Duration of Action of Inhaled vs. Intravenous β2-Adrenoceptor Agonists in an Anaesthetized Guinea-pig Model

We compared the duration of action of the short-acting α₂-adrenoceptor agonist salbutamol and the long-acting α₂-adrenoceptor agonists salmeterol and formoterol when administered iv or by inhalation in a histamine-induced bronchoconstriction model in the guinea-pig. Following aerosol dosing, maximal bronchoprotector effects were seen for salbutamol, salmeterol and formoterol at concentrations of 1 mg/ml, 100 μ g/ml and 30 μ g/ml respectively, giving a potency order of formoterol > salmeterol > salbutamol. All displayed similar maximum effects in this system. A maximal concentration of salbutamol showed bronchoprotection at 1 h but not at 3 h post-dosing whereas maximal concentrations of formoterol and salmeterol showed protection up to 5 h post-aqueous-aerosol dosing, giving a duration order of salmeterol > formoterol > salbutamol. All three α₂-adrenoceptor agonists showed dose-dependent bronchoprotection and duration of action following intravenous administration; salbutamol and salmeterol were equipotent and both were less potent than formoterol. Bronchoprotection obtained with sub-maximal concentrations of all three α₂-adrenoceptor agonists faded within 30 min following iv administration, but this could be extended by increasing the doses. These results demonstrate that the route of administration is important in determining the duration of action of α₂-adrenoceptor agonists in the lung. Furthermore, such findings lend support to the suggestion that the physico-chemical characteristics of salmeterol govern its duration of action rather than sustained binding of this agonist to a α₂-adrenoceptor exo-site.