Update on asthma pharmacotherapy

Over the past several years, newer pharmacologic agents and pharmaceutical products have been introduced to assist clinicians in providing care to children with asthma.

Beta agonists

A significant change occurred last year in the pharmaceutical availability of short-acting beta agonist (SABA) agents. After Dec. 31, 2008, all SABA metered dose inhalers (MDI) containing chlorofluorocarbon (CFC) propellants were prohibited from being sold in the United States, due to the destructive effects CFCs have on the ozone layers.

CFC propellants have been replaced by hydrofluoroalkane (HFA) propellants. Differences between CFC and HFA SABA inhalers exist. Because of differences in the spray emitted from the inhaler, patients may notice that HFA MDIs have a different taste or texture when compared with CFC inhalers. The spray emitted from HFA inhalers is less forceful and has a smaller plume.

Some patients may have difficulty determining when the MDI is empty. No reliable method is available to determine when a MDI canister is empty, including shaking and feel or placing the inhaler canister in water to float to see that it is empty. If patients are not sure when the last refill of SABA MDI was obtained or how many puffs may be remaining in their current inhaler, it is best to obtain a new inhaler.

One product – Ventolin (GlaxoSmithKline) – has a dose counter, which some patients may find useful. Albuterol MDI products contain 200 doses. The amount of active drug deposited in the lungs may be greater with higher doses of HFA inhalers compared with CFC inhalers. An unfortunate consequence of the phasing out of CFC-based MDI products is that no generic HFA-based products are available, and current HFA-based products are generally more expensive.

Three SABA agents are available – albuterol, levalbuterol, and pirbuterol. The efficacy and safety profiles of these agents are similar. Pirbuterol (Maxair) is available as a MDI and a breath-actuated metered-dose inhaler, and is labeled for use in people aged 12 and older.

While some may assess levalbuterol – the purified D-rotatory isomer of albuterol – as more effective and safer than albuterol, most generally believe that these two agents are similar. The latest asthma guidelines by the National Heart, Lung, and Blood Institute, released in 2007, states that the efficacy and safety of levalbuterol as a bronchodilator is comparable to racemic albuterol in equimolar doses.

The SABA are the drug of choice for treating acute asthma symptoms and exacerbations. Some patients continue to use SABA on a regular, scheduled dosing pattern. Several studies have evaluated this use, and found no clinical benefit to regular dosing. The NHLBI 2007 guidelines recommend that SABA be dosed only as-needed for symptoms, or for prevention of exercise-induced bronchospasm. Use of SABA more often than two days/week may be a useful indicator that a patient’s asthma is not well controlled.

Other dosage forms of SABA are available. Orally administered tablet and liquid dosage forms (eg, albuterol tablets/syrup, metaproterenol tablets/syrup) continue to be available. While convenient, these dosage forms should not be used, as their onset of action is considerably longer than orally inhaled dosage forms, and because they are systemically administered, systemic adverse effects are greater.

Orally inhaled SABA (MDI and nebulization solution) do provide a quick onset of action, within minutes. Albuterol, levalbuterol and metaproterenol are available as solutions for nebulization. When given in clinically equivalent doses (approximately 10-12 puffs of albuterol by MDI is equivalent to 2.5 mg by nebulization), and with good inhalation technique, several studies have demonstrated equivalent clinical outcomes (or superior outcomes with MDI) of albuterol when given by nebulization and MDI/spacer for mild-moderate exacerbations.

The importance of using good inhalation technique with nebulization and MDI administration cannot be underestimated, and patients should always be asked about their technique. For example, it is not uncommon for caregivers of young children to use a “blowby” technique with nebulization use. Although seemingly convenient, this administration technique should be discouraged, as little drug enters the lungs. Spacers and valued holding chambers are valuable devices, as they can increase the amount of drug delivered to the lungs when MDI dosage forms are used. Infants can also use MDI products, as a facemask can be attached to spacer or valved holding chamber devices. Nearly all patients can benefit from the use of spacer/valved holding chamber devices. Facemasks should also be used when nebulized solutions are given to infants and young children.

Two long-acting beta agonists (LABA) are available for use in children with asthma – salmeterol (Serevent Diskus and combined with fluticasone as Advair) and formoterol (Foradil Aerolizer capsules and combined with budesonide as Symbicort).

Although they are both LABA, salmeterol and formoterol have different pharmacologic properties. Formoterol has a relatively quick onset of action (within five minutes) whereas salmeterol’s onset of action is slower (15-30 minutes). Formoterol, however, is not labeled for use in the United States for quick-relief of symptoms. Both LABA agents have a black box warning due to clinical trial data indicating the potential for an increase in severe asthma exacerbations and asthma-related death with salmeterol and formoterol use. Many have assessed that this risk is negated when LABA are used in combination with inhaled corticosteroid agents. The 2007 NHLBI asthma guidelines recommend that LABA should not be used alone for long-term control of asthma, and that LABA can be added to low-medium dose inhaled corticosteroids when asthma is not well controlled.

Inhaled corticosteroids

Inhaled corticosteroids (ICS) are the most effective class of medications to control asthma long-term. Seven different ICS agents are available in a variety of dosage forms and strengths.

Two ICS are available as combined agents with a LABA (Symbicort and Advair). Budesonide is available as a solution for nebulization, which can be useful for infants and young children. The ICS agents can be considered to have equal clinical efficacy. Differences among the agents include labeled indicated age, number of daily doses, dosage form availability, among other differences. Some products have dose counters, which may aid in assessing adherence (budesonide/Pulmicort, fluticasone/Flovent and Advair, mometasone/Asmanex). The newest ICS, ciclesonide (Alvesco), is a pro-drug, as ciclesonide must be activated by esterases in the lung for pharmacologic activity. Ciclesonide is labeled for use in ages 12 years and older.

While ICS can provide very effective pharmacotherapy for asthma, their use is not without the potential for concern by patients and caregivers. Patients and caregivers often harbor concerns over systemic adverse effects of ICS, and may link ICS with negative effects of “steroids” (ie, anabolic steroids) that are often described in the media and lay press.

It is generally believed that the potential for clinically significant systemic adverse effects (eg, bone density weakening, HPA axis suppression, immunosuppression) when using low-medium dose ICS is not clinically significant. High doses of ICS may increase the risk of systemic adverse effects, and other pharmacotherapies can be used in an attempt to limit the use of high doses of ICS.

Evidence from controlled clinical trials does demonstrate that low-medium dose ICS use can affect growth velocity in children. However, this effect is most likely to occur early in the course of ICS use (first months-years), and is likely to be small (1 to 2 cm). Some data exist that demonstrate that despite this initial negative effect upon growth, final adult height of children receiving ICS is attained. ICS use may also result in local adverse effects, such as thrush or throat adverse effects. The use of a spacer device/valved holding chamber, rinsing and spitting out after inhalation, and use of appropriate inhalation technique can all limit the likelihood of these adverse effects occurring. Changing to a different ICS product may also be attempted.

Leukotriene modifiers

Three leukotriene modifiers are available for the treatment of asthma – montelukast (Singulair), zafirlukast (Accolate), and zileuton (Zyflo). Montelukast is most commonly used in the pediatric population, as it is labeled for use in children as young as 1 year of age, and is available in granule and chewable tablet formulations. Although these agents can be effective for some asthma patients, they are not as effective as an anti-inflammatory or as likely to control asthma long-term as compared with ICS. Their popularity is due in large part to once daily dosing, ease of oral administration, and perhaps because they are not corticosteroids. Leukotriene modifiers may be effective when used alone as a long-term controller for mild persistent asthma.

Edward A. Bell, PharmD, BCPS is a Professor of Pharmacy Practice at Drake University College of Pharmacy Blank Children’s Hospital, Des Moines, Iowa.

For more information:

• Expert panel report 3: guidelines for the diagnosis and management of asthma. Bethesda, MD: National Heart, Lung, and Blood Institute, 2007. NIH publication 07-4051. www.nhlbi.nih.gov/guidelines/asthma/asthgdln.htm
• Agertoft L. Effect of long-term treatment with inhaled budesonide on adult height in children with asthma. N Engl J Med.2000;343:1064-1069.
• Hendeles L. Withdrawal of albuterol inhalers containing chlorofluorocarbon propellants. N Engl J Med. 2007;356:1344-1351.
• Sharek PJ. The effect of inhaled steroids on the linear growth of children with asthma: a meta-analysis. Pediatrics.2000;106:e8