Bronchodilator
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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]
- Beta agonists have the potential to cause bronchial smooth muscle relaxation, and reduce the production of inflammatory mediators such as eosinophils, neutrophils and lymphocytes. Thereby, increase mucociliary clearance and reduce edema formation.[2][3]
- 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]
- Beta agonists have the potential to cause bronchial smooth muscle relaxation, and reduce the production of inflammatory mediators such as eosinophils, neutrophils and lymphocytes. Thereby, increase mucociliary clearance and reduce edema formation.[2][3]
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]
- Long-acting β2-agonists (LABA) has shown to be beneficial in the prevention and management of exercise induced asthma.[31][32]
- Combined therapy with 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.[33][34][35][36]
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
- Tolerance: Bronchodilator tolerance occurs after regular chronic use of formoterol [39]
- Tachycardia
- Hyperactivity, palpitations
- Very rarely, GI discomfort or insomnia
Anticholinergics
Examples
Mechanism of Benefit
Muscarinic-1 receptor facilitates neurotransmission through parasympathetic ganglia and enhances the cholinergic reflexes, and are also localized to alveolar walls. Muscarinic-3 receptors mediate contractile responses in the airway smooth muscle via phosphoinositide hydrolysis, and are the predominant receptors on submucosal glands and airway vascular endothelium.[40][41][42] M3-receptor activation results in bronchospasm secondary to decrease in intracellular cAMP.[43]
Anticholinergic drugs such as ipratropium, selectively block M3 and M1-receptors; thereby, causing bronchial smooth muscle relaxation and reducing the bronchial submucosal gland secretions.[40][44]
Duration of Action
Slow-onset of action but longer duration of action [45][46]
Mode of administration
Only available as an inhalant, ipratropium bromide relieves acute or new asthma symptoms with less than 1% systemic absorption and therefore, reduced risk of systemic toxicity.[47][48]
Uses in Asthma
Ipratropium is not the first drug of choice for asthma; however, it is extensively used in conjunction with short-acting β2-agonist for the treatment of acute exacerbations.[49][50]
Adverse Effects
- 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.[51]
Theophylline
Mechanism of Benefit
- Belongs to the chemical class, methyl xanthines (along with caffeine).
- Significant bronchodilator property.[52][53][54][55][56][57]
- Anti-inflammatory, immunomodulatory, and bronchoprotective effects.[57][58][59][60][61][62][63][64]
Duration of Action
It must be taken 1-4 times daily and doses cannot be missed.
Mode of administration
Available in oral and injectable form, theophylline is a long-acting bronchodilator that prevents asthma episodes.
Caution
Blood tests are required to monitor therapy and to indicate when dosage adjustment is necessary.
Uses in Asthma
It is prescribed in severe cases of asthma or those that are difficult to control.
Adverse Effects
- Side effects can include nausea, vomiting, diarrhea, 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.
Drug Interactions
- 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.
Brand names of common bronchodilators
Following the standard convention of medicine, the capitalized brand name is followed by the lowercased generic name in parentheses.
- Accu-Hale
- Maxair (pirbuterol)
- Primatene (epinephrine)
- Proventil (salbutamol = albuterol)
- Serevent (salmeterol)
- Ventolin (salbutamol = albuterol)
- Xopenex (levalbuterol)
References
- ↑ 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
- ↑ 2.0 2.1 Lemanske RF, Busse WW (1997) Asthma. JAMA 278 (22):1855-73. PMID: 9396647
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 11.0 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
- ↑ 12.0 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
- ↑ Williams S, Seaton A (1977) Intravenous or inhaled salbutamol in severe acute asthma? Thorax 32 (5):555-8. PMID: 594935
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ Tipton WR, Nelson HS (1987) Frequent parenteral terbutaline in the treatment of status asthmaticus in children. Ann Allergy 58 (4):252-6. PMID: 3565860
- ↑ 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
- ↑ 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
- ↑ 21.0 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ Leslie D, Coats PM (1977) Salbutamol-induced diabetic ketoacidosis. Br Med J 2 (6089):768. PMID: 410474
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ Green CP, Price JF (1992) Prevention of exercise induced asthma by inhaled salmeterol xinafoate. Arch Dis Child 67 (8):1014-7. PMID: 1355645
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ 40.0 40.1 Barnes PJ (1993) Muscarinic receptor subtypes in airways. Life Sci 52 (5-6):521-7. PMID: 8441331
- ↑ Doods HN (1991) Selective muscarinic antagonists as bronchodilators. Agents Actions Suppl 34 ():117-30. PMID: 1793059
- ↑ Barnes PJ, Minette P, Maclagan J (1988) Muscarinic receptor subtypes in airways. Trends Pharmacol Sci 9 (11):412-6. PMID: 3078078
- ↑ Barnes PJ (1990) Muscarinic receptors in airways: recent developments. J Appl Physiol 68 (5):1777-85. PMID: 1972938
- ↑ Jones CA, Madison JM, Tom-Moy M, Brown JK (1987) Muscarinic cholinergic inhibition of adenylate cyclase in airway smooth muscle. Am J Physiol 253 (1 Pt 1):C97-104. PMID: 3605331
- ↑ Gross NJ (1988) The use of anticholinergic agents in the treatment of airways disease. Clin Chest Med 9 (4):591-8. PMID: 3233900
- ↑ Ziment I, Au JP (1986) Respiratory pharmacology. Anticholinergic agents. Clin Chest Med 7 (3):355-66. PMID: 2945691
- ↑ Gross NJ, Skorodin MS (1984) Anticholinergic, antimuscarinic bronchodilators. Am Rev Respir Dis 129 (5):856-70. PMID: 6372560
- ↑ Deckers W (1975) The chemistry of new derivatives of tropane alkaloids and the pharmacokinetics of a new quarternary compound. Postgrad Med J 51 (7 SUPPL):76-81. PMID: 134360
- ↑ Rodrigo GJ, Castro-Rodriguez JA (2005) Anticholinergics in the treatment of children and adults with acute asthma: a systematic review with meta-analysis. Thorax 60 (9):740-6. DOI:10.1136/thx.2005.040444 PMID: 16055613
- ↑ Rodrigo GJ, Rodrigo C (2000) First-line therapy for adult patients with acute asthma receiving a multiple-dose protocol of ipratropium bromide plus albuterol in the emergency department. Am J Respir Crit Care Med 161 (6):1862-8. PMID: 10852758
- ↑ Kalra L, Bone MF (1988) The effect of nebulized bronchodilator therapy on intraocular pressures in patients with glaucoma. Chest 93 (4):739-41. PMID: 2964995
- ↑ Nassif EG, Weinberger M, Thompson R, Huntley W (1981) The value of maintenance theophylline in steroid-dependent asthma. N Engl J Med 304 (2):71-5. DOI:10.1056/NEJM198101083040202 PMID: 7003383
- ↑ Dusdieker L, Green M, Smith GD, Ekwo EE, Weinberger M (1982) Comparison of orally administered metaproterenol and theophylline in the control of chronic asthma. J Pediatr 101 (2):281-7. PMID: 7047707
- ↑ Joad JP, Ahrens RC, Lindgren SD, Weinberger MM (1987) Relative efficacy of maintenance therapy with theophylline, inhaled albuterol, and the combination for chronic asthma. J Allergy Clin Immunol 79 (1):78-85. PMID: 3805550
- ↑ Brenner M, Berkowitz R, Marshall N, Strunk RC (1988) Need for theophylline in severe steroid-requiring asthmatics. Clin Allergy 18 (2):143-50. PMID: 3365858
- ↑ Rivington RN, Boulet LP, Côté J, Kreisman H, Small DI, Alexander M et al. (1995) Efficacy of Uniphyl, salbutamol, and their combination in asthmatic patients on high-dose inhaled steroids. Am J Respir Crit Care Med 151 (2 Pt 1):325-32. PMID: 7842186
- ↑ 57.0 57.1 Kidney J, Dominguez M, Taylor PM, Rose M, Chung KF, Barnes PJ (1995) Immunomodulation by theophylline in asthma. Demonstration by withdrawal of therapy. Am J Respir Crit Care Med 151 (6):1907-14. PMID: 7767539
- ↑ Hendeles L, Harman E, Huang D, O'Brien R, Blake K, Delafuente J (1995) Theophylline attenuation of airway responses to allergen: comparison with cromolyn metered-dose inhaler. J Allergy Clin Immunol 95 (2):505-14. PMID: 7852666
- ↑ Sullivan P, Bekir S, Jaffar Z, Page C, Jeffery P, Costello J (1994) Anti-inflammatory effects of low-dose oral theophylline in atopic asthma. Lancet 343 (8904):1006-8. PMID: 7909049
- ↑ Magnussen H, Reuss G, Jörres R (1987) Theophylline has a dose-related effect on the airway response to inhaled histamine and methacholine in asthmatics. Am Rev Respir Dis 136 (5):1163-7. PMID: 3314612
- ↑ Koenig JQ, Dumler K, Rebolledo V, Williams PV, Pierson WE (1992) Theophylline mitigates the bronchoconstrictor effects of sulfur dioxide in subjects with asthma. J Allergy Clin Immunol 89 (4):789-94. PMID: 1560163
- ↑ Fabbri LM, Alessandri MV, De Marzo N, Zocca E, Paleari D, Pozzan M et al. (1986) Long-lasting protective effect of slow-release theophylline on asthma induced by ultrasonically nebulized distilled water. Ann Allergy 56 (2):171-6. PMID: 3946851
- ↑ Pollock J, Kiechel F, Cooper D, Weinberger M (1977) Relationship of serum theophylline concentration to inhibition of exercise-induced bronchospasm and comparison with cromolyn. Pediatrics 60 (6):840-4. PMID: 414196
- ↑ Chorostowska-Wynimko J, Kus J, Skopińska-Rózewska E (2007) Theophylline inhibits free oxygen radicals production by human monocytes via phosphodiesterase inhibition. J Physiol Pharmacol 58 Suppl 5 (Pt 1):95-103. PMID: 18204120