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Short-acting ß2-agonists continue to be the drugs of choice for the relief of acute symptoms of asthma due to bronchospasm. They are most useful as rescue medication taken as needed. In Canada, the most widely used preparation is salbutamol, but other agents (terbutaline, fenoterol and metaproterenol) are also available. Salbutamol is also available in combination with ipratroprium bromide, an anticholinergic bronchodilator.
Short-acting ß2-agonists begin to act within a few minutes and cause maximum bronchodilation within 10-15 minutes. The duration of action varies with the agent, but airflow rates remain significantly elevated for 2-6 hours following inhalation. The degree of reversal of airflow obstruction achieved by inhaled ß2-agonists depends on the nature of the obstruction and intrinsic properties of the airway wall.
The immediate adverse effects of inhaled short-acting ß2-agonists are minimal, but include mild tremor and tachycardia. These systemic effects diminish with repeated use without loss of the bronchodilator effects. However, regular or frequent use of inhaled short-acting ß2-agonists may be associated with decreased control of asthma and increased airway responsiveness to direct and indirect provoking stimuli, including allergens (both early and late asthmatic reactions are increased), exercise and methacholine challenge.
Efficacy and safety
The widespread use of short-acting ß2-agonists over 50 years attests to their general efficacy and safety, but studies in the last 10 years have highlighted several important facts. First, there is no evidence that regular 4-times-a-day treatment with short-acting ß2-agonists benefits patients with any degree of asthma severity compared with the use of these agents only when needed for symptom relief.1,2 Second, the more potent ß2-agonists seem to have adverse effects when taken regularly; this is especially true of fenoterol, whose regular use is associated with increased morbidity and mortality due to increased severity of asthma.3,4 Withdrawal of fenoterol has led to a rapid decline in both mortality and in hospital admissions, suggesting strongly that the adverse effects were related to increased severity rather than to cardiac toxicity.5,6 Third, a study of regular versus as-needed salbutamol in people with mild asthma showed a consistent trend toward more symptoms, reduced lung function and increased airway responsiveness in the group treated regularly 4 times a day with salbutamol,2 although for all outcomes except airway responsiveness, the differences were not statistically significant. More detailed mechanistic studies have shown that regular use of salbutamol may enhance early and late asthmatic reactions to allergen7,8 and the degree of bronchial constriction resulting from standardized exercise challenge.9 Numerous studies have confirmed that the regular use of short-acting ß2-agonists increases airway responsiveness to histamine or methacholine.1,2,10-14
The adverse effects of regularly inhaled short-acting ß2-agonist are not obviated by the concomitant use of inhaled glucocorticosteroid.1 No beneficial anti-inflammatory effects have been firmly attributed to short-acting inhaled ß2-agonists; indeed, these agents may increase rather than decrease the cellular inflammatory response in asthma.15,16
When ß2-agonists are used as required for symptom relief, their frequency of use is a good marker of control of asthma. A pattern of escalating use of short-acting ß2-agonists is predictive of high risk of a major life-threatening episode of asthma.17,18
There is no evidence in humans to suggest that inhaled short-acting ß2-agonists increase serious cardiac arrhythmias or induce other cardiac abnormalities.6 Although a hypokaliemic effect has been observed after inhaled ß2-agonists, this has generally been considered not clinically significant.
Long-acting ß2-agonists
The long-acting ß2-agonists provide more sustained bronchodilation and, at least initially, provide prolonged protection from natural or laboratory challenges. They can be used as additional treatment in those whose asthma is not adequately controlled with anti-inflammatory medication. Long-acting ß2-agonists may reduce the number of exacerbations when added to inhaled glucocorticosteroids. Also, unlike the short-acting ß2-agonists, they do not seem to increase airway responsiveness or decrease control of asthma. However, long-acting ß2-agonist may mask deteriorating asthma especially if glucocorticosteroid or other anti-inflammatory therapy is withdrawn while symptoms are controlled with a long-acting ß2-agonist.
Efficacy and safety
In response to the concern that regular use of short-acting inhaled ß2-agonists may be associated with increased morbidity and mortality from the loss of control of asthma, careful pre- and post-marketing studies of salmeterol and formoterol have been undertaken to determine whether such risks occur with these agents. One post-marketing surveillance study of salmeterol19 showed an odds ratio of 3.0 for death associated with use of salmeterol, but this was not statistically significant. Another prescription-event monitoring study20 provided no evidence that the use of salmeterol is associated with excess mortality. Moreover, a large well-controlled study with formoterol,21 with exacerbation as primary outcome, provided reassuring information that addition of formoterol to either low-dose or higher-dose inhaled glucocorticosteroid did not increase the frequency of mild or severe exacerbations of disease and was associated with improved control of symptoms and lung function.
The ability of these agents to induce sustained relaxation of smooth muscle in airways, preventing episodic or sustained shortening, particularly at night, is postulated to explain the observed clinical benefit.22,23 The rationale for long-acting bronchodilator treatment is not only to provide prolonged symptom relief, but also to protect against challenges from allergens or exercise and other less-identifiable stimuli. Unfortunately, tachyphylaxis to bronchoprotection is readily demonstrated after only a few doses of salmeterol24,25 and probably also occurs with formoterol.26 Although both agents protect against exercise-induced asthma for 12 hours or more following a single dose,27,28 the duration of protection following multiple doses is considerably shortened.29,30 Even once-daily dosing with salmeterol has been associated with tachyphylaxis to its bronchoprotective effect against exercise-induced asthma in children treated with inhaled glucocorticosteroids.31
Formoterol is a full agonist at ß-receptors, whereas salmeterol is a partial agonist with a different mechanism for prolonged duration of effect.32-39 These pharmacologic differences allow for a number of in vitro and in vivo differences between these two agents, including the possibility of a greater effect of formoterol when smooth muscle tone is markedly increased. In addition, formoterol induces bronchodilation more rapidly than salmeterol and the duration of its effect shows a more pronounced dose-response relation; however, these differences are of uncertain clinical relevance when the agents are used as suggested.
In a randomized crossover trial, a greater degree of inhaled glucocorticosteroid withdrawal could be achieved during salmeterol treatment before clinical features of an exacerbation were noted (increased symptoms and decreased lung function) despite increasing airway inflammation as judged by sputum eosinophilia.40 Hence, salmeterol use can mask the development of increasing airway inflammation that, if salmeterol were not used, would increase symptoms and decrease lung function and draw attention earlier to the worsening inflammatory process.
Debate continues as to whether the use of long-acting ß2-agonist leads to subsensitivity to short-acting ß2-agonists needed for rescue therapy when symptoms are acute.34,41 Experimental work suggests a lesser degree of response to short-acting ß2-agonists, but this may be due to improved baseline lung function, with less room for improvement with short-acting ß2-agonist.
Several studies have demonstrated that adding a long-acting ß2-agonist is preferable, in terms of controlling symptoms and lung function, to doubling or further increasing the dose of inhaled glucocorticosteroid in patients with persistent symptoms despite glucocorticosteroid and short-acting ß2-agonist therapy.21,42-44 These studies address the increasing concern about adverse effects of high doses of glucocorticosteroids,44,45 by suggesting that combination therapy with a moderate dose of inhaled glucocorticosteroid and long-acting ß2-agonist is preferable to high-dose inhaled glucocorticosteroid alone.
As with all forms of inhaled therapy, attention to the type of inhalation device and technique along with appropriate patient education and reinforcement is essential.46
Recommendations
• Short-acting inhaled ß2-agonists are the drugs of choice in both children and adults for relief of acute symptoms and short-term prevention of exercise-induced bronchospasm (level I).
• When daily use of short-acting inhaled ß2-agonist is needed, a controller (anti-inflammatory) medication is required (level I).
• Regular controller (anti-inflammatory) medications should be used if short-acting ß2-agonists are used more than 3 times a week in addition to their once daily use to prevent exercise-induced symptoms (level IV).
• Patients who need a short-acting ß2-agonist several times a day require urgent reassessment with a view to increasing anti-inflammatory therapy (level III).
Recommendations
• Inhaled long-acting ß2-agonists (salmeterol and formoterol) may be considered as an alternative to increased doses of inhaled glucocorticosteroids and should be used as an add-on therapy to moderate or higher doses of inhaled glucocorticosteroids to achieve control of persistent asthma symptoms (level I).
• Long-acting ß2-agonists are not recommended for relief of acute symptoms or for use in the absence of inhaled anti-inflammatory therapy (level II).
References
This article has been cited by other articles:
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  M. Cazzola and M. G. Matera Review: Safety of long-acting {beta}2 -agonists in the treatment of asthma Therapeutic Advances in Respiratory Disease, October 1, 2007; 1(1): 35 - 46. [Abstract] [PDF]
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Copyright 1995-1999, Canadian Medical Association. All rights reserved. ISSN 1488-2329
(e) 0820-3946 (p)
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