PULMONARY AND ALLERGY Edited by Gary Milavetz and H. William Kelly
BETA-ADRENERGIC AGONISTS FOR ACurE, SEVERE ASTHMA H. William Kelly and Shirley Murphy
To critically review the use of beta-adrenergic agonists in acute, severe asthma with particular focus on aerosol administration.
OBJECTIVE:
English languagearticles published since 1971 on the use of beta-agonistsfor acute asthma. Studies were identified from bibliographiesof book chapters, review articles, and other researcharticles.
DATA SOURCES:
All studies (21 total) comparing systemic with inhaled beta-agonists were reviewed, regardless of their design or outcome. Selected studies highlightingspecific aspects of betaagonist use in acute asthma such as beta-agonistsversus other bronchodilators, aerosol delivery, and intravenousbeta-agonists were also reviewed. STUDY SELECTION:
DATA EXTRACTION: Performed subjectivelyby the authors with specific aspects of quality discussed within the body of the article.
The beta-agonistsprovide superior bronchodilation in acute severe asthma compared with either the methylxanthines and/or anlicholinergics. The majority of studies found aerosolized beta-agonists 10 be either as effective as or more effective than parenteralbeta-agonistsand to produce fewer adverse cardiovasculareffects. Studies showing preference for parenteral therapy have either been of poor design or used low doses of an aerosolizedbeta-agonist.Based on studies of aerosol delivery, there is no advantage of jet nebulizationover metered-dose inhalers; however, other aspects, includingease of administration,favor nebulizationas the delivery method of choice. The articles recommending intravenousbeta-agonistsconsist of a series of uncontrolledcases. DATA SYNTHESIS:
Aerosolizedselective betaj-agonistsare the bronchodilatortreatmentsof choice for acute, severe asthma.
CONCLUSIONS:
H. WILLIAM KELLY, Phann.D .. is a Professor of Pharmacy and an Associate Professor of Pediatrics. College of Pharmacy and School of Medicine, University of New Mexico; and a Clinical Pharmacist, Pediatric Intensive Care Unit. Childrens Hospital of New Mexico; and SHIRLEY MURPHY, M.D.• is a Professor of Pediatrics, a Clinical Professor of Pharmacy. and the Chair, Pulmonary/Critical Care Division, Department of Pediatrics. School of Medicine. University of New Mexico, Albuquerque, NM. Reprints: H. William Kelly, Pharm.D., College of Pharmacy, University of New Mexico. Albuquerque, NM 87 I3 I. GARY MILAVETZ, Phann.D.• is an Associate Professor, College of Pharmacy, University of Iowa, Iowa City. fA 52242.
This article is approved for continuing education credit
Attention to the details of dosing and delivery are required for optimal results.The fmal dose and dosing interval are determined by the patient's response. Intravenousbeta-agonistsare hazardous and cannot be recommended. Ann Pharmacother 1992;26:81-91.
of the treatment of acute, severe asthma exacerbations is the rapid reversal of airflow obstruction produced by inflammation and bronchospasm. Systemic corticosteroids effectively treat the inflammation, whereas inhaled betaj-agonists are the treatments of first choice for the bronchospasm.v" The purpose of this article is to briefly review the data establishing aerosolized betajagonists as the treatments of first choice for the bronchospasm of acute, severe asthma. In addition, the following issues are explored: (1) the optimal dosing schedule, (2) the dose equivalency among various methods of aerosol delivery, and (3) the role of intravenous beta-agonists.
THE PRINCIPAL GOAL
Beta-Agonists Versus Other Bronchodilators The advantage of beta-agonists for acute, severe asthma over both methylxanthines and anticholinergics is well establishedv' and has been extensively reviewed.v An understanding of the physiology of acute, severe asthma and the pharmacology of the bronchodilators easily explains the superiority of the beta-agonists.' The physiologic changes that occur with asthma are the result of inflammatory events in the airways. These events include cellular infiltration and the release of inflammatory mediators such as histamine; prostaglandins D2 and F 2 . ; thromboxane; leukotrienes C 4, D 4, and E4; platelet-activating factor; bradykinin; adenosine; substance P; neurokinin A; and serotonin," These all produce bronchoconstriction. Some inflammatory mediators also stimulate mucus secretion, induce microvascular leakage, and act as chemotaxins to inflammatory cells," Acute, severe asthma is thought to represent a magnification of these events with significantly increased concentrations of these mediators. Many of these mediators produce bronchoconstriction through a direct effect on bronchial smooth muscle; others (e.g., prostaglandins, histamine, bradykinin) produce at least part of their
The Annals ofPharmacotherapy
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1992 January, Volume 26 •
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bronchoconstriction through stimulation of afferent cholinergic receptors," Beta.-agonists and theophylline are functional antagonists of bronchoconstricting mediators in that they reverse smooth-muscle contraction regardless of the stimulus.' Anticholinergics, on the other hand, will reverse only bronchospasm induced by cholinergic stimulation.s This is the one explanation for the inconsistent response to anticholinergics that has been reported in acute, severe asthma/ With functional antagonists, both in vitro studies using human tracheal smooth muscle" and in vivo animal models'" have shown that increasing concentrations of constricting mediators shifts the dose-response curves of the antagonist to the right. Higher dosages (often a full log-incremental shift) are therefore required to produce the same degree of relaxation. Ample evidence for this phenomenon exists in in vivo studies of bronchodilators in asthmatics, particularly with bronchoprovocation studies.P-" Therefore, the principal advantage of the beta-agonist (particularly when given as an aerosol) over theophylline in acute, severe asthma is not that they are more potent per se (in fact theophylline's dose-response curve is less shifted than that of the beta.-agonist"), but that log-incremental increases in the betaj-agonist dose can be safely administered to the patient. Doubling the usual dose of theophylline can result in serious toxicity; even small right shifts of the dose-response curve will significantly reduce the effectiveness of this agent."
Systemic VersusAerosolAdministration Historically, many clinicians felt that parenteral administration of bronchodilators was the preferred route initially in the management of severe lung obstruction. This was based on the concerns about the adequacy of delivery of aerosolized medication to the airways in the face of severe obstruction. However, clinical trials in the late 1970s and early 1980s clearly demonstrated that the aerosol route was as effective as systemic administration and often produced less toxicity (Table 1).13,33 Although the majority of studies in Table 1 were performed in emergency departments, only four were performed in patients who had been admitted to the hospitaI.1 4,16,18,20 In only one study did systemic betaj-agonist administration achieve greater overall efficacy.14 This was an open, nonblind study in which all patients received aerosolized albuterol followed by intravenous albuterol within 20 minutes. Double-blind, placebo-controlled trials in similar patients have failed to confirm these early fmdings. I6,20 Although it is difficult to compare studies due to differences in drug doses, dosage intervals, delivery systems, and patient populations, the evidence overwhelmingly implies that aerosol administration produces as effective bronchodilation as parenteral with fewer adverse effects in patients who can move enough air in and out of their lungs to measure pulmonary functions by spirometry or peak flows. Additionally, these studies further substantiate the efficacy of subcutaneous epinephrine in the emergency management of acute, severe asthma. The principal argument in favor of aerosolized betaj-agonists for first-line therapy for acute, severe asthma is safety. Fifty percent of the studies cited in Table 1 found that parenteral therapy produced a significantly greater number of adverse effects (primarily tachycardia) than aerosol 82
•
The Annals ofPharmacotherapy
•
therapy.ls.18,2S,26,30-32 These studies used standard recommended dosages as either single dosesls,I6,I8 or multiple doses to a maximum of three doses in one hour. 17,30,32 In a number of the studies, one could argue that optimal dosing of either the aerosol34-36 or parenteral drug" was not used. Regardless, parenteral administration consistently produced greater systemic effects at similar bronchodilation (see the discussion concerning intravenous beta-agonists). A study by Appel et al. underscores the problems of interpreting results when suboptimal dosages are used (Table 1). Although there was not a significant overall difference between aerosolized metaproterenol and subcutaneous epinephrine, Appel et al. found a greater proportion of patients to be initially unresponsive to metaproterenol compared with epinephrine (18 vs. 6, p
BETA-ADRENERGIC AGONISTS FOR ACurE, SEVERE ASTHMA H. William Kelly and Shirley Murphy
To critically review the use of beta-adrenergic agonists in acute, severe asthma with particular focus on aerosol administration.
OBJECTIVE:
English languagearticles published since 1971 on the use of beta-agonistsfor acute asthma. Studies were identified from bibliographiesof book chapters, review articles, and other researcharticles.
DATA SOURCES:
All studies (21 total) comparing systemic with inhaled beta-agonists were reviewed, regardless of their design or outcome. Selected studies highlightingspecific aspects of betaagonist use in acute asthma such as beta-agonistsversus other bronchodilators, aerosol delivery, and intravenousbeta-agonists were also reviewed. STUDY SELECTION:
DATA EXTRACTION: Performed subjectivelyby the authors with specific aspects of quality discussed within the body of the article.
The beta-agonistsprovide superior bronchodilation in acute severe asthma compared with either the methylxanthines and/or anlicholinergics. The majority of studies found aerosolized beta-agonists 10 be either as effective as or more effective than parenteralbeta-agonistsand to produce fewer adverse cardiovasculareffects. Studies showing preference for parenteral therapy have either been of poor design or used low doses of an aerosolizedbeta-agonist.Based on studies of aerosol delivery, there is no advantage of jet nebulizationover metered-dose inhalers; however, other aspects, includingease of administration,favor nebulizationas the delivery method of choice. The articles recommending intravenousbeta-agonistsconsist of a series of uncontrolledcases. DATA SYNTHESIS:
Aerosolizedselective betaj-agonistsare the bronchodilatortreatmentsof choice for acute, severe asthma.
CONCLUSIONS:
H. WILLIAM KELLY, Phann.D .. is a Professor of Pharmacy and an Associate Professor of Pediatrics. College of Pharmacy and School of Medicine, University of New Mexico; and a Clinical Pharmacist, Pediatric Intensive Care Unit. Childrens Hospital of New Mexico; and SHIRLEY MURPHY, M.D.• is a Professor of Pediatrics, a Clinical Professor of Pharmacy. and the Chair, Pulmonary/Critical Care Division, Department of Pediatrics. School of Medicine. University of New Mexico, Albuquerque, NM. Reprints: H. William Kelly, Pharm.D., College of Pharmacy, University of New Mexico. Albuquerque, NM 87 I3 I. GARY MILAVETZ, Phann.D.• is an Associate Professor, College of Pharmacy, University of Iowa, Iowa City. fA 52242.
This article is approved for continuing education credit
Attention to the details of dosing and delivery are required for optimal results.The fmal dose and dosing interval are determined by the patient's response. Intravenousbeta-agonistsare hazardous and cannot be recommended. Ann Pharmacother 1992;26:81-91.
of the treatment of acute, severe asthma exacerbations is the rapid reversal of airflow obstruction produced by inflammation and bronchospasm. Systemic corticosteroids effectively treat the inflammation, whereas inhaled betaj-agonists are the treatments of first choice for the bronchospasm.v" The purpose of this article is to briefly review the data establishing aerosolized betajagonists as the treatments of first choice for the bronchospasm of acute, severe asthma. In addition, the following issues are explored: (1) the optimal dosing schedule, (2) the dose equivalency among various methods of aerosol delivery, and (3) the role of intravenous beta-agonists.
THE PRINCIPAL GOAL
Beta-Agonists Versus Other Bronchodilators The advantage of beta-agonists for acute, severe asthma over both methylxanthines and anticholinergics is well establishedv' and has been extensively reviewed.v An understanding of the physiology of acute, severe asthma and the pharmacology of the bronchodilators easily explains the superiority of the beta-agonists.' The physiologic changes that occur with asthma are the result of inflammatory events in the airways. These events include cellular infiltration and the release of inflammatory mediators such as histamine; prostaglandins D2 and F 2 . ; thromboxane; leukotrienes C 4, D 4, and E4; platelet-activating factor; bradykinin; adenosine; substance P; neurokinin A; and serotonin," These all produce bronchoconstriction. Some inflammatory mediators also stimulate mucus secretion, induce microvascular leakage, and act as chemotaxins to inflammatory cells," Acute, severe asthma is thought to represent a magnification of these events with significantly increased concentrations of these mediators. Many of these mediators produce bronchoconstriction through a direct effect on bronchial smooth muscle; others (e.g., prostaglandins, histamine, bradykinin) produce at least part of their
The Annals ofPharmacotherapy
•
1992 January, Volume 26 •
81
bronchoconstriction through stimulation of afferent cholinergic receptors," Beta.-agonists and theophylline are functional antagonists of bronchoconstricting mediators in that they reverse smooth-muscle contraction regardless of the stimulus.' Anticholinergics, on the other hand, will reverse only bronchospasm induced by cholinergic stimulation.s This is the one explanation for the inconsistent response to anticholinergics that has been reported in acute, severe asthma/ With functional antagonists, both in vitro studies using human tracheal smooth muscle" and in vivo animal models'" have shown that increasing concentrations of constricting mediators shifts the dose-response curves of the antagonist to the right. Higher dosages (often a full log-incremental shift) are therefore required to produce the same degree of relaxation. Ample evidence for this phenomenon exists in in vivo studies of bronchodilators in asthmatics, particularly with bronchoprovocation studies.P-" Therefore, the principal advantage of the beta-agonist (particularly when given as an aerosol) over theophylline in acute, severe asthma is not that they are more potent per se (in fact theophylline's dose-response curve is less shifted than that of the beta.-agonist"), but that log-incremental increases in the betaj-agonist dose can be safely administered to the patient. Doubling the usual dose of theophylline can result in serious toxicity; even small right shifts of the dose-response curve will significantly reduce the effectiveness of this agent."
Systemic VersusAerosolAdministration Historically, many clinicians felt that parenteral administration of bronchodilators was the preferred route initially in the management of severe lung obstruction. This was based on the concerns about the adequacy of delivery of aerosolized medication to the airways in the face of severe obstruction. However, clinical trials in the late 1970s and early 1980s clearly demonstrated that the aerosol route was as effective as systemic administration and often produced less toxicity (Table 1).13,33 Although the majority of studies in Table 1 were performed in emergency departments, only four were performed in patients who had been admitted to the hospitaI.1 4,16,18,20 In only one study did systemic betaj-agonist administration achieve greater overall efficacy.14 This was an open, nonblind study in which all patients received aerosolized albuterol followed by intravenous albuterol within 20 minutes. Double-blind, placebo-controlled trials in similar patients have failed to confirm these early fmdings. I6,20 Although it is difficult to compare studies due to differences in drug doses, dosage intervals, delivery systems, and patient populations, the evidence overwhelmingly implies that aerosol administration produces as effective bronchodilation as parenteral with fewer adverse effects in patients who can move enough air in and out of their lungs to measure pulmonary functions by spirometry or peak flows. Additionally, these studies further substantiate the efficacy of subcutaneous epinephrine in the emergency management of acute, severe asthma. The principal argument in favor of aerosolized betaj-agonists for first-line therapy for acute, severe asthma is safety. Fifty percent of the studies cited in Table 1 found that parenteral therapy produced a significantly greater number of adverse effects (primarily tachycardia) than aerosol 82
•
The Annals ofPharmacotherapy
•
therapy.ls.18,2S,26,30-32 These studies used standard recommended dosages as either single dosesls,I6,I8 or multiple doses to a maximum of three doses in one hour. 17,30,32 In a number of the studies, one could argue that optimal dosing of either the aerosol34-36 or parenteral drug" was not used. Regardless, parenteral administration consistently produced greater systemic effects at similar bronchodilation (see the discussion concerning intravenous beta-agonists). A study by Appel et al. underscores the problems of interpreting results when suboptimal dosages are used (Table 1). Although there was not a significant overall difference between aerosolized metaproterenol and subcutaneous epinephrine, Appel et al. found a greater proportion of patients to be initially unresponsive to metaproterenol compared with epinephrine (18 vs. 6, p
