Bronchodilator Effect of Inhaled Formoterol vs Salbutamol Over 12 Hours

191

We evaluated the profile of the bronchodilatory effect of three inhaled β 2 -agonists, 24 µg formoterol, 50 µg salmeterol and 200 µg salbutamol, in patients with stable, moderately severe asthma.Thirty asthmatics (mean±SD age 54±8 yrs; forced expiratory volume in one second (FEV1) 58±12% predicted; reversibility of FEV1 21±8% from baseline) participated in a single-centre, double-blind, randomized, single-dose, cross-over study. FEV1 was obtained in baseline condition and 10, 20, 30, 60 min, and every hour up to 12 h after inhalation of the trial drug. Specific airway conductance (sGaw) was measured at baseline condition and 1, 3, 5, 7, 10, 20, 30, 60 min, and every hour up to 12 h after inhalation.Formoterol produced a mean increase in sGaw (as % of baseline) of 44% after 1 min, maximal (135%) after 2 h, and 56% after 12 h. The mean increase in FEV1 was maximal (27%) after 2h, and 10% after 12 h. After salmeterol, mean increase in sGaw amounted to 16% after 3 min, maximal (111%) after 2-4 h, and 58% after 12 h. The mean increase in FEV1 was maximally 25% after 3h, being 11% after 12 h. After salbutamol, mean increase in sGaw was 44% after 1 min and maximal (100%) after 30 min. The peak increase in FEV1 was 25%.We conclude that formoterol (24 µg) and salmeterol (50 µg) had an equal bronchodilatory capacity, which was similar to that of 200 µg salbutamol and lasted for at least 12 h in patients with asthma. However, formoterol had a more rapid onset of action than salmeterol, equal to that of salbutamol. Eur Respir J., 1996Respir J., , 9, 1684Respir J., -1688 Formoterol and salmeterol are the first two drugs of a new generation of β 2 -agonists with prolonged effect. Both compounds, when administered as an aerosol by a metered-dose inhaler (MDI) or when inhaled as a powder, have the property of retaining a bronchodilatory effect for up to 12 h, which accounts for their use in patients with nocturnal asthma. Moreover, the long duration of action allows for a twice daily treatment frequency, for example, on arising in the morning and on going to bed at night, which could be helpful in promoting patient compliance [1][2][3][4][5][6].In vitro work and noncomparative studies on formoterol and salmeterol have shown evidence that there are small differences between the two inhaled drugs with regard to the speed of onset of a bronchodilatory effect, duration of action and dose-dependency of the duration of effect [6][7][8][9][10][11][12][13]. At the present time, a few comparative studies in patients with chronic obstructive pulmonary disease (COPD) have been published [14,15], however, a direct comparison of the profile of the bronchodilatory effect in asthma is still lacking.The purpose of the present study was to compare the onset and duration of action of 24 µg formoterol, 50 µg salmeterol and 200 µg salbutamol in patients with moderately severe asthma. Patients and methodsThirty adults with asthma, 8 females and 22 males, who met the American Thoracic Society (ATS) diagnostic criteria for asthma [16], vo...

Section: Statistical Assessmentmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Salmeterol versus formoterol in patients with moderately severe asthma: onset and duration of action

Noord¹,

Smeets²,

Raaijmakers³

et al. 1996

191

“…This questions its applicability in children with asthma. Eur Respir J 1997; 10: 2105-2109 Formoterol is a highly potent, selective β 2 -agonist producing bronchodilatation of rapid onset [1] and long duration [2][3][4][5]. Inhalation of formoterol (12 µg), both from pressurized aerosol and from dry powder, has been shown to provide children with clinically significant protection against methacholine induced bronchoconstriction [4] and exercise-induced asthma (EIA) [6,7] for at least 12 h.…”

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confidence: 99%

Flow-dependent effect of formoterol dry-powder inhaled from the Aerolizer

Nielsen¹,

Skov²,

Klug³

et al. 1997

The output and size distribution of aerosols from dry powder inhalers are dependent on the flow rate through the device. Therefore, in an in vivo study, we examined the flow-dependency of the effect of formoterol when delivered from a dry powder inhaler, the Aerolizer®, in a flow range relevant to schoolchildren.In a preliminary study comprising 126 asthmatic children aged 3-10 yrs, the relationship between age and peak inspiratory flow (PIF) rate through the Aerolizer® was determined. Mean PIF was 104 L·min -1 and all children aged >5 yrs performed a PIF >60 L·min -1 . Sixteen children aged 8-15 yrs with exercise-induced asthma (EIA) took part in the main trial comparing the protective effect of 12 µg formoterol inhaled at 60 and 120 L·min -1 . The effect from high and low inspiratory flow was judged from the protective effect against EIA 12 h after drug administration.The decrease in forced expiratory volume in one second (FEV1) after exercise was 34% on the placebo day, but only 15% when formoterol was inhaled at the high flow rate. This difference was statistically significant. The decrease in FEV1 was 23% after treatment with formoterol inhaled at the low flow rate, that was not significantly different from placebo or from high-flow formoterol treatment. These clinical findings correspond with the in vitro findings of flow-dependent fine particle mass from the Aerolizer®, and corroborate the relationship between fine particle mass of aerosol and clinical effect.The results indicate a flow-dependent effect of formoterol dry powder inhaled from the Aerolizer®, within the range of inspiratory flow rate obtainable by schoolchildren. This questions its applicability in children with asthma. Eur Respir J 1997; 10: 2105-2109 Formoterol is a highly potent, selective β 2 -agonist producing bronchodilatation of rapid onset [1] and long duration [2][3][4][5]. Inhalation of formoterol (12 µg), both from pressurized aerosol and from dry powder, has been shown to provide children with clinically significant protection against methacholine induced bronchoconstriction [4] and exercise-induced asthma (EIA) [6,7] for at least 12 h.The major advantage of dry powder inhalers (DPIs) is the avoidance of propellants and lubricants, and the fact that they are actuated when the child is inhaling through the device [8,9], thereby overcoming the problem of co-ordination. Formoterol dry powder is delivered from a single-dose dry powder capsule inhaler, the Aerolizer® [10], previously known as the ISF device (ITALSEBER Farmaceutici Italy). The powder comprises micronized active substance and lactose, which serves as a bulking agent. The major disadvantage of DPIs is that the size distribution of the aerosol is dependent on the flow rate through the device, which depends on the internal resistance of the device and the effort of the child. Such effort dependency varies between the DPIs available [11].The objective of this trial was to perform an in vivo study of flow-dependency of the effect of formoterol when delivered from t...

“…Extensive clinical trial data have been obtained with these drugs, which indicate that they both cause significant bronchodilation for at least 12 h after a single administration [1][2][3][4][5]. Both compounds are well-tolerated and highly potent; the principal difference in their clinical pharmacology being the faster onset of action of formoterol compared to salmeterol [6][7][8].…”

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confidence: 99%

Why are long-acting beta-adrenoceptor agonists long-acting?

Anderson¹,

Lindén²,

Rabe³

1994

220

159

The extended duration of bronchodilation due to formoterol and salmeterol greatly exceeds that of short acting beta 2-adrenoceptor agonists, such as salbutamol or terbutaline. This extended duration and their capacity to "reassert" airway smooth muscle relaxation in vitro despite repeated washing has prompted considerable debate on the underlying mechanism(s). The comparative pharmacology, and molecular modelling of these drugs and of the beta 2-adrenoceptor and its ligand binding core have cast doubt on the exosite/exoceptor model previously proposed to explain the behaviour of salmeterol. We present evidence supporting a unifying hypothesis that the duration of action both of formoterol and salmeterol is determined principally by their physicochemical interactions with membrane lipid bilayers (plasmalemma diffusion microkinetic model), rather than putative distinct exosite/exoceptor binding sites in or near the beta 2-adrenoceptor. This model provides a clearer understanding of the pharmacological profile of these drugs (rate of onset, duration, "reassertion", interaction with hydrophilic and hydrophobic beta 2-adrenoceptor antagonists), and explains why in human airway smooth muscle in vitro a true relaxation-concentration response may not exist for salmeterol.