Time course and relative dose potency of systemic effects from salmeterol and salbutamol in healthy subjects

Background - The main adverse effects of beta(2) agonists relate to their systemic activity. The time course and dose response relations of the systemic effects of salmeterol compared with salbutamol were investigated. Methods - A double blind, randomised, crossover study was carried out in 14 healthy subjects who attended on seven days. Heart rate, QT(c) interval, blood pressure, plasma potassium and glucose concentrations were measured for four hours following inhaled placebo, salmeterol 100, 200 and 400 mu g and salbutamol 600, 1200 and 2400 mu g given by metered dose inhaler. Maximum changes from baseline and maximum absolute values following each dose of treatment were used to construct log dose response curves and calculate relative dose potency. Results - Both salmeterol and salbutamol caused dose dependent changes in heart rate, QT(c) interval, and plasma potassium and glucose concentrations. The onset of cardiac effects was rapid following both drugs, whereas changes in glucose and potassium concentrations occurred more gradually with salmeterol. The increase in heart rate and fall in potassium level were sustained over the four hours whereas glucose levels gradually returned towards baseline. The relative dose potency of salmeterol compared with salbutamol for changes from baseline was 7.1 (95% CI 3.9 to 14.4) for the QT(c) interval and 8.2 (95% CI 5.7 to 12.6) for plasma potassium concentration. Salmeterol caused steeper dose response curves for heart rate and plasma glucose concentration than salbutamol so relative dose potency values could not be calculated. Conclusions - These findings support previous data that salmeterol 100 mu g is broadly equivalent to salbutamol 800 mu g for systemic effects. The greater systemic effects of salmeterol are most likely to be due to greater potency relative to dose, although it may also have greater systemic bioavailability. The steeper dose response curve for heart rate with salmeterol indicates that it has a narrower therapeutic window than salbutamol and thus should be prescribed at the lowest effective dose.