Systemic effects of formoterol and salmeterol: a dose-responsecomparison in healthy subjects

摘要

BACKGROUND—The main adverse effects of inhaled long acting β2 agonists relate to their systemic activity. The systemic effects seen over eight hours after inhalation of three doses of salmeterol and formoterol were therefore compared in normal subjects.
METHODS—A double blind, randomised, crossover study was carried out in 16 healthy subjects who inhaled formoterol 24, 48 and 96 µg (via Turbuhaler^®), salmeterol 100, 200 and 400 µg (via Diskhaler^®), or placebo on separate days. Heart rate, systolic and diastolic blood pressure, and plasma potassium and glucose concentrations were measured for eight hours following each drug and mean values were used to plot the time course of change after each dose. Mean maximum (or minimum) absolute values were used to construct dose-response curves to calculate the relative dose potency of the two drugs. Lunch was taken after the four hour readings and, since this caused additional changes to the main outcome measures, data from the first four hours are also presented in a post hoc analysis.
RESULTS—Both salmeterol and formoterol caused an early dose dependent increase inheart rate and glucose concentrations and a fall in diastolic bloodpressure and plasma potassium concentration; formoterol also caused anearly increase in systolic blood pressure. The cardiovascular effectsoccurred more rapidly than the metabolic effects and the response toformoterol was faster than that of salmeterol, apart from theglycaemic response. The effects of salmeterol were slightly moreprolonged than those of formoterol, although some dose related effectswere apparent at eight hours with both drugs. The relative dose potencyfor formoterol compared with salmeterol at four and eight hours for thedifferent end points excluding systolic blood pressure ranged from 1.6 to 7.0after adjusting for baseline values. Relative dose potencies(95% CI) for maximum heart rate and plasma potassium concentrations were 4.1 (3.0 to 5.6) and 5.8 (4.1 to 8.6) over four hours and 2.4 (1.2 to 3.8) and 3.0 (1.2 to 5.7) over eight hours.
CONCLUSIONS—Formoteroland salmeterol cause dose related changes in heart rate, diastolicblood pressure, and plasma glucose and potassium concentrations.Formoterol has a more rapid onset for most end points whereassalmeterol has slightly more prolonged activity. Both drugs have arelatively modest therapeutic window. The relative dose potencies ofthe two drugs for the main end points were similar to the fourfolddifference in recommended doses. Some differences in thepharmacological profile of the two drugs emerged and are as yet unexplained.