New Guidelines for the Diagnosis and Management of Asthma

Release Date: October 1, 2008

Expiration Date: October 31, 2010

FACULTY:

Erin N. Adams, PharmD
Assistant Professor of Pharmacy Practice
Shenandoah University
Winchester, Virginia

Alla Marks, PharmD, MBA
Assistant Professor of Pharmacy Practice
Shenandoah University
Winchester, Virginia

FACULTY DISCLOSURE STATEMENTS:

Drs. Adams and Marks have no actual or potential conflicts of interest in relation to this program. U.S. Pharmacist does not view the existence of relationships as an implication of bias or that the value of the material is decreased. The content of the activity was planned to be balanced, objective, and scientifically rigorous. Occasionally, authors may express opinions that represent their own viewpoint. Conclusions drawn by participants should be derived from objective analysis of scientific data.

ACCREDITATION STATEMENT:

acpePharmacy Postgraduate Healthcare Education, LLC is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.
Program: 430-000-08-019-H01-P; 430-000-08-019-H01-T
Credits: 2.0 hours (0.20 ceu)

TARGET AUDIENCE:

This accredited program is targeted to pharmacists and pharmacy technicians. Estimated time to complete this monograph and posttest is 90 to 120 minutes.

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DISCLAIMER:

Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients’ conditions and possible contraindications or dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

GOAL:

To review the epidemiology of asthma and present the updated prevention and treatment guidelines for asthma therapy.

OBJECTIVES:

After reading this article, the participant should be able to:

  • Explain the epidemiology of asthma.*
  • Identify the risk factors and triggers that predispose patients to asthma.*
  • Identify the most appropriate treatment for asthma patients in a stepwise approach.*
  • Define the patient counseling techniques that should be provided to patients.

*Also applies to pharmacy technicians.


More than 22 million Americans currently suffer from asthma.1 The American Academy of Allergy, Asthma, and Immunology estimates that 9 million children have been diagnosed with this disorder, classifying it as one of the most common chronic diseases of childhood.2 Uncontrolled asthma can interfere with daily activities, including work, school, and sleep. Patients with asthma account for 14.7 million visits to physician offices and outpatient hospital departments each year. Additionally, asthma is responsible for 1.8 million emergency room visits and 497,000 hospitalizations. Due in large part to the requirements for hospitalization, the financial impact includes annual direct costs of up to $10 million. Over and above this amount, collateral expense of missed work and treatment can account for nearly $8 million in indirect costs attributable to asthmatic illness. The most extreme consequence is that asthma has led to over 5,000 deaths annually.1,2

An expert panel commissioned by the National Asthma Education and Prevention Program (NAEPP), which is coordinated by the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH), defines the national clinical guidelines pertaining to the diagnosis and management of asthma. As of August 2007, the Expert Panel Report 3 (EPR-3) updated the previous 1997 guideline and 2002 update and recommended pertinent changes in the following aspects of asthma care1:

  1. New focus on monitoring asthma control as the goal for asthma therapy and distinguishing between classifying asthma severity and monitoring asthma control
  2. New focus on impairment and risk as the two key domains of severity and control, and multiple measures for assessment
  3. Modifications in the stepwise approach to managing asthma long-term
  4. New emphasis on multifaceted approaches to patient education and to the control of environmental factors or comorbid conditions that affect asthma
  5. Modifications to treatment strategies for managing asthma exacerbations.

The following discussion will review the epidemiology of asthma, including factors that predispose an individual to the disease state, and present the current recommendations for asthma diagnosis, management, and patient education.

Asthma is a chronic inflammatory airway disorder identified clinically by recurring episodes of wheezing, dyspnea, chest tightness, and cough. Symptoms may occur spontaneously or in association with exercise or known allergens.3,4 Increased or prolonged exposure to allergens or stimuli can lead to worsening airway obstruction and inflammation.

Risk factors for the development of asthma can include genetic predisposition, ra/USPExams/ethnicity (African Americans and Hispanics are at a greater risk compared to Caucasians), as well as atopy and airway hyperresponsiveness.3 Respiratory infections, exposure to second-hand smoke, indoor and outdoor allergens, family size, occupational contaminants, and air pollution are factors that have been shown to increase susceptibility to developing and perpetuating asthma. Common triggers that can exacerbate asthmatic symptoms include environmental and emotional factors, exercise, medications, and comorbid disease states and infections, as well as occupational and chemical irritants.1,3 The common triggers can be seen in TABLE 1.

Table 1
Asthma Triggers

Allergens: airborne pollens, animal dander, house dust mites, cockroaches, fungal spores

Environment: cold air, tobacco and wood smoke, air pollution

Exercise: particularly in cold, dry climates

Emotions: anxiety, stress, laughter

Medications: aspirin, sulfites, beta-blockers, nonsteroidal anti-inflammatory agents, benzalkonium chloride

Respiratory Infections: respiratory syncytial virus, influenza, parainfluenza, rhinovirus

Comorbid Conditions: obesity, obstructive sleep apnea, gastroesophageal reflux, allergic bronchopulmonary aspergillosis, rhinitis, sinusitis

Source: References 1, 3.

Different phenotypes of asthma exist, which may have very specific patterns of inflammation that require different treatment approaches. A gene-by-environment interaction occurs in which the susceptible host is exposed to environmental factors that are capable of generating immunoglobulin (Ig)E and sensitization. Precisely why the airways of some individuals are susceptible to these allergic events has not been established. Allergen-induced acute bronchoconstriction results from an IgE-dependent release of mediators from mast cells that include histamine, tryptase, leukotrienes, and prostaglandins, which directly contract airway smooth muscle. The role of genetics in IgE production, airway hyperresponsiveness, and dysfunctional regulation of the generation of inflammatory mediators (such as cytokines, chemokines, and growth factors) is currently under investigation.1

The diagnosis of asthma should be based upon the individual patient’s medical history, physical exam, and measurement of spirometry. Key symptoms of asthma include current or recurrent wheezing, a cough that may worsen at night, difficulty breathing, and chest tightness. Symptoms may be constant or episodic and may awaken the patient during the night. The symptoms may also occur or worsen due to precipitating factors or triggers. The patient’s medical history should be obtained and include past and current symptoms and trends, precipitating factors, history of exacerbations, development of disease and treatment, family and social history, as well as the patient’s and family’s perceptions regarding the impact of asthmatic symptoms on quality of life. The physical exam should include vital signs, which may note an increased respiratory rate and pulse. Chest auscultation and examination may indicate dyspnea, cough, and wheezing, as well as visual hyperexpansion of the thorax due to use of the accessory muscles. Allergic symptoms may also be evident including eczema, nasal secretions, and polyps. The updated clinical guidelines recommend that spirometry be used in a patient who is considered to be asthmatic. Spirometry should consist of the following measurements: forced expiratory volume in one second (FEV1), forced expiratory volume in six seconds (FEV6), forced vital capacity (FVC) and FEV1/FVC.1-5

Prior to diagnosis, health care professionals should also rule out other diagnoses including allergic rhinitis, sinusitis, aspiration, obstructions of the large airways (foreign body obstruction, vocal cord dysfunction, bronchostenosis), obstructions of the small airways (cystic fibrosis, heart disease), chronic obstructive pulmonary disease, congestive heart failure, pulmonary embolism, or drug-induced cough (angiotensin-converting enzyme inhibitors).1

After confirmation of the diagnosis of asthma, the patient’s baseline severity of asthma symptoms should be classified according to three specified age-groups as depicted in TABLES 2 and 3. These age-groups are categorized as follows: 0-4 years, 5-11 years, and individuals ≥12 years. Severity and control should be assessed based upon the patient’s frequency and intensity of symptoms as well as the limitations a patient may face due to uncontrolled asthma. The previous severity classification of mild intermittent asthma (those who have <2 asthmatic symptoms per week) has now been updated to simply intermittent asthma. According to the EPR-3, this change was necessary to emphasize that patients with intermittent asthma can have severe exacerbations and should be appropriately monitored and treated.1 Persistent asthma is still classified according to the previous severity categories: mild, moderate, or severe. Asthma therapy should be approached in a stepwise manner to achieve asthma management:

  1. Prevent symptoms
  2. Decrease use of short-acting beta-agonists
  3. Maintain normal pulmonary function and prevent loss of lung function
  4. Maintain quality of life including attendance at work or school and physical activities
  5. Meet patient and family expectations for asthma care
  6. Prevent exacerbations and minimize emergency room visits and/or hospitalizations
  7. Provide optimal pharmacotherapy with minimal or no adverse effects.
Table 2
Classification of Asthma Severity and
Stepwise Approach in Children 0-4 Years
    Persistent
Severity Intermittent Mild Moderate Severe
IMPAIRMENT:
Symptoms
Nighttime awakenings
SABA use
     for symptoms
Interference with
     normal activity

≤2 days/wk
0
≤2 days/wk

None

>2 days/wk but not daily
1-2X/mo
>2 days/wk but not daily

Minor limitation

Daily
3-4X/mo
Daily

Some limitation

Throughout day
>1X/wk
Several times/day

Extremely limited
RISK: Exacerbations
requiring oral steroid
0-1/y ≥2 exacerbations in 6 mo requiring oral steroids, or ≥4 wheezing
episodes/1 y lasting >1 day AND risk factors for persistent asthma
STEPWISE
APPROACH:
Step 1
Preferred:
SABA prn
Step 2
Preferred:
Low-dose ICS.
Alternative:
Cromolyn or
montelukast
Step 3
Preferred:
Medium-dose
ICS
Step 4
Preferred:
Medium-dose
ICS + LABA or
montelukast
Step 5
Preferred:
High-dose ICS
+ LABA
or montelukast
Step 6
Preferred:
Same as step
5; + oral
steroid

SABA: short-acting beta-agonist; ICS: inhaled corticosteroid; LABA: long-acting beta-agonist.
Note: Step up or down depending on control. Persistent asthma requires daily medication.
Source: Reference 1.


Table 3
Classification of Asthma Severity and
Stepwise Approach in Individuals 5 Years or Older
    Persistent
Severity Intermittent Mild Moderate Severe
IMPAIRMENT:
Symptoms
Nighttime
SABA use for
      symptoms
Interference with
      normal activity
Lung function

≤2 days/wk
≤2X/mo
≤2 days/wk

None

FEV1 > 80%
predicted

>2 days/wk
3-4X/mo
>2 days/wk

Minor limitation

FEV1 > 80%
predicted

Daily
>1X/wk
Daily

Some limitation

FEV1 = 60-80%
predicted

Throughout day
Often, 7X/wk
Several times/day

Extremey limited

FEV1 < 60%
predicted
Normal FEV1/FVC:
8-19 y: 85%
20-39 y: 80%
40-59 y: 75%
60-80 y: 70%
5-11 y:
FEV1/FVC > 85%.
≥12 y:
FEV1FVC
normal
5-11 y:
FEV1/FVC > 80%.
≥12 y:
FEV1/FVC
normal
5-11 y:
FEV1/FVC = 75%-80%.
≥12 y:
FEV1/FVC
reduced 5%
5-11 y:
FEV1/FVC < 75%.
≥12 y:
FEV1/FVC
reduced >5%
RISK: Exacerbations
requiring oral steroid
0-1/y ≥2/y ≥2/y ≥2/y
STEPWISE
APPROACH:
Step 1
Preferred:
SABA prn
Step 2
Preferred:
Low-dose ICS.
Alternative:
Cromolyn,
nedocromil,
LTRA,
theophylline
Step 3
Preferred:
Low-dose ICS +
LABA, LTRA or
theophylline (≥12 y: +
LABA only preferred)
OR medium-dose ICS.
Alternative
(≥12 y):
Low-dose
ICS + LTRA,
theophylline, or zileuton
Step 4
Preferred:
Medium-dose ICS
+ LABA.
Alternative:
Medium-dose ICS +
LTRA or
theophylline
(≥12 y zileuton also)
Step 5
Preferred:
High-dose ICS +
LABA (≥12:
consider
omalizumab).
Alternative
(5-11 y):
High-dose
ICS + LTRA or
theophylline
Step 6
Preferred:
High-dose ICS +
LABA + oral steroid
(≥12: consider
omalizumab).
Alternative
(5-11 y):
High-dose
ICS + LTRA or
theophylline +
oral steroid

SABA: short-acting beta-agonist; ICS: inhaled corticosteroid; LABA: long-acting beta-agonist; LTRA: leukotriene receptor antagonist.
Each step: Assess control, patient education (compliance, inhaler technique, environmental control) and management of comorbidities.
Quick-relief medications for all patients: SABA prn or short course of oral steroid.
Note: Step up or down depending on control. Persistent asthma requires daily medication. Source: Reference 1.


The updated guidelines have consolidated the stepwise therapy approach to six steps and modified treatment options within each step for the three defined age groups. The progression of steps according to asthma severity includes: intermittent–Step 1, mild persistent-Step 2, moderate persistent–Step 3 or 4, and severe persistent–Step 5 or 6. The purpose is to initiate and adjust therapy to achieve the lowest level of treatment required to maintain control. The stepwise approach is meant to assist, not replace, the clinical decision making required to meet individual patient needs.1 Pharmacotherapy includes the use of quick-relief (short-acting beta2-agonists, systemic corticosteroids) and daily long-term control medications (inhaled corticosteroids, long-acting beta2-agonists, mast cell stabilizers, leukotriene modifiers, immunomodulators, and methylxanthines).1,3,6 TABLES 2 and 3 depict the updated recommendations in terms of the severity classifications and stepwise approach to therapy. Specific doses for the medications in each step are detailed in TABLES 4 and 5.

Quick-Relief Medications

Due to their rapid onset, quick-relief medications are used in all severities of asthma to control acute exacerbations. The short-acting beta2-agonists (SABAs), which are bronchodilators that relax smooth muscle, are the preferred therapy in Step 1 for intermittent asthmatics.1 Moreover, exercise-induced bronchospasms in any severity classification can be prevented by the administration of a SABA 15 minutes prior to the anticipated exertion.4 Metered-dose inhalers include albuterol, pirbuterol, and levalbuterol, and nebulizer solutions are available for albuterol and levalbuterol. The use of oral systemic beta2-agonists and regularly scheduled inhaled SABAs is not recommended due to increased adverse events and the potential for poorly controlled asthma. The use of a SABA more than two days per week for symptom relief, excluding exercise-induced bronchospasms, generally indicates inadequate asthma control and the need for initiating or intensifying long-term control therapy.1

Due to their ability to inhibit inflammatory cell migration and activation, decrease airway hyperresponsiveness, and block late-phase reaction to allergen, oral systemic corticosteroids (prednisone, methylprednisolone, and prednisolone) can be administered in patients experiencing moderate to severe acute exacerbations despite the use of quick-relief or long-term control medications. Anti-inflammatory medications can prevent progression of the exacerbating episode, speed recovery, and prevent further relapses resulting in a reduction of emergency room visits.1 Corticosteroid tapering is not necessary if the course of treatment is continued for a period of fewer than two weeks. Short-term rather than long-term adverse effects are more likely to occur from daily use of oral systemic corticosteroids for the quick-relief of exacerbations. Short courses of oral systemic corticosteroids may lead to gastrointestinal irritation, facial flushing, appetite stimulation, weight gain, headache, mood changes, hyperglycemia, leukocytosis, and hypokalemia. In context with these side effects, the benefits of systemic corticosteroids are currently deemed to outweigh the risks. Adequate long-term control of asthma can prevent exacerbations as well as the need for corticosteroids, thereby minimizing the adverse effects associated with them.5

Table 4
Asthma Medication Dosing, Quick Relief

Medication

<5 y 5-11 y ≥12 y
SABAs
HFA MDI
Albuterol 90 mcg/puff
Levalbuterol 45 mcg/puff

2 puffs q4-6h prn
NA <4 y

2 puffs q4-6h prn
2 puffs q4-6h prn

2 puffs q4-6h prn
2 puffs q4-6h prn
Nebulizer
Albuterol 0.63,1.25,
    2.5 mg/3mL, 5 mg/mL
Levalbuterol 0.31,0.63,
    1.25 mg/3mL, 1.25 mg/0.5mL

0.63-2.5 mg q4-6h prn

0.31-1.25 mg q4-6h prn

1.25-5 mg q4-8h prn

0.31-0.63 mg q8h prn

1.25-5 mg q4-8h prn

0.63-1.25 mg q8h prn
Anticholinergics
HFA MDI
Ipratropium 17 mcg/puff

NA

NA

2-3 puffs q6h
Nebulizer
Ipratropium sol 0.25 mg/mL

NA

NA

0.25 mg q6h
Systemic Corticosteroids (Dosing Applies to All 3)
Methylprednisolone
     2-, 4-, 6-, 8-, 16-,
32-mg tabs
Prednisolone 5-mg tabs,
     5, 15 mg/tsp
Prednisone 1-, 2.5-, 5-, 10-, 20-,
     50-mg tabs, 5 mg/mL, 5 mg/tsp
Short course: 1-2 mg/kg/day
for 3-10 days
(max 60 mg/day)
Short course: 1-2 mg/kg/day
for 3-10 days
(max 40-60 mg/day in
single or 2 divided doses
for 3-10 days)
Short course: 40-60 mg/day
in single or 2 divided doses
for 3-10 days

HFA: hydrofluoroalkane; MDI: metered-dose inhaler; NA: not applicable.
Source: Reference 1.

Long-Term Control Medications

Daily use of long-term control medications is necessary to achieve and maintain control of persistent asthma, regard less of the severity classification. The medications are divided into two classes: bronchodilators and anti-inflammatory agents. Anti-inflammatory agents include inhaled corticosteroids, leukotriene modifiers, cromolyn sodium, and nedocromil. Bronchodilators include long-acting beta2-agonists (LABAs) and methylxanthines. As asthma severity progresses from intermittent to persistent, long-term control medications are added to a patient’s regimen to achieve control of and to minimize symptoms. An important point to note is that the beneficial effects of long-term control medications generally do not occur for one to two weeks.1,3

Inhaled corticosteroids (ICSs) are the most consistently effective long-term control medication at all steps of care for persistent asthma, reducing impairment, and risk of exacerbations. Low-dose ICSs are the preferred daily medication to be added to a patient who has progressed in severity from intermittent to mild persistent asthma.1 ICSs for asthma therapy include beclomethasone, budesonide, flunisolide, fluticasone, mometasone, and triamcinolone. Adverse effects associated with the use of ICSs include dysphonia and oropharyngeal fungal infections (candidiasis), which can be prevented by having the patient use a spacer device with a metered-dose inhaler, rinse with water, and spit after each dose.1,3,6 For asthmatics in which low-dose inhaled corticosteroids do not control symptoms, medium- and high-dose ICS therapy can be initiated; however, increasing the ICS dose may place the patient at greater risk for long-term corticosteroid adverse effects.1 Long-term adverse side effects that are associated with chronic use of oral systemic corticosteroids include adrenal suppression, osteoporosis, and cataracts. In a 2000 study, 56 women with asthma on varying long-term ICS regimens were selected to have bone mineral densitometry to determine the prevalence of bone mineral density (BMD) loss with ICS use. The authors concluded that increasing BMD loss with increasing ICS dose (medium and high doses) reinforced the need to monitor BMD.7 Low, medium, and high doses for select ICSs can be found in TABLE 5.

Leukotriene modifiers interfere with the pathway of leukotriene mediators, which are released from mast cells, eosinophils, and basophils and may be used as an alternative, but not preferred, therapy for the treatment of patients who require Step 2 care for mild persistent asthma, as well as adjunctive therapy with ICSs in specific age-groups.1 These medications have also been shown to improve the FEV1 after exercise.1,3,8 Leukotriene modifiers block cysteinyl leukotriene effects such as smooth muscle contraction, airway edema, and the inflammatory process. Current leukotriene modifiers include the receptor antagonists montelukast sodium and zafirlukast and the 5-lipoxygenase inhibitor zileuton.3,5 While varying levels of drug–drug interactions can be observed with each leukotriene modifier, montelukast has the lowest incidence of these interactions. Zafirlukast can interact with warfarin by increasing the prothrombin time, increasing the effect of aspirin, and decreasing the effect of erythromycin and theophylline.4,6 Patients receiving zafirlukast who currently use or have previously used chronic oral systemic corticosteroids should also be monitored for a form of eosinophilic vasculitis-Churg-Strauss syndrome—in which patients may develop a vasculitic rash, eosinophilia, and increasing pulmonary, cardiac, and neuropathic symptoms.1,4,8 Drug interactions with theophylline and warfarin have also been reported with zileuton; however, the use of zileuton is low due to the potential for hepatotoxicity. Recommended dosing for the leukotriene modifiers can be found in TABLE 5.

Table 5
Asthma Medication Dosing, Long-Term Control

Medication

<5 y 5-11 y ≥12 y
ICSs (Select) Daily Dose (in mcg):
HFA MDI
Beclomethasone
    40, 80 mcg/puff

Flunisolide
    80 mcg/puff

Fluticasone
    44, 110, 220 mcg/puff

NA


NA


Low: 176;
medium: >176-352;
high: >352

Low: 80-160;
medium: >160-320;
high: >320
Low: 160;
medium: 320;
high: ≥640
Low: 88-176;
medium: >176-352;
high: >352

Low: 80-240;
medium: >240-480;
high: >480
Low: 320;
medium: >320-640;
high: >640
Low: 88-264;
medium: >264-440;
high: >440
DPI
Budesonide
90, 180, 200 mcg/inh

Fluticasone
50, 100, 250 mcg/inh

Mometasone
200 mcg/inh

NA


NA


NA

Low: 180-400;
medium: >400-800;
high: >800
Low: 100-200;
medium: >200-400;
high: >400
NA

Low: 180-600;
medium: >600-1200;
high: >1200
Low: 100-300;
medium: >300-500;
high: >500
Low: 200;
medium: 400;
high: >400 mcg
Nebulizer
Budesonide
    0.25, 0.5, 1 mg/2mL

Low: 0.25-0.5 mg;
medium: >0.5-1 mg;
high: >1 mg

Low: 0.5 mg;
medium: 1 mg;
high: 2 mg

NA
LABAs and LABA/ICS Combinations
HFA MDI
Fluticasone/salmeterol
    45, 115, 230 mcg/21 mcg
Budesonide/formoterol
    80, 160 mcg/4.5 mcg

NA

NA

1 puff bid

2 puffs bid

1 puff bid

2 puffs bid
DPI
Salmeterol 50 mcg/blister
Formoterol 12 mcg/capsule
Fluticasone/salmeterol
    100, 250, 500 mcg/50 mcg

NA
NA
NA

1 blister q12h
1 capsule q12h
1 inh bid

1 blister q12h
1 capsule q12h
1 inh bid
Leukotriene Modifiers
Montelukast 4-, 5-mg chew tab,
    4-mg granules, 10-mg tab
Zafirlukast 10-, 20-mg tab
Zileuton CR 600-mg tab
1-5 y: 4 mg HS

NA
NA
6-14 y: 5 mg HS

7-11 y: 10 mg bid
NA
10 mg HS

40 mg QD/20 mg bid
1,200 mg bid
Mast Cell Stabilizers
MDI
Cromolyn 0.8 mg/puff
Nedocromil 1.75 mg/puff

NA
NA <6 y

2 puffs qid
2 puffs qid

2 puffs qid
2 puffs qid
Nebulizer
Cromolyn 20 mg/ampule

≥2 y: 1 ampule qid

1 ampule qid

1 ampule qid
Methylxanthines
Theophylline liquid,
    sustained release tabs/caps
Initial dose: 10 mg/kg/day
(max depends on age)
Initial dose: 10 mg/kg/day
(max 16 mg/kg/day)
Initial dose: 10 mg/kg/day up
to 300 mg (max 800 mg/day)

HFA: hydrofluoroalkane; MDI: metered-dose inhaler; DPI: dry powder inhaler; NA: not available (not approved, no data available, or safety and efficacy not established for age-group); ICS: inhaled corticosteroid; LABA: long-acting beta-agonist; HS: bedtime; tsp: teaspoon; inh: inhalation. Source: Reference 1.

Cromolyn sodium and nedocromil are anti-inflammatory agents that stabilize mast cells and inhibit the acute response to exercise, allergens, and changes in air temperature.3,4,9 According to the EPR-3, they can be used as an alternative to low-dose inhaled corticosteroids in Step 2 care for mild persistent asthma or as preventive treatment before exercise or exposure to allergens.1 Prophylactic dosing consists of oral inhalation three to four times daily, and no difference in efficacy is evident between the two medications. Common side effects of cromolyn sodium and nedocromil include dysphonia, throat irritation, dizziness, cough, wheezing, nausea, and headache. Nedocromil may also produce symptoms of unpleasant taste and chest pain.3,4,9,10

LABAs are bronchodilators that relax bronchial smooth muscle by selective action on the beta2 receptors, similarly to the SABAs, but elicit an effect of at least 12 hours.3,6 Side effects include headache, tremor, tachycardia, palpitations, and nervousness. LABAs that are currently available include salmeterol and formoterol.4 LABAs are indicated for use with ICSs for long-term control and prevention of symptoms in moderate or severe persistent asthma, especially in individuals 12 years or older. LABAs are not to be used as monotherapy, except before exercise to prevent exercise-induced bronchospasm. Frequent use before exercise is discouraged due to decreased duration of action and the possibility that poorly controlled persistent asthma may be masked.1 Combination products containing an ICS and LABA include fluticasone/salmeterol and budesonide/formoterol. In a 2007 study comparing fluticasone/salmeterol versus budesonide/formoterol, the authors concluded that twice-daily treatment with fluticasone/salmeterol and budesonide/formoterol improved symptoms and lung function in patients with persistent asthma. Fluticasone/salmeterol was also found to significantly reduce the rate of moderate to severe exacerbations.11

The safety of LABA therapy has been reviewed by the FDA based on the Salmeterol Multicenter Asthma Research Trial (SMART).12 A black box warning has now been added to the labeling of any product containing a LABA.13 The results of the SMART study showed that there were small, yet statistically significant, increases in respiratory related deaths and life-threatening experiences in the population receiving salmeterol. Subgroup analyses suggested that there may be a greater risk in African Americans compared to Caucasians. Identification was not made regarding the mechanism behind the increased risk, but overall, the African American subjects exhibited lower baseline peak expiratory flows, higher rates of hospitalizations, and decreased use of inhaled corticosteroids than their Caucasian counterparts.14 This ethnic imbalance did not contribute to the fact that subjects recruited during phase I through an advertising campaign were more than three times as likely to die or have a life-threatening experience compared to phase II subjects, who were directly recruited through study investigators and had an established relationship with a health care provider.14 Studies have not identified an increased risk of deaths in patients using both LABAs and ICSs.14 Despite the black box warning, the EPR-3 modified the previous 2002 recommendations and concluded that the option of increasing the ICS dose should be given equal weight to adding a LABA to an ICS in patients with asthma whose condition is not sufficiently controlled by inhaled corticosteroid monotherapy.1

The methylxanthine, theophylline, is a mild to moderate bronchodilator used as alternative, not preferred, therapy for Step 2 care for mild persistent asthma or as adjunctive therapy with an ICS in patients 5 years or older.1 Theophylline causes bronchodilation by blocking phosphodiesterase, which results in an increase in cyclic AMP and may have mild anti-inflammatory effects. Theophylline tends to be used as a last-line therapy due to the need to monitor serum levels (therapeutic window is 5-15 mcg/mL), as well as the high incidence of drug–drug interactions. Side effects include tachycardia, nausea, vomiting, and headache, as well as central nervous system stimulation. Moreover, many drugs interact with theopylline, including CYP450 1A2 and 3A4 inducers such as carbamazepine and phenytoin, which may decrease theophylline levels.1,3,4

In 2003, the FDA approved omalizumab, a recombinant humanized monoclonal anti-IgE antibody, for adjunctive treatment in uncontrolled moderate to severe persistent asthma in patients 12 years or older who have had a positive skin test to a perennial aeroallergen. Dosing is based on patient weight and baseline IgE serum level and administered every two to four weeks via subcutaneous injection. No more than 150 mg can be given per injection site, so patients may require several injections at one time to achieve the appropriate dose.15 In a clinical trial review of 19 studies, the authors concluded that omalizumab was a safe and effective treatment in patients with IgE-mediated asthma; however, another study was conducted to determine the cost-effectiveness of omalizumab.16 The authors concluded that because of the high cost of the medication, omalizumab is not cost-effective and that other therapeutic alternatives should be explored prior to use.17 Omalizumab treatments range from $1,000 to $2,700 per month depending on the dosage, which does not include administrative or office fees.18 Furthermore, the FDA requested in 2007 that the manufacturer of omalizumab add a black box warning to the labeling indicating that anaphylaxis may develop after any dose of omalizumab up to 24 hours postinjection.19 Other potential side effects include injection-site reactions, headache, sinusitis, pharyngitis, and viral and upper respiratory tract infections.15,18 The EPR-3 only recommends omalizumab as adjunctive therapy in patients 12 years or older who require Step 5 or 6 care for severe persistent asthma.1

Routes of Administration and Technique

The primary route of administration for most preferred medications, both for quick-relief and long-term control, is through metered-dose or dry powder inhalers. Effective patient counseling is required to ensure the delivery of an adequate dose. Metered-dose inhalers (MDIs) require correct timing of breathing and actuating the dose from the canister, whereas dry powder inhalers (DPIs) consist of a measured dose that requires less coordination. Individuals 5 years and older can generally use an MDI or DPI, whereas younger children need to use valved-holding chambers with or without face masks to receive an adequate dose from an MDI. Valved holding chambers attach to the MDI and permit the medication to be delivered into the chamber, allowing the patient to inhale the medication when ready.20 Valved holding chambers should always be used with MDI corticosteroids to prevent the adverse events of dysphonia and thrush. An important point to note is that breath-actuated MDIs and DPIs cannot be used with a valved holding chamber. Priming of the MDI is necessary for new inhalers and inhalers that have not been used for several days to ensure that the full dose is received. Before each MDI use, the patient should be counseled to take off the inhaler cap, shake the MDI, breathe out, then breathe in slowly while pressing down on the canister to actuate the dose. The patient should then hold his or her breath for up to 10 seconds or as long as possible.1,4,5 For quick-relief medications, if taking more than one dose at a time, the patient should wait approximately 15 to 30 seconds prior to the next dose, then repeat the technique. There is no need to wait between the use of other medications.1 MDI actuators must be cleaned frequently with warm water and thoroughly dried before use. When using DPIs, patients should move the lever into position to open the mouthpiece, load the dose, and inhale forcefully and rapidly, in contrast to the slow inhalation required by MDIs.4 Patients must not exhale directly into the DPI to prevent the introduction of moisture. Some medications are available in nebulizer solutions, which are delivered as a fine mist through mouthpieces, face masks, or T-tubes. Nebulizer solutions are especially useful in patients who are unable or too young to correctly use an MDI with a valved holding chamber and face mask.1

CFC Versus HFA Inhalers

Due to negative effects on the ozone, the FDA has required all inhaler manufacturers to completely withdraw all inhalers containing the propellant chlorofluorocarbon (CFC) from the market by December 31, 2008.20 CFC propellant inhalers will be replaced with hydrofluoroalkane (HFA) inhalers, which are considered to be more environmentally friendly. Compared to CFC inhalers, HFA inhalers have the following characteristics: a shorter and less forceful spray, different smell and taste, shorter expiration date, and stickier consistency that requires more frequent cleaning.21 The reformulated albuterol inhalers are not AB-rated and are not considered equivalent; a new prescription is required to switch patients from a CFC to an HFA product or to switch between HFA products.20

Patient Counseling

Self-management education is emphasized in the EPR-3, and asthmatic patients should be able to assess asthma control and worsening symptoms and signs of asthma; understand and utilize an Asthma Action Plan; administer the appropriate medications correctly; and avoid triggers that worsen asthma.

Asthma control is classified into three categories according to the EPR-3: well controlled, not well controlled, and very poorly controlled.1 The components of control measure the patient’s impairment and consist of the frequency of respiratory symptoms, nighttime awakenings, interference with normal activity, use of a SABA, and FEV1 or peak flow measurement.1 An asthmatic patient who is well controlled is defined as having symptoms no more than two days per week, nighttime awakenings no more than once a month, no interference with normal activity, and SABA use no more than twice a week. In contrast, a very poorly controlled patient would have symptoms throughout the day, nighttime awakenings more than four times a week, extremely limited activity, and use of the SABA several times a day.1

The peak flow meter is a useful and inexpensive device to determine asthma severity, control, and response to therapy. The patient blows quickly and forcefully into the device and generates an objective measurement of his or her lung function. The patient’s peak flow meter result will fall within a “traffic light” system of green, yellow, and red zones.22 The Asthma Action Plan, which is emphasized within the EPR-3, provides the patient with instructions regarding asthma management based on the zone indicated by the use of the peak flow meter.1 The patient obtains a personal best measurement over a period of two weeks by using the peak flow meter twice a day. The patient’s personal best is the highest number achieved over the two-week period. The green zone indicates that the patient’s lung function (FEV1) is within 80% to 100% of personal best, current therapy is adequate, and the patient is well controlled. Once the patient has been within the green zone for a period of time (at least three months), step-down therapy may be warranted to reduce the medication load. The yellow zone indicates that the patient’s lung function is within 50% to 80% of personal best, that the patient should use a quick-relief medication immediately, and that long-term control therapy may need to be added or adjusted, since the patient is not well controlled. The red zone indicates a medical alert and that the patient is very poorly controlled. Within this zone, current lung function is less than 50% of personal best and quick-relief medication should be administered immediately and repeated every 20 minutes until paramedics arrive. The patient’s long-term control medications should be adjusted for better asthma control since the patient’s asthma classification has likely deteriorated to a severe persistent classification.1,5,6,23

As described previously, asthma triggers can exacerbate symptoms and decrease control. Individual triggers and sensitivities should be determined for both indoor and outdoor allergens. Avoidance of tobacco use and secondhand smoke should also be emphasized. Skin or in vitro testing may be used to determine sensitivity to perennial indoor allergens.1 Patients with asthma are at greater risk of influenza complications if they are exposed to the virus. Therefore, patients with asthma who are at least six months of age and have no contraindications to the vaccine should get immunized annually.1

When asthma symptoms worsen, the patient should be encouraged to follow up with a health care provider. Follow-up visits should be scheduled at two- to six-week intervals upon initiation of medications to verify symptom control and maintenance of the disease state. Regular follow-up appointments with a health care professional should be made at one- to six-month intervals to periodically assess control. If a patient has been therapeutic and symptom free for approximately three or more consecutive months, step-down therapy can be initiated with three- to six-month-interval follow-up appointments. At every visit with a health care professional, asthma control, inhaler technique and compliance, environmental control, and management of comorbidities should be reassessed.1

Special Populations

Special consideration should be given to patients with asthma who are pregnant or of different ethnic backgrounds. Patients who are pregnant and have asthma should be monitored for control at every prenatal visit, since 33% of asthma symptoms worsen in women who are pregnant.1 Medications need to be adjusted according to the current asthma classification based on control to reduce complications to both the mother and fetus. For the mother, exacerbations can lead to preeclampsia, hospitalization, work loss, and disability. The fetus can suffer from decreased fetal growth and lack of oxygen, leading to failure to survive. The benefit of asthma therapy in pregnancy outweighs the risk and complications of uncontrolled asthma.24

Additionally, the patient who is pregnant should be advised to quit smoking, since smoking increases the risk of the child developing asthma within the first five years of life. Albuterol is the preferred SABA for quick-relief (Pregnancy Category C), and budesonide is the preferred inhaled corticosteroid for long-term control (Pregnancy Category B), because these medications have the most data regarding safety in pregnancy. Intranasal corticosteroids may be utilized in the patient who is pregnant and has asthma with allergic rhinitis due to the low risk for systemic adverse effects. The updated guidelines state that leukotriene modifiers may be used in long-term control, but limited studies are available in pregnancy.1

Awareness of ethnic and racial differences in asthma should be monitored by the health care professional. Minorities often receive a lower level of care than Caucasians and morbidity and mortality rates among these patients have not improved, despite the availability of effective medications to control the disease state. A large portion of minorities live in large urban cities in which exposure to asthma triggers and allergens is extremely high. Education regarding these triggers should be emphasized to the asthmatic patient and cohabitating family members.1

Pharmacist’s Role

The pharmacist is in an opportune position to provide asthma patients with self-management education as emphasized in the EPR-3. Self-management education has been shown to reduce urgent care visits and hospitalizations.1 A partnership between the pharmacist and asthma patient or child’s caregiver is required for effective asthma management. Regardless of the setting in which the pharmacist operates, the first step the pharmacist can take to establish this partnership is to identify the patient who is poorly controlled: asthma symptoms throughout the day, nighttime awakenings at least one to four times weekly, interference with normal activity, and increased use of a SABA several times per day for symptom control.1

The pharmacist, as part of the health care team, can assist in improving health outcomes by

  1. Assisting the patient with identifying and removing asthma triggers
  2. Educating the patient regarding the use of quick-relief and long-term control medications, including the proper technique for inhaling medications
  3. Educating the patient regarding the use of the peak flow meter to monitor asthma control
  4. Assisting the patient to establish and/or use a personal Asthma Action Plan
  5. Assisting the patient’s health care provider with assessment of asthma control
  6. Monitoring the patient’s medication use and refill intervals to assess asthma control
  7. Identifying OTC inhaler use and directing the patient to seek medical care.23

References

  1. National Heart, Lung, and Blood Institute, National Asthma Education and Prevention Program. Expert panel report 3: guidelines for the diagnosis and management of asthma. U.S. Department of Health and Human Services. August 2007. NIH publication 07-4051. www.nhlbi.nih.gov/guidelines/asthma/asthgdln.htm. Accessed February 15, 2008.
  2. American Academy of Allergy Asthma & Immunology. Asthma statistics. www.aaaai.org/media/resources/media_kit/asthma_ statistics.stm. 2008. Accessed February 15, 2008.
  3. Kelly HW, Sorkness CA. Asthma. In: Dipiro JT, Talbert RL, Yee GC, et al, eds. Pharmacotherapy: A Pathophysiologic Approach. 6th ed. New York, NY: McGraw-Hill Co.; 2005:503-535.
  4. Tsoukleris MG, Katona BG. Asthma and chronic obstructive pulmonary disease. In: Shargel, et al, eds. Comprehensive Pharmacy Review. 5th ed. Baltimore, MD: Lippincott Williams & Wilkins; 2004:1042-1065.
  5. Self TH. Asthma. In: Koda-Kimble MA, Young LY, Kradjan WA, et al, eds. Applied Therapeutics: The Clinical Use of Drugs. 8th ed. New York, NY: Lippincott Williams & Wilkins; 2005:23-1-40.
  6. Knudsen D, Wells Q. Asthma treatment guidelines and use of inhalers. Pharmacy Times. https://secure.pharmacytimes.com/lessons/200611-03.asp. Accessed April 1, 2008.
  7. Bonala SB, et al. Bone mineral density in women with asthma on long-term inhaled corticosteroid therapy. Ann Allergy Asthma Immunol. 2000;85:495-500.
  8. Horwitz RJ, et al. The role of leukotriene modifiers in the treatment of asthma. Am J Respir Crit Care Med. 1998;157:1363-1371.
  9. Cromolyn sodium. In: Klasco RK, ed. DRUGDEX System. Greenwood Village, CO; Thomson Micromedex; 2008.
  10. Nedocromil. In: Klasco RK, ed. DRUGDEX System. Green-wood Village, CO: Thomson Micromedex; 2008.
  11. Dahl R, et al. EXCEL: a randomized trial comparing salmeterol/fluticasone propionate and formoterol/budesonide combinations in adults with persistent asthma. Respir Med. 2006;100:1152-1162.
  12. Nelson NS, et al. The salmeterol multicenter asthma research trial (SMART): a comparison of usual pharmacotherapy for asthma or usual pharmacotherapy plus salmeterol. Chest. 2006;129:15-26.
  13. Food and Drug Administration. FDA public health advisory: serevent diskus (salmeterol xinafoate inhalation powder), advair diskus (fluticasone propionate & salmeterol inhalation powder), foradil aerolizer (formoterol fumarate inhalation powder).www.fda.gov/cder/drug/advisory/LABA.htm. 2006. Accessed April 4, 2008.
  14. Nelson HS. Is there a problem with inhaled long-acting beta-adrenergic agonists? J Allergy Clin Immunol. 2006;117:3-16.
  15. Xolair [package insert]. San Francisco, CA: Genentech, Inc.; 2007. www.xolairhcp.com/xolairhcp/pdf/xolair-prescribing.pdf. Accessed April 4, 2008.
  16. Hendeles L, et al. Anti-immunoglobulin E therapy with omalizumab for asthma. Ann Pharmacotherapy. 2007;41:1397-1410.
  17. Wu AC, et al. Cost-effectiveness of omalizumab in adults with severe asthma: results from the asthma policy model. J Allergy Clin Immunol. 2007;120:1146-1152.
  18. Davydov L. Omalizumab (xolair) for treatment of asthma. Am Fam Physician. www.aafp.org/afp/20050115/steps.html. Accessed April 4, 2008.
  19. Food and Drug Administration. Stronger warning proposed for xolair. www.fda.gov/consumer/updates/xolairup.html. 2007. Accessed April 5, 2008.
  20. American Society of Health-System Pharmacists. Albuterol meter-dosed inhalers.www.ashp.org/s_ashp/bulletin.asp?CID=1500&DID=1544&id=11. 2008. Accessed February 1, 2008.
  21. American Lung Association. CFC-free inhalers: time to make the switch.www.lungusa.org/site/pp.asp?c=dvLUK9O0E&b=2222599.2007. Accessed February 1, 2008.
  22. American Lung Association. Peak flow meters.www.lungusa.org/site/pp.asp?c=dvLUK9O0E&b=22586. 2006. Accessed April 6, 2008.
  23. Lenfant C. The role of the pharmacist in improving asthma care. NIH 95-3280.www.nhlbi.nih.gov/health/prof/lung/asthma/asmapmcy.pdf. 1995. Accessed April 6, 2008.
  24. American Academy of Allergy Asthma and Immunology. Tips to remember: asthma and pregnancy. www.aaaai.org/patients/ publicedmat/tips/asthmaandpregnancy.stm. 2007. Accessed April 5, 2008.

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