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Fenoterol in exercise-induced asthma. Effect of dose on efficacy and duration of action.
Abstract
The effectiveness of inhaled fenoterol doses of 0.4 mg and 0.8 mg in preventing exercise-induced asthma was investigated in 12 patients. Exercise-induced asthma was prevented by both doses for two hours after administration, but the effect of neither dose was significantly different from that of placebo four hours after. There was no statistically significant difference between the effects of the two fenoterol doses; and only a few patients were protected for more than two hours by the higher dose.
IntroductionTreatment OptionsCorticosteroidsInhaled β2,-AgonistsCromones—Cromolyn Sodium and Nedocromil SodiumAntileukotriene AgentsAnticholinergicsAnti HistaminesTheophyllineProstaglandin E2Non-Pharmacological Attenuation of ExerciseinducedSummaryReferences
Background:
It is well known that physical exercise can trigger asthma symptoms and can induce bronchial obstruction in people without clinical asthma. International guidelines on asthma management recommend the use of beta2-agonists at any stage of the disease. At present, however, no consensus has been reached about the efficacy and safety of beta2-agonists in the pretreatment of exercise-induced asthma and exercise-induced bronchoconstriction. For the purpose of the present review, both of these conditions are referred to by the acronymous EIA, independently from the presence of an underlying chronic clinical disease.
Objectives:
To assess the effects of inhaled short- and long-acting beta2-agonists, compared with placebo, in the pretreatment of children and adults with exercise-induced asthma (or exercise-induced bronchoconstriction).
Search methods:
Trials were identified by electronic searching of the Cochrane Airways Group Specialised Register of Trials and by handsearching of respiratory journals and meetings. Searches are current as of August 2013.
Selection criteria:
We included randomised, double-blind, placebo-controlled trials of any study design, published in full text, that assessed the effects of inhaled beta2-agonists on EIA in adults and children. We excluded studies that did not clearly state diagnostic criteria for EIA.
Data collection and analysis:
We used standard methodological procedures as expected by The Cochrane Collaboration.
Main results:
We included 53 trials consisting of 1139 participants. Forty-eight studies used a cross-over design, and five were performed in accordance with a parallel-group design. Forty-five studies addressed the effect of a single beta2-agonist administration, and eight focused on long-term treatment. We addressed these two different intervention regimens as different comparisons.Among primary outcomes for short-term administration, data on maximum fall in forced expiratory volume in 1 second (FEV1) showed a significant protective effect for both short-acting beta-agonists (SABA) and long-acting beta-agonists (LABA) compared with placebo, with a mean difference of -17.67% (95% confidence interval (CI) -19.51% to -15.84%, P = 0.00001, 799 participants from 72 studies). The subgroup analysis of studies performed in adults compared with those performed in children showed high heterogeneity confined to children, despite the comparable mean bronchoprotective effect.Secondary outcomes on other pulmonary function parameters confirmed a more positive and protective effect of beta2-agonists on EIA compared with placebo. Occurrence of side effects was not significantly different between beta2-agonists and placebo.Overall evaluation of the included long-term studies suggests a beta2-agonist bronchoprotective effect for the first dose of treatment. However, long-term use of both SABA and LABA induced the onset of tolerance and decreased the duration of drug effect, even after a short treatment period.
Authors' conclusions:
Evidence of low to moderate quality shows that beta2-agonists, both SABA and LABA, when administered in a single dose, are effective and safe in preventing EIA.Long-term regular administration of inhaled beta2-agonists induces tolerance and lacks sufficient safety data. This finding appears to be of particular clinical relevance in view of the potential for prolonged regular use of beta2-agonists as monotherapy in the pretreatment of EIA, despite the warnings of drug agencies (FDA, EMA) regarding LABA.
Beta-adrenoceptor agonists such as albuterol are very effective in preventing exercise-induced asthma (EIA) when they are given as an aerosol immediately before exercise. However, their duration of protection against EIA is usually less than 2 h. This may be due partly to their rapid clearance from the airways. Salmeterol is a highly lipophylic compound that is thought to bind to an exoreceptor near the beta-receptor. The objective of this study was to compare the protective effect of salmeterol with albuterol against EIA. Exercise was performed 0.5, 2.5, 4.5, and 6.5 hours after administration of the active drugs. Subjects attended the laboratory on four days within six weeks and cycled for 8 min breathing dry compressed air. We studied 17 asthmatic subjects (aged 19 to 49 years) with moderate to severe EIA. Salmeterol (50 micrograms) or albuterol (200 micrograms) was given from a metered dose inhaler via a spacer (Volumatic). On the control day, the mean work load +/- 1 SD was 174 +/- 47 W, ventilation (VE) was 77.9 percent +/- 11.2 percent of the target ventilation (60 percent maximum voluntary ventilation [MVV]), and heart rate was 170 +/- 14 beats per minute. This intensity was maintained for all tests. FEV1 was measured before and after exercise and was expressed as percent predicted and as percentage of the preexercise value (percentage of fall). Thirty minutes after treatment, both drugs were effective in inhibiting EIA--percentage of fall in FEV1, 17 +/- 12 after salmeterol; percentage of fall in FEV1, 15 +/- 15 after albuterol. At 2.5, 4.5, and 6.5 hours, the reduction in FEV1 was significantly less (p less than 0.01) after salmeterol compared with albuterol. At 6.5 hours, the percentage of fall in FEV1 was 20 +/- 10 after salmeterol and 36 +/- 12 after albuterol. Salmeterol also had a more prolonged action as a bronchodilator and values for FEV1 were significantly higher compared with those on albuterol at 4.5 and 6.5 hours. At 6.5 hours, the FEV1 percent predicted was 96 +/- 10 after salmeterol and 84 +/- 12 after albuterol (p less than 0.01). We conclude that the extent of protection against EIA and the bronchodilation induced by both drugs was similar, but that salmeterol has a longer duration of action compared with albuterol. The reason for its superior duration of action may be due to a slower clearance of the drug from the airways.
Regularly monitoring peak expiratory flow with peak flow meters is an important part of asthma treatment.
Immunotherapy can be beneficial in treating childhood asthma.
Anti-inflammatory therapy is the most important pharmacological intervention in treating childhood asthma.
Patient education is of utmost importance.
With proper anti-inflammatory medications and good patient education, children should be able to lead a normal life, including school attendance and sports.
With proper management of childhood asthma, we should be able to significantly decrease asthma mortality.
Environmental control should be incorporated into any asthma treatment strategy.
Passive exposure to cigarette smoke can negate the beneficial effects of pharmacological treatment of asthma.
A total asthma treatment plan should be customized for each asthma patient. This can lead to a decrease in both the indirect and direct costs of treating asthma, and can lead to a decrease in asthma hospitalizations and mortality.
Developing optimal technique in the use of metered dose inhalers in children under 12 is difficult. Ongoing instruction and review may be necessary to ensure good technique. Spacers can help as well.
Quality of life is an important issue in asthmatic children. Asthma in children should be managed with the goal towards optimizing quality of life.
Asthma is a chronic disease that has a significant impact on quality of life and is particularly important in children and adolescents, in part due to the higher incidence of allergies in children. The incidence of asthma has increased dramatically during this time period, with the highest increases in the urban areas of developed countries. It seems that the incidence in developing countries may follow this trend as well. While our knowledge of the pathophysiology of asthma and the available of newer, safer medication have both improved, the mortality of the disease has undergone an overall increase in the past 30 years. Asthma treatment goals in children include decreasing mortality and improving quality of life. Specific treatment goals include but are not limited to decreasing inflammation, improving lung function, decreasing clinical symptoms, reducing hospital stays and emergency department visits, reducing work or school absences, and reducing the need for rescue medications. Non-pharmacological management strategies include allergen avoidance, environmental evaluation for allergens and irritants, patient education, allergy testing, regular monitoring of lung function, and the use of asthma management plans, asthma control tests, peak flow meters, and asthma diaries. Achieving asthma treatment goals reduces direct and indirect costs of asthma and is economically cost-effective. Treatment in children presents unique challenges in diagnosis and management. Challenges in diagnosis include consideration of other diseases such as viral respiratory illnesses or vocal cord dysfunction. Challenges in management include evaluation of the child's ability to use inhalers and peak flow meters and the management of exercise-induced asthma.
The results of previous studies comparing bronchodilatation from beta agonists administered by metered-dose inhaler (MDI) and nebulizer solution have been conflicting. We therefore evaluated a range of albuterol doses administered by these two methods, using histamine bronchoprovocation as a bioassay for the amount of drug reaching the beta 2 receptors in the lung. Twelve stable asthmatic volunteers received, in a double-blind, randomized, crossover design on different days, placebo or one, two, four, or six puffs from an MDI attached to an InspirEase device (90 micrograms per puff) or 0.625, 1.25, 2.5, or 5.0 mg of solution delivered in 2 ml of buffered saline through a Hudson Updraft II nebulizer. The histamine concentration required to decrease FEV1 by 20 percent (PC20) was measured 1 h before and 30 min after administration of each treatment and expressed as the increase in PC20 from baseline. The dose-response curves for change in PC20 indicated that the higher doses of the nebulizer solution delivered more drug to beta 2 receptors in the lung than the lower doses from the MDI. For example, the geometric mean increase in PC20 was 1.1 +/- 1.6 (SD) after placebo, 7.5 +/- 2.7 after two puffs from the MDI, and 20.0 +/- 2.1 after 2.5 mg of nebulizer solution (p less than 0.05). Using this bioassay method and administration technique, we estimated that ten puffs from the MDI (0.9 mg) would deliver approximately the same amount of albuterol to lung receptors as 2.5 mg of the nebulizer solution. Taking into account previously published reports and the results of the present study, we conclude that differences in dose, administration technique, nebulizer system efficiency, and severity of airway obstruction can alter the amount of drug reaching the beta 2 receptors in the lungs and, thus, the clinical response.
The purpose of the study was to investigate whether a constant submaximal exercise challenge affected the plasma pharmacokinetics of an inhaled beta 2-adrenoceptor agonist, terbutaline sulfate. Eight healthy nonsmokers participated in a study comprising measurements of plasma concentrations of terbutaline on two separate study days. Plasma samples were frequently collected at rest during study day 1, and on the second study day, during and after a 30-min exercise challenge, which was performed immediately after inhalation of the drug. The rate of increase of plasma concentrations and the maximal plasma concentrations were higher during exercise than during rest (p less than 0.01 and p less than 0.05, respectively). The plasma concentration fell rapidly after cessation of the exercise and approached those obtained at rest. We suggest that increased pulmonary and/or bronchial blood flow and altered surface tension of the liquid lining of the air space may contribute to the enhancement of absorption of this hydrophilic compound during exercise. Based on the levels of the maximal plasma concentrations reached during exercise in this study, the results would be to increase the frequency of administration of the drug, rather than to increase the administered doses, if the aim is to prevent or ameliorate exercise-induced asthma and potential systemic side effects.
For subjects with EIA participating in physical activities throughout the day, prolonged duration of protection is desirable. The purpose of this study was to determine whether in EIA a combination of the recommended aerosol doses of the beta 2-adrenergic receptor agonist, terbutaline sulfate (0.5 mg), and cromolyn sodium (disodium cromoglycate; 2 mg) provides longer protection against EIA than either drug alone. On four separate days, following the administration of either placebo, terbutaline alone, cromolyn sodium alone or terbutaline and cromolyn sodium together, 12 subjects (seven men and five women; aged 18 to 28 years) with EIA performed four identical eight minute treadmill runs, each separated by two-hour intervals. Drug treatments were given double-blind, with the order counterbalanced using a Latin-square design. Pulmonary function was recorded before the drug, immediately before and after exercise, and at 3, 4, 5, 6, 7, 10, 15, and 30 minutes after exercise. Inspired ventilation, heart rate, and environmental conditions were monitored during exercise. A two-way analysis of variance was performed to investigate the main effects of time and drug treatment. Results indicated that in comparison with placebo, EIA was significantly reduced by either cromolyn sodium or terbutaline administered up to two hours (p less than 0.01) and by the combination (cromolyn sodium and terbutaline) up to four hours after inhalation (p less than 0.05). No significant differences were found between the combination and terbutaline during the initial two hours (p less than 0.5). We conclude that a combination of beta 2-adrenergic receptor agonist and cromolyn sodium is the treatment of choice for prolonged effective protection from EIA.
Inhaled beta-agonists can produce bronchodilatation and reduce airway hyperreactivity in patients with asthma. Using these two measures, we compared inhaled bitolterol (three puffs, 1110 micrograms), albuterol (two puffs, 180 micrograms), and placebo administered by metered-dose inhaler in a blinded, crossover study of 40 subjects with chronic asthma. On each study day, subjects underwent histamine challenges at 1 1/2 hours before, and 1/2, 2, 4, 6, and 8 hours after inhaling one of the three test-drug treatments. Both drugs produced significant bronchodilatation at 30 minutes through 4 hours and significant effects on airway reactivity at 30 minutes through 2 hours (p less than 0.05). Bitolterol also produced small but significant bronchodilator effects at 6 hours and effects on airway reactivity at 4 hours (p less than 0.05). Effects of bitolterol on airway reactivity diminished significantly more slowly than effects of albuterol in subjects with baseline provocative concentration causing a 20% fall in FEV1 greater than or equal to 1.0 mg/ml of histamine (half-life of biologic effect 1.37 versus 0.92 hours; p less than 0.05) but not in subjects with baseline provocative concentration causing a 20% fall in FEV1 less than or equal to 1.0 mg/ml (half-life of biologic effect of 1.01 versus 1.00 hours; p greater than 0.05).
We compared the duration of the protective effect of two beta-adrenoceptor agonists, fenoterol (200 micrograms) and salbutamol (200 micrograms), the anticholinergic agent ipratropium (80 micrograms), and the combination of fenoterol (200 micrograms) and ipratropium (80 micrograms) against challenge by eucapnic voluntary hyperventilation (EVH). Twelve patients with asthma performed EVH for two or four min at 60 percent maximal voluntary ventilation, 30 min, 2 and 4 h after treatment. All treatments (Rx) produced significant bronchodilation after 30 min. The Rx containing a beta-adrenoceptor agonist maintained this bronchodilation for at least 2 h. While all the Rx with a beta-adrenoceptor agonist significantly reduced the fall in forced expiratory volume in one second after EVH at 30 min, only the combination of fenoterol and ipratropium provided significant protection after 2 h. We advise that the duration of protective effect of beta-adrenoceptor agonists is short and patients with moderate to severe exercise-induced asthma may be better controlled by combination therapy.
Fenoterol (hydroxyphenylorciprenaline) is chemically closely related to metaproterenol (orciprenaline). It has a higher bronchodilating potency than metaproterenol, albuterol (salbutamol in Europe) or terbutaline. The beta 2 selectivity of fenoterol at normal oral and inhaled doses is the same as for albuterol and terbutaline. Its pharmacodynamic effects are similar to those of other selective beta 2-adrenoceptor agonists. It has a high first-pass metabolism. The long half-life previously reported in the literature (7 hours) is mainly the half-life of inactive fenoterol metabolites. The duration of action at equipotent bronchodilating doses seems to be the same as for albuterol and terbutaline, and not longer, as previously reported. Inhalation of beta-adrenoceptor agonists is the superior route of administration. Side effects do not usually occur at normal therapeutic doses. One puff of fenoterol (200 micrograms) is about equipotent to 2 puffs of albuterol (2 X 100 micrograms) or 2 puffs of terbutaline (2 X 250 micrograms) with the same duration of effect. In patients who overdose with the metered-dose inhaler (MDI), side effects occur at half the number of puffs with fenoterol. Dosage for an acute attack in children is 1 puff (200 micrograms), repeated within 5 minutes if necessary; in adults 1-3 puffs can be given. For maintenance therapy, the dose in adults is 1-2 puffs 2-4 times daily, while in children 1 puff at night and 1 in the morning may be sufficient. The usual oral dosage has been 5-10 mg 3 times daily.
Three doses of fenoterol were administered by metered-dose inhaler to 20 adult subjects with asthma in order to determine the optimal dose for routine administration. Inhaled doses of 100 micrograms, 200 micrograms, and 400 micrograms of fenoterol with isoproterenol and placebo controls were administered in a randomized double-blind crossover regimen. We found that 200 micrograms of fenoterol by metered-dose inhaler produced a longer duration of action, greater peak response, and greater overall time-weighted responses in the forced expiratory volume in one second, in the mean forced expiratory flow during the middle half of the forced vital capacity, and in airway resistance than did the other drug regimens. The 400 micrograms dose of fenoterol produced no increase in response over that seen after the 200 micrograms dose. Side effects were minimal and no greater than with isoproterenol.
Dry air exercise challenges are frequently used to screen medications that have potential utility in the management of exercise−induced bronchoconstriction (EIB). The purpose of this study was to determine the reproducibility of three outcome measurements made using such challenges, and sample size requirements for drug evaluation studies based on these outcomes.
Forty adult subjects with asthma, who tested positively on a screening exercise challenge, were subjected to two further identical challenges, separated by 1 to >35 days. Outcome measurements included the maximum per cent fall in forced expiratory volume in one second (FEV 1 ), after exercise (% fall max ), and the area under the per cent fall in FEV 1 /time curve for 30 min (AUC 30 ) and 60 min (AUC 60 ) after exercise.
The reproducibility of these outcomes, as assessed by intraclass correlation coefficients was 0.72, 0.53 and 0.35 for % fall max , AUC 30 and AUC 60 measurements, respectively. The sample size requirements to demonstrate an attenuation of EIB equivalent to a 50% reduction in % fall max was 9, 14 and 19 subjects for the % fall max , AUC 30 and AUC 60 responses, respectively (90% power).
It is concluded that the maximum percentage fall in forced expiratory volume in one second has greater reproducibility and results in greater power in clinical trials than area under the curve measurements. Sample size calculation curves are provided which may be used in study design and interpretation of published studies.
Asthmatic children, known to be susceptible to exercise-induced bronchoconstriction, exercised by running or walking on a treadmill. Changes in airways obstruction were estimated by measurement of peak expiratory flow rate before, during, and after exercise. Post exercise bronchoconstriction reached a maximum when the duration of exercise was 6 to 8 minutes and when the gradient of the treadmill was 10 to 15%; exercise for longer periods or at steeper gradients produced no significant increase in bronchoconstriction. Bronchoconstriction was much greater after running than after walking at the same oxygen consumption in 4 out of the 5 subjects tested.The reproducibility of bronchoconstriction was good in individual patients when tests performed within one day or within one week were compared. Reproducibility diminished as the interval between tests increased to one month or one year. When tests were repeated at 2-hourly intervals throughout the day, no significant diminution in exercise-induced bronchoconstriction was noted. Variations in pre-exercise peak expiratory flow rate had no significant effect on exercise-induced bronchoconstriction in individual subjects.The range of response of normal children to treadmill exercise is defined and the value of the test in discriminating between asthmatic and other children is shown.If several tests are to be carried out by an individual patient, they should be performed on separate days at the same time of day and should be completed within one week. This will allow accurate comparisons to be made between tests in, for example, the assessment of the effect of different drugs in an individual patient.
The effects of inhaling 0.4 mg of fenoterol hydrobromide (Berotec), 0.2 mg of albuterol (salbutamol), or placebo were compared in a double-blind three-way crossover study in a group of 12 asthmatic patients. After inhalation of fenoterol, the maximum increase in the forced expiratory volume in the first second (FEV1) was 0.76 L (48 percent) and in the peak expiratory flow (PEF) was 100 L/min (47 percent). The corresponding figures after inhalation of albuterol were 0.68 L (46 percent) and 98 L/min (48 percent), respectively. In comparison with administration of placebo, the FEV1 was significantly increased until six hours after inhalation of either drug. From three to six hours after inhalation, the effect of administration of fenoterol (as measured by FEV1 or PEF) significantly exceeded that of albuterol. Administration of either drug resulted in approximately equal bronchodilation (as measured by the increase in FEV1 or PEF), the effect of inhalation of fenoterol being of longer duration.
Exercise-induced asthma (EIA) was provoked by standardized treadmill running for 6 minutes in 15 asthmatic children. The tests were carried out after the administration of a placebo, salbutamol, sodium cromoglycate, choline theophyllinate, and atrophine methonitrate aerosol in randomized fashion on different days. The mean post-exercise percent fall in peak expiratory flow rate was 45-2, 4-1, 19-6, 18-3, and 24-9 respectively. The proportion of children having significant amelioration of their EIA compared with those taking the placebo was 100% for salbutamol, 80% for cromoglycate and theophyllinate, and 60% for atropine. Salbutamol, choline theophyllinate, and atropine were bronchodilators at rest whereas cromoglycate was not, and the ability to suppress EIA was unrelated to bronchodilator effect. Even after bronchodilatation at rest, further broncho-dilatation occurred during the exercise period.
The effectiveness of inhaled versus oral metaproterenol in preventing exercise-induced asthma (EIA) was studied.
Inhaled metaproterenol given 10 min before the exercise significantly reduced the degree of EIA in a group of twenty-four patients, and in 75% of them completely prevented it. The mean percentage decrease in FEV1 was 6-5% with the inhaler and 30.1%, with placebo. When inhaled 1 hr before the exercise, metaproterenol was still better than placebo but its effectiveness was considerably lower. Metaproterenol tablets had a slight protective effect given I hr before, and none when administered 2 hr before exercise.
There was no correlation between the protective effect against EIA and the bronchodilating effect obtained before exercise. Metaproterenol administered by metered-dose inhaler is a very effective prophylactic medication against clinically troublesome EIA, while metaproterenol tablets should not be recommended for this purpose.
Controlled comparison of berotec and salbutamol metered dose aerosols
- Riedel-Dibbern