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