2. INTRODUCTION
• The National Asthma Education and Prevention Program (NAEPP) defines
asthma as a chronic inflammatory disorder of the airways in which many
cells and cellular elements play a role.
• In susceptible individuals, inflammation causes recurrent episodes of
wheezing, breathlessness, chest tightness, and coughing.
• These episodes are usually associated with airflow obstruction that is
often reversible either spontaneously or with treatment.
• The inflammation also causes an increase in bronchial hyper
responsiveness (BHR) to a variety of stimuli.
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3. PATHOPHYSIOLOGY
• The major characteristics of asthma include a variable degree of airflow
obstruction (related to bronchospasm, edema, and hypersecretion), BHR,
and airway inflammation.
• Inhaled allergens cause an early-phase allergic reaction characterized by
activation of cells bearing allergen-specific immunoglobulin E (IgE)
antibodies.
• There is rapid activation of airway mast cells and macrophages, which
release proinflammatory mediators such as histamine and eicosanoids
that induce contraction of airway smooth muscle, mucus secretion,
vasodilation, and exudation of plasma in the airways.
• Plasma protein leakage induces a thickened, engorged, edematous airway
wall and a narrowing of the airway lumen with reduced mucus clearance.
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4. • The late-phase inflammatory reaction occurs 6 to 9 hours after allergen
provocation and involves recruitment and activation of eosinophils, T
lymphocytes, basophils, neutrophils, and macrophages.
• Eosinophils migrate to the airways and release inflammatory mediators
(leukotrienes and granule proteins), cytotoxic mediators, and cytokines.
• T-lymphocyte activation leads to release of cytokines from type 2 T-helper
(TH2) cells that mediate allergic inflammation (interleukin [IL]-4, IL-5, and
IL-13).
• Conversely, type 1 T-helper (TH1) cells produce IL-2 and interferon- γ that
are essential for cellular defense mechanisms. Allergic asthmatic
inflammation may result from an imbalance between TH1 and TH2 cells.
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5. • Mast cell degranulation in response to allergens results in release of
mediators such as histamine; eosinophil, and neutrophil chemotactic
factors; leukotrienes C4, D4, and E4; prostaglandins; and platelet-
activating factor (PAF).
• Histamine is capable of inducing smooth muscle constriction and
bronchospasm and may play a role in mucosal edema and mucus
secretion.
• Alveolar macrophages release a number of inflammatory mediators,
including PAF and leukotrienes B4, C4, and D4. Production of neutrophil
chemotactic factor and eosinophil chemotactic factor furthers the
inflammatory process.
• Neutrophils are also a source of mediators (PAFs, prostaglandins,
thromboxanes, and leukotrienes) that contribute to BHR and airway
inflammation.
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6. • The 5-lipoxygenase pathway of arachidonic acid metabolism is responsible
for production of cysteinyl leukotrienes. Leukotrienes C4, D4, and E4 are
released during inflammatory processes in the lung and produce
bronchospasm, mucus secretion, microvascular permeability, and airway
edema.
• Bronchial epithelial cells participate in inflammation by releasing
eicosanoids, peptidases, matrix proteins, cytokines, and nitric oxide.
• Epithelial shedding results in heightened airway responsiveness, altered
permeability of the airway mucosa, depletion of epithelial-derived
relaxant factors, and loss of enzymes responsible for degrading
inflammatory neuropeptides.
• The exudative inflammatory process and sloughing of epithelial cells into
the airway lumen impair mucociliary transport. The bronchial glands are
increased in size, and the goblet cells are increased in size and number.
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7. • Expectorated mucus from patients with asthma tends to have high
viscosity. The airway is innervated by parasympathetic, sympathetic, and
nonadrenergic inhibitory nerves.
• The normal resting tone of airway smooth muscle is maintained by vagal
efferent activity, and bronchoconstriction can be mediated by vagal
stimulation in the small bronchi.
• Airway smooth muscle contains noninnervated β2-adrenergic receptors
that produce bronchodilation.
• The nonadrenergic, noncholinergic nervous system in the trachea and
bronchi may amplify inflammation in asthma by releasing nitric oxide.
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9. CHRONIC ASTHMA
• Classic asthma is characterized by episodic dyspnea associated with
wheezing, but the clinical presentation of asthma is diverse.
• Patients may also complain of episodes of dyspnea, chest tightness,
coughing (particularly at night), wheezing, or a whistling sound when
breathing. These often occur with exercise but may occur spontaneously
or in association with known allergens.
• Signs include expiratory wheezing on auscultation, dry hacking cough, or
signs of atopy (e.g., allergic rhinitis or eczema). Asthma can vary from
chronic daily symptoms to only intermittent symptoms.
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10. • The intervals between symptoms may be days, weeks, months, or years.
• The severity is determined by lung function, symptoms, nighttime
awakenings, and interference with normal activity prior to therapy.
• Patients can present with mild intermittent symptoms that require no
medications or only occasional use of short-acting inhaled β2-agonists to
severe chronic asthma symptoms despite receiving multiple medications.
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12. SEVERE ACUTE ASTHMA
• Uncontrolled asthma can progress to an acute state where inflammation,
airway edema, excessive mucus accumulation, and severe bronchospasm
result in profound airway narrowing that is poorly responsive to usual
bronchodilator therapy.
• Patients may be anxious in acute distress and complain of severe dyspnea,
shortness of breath, chest tightness, or burning. They may be able to say
only a few words with each breath. Symptoms are unresponsive to usual
measures.
• Signs include expiratory and inspiratory wheezing on auscultation, dry
hacking cough, tachypnea, tachycardia, pallor or cyanosis, and
hyperinflated chest with intercostal and supraclavicular retractions. Breath
sounds may be diminished with very severe obstruction.
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14. CHRONIC ASTHMA
• The diagnosis of asthma is made primarily by a history of recurrent
episodes of coughing, wheezing, chest tightness, or shortness of breath
and confirmatory spirometry.
• The patient may have a family history of allergy or asthma or have
symptoms of allergic rhinitis. A history of exercise or cold air precipitating
dyspnea or increased symptoms during specific allergen seasons also
suggests asthma.
• Spirometry demonstrates obstruction (forced expiratory volume in 1
second [FEV1]/forced vital capacity less than 80%) with reversibility after
inhaled β2-agonist administration (at least a 12% improvement in FEV1).
• Failure of pulmonary function to improve acutely does not necessarily rule
out asthma. If baseline spirometry is normal, challenge testing with
exercise, histamine, or methacholine can be used to elicit BHR.
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15. ACUTE SEVERE ASTHMA
• Peak expiratory flow (PEF) and FEV1 are less than 50% of normal predicted
values. Pulse oximetry reveals decreased arterial oxygen and O2 saturations.
The best predictor of outcome is early response to treatment as measured by
improvement in FEV1 at 30 minutes after inhale β2-agonists.
• Arterial blood gases may reveal metabolic acidosis and a low PaO2.
• The history and physical examination should be obtained while initial therapy
is being provided. A history of previous asthma exacerbations (e.g.,
hospitalizations, intubations) and complicating illnesses (e.g., cardiac disease,
diabetes) should be obtained.
• The patient should be examined to assess hydration status; use of accessory
muscles of respiration; and the presence of cyanosis, pneumonia,
pneumothorax, pneumomediastinum, and upper airway obstruction. A
complete blood count may be appropriate for patients with fever or purulent
sputum.
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17. NON PHARMACOLOGIC THERAPY
• Patient education and the teaching of self-management skills should be
the cornerstone of the treatment program. Self-management programs
improve adherence to medication regimens, self-management skills, and
use of healthcare services.
• Objective measurements of airflow obstruction with a home peak flow
meter may not necessarily improve patient outcomes. The NAEPP
advocates use of PEF monitoring only for patients with severe persistent
asthma who have difficulty perceiving airway obstruction.
• Avoidance of known allergenic triggers can improve symptoms, reduce
medication use, and decrease BHR. Environmental triggers (e.g., animals)
should be avoided in sensitive patients, and those who smoke should be
encouraged to stop.
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18. • Patients with acute severe asthma should receive supplemental oxygen
therapy to maintain arterial oxygen saturation above 90% (above 95% in
pregnant women and patients with heart disease).
• Significant dehydration should be corrected; urine specific gravity may
help guide therapy in young children, in whom assessment of hydration
status may be difficult.
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20. Β2-AGONISTS
• The short-acting β2-agonists are the most effective bronchodilators
available.
• β2-Adrenergic receptor stimulation activates adenyl cyclase, which
produces an increase in intracellular cyclic adenosine monophosphate.
• This results in smooth muscle relaxation, mast cell membrane
stabilization, and skeletal muscle stimulation.
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24. • Aerosol administration enhances bronchoselectivity and provides a more rapid
response and greater protection against provocations that induce
bronchospasm (e.g., exercise, allergen challenges) than does systemic
administration.
• Albuterol and other inhaled short-acting selective β 2 -agonists are indicated
for treatment of intermittent episodes of bronchospasm and are the first
treatment of choice for acute severe asthma and EIB. Regular treatment (four
times daily) does not improve symptom control over as-needed use.
• Formoterol and salmeterol are inhaled long-acting β 2 -agonists indicated as
adjunctive long-term control for patients with symptoms who are already on
low to medium doses of inhaled corticosteroids prior to advancing to medium-
or high-dose inhaled corticosteroids. Short-acting β 2 –agonists should be
continued for acute exacerbations. Long-acting agents are ineffective for acute
severe asthma because it can take up to 20 minutes for onset and 1 to 4 hours
for maximum bronchodilation after inhalation.
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25. • In acute severe asthma, continuous nebulization of short-acting β 2 –
agonists (e.g., albuterol) is recommended for patients having an
unsatisfactory response after three doses (every 20 minutes) of
aerosolized β 2 -agonists and potentially for patients presenting initially
with PEF or FEV 1 values <30% of predicted normal.
• Inhaled β 2 -agonists agents are the treatment of choice for EIB.
Shortacting agents provide complete protection for at least 2 hours after
inhalation; long-acting agents provide significant protection for 8 to 12
hours initially, but the duration decreases with chronic regular use.
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26. • In nocturnal asthma, long-acting inhaled β 2 -agonists are preferred over
oral sustained-release β 2 -agonists or sustained-release theophylline.
However, nocturnal asthma may be an indicator of inadequate
antiinflammatory treatment.
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27. CORTICOSTEROIDS
• Corticosteroids increase the number of β 2 -adrenergic receptors and
improve receptor responsiveness to β 2 -adrenergic stimulation, thereby
reducing mucus production and hypersecretion, reducing BHR, and
reducing airway edema and exudation.
• Inhaled corticosteroids are the preferred long-term control therapy for
persistent asthma in all patients because of their potency and consistent
effectiveness; they are also the only therapy shown to reduce the risk of
death from asthma.
• Most patients with moderate disease can be controlled with twice-daily
dosing; some products have once-daily dosing indications. Patients with
more severe disease require multiple daily dosing. Because the
inflammatory response of asthma inhibits steroid receptor binding,
patients should be started on higher and more frequent doses and then
tapered down once control has been achieved.
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28. • The response to inhaled corticosteroids is delayed; symptoms improve in
most patients within the first 1 to 2 weeks and reach maximum
improvement in 4 to 8 weeks. Maximum improvement in FEV1 and PEF
rates may require 3 to 6 weeks.
• Systemic toxicity of inhaled corticosteroids is minimal with low to
moderate inhaled doses, but the risk of systemic effects increases with
high doses. Local adverse effects include dose-dependent oropharyngeal
candidiasis and dysphonia, which can be reduced by the use of a spacer
device.
• The ability of spacer devices to enhance lung delivery is inconsistent and
should not be relied on.
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30. • Systemic corticosteroids are indicated in all patients with acute severe
asthma not responding completely to initial inhaled β2- agonist
administration (every 20 minutes for three to four doses).
• Prednisone, 1 to 2 mg/kg/day (up to 40 to 60 mg/day), is administered
orally in two divided doses for 3 to 10 days. Because short-term (1 to 2
weeks), high-dose systemic steroids do not produce serious toxicities, the
ideal method is to use a short burst and then maintain the patient on
appropriate long-term control therapy with inhaled corticosteroids.
• In patients who require chronic systemic corticosteroids for asthma
control, the lowest possible dose should be used. Toxicities may be
decreased by alternate-day therapy or high-dose inhaled corticosteroids.
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31. METHYLXANTHINES
• Theophylline appears to produce bronchodilation by inhibiting
phosphodiesterases, which may also result in antiinflammatory and other
nonbronchodilator activity through decreased mast cell mediator release,
decreased eosinophil basic protein release, decreased T-lymphocyte
proliferation, decreased T-cell cytokine release, and decreased plasma
exudation.
• Methylxanthines are ineffective by aerosol and must be taken systemically
(orally or IV). Sustained-release theophylline is the preferred oral
preparation, whereas its complex with ethylenediamine (aminophylline) is
the preferred parenteral product due to increased solubility. IV
theophylline is also available.
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32. • Theophylline is eliminated primarily by metabolism via hepatic
cytochrome P450 mixed-function oxidase microsomal enzymes (primarily
CYP1A2 and CYP3A4) with 10% or less excreted unchanged in the kidney.
• The hepatic cytochrome P450 enzymes are susceptible to induction and
inhibition by various environmental factors and drugs.
• The addition of theophylline to optimal inhaled corticosteroids is similar to
doubling the dose of the inhaled corticosteroid and is less effective overall
than the long-acting β2-agonists as adjunctive therapy.
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33. Anticholinergics
• Ipratropium bromide and tiotropium bromide are competitive inhibitors of
muscarinic receptors; they produce bronchodilation only in cholinergic
mediated bronchoconstriction. Anticholinergics are effective bronchodilators
but are not as potent as β2-agonists.
• The time to reach maximum bronchodilation from aerosolized ipratropium is
longer than from aerosolized short-acting β2-agonists (30 to 60 minutes vs. 5
to 10 minutes).
• This is of little clinical consequence because some bronchodilation is seen
within 30 seconds and 50% of maximum response occurs within 3 minutes.
• Ipratropium bromide has a duration of action of 4 to 8 hours; tiotropium
bromide has a duration of 24 hours.
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34. • Inhaled ipratropium bromide is only indicated as adjunctive therapy in
severe acute asthma not completely responsive to β2-agonists alone
because it does not improve outcomes in chronic asthma.
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35. Mast cell stabilizers
• Cromolyn sodium and nedocromil sodium have beneficial effects that are
believed to result from stabilization of mast cell membranes. They inhibit
the response to allergen challenge as well as EIB but do not cause
bronchodilation.
• These agents are effective only by inhalation and are available as metered
dose inhalers; cromolyn also comes as a nebulizer solution.
• Both drugs are remarkably nontoxic. Cough and wheezing have been
reported after inhalation of each agent, and bad taste and headache after
nedocromil.
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36. • Cromolyn and nedocromil are indicated for the prophylaxis of mild persistent
asthma in children and adults regardless of etiology. Their effectiveness is
comparable to theophylline or leukotriene antagonists for persistent asthma.
• Neither agent is as effective as inhaled corticosteroids for controlling persistent
asthma. Neither is as effective as the inhaled β2- agonists for preventing EIB,
but they can be used in conjunction for patients not responding completely to
inhaled β2-agonists.
• Most patients experience improvement in 1 to 2 weeks, but it may take longer
to achieve maximum benefit. Patients should initially receive cromolyn or
nedocromil four times daily; after stabilization of symptoms the frequency may
be reduced to two times daily for nedocromil and three times daily for
cromolyn.
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37. Leukotriene Modifiers
• Zafirlukast (Accolate) and montelukast (Singulair) are oral leukotriene
receptor antagonists that reduce the proinflammatory (increased
microvascular permeability and airway edema) and bronchoconstriction
effects of leukotriene D4.
• In adults and children with persistent asthma, they improve pulmonary
function tests, decrease nocturnal awakenings and β2-agonist use, and
improve asthma symptoms. However, they are less effective in asthma than
low-dose inhaled corticosteroids.
• They are not used to treat acute exacerbations and must be taken on a regular
basis, even during symptom-free periods. The adult dose of zafirlukast is 20
mg twice daily, taken at least 1 hour before or 2 hours after meals; the dose
for children aged 5 through 11 years is 10 mg twice daily.
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38. • For montelukast, the adult dose is 10 mg once daily, taken in the evening
without regard to food; the dose for children aged 6 to 14 years is one 5-mg
chewable tablet daily in the evening.
• Zileuton is an inhibitor of leukotriene synthesis. The dose of zileuton tablets
is 600 mg four times daily with meals and at bedtime. The recommended
dose of zileuton extended-release tablets is two 600-mg tablets twice daily,
within 1 hour after morning and evening meals (total daily dose 2,400 mg).
• Use of zileuton is limited due to the potential for elevated hepatic enzymes
(especially in the first 3 months of therapy), and inhibition of the
metabolism of some drugs metabolized by CYP3A4 (e.g., theophylline,
warfarin).
• Serum alanine aminotransferase should be monitored before treatment and
then periodically thereafter
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39. COMBINATION CONTROLLER THERAPY
• The addition of a second long-term control medication to inhaled
corticosteroid therapy is one recommended treatment option in moderate
to severe persistent asthma.
• Single-inhaler combination products containing fluticasone propionate
and salmeterol or budesonide and formoterol are currently available. The
inhalers contain varied doses of the inhaled corticosteroid with a fixed
dose of the long-acting β2-agonist.
• The addition of a long-acting β2-agonist allows a 50% reduction in inhaled
corticosteroid dosage in most patients with persistent asthma.
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40. • Combination therapy is more effective than higher-dose inhaled
corticosteroids alone in reducing asthma exacerbations in patients with
persistent asthma.
• Leukotriene receptor antagonists also are successful as additive therapy in
patients inadequately controlled on inhaled corticosteroids alone and as
corticosteroid-sparing therapy. However, the magnitude of these benefits
is less than that reported with the addition of long-acting β2-agonists.
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41. Omalizumab
• Omalizumab is an anti-IgE antibody approved for the treatment of
allergic asthma not well controlled by oral or inhaled corticosteroids.
• The dosage is determined by the patient’s baseline total serum IgE
(international units/mL) and body weight (kg). Doses range from 150 to
375 mg given subcutaneously at either 2- or 4-week intervals.
• Because of its high cost, it is only indicated as step 5 or 6 care for patients
who have allergies and severe persistent asthma that is inadequately
controlled with the combination of high-dose inhaled corticosteroids and
long-acting β2-agonists.
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42. • Because it is associated with a 0.1% incidence of anaphylaxis, patients
should remain in the physician’s office for a reasonable period after the
injection because 70% of reactions occur within 2 hours. Some reactions
have occurred up to 24 hours after injection.
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