Version October 2024
INTRODUCTION — Beta adrenergic drugs are the most potent bronchodilators approved for clinical use in asthma and obstructive lung disease. Among the beta agonists, the individual agents vary in their rapidity of onset and duration of action. Inhaled, short-acting, selective beta-2 adrenergic agonists are the traditional mainstay of acute asthma therapy, while inhaled, long-acting, selective beta-2 adrenergic agonists (in combination with inhaled glucocorticoids) play a role in long-term control of moderate to severe asthma [1].
The mechanism of action of beta adrenergic medications and their clinical use in the management of asthma will be reviewed here. The general approach to asthma management, the treatment of acute exacerbations of asthma, and an overview of the delivery of inhaled medications are discussed separately. (See "An overview of asthma management in children and adults" and "Delivery of inhaled medication in adults" and "Acute exacerbations of asthma in adults: Emergency department and inpatient management", section on 'Inhaled beta-agonists'.)
MECHANISM OF ACTION — Beta-2 agonists were developed for treatment of asthma through modifications of the epinephrine molecule to allow selective interaction with beta-2 receptors on bronchial smooth muscle to achieve bronchodilation with less tachycardia associated with activation of beta-1 receptors on cardiac muscle.
Beta-2 receptors are G protein-coupled transmembrane receptors that activate the enzyme adenylyl cyclase [2]. Activation of adenylyl cyclase produces cyclic adenosine monophosphate (cAMP). The exact mechanism by which cAMP causes smooth muscle relaxation is not fully understood but likely involves activation of protein kinase A and changes in intracellular calcium concentrations. Activation of beta-2 receptors also affect potassium channels through a separate mechanism. The function of the beta-2 adrenergic receptor and the role of polymorphisms of the receptor in individual responses to beta agonists are discussed separately. (See "Beta-2 adrenergic receptor dysfunction and polymorphism in asthma".)
Variations in the molecular structure of beta agonists affect the onset and duration of bronchodilation. As an example, prolongation of the bronchodilator effect (relative to isoproterenol) is achieved by modifications that reduce susceptibility to degradation by catechol O-methyl transferase (COMT) and monoamine oxidase [3]. In addition, the long, lipophilic side chains of long-acting beta-agonists (LABAs; eg, formoterol and salmeterol) attach to the plasma membrane and increase the duration of binding of the drugs to the adrenergic receptor.
The lipophilic side chain of salmeterol leads to incorporation of the drug into the cell membrane and activation of the beta adrenergic receptor through an alternate binding site, rather than the usual site in the aqueous surface of the cell membrane [2]. It is thought that accessing the alternate binding site deeper in the cell membrane slows the onset of action of salmeterol.
By contrast, formoterol has a different lipophilic side chain that gives it a rapid onset of action comparable to that of albuterol (also known as salbutamol) and enables use of formoterol in combination inhalers (with inhaled glucocorticoids) for both maintenance and rescue treatment (termed single maintenance and reliever therapy [SMART]) [4]. (See 'Quick relief of asthma symptoms' below.)
Beta-2 agonists also interact with beta adrenergic receptors on the surface of a variety of other cells that play a role in asthma pathogenesis. As examples, beta agonists have the potential to decrease mast cell mediator release, inhibit neutrophil, eosinophil, and lymphocyte functional responses, increase mucociliary transport, and affect vascular tone and edema formation [3,5]. (See "Pathogenesis of asthma".)
USE IN ACUTE EXACERBATIONS OF ASTHMA — Short-acting beta-2 agonists (SABAs) are the drug of choice for acute treatment of asthma symptoms and exacerbations [4,6,7].
Heterogeneity of response — The responsiveness to beta agonists varies among patients. While some patients respond promptly to SABA administration, other patients with asthma exacerbations appear to require substantially higher doses of beta agonists to achieve reversal of bronchoconstriction [8,9]. Repetitive or continuous administration of a SABA may be needed, particularly for patients with moderate to severe exacerbations [6,7]. The management of acute exacerbations of asthma is discussed separately. (See 'Adverse effects' below and "Acute exacerbations of asthma in adults: Emergency department and inpatient management", section on 'Inhaled beta-agonists'.)
The individual response to beta agonist therapy for an acute exacerbation of asthma is related to many factors, including:
●The relative contribution of bronchoconstriction versus airway inflammation and edema in producing the underlying airway obstruction; bronchoconstriction is usually more responsive whereas the other components are not.
●Route of medication delivery (oral, inhaled, parenteral). (See 'Route of delivery' below.)
●The triggering mechanism (exercise, allergen exposure, infection).
●Concurrent medication and baseline frequency of beta agonist use. Downregulation of beta receptors can occur with frequent use of beta agonists. (See 'Tolerance' below.)
●Age and proper device technique, since airway geometry and the ability to utilize various delivery systems are important factors in children.
●Duration of symptoms; a longer duration of symptoms (eg, days rather than minutes) typically suggests concomitant airway inflammation.
●The outcome measure(s) used to evaluate the response, both subjective (eg, ease of breathing) and objective (eg, improvements in peak flow or spirometry).
Route of delivery — The route of delivery (eg, metered dose or dry powder inhaler, nebulized, oral, subcutaneous, intravenous) of the beta agonist is an important determinant of efficacy. It might be expected that oral or parenteral administration would be more effective than inhaled use, since mucous plugging might prevent adequate airway penetration of inhaled forms. However, studies evaluating the relative efficacy have shown that inhaled and subcutaneous routes are superior to oral therapy. (See "Delivery of inhaled medication in adults" and "Delivery of inhaled medication in children" and "Use of medication nebulizers in children" and "The use of inhaler devices in children".)
●Many patients report superior symptom relief following nebulized therapy compared with metered dose inhalation; however, objective pulmonary function data after equal drug dosages generally do not support a difference in physiologic response [10,11]. On the other hand, nebulizer therapy would be preferred for patients who are unable to cooperate effectively with use of a pressurized metered dose inhaler (pMDI) because of their agitation, coordination difficulties, severity of exacerbation, or other disability [6].
●Oral beta agonists are avoided as higher doses are required to achieve a bronchodilator response comparable to inhaled preparations, and higher doses have a greater likelihood of systemic adverse effects [3]. Factors reducing efficacy of oral administration include poor absorption and rapid gastrointestinal metabolism. Further, the therapeutic effect is delayed; peak bronchodilation does not occur until two hours after ingestion [12], making oral administration appropriate only for mild to moderate asthmatic symptoms and perhaps in patients unable to use other delivery methods due to age or lack of immediate availability.
●Overall, data do not support use of intravenous over inhaled beta-2 agonists, although there is some variability among studies [7,13-17]. A systematic review that analyzed data from three trials (104 patients) found limited evidence that intravenous beta-2 agonist shortened recovery time when added to inhaled beta-2 agonist in children presenting to an emergency department with acute asthma, but no benefit in a trial that included 29 adults with acute exacerbations [18]. Parenteral beta agonists are not recommended for adults, except in rare situations such as anaphylaxis manifesting as an asthma exacerbation or inability to use inhaled bronchodilators. (See "Acute exacerbations of asthma in adults: Emergency department and inpatient management", section on 'Parenteral beta-agonists (epinephrine and terbutaline)'.)
Intravenous administration of beta agonists is clearly associated with the development of more severe adverse effects [16-21]. A higher incidence of tremor was noted in one study [20], and an elevated troponin was noted in 3 of 46 children in another study [21]. (See 'Adverse effects' below.)
Quick relief of asthma symptoms — Quick relief of acute asthma symptoms (eg, shortness of breath, cough, wheeze, chest tightness) outside the hospital can usually be accomplished either with a SABA (eg, albuterol, levalbuterol) or the rapid-onset, long-acting beta-agonist (LABA) formoterol, in combination with an inhaled glucocorticoid (table 1) [4,6,7].
Of note, the LABA formoterol has an onset of action similar to albuterol (5 to 20 minutes), so combination inhalers that contain inhaled glucocorticoid and formoterol (eg, budesonide-formoterol) can be used for relief of acute asthma symptoms in addition to long-term maintenance, termed single maintenance and reliever therapy (SMART; off-label in the United States) [4,22,23]. (See 'Long-term maintenance therapy with LABAs' below and "Initiating asthma therapy and monitoring in adolescents and adults", section on 'Low-dose maintenance and reliever therapy (MART)' and "Ongoing monitoring and titration of asthma therapies in adolescents and adults", section on 'Patients using anti-inflammatory relievers alone (Step 1 or 2)'.)
The maximum total daily dose of budesonide-formoterol should not exceed eight puffs (36 mcg) for ages 4 to 11 years and 12 inhalations (54 mcg) for ages 12 years and older. Patients are encouraged to contact their asthma specialist if they require eight or more inhalations of budesonide-formoterol in a day.
Similar to formoterol-ICS, patient-activated reliever-triggered corticosteroid strategy (PARTICS) involves the administration of ICS whenever a bronchodilator is used for immediate symptom relief. This "symptom-driven" approach appears more effective than as-needed albuterol alone, although data are more limited than for combination glucocorticoid-formoterol inhalers. Combination glucocorticoid-albuterol inhalers are increasingly available in many parts of the world. Albuterol-budesonide (90 mcg-80 mcg) has been approved in the United States for patients aged 18 years and older [24]; its maximum daily dose should not exceed twelve puffs in a day.
Escalating need for a SABA (eg, >2 days per week or >6 to 8 puffs per day or exceeding one canister per month) is a warning sign that the patient's underlying disease activity is inadequately controlled and that additional intervention is warranted (table 2) [6]. In addition, data from the SABINA cohort studies demonstrate that SABA overuse is associated with increased exacerbation risk, asthma hospitalizations, and mortality [25-28].
The Global Initiative for Asthma guidelines advise that asthma in adolescents and adults should not be treated with a SABA alone due to the risks of SABA-only treatment, SABA overuse, and evidence for benefit of inhaled corticosteroids (ICS) [7,29]. By contrast, the National Asthma Education and Prevention Program (NAEPP) 2020 Update continues to support use of SABA for quick symptom relief. The advantages and disadvantages of these two approaches are discussed separately. (See "Initiating asthma therapy and monitoring in adolescents and adults" and "An overview of asthma management in children and adults".)
Use in emergency department and hospital — Preparations of inhaled beta agonists, associated delivery systems, and dosing guidelines for SABAs used in the emergency department and hospital are listed in the table (table 1). As noted above, the response of patients with acute exacerbations of asthma to beta agonist therapy is variable. Nevertheless, a few initial guidelines can be proposed for asthmatic exacerbations severe enough to require presentation to the emergency department. Other aspects of treatment of asthma exacerbations are discussed separately. (See "Acute exacerbations of asthma in adults: Emergency department and inpatient management" and "Acute asthma exacerbations in children younger than 12 years: Emergency department management".)
●If the patient can demonstrate proper pMDI technique, two to eight inhalations of a SABA (such as albuterol) can be administered using a spacer or chamber device (eg, AeroChamber, InspirEase) (picture 1 and table 1). Alternatively, the dry powder inhaler (DPI) preparation of albuterol can be administered without a spacer or chamber device. Therapy can be repeated every 20 minutes for 3 doses, if needed, then tapered depending on response to therapy. (See "The use of inhaler devices in adults" and "Delivery of inhaled medication in children".)
●If the patient is unable to use the pMDI or DPI, does not exhibit a satisfactory clinical response, or if nebulizer treatment is preferred by patient or provider, the SABA is administered by nebulizer. Doses of SABAs for nebulization are provided in the table (table 1). Within the range of doses, the higher doses and continuous nebulization are used for more severe exacerbations in a monitored setting. The cumulative dose should be monitored because of the potential adverse effects and should not exceed the recommended limits. (See 'Heterogeneity of response' above and 'Adverse effects' below and "Delivery of inhaled medication in adults", section on 'Continuous nebulization'.)
●SABAs may be mixed with ipratropium for the initial management (first three hours) of severe exacerbations [6,7]. (See "Acute exacerbations of asthma in adults: Emergency department and inpatient management", section on 'Inhaled muscarinic antagonists'.)
●Rarely, epinephrine (0.01 mg/kg to a maximum dose of 0.3 to 0.5 mg) is administered subcutaneously or intramuscularly if nebulized therapy is either unavailable, ineffective clinically, or anaphylaxis is suspected as a cause of the asthma flare. (See "Acute exacerbations of asthma in adults: Emergency department and inpatient management", section on 'Parenteral beta-agonists (epinephrine and terbutaline)'.)
●Intravenous beta agonist therapy, particularly with isoproterenol, is not recommended, since it has been associated with adverse cardiac effects [3,19]. (See 'Route of delivery' above and 'Adverse effects' below.)
●Beta agonist therapy is associated with a decrease in arterial oxygen tension (PaO2) of 5 mmHg or more, so supplemental oxygen is provided to maintain the pulse oxygen saturation above 90 percent (above 95 percent in pregnant women and patients with coexistent cardiac disease), for severe exacerbations, or when continuous measurement of pulse oximetry is not available [6]. (See "Pulse oximetry".)
Levalbuterol — Albuterol is a racemic mixture with a 1:1 ratio of the isomers R-albuterol (levalbuterol) and S-albuterol; the R-isomer is responsible for the drug's bronchodilating activity. It is hypothesized that the S-isomer of albuterol activates proconstrictive and proinflammatory pathways in bronchial smooth muscle cells [30], which would theoretically diminish the beneficial effects of the R-isomer (levalbuterol). However, the clinical importance of these detrimental effects is unclear [31-36] and do not provide a clinically significant advantage over racemic albuterol for most patients [31,36-40].
PREVENTION OF ASTHMA SYMPTOMS
Allergen-induced asthma — In immunoglobulin E (IgE) sensitized patients, relevant allergen exposure can elicit both an immediate (within minutes) bronchoconstrictive response and a late (hours) inflammatory response that is often accompanied by recurrent bronchoconstriction. When exposure is unavoidable, bronchoconstriction can be attenuated by use of a beta agonist prior to exposure. However, as pretreatment with a beta agonist does not block the initiation and/or propagation of airway inflammation by allergen or the resultant increase in bronchial hyperresponsiveness, allergen avoidance is always preferred over pretreatment. (See "Allergen avoidance in the treatment of asthma and allergic rhinitis".)
There are important differences in the ability of short- and long-acting beta-agonists to block early and late airway responses to allergen (see "Pathogenesis of asthma"):
●Short-acting beta-agonists (SABAs) given prior to exposure can attenuate the immediate response but are generally ineffective in preventing or reversing the late response [41,42], as they do not substantially inhibit the inflammatory response.
●The long-acting beta-agonists (eg, formoterol, salmeterol, vilanterol) can block both the immediate- and late-phase bronchoconstrictive responses but not the inflammatory response (unless an inhaled glucocorticoid is given concomitantly) [43].
Use in exercise-induced asthma — SABAs are the traditional drug of choice for the prevention and treatment of exercise-induced bronchoconstriction (EIB) [44-46]. Combination inhalers containing glucocorticoid and formoterol (eg, budesonide-formoterol) are an effective alternate choice. (See "Exercise-induced bronchoconstriction".)
Proposed mechanisms — Several mechanisms have been proposed to explain how beta agonists inhibit EIB:
●The bronchodilation that they induce before exercise may counterbalance the asthma induced by exercise.
●The normal bronchodilator response seen within the first few minutes of exercise may be enhanced, thereby overriding or attenuating the airway obstruction that follows exercise.
●The mediator release associated with EIB may be inhibited due to activation of mast cell beta adrenergic receptors.
●The effect of beta agonists on smooth muscle may prevent mediator-induced bronchoconstriction.
●Beta agonists may increase bronchial blood flow, which would reduce the heat loss in the airway that is thought to be one of the mechanisms of EIB [47,48].
Efficacy of different preparations — The ability of various beta agonists to inhibit or attenuate EIB is dependent upon the minute ventilation (workload) and the particular drug administered. SABAs such as albuterol, levalbuterol, or fenoterol attenuate EIB if taken 5 to 20 minutes before exercise. The duration of protection varies with the agent used. Albuterol may attenuate EIB for four to six hours [49], whereas other bata-agonists have different durations of protective effect [50]. (See "Exercise-induced bronchoconstriction", section on 'Pre-exercise treatments for EIB'.)
The long-acting beta-agonists (LABAs) salmeterol and formoterol are also very effective in attenuating EIB [51,52]. However, single-agent LABA inhalers are avoided in asthma due to increased risks of exacerbations and mortality with LABA monotherapy (see 'Evidence against LABA monotherapy' below). Instead, a combination inhaler containing a glucocorticoid plus formoterol (eg, budesonide-formoterol 160 mcg/4.5 mcg) can be given one inhalation 5 to 20 minutes prior to exercise [7]. As one would expect, the duration of action of formoterol is longer than the SABAs; the mean duration of a 50 percent reduction in EIB is 6.5 hours with formoterol and 1.5 hours with albuterol [51]. (See "Exercise-induced bronchoconstriction", section on 'Pre-exercise treatments for EIB'.)
We do not use the LABA salmeterol as monotherapy to prevent EIB, even though it produces significant bronchodilation for at least nine hours (figure 1A-B) [52], because it must be administered at least an hour before exercise for prevention and it is not useful for treatment of breakthrough symptoms. The duration of protection induced by the long-acting preparations may decrease with chronic use in the absence of concomitant inhaled glucocorticoid (figure 2) [53]. (See 'Tolerance' below.)
Low-dose inhaled corticosteroids (ICS)-SABA combination inhalers have been approved for use in some regions, including the United States [24]. A budesonide/albuterol combination inhaler reduced bronchoconstriction postexercise compared with placebo (TYREE trial), consistent with the known effects of albuterol [54]. The National Asthma Education and Prevention Program (NAEPP) and Global Initiative for Asthma (GINA) guidelines include the alternative of combination ICS-SABA or low-dose ICS plus SABA taken concomitantly when needed for patients with Step 2/mild persistent asthma (table 3).
LONG-TERM MAINTENANCE THERAPY WITH LABAs — The long-acting beta-agonists (LABAs) formoterol, salmeterol, and vilanterol [55] are used in combination with inhaled glucocorticoids to improve asthma control and minimize the dose of inhaled glucocorticoids needed to achieve control (table 4 and table 5) [7]. LABAs have additive effects with inhaled glucocorticoids when the two agents are used in combination [56-59]. The use of LABAs to treat persistent asthma and the safety of these medications for chronic maintenance therapy are discussed separately. (See "Ongoing monitoring and titration of asthma therapies in adolescents and adults" and "Treatment of severe asthma in adolescents and adults".)
As noted above, guidelines include the option of using combination inhalers containing glucocorticoid-formoterol for both maintenance and relief of acute asthma symptoms. (See 'Quick relief of asthma symptoms' above and "Initiating asthma therapy and monitoring in adolescents and adults", section on 'Low-dose maintenance and reliever therapy (MART)' and "Ongoing monitoring and titration of asthma therapies in adolescents and adults", section on 'Increasing (stepping up) therapy, for persistent poor symptom control'.)
In addition, a combination triple-therapy inhaler containing ICS, LABA, and a long-acting muscarinic antagonist (LAMA) is approved for the treatment of severe persistent asthma (eg, fluticasone furoate-umeclidinium-vilanterol). (See "Treatment of severe asthma in adolescents and adults", section on 'Inhaled GC/LAMA or GC/LAMA/LABA'.)
Evidence of LABA-ICS safety — Clinical trials and systematic reviews have been increasingly reassuring with respect to the safety of LABAs when used with ICS in fixed-combination inhalers [60-69], in contrast to prior studies that had raised concerns about LABA safety [70-74]. The more recent data from sufficiently powered clinical trials have enabled the US Food and Drug Administration (FDA) to make a firm statement regarding the safety of LABAs when used in combination with ICS and to warn against the use of LABA monotherapy [75].
●For adults, an analysis of the four FDA-mandated trials [65,68,76,77] comparing combination ICS plus LABA with ICS alone (36,010 participants) found that serious asthma-related adverse events (composite of hospitalization, intubation, or death) occurred in 119 of 18,004 participants (0.66 percent) taking the combination inhaler and in 108 of 18,006 participants (0.6 percent) taking ICS, for a relative risk (RR) of 1.09 (95% CI 0.83-1.43) [69]. Thus, combination therapy did not result in a significantly increased risk of serious adverse asthma events compared with ICS alone. A lower risk of asthma exacerbation was noted in the combination inhaler group compared with ICS alone (RR 0.83, 95% CI 0.78-0.89). A study comparing the safety and efficacy of SABA to LABA-ICS in stable asthmatics showed less systemic and cardiovascular adverse effects with combination therapy [78].
●For children, a multicenter trial (VESTRI) randomly assigned 6208 children 4 to 11 years of age who had an asthma exacerbation in the previous year to a combination inhaler with fluticasone propionate (100 mcg or 250 mcg/inhalation) plus salmeterol or to monotherapy with fluticasone propionate (100 mcg or 250 mcg/inhalation), one inhalation twice daily for 26 weeks [67]. Serious adverse events (hospitalization due to asthma exacerbation) occurred in 27 of 3107 patients in the fluticasone-salmeterol group and in 23 of the 3101 patients in the fluticasone group, hazard ratio 1.28 (95% CI 0.73-2.27). No deaths or endotracheal intubations were reported. This hazard ratio suggests that the risk of serious asthma-related events was similar between the two groups.
These studies support the stepwise approach to asthma outlined in national and international guidelines [4,6,7,79]. (See "An overview of asthma management in children and adults".)
Glucocorticoid-sparing effect — A glucocorticoid-sparing effect refers to the ability of a pharmacologic agent to permit ICS dose reduction following its addition to a pre-existing ICS regimen. The efficacy of chronic LABAs as glucocorticoid-sparing agents was examined in a meta-analysis of 10 randomized trials comparing high-dose ICS versus combined low-dose ICS plus chronic LABA [80]. Addition of a chronic LABA permitted 37 to 60 percent reduction of the ICS dose without deterioration of asthma control.
Other studies have confirmed the efficacy of LABAs as glucocorticoid-sparing agents [81,82]. Tapering of the ICS was associated with increased sputum eosinophils in one study, but this was not accompanied by increased symptoms.
Ultra long-acting beta-agonists — Once-daily LABAs (24-hour duration of action), such as indacaterol, olodaterol, and vilanterol [83-87], have been approved by the FDA for use in patients with chronic obstructive pulmonary disease (COPD), but only vilanterol is approved for use in patients with asthma.
Clinically important tolerance seems unlikely during combined treatment with vilanterol and ICS, based on a randomized trial that compared fluticasone furoate-vilanterol (varying doses) with placebo once daily in 613 patients with asthma [84]. After 28 days, no significant diminution was noted in the mean FEV1 after salbutamol (albuterol) in the fluticasone furoate-vilanterol groups relative to placebo.
Evidence against LABA monotherapy — While LABAs reduce asthma symptoms and reduce airflow limitation in the short term, LABAs should not be prescribed as monotherapy for asthma [4,7,75,79,88,89].
Several systematic reviews have concluded that LABA monotherapy increases the risk of serious adverse events (SAEs) compared with placebo [90-92]. In a systematic review and meta-analysis (72,092 subjects), LABA monotherapy was associated with an increased risk of asthma-related death (RR 3.83, 95% CI 1.21-12.14), particularly in children, in subjects receiving salmeterol, and when the duration of treatment was >12 weeks [91]. However, LABA monotherapy reduced exacerbations requiring oral glucocorticoids. In a separate systematic review (22 studies, 8032 participants), formoterol monotherapy was associated with an increase in SAEs compared with placebo, particularly in children (odds ratio [OR] 1.57; 95% CI 1.06-2.31); the difference in deaths was not significant [90].
TOLERANCE — Decreased sensitivity to beta agonists with chronic use (also known as tolerance or tachyphylaxis) has been identified in laboratory studies and is believed to be primarily mediated by downregulation of beta-2 adrenergic receptors [2,93]. However, the clinical importance of this effect is unclear. Most investigators believe that the duration of action of the bronchodilator response is affected more than the peak effect [3] and that oral routes are more likely to induce tolerance than inhaled methods of delivery. Baseline levels of airway inflammation and beta-2 adrenergic receptor polymorphisms appear to influence this effect. (See "Beta-2 adrenergic receptor dysfunction and polymorphism in asthma", section on 'Receptor polymorphisms'.)
Based on the expectation that longer duration of action (and thus more continuous stimulation of the beta receptors) would increase the development of tolerance, long-acting beta-agonists (LABAs; eg, formoterol, salmeterol) would be more likely to induce tolerance than shorter-acting agents. However, clinical studies have yielded mixed results.
●Salmeterol and tolerance – One randomized trial found that 12 weeks of regular therapy with salmeterol did not result in a diminution in bronchodilating efficacy or a change in the use of rescue albuterol therapy (figure 3) [94]. In this trial, 234 patients were assigned to receive regularly scheduled LABA (salmeterol), short-acting beta-agonist (SABA; eg, albuterol), or placebo (figure 3) [94]. Salmeterol was more effective at increasing the morning peak expiratory flow rate than albuterol or placebo (+24, -6, +1 L/min, respectively, p<0.001). The mean overall symptom score was improved most by salmeterol treatment (p<0.05), with the number of days with symptoms and of nights with awakenings decreasing by 22 percent and 52 percent, respectively.
By contrast, other reports have noted a decrease in the ability of salmeterol to protect against a bronchoconstrictive stimulus following a similar duration of salmeterol therapy (figure 2) [53,95-98].
●Formoterol and tolerance – Chronic use of formoterol reduced the acute bronchodilator response to albuterol following methacholine-induced bronchoconstriction in a small study [99]. Bronchodilator tolerance occurred after one dose of formoterol and progressively increased with longer durations of formoterol dosing up to one week. Tolerance resolved three days after discontinuation of the formoterol.
A greater degree of airway inflammation may increase the induction of tolerance to LABAs. Since baseline levels of exhaled nitric oxide (FeNO) may be a surrogate biomarker for the presence of increased airway inflammation [100], these relationships were examined in study of 26 subjects not on controller therapy for asthma who underwent exercise challenge testing before and after two weeks of salmeterol monotherapy [101]. A 74±13 percent loss of bronchoprotection was noted among subjects with a FeNO greater than 50 ppb (consistent with eosinophilic airway inflammation) in contrast to a 7±16 percent gain in bronchoprotection among those with a FeNO less than 25 ppb. This observation lends support to the practice of avoiding monotherapy with LABAs and suggests that any observed reductions in bronchoprotection with chronic LABA use may be a reflection of the degree of airway inflammation. (See "Exhaled nitric oxide analysis and applications".)
In addition to a potential problem with tolerance, chronic reliance on beta agonist inhalers may disadvantage patients whose disease process involves mechanisms other than bronchial smooth muscle constriction, such as bronchial wall inflammation. Without proper recognition and intervention, patients may use more short-acting beta-agonist (SABA) inhalations at progressively more frequent intervals to obtain symptom relief. This overuse has the disadvantages of delaying addition of other therapeutic agents (such as antiinflammatory drugs) that can reverse or attenuate other important pathophysiologic factors, such as airway edema, mucus secretion, and inflammation.
ADVERSE EFFECTS — Beta agonists are associated with several side effects including the following [102]:
●Tremor – Tremor is the most frequent acute side effect and is more noticeable with oral therapy than with inhaled agents. Patient acceptance of tremor is often related to diminished awareness of the tremor due to decreased peak-trough variations over time [3,103].
●Tachycardia and palpitations – Increased heart rate and palpitations are dose-dependent and are less common with the inhaled selective beta-2 agonists (such as albuterol) than with nonselective agents. Use of a spacer or chamber device reduces these side effects by reducing oral deposition of medication, which contributes to side effects but not bronchodilation.
●Stress cardiomyopathy – Stress-induced (takotsubo) cardiomyopathy has been associated with treatment of status asthmaticus in case reports [104-106]. (See "Clinical manifestations and diagnosis of stress (takotsubo) cardiomyopathy", section on 'Role of catecholamines'.)
●Metabolic disturbances – Metabolic disturbances, such as transient decrease in serum potassium, phosphate, and magnesium, and increase in serum glucose, are also well-known adverse effects, although they are rarely of clinical significance [107-110].
In some patients, levalbuterol may reduce the incidence of tachycardia and mild hypokalemia compared with albuterol (a racemic mixture) [33], although the clinical importance of this possible difference is uncertain. (See "Causes of hypokalemia in adults", section on 'Elevated beta-adrenergic activity'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Asthma in adolescents and adults".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Asthma in children (The Basics)" and "Patient education: Asthma in adults (The Basics)" and "Patient education: Medicines for asthma (The Basics)" and "Patient education: How to use your metered dose inhaler (adults) (The Basics)")
●Beyond the Basics topics (see "Patient education: Asthma treatment in adolescents and adults (Beyond the Basics)" and "Patient education: Trigger avoidance in asthma (Beyond the Basics)" and "Patient education: How to use a peak flow meter (Beyond the Basics)" and "Patient education: Inhaler techniques in adults (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Mechanism of action – Beta adrenergic agonists are the most potent and rapidly acting bronchodilator medications available for asthma treatment. Beta agonists interact with beta adrenergic receptors on a variety of cells to relax bronchial smooth muscle, decrease mast cell mediator release, inhibit neutrophil, eosinophil, and lymphocyte functional responses, increase mucociliary transport, and affect vascular tone and edema formation. (See 'Mechanism of action' above.)
●Short-acting beta-agonists – The primary use of short-acting beta-agonists (SABAs) is the quick relief of acute asthma symptoms (eg, shortness of breath, cough, wheeze, chest tightness). SABAs (eg, albuterol, levalbuterol) are prescribed for use as needed, rather than on a routine basis. Acute exacerbations of asthma are heterogeneous, and the response to therapy is not uniformly predictable. Inhaled and systemic beta agonist preparations, delivery systems, and dosing guidelines are listed in the tables (table 1). (See 'Use in acute exacerbations of asthma' above.)
●Acute exacerbations – Inhaled SABAs (such as albuterol) remain the drug of choice for asthma exacerbations requiring emergency department treatment. Those who can demonstrate proper technique for using a pressurized metered dose inhaler (pMDI) are initially treated with two to eight inhalations of a SABA administered from a pMDI using a spacer or chamber device (eg, AeroChamber, InspirEase) (picture 1). Alternatively, albuterol is administered by nebulizer (table 1). SABA MDI or nebulizer therapy can be repeated in 30 to 60 minutes until maximal improvement in pulmonary function can be demonstrated. (See 'Use in acute exacerbations of asthma' above and "Acute exacerbations of asthma in adults: Emergency department and inpatient management", section on 'Inhaled beta-agonists'.)
If a satisfactory clinical response to pMDI administration of a SABA is not achieved or if the exacerbation is severe, a SABA is administered by nebulizer, either as individual treatments every 20 minutes or as a continuous treatment (eg, for more severe exacerbations); the doses are listed in the table (table 1). (See 'Use in emergency department and hospital' above and "Delivery of inhaled medication in adults", section on 'Continuous nebulization'.)
Rarely, epinephrine (0.01 mg/kg to a maximum dose of 0.3 mg) is administered subcutaneously or intramuscularly to treat acute asthma exacerbations and is reserved for patients with concomitant anaphylaxis or times when nebulized therapy is either unavailable or ineffective clinically. (See 'Use in acute exacerbations of asthma' above.)
●Pretreatment and allergen exposure – Despite the ability of beta agonists to prevent or attenuate allergen-induced bronchoconstriction, avoidance of allergen exposure by sensitized patients is always preferred over pretreatment with a SABA. Pretreatment does not block the airway inflammation and resultant increase in bronchial hyperresponsiveness associated with allergen exposure. (See 'Allergen-induced asthma' above and "Allergen avoidance in the treatment of asthma and allergic rhinitis".)
●Exercise-induced bronchoconstriction (EIB) – SABAs and combination inhalers with glucocorticoid and formoterol are effective in both treatment and prevention of EIB. (See 'Use in exercise-induced asthma' above and "Exercise-induced bronchoconstriction", section on 'Selection of pharmacologic therapy'.)
●Controller therapy for asthma – Long-acting beta-agonists (LABAs) are used in combination with inhaled glucocorticoids for patients with persistent asthma. The LABA formoterol has a rapid onset of action (similar to albuterol); combination inhalers containing glucocorticoid-formoterol can be used in some settings for relief of acute symptoms and for maintenance (off-label in the United States). LABAs should never be prescribed as monotherapy. (See 'Long-term maintenance therapy with LABAs' above.)
●Tolerance – Decreased sensitivity, also called tolerance (tachyphylaxis), to beta agonists may occur with chronic, frequent use of beta agonists. The effect appears primarily mediated by downregulation of beta-2 adrenergic receptors, such that increasing agonist doses are required for the same degree of bronchodilation. The clinical significance of tolerance largely relates to patients who overuse beta agonist inhalers, rather than appropriately avoiding the relevant exposure (eg, allergen) or adding appropriate antiinflammatory controller medication. (See 'Tolerance' above.)
●Adverse effects – Tremor is the most frequent acute side effect associated with beta agonists. Other side effects include palpitations, tachycardia, metabolic disturbances, and rarely stress-induced (takotsubo) cardiomyopathy. (See 'Adverse effects' above and "Clinical manifestations and diagnosis of stress (takotsubo) cardiomyopathy".)
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