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Therapeutic Responses in Asthma and COPD^*

Bronchodilators

^* From the Division of Pulmonary/Critical Care Medicine, University of North Carolina School of Medicine, Chapel Hill, NC.

Correspondence to: James F. Donohue, MD, FCCP, University of North Carolina School of Medicine, 4125 Bioinformatics Building, CB7020, Chapel Hill, North Carolina 27599; e-mail: jdonohue{at}med.unc.edu

	Abstract

TOP Abstract Introduction Comparison of Bronchodilator... Does Reversibility to Albuterol... Effects of Inhaled... Albuterol, Other Short-Acting... Tolerance to Bronchodilators in... LABAs for Asthma and... Theophylline PDE Inhibitors Leukotriene Receptor Antagonists Anticholinergics and the Dutch... Anticholinergics in the Acute... Stereoisomers or Enantiomers of... Bronchodilator Effects on... Conclusions References

 
The presence of acute reversibility to bronchodilators does not distinguish asthma from COPD. Patients with either condition can benefit from bronchodilators, and should be given a trial to assess their response. Some respond with a change in lung volume with less hyperinflation; others improve their forced inspiratory flow and become much more comfortable. The combination of long-acting ß-agonists (LABAs) and inhaled steroids is useful in both conditions. While anticholinergics seem to yield the best results in COPD, some patients with asthma benefit from their use. Tiotropium may be the most effective agent as monotherapy in COPD, but the combination of an inhaled steroid and a LABA may produce similar results in improving lung function. Long-acting bronchodilators are effective agents as monotherapy in COPD, but in asthma should be combined with a controller medication. Short-acting ß-agonists should be used intermittently in asthma, but may be used regularly or combined with an anticholinergic in COPD. The roles of stereoisomers, leukotriene receptor antagonists, and type 4 phosphodiesterase inhibitors in asthma and COPD remain uncertain at this time.

Key Words: asthma • COPD • inhaled corticosteroids • long-acting ß-agonist • short-acting ß-agonist

	Introduction

TOP Abstract Introduction Comparison of Bronchodilator... Does Reversibility to Albuterol... Effects of Inhaled... Albuterol, Other Short-Acting... Tolerance to Bronchodilators in... LABAs for Asthma and... Theophylline PDE Inhibitors Leukotriene Receptor Antagonists Anticholinergics and the Dutch... Anticholinergics in the Acute... Stereoisomers or Enantiomers of... Bronchodilator Effects on... Conclusions References

 
Both the prevalence and health-care costs of asthma and COPD continue to rise, and are predicted to increase for the foreseeable future. ß-Agonist bronchodilators, inhaled corticosteroids (ICSs), and other anti-inflammatory agents form the basis of treatment to control the symptoms and progression of asthma. Therapies for COPD have a much more limited effect. In fact, bronchodilators and ICSs have little effect on the progression of COPD, as shown by the Lung Health Study.¹²

The role of bronchodilators in relationship to the Dutch hypothesis will be reviewed. To shed light on the similarities and differences between asthma and COPD, several questions will be addressed. Specifically, do patients with asthma and COPD react selectively to different bronchodilators such as short-acting ß-agonists (SABAs), long-acting ß-agonists (LABAs), theophyllines, anticholinergics, leukotriene modifiers, and type 4 phosphodiesterase (PDE) inhibitors? Does the response, for example, the reversibility to these specific agents, discriminate between asthma and COPD, or do the two represent a continuum? Do asthmatics and patients with COPD respond similarly in terms of changes in FEV₁ and FVC? Are dynamic hyperinflation and its response to bronchodilators more typical of COPD or asthma? Also, the role of stereoisomers and the concept of tolerance to bronchodilators will be discussed, as will side effects of bronchodilators in both conditions.

The presence or absence of reversibility was once thought to be the major distinction between asthma and COPD, with reversibility of airflow obstruction being the hallmark of asthma, and mainly irreversible obstruction the hallmark of COPD.³ Newer definitions of both asthma and COPD acknowledge the overlap between these conditions and highlight their similarities and differences. Chronic inflammation underlies both conditions, but the nature of the inflammation differs, as does the response to different classes of medications.

Asthma is defined as a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role. Chronic inflammation causes an associated increase in airway hyperresponsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness, and coughing, particularly at night or in the early morning. The episodes are usually associated with widespread but variable airflow obstruction that is often reversible, either spontaneously or with treatment.⁴

The Global Initiative for Chronic Obstructive Lung Disease guidelines⁵ define COPD as a disease state characterized by airflow limitation that is not fully reversible. The airflow limitation is usually progressive and associated with an abnormal response of the lungs to noxious particles or gases.

These guidelines have different recommendations for bronchodilator use in asthma and COPD. Whereas ß₂-agonist bronchodilators are used "as needed" in asthma management, regular bronchodilator therapy with an anticholinergic drug or ß₂-agonist is the usual first-line approach in COPD.

	Comparison of Bronchodilator Responses in Asthma and COPD

TOP Abstract Introduction Comparison of Bronchodilator... Does Reversibility to Albuterol... Effects of Inhaled... Albuterol, Other Short-Acting... Tolerance to Bronchodilators in... LABAs for Asthma and... Theophylline PDE Inhibitors Leukotriene Receptor Antagonists Anticholinergics and the Dutch... Anticholinergics in the Acute... Stereoisomers or Enantiomers of... Bronchodilator Effects on... Conclusions References

 
The bronchodilator responses in asthma and COPD differ both quantitatively and in their spirometric patterns. Chhabra and Bhatnagar⁶ studied 133 patients with asthma and 116 patients with COPD and found three different response patterns: a difference in FVC alone, in FEV₁ alone, or in both. A positive response to bronchodilation was a 12% or 200-mL increase in the FEV₁. Patients with asthma more frequently increased their FEV₁ by > 200 mL. The average increase in FEV₁ was 307 mL in asthma and 120 mL in COPD. In asthma, most showed an increase in FEV₁ alone or in both FVC and FEV₁; in COPD, an FVC response alone was most common. Rarely in COPD was an isolated FEV₁ increase noted. Younger patients have an increase primarily in the FEV₁ or both FEV₁ and FVC.

	Does Reversibility to Albuterol Differ Between Asthma and COPD?

TOP Abstract Introduction Comparison of Bronchodilator... Does Reversibility to Albuterol... Effects of Inhaled... Albuterol, Other Short-Acting... Tolerance to Bronchodilators in... LABAs for Asthma and... Theophylline PDE Inhibitors Leukotriene Receptor Antagonists Anticholinergics and the Dutch... Anticholinergics in the Acute... Stereoisomers or Enantiomers of... Bronchodilator Effects on... Conclusions References

 
Does reversibility to albuterol (ie, improvement in FEV₁ of 12% or 200 mL) differ between asthma and COPD? The bronchodilator effect is greater in peak FEV₁ and FEV₁ area under the curve in asthma. However, many patients with COPD have reversibility to albuterol. Dorinsky and colleagues⁷ reviewed > 1,000 patients and found that > 75% had some reversibility, particularly when albuterol and ipratropium were combined.

Donohue and associates⁸ found that approximately 73% of patients increased their FEV₁ 12% or 200 mL in studies of salmeterol treatment in 813 patients with COPD. Prior to randomization, patients were tested by inhaling two to four puffs of albuterol, and two puffs of ipratropium. Eleven percent reversed to ipratropium alone, while 27% reversed to albuterol alone. Thirty-five percent reversed to both agents (Fig 1 ). Mahler and coworkers⁹ found that 56% of patients in the trial of the combination of fluticasone and salmeterol had reversibility to albuterol at baseline.

View larger version (37K): [in this window] [in a new window] [Download PPT slide]   Figure 1.. Responses to albuterol sulfate and ipratropium bromide.

View larger version (17K): [in this window] [in a new window] [Download PPT slide]   Figure 2.. Mean FEV1 before and after salbutamol, ipratropium, and the combination on three occasions at monthly intervals. Note the differences in prebronchodilator values between visits and the lack of change in postbronchodilator FEV1 after the combination at visits 1 and 2. Reprinted with permission from Calverley et al.10

It is important to note that in some persons, asthma has an irreversible component. Vonk and colleagues¹² followed up 228 asthmatic patients for 21 to 33 years. In this population, 41% had no obstruction, 43% had reversible obstruction, and 16% had irreversible obstruction, while 23% of the 228 had low diffusing capacity. This pattern is usually associated with COPD and emphysema. Ulrick and Backer¹³ followed up 92 patients for 10 years; 23% had nonreversible disease and experienced steep decline in FEV₁. Fabbri and associates¹⁴ compared older asthmatics and COPD patients with relatively fixed airflow obstruction, FEV₁ of 56% in both, and airway hyperresponsiveness. The improvement in FEV₁ following bronchodilators was an increase of 252 mL in patients with a history of asthma and 123 mL in those with a history of COPD. The residual volume as a percentage of predicted value was greater in patients with a history of COPD than in those with a history of asthma. ten Brinke et al¹⁵ found that 49% of 136 asthmatics had some persistence of obstruction.

Therefore, Kesten and Rebuck¹⁶ tried to answer the question of whether the short-term response to an inhaled ß-agonist is a sensitive or specific means for distinguishing between asthma and COPD. They found that the mean change in FEV₁ in patients assessed to have asthma was different from that found in patients with COPD, 16.4% vs 10.6%, respectively. However, the change in FVC in the two conditions was similar, 9.8% vs 10.3%. Nevertheless, the sensitivities and specificities of postbronchodilator changes in FEV₁ were not generally sufficient to diagnose or exclude asthma reliably. The authors concluded that the acute responses of FEV₁ and FVC following a standard dose of inhaled bronchodilator are neither sensitive nor sufficiently specific to differentiate asthma from COPD. Furthermore, neither residual volume (RV) nor total lung capacity (TLC) reflected degrees of airflow limitation as well as did the RV/TLC ratio.¹⁶

	Effects of Inhaled Bronchodilators on Inspiratory Capacity, Lung Volume, Forced Inspiratory Volume, and Dyspnea at Rest in COPD and Asthma

TOP Abstract Introduction Comparison of Bronchodilator... Does Reversibility to Albuterol... Effects of Inhaled... Albuterol, Other Short-Acting... Tolerance to Bronchodilators in... LABAs for Asthma and... Theophylline PDE Inhibitors Leukotriene Receptor Antagonists Anticholinergics and the Dutch... Anticholinergics in the Acute... Stereoisomers or Enantiomers of... Bronchodilator Effects on... Conclusions References

 
Dynamic hyperinflation develops in patients with COPD and asthma, which contributes greatly to dyspnea and exercise intolerance. Di Marco et al¹⁷ found that in patients with decreased baseline inspiratory capacity, there was a much greater increase of inspiratory capacity after administration of bronchodilators such as salbutamol, formoterol, salmeterol, and oxitropium. This increase correlated closely with improvement in a sensation of dyspnea.

Newton et al¹⁸ found that bronchodilators reduce hyperinflation, comparing 281 patients with severe hyperinflation (SH) [with TLC > 133%] and 675 patients with moderate hyperinflation (MH) [with TLC between 115% and 133%]. FEV₁ improved in a minority of patients (33% of those with SH, and 26% of those with MH), but if lung volume measurements were considered, the overall bronchodilator response improved in up to 76% of the SH group and 62% of the MH group. In the SH and MH groups, respectively, the reduction in TLC was 222 mL and 150 mL; in functional residual capacity, 442 mL and 260 mL; and in RV, 510 mL and 300 mL. Thus, measurement of lung volume before and after bronchodilator use adds sensitivity to the evaluation of bronchodilator responsiveness.

Similarly, Ramirez-Venegas et al¹⁹ found that the use of salmeterol reduced not only dyspnea but improved lung function in patients with COPD. Patients showed an increase in FVC, a reduction in RV and functional residual capacity, and no changes in TLC following inhalation of salmeterol. The improvement in reduced hyperinflation appears to be of a greater magnitude in COPD than asthma, although there are few comparisons.

The forced inspiratory volume in 1 s can be useful. While it provides no additional benefit over FEV₁ in asthma and mild COPD, it can identify patients with severe COPD who benefit from bronchodilators with reduction in dyspnea.²⁰

	Albuterol, Other Short-Acting ß-Agonists, and the Dutch Hypothesis

TOP Abstract Introduction Comparison of Bronchodilator... Does Reversibility to Albuterol... Effects of Inhaled... Albuterol, Other Short-Acting... Tolerance to Bronchodilators in... LABAs for Asthma and... Theophylline PDE Inhibitors Leukotriene Receptor Antagonists Anticholinergics and the Dutch... Anticholinergics in the Acute... Stereoisomers or Enantiomers of... Bronchodilator Effects on... Conclusions References

 
A systematic review of inhaled SABAs in asthma was undertaken by Walters and Walters.²¹ Regular use was compared with as-needed use in 31 trials. Evening peak flow was better by 13.1 L/min (130 mL). In contrast, the increase in regular FEV₁ was 157 mL (weighted mean difference [WMD]) better with drug use as needed. Bronchial hyperreactivity was improved with as-needed use. The conclusion, as in current guidelines, was that there was no advantage to regular use of SABAs in asthma. Furthermore, the Asthma Clinical Research Network has shown that persons with the arg/arg mutation at position 16 of the ß-receptor gene who regularly use SABAs such as albuterol have a decrease in lung function further exacerbated by withdrawal of the drug.²² A larger clinical trial of this has been undertaken.

Sestini and colleagues²³ reviewed 13 studies of inhaled SABAs in COPD. The average postbronchodilator WMD increase in FEV₁ was 0.14 L. The WMD increase in morning peak flow was 29.2 mL, and the WMD increase in evening peak flow was 36.8 mL. The author concluded that the use of SABAs administered via measured-dose inhaler on a regular basis improves lung function and breathlessness but not exercise performance. There is no evidence of long-term side effects, and these agents probably would be considered first-line therapy. Ram and Sestini²⁴ found that use for 7 days was associated with improvement in lung function and decreases in breathlessness and treatment failure.

SABAs can regularly be added to anticholinergics to produce a very useful combination that works both peripherally and on the central airways. There are very few side effects with this combination; however, it has to be administered every 4 to 6 h. Recommendations differ for the use of SABAs: intermittent use is recommended in asthma, while regular use is recommended in COPD.

	Tolerance to Bronchodilators in Asthma and COPD

TOP Abstract Introduction Comparison of Bronchodilator... Does Reversibility to Albuterol... Effects of Inhaled... Albuterol, Other Short-Acting... Tolerance to Bronchodilators in... LABAs for Asthma and... Theophylline PDE Inhibitors Leukotriene Receptor Antagonists Anticholinergics and the Dutch... Anticholinergics in the Acute... Stereoisomers or Enantiomers of... Bronchodilator Effects on... Conclusions References

 
There seems to be much more tolerance to bronchodilators in asthma than in COPD. Tolerance is more noticeable with bronchoprotection than bronchodilation, perhaps reflecting the smaller number of ß-receptors on inflammatory cells vs the 40,000 receptors on human airway smooth-muscle cells. Regular bronchodilator use is associated with early decline in bronchoprotection but not complete loss, and to a lesser extent, loss of bronchodilation. A stable nadir or plateau seems to be reached within the first few weeks without further loss. Tolerance is more likely to be seen with indirect stimuli. As previously mentioned, there is a noticeable reduction in bronchodilation with regular use of SABAs in persons with an arg/arg mutation at position 16.

There seems to be minimal early tolerance to bronchoprotection with LABAs, but it is much less pronounced than with SABAs. The decline is seen within the first few weeks of use, but then it stabilizes with no further loss in lung function or bronchoprotection. However, most studies in asthma and COPD show no reduction in bronchodilation over 6 months with LABAs. Donohue and associates²⁵²⁶ described an exception with salmeterol, where bronchodilator efficacy declines modestly over a period of 6 months.

	LABAs for Asthma and COPD

TOP Abstract Introduction Comparison of Bronchodilator... Does Reversibility to Albuterol... Effects of Inhaled... Albuterol, Other Short-Acting... Tolerance to Bronchodilators in... LABAs for Asthma and... Theophylline PDE Inhibitors Leukotriene Receptor Antagonists Anticholinergics and the Dutch... Anticholinergics in the Acute... Stereoisomers or Enantiomers of... Bronchodilator Effects on... Conclusions References

 
LABAs, including salmeterol and formoterol, are approved for use in both asthma and COPD. In asthma, LABAs should be combined with an anti-inflammatory controller medication. Monotherapy with LABAs alone is associated with deterioration in asthma control and more frequent exacerbations.²⁷

In contrast, in COPD, salmeterol and formoterol can be used on a regular basis as monotherapy. As in asthma, they can be combined with agents from other bronchodilator classes and ICSs for better symptom control. In patients with nocturnal symptoms despite low to high doses of inhaled steroids, the addition of a LABA is superior to doubling the dose of an ICS. The inhaled LABA is also more effective than an oral LABA or sustained-release theophylline in relieving nocturnal symptoms due to asthma.

Walters and colleagues²⁸ recently conducted a systematic review of regular treatment with LABAs compared with daily regular treatment with SABAs in adults and children with stable asthma. Thirty-one studies met the inclusion criteria; 24 were parallel studies and 7 were crossover studies. Salmeterol was used as a long-acting agent in 22 studies and formoterol in 9 studies. Salbutamol was the short-acting agent in 27 of the investigations. LABAs were significantly more effective than short-acting agents, as shown by a variety of lung function measurements including morning peak expiratory flow rate (WMD 33 L/min) or nighttime peak flow rate (WMD 26 L/min). LABAs had significantly lower scores for day and nighttime asthma symptom scores and higher percentages of days and nights without symptoms. They were also associated with a significantly lower use of rescue medication during both day and night. Risk of exacerbations was not different between the two types of agents, but most studies were of short duration. The reviewer’s conclusion was that LABAs have advantages across a wide range of physiologic and clinical outcomes for regular treatment. In asthma, of course, these agents are not recommended as monotherapy but should be combined with a controller medication.

In contrast, Appleton et al²⁹ performed a review of LABAs in poorly reversible COPD, identifying 33 abstracts as potentially relevant. However, only four randomized controlled trials were included in the review. The mean WMD increases in FEV₁ were 0.1 L in the 50-µg salmeterol group and 0.12 L in the 100-µg salmeterol group. In two crossover studies of 4 weeks of treatment, salmeterol did not produce a significant increase in FEV₁ (WMD 0.04 L). The reviewer’s conclusion was that treatment of patients with COPD with LABAs produced only small increases in FEV₁, small reductions in breathlessness, and a clinically significant improvement in quality of life, which, however, was not consistent across all studies. Similarly, morning and nighttime peak flow were not significantly improved with salmeterol treatment. In contrast, Maesen et al³⁰ found that formoterol in a small study improved work of breathing despite a modest effect on FEV₁ in poorly reversible patients with COPD.

In a 16-week study,³¹ quality of life showed a significant improvement after treatment with 50 µg of salmeterol but not after 100 µg. General health status as reflected on the medical outcome short form-36 did not improve, nor was there any difference in the mean change from baseline in the 6-min walk distance. Breathlessness was reduced in one study.

Salmeterol has been compared with theophylline in mild-to-moderate asthma and COPD. In one study of 178 patients, the increase in FEV₁ was 0.13 L greater with salmeterol than with theophylline.³² Adverse event rates were fairly comparable between the two agents.³² Both improved quality of life, but salmeterol achieved greater improvement. The author concluded that salmeterol was superior to theophylline. LABAs were more effective than theophylline in reducing asthma symptoms and improving lung function in a review of six studies.³³

Celik and coworkers³⁴ compared the LABA salmeterol with formoterol in patients with COPD. Formoterol had a faster onset of bronchodilator action (FEV₁ increase 0.2 L at 10 min); however, both agents were effective at 20 min (salmeterol, 0.20 L; formoterol, 0.25 L). The peak bronchodilator effects were the same (salmeterol, 0.40 L; formoterol, 0.39 L) at 60 to 120 min, and the duration of action was the same. Thus, both agents are comparable in COPD in efficacy and side effects. Similarly, salmeterol and formoterol are comparable in asthma, although formoterol has a faster onset of action.³⁵

LABAs are frequently combined with ICSs. This combination is associated with a marked increase in lung function, improvement in trough FEV₁, improvement in quality of life, and reduction in exacerbations, and may have a survival advantage.³⁶³⁷

LABAs have a good safety record in COPD. Ferguson and colleagues³⁸ reviewed 17 studies including 1,443 patients and found no increase in cardiovascular adverse effects compared with placebo. Holter data revealed no significant differences from placebo in arrhythmias, QT intervals, or other parameters. LABAs have also been used extensively in high-risk asthma. Lanes and associates³⁹ found no increased incidence rates for emergency care, hospitalization, or ICU stays among asthmatic patients receiving salmeterol. However, the recent Salmeterol Multicenter Asthma Research Trial in > 23,000 patients was terminated early because of an increase in deaths, especially among African Americans.

	Theophylline

TOP Abstract Introduction Comparison of Bronchodilator... Does Reversibility to Albuterol... Effects of Inhaled... Albuterol, Other Short-Acting... Tolerance to Bronchodilators in... LABAs for Asthma and... Theophylline PDE Inhibitors Leukotriene Receptor Antagonists Anticholinergics and the Dutch... Anticholinergics in the Acute... Stereoisomers or Enantiomers of... Bronchodilator Effects on... Conclusions References

 
Theophylline remains one of the most widely prescribed drugs for the treatment of airways disease worldwide, since it is inexpensive.⁴⁰ However, theophylline is a third-line agent in industrialized countries because of the frequency of side effects and relative low efficacy. A study by van Andel et al⁴¹ found that in 10 trials of bronchodilators in COPD from 1987 to 1995, inhaled steroid use increased from 13 to 41%, while theophylline use declined from 63 to 29%.

Theophylline is useful in both asthma and COPD. In asthma, it has been used as an adjunct to aerosol ß-agonists and inhaled steroids. The patient with COPD may benefit most from an empiric trial. Recommended doses today are lower than those used in the past. Lower doses have both anti-inflammatory and immunomodulatory effects in both COPD and asthma. Sustained-release theophylline is useful in controlling nocturnal symptoms.

Theophylline initially was used as a bronchodilator, and an early dose-response effect was demonstrated. There was increasing acute bronchodilator response above plasma concentrations of 10 mg/L. The recommended upper limit was 20 mg/L, and doses were adjusted to meet this parameter. The molecular mechanism of bronchodilation is partially explained by PDE inhibition, resulting in an increase in cyclic adenosine monophosphate by inhibition of PDE₃ and PDE₄ and in cyclic guanosine 3,5 monophosphate by inhibition of PDE₅.⁴²

Theophylline is also an adenosine-receptor antagonist. It inhibits intracellular calcium release and increases histone deacetylase activity, resulting in an increase in the efficacy of corticosteroids.

Theophylline has been compared with other therapies in COPD. Rossi et al⁴³ compared the efficacy of oral slow-release theophylline with formoterol in 854 patients with COPD. Both agents improved lung function (area under the FEV₁ 12-h curve). Formoterol was more effective in reducing symptoms and use of rescue medications, and preventing falls in peak expiratory flow. More treatment-related side effects and withdrawals were seen with theophylline. Cazzola and colleagues⁴⁴ found that salbuterol combined with titrated theophylline increased the FEV₁ by 0.157 L over baseline at 3 months. This was less than salbuterol combined with fluticasone 250 µg (0.188 L) or salbuterol with fluticasone 500 µg (0.239 L) but similar to salbuterol alone (0.163 L). Theophylline has been compared with LABAs in asthma Salmeterol improved FEV₁ more than theophylline in most of the asthma trials reported and had fewer side effects.³³ Hence, it was associated with more symptom-free management.

ZuWallack et al⁴⁵ in a study of 943 patients, found salmeterol to be better than theophylline in improving lung function and producing fewer side effects. However, therapy with both agents combined was more effective and resulted in no increase in side effects compared with either agent alone.

Sustained-release theophylline must be monitored very carefully, particularly when used in elderly patients with asthma and COPD. Armijo and associates⁴⁶ studied the steady-state pharmacokinetics of an ultralong–sustained-release formulation of theophylline in elderly hospitalized patients with COPD. There was no significant correlation between the patient’s age and apparent clearance within this elderly population. Interpatient variability and peak/trough fluctuations with this formulation were higher than those described in healthy volunteers. Therefore, the importance of theophylline monitoring is emphasized.

In a pharmacogenetics study, it emerged that theophylline may need to be used with care in patients with the A allele at site –2964(G/A) in the CYP 1A2 gene, because theophylline metabolism levels are lower in such patients, particularly in young asthmatic individuals.⁴⁷ This finding may provide insight into those individuals most at risk for theophylline toxicity and, thus, those who need more careful monitoring.

IV aminophylline may still have a role in acute asthma in the emergency department. Roberts and coworkers⁴⁸ studied children aged 1 to 16 years with acute severe asthma. Forty-four subjects were randomized to receive IV aminophylline or IV salbutamol. There was no significant difference in the effectiveness of the two agents; however, the aminophylline infusion significantly reduced the length of stay in the hospital.

	PDE Inhibitors

TOP Abstract Introduction Comparison of Bronchodilator... Does Reversibility to Albuterol... Effects of Inhaled... Albuterol, Other Short-Acting... Tolerance to Bronchodilators in... LABAs for Asthma and... Theophylline PDE Inhibitors Leukotriene Receptor Antagonists Anticholinergics and the Dutch... Anticholinergics in the Acute... Stereoisomers or Enantiomers of... Bronchodilator Effects on... Conclusions References

 
PDE inhibitors increase the level of cyclic adenosine monophosphate. This increase leads to inhibition of proinflammatory mediator release and augmentation of the release of anti-inflammatory mediators. It also precipitates the blocking of lymphocyte and smooth-muscle cell proliferation. PDE inhibitors have weak bronchodilator properties.

Cilomilast, an orally active second-generation PDE inhibitor, may be effective in the treatment of asthma and is especially useful in COPD. It possesses high selectively for the PDE₄ isoenzyme. Cilomilast suppresses the activity of many of the inflammatory and immune cells involved in the pathogenesis of asthma and COPD. It possesses a better side effect profile than does rolipram because of less CNS penetration. Its use usually leads to a small but clinically significant increase in lung function and quality of life in COPD. In asthma, the improvements in lung function are less impressive. Cilomilast has a half-life of 7 h. No dose adjustment is necessary in smokers; the usual dosage is 15 mg bid. Cilomilast does not interact with salbutamol.

Grootendorst and coworkers⁴⁹ studied the acute effects of cilomilast. With a single dose, there was no acute increase in FEV₁, and no acute bronchodilator effect in COPD. The combination of cilomilast with salbutamol produced an increase of 280 mL in FEV₁. When cilomilast was combined with ipratropium the increase was 297 mL, while it was 379 mL following cilomilast combined with both salbutamol and ipratropium. The class-associated side effects, mainly nausea and emesis, appear to have been at least partially overcome by the so-called second-generation PDE₄ inhibitors, but still are a problem.

Roflumilast is in development for the treatment of asthma and COPD. This once-daily oral formulation possesses potent anti-inflammatory properties in both asthma and COPD and may be a useful alternative to ICSs. Roflumilast has been tested in > 1,500 patients with COPD and 3,000 patients with asthma. Like cilomilast, roflumilast also possesses a great deal of selectivity for the PDE₄ receptor in human neutrophils. PDE₄ inhibition increases cyclic adenosine monophosphate, which leads to its clinical properties. Its metabolite roflumilast n-oxide is also active. This drug, too, has fewer side effects than rolipram. It is administered once daily.

Roflumilast offers good protection against exerciseinduced bronchospasm in asthma. In one study of lung function, roflumilast was almost equal to beclomethasone and was more effective than leukotrienes in improving FEV₁ and morning peak flow. It may be useful in reducing the number of exacerbations of asthma or COPD because of its anti-inflammatory properties. Further clinical testing of this unapproved agent is continuing.

	Leukotriene Receptor Antagonists

TOP Abstract Introduction Comparison of Bronchodilator... Does Reversibility to Albuterol... Effects of Inhaled... Albuterol, Other Short-Acting... Tolerance to Bronchodilators in... LABAs for Asthma and... Theophylline PDE Inhibitors Leukotriene Receptor Antagonists Anticholinergics and the Dutch... Anticholinergics in the Acute... Stereoisomers or Enantiomers of... Bronchodilator Effects on... Conclusions References

 
Leukotrienes are derived from a cell membrane phospholipid, arachidonic acid, and are members of a larger group of molecules known as eicosanoids. It is possible to inhibit the production of leukotrienes by inhibiting their synthesis or by antagonizing their receptor, the cysteinyl leukotriene receptor. Several drugs in this class are available worldwide. These include one enzyme inhibitor of 5-lipoxygenase, zileuton, and three chemically distinct cysteinyl leukotriene receptor antagonists—zafirlukast, montelukast, and pranlukast—not available in the United States. Antileukotrienes inhibit allergen-induced early and late responses, exercise-induced asthma, airway hyperresponsiveness, and allergen-induced airway inflammation. These agents also have bronchodilating properties in asthma.

Zafirlukast and montelukast are especially effective in exercise-induced bronchospasm, while zileuton is less effective. Zileuton, however, may be particularly useful for acetylsalicylic acid-intolerant asthmatics. Responses to leukotriene receptor antagonists appear to depend on an individual patient’s genetic polymorphisms related to the ILO promoter gene. Safety issues include hepatic dysfunction with zileuton and all agents in high doses. All are quite well tolerated at normal doses. The Churg-Strauss syndrome appears to be more related to the withdrawal of corticosteroids rather than to a leukotriene receptor antagonist toxicity or a hypersensitivity reaction.

These agents inhibit antigen-induced contraction of bronchial smooth muscle, inhibit eosinophil activity, reduce the number of eosinophils in the sputum, reduce exhaled nitric oxide levels, and improve allergen-induced decline in FEV₁. They reduce bronchial hyperresponsiveness due to methacholine and cold air, but this activity is not consistent with other stimuli for bronchoconstriction such as histamine and adenosine.

The role of leukotriene receptor antagonists in asthma is not precisely established. They are used as an alternative to low-dose inhaled steroids in mild persistent asthma. They are also used as an addition to inhaled steroids to improve asthma control or to reduce the dose of inhaled steroids. Most studies in adults and most consensus statements report ICSs to be superior to leukotriene antagonists in asthma. The results in patients < 12 years old are not quite as convincing. Some investigators have found better compliance and better quality of life with leukotriene receptor antagonists.

Pranlukast, montelukast, and zafirlukast are selective competitive antagonists of the cysteinyl leukotrienes C₄, D₄, and E₄. While these agents are not acute bronchodilators, they do improve lung function within the first 1.5 h after administration and have mild bronchodilator effects, usually of the magnitude of an increase in FEV₁ of 9 to 11% within the first 4 h. Tolerance to these agents does not appear to develop. One study⁵⁰ in which pranlukast was administered for > 4 years showed no tachyphylaxis in asthma.

The role of leukotriene-receptor antagonists is not well defined in COPD. Patients with rhinitis and asthma might benefit; hence, patients with allergic rhinitis and COPD probably could have some benefit, as would those who have a mixed pattern of asthma and COPD. The most relevant leukotriene in COPD is leukotriene B₄, which is not inhibited by pranlukast, montelukast or zafirlukast. Zileuton might have some inhibitory effect, but this has not been studied.

Cazzola et al⁵¹ studied 16 patients with COPD and 10 asthmatics, administering monotherapy with zafirlukast 40 mg bid, salmeterol, the combination of salmeterol and zafirlukast, or placebo. Pulmonary functions were measured at 30, 60, 120, 180, and 240 min. At the end of 4 h, albuterol was administered, and spirometry was repeated in 30 min. Maximum bronchodilation was seen at 120 min in COPD. Salmeterol increased the FEV₁ by 21.7%, while zafirlukast increased it by 11.2%.

For asthmatics, maximum bronchodilation was noted at 180 min, with an increase of 20.7% with salmeterol and 11.0% with zafirlukast. Zafirlukast added no acute bronchodilator effects to the effect of salmeterol alone, but 7 of 16 patients with COPD and 7 of 10 patients with asthma did obtain additional benefit after the first few hours. Salbutamol produced no additional increase after patients received salmeterol or the combination, but there was an increase after zafirlukast and placebo.

Another study by Cazzola and coworkers⁵² showed that zafirlukast improves lung function in smokers with COPD. Sixteen outpatients with stable COPD received 40 mg of oral zafirlukast. Lung function was measured at 30, 60, 120, 180, and 240 min. At the end of the 4-h period, the patients received 400 µg of salbutamol. Zafirlukast produced a significant bronchodilation between 30 min and 4 h following administration, with a maximum mean increase of 0.134 L above baseline after 2 h. Nine of the 16 patients showed an increase in FEV₁ of at least 15% above baseline after zafirlukast. The responders had an increase of 0.22 L, or 19%. However, there was no difference in the post-salbutamol FEV₁ values after placebo or zafirlukast.

Nannini et al⁵³ measured the bronchodilator effects of zafirlukast in subjects with COPD. The mean increase in FEV₁ was 75 mL, and the response to zafirlukast correlated with the response to salbutamol.

Coreno and associates⁵⁴ studied exercise-induced asthma and compared LABAs with leukotrienemodifying compounds. The participants performed 4 min of cycle ergometry while breathing frigid air at 1, 4, 8, and 12 h after the administration of the test agents. The primary end point was the extent of the decrement in FEV₁ 10 min after exertion.

Salmeterol acted quickly and significantly blunted the obstructive response for 12 h. Compared with placebo, the difference in FEV₁ at 1 h and at 12 h was 8%. The leukotriene agents produced effects within 1 h of ingestion. They also offered long-lasting protection, but there were no significant differences between them. However, zileuton provided equivalent prophylaxis for only the first 4 h. By 8 h, it was less efficacious than all of the other compounds; by 12 h, its effect was similar to that of placebo.

In summary, single doses of the currently available leukotriene receptor antagonists provide prompt, effective, and persistent defense against exercise-induced asthma that equals that seen with LABAs. These agents are useful bronchodilators in asthma but are of little value in most patients with COPD.

	Anticholinergics and the Dutch Hypothesis

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Anticholinergics are more effective in COPD than in asthma. In usual doses, they are more potent than SABAs in COPD, yielding greater increases in FEV₁ area under the curve. Calverley et al¹⁰ studied the acute response to inhaled salbutamol at one visit, then the response to ipratropium at another and then combined the two. The increases in FEV₁ were similar, with a slight advantage to ipratropium (Fig. 2).¹⁰ There is a dose response in COPD whereby increasing doses of anticholinergics is associated with increasing improvement in FEV₁.⁵⁵ In head-to-head comparisons, short-acting anticholinergics such as ipratropium are less potent than LABAs and long-acting anticholinergics such as tiotropium.⁵⁶ Anticholinergics in COPD are useful when combined with SABAs and/or theophyllines. Anticholinergics, particularly when administered by nebulized solution or by metered-dose inhaler and spacer in higher doses such as four puffs every 4 h, are useful in acute attacks of asthma and COPD. The longer-acting agents such as tiotropium are effective in stable patients with COPD for up to 24 h.

In COPD, it appears that the longer-acting anticholinergic agents are superior to salmeterol, ipratropium, or placebo. In asthma, tiotropium bronchoprotects for up to 48 h. While useful, anticholinergic bronchodilators do not protect against a decline in lung function when patients continue to smoke. This was amply demonstrated in the first Lung Health Study.¹

There has been a great deal of interest in whether bronchodilation responses to ipratropium or albuterol distinguish asthma from COPD. Taube et al²⁰ found that the increase in FEV₁ was 618 mL with fenoterol and 482 mL with oxitropium in asthma. In COPD, the increase was 221 mL after fenoterol and 235 mL after oxitropium.²⁰ Thus, it appears that there is substantial overlap. In asthma, SABAs are superior to anticholinergics, while in COPD the number of responders is approximately equal.

Ipratropium bromide and tiotropium bromide are structural analogs of atropine with little systemic absorption following inhalation because of their quaternary ammonia structure. Cholinergic nerve fibers arise in the nucleus ambiguus and the dorsal motor nucleus of the vagus nerve. Impulses travel down the vagus nerve to parasympathetic ganglia within the walls of airways. From these ganglia, postganglionic fibers innervate airway smooth muscle, the submucosal glands, and the lung. Activation of these nerves releases acetylcholine at the neural effector junctions, where it binds to postsynaptic receptors, resulting in bronchoconstriction and increased secretion.

The effects of vagal stimulation in the lung are mediated via muscarinic receptors, of which there are several types and subtypes. The subtypes of muscarinic receptors on airway smooth muscle are M₁, M₂, and M₃. M₂ subreceptors are called autoreceptors; their activation inhibits further release of acetylcholine. Tiotropium selectively blocks the M₃ muscarinic receptor. The receptor half-life is 36 h, whereas the receptor binding half-life of ipratropium is 3 h. Large-scale clinical trials comparing tiotropium to ipratropium and other studies against placebo for up to 1 year show the superiority of this agent.⁵⁷⁵⁸ There is no tolerance to the bronchodilating effects of tiotropium bromide.

Unfortunately, ipratropium has a short duration of action, requiring administration every 6 h. Such a regimen decreases adherence to drug therapy. Therefore, the 24-h tiotropium was developed. Dry mouth is much more common with tiotropium than with ipratropium. The safety profiles of these drugs appear to be otherwise similar.

van Noord and coworkers⁵⁷ performed a single-center, double-blind, ipratropium-controlled study to characterize the onset of the pharmacodynamic steady state of tiotropium. Trough FEV₁ following 8 days of tiotropium therapy was 0.19 L, 18% above baseline. Approximately 90% of this increase (0.17 L, 16% above baseline) was achieved within 24 h of the first dose. The trough FVC increased by 0.67 L (27%) on test day 8. Approximately 70% of the improvement (0.47 L, 19%) was observed after two tiotropium doses. Achievement of an FVC steady state was delayed compared with the FEV₁ steady state. Onset of ipratropium action was within 30 min, with peak response at 1 to 2 h and duration of 4 h. Thus, it appears that FEV₁ steady state is reached within 48 h, while a FVC increase can be expected during the first week of therapy.

Casaburi and colleagues⁵⁸ found that tiotropium was a safe and effective once-daily anticholinergic agent when compared with placebo. The FEV₁ and FVC were 12% above baseline on day 8. These improvements were maintained at day 50 and day 92. The average postdose FEV₁ was 16% higher than baseline on day 1, and 20% higher than baseline at day 92. FVC was 17% higher than baseline at day 1, and 19% higher on day 92.

	Anticholinergics in the Acute Setting

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Anticholinergics may be used to treat bronchial obstruction of various etiologies in COPD, including mucous hypersecretion and increased bronchial smooth-muscle tone, which is triggered in part by cholinergic mechanisms. Anticholinergic bronchodilators such as ipratropium, oxitropium, and tiotropium reduce vagal cholinergic tone, one of the main reversible components of COPD. They are first-line maintenance treatments for bronchial obstruction in COPD and also are quite useful in the in-hospital treatment of acute exacerbations of asthma and COPD. They have few side effects other than dry mouth. Anticholinergics can also be effectively combined with other bronchodilators.

Levin et al⁵⁹ studied the addition of the anticholinergic solution ipratropium bromide, 500 µg, to albuterol, 2.5 mg, in 195 patients. The peak increase in FEV₁ for subjects who received ipratropium bromide plus albuterol was 26% greater than in those who received placebo plus albuterol. The area under the 8-h FEV₁ curve was 64% greater in those receiving ipratropium bromide on test day 1. Similar increases were seen in FVC and forced expiratory flow, midexpiratory phase. Peak improvements in FEV₁ and FVC with the addition of ipratropium to albuterol were maintained on test days 43 and 85. Thus, ipratropium bromide should be considered first-line therapy for patients with COPD requiring small-volume nebulizer treatment.

In contrast, McCrory and associates⁶⁰ did a comprehensive search of the literature to assess the effects of anticholinergic agents on lung function in dyspneic patients with acute exacerbations of COPD. Four trials compared the short-term effects of ipratropium vs the ß₂-agonists. Short-term changes in FEV₁ showed no difference between ß₂-agonist–treated and ipratropium-treated patients: The WMD was 0.0 L. There was no significant additional change in FEV₁ on adding ipratropium to the ß₂-agonist (WMD 0.02 L). The reviewers’ conclusion was that there was no evidence that the degree of bronchodilation achieved with ipratropium bromide was greater than that using the SABAs. The combination of a ß₂-agonist and ipratropium had no greater effect on FEV₁ than either agent alone.

	Stereoisomers or Enantiomers of Albuterol in Asthma and COPD

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Racemic albuterol is regularly used in asthma and COPD for rescue from acute symptoms and to some degree in controlling chronic symptoms. For asthma, as-needed use is recommended; in COPD, many receive albuterol regularly, on an as-needed basis, or both.

Albuterol is a racemic mixture containing equal parts of R and S albuterol, which have differing affinities for the ß₂-adrenergic receptor. The S isomer may have some proinflammatory effects and binds to the ß₂-receptor weakly, but for a longer period. The R isomer, or levalbuterol, is more active and produces greater bronchodilation over a longer period in both adults and children in long-term–dosing studies.⁶¹⁶²

In the emergency department, Nowak⁶³ found greater improvements in the FEV₁ at 1 h with levalbuterol than with albuterol. Patients with lower baseline lung function and flat responses to multiple doses of albuterol came into the emergency department with higher baseline levels of S albuterol because of use of high doses at home. Carl et al⁶⁴ found a lower hospitalization rate in children, shorter lengths of stay, and less use of aerosols with levalbuterol as opposed to racemic albuterol in a well-designed study in an academic setting.

Few studies are available and many are ongoing with levalbuterol as well as R,R’-formoterol for patients with COPD. Truitt and colleagues⁶⁵ reported a retrospective observational study of 125 hospitalized patients with asthma and/or COPD. Patients receiving levalbuterol required fewer ß-agonist treatments and fewer doses of ipratropium. Patients receiving levalbuterol had a shorter length of stay, needed fewer rescue medications, and had fewer readmissions than those receiving racemic albuterol.

Recently, some concern has been voiced about the safety of ß-agonist agents in African Americans. A recent change in the prescribing information for salmeterol cautions that subgroup analyses suggest that the risk for asthma-related deaths may be greater in African Americans based on the Salmeterol Multicenter Asthma Research Trial.⁶⁶ It is unclear if the use of levalbuterol in lower doses will lessen this risk. Lower doses of levalbuterol were effective in the treatment of chronic asthma in African Americans, with a greater increase in trough FEV₁.

	Bronchodilator Effects on Mucociliary Clearance in Asthma and COPD

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Mucus in COPD differs from that in asthma, since the former is less viscous and without marked plasma exudation. The ratio of mucin 5AC to mucin 5B is reduced.⁶⁷ In COPD, there is full release of mucin into the airway lumen rather than tethering of mucus as in asthma. Bronchodilators may have varying effects on the mucociliary clearance (MCC) apparatus in asthma and COPD. ß-Agonists increase ciliary beat frequency, enhance mucus secretion, and stimulate chloride-ion secretion toward the lumen, suggesting enhanced water secretion onto the airway surface.

In short-term studies, SABAs enhance MCC rates, but less in disease states than in normal controls. MCC is higher in asthma than in COPD, and larger doses of ß-agonists are required to improve clearance than are needed to bronchodilate in both asthma and COPD.⁶⁸ LABAs enhance clearance in control subjects and, in preliminary studies, in those with either airway disease. Anticholinergics reduce mucus hypersecretion. Few long-term dosing studies have been done, but 1-week studies with SABAs show enhancement in MCC. Enantiomers have not been studied in humans, but in the rat trachea the R isomer enhances MCC.

	Conclusions

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There are many similarities and differences between patients with asthma and those with COPD with respect to the use of bronchodilators. The presence or absence of reversibility to bronchodilators does not distinguish asthma from COPD, as reversibility is noted in both diseases. While reversible airflow obstruction is the hallmark of asthma and mainly irreversible airflow obstruction the hallmark of COPD, many patients with asthma have persistent obstruction, while many with COPD have a reversible component. Chronic inflammation underlies both diseases. Both conditions involve small airways, perhaps slightly more in COPD, causing a slightly larger decrease in FVC. Both cause obstruction with mucus and constriction of smooth muscle, and both are affected by genetic-environmental interactions. There is considerable overlap in older asthmatics and COPD patients in the nature of their response to bronchodilators.

Treatment of asthma is characterized by suppression of inflammation, while treatment of COPD is characterized by relief of symptoms. Anticholinergic bronchodilators are more effective in COPD, and tiotropium may be the most effective single agent in this disease state. Important benefits may be realized by combining ICSs and LABAs or leukotriene modifiers in asthma. Corticosteroids are added for patients with more severe COPD who experience frequent exacerbations. In COPD, combining multiple classes of bronchodilators often proves to be effective in relieving symptoms.

Some patients respond more markedly than others to treatment, with more of a change in lung volume and a more marked reduction in dynamic hyperinflation and dyspnea. Combination therapy using SABAs or LABAs, theophyllines, and ICSs may be useful in both conditions. SABAs should be used intermittently in asthma but can be used regularly or combined with an anticholinergic agent in COPD. Anticholinergics can be used regularly in persons with COPD and may benefit some with asthma, particularly the elderly, those who have a history of cigarette smoking, and those who have used beta-blockers.

	Footnotes

 
Abbreviations: ICS = inhaled corticosteroid; LABA = long-acting ß-agonist; MCC = mucociliary clearance; MH = moderately hyperinflated; PDE = phosphodiesterase; RV = residual volume; SABA = short-acting ß-agonist; SH = severely hyperinflated; TLC = total lung capacity; WMD = weighted mean difference

The author has received research grants from Altana, Aventis, Boehringer Ingelheim, Centocor, GlaxoSmithKline, and Sepracor. He is also a consultant for Altana, Astra-Zeneca, GlaxoSmithKline, Sepracor, Otsuka, Dey, and Novartis.

	References

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