Airways and systemic responses to β₂-agonists in man
The primary aim of this thesis was to evaluate the two following hypotheses: (i) the β-adrenoceptor selectivity of fenoterol and salbutamol is comparable, but fenoterol is more potent for β2-adrenoceptors, and (ii) subsensitivity of β2-adrenoceptors develops following chronic-dosing with the long-acting β2-agonist, eformoterol. Subsequent data demonstrated no significant differences in relative cardiac β1/β2-activity between inhaled fenoterol and salbutamol. However, fenoterol was significantly more potent for hypokalaemic and finger tremor responses but not bronchodilator or chronotropic effects. Furthermore, in two chronic dosing studies, significant subsensitivity of β2-adrenoceptors in-vivo and in-vitro, was demonstrated in asthmatic patients after chronic-dosing with eformoterol. Three secondary hypotheses, generated from the results of the preliminary studies, were also evaluated, and data showed that (i) the hypokalaemic response to inhaled terbutaline was additive to that of frusemide, but was not attenuated by the addition of triamterene, (ii) enhanced in-vivo β2-responsiveness to salbutamol was demonstrated in female subjects compared with male controls, and this may be explained by ovarian hormone regulation of β2-adrenoceptor function, and (iii) when inhaled after ipratropium bromide, no significant improvement occurred in the bronchodilator response to high dose terbutaline, over and above a low dose, in patients with COPD suggesting that prior attenuation of vagal tone permits optimal achievable bronchodilatation to be attained by low-dose β2-agonist alone.