Salmeterol Xinafoate

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Abstract
Salmeterol xinafoate, like salbutamol (albuterol), is a saligenin derivative, and a selective β2-adrenoceptor agonist. It produces bronchodilation for at least 12 hours following inhalation of a single 50μg dose. Salmeterol is intended for regular twice-daily treatment of reversible airways obstruction and not for immediate symptomatic relief and when used in this manner, 50μg twice daily is more effective than salbutamol 200μg or terbutaline 500μg administered 4 times daily, or individually titrated oral doses of theophylline in improving objective and subjective criteria of efficacy in patients with mild to moderate asthma. Salmeterol 100μg inhaled twice daily may provide better control than the lower dose in patients with severe asthma. The long duration of effect of salmeterol makes it particularly suitable for treating patients with nocturnal asthma in whom it improves sleep quality. The place of salmeterol, like that of other β2-adrenoceptor agonists used regularly in the treatment of asthma, is being debated. Patients in need of regular β2-agonist therapy should also be regarded as candidates for inhaled corticosteroids to counteract underlying inflammation. Thus, salmeterol may be particularly useful in patients requiring regular treatment with β2-agonists for nocturnal asthma and results of trials in progress involving large numbers of patients are awaited with interest. Salmeterol is a long-acting selective β2-adrenoceptor agonist which produces significant bronchodilation in animals and in patients with asthma. Median time to 15% improvement in FEVμg was 17 and 13 minutes after inhalation of salmeterol 50 and l00μg, respectively, compared with 14 minutes after salbutamol 200μg. Peak bronchodilation usually occurred 3 to 4 hours after a single dose and was generally of similar magnitude after inhalation of salmeterol50μg and salbutamol 200μg. Although the onset of bronchodilation was slower with salmeterol than with salbutamol, its duration was much longer with forced expiratory volume in 1 second (FEV1) remaining ≥15% above baseline values for up to 17.5 hours after single-dose inhalation of 25μg or more. There was no evidence of tachyphylaxis to the pulmonary effects of salmeterol following 2 weeks’ administration of usual therapeutic dosages to patients with asthma. Longer studies to test for tachyphylaxis are needed in patients not receiving inhaled corticosteroids concomitantly. Inhalation of salmeterol inhibits bronchoconstriction induced by histamine, methacholine or exercise in healthy volunteers and patients with asthma for a longer time than does salbutamol, and appears to prevent the rise in nonspecific bronchial hyper-responsiveness and the late phase of allergen-induced bronchoconstriction after bronchodilation has ceased. Salmeterol, like other selective β2-adrenoceptor agonists, has some cardiovascular effects resulting from stimulation of nonpulmonary β2-receptors. At high dosages (200 and 400μg), increases in heart rate were greater than with equal doses of salbutamol, but were attenuated within 2 weeks during regular twice-daily inhalation of salmeterol. Tachyphylaxis to other nonpulmonary effects of salmeterol also occurred within 2 weeks. There is evidence, mainly from in vitro studies, that salmeterol may differ in its mechanism of action from short-acting β-adrenoceptor agonists. Thus, the pharmacological activity of salmeterol is rapidly and fully reversed by β-adrenoceptor antagonists, indicating a competitive interaction with the β-adrenoceptor, but is re-established once the antagonist is removed — an effect hypothesised to result from binding to a region of the β-receptor protein termed an ‘exosite’. Inhibition of histamine-induced plasma protein extravasation and inflammatory cell infiltration in guinea-pig lungs and of inflammatory mediator release from sensitised human lung fragments suggest that salmeterol has anti-inflammatory activity, although it has still to be determined whether salmeterol has any clinically important effects on the underlying inflammatory processes in asthma. After inhalation of salmeterol 50μg twice daily, maximum plasma concentrations of about 0.1 to 0.2 and 1 to 2. μg/L are attained 5 to 15 minutes after inhalation of single 50 and 400μg doses, respectively. Salmeterol is extensively metabolised by hydroxylation with the majority of a dose being eliminated within 72 hours. 23% of administered radioactivity was recovered in urine and 57% in faeces over a period of 168 hours. Dose-ranging studies have shown that salmeterol 50μg twice daily is the optimum dosage in the treatment of patients with mild to moderate asthma, with 100μg twice daily providing further benefit in patients with more severe disease. Published therapeutic trials, some involving large numbers of patients with mild to moderate asthma, most of whom were receiving concomitant inhaled corticosteroids, have consistently shown salmeterol 50μg twice daily to be more effective than salbutamol 200μg 4 times daily (both administered by pressurised inhaler) in improving lung function, and in reducing respiratory symptoms during day and night, diurnal variation, and requirement for supplementary salbutamol. Similar results in favour of salmeterol were also achieved in comparisons of salmeterol 50μg twice daily and salbutamol 400μg 4 times daily inhaled as dry powder, salmeterol 50μg twice daily and terbutaline 500μg 4 times daily, and salmeterol 50μg twice daily compared with individually titrated oral dosages of theophylline, particularly in patients not previously treated with theophylline. In patients with nocturnal asthma, salmeterol 50 and 100μg twice daily improved overnight peak expiratory flow rate and significantly increased the median percentage of nights without awakenings due to asthma compared with placebo. Salmeterol 50μg improved objective sleep measurements relative to placebo. In the majority of patients studied salmeterol also improved subjective sleep quality. Salmeterol inhaled at dosages of 50 or 100μg twice daily has been well tolerated in clinical trials. The incidence of expected adverse effects resulting from stimulation of extrapulmonary β2-adrenoceptors (tremor, tachycardia and/or palpitations, headache) exceeded that with placebo only during administration of salmeterol 100gmg and was generally similar during administration of salmeterol 50μg or salbutamol 200μg. The usual dosage for adults with mild to moderate asthma is 50μg salmeterol twice daily either by metered dose inhaler or dry powder. Dosage may be increased to 100μg twice daily in patients with more severe disease.