Asthma Treatment

Joel M. Hartman

Jason W. Caldwell

Rodolfo M. Pascual

Stephen P. Peters

I. GENERAL PRINCIPLES OF TREATMENT

A. Asthma heterogeneity

There is considerable heterogeneity with respect to clinical presentation, severity, natural history, response to therapy, and pathogenetic factors among patients with asthma. Asthma should be considered as a syndrome rather than a single entity because it probably consists of multiple disorders having common clinical manifestations. Response to asthma therapy is also variable, underscoring the importance of ongoing follow-up and evaluation to assess impairment and disease control.

B. Main components of therapy

Recent Expert Panel Reports and practice guidelines have anchored effective asthma care to four key components:

1. Assessment and monitoring of severity and control

2. Control of environmental factors and comorbid conditions

3. Partnering with patients and families

4. Pharmacologic therapy

C. Asthma severity and control as the basis for treatment

1. Severity versus control. Ongoing assessment and monitoring are integral to achieving adequate disease control and minimizing functional limitations from the disease. Appropriate patient surveillance is linked to two key concepts: severity and control. Severity is defined as the intrinsic intensity of the disease process, whereas control is defined by the degree to which asthma manifestations are minimized and goals of therapy are met. Asthma severity is assessed and used to guide appropriate decision making with regard to medication choices and other therapeutic interventions. Although assessing severity is most accurate in patients prior to starting therapy, many patients present on preexisting regimens to a new health care provider. Once medication is initiated, the focus shifts to the assessment of control, guiding decisions regarding medication maintenance and adjustment.

2. Impairment versus risk. Both asthma severity and control include the domains of impairment and risk. Impairment encompasses symptom intensity and the resultant functional limitations. While evaluation of impairment can usually be elicited by careful history, questionnaires (e.g., Asthma Control Test) have been developed to help standardize the assessment of impairment. The risk domain encompasses the likelihood of exacerbations, decline in lung function, reduced growth in children, and risk of adverse medication effect. The test most used to evaluate the risk domain is spirometry. Particularly important in risk assessment is the use of the forced expiratory volume in 1 second (FEV₁) expressed
as a percent of the predicted value or as a proportion of the forced vital capacity (FVC) or FEV₁/FVC. Regardless of the methods used for assessment, both impairment and risk are key domains in the evaluation of asthma severity and control.

D. Objectives of treatment

With regard to treatment, objectives for the short term include the immediate relief of symptoms and airflow obstruction. Long-term objectives include preventing chronic and troublesome symptoms; the maintenance of as “normal” pulmonary function as possible; maintaining normal activity levels; preventing exacerbations, emergency department visits, and hospitalizations; minimizing the side effects of medications; and meeting the patient’s and family’s expectations for asthma treatment.

E. Stepped care. Current guidelines emphasize classifying asthma severity as intermittent or persistent; persistent asthma is further categorized as mild, moderate, or severe. In practice, the emphasis is on assessment of asthma severity prior to initiating therapy with future assessment of control for monitoring and adjusting therapy. Patients at any level of impairment may have severe exacerbations, usually due to infections or airborne exposures (e.g., allergens, irritants). It is for this reason that recent guidelines modified the designation of “mild intermittent asthma” to become “intermittent asthma,” acknowledging that a patient at any level of severity can have severe exacerbations.

Tables 9-1 and 9-2 summarize an overview of the pharmacology of asthma therapy as outlined by NAEPP Expert Panel Report according to asthma phenotype classification. In order to avoid unnecessary long-term medication side effects, the minimal amount of medication that is required to provide control of inflammation, symptoms, and airflow limitation should be used. The key principle is that severe asthma requires aggressive pharmacological therapy, whereas mild or improving asthma requires less medication, and therapy should be stepped-up and stepped-down accordingly. In newly diagnosed symptomatic asthmatics, it is often recommended that asthma therapy begin at one step higher than the patient’s current status, followed by a cautious reduction in therapy once the patient is clinically stable. With regard to categorization of asthma severity, it should be based on the lowest level of treatment required to maintain control.

II. CONSIDERATIONS IN DELIVERY OF ASTHMA MEDICATIONS

A. Route and delivery. Medications for asthma can be administered by either local (inhaled) or systemic (ingested or parenteral) routes. The major advantage to inhaled therapy is delivering higher concentrations of drug directly to the airways while minimizing systemic side effects. When compared to systemic administration, local/aerosol delivery provides a more rapid onset of action with fewer side effects. When used properly, the traditional metered dose inhaler (MDI), dry powder inhalers (DPI), and nebulized forms provide comparable effects. However, the current Expert Panel Report (EPR-3) recommends the use of nebulized forms of bronchodilators for acute asthma in the emergency room.

Table 9-1 Stepwise Approach for Managing Asthma in Patients ≥12 Years of Age

Intermittent Asthma	Persistent Asthma: Daily Medication (Step Up or Down Based on Assessment of Control)
Step 1 Preferred: SABA prn	Step 2 Preferred: Low-dose ICS *Alternative:* LTRA, nedocromil, or theophylline	Step 3 Preferred: Low-dose ICS + LABA or medium-dose ICS *Alternative:* Low-dose ICS + either LTRA, theophylline, or Zileuton	Step 4 Preferred: Medium-dose ICS + LABA *Alternative:* Medium-dose ICS + either LTRA, theophylline, or zileuton	Step 5 Preferred: High-dose ICS + LABA and Consider omalizumab for patients with allergic asthma	Step 6 Preferred: High-dose ICS + LABA + oral corticosteroid and Consider omalizumab for patients with allergic asthma
At each step: Patient education, environmental control, and management of comorbidities
(Reproduced 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.)

Table 9-2 Long-Term Controller Medications

Name/Products

Indications/Mechanisms

Potential Adverse Effects

Therapeutic Issues

Corticosteroids

Inhaled (ICS):

Beclomethasone dipropionate

Budesonide

Ciclesonide

Flunisolide

Fluticasone propionate

Mometasone furoate

Triamcinolone acetonide

Indications

Long-term prevention of symptoms; suppression, control, and reversal of inflammation

Reduce need for oral steroid

Mechanisms

Block late reaction to allergen and reduce BHR

Inhibit cytokine production, adhesion protein activation, and inflammatory cell migration and activation

Reverse beta2 receptor downregulation Inhibit microvascular leakage

Cough, dysphonia, oral thrush

In high doses, systemic effects may occur (e.g., adrenal suppression, osteoporosis, skin thinning, easy bruising).

In low to medium doses, suppression of growth velocity in children, but this effect might be transient (clinical significance has not been established).

Spacer/holding chamber devices with nonbreath-activated MDIs and mouth washing after inhalation decrease local side effects.

Preparations not absolutely interchangeable on a mcg or per puff basis

Risks of uncontrolled asthma should be weighed against the limited risks of ICS therapy.

“Adjustable dose” approach to treatment may enable reduction in cumulative dose of ICS treatment over time without sacrificing maintenance of asthma control.

Dexamethasone is not included as an ICS for long-term control because it is highly absorbed and has long-term suppressive side effects.

Systemic:

Methylprednisolone

Prednisolone

Prednisone

Indications

Short-term (3-10 d) “burst”: to gain prompt control of inadequately controlled persistent asthma

Long-term prevention of symptoms in severe persistent asthma: suppression, control, and reversal of inflammation

Mechanisms

Same as inhaled

Short-term use: reversible abnormalities in glucose metabolism, increased appetite, fluid retention, weight gain, mood alteration, hypertension, peptic ulcer, and rarely aseptic necrosis

Long-term use: adrenal axis suppression, growth suppression, dermal thinning, hypertension, diabetes, Cushing’s syndrome, cataracts, muscle weakness, and—in rare instances—impaired immune function

Consideration should be given to coexisting conditions that could be worsened.

Use at lowest effective dose. For long-term use, alternate-day am dosing produces the least toxicity.

Immunomodulators

Omalizumab (anti-IgE) for subcutaneous use

Indications

Long-term control and prevention of symptoms in adults (≥12 y) with moderate to severe persistent allergic asthma inadequately controlled on ICS

Mechanisms

Binds circulating IgE preventing it from binding to FcεR1 receptors on basophils and mast cells

Decreases mast cell mediator release from allergen exposure

Decreases the number of Fc ε R1s in basophils and submucosal cells

Pain and bruising of injection sites in 15%-20% of patients

Anaphylaxis reported

Malignant neoplasms reported in 0.5% of patients compared to 0.2% receiving placebo; relationship to drug is unclear.

Monitor patients following injection. Be prepared to identify and treat anaphylaxis that may occur.

Dose is administered every 2-4 wk and is dependent on body weight and IgE level before therapy.

A maximum of 150 mg can be given in one injection.

Needs to be stored under refrigeration at 2°C-8°C

Whether patients will develop significant antibody titers with long-term use is unknown.

Leukotriene receptor antagonists (LTRAs)

Mechanisms

Selective competitive inhibitor of CysLT₁ receptor

May attenuate EIB in some patients

Do not use LTRA + LABA as a substitute for ICS + LABA.

Montelukast tablets and granules

Indications

Long-term control and prevention of symptoms in mild persistent asthma for patients ≥1 y. May be used in combination with ICS as combination therapy in moderate persistent asthma

No specific adverse effects have been identified

Rare cases of Churg-Strauss have occurred but the association is unclear

A flat dose-response curve, without further benefit, if dose is increased above those recommended

Administration with meals decreases bioavailability; take at least 1 h before or 2 h after meals.

Zafirlukast is a microsomal P450 inhibitor that can inhibit metabolism of warfarin. Monitor INR during administration.

Patients should be warned to discontinue if they experience signs and symptoms of liver dysfunction, and patients’ LFTs should be monitored.

Zafirlukast tablets

Indications

Long-term control and prevention of symptoms in mild persistent asthma for patients ≥7 y. May also be used with ICS as combination therapy in moderate persistent asthma

Postmarketing surveillance has reported cases of reversible hepatitis and, rarely, irreversible hepatic failure resulting in death and liver transplant.

5-Lipoxygenase inhibitor

Zileuton tablets

Mechanisms

Inhibits the production of LTs from arachidonic acid, both LTB₄ and the cysteinyl leukotrienes

Indications

Long-term control and prevention of symptoms in mild persistent asthma for patients ≥12 y

May be used with ICS as combination therapy in moderate persistent asthma

Elevation of liver enzymes reported. Limited case reports of reversible hepatitis and hyperbilirubinemia

Microsomal P450 inhibitor that can inhibit the metabolism of warfarin and theophylline.

Monitor hepatic enzymes (ALT).

Long-acting beta₂-agonists (LABAs)

Inhaled LABA:

Formoterol

Salmeterol

Oral:

Albuterol, sustained-release

Indications

Long-term prevention of symptoms, added to ICS

Prevention of EIB

Not to be used to treat acute symptoms or exacerbations.

Mechanisms

Smooth muscle relaxation following adenylate cyclase activation and increase in cyclic AMP, producing function antagonism of bronchoconstriction

Compared to SABA, salmeterol (but not formoterol) has a slower onset of action. Both salmeterol and formoterol have longer duration of action (>12 h) compared to SABA.

Tachycardia, skeletal muscle tremor, hypokalemia, QTc prolongation in overdose

A diminished bronchoprotective effect may occur within 1 wk of chronic therapy. Clinical significance has not been established.

Potential risk of uncommon, severe, life-threatening or fatal exacerbation

Not to be used to treat acute symptoms or exacerbations

Should not be used as monotherapy for long-term control of asthma or as anti-inflammatory therapy

May provide more effective symptom control when added to standard doses of ICS compared to increasing ICS dosage

Clinical significance of potentially developing tolerance is uncertain.

Decreased duration of protection against EIB may occur with regular use.

Inhaled route preferred because LABAs are longer acting and have fewer side effects than oral sustained-release agents.

Methylxanthines

Theophylline, sustained-release tablets and capsules

Indications

Long-term control and prevention of symptoms in mild persistent asthma or as adjunctive with ICS in moderate or persistent asthma

Mechanisms

Smooth muscle relaxation from phosphodiesterase inhibition and possibly adenosine antagonism

May affect eosinophilic infiltration into bronchial mucosa as well as decreases T cell numbers in epithelium

Increases diaphragm contractility and mucociliary clearance

Dose-related acute toxicities include tachycardia, nausea and vomiting, tachyarrhythmias (SVT), CNS stimulation, headache, seizures, hematemesis, hyperglycemia, and hypokalemia.

Adverse effects at usual therapeutic doses include insomnia, gastric upset, aggravation of ulcer or reflux, increase in hyperactivity in some children, and difficulty in urination in elderly males who have prostatism.

Maintain steady-state serum concentrations between 5 and 15 µg/mL. Routine serum concentration monitoring is essential due to significant toxicities, narrow therapeutic window, and individual differences in clearance.

Patients should be told to discontinue if they experience toxicity.

Not generally recommended for exacerbations. There is minimal evidence for added benefit to optimal doses of SABA.

Quick-relief medications

Short-acting beta₂-agonists (SABAs)

Inhaled SABA:

Albuterol

Levalbuterol

Pirbuterol

Indications

Relief of acute symptoms

Preventative treatment for EIB prior to exercise

Mechanisms

Binds to beta-2 adrenergic receptor, producing smooth muscle relaxation following adenylate cyclase activation and increase in cyclic AMP producing functional antagonism of bronchoconstriction

Tachycardia, skeletal muscle tremor, hypokalemia, increased lactic acid, headache, and hyperglycemia. Inhaled route, in general, causes few systemic adverse effects.

Patients with preexisting cardiovascular disease, especially the elderly, may have adverse cardiovascular reactions with inhaled therapy.

Drugs of choice for acute bronchospasm. Inhaled route has faster onset, fewer adverse effects, and is more effective than systemic routes. Oral systemic beta₂-agonists are not recommended.

For patients who have intermittent asthma, regularly scheduled daily use neither harms nor benefits asthma control. Regularly scheduled daily use is not recommended.

Regular use >2 d/wk for symptoms control (not EIB prevention), increasing use, or lack of expected effect indicates inadequate control

For patients frequently using SABA, anti-inflammatory medication should be initiated or intensified.

Levalbuterol at one-half the mcg dose produces clinically comparable bronchodilation and systemic side effects as racemic 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.)

B. Spacers and valved holding chambers (VHCs). The principal function of both spacers and VHCs is to retain large particles emitted from the MDI so that they do not deposit in the oropharynx, thereby allowing a higher proportion of small, respirable particles to be inhaled. There is a large variability between devices regarding delivery of the respirable dose. Generally, VHCs are preferred over spacers as they both aggregate larger particles in the perimeter of the tube and allow patients a brief period in which to coordinate their inhalation. Currently, no specific combination of MDI and VHC has been specifically approved for use by the FDA.

III. SPECIFIC MEDICATIONS

A. Beta-2 adrenergic receptor agonists

1. Inhaled short-acting beta-2 adrenergic agonists (SABAs). The SABAs are the most important class of quick relief medications for asthma. Agonist-mediated stimulation of β₂ adrenergic receptors activates adenylyl cyclase, causing formation of intracellular cyclic-AMP with resultant bronchial smooth muscle relaxation. Significant effects of β-adrenergic stimulation in asthma include bronchodilation, facilitation of mucociliary clearance, and inhibition of mast cell mediator release, although whether β-agonists produce significant inhibition of mast cell mediator release in vivo is questionable. Several selective β₂-agonists are available including pirbuterol, albuterol, and levalbuterol (purified R-isomer of albuterol). In general, these agents are safe with few toxic effects even when used in high doses. However, some dose-dependent side effects are seen with β₂

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