 
         
         
         ABSTRACT
         
         The prevalence of chronic obstructive pulmonary disease (COPD) continues to be on
            the rise. Bronchodilators are first line agents for the symptomatic management of
            this disease and have proven to be effective in both stable disease status and exacerbations.
            The stepwise escalation of therapy for COPD according to severity has been outlined
            in international guidelines. Different classes of bronchodilators exist. The most
            experience is available for short-acting β-agonists and anticholinergics. These agents
            are mainly recommended for the treatment of mild COPD and for symptomatic patients
            on an as needed basis. Long-acting β-agonists and anticholinergics have been developed
            more recently. They are more convenient to use for patients with advanced disease
            who require maintenance therapy with bronchodilators, and have been shown in this
            group of patients to provide superior efficacy compared with short-acting agents.
            Tiotropium, a long-acting anticholinergic, appears to be particularly powerful and
            may eventually replace ipratropium as the primary agent for COPD treatment. In contrast,
            the usage of theophylline, which used to be part of the mainstay of treatment for
            COPD, has declined, mainly secondary to a narrow therapeutic margin and side effects,
            but it is inexpensive and still has its role. New agents like phosphodiesterase-4-inhibitors
            are interesting substances that may become important adjuncts in COPD management,
            but there is limited experience so far. None of the bronchodilators have been shown
            to change outcome in COPD, but this issue is under active investigation.
         
         
         
            
KEYWORDS
         
         
            COPD - bronchodilators - therapy guidelines
          
      
    
   
      
         REFERENCES
         
         
            - 1 
               Pauwels R A, Buist A S, Calverley P M, Jenkins C R, Hurd S S. 
               Global strategy for the diagnosis, management, and prevention of chronic obstructive
               pulmonary disease. NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease
               (GOLD) Workshop summary. 
               Am J Respir Crit Care Med. 
               2001; 
               163 
               1256-1276 
               
- 2 
               Hogg J C, Chu F, Utokaparch S et al.. 
               The nature of small-airway obstruction in chronic obstructive pulmonary disease. 
               N Engl J Med. 
               2004; 
               350 
               2645-2653 
               
- 3 
               Celli B R, Cote C G, Marin J M et al.. 
               The body-mass index, airflow obstruction, dyspnea, and exercise capacity index in
               chronic obstructive pulmonary disease. 
               N Engl J Med. 
               2004; 
               350 
               1005-1012 
               
- 4 
               Anthonisen N R, Connett J E, Kiley J P et al.. 
               Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator
               on the rate of decline of FEV1. The Lung Health Study. 
               JAMA. 
               1994; 
               272 
               1497-1505 
               
- 5 
               Vestbo J. 
               The TORCH (towards a revolution in COPD health) survival study protocol. 
               Eur Respir J. 
               2004; 
               24 
               206-210 
               
- 6 
               Calverley P M, Burge P S, Spencer S, Anderson J A, Jones P W. 
               Bronchodilator reversibility testing in chronic obstructive pulmonary disease. 
               Thorax. 
               2003; 
               58 
               659-664 
               
- 7 
               Dorinsky P M, Reisner C, Ferguson G T, Menjoge S S, Serby C W, Witek Jr T J. 
               The combination of ipratropium and albuterol optimizes pulmonary function reversibility
               testing in patients with COPD. 
               Chest. 
               1999; 
               115 
               966-971 
               
- 8 
               Donohue J F, Anderson W, Wiesniewski M et al.. 
               Demographics and bronchoreversibility of salmeterol and ipratropium in a large population
               of patients with mild-to-moderate COPD [abstract]. 
               Am J Respir Crit Care Med. 
               1997; 
               155 
               A227 
               
- 9 
               Mahler D A, Wire P, Horstman D et al.. 
               Effectiveness of fluticasone propionate and salmeterol combination delivered via the
               Diskus device in the treatment of chronic obstructive pulmonary disease. 
               Am J Respir Crit Care Med. 
               2002; 
               166 
               1084-1091 
               
- 10 
               Anthonisen N R, Wright E C. 
               Bronchodilator response in chronic obstructive pulmonary disease. 
               Am Rev Respir Dis. 
               1986; 
               133 
               814-819 
               
- 11 
               Tashkin D, Kesten S. 
               Long-term treatment benefits with tiotropium in COPD patients with and without short-term
               bronchodilator responses. 
               Chest. 
               2003; 
               123 
               1441-1449 
               
- 12 
               Di Marco F, Milic-Emili J, Boveri B et al.. 
               Effect of inhaled bronchodilators on inspiratory capacity and dyspnoea at rest in
               COPD. 
               Eur Respir J. 
               2003; 
               21 
               86-94 
               
- 13 
               Newton M F, O'Donnell D E, Forkert L. 
               Response of lung volumes to inhaled salbutamol in a large population of patients with
               severe hyperinflation. 
               Chest. 
               2002; 
               121 
               1042-1050 
               
- 14 
               Goodman D E, Israel E, Rosenberg M, Johnston R, Weiss S T, Drazen J M. 
               The influence of age, diagnosis, and gender on proper use of metered-dose inhalers. 
               Am J Respir Crit Care Med. 
               1994; 
               150(5 Pt 1) 
               1256-1261 
               
- 15 
               Dhand R. 
               Nebulizers that use a vibrating mesh or plate with multiple apertures to generate
               aerosol. 
               Respir Care. 
               2002; 
               47 
               1406-1416 
               , discussion
               1416-1418 
               
- 16 
               Green S A, Spasoff A P, Coleman R A, Johnson M, Liggett S B. 
               Sustained activation of a G protein-coupled receptor via “anchored” agonist binding:
               molecular localization of the salmeterol exosite within the 2-adrenergic receptor. 
               J Biol Chem. 
               1996; 
               271 
               24029-24035 
               
- 17 
               Barnes P J. 
               Beta-adrenergic receptors and their regulation. 
               Am J Respir Crit Care Med. 
               1995; 
               152 
               838-860 
               
- 18 
               Ram F S, Sestini P. 
               Regular inhaled short acting beta2 agonists for the management of stable chronic obstructive
               pulmonary disease: Cochrane systematic review and meta-analysis. 
               Thorax. 
               2003; 
               58 
               580-584 
               
- 19 
               Sin D D, McAlister F A, Man S F, Anthonisen N R. 
               Contemporary management of chronic obstructive pulmonary disease: scientific review. 
               JAMA. 
               2003; 
               290 
               2301-2312 
               
- 20 
               Sears M R. 
               Adverse effects of beta-agonists. 
               J Allergy Clin Immunol. 
               2002; 
               110(suppl 6) 
               S322-S328 
               
- 21 
               Schultze-Werninghaus G. 
               Multicenter 1-year trial on formoterol, a new long-acting beta 2-agonist, in chronic
               obstructive airway disease. 
               Lung. 
               1990; 
               168(suppl): 
               83-89 
               
- 22 
               Appleton S, Poole P, Smith B, Veale A, Bara A. 
               Long-acting beta2-agonists for chronic obstructive pulmonary disease patients with
               poorly reversible airflow limitation. 
               Cochrane Database Syst Rev. 
               2002; 
               3CD002986 
               
- 23 
               Jones P W, Bosh T K. 
               Quality of life changes in COPD patients treated with salmeterol. 
               Am J Respir Crit Care Med. 
               1997; 
               155 
               1283-1289 
               
- 24 
               Taccola M, Bancalari L, Ghignoni G, Paggiaro P L. 
               Salmeterol versus slow-release theophylline in patients with reversible obstructive
               pulmonary disease. 
               Monaldi Arch Chest Dis. 
               1999; 
               54 
               302-306 
               
- 25 
               Celik G, Kayacan O, Beder S, Durmaz G. 
               Formoterol and salmeterol in partially reversible chronic obstructive pulmonary disease:
               a crossover, placebo-controlled comparison of onset and duration of action. 
               Respiration. 
               1999; 
               66 
               434-439 
               
- 26 
               Ferguson G T, Funck-Brentano C, Fischer T, Darken P, Reisner C. 
               Cardiovascular safety of salmeterol in COPD. 
               Chest. 
               2003; 
               123 
               1817-1824 
               
- 27 
               Donohue J F, Menjoge S, Kesten S. 
               Tolerance to bronchodilating effects of salmeterol in COPD. 
               Respir Med. 
               2003; 
               97 
               1014-1020 
               
- 28 
               Nelson H S, Bensch G, Pleskow W W et al.. 
               Improved bronchodilation with levalbuterol compared with racemic albuterol in patients
               with asthma. 
               J Allergy Clin Immunol. 
               1998; 
               102(6 Pt 1) 
               943-952 
               
- 29 
               Gawchik S M, Saccar C L, Noonan M, Reasner D S, DeGraw S S. 
               The safety and efficacy of nebulized levalbuterol compared with racemic albuterol
               and placebo in the treatment of asthma in pediatric patients. 
               J Allergy Clin Immunol. 
               1999; 
               103 
               615-621 
               
- 30 
               Nowak R M, Emerman C L, Schaefer K, Disantostefano R L, Vaickus L, Roach J M. 
               Levalbuterol compared with racemic albuterol in the treatment of acute asthma: results
               of a pilot study. 
               Am J Emerg Med. 
               2004; 
               22 
               29-36 
               
- 31 
               Carl J C, Myers T R, Kirchner H L, Kercsmar C M. 
               Comparison of racemic albuterol and levalbuterol for treatment of acute asthma. 
               J Pediatr. 
               2003; 
               143 
               731-736 
               
- 32 
               Truitt T, Witko J, Halpern M. 
               Levalbuterol compared to racemic albuterol: efficacy and outcomes in patients hospitalized
               with COPD or asthma. 
               Chest. 
               2003; 
               123 
               128-135 
               
- 33 
               Salathe M. 
               Effects of beta-agonists on airway epithelial cells. 
               J Allergy Clin Immunol. 
               2002; 
               110(suppl 6) 
               S27 5-S281 
               
- 34 
               Farmer P, Pugin J. 
               Beta-adrenergic agonists exert their “anti-inflammatory” effects in monocytic cells
               through the IkappaB/NF-kappaB pathway. 
               Am J Physiol Lung Cell Mol Physiol. 
               2000; 
               279 
               L675-L682 
               
- 35 
               Factor P, Adir Y, Mutlu G M, Burhop J, Dumasius V. 
               Effects of beta2-adrenergic receptor overexpression on alveolar epithelial active
               transport. 
               J Allergy Clin Immunol. 
               2002; 
               110(suppl 6) 
               S242-S246 
               
- 36 
               Philipson L H. 
               Beta-agonists and metabolism. 
               J Allergy Clin Immunol. 
               2002; 
               110(6 Suppl) 
               S313-S317 
               
- 37 
               Adcock I M, Maneechotesuwan K, Usmani O. 
               Molecular interactions between glucocorticoids and long-acting beta2-agonists. 
               J Allergy Clin Immunol. 
               2002; 
               110(suppl 6) 
               S261-S268 
               
- 38 
               Hanania N A, Darken P, Horstman D et al.. 
               The efficacy and safety of fluticasone propionate (250 microg)/salmeterol (50 microg)
               combined in the Diskus inhaler for the treatment of COPD. 
               Chest. 
               2003; 
               124 
               834-843 
               
- 39 
               Calverley P, Pauwels R, Vestbo J et al.. 
               Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary
               disease: a randomised controlled trial. 
               Lancet. 
               2003; 
               361 
               449-456 
               
- 40 
               Nannini L, Cates C J, Lasserson T J, Poole P. 
               Combined corticosteroid and long-acting beta-agonist in one inhaler for chronic obstructive
               pulmonary disease. 
               Cochrane Database Syst Rev. 
               2004; 
               3CD003794 
               
- 41 
               Donohue J F, Kalberg C, Emmett A, Merchant K, Knobil K. 
               A short-term comparison of fluticasone propionate/salmeterol with ipratropium bromide/albuterol
               for the treatment of COPD. 
               Treat Respir Med. 
               2004; 
               3 
               173-181 
               
- 42 
               Szafranski W, Cukier A, Ramirez A et al.. 
               Efficacy and safety of budesonide/formoterol in the management of chronic obstructive
               pulmonary disease. 
               Eur Respir J. 
               2003; 
               21 
               74-81 
               
- 43 
               Calverley P M, Boonsawat W, Cseke Z, Zhong N, Peterson S, Olsson H. 
               Maintenance therapy with budesonide and formoterol in chronic obstructive pulmonary
               disease. 
               Eur Respir J. 
               2003; 
               22 
               912-919 
               
- 44 
               van Noord J A, Bantje T A, Eland M E, Korducki L, Cornelissen P J. 
               A randomised controlled comparison of tiotropium and ipratropium in the treatment
               of chronic obstructive pulmonary disease. The Dutch Tiotropium Study Group. 
               Thorax. 
               2000; 
               55 
               289-294 
               
- 45 
               Casaburi R, Briggs Jr D D, Donohue J F, Serby C W, Menjoge S S, Witek Jr T J. 
               The spirometric efficacy of once-daily dosing with tiotropium in stable COPD: a 13-week
               multicenter trial. The US Tiotropium Study Group. 
               Chest. 
               2000; 
               118 
               1294-1302 
               
- 46 
               Casaburi R, Mahler D A, Jones P W et al.. 
               A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary
               disease. 
               Eur Respir J. 
               2002; 
               19 
               217-224 
               
- 47 
               Gross N J, Petty T L, Friedman M, Skorodin M S, Silvers G W, Donohue J F. 
               Dose response to ipratropium as a nebulized solution in patients with chronic obstructive
               pulmonary disease: a three-center study. 
               Am Rev Respir Dis. 
               1989; 
               139 
               1188-1191 
               
- 48 
               Dahl R, Greefhorst L A, Nowak D et al.. 
               Inhaled formoterol dry powder versus ipratropium bromide in chronic obstructive pulmonary
               disease. 
               Am J Respir Crit Care Med. 
               2001; 
               164 
               778-784 
               
- 49 
               Matera M G, Cazzola M, Vinciguerra A et al.. 
               A comparison of the bronchodilating effects of salmeterol, salbutamol and ipratropium
               bromide in patients with chronic obstructive pulmonary disease. 
               Pulm Pharmacol. 
               1995; 
               8 
               267-271 
               
- 50 
               van Noord J A, Smeets J J, Custers F L, Korducki L, Cornelissen P J. 
               Pharmacodynamic steady state of tiotropium in patients with chronic obstructive pulmonary
               disease. 
               Eur Respir J. 
               2002; 
               19 
               639-644 
               
- 51 
               Donohue J F, van Noord J A, Bateman E D et al.. 
               A 6-month, placebo-controlled study comparing lung function and health status changes
               in COPD patients treated with tiotropium or salmeterol. 
               Chest. 
               2002; 
               122 
               47-55 
               
- 52 
               Brusasco V, Hodder R, Miravitlles M, Korducki L, Towse L, Kesten S. 
               Health outcomes following treatment for six months with once daily tiotropium compared
               with twice daily salmeterol in patients with COPD. 
               Thorax. 
               2003; 
               58 
               399-404 
               
- 53 
               McNicholas W T, Calverley P M, Lee A, Edwards J C. 
               Long-acting inhaled anticholinergic therapy improves sleeping oxygen saturation in
               COPD. 
               Eur Respir J. 
               2004; 
               23 
               825-831 
               
- 54 
               Celli B, ZuWallack R, Wang S, Kesten S. 
               Improvement in resting inspiratory capacity and hyperinflation with tiotropium in
               COPD patients with increased static lung volumes. 
               Chest. 
               2003; 
               124 
               1743-1748 
               
- 55 
               O'Donnell D E, Fluge T, Gerken F et al.. 
               Effects of tiotropium on lung hyperinflation, dyspnoea and exercise tolerance in COPD. 
               Eur Respir J. 
               2004; 
               23 
               832-840 
               
- 56 
               Van Andel A E, Reisner C, Menjoge S S, Witek T J. 
               Analysis of inhaled corticosteroid and oral theophylline use among patients with stable
               COPD from 1987 to 1995. 
               Chest. 
               1999; 
               115 
               703-707 
               
- 57 
               Rossi A, Kristufek P, Levine B E et al.. 
               Comparison of the efficacy, tolerability, and safety of formoterol dry powder and
               oral, slow-release theophylline in the treatment of COPD. 
               Chest. 
               2002; 
               121 
               1058-1069 
               
- 58 
               Cazzola M, Di Lorenzo G, Di Perna F, Calderaro F, Testi R, Centanni S. 
               Additive effects of salmeterol and fluticasone or theophylline in COPD. 
               Chest. 
               2000; 
               118 
               1576-1581 
               
- 59 
               ZuWallack R L, Mahler D A, Reilly D et al.. 
               Salmeterol plus theophylline combination therapy in the treatment of COPD. 
               Chest. 
               2001; 
               119 
               1661-1670 
               
- 60 
               Sturton G, Fitzgerald M. 
               Phosphodiesterase 4 inhibitors for the treatment of COPD. 
               Chest. 
               2002; 
               121(5 Suppl) 
               192S-196S 
               
- 61 
               Compton C H, Gubb J, Nieman R et al.. 
               Cilomilast, a selective phosphodiesterase-4 inhibitor for treatment of patients with
               chronic obstructive pulmonary disease: a randomised, dose-ranging study. 
               Lancet. 
               2001; 
               358 
               265-270 
               
- 62 
               Bredenbröker D S J, Leichtl S, Rathgeb F, Wurst W. 
               Roflumilast, a new orally active, selective phosphodiesterase 4 inhibitor, is effective
               in the treatment of chronic obstructive pulmonary disease [abstract]. 
               Eur Respir J. 
               2002; 
               20(Suppl 38) 
               374S 
               
- 63 
               Agnew J E, Little F, Pavia D, Clarke S W. 
               Mucus clearance from the airways in chronic bronchitis: smokers and ex-smokers. 
               Bull Eur Physiopathol Respir. 
               1982; 
               18 
               473-484 
               
- 64 
               Bennett W D, Chapman W F, Mascarella J M. 
               The acute effect of ipratropium bromide bronchodilator therapy on cough clearance
               in COPD. 
               Chest. 
               1993; 
               103 
               488-495 
               
- 65 
               Bennett W D. 
               Effect of beta-adrenergic agonists on mucociliary clearance. 
               J Allergy Clin Immunol. 
               2002; 
               110(6 Suppl) 
               S291-S297 
               
- 66 
               Frohock J I, Wijkstrom-Frei C, Salathe M. 
               Effects of albuterol enantiomers on ciliary beat frequency in ovine tracheal epithelial
               cells. 
               J Appl Physiol. 
               2002; 
               92 
               2396-2402 
               
James F DonohueM.D. 
            Division of Pulmonary and Critical Care Medicine, University of North Carolina at
            Chapel Hill
            
            130 Mason Farm Rd., CB# 7020, 4125 Bioinformatics Bldg.
            
            Chapel Hill, NC 27599-7020
            
            Email: james_donohue@med.unc.edu