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==Overview==
==Overview==
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==Long-acting β2-agonists==
==Long-acting β2-agonists==
These are long-term medications taken routinely in order to control and prevent bronchoconstriction. They are not intended for fast relief. These medications take longer to begin working, but relieve airway constriction for up to 12 hours.
====Examples====
*Inhaled - Commonly taken twice a day with an anti-inflammatory medication, they maintain open airways and prevent asthma symptoms, particularly at night.
*[[Salmeterol]]
*Oral - Long-acting [[albuterol]] is available in pill or syrup form.
*[[Formoterol]]
Effective for 12 hours, albuterol is particularly helpful for nighttime asthma symptoms.
 
Because this medication requires high dosing, there tend to be increased side effects. Therefore it is not commonly prescribed. Side effects include increased heart rate, hyperactivity, feeling nervous, shaky, or over-excited, and very rarely, upset stomach or difficulty sleeping.
====Mechanism of Benefit====
*[[Beta-2 adrenergic receptor|Beta-2 receptor]] is a G protein-coupled transmembrane receptor that is widely distributed in the respiratory tract and activates the enzyme [[adenylyl cyclase]] that produces [[cAMP]] to cause bronchial smooth muscle relaxation.<ref name="pmid16263481">Johnson M (2001) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=16263481 Beta2-adrenoceptors: mechanisms of action of beta2-agonists.] ''Paediatr Respir Rev'' 2 (1):57-62. [http://dx.doi.org/10.1053/prrv.2000.0102 DOI:10.1053/prrv.2000.0102] PMID: [http://pubmed.gov/16263481 16263481]</ref>
 
*[[Beta2-adrenergic receptor agonist|Beta agonists]] have the potential to cause bronchial smooth muscle relaxation, and reduce the production of inflammatory mediators such as [[eosinophil]]s, [[neutrophil]]s and [[lymphocyte]]s. Thereby, increase mucociliary clearance and reduce edema formation.<ref name="pmid9396647">Lemanske RF, Busse WW (1997) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=9396647 Asthma.] ''JAMA'' 278 (22):1855-73. PMID: [http://pubmed.gov/9396647 9396647]</ref><ref name="pmid16387578">Johnson M (2006) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=16387578 Molecular mechanisms of beta(2)-adrenergic receptor function, response, and regulation.] ''J Allergy Clin Immunol'' 117 (1):18-24; quiz 25. [http://dx.doi.org/10.1016/j.jaci.2005.11.012 DOI:10.1016/j.jaci.2005.11.012] PMID: [http://pubmed.gov/16387578 16387578]</ref>
 
====Duration of Action====
These medications take longer to begin working, but relieve airway constriction for up to 12 hours.
 
====Mode of administration====
*''Inhaled:'' Commonly taken twice a day with an anti-inflammatory medication, they maintain open airways and prevent asthma symptoms, particularly at night.
 
*''Oral:'' Long-acting [[albuterol]] is available in pill or syrup form. Effective for 12 hours, albuterol is particularly helpful for nighttime asthma symptoms.
 
====Uses in Asthma====
*These are long-term medications taken routinely in order to '''control and prevent''' bronchoconstriction. They are not intended for fast relief.
 
*[[Formoterol]] has been shown to be effective as a rescue medication for the immediate relief of asthma symptoms similar to [[albuterol]].<ref name="pmid12406669">Grembiale RD, Pelaia G, Naty S, Vatrella A, Tranfa CM, Marsico SA (2002) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=12406669 Comparison of the bronchodilating effects of inhaled formoterol, salmeterol and salbutamol in asthmatic patients.] ''Pulm Pharmacol Ther'' 15 (5):463-6. [http://dx.doi.org/10.1006/pupt.2002.0387 DOI:10.1006/pupt.2002.0387] PMID: [http://pubmed.gov/12406669 12406669]</ref><ref name="pmid11587972">Kips JC, Pauwels RA (2001) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=11587972 Long-acting inhaled beta(2)-agonist therapy in asthma.] ''Am J Respir Crit Care Med'' 164 (6):923-32. PMID: [http://pubmed.gov/11587972 11587972]</ref> However, [[formoterol]] has not been approved as a quick relief medication.<ref name="pmid18240881">Urbano FL (2008) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=18240881 Review of the NAEPP 2007 Expert Panel Report (EPR-3) on Asthma Diagnosis and Treatment Guidelines.] ''J Manag Care Pharm'' 14 (1):41-9. PMID: [http://pubmed.gov/18240881 18240881]</ref>
 
*[[Salmeterol]], has shown to block both the immediate and late phase [[bronchospasm|bronchospastic]] responses; however, has no anti-inflammatory properties.<ref name="pmid1978163">Twentyman OP, Finnerty JP, Harris A, Palmer J, Holgate ST (1990) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=1978163 Protection against allergen-induced asthma by salmeterol.] ''Lancet'' 336 (8727):1338-42. PMID: [http://pubmed.gov/1978163 1978163]</ref>
 
*[[Beta2-adrenergic receptor agonist|Long-acting β2-agonists (LABA)]] has shown to be beneficial in the prevention and management of [[exercise induced asthma]].<ref name="pmid1351489">Henriksen JM, Agertoft L, Pedersen S (1992) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=1351489 Protective effect and duration of action of inhaled formoterol and salbutamol on exercise-induced asthma in children.] ''J Allergy Clin Immunol'' 89 (6):1176-82. PMID: [http://pubmed.gov/1351489 1351489]</ref><ref name="pmid1355645">Green CP, Price JF (1992) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=1355645 Prevention of exercise induced asthma by inhaled salmeterol xinafoate.] ''Arch Dis Child'' 67 (8):1014-7. PMID: [http://pubmed.gov/1355645 1355645]</ref>
 
*Combined therapy with [[Beta2-adrenergic receptor agonist|Long-acting β2-agonists (LABA)]] and inhaled [[steroids]] have shown to be additive and provide greater improvement in lung function and reduce the rate of exacerbations.<ref name="pmid20197425">Lemanske RF, Mauger DT, Sorkness CA, Jackson DJ, Boehmer SJ, Martinez FD et al. (2010) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=20197425 Step-up therapy for children with uncontrolled asthma receiving inhaled corticosteroids.] ''N Engl J Med'' 362 (11):975-85. [http://dx.doi.org/10.1056/NEJMoa1001278 DOI:10.1056/NEJMoa1001278] PMID: [http://pubmed.gov/20197425 20197425]</ref><ref name="pmid16235409">Greenstone IR, Ni Chroinin MN, Masse V, Danish A, Magdalinos H, Zhang X et al. (2005) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=16235409 Combination of inhaled long-acting beta2-agonists and inhaled steroids versus higher dose of inhaled steroids in children and adults with persistent asthma.] ''Cochrane Database Syst Rev''  (4):CD005533. [http://dx.doi.org/10.1002/14651858.CD005533 DOI:10.1002/14651858.CD005533] PMID: [http://pubmed.gov/16235409 16235409]</ref><ref name="pmid16235410">Ni Chroinin M, Greenstone IR, Danish A, Magdolinos H, Masse V, Zhang X et al. (2005) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=16235410 Long-acting beta2-agonists versus placebo in addition to inhaled corticosteroids in children and adults with chronic asthma.] ''Cochrane Database Syst Rev''  (4):CD005535. [http://dx.doi.org/10.1002/14651858.CD005535 DOI:10.1002/14651858.CD005535] PMID: [http://pubmed.gov/16235410 16235410]</ref><ref name="pmid15502112">O'Byrne PM, Bisgaard H, Godard PP, Pistolesi M, Palmqvist M, Zhu Y et al. (2005) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=15502112 Budesonide/formoterol combination therapy as both maintenance and reliever medication in asthma.] ''Am J Respir Crit Care Med'' 171 (2):129-36. [http://dx.doi.org/10.1164/rccm.200407-884OC DOI:10.1164/rccm.200407-884OC] PMID: [http://pubmed.gov/15502112 15502112]</ref>
 
====Caution====
Because this medication requires high dosing, there tend to be increased side effects. Therefore, [[Beta2-adrenergic receptor agonist|long-acting β2-agonists (LABA)]] are never prescribed as monotherapy.<ref name="pmid20181964">Chowdhury BA, Dal Pan G (2010) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=20181964 The FDA and safe use of long-acting beta-agonists in the treatment of asthma.] ''N Engl J Med'' 362 (13):1169-71. [http://dx.doi.org/10.1056/NEJMp1002074 DOI:10.1056/NEJMp1002074] PMID: [http://pubmed.gov/20181964 20181964]</ref><ref name="pmid20692690">Lemanske RF, Busse WW (2010) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=20692690 The US Food and Drug Administration and long-acting beta2-agonists: the importance of striking the right balance between risks and benefits of therapy?] ''J Allergy Clin Immunol'' 126 (3):449-52. [http://dx.doi.org/10.1016/j.jaci.2010.05.039 DOI:10.1016/j.jaci.2010.05.039] PMID: [http://pubmed.gov/20692690 20692690]</ref>
 
====Adverse Effects====
*'''Tolerance:''' Bronchodilator tolerance occurs after regular chronic use of [[formoterol]] <ref name="pmid15823453">Haney S, Hancox RJ (2005) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=15823453 Rapid onset of tolerance to beta-agonist bronchodilation.] ''Respir Med'' 99 (5):566-71. [http://dx.doi.org/10.1016/j.rmed.2004.10.014 DOI:10.1016/j.rmed.2004.10.014] PMID: [http://pubmed.gov/15823453 15823453]</ref>
*[[Tachycardia]]
*Hyperactivity, [[palpitations]]
*Very rarely, GI discomfort or [[insomnia]]


==Anticholinergics==
==Anticholinergics==

Revision as of 03:46, 30 September 2011

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief: Lakshmi Gopalakrishnan, M.B.B.S. [2]

Overview

A bronchodilator is a substance that dilates the bronchi and bronchioles, increasing airflow and relieving bronchial obstruction. Bronchodilators may be endogenous (originating naturally within the body), or they may be medication administered for the treatment of breathing difficulties. Bronchial asthma is the most common application of these drugs. They are also intended to help improve the breathing capacity of patients with emphysema, pneumonia and bronchitis.

Pharmaceutically bronchodilators belong to β2 mimetics as they act on β2 receptors present in the bronchial smooth muscle and bronchial mucous membranes. Bronchodilators, particularly non-prescription ones, are often misused as stimulants. A common side effect of these medications is desensitization, which may produce refractory bronchospasm.

Bronchodilators are either short-acting or long-acting. Short-acting medications (also known as SABA) provide quick or rescue relief from acute bronchoconstriction. Long-acting bronchodilators (known as LABA) help to control and prevent symptoms. The three types of prescription bronchodilator drugs are β2-agonists (short- and long-acting), anticholinergics (short-acting), and theophylline (long-acting).

Short-acting β2-agonists

Examples

Mechanism of Benefit

  • Beta-2 receptor is a G protein-coupled transmembrane receptor that is widely distributed in the respiratory tract and activates the enzyme adenylyl cyclase that produces cAMP to cause bronchial smooth muscle relaxation.[1]
  • Short-acting beta agonists provide immediate symptomatic benefit; however, are unsuccessful in inhibiting chronic inflammatory responce. Thereby, provide no benefit for prophylactic use.[4][5]

Duration of Action

These medications usually take effect within 20 minutes or less, and can last from four to six hours.

Mode of administration

  • Albuterol by metered dose inhaler provided similar bronchodilation to that achieved by wet nebulization in patients with acute asthma. No significant difference in the effectiveness of albuterol administered by nebulizer or the inhaler system.[6][7]
  • Oral beta agonists have a delayed therapeutic effect and peak bronchodilation occurs only two hours after ingestion; hence, making it suitable for the treatment of mild to moderate asthma and not for acute exacerbation.[8]
  • Inhaled medications are best for treating sudden and severe or new asthma symptoms. In patients with severe asthma, only after a failed or absent response observed with inhaled beta agonist, is parenteral administration indicated; as the nebulized route is associated with a greater efficacy and fewer side effect.[9][10][11][12][13]

Uses in Asthma

  • Quick-relief or rescue medications that provide fast, temporary relief from asthma symptoms or flare-ups.[14]
  • Short-acting β2-agonists (SABA) along with ipratropium may be administered within the first three hours of acute severe exacerbation.[14]
  • Taken 15 to 20 minutes ahead of time, these medications can also prevent asthma symptoms triggered by exercise or exposure to cold air.
  • Few patients may require higher-dose of nebulized beta-2 agonist to provide effective treatment of acute severe asthma.[15][16][17][18][19]

Caution/Contra-indication

  • Patients who chronically or frequently take short-acting β2-agonists, may be subjected to resistance secondary to the down-regulation of beta receptor and may indicate towards uncontrolled asthma.[20]
  • Intravenous administration of beta agonists is associated with the development systemic adverse effects.[12][11][21]
  • Intravenous isoproterenol is not used as it is associated with severe cardiac toxicity.[21]

Adverse Effects

Long-acting β2-agonists

Examples

Mechanism of Benefit

  • Beta-2 receptor is a G protein-coupled transmembrane receptor that is widely distributed in the respiratory tract and activates the enzyme adenylyl cyclase that produces cAMP to cause bronchial smooth muscle relaxation.[1]

Duration of Action

These medications take longer to begin working, but relieve airway constriction for up to 12 hours.

Mode of administration

  • Inhaled: Commonly taken twice a day with an anti-inflammatory medication, they maintain open airways and prevent asthma symptoms, particularly at night.
  • Oral: Long-acting albuterol is available in pill or syrup form. Effective for 12 hours, albuterol is particularly helpful for nighttime asthma symptoms.

Uses in Asthma

  • These are long-term medications taken routinely in order to control and prevent bronchoconstriction. They are not intended for fast relief.
  • Formoterol has been shown to be effective as a rescue medication for the immediate relief of asthma symptoms similar to albuterol.[28][29] However, formoterol has not been approved as a quick relief medication.[14]
  • Salmeterol, has shown to block both the immediate and late phase bronchospastic responses; however, has no anti-inflammatory properties.[30]

Caution

Because this medication requires high dosing, there tend to be increased side effects. Therefore, long-acting β2-agonists (LABA) are never prescribed as monotherapy.[37][38]

Adverse Effects

Anticholinergics

Only available as an inhalant, ipratropium bromide relieves acute or new asthma symptoms. Because it has no effect on asthma symptoms when used alone, it is most often paired with a short-acting β2-agonist.While it is considered a relief or rescue medication, it can take a full hour to begin working. For this reason it plays a minor role in asthma treatment. Dry throat is the most common side effect. If the medication gets in contact with the eyes, it may cause blurred vision for a brief time.

Theophylline

Available in oral and injectable form, theophylline is a long-acting bronchodilator that prevents asthma episodes. It belongs to the chemical class, methyl xanthines (along with caffeine). It is prescribed in severe cases of asthma or those that are difficult to control. It must be taken 1-4 times daily and doses cannot be missed. Blood tests are required to monitor therapy and to indicate when dosage adjustment is necessary. Side effects can include nausea, vomiting, diarrhea, stomach or headache, rapid or irregular heart beat, muscle cramps, nervous or jittery feelings, and hyperactivity. These symptoms may signal the need for an adjustment in your medication. It may promote acid reflux, also known as GERD, by relaxing the lower esophageal sphincter muscle. Some medications, such as seizure and ulcer medications and antibiotics containing erythromycin, can interfere with the way theopylline works. Coffee, tea, colas, cigarette smoking, and viral illnesses can all affect the action of theophylline and change its effectiveness. A physician should monitor dosage levels to meet each patient's profile and needs.

Brand names of common bronchodilators

Following the standard convention of medicine, the capitalized brand name is followed by the lowercased generic name in parentheses.

References

  1. ↑ 1.0 1.1 Johnson M (2001) Beta2-adrenoceptors: mechanisms of action of beta2-agonists. Paediatr Respir Rev 2 (1):57-62. DOI:10.1053/prrv.2000.0102 PMID: 16263481
  2. ↑ 2.0 2.1 Lemanske RF, Busse WW (1997) Asthma. JAMA 278 (22):1855-73. PMID: 9396647
  3. ↑ 3.0 3.1 Johnson M (2006) Molecular mechanisms of beta(2)-adrenergic receptor function, response, and regulation. J Allergy Clin Immunol 117 (1):18-24; quiz 25. DOI:10.1016/j.jaci.2005.11.012 PMID: 16387578
  4. ↑ Cockcroft DW, Murdock KY (1987) Comparative effects of inhaled salbutamol, sodium cromoglycate, and beclomethasone dipropionate on allergen-induced early asthmatic responses, late asthmatic responses, and increased bronchial responsiveness to histamine. J Allergy Clin Immunol 79 (5):734-40. PMID: 3106449
  5. ↑ Howarth PH, Durham SR, Lee TH, Kay AB, Church MK, Holgate ST (1985) Influence of albuterol, cromolyn sodium and ipratropium bromide on the airway and circulating mediator responses to allergen bronchial provocation in asthma. Am Rev Respir Dis 132 (5):986-92. PMID: 2932989
  6. ↑ Colacone A, Afilalo M, Wolkove N, Kreisman H (1993) A comparison of albuterol administered by metered dose inhaler (and holding chamber) or wet nebulizer in acute asthma. Chest 104 (3):835-41. PMID: 8365298
  7. ↑ Idris AH, McDermott MF, Raucci JC, Morrabel A, McGorray S, Hendeles L (1993) Emergency department treatment of severe asthma. Metered-dose inhaler plus holding chamber is equivalent in effectiveness to nebulizer. Chest 103 (3):665-72. PMID: 8449049
  8. ↑ Wolfe JD, Yamate M, Biedermann AA, Chu TJ (1985) Comparison of the acute cardiopulmonary effects of oral albuterol, metaproterenol, and terbutaline in asthmatics. JAMA 253 (14):2068-72. PMID: 3974097
  9. ↑ Travers AH, Rowe BH, Barker S, Jones A, Camargo CA (2002) The effectiveness of IV beta-agonists in treating patients with acute asthma in the emergency department: a meta-analysis. Chest 122 (4):1200-7. PMID: 12377842
  10. ↑ Travers A, Jones AP, Kelly K, Barker SJ, Camargo CA, Rowe BH (2001) Intravenous beta2-agonists for acute asthma in the emergency department. Cochrane Database Syst Rev (2):CD002988. DOI:10.1002/14651858.CD002988 PMID: 11406055
  11. ↑ 11.0 11.1 Salmeron S, Brochard L, Mal H, Tenaillon A, Henry-Amar M, Renon D et al. (1994) Nebulized versus intravenous albuterol in hypercapnic acute asthma. A multicenter, double-blind, randomized study. Am J Respir Crit Care Med 149 (6):1466-70. PMID: 8004299
  12. ↑ 12.0 12.1 Pierce RJ, Payne CR, Williams SJ, Denison DM, Clark TJ (1981) Comparison of intravenous and inhaled terbutaline in the treatment of asthma. Chest 79 (5):506-11. PMID: 7014120
  13. ↑ Williams S, Seaton A (1977) Intravenous or inhaled salbutamol in severe acute asthma? Thorax 32 (5):555-8. PMID: 594935
  14. ↑ 14.0 14.1 14.2 Urbano FL (2008) Review of the NAEPP 2007 Expert Panel Report (EPR-3) on Asthma Diagnosis and Treatment Guidelines. J Manag Care Pharm 14 (1):41-9. PMID: 18240881
  15. ↑ Boulet LP, Turcotte H, Tennina S (1989) Comparative efficacy of salbutamol, ipratropium, and cromoglycate in the prevention of bronchospasm induced by exercise and hyperosmolar challenges. J Allergy Clin Immunol 83 (5):882-7. PMID: 2523921
  16. ↑ Schuh S, Parkin P, Rajan A, Canny G, Healy R, Rieder M et al. (1989) High-versus low-dose, frequently administered, nebulized albuterol in children with severe, acute asthma. Pediatrics 83 (4):513-8. PMID: 2927990
  17. ↑ Rohr AS, Siegel SC, Katz RM, Rachelefsky GS, Spector SL, Lanier R (1987) A comparison of inhaled albuterol and cromolyn in the prophylaxis of exercise-induced bronchospasm. Ann Allergy 59 (2):107-9. PMID: 3113295
  18. ↑ Tipton WR, Nelson HS (1987) Frequent parenteral terbutaline in the treatment of status asthmaticus in children. Ann Allergy 58 (4):252-6. PMID: 3565860
  19. ↑ Bundgaard A, Buch D, Schmidt A, Bach-Mortensen N (1983) Pretreatment of exercise-induced asthma in children using disodium cromoglycate and fenoterol inhalation powder. Eur J Respir Dis Suppl 130 ():36-41. PMID: 6418561
  20. ↑ Hausdorff WP, Caron MG, Lefkowitz RJ (1990) Turning off the signal: desensitization of beta-adrenergic receptor function. FASEB J 4 (11):2881-9. PMID: 2165947
  21. ↑ 21.0 21.1 Maguire JF, O'Rourke PP, Colan SD, Geha RS, Crone R (1991) Cardiotoxicity during treatment of severe childhood asthma. Pediatrics 88 (6):1180-6. PMID: 1956735
  22. ↑ Jenne JW, Valcarenghi G, Druz WS, Starkey PW, Yu C, Shaughnessy TK (1986) Comparison of tremor responses to orally administered albuterol and terbutaline. Am Rev Respir Dis 134 (4):708-13. PMID: 3767127
  23. ↑ Kurisu S, Inoue I, Kawagoe T, Ishihara M, Shimatani Y, Nakama Y et al. (2009) Assessment of medications in patients with tako-tsubo cardiomyopathy. Int J Cardiol 134 (3):e120-3. DOI:10.1016/j.ijcard.2008.01.026 PMID: 18499288
  24. ↑ Osuorji I, Williams C, Hessney J, Patel T, Hsi D (2009) Acute stress cardiomyopathy following treatment of status asthmaticus. South Med J 102 (3):301-3. DOI:10.1097/SMJ.0b013e31818f5bd8 PMID: 19204641
  25. ↑ Leslie D, Coats PM (1977) Salbutamol-induced diabetic ketoacidosis. Br Med J 2 (6089):768. PMID: 410474
  26. ↑ van den Berg BT, Louwerse RT, Luiken GJ, Jonkers RE, van Boxtel CJ (1998) Hypokalaemia in healthy volunteers after single and multiple doses of formoterol or salbutamol. Clin Drug Investig 15 (6):523-9. PMID: 18370510
  27. ↑ Guhan AR, Cooper S, Oborne J, Lewis S, Bennett J, Tattersfield AE (2000) Systemic effects of formoterol and salmeterol: a dose-response comparison in healthy subjects. Thorax 55 (8):650-6. PMID: 10899240
  28. ↑ Grembiale RD, Pelaia G, Naty S, Vatrella A, Tranfa CM, Marsico SA (2002) Comparison of the bronchodilating effects of inhaled formoterol, salmeterol and salbutamol in asthmatic patients. Pulm Pharmacol Ther 15 (5):463-6. DOI:10.1006/pupt.2002.0387 PMID: 12406669
  29. ↑ Kips JC, Pauwels RA (2001) Long-acting inhaled beta(2)-agonist therapy in asthma. Am J Respir Crit Care Med 164 (6):923-32. PMID: 11587972
  30. ↑ Twentyman OP, Finnerty JP, Harris A, Palmer J, Holgate ST (1990) Protection against allergen-induced asthma by salmeterol. Lancet 336 (8727):1338-42. PMID: 1978163
  31. ↑ Henriksen JM, Agertoft L, Pedersen S (1992) Protective effect and duration of action of inhaled formoterol and salbutamol on exercise-induced asthma in children. J Allergy Clin Immunol 89 (6):1176-82. PMID: 1351489
  32. ↑ Green CP, Price JF (1992) Prevention of exercise induced asthma by inhaled salmeterol xinafoate. Arch Dis Child 67 (8):1014-7. PMID: 1355645
  33. ↑ Lemanske RF, Mauger DT, Sorkness CA, Jackson DJ, Boehmer SJ, Martinez FD et al. (2010) Step-up therapy for children with uncontrolled asthma receiving inhaled corticosteroids. N Engl J Med 362 (11):975-85. DOI:10.1056/NEJMoa1001278 PMID: 20197425
  34. ↑ Greenstone IR, Ni Chroinin MN, Masse V, Danish A, Magdalinos H, Zhang X et al. (2005) Combination of inhaled long-acting beta2-agonists and inhaled steroids versus higher dose of inhaled steroids in children and adults with persistent asthma. Cochrane Database Syst Rev (4):CD005533. DOI:10.1002/14651858.CD005533 PMID: 16235409
  35. ↑ Ni Chroinin M, Greenstone IR, Danish A, Magdolinos H, Masse V, Zhang X et al. (2005) Long-acting beta2-agonists versus placebo in addition to inhaled corticosteroids in children and adults with chronic asthma. Cochrane Database Syst Rev (4):CD005535. DOI:10.1002/14651858.CD005535 PMID: 16235410
  36. ↑ O'Byrne PM, Bisgaard H, Godard PP, Pistolesi M, Palmqvist M, Zhu Y et al. (2005) Budesonide/formoterol combination therapy as both maintenance and reliever medication in asthma. Am J Respir Crit Care Med 171 (2):129-36. DOI:10.1164/rccm.200407-884OC PMID: 15502112
  37. ↑ Chowdhury BA, Dal Pan G (2010) The FDA and safe use of long-acting beta-agonists in the treatment of asthma. N Engl J Med 362 (13):1169-71. DOI:10.1056/NEJMp1002074 PMID: 20181964
  38. ↑ Lemanske RF, Busse WW (2010) The US Food and Drug Administration and long-acting beta2-agonists: the importance of striking the right balance between risks and benefits of therapy? J Allergy Clin Immunol 126 (3):449-52. DOI:10.1016/j.jaci.2010.05.039 PMID: 20692690
  39. ↑ Haney S, Hancox RJ (2005) Rapid onset of tolerance to beta-agonist bronchodilation. Respir Med 99 (5):566-71. DOI:10.1016/j.rmed.2004.10.014 PMID: 15823453

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