Salmeterol

Abstract

Salmeterol xinafoate is a selective β₂-adrenoceptor agonist indicated for the maintenance treatment of adults and children with asthma. When administered as a dry powder or aerosol, salmeterol produces bronchodilation for at least 12 hours and protects against methacholine and exercise-induced bronchoconstriction. Salmeterol is not recommended for the treatment of acute exacerbations of asthma. Recent clinical studies have demonstrated the efficacy and tolerability of inhaled salmeterol in the management of asthma in children. Salmeterol improved symptom control and lung function more effectively than placebo or regularly administered salbutamol. In children who were symptomatic despite regular inhaled corticosteroid therapy, the addition of salmeterol to treatment produced a significant improvement in morning and evening peak expiratory flow and forced expiratory volume in 1 second, and a significant reduction in the incidence of asthma exacerbations compared with placebo. Notably, the long duration of action of salmeterol makes it particularly suitable for the prevention of nocturnal asthma symptoms and exercise-induced asthma (EIA) in children. Current data suggest that salmeterol should not be used as a substitute for corticosteroid therapy in children, but rather as an adjunct to therapy. Thus, salmeterol may be a suitable adjunct to therapy in children with asthma receiving inhaled corticosteroids. In addition, salmeterol also has a potentially important role in the prevention of EIA and nocturnal asthma symptoms. Although slower in onset of action than salbutamol, inhaled salmeterol exerts a significant bronchodilating effect within 10 to 20 minutes of single-dose administration in children with asthma; this effect lasts for up to 12 hours or more. High affinity binding of the drug to an exosite located within the β₂-adrenoceptor is considered to be responsible for the long duration of action of this compound. In children, inhalation of salmeterol 25 or 50μg provided significantly greater protection against methacholine-induced bronchoconstriction for up to 12 hours compared with salbutamol 200μg. In the prevention of exercise-induced asthma (EIA), salmeterol was at least as effective as sodium cromoglycate and significantly more effective than placebo, producing a greater attenuation in the maximum percentage fall in forced expiratory volume in 1 second (FEV₁) after exercise. Whether clinically relevant tolerance develops to the protective effect of salmeterol against bronchoconstrictor stimuli such as methacholine and exercise after chronic administration of the drug is unclear. Salmeterol has demonstrated anti-inflammatory activity in vitro and in vivo in animals as shown by its inhibitory effect on the cellular release of inflammatory mediators, inflammatory cell infiltration and plasma protein extravasation. Although anti-inflammatory effects have been reported with salmeterol in some studies in humans, there is currently insufficient data to suggest that the drug has a clinically important effect on the underlying inflammatory processes in asthma. Preliminary data suggest that salmeterol may have a beneficial effect on airway mucociliary clearance in vitro and may be associated with a reduction in the incidence of respiratory tract infections. No data on the pharmacokinetic properties of salmeterol in children are currently available. Due to the localised action of salmeterol in the lung, plasma concentrations of the drug are not predictive of therapeutic efficacy and are generally low or undetectable following chronic administration of standard doses (50μg twice daily). Salmeterol is extensively hydroxylated by cytochrome P450 and is eliminated predominantly in the faeces with most of the dose recovered within 72 hours; less than 5% of a dose is excreted unchanged in the urine. The drug is extensively bound to human plasma proteins in vitro (≈95%). Large double-blind comparative studies have demonstrated the superior efficacy of treatment with inhaled salmeterol compared with regularly administered salbutamol or placebo for up to 12 months, in terms of lung function measurements [morning and evening peak expiratory flow (PEF) and FEV₁] and symptom control in children with mild to moderate asthma. In children who were symptomatic despite receiving inhaled corticosteroid therapy (approximately 800μg daily), adjunctive treatment with salmeterol 50 or 100μg twice daily, compared with placebo, produced an improvement in morning and evening PEF and FEV₁ values and a reduction in the number of asthma exacerbations. The results of a multicentre randomised double-blind study evaluating the effect of adding salmeterol 50μg twice daily to existing corticosteroid therapy compared with an increase in the dose of inhaled corticosteroids are awaited with interest. Although salmeterol has demonstrated efficacy as an adjunct to existing inhaled corticosteroid therapy in children, it should not be used as a substitute for such treatment; 2 recent randomised studies have shown that salmeterol 50μg twice daily is less effective in terms of improving lung function and symptom control and in reducing the number of asthma exacerbations than inhaled beclomethasone dipropionate 200μg twice daily in children with asthma. The effect of salmeterol on nocturnal asthma symptoms has not been specifically evaluated in children. However, in studies which included a subjective assessment of asthma symptoms, inhaled salmeterol 25 or 50μg twice daily was more effective than salbutamol 200μg twice daily or placebo but less effective than beclomethasone dipropionate 200μg twice daily in reducing nocturnal asthma symptoms in children. Current evidence suggests that when used as an adjunct to existing antiasthma therapy, long term treatment with salmeterol produces a sustained...