosphorylation, and membrane-
delimited Gs pathways (Kume et al, 1994). Hyperpolarization resulting from this mechanism will
result in deactivation of voltage-dependent Ca channels, resulting in decreased Ca influx, which will
favor smooth muscle relaxation.

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Figure 7. Bronchodilator mechanisms for beta-2 agonists and theophylline. Activation of Beta-2
receptors results in a Gs-protein mediated stimulation of adenylyl cyclase (AC) and opening of Ca-
activated K channels (KCa). Activation agents increase intracellular cAMP levels, which in turn
stimulate protein kinase (PKA).

Selective beta-2 agonists differ in terms of their speed of onset and duration of action, and are
categorized into Short Acting Beta-2 Agonists (SABAs) and Long Acting Beta-2 Agonists (LABAs)
which, despite their common site of action, have different indications in the treatment of asthma.

SABAs: Inhaled Short Acting Beta-2 Agonists

Inhaled short-acting beta-2 agonists (SABAs) are the mainstay of acute asthma therapy
(rescue therapy), while long-acting beta-2 agonists (LABAs) are used in combination with inhaled
glucocorticoids for long-term control of moderate to severe symptoms (e.g. LABAs are considered
“control” medications and not “rescue” medications) (Galanter et al, 2015; Lemanske, 2015).

Common Characteristics of SABAs

● Metered Dose Inhaler (MDI) & nebulizer inhalable formulations

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● Rapid acting (1-5 minutes)

● Half lives of 6 hours or less
● Fewer systemic effects (compared to systemic administration)
● Significantly increases the one second forced expiratory volume in the forced vital capacity test
(FEV1)

Commonly Used SABAs

● Albuterol (ProAir, Ventolin, Proventil ®)

● Levalbuterol (Xopenex ®) - the R isomer of albuterol
● Metaproterenol (Alupent ®) - liquid taken by mouth or for use in nebulizers
● Pirbuterol (Maxair ®)

Figure 8. Methods for Inhalation of asthma medications. A) Metered Dose Inhaler (MDI) devices use a
metered valve to deliver a specific amount of drug to the lungs in the form of a short burst of
aerosolized medication during each actuation that is self-administered by the patient during
inhalation. B) Nebulizers use oxygen, compressed air, or ultrasonic power to convert solutions into
small liquid aerosol droplets that can be inhaled into the mouth or nosepiece of the device. Figures
reproduced from Wikipedia Commons.

Acute Bronchodilators of Historical Interest

● Epinephrine (Primatene Mist inhaler ®)

❍an inhaled formulation that was previously sold over the counter.
❍it was removed from the market due to environmental concerns about its
chlorofluorocarbon propellant.
❍produces a much higher incidence of unwanted side effects including

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tremor, anxiety (CNS effects), increased heart rate & blood pressure
● Isoproterenol (Medihaler-Iso; Isoproterenol Mistometer ®)
❍ inhaled formulations were introduced in the 1960s.
❍ isoproterenol's short duration of action & bothersome side effects (tremor,
tachycardia) reduced its popularity once inhaled formulations of selective
beta-2 agonists became available
❍ isoproterenol continues to carry an FDA-approved indication for treatment
of bronchospasm during anesthesia

Subcutaneous SABA Formulations

Formulations for subcutaneous injection are useful for treating severe asthma requiring emergency
treatment when either aerosolized therapy is not available, or has been ineffective (e.g.
due to a severely constricted airway). Parenteral administration is associated with a higher
incidence of systemic side effects including skeletal muscle tremor and anxiety
/nervousness.

● Terbutaline

LABAs: Inhaled Long Acting Beta-2 Agonists

● Formoterol
● Salmeterol

Combined with ICS:

● Symbicort ® (Budesonide + Formoterol)

● Advair ® (Fluticasone + Salmeterol)

A newer generation of beta-2 agonists achieve a long duration of action due to their high lipid
solubility which causes them to concentrate in the lipid bilayer of smooth muscle cell membranes
(Figure 9). These agents, which include formoterol and salmeterol have a duration of action of 12
hours or more. Formoterol has a relative “fast” onset of action compared to salmeterol, perhaps due
to its more intermediate lipid solubility (Figure 9). These drugs can suppress asthma symptoms for
long time periods. However, because they have no anti-inflammatory properties (but have the
potential to mask inflammatory symptoms), they should always be used in combination
with an anti-inflammatory corticosteroid in order to reduce the risk of a potentially fatal
asthma attack resulting from uncontrolled tissue inflammation (see BLACK BOX
WARNING).

Black Box Warning: ASTHMA RELATED DEATH with LABA MONOTHERAPY

Long acting beta-2 agonists such as salmeterol or formoterol may increase the
risk of asthma-related death. These medications should ONLY be used as
additional therapy for patients not adequately controlled by low to
medium dose inhaled corticosteroids. Data from a large placebo-controlled
US trial (Salmeterol Multi-center Asthma Research Trial) that compared
salmeterol (Serevent ®) with placebo added to usual therapy found an
increased incidence of asthma-related deaths in patients on salmeterol (13 out
of 13,176 patients treated for 28 weeks) vs patients on placebo (3 deaths out
of 13, 179 patients).This finding with is considered a class effect of all LABA,
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including formoterol.

One hypothesis that can account for the observation of an increased risk for asthma attacks with
LABA monotherapy is that patients may feel better when taking long-acting beta agonists, and as a
result take either lower doses of inhaled corticosteroids, or no corticosteroids at all. This could result
in an increase of underlying tissue inflammation, putting patients at an increased risk for a fatal
asthma attack.

A second hypothesis is that chronic (round the clock) exposure of beta-2 receptors to long-acting
beta-2 agonists results in the development of desensitization (tolerance) to all beta-2 agonists. The
loss of beta-2 effect then results in an inability to reverse inflammation-induced bronchoconstriction,
and an increased incidence of severe asthma-related bronchoconstriction.

Figure 9. It is postulated that the lipid bilayer of airway smooth muscle acts as a storage depot for
beta-2 agonists, such that beta-2 agonists that partition into the bilayer to a large extent remain
available to bind to the beta-2 receptor for extended time periods after they are administered
(Anderson et al, 1994). Salmeterol is believed to have a slower onset of action due to its high degree
of partitioning into the lipid bilayer, and slower rate of drug diffusion through the bilayer to its
receptor site (in contrast to other beta-2 agonists that gain access to the same receptor via an
aqueous pathway where diffusion is much more rapid).

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Beta-2 Side Effects

High doses of inhaled beta-2 agonists can produce systemic side effects, and commonly include:

● tremor
● nervousness
● tachycardia (with the potential to worsen angina)

Antimuscarinics

As shown in Figure 2, bronchial cholinergic hyper-reactivity stimulated by the release of allergen-

induced mediators can contribute to airway bronchoconstriction and mucus secretion in
patients with severe forms of asthma. Aerosols containing atropine-like antimuscarinics have
been found to markedly reduce or abolish airway bronchoconstriction to a variety of spasmogens (e.g.
bradykinin, histamine, prostaglandin D2, capsaicin) that reduce FEV1 in patients with severe asthma
(Canning & Fischer, 2001).

Ipratropium bromide is a quaternary analog of atropine that can be delivered into the lung by
inhalation, but is not readily absorbed into the systemic circulation. It has been observed to produce
an effective degree of bronchodilation (rivaling the efficacy of beta-2 agonists), while (on average) it
seems to provide less benefit in patients with mild to moderate asthma attacks (Qureshi et al, 1998;
Fanta, 2017; Kirkland et al, 2017) (see Figure 10).

Ipratropium is available in several inhaler dosage forms, including monotherapy (Atrovent ®), and as
an inhaler combination with albuterol (Combivent ®). Ipratropium is also used in the treatment of
Chronic Obstructive Pulmonary Disease (COPD), as are longer duration analogs such as tiotropium
and aclidinium. Tiotropium was also recently approved by the FDA for long-term maintenance
(control) of severe asthma in adults, at a lower dosage than used for treating COPD (Chin et al, 2016).

● ipratropium
● tiotropium (a LAMA: Long-Acting Muscarinic Antagonist)

Combined with SABA:

● Combivent ® (Albuterol + Ipratropium)

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Figure 10. The mechanism of action of ipratropium bromide in asthma. Ipratropium is a quaternary
analog of atropine that when inhaled can antagonize the effects of heightened cholinergic tone on
bronchial smooth muscle and mucus secretion, a condition most commonly associated with severe (vs
mild) asthma. Cholinergic stimulation produces increased bronchoconstriction in airway smooth
muscle and increased mucus secretion in mucous-secreting cells via the same IP3 signal transduction
pathway (Williams et al, 2006; Bulkhi et al, 2016). As illustrated in the inset, children with severe
asthma treated with inhaled ipratropium (ipratropium group) in addition to the established standard
of care (control group: inhaled albuterol and oral corticosteroids) had a lower rate of needing to be
admitted to hospital compared to those given only albuterol and corticosteroid alone (modified from
Qureshi et al, 1998). (Ipratropium structure reproduced from Wikipedia Commons).

Inhaled Corticosteroids (ICS)

Inhaled formulations of anti-inflammatory corticosteroids (ICS) are the drugs of choice to

“control” asthma symptoms in patients with persistent asthma (Figure 5). Patients typically
require one or two “puffs” of ICS per day (once or twice a day) using a metered dose inhaler to
adequately control their asthma.

Commonly used ICS formulations include:

● beclomethasone (QVAR ®)
● budesonide (Pulmicort ®)
● fluticasone (Flovent ®)

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Additional ICS formulations (not emphasized):

● ciclesonide (Alvesco ®)
● flunisolide (Aerobid ®)
● mometasone (Asmanex HFA ®)

Inhaled formulations have similar therapeutic efficacy as oral or i.v. drug formulations, but have
significanly fewer systemic side effects. Daily ICS treatment can produce measurable effects to
increase FEV1 within several days after the onset of therapy, however maximal improvement
may require a month or more of daily therapy (see Rx.com: Budesonide Clinical Pharmacology).
The slow onset of therapeutic effect is attributed to the time it takes for these compounds to alter
gene expression (see glucocorticoid_pharmacology, which produces:

● reduced synthesis of inflammatory cytokines

● reversal of inflammation-induced increases of capillary permeability
● reduced tissue edema
● depression of the migration of a host of inflammatory cells into lung tissue (e.g. mast cells,
eosinophils, basophils, neutophils)

Corticosteroids can also help restore the responsiveness to beta-2 agonist in patients who have
developed some degree of tolerance to these agonists. Corticosteroids suppress the symptoms of
asthma, but are not a cure.

Oral & Parenteral Corticosteroids

If asthma symptoms become severe, tissue swelling & edema (see Figure 3) can produce
significant obstruction of air flow such that inhaled SABAs or ICS cannot be adequately
inhaled. In this situation, either oral or i.v. injection of a corticosteroid may be necessary (and even
life-saving). Corticosteroids commonly used for this indication include:

● prednisone (oral; prodrug)

● prednisolone (oral)
● methylprednisolone (oral or i.v.)

Systemic corticosteroids have similar therapeutic efficacy for controlling asthma

symptoms as ICS, but their use is otherwise curtailed due to their much more significant
systemic side effects (e.g. Cushingoid features, growth retardation, increased risk for infections),
and suppression of the hypothalamic-pituitary-adrenal (HPA) axis, which can result in an adrenal crisis
if doses are not carefully tapered after a patient has been on systemic steroids for more than 15 days
(Aljebab et al, 2017).

Leukotriene Pathway Inhibitors

Leukotrienes are inflammatory mediators produced by activated leukocytes in which increased

phospholipase A2 activity increases the production of arachidonic acid. Because leukocytes express
lipoxygenase vs cyclooxygenase, this results in the formation of a variety of leukotrienes, instead of
prostanoids & prostaglandins (see Figure 11).

Leukotriene pathway inhibitors consist of both inhibitors of 5-lipoxygenase, and leukotriene receptor

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antagonists. Both classes of drugs are typically given orally, and can have been documented to
produce beneficial effects in the chronic management of asthma. They do not have a
recognized benefit in treating asthma flare-ups (i.e. they are used as control medications, and not
rescue medications) (Fanta, 2017).

● 5-lipoxygentase inhibitor: zileuton

● Receptor Antagonists: montelukast, zafirlukast

Figure 11. The metabolic pathway by which leukotrienes are formed by leukocytes in response to
stimulation by inflammatory conditions. Corticosteroids can reduce leukotriene formation by
upregulating the expression of annexin A1, which inhibits phospholipase A2 (PLA2). Zileuton is a
selective inhibitor of 5-lipoxygenase (LOX), an early step in the synthesis of leukotrienes. Montelukast
and zafirlukast are leukotriene receptor antagonists.

Anti-IgE Therapy

● omalizumab

Omalizumab is a humanized monoclonal antibody that blocks the binding of IgE to receptors on a
variety of cell types involved in producing inflammation (e.g. mast cells, macrophages, T & B
lymphocytes), preventing their activation by allergens (see Figures 2 & 12). Because of its very high
cost, it has been approved for use ONLY in patients with moderate to severe persistent

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asthma who:

● have a positive skin test or in vitro reactivity to a perennial aeroallergen

● whose symptoms are not adequately controlled by inhaled corticosteroids

Omalizumab is administered by s.c. injection every 2-4 weeks, with the dose being determined by the
titer of circulating IgE.

● NOTE on ANAPHYLACTIC RISK:

❍Because omalizumab is a humanized antibody (but not 100% human in origin) it has the potential
for producing anaphylactic reactions. Life-threatening anaphylaxis has been reported in ~0.2% of
patients. It has been observed as early as after the first dose (within 1.5-2 hours), and as late as
a year after the onset of regular treatment.
❍When initiating treatment, omalizumab should only be given in a healthcare setting where
patients can be closely observed for an appropriate time after administration & where health
care providers are prepared to manage anaphylaxis.
❍Epinephrine (i.m. or i.v.) is commonly used in the treatment of anaphylaxis due to its ability to
cause:
beta-2 mediated bronchodilation
■

beta-2 mediated decrease in release of inflammatory mediators by mast cells & basophils
■

alpha-1 & alpha-2 mediated vasoconstriction resulting in decreased mucosal edema in the
■

upper airway, as well as increased blood pressure (to counteract histamine-induced

hypotension)

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Figure 12. Omalizumab is a humanized monoclonal antibody that binds to the Cε3 domain of
circulating IgE, which prevents IgE from binding to and activating receptors on mast cells and
lymphocytes. In this illustration, a mast cell is used to illustrate the beneficial effects of omalizumab.

Rarely Used Treatments

Theophylline

Several decades ago, theophylline was used as a bronchodilator of choice in the treatment of severe
asthmatic attacks. However, the development of beta-2 agonists that are more efficacious
bronchodilators, with relatively few clinically significant side effects, has resulted in almost a complete
discontinuation of theophylline's use in the treatment of asthma. However, theophylline is still
included in the most recent clinical guidelines as an alternative oral tablet “control” medication
(Figure 5).

Theophylline is a naturally occurring methylxanthine with multiple mechanisms of action, including: 1)

antagonism of adenosine receptors on the cell membrane, 2) inhibition of phosphodiesterases that
inactivate cAMP; and 3) enhancement of deacetylation of histones involved in the transcription of
inflammatory genes. Available data suggest that inhibition of PDE is the most important

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mechanism involved in its acute effects to produce bronchodilation (Figure 7). Xanthine
derivatives that do not antagonize adenosine receptors are effective bronchodilators. There is also
some clinical evidence suggesting a slower anti-inflammatory effect that may contribute to long-term
effects as well (Galanter & Boushey, 2015).

● theophylline
❍very rarely used - not as effective as SABAs
❍has a very narrow TI
Pharmacokinetics:
■

Theophylline should only be used where methods to measure blood levels are available due
●

to its narrow therapeutic index.

Therapeutic levels range from 5-20 mg/L, and levels above 40 mg/L may cause seizures or
●

arrhythmias.
Side Effects:
■

Low doses - mild cortical arousal & deferral of fatigue

●

High doses - convulsions, cardiac arrhythmias, death

●

Because of the high morbidity and mortality associated with theophylline-induced

❍

seizures, treatment of seizures should be rapid and aggressive.

The initial treatment for seizures is i.v. diazepam. Repetitive seizures are treated with
❍

phenobarbital.
The drug doses required to control theophylline-induced seizures may be close to those
❍

causing respiratory arrest.

Degranulation inhibitors

● cromolyn sodium (rarely used)

Cromolyn sodium is the only degranulation inhibitor still available in the US, and it is available in a
nebulizer formulation only (it had previously been available in a metered-dose inhaler formulation).
These agents must be given prior to exposure to an allergen (they are largely ineffective after
exposure to allergen). They exert an effect on chloride channels that results in reduced granular
release of mediators contributing to allergic reactions (as depicted in Figure 12) when mast cells &
eosinophils are stimulated by an IgE-allergen complex. They have fallen out of favor due to their
relatively low clinical efficacy, although they are still listed in current clinical guidelines (e.g. Fanta,
2017b).

Self Assessment Quizzes

● Treatment of Asthma Quiz 1 (10 Qs)

● Treatment of Asthma Quiz 2 (8 Qs)

References

● Aljebab F et al (2017): Systematic Review of the Toxicity of Long-Course Oral Corticosteroids in

Children. PLoS One. 12(1):e0170259. doi: 10.1371/journal.pone.0170259.
● Barnes PH (2001): Th2 cytokines and asthma: an introduction. Respir Res 2(2):64-65. doi:
10.1186/rr39

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● Barnes PJ (2011): Pulmonary Pharmacology (Chapter 36). In: Goodman and Gilman's: The
Pharmacological Basis of Therapeutics, 12e. Brunton LL, Chabner BA, Knollmann BC (Editors);
McGraw-Hill (Access Medicine).
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Medicine. Fauci, Brauwald, Kasper, Hauser, Longo, Jameson & Loscalzo. Vol 2 17th Ed. McGraw Hill.
● Barnes PJ (2015): Asthma. Chapter 309. In: Harrison's Principles of Internal Medicine 19th Ed.
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DS (Ed), Waltham, MA. Cited 9/18/17
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the emergency department. Pediatric Drugs 4(3) 141-148.

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34(5): 527–536. doi: 10.1165/rcmb.2005-0436SF
1)

Antibiotics are frequently over-prescribed This was a misdiagnosis

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