Transcript Slide 1

Clinical Pharmacy
Chapter 11
Asthma
Rowa’ Al-Ramahi
DEFINITION

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.
CLINICAL PRESENTATION
CHRONIC ASTHMA
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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. Asthma can vary from chronic daily
symptoms to only intermittent symptoms. The intervals
between symptoms may be days, weeks, months, or
years.
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.
SEVERE ACUTE ASTHMA
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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.
Breath sounds may be diminished with very severe
obstruction.
DIAGNOSIS
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CHRONIC ASTHMA
The diagnosis of asthma is made primarily by a history
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.
ACUTE SEVERE ASTHMA
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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
inhaled β2-agonists.
Arterial blood gases may reveal metabolic acidosis and a
low PaO2.
DESIRED OUTCOME
CHRONIC ASTHMA
 The NAEPP provides the following goals for chronic
asthma management:
 Reducing
impairment: (1) prevent chronic and
troublesome symptoms (e.g., coughing or breathlessness
in the daytime, at night, or after exertion); (2) require
infrequent use ( ≤2 days/wk) of inhaled short-acting β2agonist for quick relief of symptoms (not including
prevention of exercise-induced bronchospasm [EIB]);
(3) maintain (near-) normal pulmonary function; (4)
maintain normal activity levels (including exercise and
attendance at work or school); (5) Meet patients’ and
families’ expectation of and satisfaction with care.
 Reducing risk: (1) prevent recurrent exacerbations and
minimize the need for visits or hospitalizations; (2)
prevent loss of lung function; for children, prevent
reduced lung growth; (3) minimal or no adverse effects
of therapy.
ACUTE SEVERE ASTHMA

The goals of treatment include: (1) correction of
significant hypoxemia; (2) rapid reversal of airway
obstruction (within minutes); (3) reduction of the
likelihood of recurrence of severe airflow obstruction;
and (4) development of a written action plan in case of a
future exacerbation.
TREATMENT
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NONPHARMACOLOGIC THERAPY
Patient education and the teaching of self-management
skills should be the cornerstone of the treatment program.
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.
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.
PHARMACOTHERAPY
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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.
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 β2agonists 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.
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Formoterol and salmeterol are inhaled long-acting β2agonists 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 highdose inhaled corticosteroids. Short-acting β2–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 1-4 hours for maximum
bronchodilation after inhalation.
In acute severe asthma, continuous nebulization of shortacting β2–agonists (e.g., albuterol) is recommended for
patients having an unsatisfactory response after three doses
(every 20 minutes) of aerosolized β2-agonists and potentially
for patients presenting initially with PEF or FEV1 values <30%
of predicted normal. Short acting 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.
In nocturnal asthma, long-acting inhaled β2-agonists are
preferred over oral sustained-release β2-agonists or
sustained-release theophylline.
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Corticosteroids
Corticosteroids increase the number of β2-adrenergic receptors
and improve receptor responsiveness to β2-adrenergic
stimulation, thereby reducing mucus production and hyper
secretion, 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 twicedaily 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. 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.
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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.
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 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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Methylxanthines
Theophylline appears to produce bronchodilation by
inhibiting phosphodiesterases, which may also result in
antiinflammatory and other nonbronchodilator activity.
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.
Theophylline is eliminated primarily by metabolism via
hepatic cytochrome P450 (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. Clinically significant reductions in clearance can result
from
cotherapy
with
cimetidine,
erythromycin,
clarithromycin,
allopurinol,
propranolol,
ciprofloxacin,
interferon, ticlopidine, zileuton, and other drugs. Some
substances that enhance clearance include rifampin,
carbamazepine, phenobarbital, phenytoin, charcoal-broiled
meat, and cigarette smoking.
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Because of large interpatient variability in theophylline
clearance, routine monitoring of serum theophylline
concentrations is essential. A steady-state range of 5 to 15
mcg/mL is effective and safe for most patients.
Sustained-release oral preparations are favored for
outpatient therapy, but each product has different release
characteristics and some products are susceptible to
altered absorption from food or gastric pH changes.
Preparations unaffected by food that can be administered
a minimum of every 12 hours are preferable.
Adverse effects include nausea, vomiting, tachycardia,
jitteriness, and difficulty sleeping; more severe toxicities
include cardiac tachyarrhythmias and seizures.
Sustained-release theophylline is less effective than
inhaled corticosteroids and no more effective than oral
sustained-release β2-agonists, cromolyn, or leukotriene
antagonists.
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.
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.
They attenuate, but do not block, allergen- or exerciseinduced asthma in a dose-dependent fashion. 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.
 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.
Tiotropium bromide has not been studied in asthma.
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.
 They 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.
Leukotriene Modifiers

Zafirlukast and montelukast 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.
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Zafirlukast and montelukast are generally well tolerated.
Rare
elevations
in
serum
aminotransferase
concentrations and clinical hepatitis have been reported.
An idiosyncratic syndrome similar to the Churg-Strauss
syndrome, with marked circulating eosinophilia, heart
failure, and associated eosinophilic vasculitis, has been
reported in a small number of patients; a direct causal
association has not been established.
Zileuton is an inhibitor of leukotriene synthesis. 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.
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 (Advair) or budesonide and
formoterol (Symbicort) 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. 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 β2agonists.
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.
 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.
EVALUATION OF THERAPEUTIC OUTCOMES
CHRONIC ASTHMA
 Regular follow-up is essential (at 1- to 6-month intervals,
depending on control).
 Components of the assessment of control include symptoms,
nighttime awakenings, interference with normal activities,
pulmonary function, quality of life, exacerbations, adherence,
treatment-related adverse effects, and satisfaction with care.
The categories of well controlled, not well controlled, and very
poorly controlled are recommended. Validated questionnaires
can be administered regularly, such as the Asthma Therapy
Assessment Questionnaire, Asthma Control Questionnaire,
and Asthma Control Test.
 Spirometric tests are recommended at initial assessment,
after treatment is initiated, and then every 1 to 2 years. Peak
flow monitoring is recommended in moderate to severe
persistent asthma.
 Patients should also be asked about exercise tolerance.
 All patients on inhaled drugs should have their inhalation
technique evaluated monthly initially and then every 3 to 6
months.
After initiation of antiinflammatory therapy or an increase
in dosage, most patients should begin experiencing a
decrease in symptoms within 1 to 2 weeks and achieve
maximum symptomatic improvement within 4 to 8 weeks.
Improvement in baseline FEV1 or PEF should follow a
similar time frame, but a decrease in BHR as measured by
morning PEF, PEF variability, and exercise tolerance may
take longer and improve over 1 to 3 months.
ACUTE SEVERE ASTHMA
 Patients at risk for acute severe exacerbations should
monitor morning peak flows at home.
 Lung function, either spirometry or peak flows, should be
monitored 5 to 10 minutes after each treatment.
 Oxygen saturations can be easily monitored continuously
with pulse oximetry. For young children and adults, pulse
oximetry, lung auscultation, and observation for
supraclavicular retractions is useful.
 Most patients respond with the first hour of initial inhaled
β-agonists. Patients not achieving an initial response
should be monitored every 0.5 to 1 hour.
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‫َّللا َيجْ َع ْل َل ُه َم ْخ َر ًجا َو َيرْ ُز ْق ُه ِمنْ َح ْي ُ‬
‫ث ََل‬
‫” َو َمنْ َي َّت ِق َّ َ‬
‫َّللا َفه َُو َحسْ ُب ُه إِنَّ ََّ‬
‫َّللا َبالِ ُغ‬
‫َيحْ َت ِسبُ َو َمنْ َي َت َو َّك ْل َع َلى َّ ِ‬
‫أَ ْم ِر ِه َق ْد َج َع َل َّ‬
‫َّللاُ لِ ُك ِّل َشيْ ٍء َق ْد ًرا“‬