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

Abstract

Background-The main adverse eVects of inhaled long acting 2 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 in heart rate and glucose concentrations and a fall in diastolic blood pressure and plasma potassium concentration; formoterol also caused an early increase in systolic blood pressure. The cardiovascular eVects occurred more rapidly than the metabolic eVects and the response to formoterol was faster than that of salmeterol, apart from the glycaemic response. The eVects of salmeterol were slightly more prolonged than those of formoterol, although some dose related effects were apparent at eight hours with both drugs. The relative dose potency for formoterol compared with salmeterol at four and eight hours for the diVerent end points excluding systolic blood pressure ranged from 1.6 to 7.0 after 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-Formoterol and salmeterol cause dose related changes in heart rate, diastolic blood pressure, and plasma glucose and potassium concentrations. Formoterol has a more rapid onset for most end points whereas salmeterol has slightly more prolonged activity. Both drugs have a relatively modest therapeutic window. The relative dose potencies of the two drugs for the main end points were similar to the fourfold diVerence in recommended doses. Some diVerences in the pharmacological profile of the two drugs emerged and are as yet unexplained. (Thorax 2000;55:650-656)

The Association of Weight With the Detection of Airflow Obstruction and Inhaled Treatment Among Patients With a Clinical Diagnosis of COPD

“…Patient overuse of inhaled medications is not uncommon in COPD; patients without COPD who receive and overuse inhaled medications may be at greater risk of dose-dependent adverse eff ects without the benefi t of symptom relief. [28][29][30] Furthermore, studies have shown that as the number of medications increases, medication adherence oft en decreases; thus, the addition of medications that are not indicated may aff ect patient adherence with other necessary medications, further compromising health. 31 Overweight and obese patients could be especially vulnerable to such eff ects because they have more comorbidities, greater use of prescription medications, and higher pharmacy costs than normal weight patients.…”

Comparative lung bioavailability of fluticasone/salmeterol via a breath-actuated spacer and conventional plastic spacers

“…They increase the fine respirable dose fraction by causing impaction of larger particles within the walls of the holding chamber, reduce aerosol velocity and consequently reduce oropharyngeal deposition and local adverse effects. This leads to increased systemic drug absorption from the lung and therefore increased systemic bioavailability which can be measured by using sensitive surrogates of systemic bioactivity [3][4][5][6][7]. The propensity for dose related systemic and local adverse effects with ICS is often dictated by the choice of inhaled steroid, its pharmacokinetic and pharmacodynamic properties, its respirable particle size and site of lung deposition, and type of drug delivery device used.…”

Comparison of Pharmacokinetic and Pharmacodynamic Effects of Two Hydrofluoroalkane Formulations of Salmeterol

“…The pulmonary absorption peak observed in all PK studies was within 5 min which indicates that all subjects had performed the were evaluated to estimate relative potency between the two drugs [33]. Relative potency was adequately estimated in this study as both drugs had dose-related effects on the systemic parameters.…”

“…The ratio of doses giving equivalent effects (potency ratio) indicates relative potency of two formulations [32,33]. In a previous study, three doses of formoterol (24,48, and 96 µg) and salmeterol (100, 200 and 400 µg)…”