To the Rescue: Fast-Acting Medications for Asthma Attacks

A chronic inflammatory disease with acute inflammatory occurrences, asthma is a major disease of the industrialized world, and it is alarmingly on the rise.^1,2 It is the most common medical emergency among children, and it is associated with morbidity and mortality in all age groups. Pollution (including cigarette smoke), delays seeking medical attention, and sympathomimetic side effects of asthma medications have been blamed for the recent increase in asthma incidence.¹

Asthmatic bronchoconstriction consists of 2 stages?early and late?and it appears to be a response to allergens or triggers. Mast cells and neutrophils are early responders to allergens or triggers such as exercise, cold air, and fog, whereas eosinophils and possibly basophils respond in the later phase.² Asthmatic airways display mucus plugging, edema, and contraction of the smooth muscle, resulting in resistance and difficulty with both inhaled and exhaled airflow.

As the inflammation worsens and breathing becomes more difficult, the patient uses accessory muscles to work harder to overcome the resistance, causing expiration to become an active process instead of a passive one. Lung volume increases to permit expiration, eventually leading to hyperinflation and gas trapping. Asthmatic patients often present with tachycardia, tachypnea, wheeze, and diaphoresis. Eventually, acid-base abnormalities may develop as the obstruction worsens.¹

Despite an array of treatment options, inadequate medical treatment and undermedication often lead to emergent situations and may even be responsible for the increasing trend in asthma mortality.¹ Whereas maintenance medications?such as long-acting beta² agonists, leukotriene receptor antagonists, and inhaled steroids?prevent asthma attacks, fast-acting or "rescue"medications are designed to stop the attack immediately. Rescue medications vary by setting and patient needs and include inhaled or intravenous (IV) beta²-agonist therapy, aminophylline, and magnesium.

Inhaled Treatments

Frequently prescribed for acute asthma attacks, beta-adrenergic medications?such as albuterol (Proventil, Ventolin)?work quickly and reliably to open airways and calm the attack. Beta-adrenergic medications stimulate adenyl cyclase, the enzyme responsible for catalyzing formation of 3',5'-cyclic adenosine monophosphate (cAMP) from adenosine triphosphate. cAMP then mediates cellular responses and is associated with bronchial smooth muscle relaxation and the inhibition of immediate hypersensitivity mediators, especially from mast cells.³

Albuterol has been shown to have a preferential affinity to beta² receptors. Other short-acting inhaled beta² agonists with beta² preference are shown in the Table.⁴

Although the beta² receptors are primarily located in the bronchial smooth muscle, a concentration ranging from 10% to 50% has been found in the heart as well.³ Logically, cardiotoxicity is a potential yet serious concern. As a result, albuterol and other inhaled beta² agonists were initially prescribed at 2-to 4-hour intervals. Interval dosing was expected to minimize patient overexposure to the beta² agonist, thus preventing adverse effects. Recent studies, however, suggest that, for acute patients, continuous nebulization may be more effective and as safe as interval treatment. Side effects, although infrequent with inhaled treatment, include hypokalemia, tremor, and hyperglycemia.¹

A recent advancement in beta²-agonist therapy is the marketing of levalbuterol (Xopenex). Traditional albuterol is a racemic 50:50 mixture of Rand S-albuterol. Its beneficial bronchodilation properties have been attributed to the R-albuterol isomer.

Whereas S-albuterol had been thought to be inert, preclinical studies suggest the opposite: S-albuterol may exert an effect on the bronchiolar tissue, and its effect may be potentially harmful. Studies suggest that Salbuterol may exhibit contractile-agent characteristics by increasing reactivity to histamine, promoting eosinophil activation, and increasing intracellular calcium levels, which causes the airway cells to shorten. Additionally, Salbuterol appears to be retained in the lung tissue longer than the R isomer, thus possibly decreasing the efficacy of additional racemic albuterol doses.⁵

The rationale for developing the levalbuterol solution is clear: levalbuterol, the isolated R-albuterol isomer, would provide the efficacy of the racemic solution without the detrimental effects of the S isomer. Although levalbuterol is more potent than racemic albuterol, drawbacks still exist. The cost of levalbuterol solution (~6 times the cost of racemic solution) presents a potential barrier for patients. Additionally, levalbuterol is available only as a nebulizing solution. Because it is not available as a metered-dose inhaler (MDI), levalbuterol is not portable for school-aged children or patients on the go.⁵

Racemic albuterol is available in several branded and generic formulations, including an MDI, a solution for nebulization, immediate-and extendedrelease oral tablets, and an oral solution.

Inhaled anticholinergic medications also aid bronchodilation. Ipratropium bromide prevents bronchoconstriction by blocking cholinergic receptors in the airways. Systemic anticholinergic side effects are minimal; less than 1% of the inhaled therapy is absorbed. Its onset is slower than that of the beta² agonists. When used in conjunction with racemic albuterol, ipratropium is more effective than racemic albuterol alone. Ipratropium is available as both an MDI and a nebulizing solution.⁵

Parenteral Treatments

Parenteral treatments for asthma induced bronchoconstriction are primarily administered in acute-care situations. In critical illness, severe bronchoconstriction and mucus plugs in the airways may obstruct inhaled drug delivery to the lung tissue.¹ If the drug is unable to reach the affected tissue, maximizing or even exceeding the dose will not be advantageous. Thus parenteral administration of beta² agonists is warranted.

Terbutaline (Brethine) is typically the parenteral beta² agonist drug of choice, because it has fewer adverse effects than epinephrine.⁵ Adverse effects still exist, however, and they include dysrhythmias, hypertension, and myocardial ischemia,⁵ along with the adverse effects associated with inhaled beta²-agonists.¹ Terbutaline is administered subcutaneously?never intravenously?as a 0.25-mg dose. A second dose may be given in 15 to 20 minutes if no improvement is noted. The total dose over 4 hours should not exceed 0.5 mg.⁶ Initiating parenteral beta²-agonist treatment in an acute situation often reverses bronchoconstriction and may even prevent hospital admission.¹

Administering IV magnesium sulfate is another option for bronchoconstriction in children who are unresponsive to inhaled therapies. Magnesium antagonizes the uptake of calcium by smooth muscle, causing relaxation and bronchodilation.¹ Doses of 0.25 mg per kilogram with a maximum of 2 g have been used in pediatric patients.⁷ The most common side effect is hypotension. Clinical data are insufficient to recommend routine IV magnesium treatment. If it is used only as a second- or third-line therapy, however, magnesium sulfate has shown efficacy in emergency department or intensive care patients.¹

IV aminophylline, although not popular in the United States, remains an option for asthmatic patients who are refractory to maximized beta²-agonist therapy. Its oral counterpart, theophylline, often is used for maintenance therapy. Benefits of aminophylline therapy include an inotropic effect on the respiratory muscles and antiinflammatory effects. Its disadvantages include a narrow therapeutic window and side effects such as seizure, fever, and excitability. In one case, brain damage was associated with theophylline overdose. The clinician is encouraged to weigh the pros and cons of aminophylline carefully before initiating therapy.¹

Acute asthma can be a scary situation for everyone who may involved: the patient, the family, a caregiver, a colleague, a friend, or a classmate. Whereas maintenance medications work to prevent acute asthma symptoms, breakthrough attacks are still quite likely to occur. Whether in an ambulatory or an acute care situation, rescue medications are essential as asthma treatments in emergent situations.

Dr. Holmberg is a pharmacist with Phoenix Children's Hospital, Phoenix, Ariz.

For a list of references, send a stamped, self-addressed envelope to: References Department, Attn. A. Stahl, Pharmacy Times, 241 Forsgate Drive, Jamesburg, NJ 08831; or send an e-mail request to: astahl@ascendmedia.com.