Asthma medications are routinely categorized as either controllers or relievers. The controllers include inhaled corticosteroids, systemic corticosteroids, leukotriene modifiers, and long-acting beta^sub 2^-agonists. The relievers include anticholinergics, short-acting inhaled beta^sub 2^-agonists, and systemic corticosteroids.1

This article focuses on some of the newer asthma medications, including budesonide (Pulmicort Turbuhaler and Pulmicort Respules), an inhaled corticosteroid (ICS); montelukast (Singulair), a leukotriene modifier; levalbuterol (Xopenex), a short-acting beta^sub 2^-agonist; and fluticasone propionate and salmeterol inhalation powder (Advair), a combination ICS and long-acting beta^sub 2^-agonist.

Steroid Therapies

ICS therapy has been widely recognized as the most effective anti-inflammatory treatment for persistent asthma.1 The agents are generally well tolerated and safe at recommended dosages2,3 and they should produce significant improvement in lung function.

However, mention of the word steroid often terrifies parents of pediatric patients. They have learned just enough about steroid usage to associate it with growth retardation. However, the latest research strongly suggests that when properly used, steroids pose no threat to growth.2,3 The worst that might occur is an initial slight reduction in growth velocity. However, patients with asthma eventually catch up to their nonasthmatic peers.

Although no one can predict with absolute accuracy how tall a 6-year-old child should or will be when he or she is 18, the data show perhaps a centimeter's difference between the adult height of healthy children and that of youngsters on controlled regimens of ICS.2,3 Moreover, patients with asthma who forego ICS therapy may develop avoidable symptom exacerbations, irreversible airway remodeling, and chronic lung disease.

When prescribing ICS agents to pediatric patients, clinicians should follow a few simple rules or considerations:2

* Use the lowest effective dose.

* Reduce potential local adverse effects-such as dysphonia and oral moniliasis-by encouraging use of the spacer and by reminding patients to rinse their mouth after treatment.

* Combine lower doses of steroids with long-acting beta^sub 2^-agonists.

* Monitor patients' growth velocity.

Initiating pediatric patients on ICS therapy is important, especially if they tend not to go outside to play, preferring instead to sit in front of the television or to play video games. The problem that many of these patients have is poor reserve volume. Health care providers must focus on these children and treat them aggressively with ICS therapy and perhaps with one or more of the other agents described in this article.

The ICS class includes the following drugs in the following strengths:

* beclomethasone-The dosage of beclomethasone (Vanceril and Beclovent) is 42 mcg per actuation.4,5 A beclomethasone formulation delivered by an ozone-safe propellant (QVAR) is available as 40 mcg and 80 mcg per actuation.6

* budesonide-An inhaler version of budesonide (Pulmicort Turbuhaler) has been available with 200 mcg per actuation dose.7 More recently, a nebulized form for pediatric patients (Pulmicort Respules) has been approved in two strengths: 0.25 mg and 0.5 mg.8

Approved for marketing by the Food and Drug Administration (FDA) in 2000,12 the newer nebulized pediatric formulation of budesonide is the first anti-inflammatory corticosteroid formulated for inhalation with a nebulizer in children between the ages of 12 months and 8 years. Previously, no other inhaled corticosteroid had been approved for use in children younger than 4 years. This approval gives practitioners an approved treatment option for a significant and unserved part of the pediatric asthma population.12

Dosage strengths for this drug are 0.25 mg given twice a day and 0.5 mg nebulized once a day. It is indicated for the maintenance treatment of asthma and as prophylactic therapy in children 12 months to 8 years of age.8 Prophylactically, one or two nebulizer treatments once or twice a day controls pediatric asthma in many patients.

The literature suggests that either the 0.25-mg dose of nebulized budesonide twice a day or the 0.5-mg dose once a day will be successful;8 however, those dosages may be adjusted. In a younger child, 0.25 mg once a day may be all that is needed. Jet nebulizers were utilized during clinical trials to standardize the equipment and should be used for the best deposition of the medication into the lungs.

When nebulizing the newer form of budesonide, protect the young patient's eyes from steroids inhaled through the nebulizer mask. According to ophthalmologists, steroid mist in the eyes increases the risk of cataracts after prolonged use. The risk is small with inhaled corticosteroids,13 especially for children,14,15 but as a precaution, parents should be advised to apply tape to the mask holes in such a way as to direct any errant mist away from the child's eyes.

* fluticasone-Available in several strengths-44 mcg, 110 mcg, and 220 mcg per actuation-fluticasone (Flovent)9 seems to be quickly superseding beclomethasone as the gold standard among ICS agents.

* flunisolide-Flunisolide (AeroBid and AeroBid-M) is available as a metered-dose inhaler, with each actuation delivering 250 mcg. AeroBid-M contains menthol as a flavoring agent.10

* triamcinolone-Available as a metered-dose inhaler, triamcinolone (Azmacort)11 delivers 100 mcg per activation.

Other Maintenance Medications

Leukotrienes are inflammatory mediators that cause increased edema formation, vascular permeability, mucus production, and bronchoconstriction.16 They facilitate the expression of eosinophils into lung and airway tissue, which begins to swell and constrict.16 Leukotriene-modifying agents, therefore, would be useful in controlling asthma.

A number of leukotriene modifiers are available, including zafirlukast (Accolate) and montelukast (Singulair). The major drawback of zafirlukast, however, is timing: The patient needs to take it twice a day, either 1 hour prior to or 2 hours after meals.17 Montelukast can be taken anytime, once a day.18 It is indicated for children 2 years or older. Next year, montelukast will be available in a sprinkle form, which will make the drug usable in children under 2 years of age. Montelukast is safe and effective, especially in reducing reliance on short-acting beta^sub 2^-- agonists.18

Quick-Relief Medications

The reliever medications include the short-acting beta^sub 2^-agonists such as albuterol (Ventolin and Proventil) and levalbuterol (Xopenex, an isomerically pure albuterol)19-21 and the systemic corticosteroids prednisolone (a syrup marketed as Pediapred and Prelone)22,23 and prednisone (a pill sold under a number of brand names). Short-acting, or systemic, corticosteroids are effective but carry the possibility of serious adverse effects. Thus, the short-acting beta^sub 2^-agonists are the main rescue medications for asthma, with albuterol being the most widely used. Note that these medications are for rescue. They should be used only when the patient is having an asthma attack. Ideally, these relievers should never be needed because the patient's asthma should be so well controlled by maintenance drugs that he or she will not experience an attack. If these relievers are used frequently, the patient's asthma is not well controlled. In that case, the controller agents should be changed or the dosage increased or the health care provider should explore whether the patient is adherent to the existing therapy.

Levalbuterol (Xopenex), also a beta^sub 2^-agonist, is a derivative of, or successor to, albuterol21 and it is a product of improved chemical entity technology. Albuterol is a racemic drug, which means that it is composed of two enantiomers with opposite 3-- dimensional structures: an (R)-isomer and an (S)-isomer. Levalbuterol is composed entirely of the (R)-isomer, which numerous studies have established as the component of albuterol that provides the therapeutic and clinical benefit.24-26 Only the (R) -isomer binds to beta^sub 2^ receptors with high affinity27; in a study of bronchial hyperreactivity, only the (R)-isomer provided the bronchoprotection associated with racemic albuterol.28

By contrast, the (S)-isomer is therapeutically inert and may interfere with or negate the effects of the (R)-isomer. For example, although (R)-albuterol decreases intracellular calcium levels in airway smooth muscle cells (consistent with a bronchodilator), (S) -albuterol actually increases calcium levels (a pro-bronchoconstrictive effect).25 (R)-Albuterol also decreases superoxide production from eosinophils (an anti-- inflammatory effect), while (S)-- albuterol has the pro-inflammatory effect of increasing superoxide production.29 In addition, (S)-- albuterol has been shown to increase bronchial hyperreactivity to methacholine challenge.28

Because (S)-albuterol is metabolized 10-fold more slowly than the therapeutically active (R)-albuterol, (S) -albuterol may accumulate and exert its negative effects with chronic or overuse of racemic albuterol.26,30,31 In fact, if albuterol were a new drug today, the FDA might not approve it unless and until the (S)-- enantiomer were stripped away-which is precisely what has been done with levalbuterol. Since 1992, the FDA has had a policy that requires testing of individual isomers for racemic mixtures and development of single-isomer drugs in cases of toxicity concerns associated with the inactive isomer.32

Because levalbuterol is composed solely of (R)-albuterol, it can be clinically effective at significantly lower dosages. At these reduced dosages (as low as 0.31 mg in children), levalbuterol is associated with fewer beta^sub 2^-agonist-associated adverse effects, such as tremor, hyperactivity, changes in heart rate, and changes in glucose and potassium levels.33 This may be the answer for parents who do not want to give their child asthma medication before bedtime because the child would become too active. Although the recommended dosage is 0.63 mg every 6 to 8 hours, the dosage can be safely increased to 1.25 mg if required. For children ages 6 to 11 years, the recommended starting dosage is 0.31 mg three times a day, increased to 0.63 mg three times a day if needed.21

A study of the effectiveness of levalbuterol in the emergency department is ongoing.34 Wheezing asthmatic patients who make emergency 911 calls are being randomized into a levalbuterol 1.25-mg group and an albuterol 2.5-mg group. Preliminary findings indicate that the majority of patients on levalbuterol are experiencing, on average, a 50% reduction in time spent in the emergency department.34 That represents both a positive clinical outcome and a significant cost savings.

Finally, new combination therapies are being used for asthma control. When a long-acting beta^sub 2^-agonist and ICS are combined, a synergistic effect occurs. Each drug seems to complement the characteristic action of the other: the long-acting beta^sub 2^-agonists offer sustained bronchodilation and the ICS agents provide powerful anti-inflammatory action.34,35 ICS agents also upregulate beta^sub 2^-receptors, and long-acting beta^sub 2^-agonists may serve to enhance ICS therapy by priming the glucocorticoid receptor. For example, in a recent study by Kavuru et al.,36 subjects receiving a combination of salmeterol (50 mcg) and fluticasone (100 mcg) demonstrated a significant improvement in forced expiratory volume in 1-second values compared with subjects given a placebo or salmeterol or fluticasone alone.

In summary, health care providers must: (1) identify individuals with asthma, (2) identify asthma triggers in these individuals, (3) educate the patient and his or her caregivers so that they can reduce exposure to those triggers, (4) implement an action plan to relieve and control asthma, and (5) ensure that each patient remains compliant with their action plan. With these steps as a foundation, asthma can ultimately be controlled-thereby improving the lives of children coping with this disease.

NOTES:

Pulmicort Turbuhaler, Vanceril, Beclovent-Safety and effectiveness in children under the age of 6 years have not been established.

QVAR, Flovent-Safety and effectiveness in children under the age of 12 years have not been established.

Pulmicort Respules-Safety and effectiveness in children under the age of 12 months have not been established.

Accolate-Safety and effectiveness in children under the age of 5 years have not been established.

Ventolin, Proventil-Safety and effectiveness in children under the age of 4 years have not been established.

REFERENCES

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2. Steinbach SF: Four controversies in pediatric asthma. Contemporary Pediatrics 2000;17(10):150-152, 155-156, 159-160, 162, 164, 171.

3. Welch MJ: Putting research into practice. Pediatric Basics 2001;96:editorial.

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5. Beclovent Inhaler. In: Physicians' Desk Reference. Montvale, NJ.: Medical Economics, 2001;1354-56.

6. QVAR product information. Northridge, Calif.: 3M Pharmaceuticals; 2001.

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8. Pulmicort Respules full prescribing information. Wilmington, Del.: AstraZeneca LP; 2001. 9. Flovent product information. Research Triangle Park, N.C.: GlaxoSmithKline; September 2001.

10. AeroBid prescribing information. St. Louis, Mo.: Forest Pharmaceuticals, Inc.; April 1996. 11. Azmacort prescribing information. Bridgewater, N.J.: Aventis Pharmaceuticals Inc.; February 2001.

12. FDA Talk Paper, FDA approves Pulmicort Respules for asthma, August 8, 2000. Available at http://www.fda.gov/bbs/topics/ANSWERS/ANS01028.html. Accessed March 19, 2002.

13. Jick SS, Vasilakis-Scaramozza C, Maier WC: The risk of cataract among users of inhaled steroids. Epidemiology 2001;12(2):229-34.

14. Abuekteish F, Kirkpatrick JN, Russell G: Posterior subcapsular cataract and inhaled corticosteroid therapy. Thorax 1995;50(6):674-6.

15. Simons FE, Persaud MP, Gillespie CA, Cheang M, Shuckett EP: Absence of posterior subcapsular cataracts in young patients treated with inhaled glucocorticoids. Lancet 1993;342:776-8.

16. Spector SL: Leukotriene inhibitors and antagonists in asthma. Ann Allergy Asthma Immunol 1995;75(6 Pt 1):463-73.

17. Accolate product information. Wilmington, Del.: AstraZeneca LP; 2001.

18. Singulair prescribing information. Whitehouse Station, N.J.: Merck & Co., Inc.; 2001.

19. Ventolin product information. Research Triangle Park, N.C.: GlaxoSmithKline; August 2001. 20. Proventil HFA product information. Kenilworth, NJ.: Schering Corporation; January 2000. 21. Xopenex full prescribing information. Marlborough, Mass.: Sepracor Inc. Available at: http://www.xopenex.com/fullPres.html. Accessed January 30, 2002.

22. Pediapred prescribing information. Rochester, N.Y.: Celltech Pharmaceuticals, Inc.; 2001. 23. Prelone prescribing information. Tewksbury, Mass.: Muro Pharmaceutical Inc; January 1999. 24. Handley DA, Morley J: The pursuit of precison pharmaceuticals: divergent effects of P2-agonist isomers. Expert Opin Investig Drugs 1998;7(10):1601-16.

25. Mitra S, Ugur M, Ugur 0, et al.: (S)-Albuterol increases intracellular free calcium by mus

carinic receptor activation and a phospholipase C-dependent mechanism in airway smooth muscle. Mol Pharmacol 1998;53(3):347-54.

26. Nelson HS, Bensch G, Pleskow WW, et al.: Improved bronchodilation with levalbuterol compared with racemic albuterol in patients with asthma. I Allergy Clin Immunol 1998;102(6, pt 1):943-52.

27 Penn RB, Frielle T, McCullough JR, Aberg G, Benovic JL: Comparison of R-, S-, and RS-albuterol interaction with human beta 1- and beta 2-adrenergic receptors. Clin Rev Allergy Immunol 1996;14:37-45.

28. Perrin-Fayolle M. Salbutamol in the treatment of asthma [letter]. Lancet 1995;346:1101. 29. Volcheck GW, Gleich GJ, Kita H: Pro- and anti-inflammatory effects of beta adrenergic agonists on eosinophil response to IL-5. J Allergy Clin Immunol 1998;10]:535.

30. Walle T, Walle UK, Thornburg KR, Schey KL: Stereoselective sulfation of albuterol in humans. Biosynthesis of the sulfate conjugate by HEP G2 cells. Drug Metab Dispos 1993;21:76-80.

31. Gumbhir-Shah K, Kellerman DJ, DeGraw S, Koch P, Jusko WJ: Pharmacokinetic and pharmacodynamic characteristics and safety of inhaled albuterol enantiomers in healthy volunteers. J Clin Pharmacol 1998;38:1096-1106.

32. FDA's policy statement for the development of new stereoisomeric drugs. Chirality 1992;4:338-40.

33. Milgrom H, Skoner DP, Bensch G, et al.: Low-dose levalbuterol in children with asthma: safety and efficacy in comparison with placebo and racemic albuterol. J Allergy Clin Immunol 2001;108:938-45.

34. Carl J, Myers T, Kercsmar C: Comparison of levalbuterol and racemic albuterol for treatment of acute asthma in pediatric patients. Presented at: Chest 2001, Annual Meeting of the American College of Chest Physicians; November 5, 2001; Philadelphia, Pa.

35. Advair Diskus product information. Research Triangle Park, N.C.: Glaxo Wellcome Inc; August 2000.

36. Kavuru M, Melamed J, Gross G, et al.: Salmeterol and fluticasone propionate combined in a new powder inhalation device for the treatment of asthma: a randomized, double-blind, placebo-controlled trial. J Allergy Clin Immunol 2000;105(6 Pt 1):1108-16.

Nancy Runton, CRNP, MSN

Nancy Runton, CRNP, MSN, is a Pediatric Nurse Practitioner at Virginia Pediatric Group, LTD, Fairfax Va., and the owner of Runton Associates, Alexandria, Va.; http://www.PediatricHealth.org.

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