Allergology International (2004) 53: 69–75 Review Article β Long-acting 2-adrenergic receptor agonist in pediatric asthma Shigemi Yoshihara, Yumi Yamada, Toshio Abe and Osamu Arisaka Department of Pediatrics, Dokkyo University School of Medicine, Tochigi, Japan β ABSTRACT effects, such as 2-adrenergic receptor agonists, have long been used as first-choice agents for asthma attacks. Long-acting β -adrenergic receptor agonists (LABA), 2 In recent years, the pathology of bronchial asthma has a class of agents for the long-term management of come to be recognized as eosinophil-mediated chronic childhood bronchial asthma, are recommended for inflammation of the airways and the clinical value of use in combination with steroid inhalation for the treat- various anti-inflammatory agents, such as inhaled corti- ment of the morning dip in severe childhood asthma. costeroids, has been emphasized,1 even in children. In the present review, salmeterol (SM), a LABA inhalant Therefore, the place of β -adrenergic receptor agonists with a long-acting bronchodilator effect, was com- 2 as therapeutic agents has been reviewed and short- pared with the recently introduced tulobuterol patch acting β -adrenergic receptor agonists (SABA) are pre- (TBP) in terms of safety and efficacy, based on their 2 ferred as relievers, whereas long-acting β -adrenergic respective clinical effects on childhood asthma. From a 2 receptor agonists (LABA) are recommended as controllers clinical perspective, both drugs had a preventive effect (Fig. 1). Salmeterol (SM) is an LABA and the tulobuterol by suppressing the morning dip and exercise-induced patch (TBP), a recently developed β -adrenergic receptor asthma when used concomitantly with an inhaled 2 agonist transdermal absorption system, is a drug delivery corticosteroid, and both agents were associated with a system (DDS) that provides long-acting and effective lower incidence of adverse effects on the cardio- bronchodilation. In the present paper, we review the role vascular system than oral β -adrenergic receptor ago- 2 of these agents as controllers in the treatment of nists. Based on these findings, both SM and TBP are childhood asthma. concluded to be highly efficacious and safe broncho- dilator agents that are appropriate for the long-term management of childhood asthma. β LONG-ACTING 2-ADRENERGIC RECEPTOR AGONISTS Key words: bronchodilator, long-acting β2-adrenergic β receptor agonist, pediatric asthma, salmeterol, short- Of the many formulations of 2-adrenergic receptor actingβ2-adrenergic receptor agonist, tulobuterol agonists available, oral preparations, inhalants, quanti- patch. tative inhalation-type aerosols (aerosol, metered dose inhalers) and patch compounds are currently used. β2- Adrenergic receptor agonists are classified according to INTRODUCTION their β2-adrenergic receptor selectivity, duration of effec- Bronchial asthma is defined as a reversible bronchial tiveness and formulation (Table 1). The SABA have been occlusive disease and agents with potent bronchodilator used to treat acute attacks (relievers) and the oral drugs procaterol, clenbuterol and formoterol have recently been classified as controllers. In recent years LABA, such Correspondence: Dr S Yoshihara, Department of Pediatrics, as salmeterol or TBP, have been shown to have high Dokkyo University School of Medicine, 880 Kitakobayashi, Mibu, Tochigi 321-0293, Japan. efficacy in the treatment of severe asthma when com- Email: [email protected] bined with anti-inflammatory agents, such as inhaled Received 27 December 2003. corticosteroids (Fig. 1). 70 S YOSHIHARA ET AL. Fig. 1 Rank of long-acting β2-adrenergic receptor agonists as agents for the treatment of pediatric bronchial asthma. DSCG, disodium cromoglycate; MDI, metered dose inhaler. Table 1 Types and special features of β2-adrenergic receptor agonists Generic name Selectivity Duration of Formulation action (h) (adrenergic receptors) First generation Epinephrine α1, β1, β2 < 1 Injection, inhalant Isoproterenol α1, β1 = β2 < 1 Injection, inhalant Second generation Salbutamol β1 < β2 4–5 Tablet, syrup, dry syrup, inhalant, MDI Terbutaline β1 < β2 4–6 Tablet, syrup, granule Third generation Fenoterol β1 < < β2 8 Tablet, syrup, dry syrup, MDI Procaterol β1 < < β2 8–10 Tablet, minitablet, syrup, inhalant, MDI Tulobuterol β1 < < β2 8 Tablet, dry syrup, patch* Formoterol β1 < < β2 10 Tablet, dry syrup, inhalant Clenbuterol β1 < < β2 10–12 Tablet Salmeterol β1 < < β2 12 Inhalant *Only for Hokunalin®. MDI, metered dose inhaler. Salmeterol Suppressive effect of salmeterol on the morning dip Special features of salmeterol In a randomized double-blind trial of 207 asthmatic β The selectivity of salmeterol for the 2-adrenergic recep- patients ranging in age from 4 to 11 years, changes in tors of airway smooth muscle is approximately 85 000- forced expiratory volume in 1 s (FEV1.0) were compared β fold its selectivity for the 1-adrenergic receptors of the during 12 weeks of treatment with salmeterol (50 µg) β heart, indicating very high 2-adrenergic receptor selec- and a placebo inhalant. The FEV1.0 increased signifi- tivity of the drug.2 Salmeterol manifests efficacy within cantly with improvement in lung function for 12 h on day 15–17 min after inhalation. Although it is slightly slower 1 in the group treated with salmeterol compared with acting than salbutamol, its duration of action is more controls and a similar tendency was observed even after than 12 h, implying that two doses a day are sufficient. the 12 week regimen.3 BRONCHODILATORS IN PEDIATRIC ASTHMA 71 Combined effect of salmeterol and an inhaled > 15%. Exercise loading was performed 1.5 and 9 h corticosteroid in childhood asthma after administration and FEV1.0 was measured 30 min after loading-indicated reductions. The salmeterol inha- The effect of salmeterol combined with an inhaled lant had a prophylactic effect on EIA.11 No differences in corticosteroid was examined in a total of 206 moderate EIA were observed when two salmeterol powder-delivery to severe cases.4 Patients currently being treated with devices were used12 and salmeterol inhalation had a beclomethasone propionate (BDP) or budesonide at a longer-acting prophylactic effect on EIA than the SABA mean dose of 750 µg/day were divided into two groups, albuterol.13 one treated with salmeterol inhalant (50 µg) in combi- nation twice a day for 12 weeks and the other treated without the salmeterol inhalant. The time-related Safety of salmeterol changes (%) in morning peak expiratory flow (PEF) were The safety margin of salmeterol and salbutamol have monitored in the two groups. The results showed marked already been established in a double-blind study on improvement in morning PEF measured at 4 week childhood asthma comparing the two drugs.14 The inci- intervals (during 1–4 weeks, 5–8 weeks and 9–12 weeks) dence of adverse reactions in children in Japan is 2.8% in the combined-treatment group compared with the and one case of palpitations (0.31%) and two cases of monotherapy group, suggesting that the morning dip in tremors (0.62%) have been documented (Table 2). The the former group was markedly suppressed.4 A meta- incidence of adverse effects in the cardiovascular and analysis of the results in patients over 12 years of age nervous systems was significantly lower than with oral showed highly convincing efficacy in patients treated β2-adrenergic receptor agonists. with combination therapy.5,6 Interestingly, methacholine- induced airway hypersensitivity was no more severe in Ranking of salmeterol according to pediatric patients treated with salmeterol alone for 4 months than asthma treatment guidelines in patients treated with salbutamol alone.7 However, controversial findings, such as absence of improvement Salmeterol inhalant is a useful agent with sufficient of airway hypersensitivity in patients treated with salme- efficacy for the long-term management or control of terol alone but improvement in those treated with BDP childhood asthma in ordinary family life. The Global alone, have been reported in patients treated with Initiative for Asthma (GINA) 2002 Guidelines (Fig. 2) salmeterol or BDP alone for 1 year.8 Therefore, the results recommend combined use with an anti-inflammatory cited above do not support treatment with salmeterol agent, such as inhaled corticosteroid, from step 3 1 alone on a long-term basis8,9 and, instead, support onward. In addition, salmeterol has again been recom- therapy with a combination of an LABA and inhaled mended for combined therapy with anti-inflammatory agents, such as inhaled corticosteroids, for 6–15-year- corticosteroid. One reason for this is that β2-adrenergic receptor agonists prevent the decrease in steroid recep- old asthma patients in Japan according to the 2002 tor sensitivity caused by repeated exposure to inhaled Japanese Pediatric Allergy Guidelines on Childhood 15 corticosteroids and, because steroids reverse the down- Asthma Management and Treatment. regulation and reduction in number of β2-adrenergic receptors induced by repeated dosing with β2-adrenergic 10 β receptor agonist, corticosteroids and 2-adrenergic recep- Table 2 Comparison of the adverse effects of salmeterol and tor agonists compensate for the shortcomings of each the tulobuterol patch giving the incidence of adverse effects in other. children after official approval for use in Japan Item TBP Salmeterol Clinical benefits of salmeterol in exercise-induced No. subjects evaluated 401 322 asthma No. with adverse effects 41 9 Incidence adverse