Focus on Inhaled β 2 -Agonists: Efficacy, Safety, and Patient Preference

Focus on Inhaled b2-Agonists: Efficacy, Safety, and Patient Preference

Roy A. Pleasants, II, Pharm.D.

Inhaled b2-agonists are a standard therapy for patients with obstructive lungdiseases. Clinical efficacy, safety, and patient preference are important reasonsthat these agents have become so widely used. In addition to significantbronchodilatory effects, b2-agonists have potentially clinically importanteffects on the lungs including promotion of mucociliary clearance and effectson inflammation. Albuterol, levalbuterol, and salmeterol are the mostfrequently used agents in the United States. In the acute care setting, short-acting b2-agonists are standard therapy for obstructive lung disease whereasthe use of long-acting b2-agonists in this setting is less clear. Potential clinicalissues regarding the use of b2-agonists in the acute care setting include type ofinhalational delivery method used, such as metered-dose inhaler versusnebulization, use of heliox instead of oxygen, safety issues, and selection ofagent. The role of the more recently available b2-agonists—levalbuterol (theR-isomer of albuterol) and formoterol—are evolving. Levalbuterol may haveclinical and economic advantages in the emergency department setting,however, additional research is necessary to validate this observation.Key Words: albuterol, levalbuterol, b2-agonist, nebulization, metered-doseinhaler, heliox, forced expiratory volume in 1 second, FEV1.(Pharmacotherapy 2004;24(5 Pt 2):44S–54S)

Patients with obstructive lung diseases—asthma and chronic obstructive pulmonary disease(COPD)—account for more than 10% of theUnited States population; thus, these diseasessignificantly affect society. The increasingrecognition and prevalence of obstructive diseaseswill certainly cause even greater impact. Overall,these patients are frequent users of outpatient andinpatient health care systems. Obvious opportunitiesexist in both settings for pharmacists to influencepatients positively. In fact, most research studiesconfirm pharmacists’ positive interventions inobstructive lung disease.1–3

b2-Agonists are valuable in the treatment ofpatients with obstructive lung disease(s), andsubsequently, most of these patients use one or

more, typically by the inhaled route. Pharmacistscan assist in b2-agonist selection, dosing, properadministration, monitoring, and patienteducation.

In the U.S. market, b2-agonist therapy isdominated by albuterol, salmeterol, andlevalbuterol. Albuterol and salmeterol have beenavailable for a number of years, and their clinicalrole has largely been established, although newdata have led to some changes in their use.Levalbuterol (the R-isomer of albuterol) andformoterol (a long-acting inhaled b2-agonist) arerelatively new agents on the market and theirclinical role is still evolving. Table 1 lists theavailable agents used for treating asthma andCOPD.4 When administered at appropriatedosages, all agents are roughly equivalent in peakbronchodilator activity, but their onset andduration of effects are somewhat different.

Mechanism of Action

Figure 1 is a detailed representation of how b2-receptors are activated by b2-agonists. b2-

From the Division of Pulmonary, Allergy, and CriticalCare Medicine, Department of Medicine, Duke UniversityMedical Center, Durham, North Carolina, and the School ofPharmacy, Campbell University, Buies Creek, NorthCarolina.

Address reprint requests to Roy A. Pleasants, II,Pharm.D., BCPS, Department of Medicine, Duke UniversityMedical Center, Box 31166, Durham, NC 27710.

INHALED b2-AGONISTS Pleasants

Receptors are present in the smooth musclefibers that surround the bronchioles and are alsopresent in a variety of other parts of theasthmatic bronchi including the epithelium,eosinophils, mucus-producing glands, andmacrophages. b2-Agonists interact with b2-receptors in various cells; effects on airway b2-receptors cause bronchodilation. b2-Adrenergicreceptors are linked to a stimulatory bindingprotein. When the b2-agonist occupies thereceptor, the conformation of the proteinchanges, leading to activation of adenylatecyclase. Adenylate cyclase catalyzes the

conversion of adenosine 5′-triphosphate to cyclicadenosine 3 ′ ,5 ′ -monophosphate, causingbronchodilation as smooth airway muscle relaxes(functional antagonism of the stimulatoryprocess). b2-Agonists provide symptomatic reliefafter a wide variety of stimuli: exercise,pharmacologic agonists (e.g., methacholine),physiologic stimuli, and chemical irritants. Inaddition to their bronchodilatory effects, theseagents appear to inhibit mast cell degranulation,inhibit pulmonary vascular leakage, and increasemucociliary clearance. The ability to promotemucus clearance is partially related to their

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Table 1. b2-Agonist Agents Available for Treatment of Asthma and Chronic Obstructive PulmonaryDisease4

Onset of Action Duration of ActionAgent Availability (min) (hrs)Albuterol, immediate release Oral 30 6–8Albuterol Inhaler, solution 5 4–6Bitolterol Inhaler 2–4 4–6Formoterola Inhaler 5 > 12Levalbuterol Solution for inhalation 5 6–8Metaproterenol Oral ~30 4Metaproterenol Inhaler, solution 5 3–4Pirbuterol Inhaler 5 3–4Salmeterola Inhaler 20 > 12aLong-acting b2-agonists.

Figure 1. b2-Receptor activation leads to multiple cellular response. AC = adenylate cyclase; ATP = adenosine triphosphate;cAMP = cyclic adenosine monophosphate; 5′AMP = 5′monophosphate; Gs = intermediary G protein; KCa = calcium-activatedpotassium channel; PDE = phosphodiesterase; PI = phosphatidylinositol.

b2-Agonists

ATPcAMP

PDE isoenzymesInactive protein kinase A

Regulatory subunitActive protein kinase A

5'AMP

Gs AC

PDE inhibitors

Inhibition ofPI hydrolysis

↑ calciumsequestrationand removal

Phosphorylationof myosin

light chain kinase

Hyperpolarization Activation ofKCa channels

Smooth musclerelaxation,

inhibition ofmediator releasefrom mast cells

Supplement to PHARMACOTHERAPY Volume 24, Number 5, 2004

effects on the respiratory cilia.5

Some evidence suggests that b2-agonists havemild antiinflammatory effects.6, 7 Although b2-agonists reduce inflammation in vitro, theclinical relevance of this is ambiguous. Clearly,these agents do not have adequate antiinflam-matory activity in asthma by themselves, asevidenced by a 2001 study in which salmeterolmonotherapy resulted in poor control of chronicasthma compared with treatment with an inhaledsteroid.8

The b2-adrenergic receptor exists in manypolymorphisms; approximately nine have beenidentified. The two principal polymorphismsoccur at amino acid 16. Approximately 50% ofpatients with asthma who have moderate-to-severe disease have a Gly 16 polymorphism,making this polymorphism clinically relevant. Itpredisposes patients to receptor downregulationand development of tolerance to b2-agonistactions. Also, these patients are more likely tohave nocturnal asthma. A Gly 16 polymorphismdoes not cause asthma and is not considered arisk factor, but it influences response totreatment and airway responsiveness.9

b2-Agonists arose from modifications of thebasic catecholamine molecule, epinephrine.Modifications slowed its metabolism andextended the half-life. These modifications alsoresulted in greater b2 selectivity. However, eventhe most b2-selective agent still causestachycardia. Although b2-receptors predominatein bronchial smooth muscle and b1-receptorspredominate in the cardiac muscle, b2-receptorsin the human heart compose 14–25% of its totalb-receptors. None of the available b2-agonistsare completely b2 selective, and selectivitydecreases with increasing doses.

Current b2-agonists are conjugated, oxidated,or sulfated in the liver and other tissues, andexcreted in their metabolized form in the urineand feces. b2-Agonists have metabolic pathwaysdifferent from those of endogenous catecholaminebecause of alterations in the basic catecholaminemolecule.

Oral absorption of inhaled drug, as well asdrug delivered into the lung and then absorbedinto systemic circulation, causes systemic effects.Albuterol is orally active, and patients who inhalealbuterol typically swallow some drug.Although less efficient drug delivery occurs withnebulizers than with metered-dose inhalers(MDIs), the amount of drug reaching thesystemic circulation is greater when receivingnebulizer treatments than when receiving

treatment through an MDI, as a larger dose isused (e.g., albuterol 2.5 mg by nebulization vs180–360 µg [90 µg/inhalation] through anMDI).10

Tolerance

Patients can develop varying degrees oftolerance to the b2-agonists with regular use.11, 12

Some controversy surrounds the exactmechanism. Researchers have confirmed thatlong-term therapy with b2-agonists causesinternalization and downregulation of b2-receptors and results in a time- and dose-dependent loss of agonist activity. Certain typesof cells are more affected than others. Typically,tolerance in the lungs does not change thebronchodilator’s peak effect but is more likely toaffect its duration.13 In other words, the forcedexpiration volume in 1 second (FEV1) shortlyafter administration of the b2-agonist will beunchanged (probably because of the largenumbers of b-receptors in airways), but the b2-agonist’s effects may not last as long. Astolerance develops, for example, some ofsalmeterol’s effects may decrease from 8–12 hoursto approximately 6 hours.14

A variety of different cells in the body have b2-receptors, and their density is lower than that inairway smooth muscle. Tolerance occurs muchmore rapidly on mast cells’ b2-receptors than itdoes in the lungs, probably because the numberof b2-receptors is lower. In addition, mostpatients quickly develop some degree oftolerance to b2-agonist–induced tremors andtachycardia with regular use; however, theseadverse effects often never completely disappearand may acutely worsen when dosages areincreased such as in an acute flare and/or withthe addition of systemic steroids. In the author’sexperience, patients who do not experience anytremor with inhaled b2-agonists usually are notinspiring the drug into their lungs. Also, thebronchoprotective effects of b2-agonists maydissipate; patients exposed to an allergen orprocess that induces bronchial hyperactivity may,after having once been relieved by the b2-agonists, experience bronchospasm again.15

Long-Acting Inhaled b2-Agonists in the AcuteCare Setting

Long-acting b2-agonists are not indicated assole therapy for treatment of acute exacerbationsof asthma or COPD. A significant proportion ofpatients with COPD or asthma receive long-term

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therapy with salmeterol or formoterol, often withshort-acting bronchodilators. Consensus on howto treat these patients who come to a hospitalwith an acute exacerbation of asthma or COPD islacking. The National Asthma Education andPrevention Program guidelines16 and the GlobalInitiative for Obstructive Lung Diseaseguidelines17 state that long-acting b2-agonists arenot indicated for the treatment of acuteexacerbations. This implies that these agentsshould not be used as the principal broncho-dilator in acute exacerbations. A questionremains, should clinicians continue long-actingb2-agonists (e.g., salmeterol or formoterol) whilereceiving aggressive short-acting b2-agonists, or ifpatients are not receiving a long-acting b2-agonist, is there any benefit to adding one?

Some clinicians continue long-acting b2-agonists and then add or increase the dosage of ashort-acting b2-agonist as well. Some pedia-tricians will discontinue salmeterol and manybelieve that long-acting b2-agonists are lesseffective in children than in adults.18, 19 Thoughmany patients take these long-acting broncho-dilators or the new salmeterol-fluticasonecombination inhaler, little guidance is availablein the literature to address the use of these agentsin acute flares of asthma or COPD. Adding anagent leads to concerns about cardiac over-stimulation, excessive tremors, excitation, orhypokalemia.

A prospective, double-blind, randomizedplacebo-controlled trial was conducted to assesssalmeterol’s safety and efficacy as an adjunct toconventional therapy for inpatient managementof acute asthma.20 Forty-three patients who wereadmitted through the emergency departmentwith an acute exacerbation of asthma wererandomly assigned to either salmeterol 42 µg ortwo puffs of placebo every 12 hours in additionto standard therapy of albuterol, corticosteroids,and anticholinergic agents. The addition ofsalmeterol resulted in no clinically significantadverse effects. Standard outcome measuresremained unchanged after salmeterol, butsalmeterol-treated patients had greater improve-ments in FEV1 than did the placebo–standard-care group at 12, 24, 36, and 48 hours (a findingthat lacked statistical significance). By pairedStudent t tests, the salmeterol group demonstratedsignificant improvements in FEV1 after 48 hoursof treatment, a finding absent in the placebo–standard-care group. The investigatorsconcluded that adding salmeterol to conventionaltherapy is safe and may benefit hospitalized

patients with asthma.20 Recently, however,warnings have been issued about the potentialassociation between salmeterol and rare, butpotentially serious, respiratory adverse events inthe ambulatory setting.21

That warning was based on the finding of alarge, placebo-controlled trial, started in 1996 toaddress U.S. Food and Drug Administration(FDA) concerns about the safety of long-actingb2-agonists, particularly salmeterol, since it wasthe only available agent in this class at the time.21

(Formoterol is now available also.) Earlystopping rules were invoked amid concerns thatsalmeterol may be associated with life-threateningasthmatic episodes and asthma-related deaths.Trial details are yet unpublished, but themanufacturer issued a Dear HealthcareProfessional letter (posted on the FDA’s Web siteat www.fda.gov/medwatch/SAFETY/2003/serevent.htmwww.fda.gov/medwatch/SAFETY/2003/serevent.htm) that provided some information.

In that study, the Salmeterol Multi-CenterAsthma Research Trial (SMART), patients wererandomly assigned to their usual asthma therapyand either salmeterol 42 µg twice/day or placebofor 28 weeks.21 The combined number ofrespiratory-related deaths and life-threateningevents (requiring intubation and mechanicalventilation) was the primary end point, withsecondary end points including asthma-relatedevents (including deaths). A nonsignificanttrend toward more asthma-related life-threatening events (including deaths) in thesalmeterol-treated group was revealed duringroutine interim data analysis of nearly 26,000patients. Among the 17% of participants whowere African-American, significantly moreasthma-related life-threatening events occurred inthe salmeterol group than in the placebo–standard-care group. This difference was absentin the Caucasian patients. Researchers did notanalyze other ethnic subgroups, which weresmall. African-American patients had highersymptom frequencies and poorer peak expiratoryflow rates at baseline. They also experiencedmore intubations, emergency department visits,and hospital admissions before study entry.

Among the 50% of Caucasian patients and 38%of African-American patients taking inhaledcorticosteroids, outcomes in the salmeterol andplacebo–standard-care groups did not differsignificantly. Significantly more patients nottaking inhaled corticosteroids died from asthma-related causes in the salmeterol group than in theplacebo group.

The message from this study is clear. Salmeterol

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cannot replace inhaled asthma antiinflammatorytherapy and should not be started in patients withasthma whose condition is deteriorating rapidly.For patients already taking the drug, acutesymptoms should not be treated with salmeterolinstead of short-acting b2-agonists. In patientswho increasingly need additional short-acting b2-agonists, their condition may be deteriorating.Reassessment should be prompt. Abruptdiscontinuation of salmeterol should be avoided,as it can exacerbate serious asthma or COPD.Although this study was principally done in theoutpatient setting, it does point to concernsabout the use of long-acting b2-agonists in theacute care setting.

Metered-Dose Inhaler or Nebulization

Every specialty has its debates, and inpulmonary medicine, for decades, a commondebate concerns nebulization and MDIs: whichis best and for which patients? Several studies ofb2-agonists suggest that the MDI plus spacerworks just as well as a nebulizer. In a studyconducted during a 2.5-year period in the busyemergency department of the University ofCincinnati, researchers allowed and observedusual nebulization for 1 year.22 They treatedmore than 900 patients. During the next 18months, they converted to a standard of albuterolthrough an MDI plus spacer. The researcherscompared pulmonary function tests, clinicaloutcome, laboratory data, and costs betweenthese two time periods. Baseline characteristicsbetween the patient groups in phase one andphase two were no different.

Researchers found that in adults, hospitaladmission rates between patients in the MDI plusspacer group and those in the nebulizer groupwere similar (13–15%), but patients in the MDIplus spacer group experienced greater peak flowrate improvement, spent significantly less time inthe emergency department, and required a lowertotal albuterol dose (1125 vs 6700 µg, respec-tively). At 14 and 21 days, relapse rates weresignificantly lower among patients treated withthe MDI plus spacer. Thus, albuterol adminis-tered by an MDI plus spacer is an efficacious andcost-effective alternative to nebulization in adultswith acute asthma.

Several other studies have come to the sameconclusion in adults and children,23–25 and in fact,a meta-analysis in 1997 confirmed that at least inthe emergency department setting the MDI plusspacer worked equally as well as nebulization,

and typically patients are discharged from theemergency department faster after MDI plusspacer use.26 This can translate into a savings ofthousands of dollars/year if an MDI plus spacer isincorporated into an institution’s protocol.

Continuous b2-Agonist Nebulization

Continuous nebulization of b2-agonists,especially albuterol, has been used in differentacute care settings since the 1980s. Manyclinicians consider it a more aggressive way oftreating acute bronchospasm. Some studies havesuggested similar or greater efficacy of albuterolby continuous nebulization than by traditionalintermittent nebulization.27–29 When thisapproach initially was developed, the dose wasprepared similar to an intravenous admixture,and it was infused into a nebulizer by anintravenous infusion pump. Today, large-volumenebulizers (e.g., miniHEART; Vortran MedicalTechnology, Sacramento, CA) are used forcontinuous nebulization of b2-agonists.

A recent meta-analysis examined six studiesthat included 393 adults with acute asthma andconcluded that the two therapies (continuousand intermittent) were similarly effective.30 Itnoted a lower adverse-effect rate and lessfrequent tachycardia and hypokalemia with thecontinuous than with the intermittent therapy.Overall, this meta-analysis found continuous andintermittent albuterol nebulization for adultswith acute asthma equivalent in efficacy.Pulmonary function measures obtained after 1hour of treatment were similar. No significantdifferences were demonstrated between the twodelivery methods.

Even with these findings, some institutionsrequire patients receiving continuous nebulizationto be monitored by telemetry, and its use often islimited to the most seriously ill patients in theemergency department and intensive care units.

Heliox and Lung Deposition of Inhaled b-Agonists

Clinicians also have concerns about the effectsof heliox on drug delivery in the lungs of peoplewith asthma. Heliox is a mixture of oxygen andhelium (usually 80% helium). The airwayobstruction found in asthma increases turbulencein the airways. Owing to its lower density, helioxpenetrates to parts of the lungs that oxygencannot necessarily reach because of obstruction.Also, helium is inert and does not interact withany biologic process. Heliox sometimes is used

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for acute asthma flares.In a study conducted to evaluate heliox-

powered nebulizer performance, conventionaland continuous nebulizer designs wereevaluated.31 The conventional nebulizer withalbuterol 5 mg was assessed by using two rates offlow with heliox, 8 and 11 L/minute (the formercloser to flow from a typical nebulizer), versus 8L/minute for air. The continuous nebulizer wasset to deliver albuterol 5 and 10 mg at 2 L/minuteand 3 L/minute using heliox. Particle size andinhaled mass of albuterol decreased significantlywhen either of the nebulizers was powered withheliox. Thus, using heliox to power a nebulizeraffects both the drug’s inhaled and aerosolparticle size. Administering albuterol by helioxrather than air requires higher flow rates (11 vs 8L/min for conventional nebulizer and 3 vs 2L/min for continuous nebulization) to deliver thesame amount of albuterol. It was also noted thathigher doses (concentrations) of albuterol byheliox affected particle size for continuousnebulization, but not conventional nebulization.The clinical implications of this study areuncertain, but a conservative approach would beto use higher flow rates of heliox when nebulizing

albuterol in a severely ill patient having an acuteasthmatic attack. However, other studies suggestgreater lung deposition of albuterol whenadministered with heliox.32, 33

Albuterol versus Levalbuterol

Like other b2-agonists, albuterol is a 50:50racemic mixture of S- and R-isomers. The R-isomer has a greater affinity for the b2-receptorthan does the S-isomer (Figure 2). Levalbuterol,the R-isomer, is responsible for albuterol’s abilityto cause bronchodilation. S-albuterol has nobronchodilation properties at acceptable doses.It is not without action, however. At high doses,the S-isomer can be lethal to laboratory animalsin a similar dose to the racemic mixture or R-isomer (median lethal dose by the intravenousroute 25–75 mg/kg).34 Acute intravenous andoral toxicology of S-albuterol in rats indicatesthat S-albuterol can be lethal.34

Of the two isomers, the R-isomer is cleared bythe body more rapidly. The S-isomer has a half-life of 5–7 hours or longer, whereas the R-isomer’s half-life is approximately 3.3–4 hours.35

R-albuterol is sulfated about 10-fold faster than

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Figure 2. Artist’s rendition of conformational fit at the b2-adrenergic receptor.


S-albuterol. Accumulation of the S-isomer withrepeated dosing has been shown.36

Concern that limited dose-response informationis available for nebulized b2-agonists in youngchildren prompted several researchers to constructa placebo-controlled study to determine the safetyand efficacy of increasing dosages of nebulizedlevalbuterol and racemic albuterol in childrenwith asthma.37 Patients aged 3–11 years weretreated with levalbuterol, racemic albuterol, orplacebo. At each of four treatment visits, isomerlevels were drawn, serial pulmonary functiontests were completed, and safety was evaluated.Thirty-three children completed the study, with87 doses administered. Levalbuterol caused asignificantly greater increase in FEV1 than didplacebo, and FEV1 values were comparable to orbetter than those observed with racemic albuterol.The adverse-effect profile for levalbuterol wasmore tolerable than that produced by racemicalbuterol.

In a 1998 study, researchers examined theefficacy of two doses of levalbuterol, 0.63 and1.25 mg, and equivalent amounts of levalbuteroladministered as racemic albuterol with placebo inpatients with moderate-to-severe asthma.38 Thestudy design was a randomized, double-blind,parallel-group trial in 362 patients older than 12years. The researchers administered study drugby nebulization 3 times/day for 28 days andmonitored FEV1. After the first dose of combinedlevalbuterol, the change in peak FEV1 wassignificantly greater than that in the combinedracemic albuterol group, with similar (butnonsignificant) results after 4 weeks. The datasuggest that a greater percentage of patients willrespond to levalbuterol than albuterol.

In patients who had the poorest lung function,defined as a FEV1 less than 60% of predicted,levalbuterol 1.25 mg was more efficacious basedon change in FEV1 than was racemic albuterol.Racemic albuterol 1.25 mg demonstrated theweakest bronchodilator effect, particularly afterlong-term dosing.38 Although well tolerated,active treatments had varying magnitudes ofadverse effects, with levalbuterol 0.63 mgproducing fewer than levalbuterol 1.25 mg orracemic albuterol 2.5 mg. At week 4, levalbuterol-or placebo-treated patients had greater predoseFEV1 values than those of albuterol-treatedpatients, especially if they were not receivinginhaled corticosteroids.

Mucociliary Clearance

b2-Agonists have been used for decades topromote mucociliary clearance, or in otherwords, help mobilize respiratory tract secretions.A variety of studies have concluded that b2-agonists do promote mucociliary clearance.39, 40

Essentially, these drugs cause rapid movement ofthe respiratory cilia, so they beat more rapidlylike a windblown wheat field in the summertime.Movement of secretions upward allowsexpectoration.

Figure 3 depicts data collected in a bovinemodel, using different isomers and monitoringmucociliary transport.41 The S-isomer hadnegative effects on this model’s mucociliarytransport.

Adverse Effects

b2-Agonists are associated with a number ofadverse events. In terms of cardiac events,tachycardia and worsening of angina and/orarrhythmias can be a concern, especially in thepatient who has or has had a recent myocardialinfarction. Skeletal-muscle effects often causetremor and may result in leg cramps.

Debate continues regarding the risks of b2-agonists causing a myocardial infarction orwhether to continue the b2-agonist in the settingof an acute myocardial infarction when thepatient has obstructive lung disease. Aretrospective, case-control study of patients withan acute myocardial infarction showed thatpatients who took b2-agonists were approximately1.7-fold more likely to have a myocardialinfarction.42 The risk of using b2-agonists in apatient with obstructive lung disease who isexperiencing a myocardial infarction must bebalanced with the benefits that the agents have

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Figure 3. Effect of albuterol isomers on mucociliarytransport in the bovine trachea.41

-10 -9 -8 -7 -6 -5 -4 -3-20

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R-albuterol unidirectional flow (n=60)R,S-albuterol swirling (n=68)S-albuterol unidirectional flow (n=59)

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on improving airflow. At higher doses, hypo-kalemia may be an undesirable effect. b2-Agonistsalso have been associated with mild hyperglycemia,proinflammatory effects, and hyperactivity. b2-Agonists may be associated with a risk of deathin certain situations (e.g., due to overreliance onb2-agonists during flares).43

In the study that compared levalbuterol withracemic albuterol discussed previously,38 theauthors looked closely at adverse events. Theysuggested that levalbuterol affects heart rate andpotassium less than albuterol does, a finding thatis still controversial. Using equivalent doses oflevalbuterol and albuterol (1.25 and 2.5 mg,respectively), the difference in heart rate ortremor in the average patient is negligible.However, some data suggest that levalbuterol0.63 mg is as efficacious as albuterol 2.5 mg;when using the lower dose of levalbuterol, somedifference in tachycardia or heart rate might beobserved in some patients.

Several studies have compared levalbuterol andalbuterol in patients with COPD. The mostrecent was a randomized, double-blind, placebo-controlled study (30 patients, mean age 69 yrs)evaluating the effectiveness of a single dose ofnebulized levalbuterol in patients with stableCOPD.44 It compared single doses of levalbuterolwith racemic albuterol, combined racemicalbuterol and ipratropium, and placebo. Patientsavoided their usual bronchodilator agents forappropriate washout periods before random-ization. The researchers measured FEV1, pulserate, oxygen saturation, and hand tremor (using ascale they developed). All nebulized bronchodilatortreatments led to similar persistent, significantimprovements in FEV1 compared with placebountil hour 3.

At that time, only the combined albuterol-ipratropium group had a mean change in FEV1significantly greater than that in the placebogroup. Mildly increased pulse rate was observedin all treatment groups. Oxygen saturation andhand tremor were not significantly differentbetween the placebo and treatment arms. Theauthors concluded that levalbuterol appears tooffer no advantage for single-dose, as-needed usein COPD over conventional nebulizedbronchodilators. However, tolerability is unlikelyto be adequately assessed with single doses ofalbuterol or levalbuterol.

Proinflammatory Effects

Clinicians have wondered if albuterol’s S-

isomer has proinflammatory effects. Aninteresting study postulated that since R-albuterol relaxes human isolated bronchus, thecapacity of S-albuterol to enhance contractileresponses to histamine or leukotriene C4 cannotbe attributed to activation of b2-receptors.45

Researchers bathed surgically removed humanbronchi with histamine and then exposed themto S-albuterol or R-albuterol. R-albuterol almostcompletely blocked the contractile response thathistamine induced on these bronchi, whereas S-albuterol heightened the effect of histamine.This suggests that the S-albuterol may havedeleterious effects relative to contractile stimuli.S-albuterol’s effects represent distinct pharmaco-logic actions of the d-isomer. Its capacity toaugment airway smooth muscle contraction maycontribute to hyperreactivity toward spasmogenswhen racemic albuterol is used for symptomrelief in asthma and COPD.

One group of authors looked at interleukin 4and histamine release by mast cells after earlierstudies suggested that S-albuterol may exertproinflammatory effects.46 Two types of murinemast cells (unstimulated or stimulated byimmunoglobulin E–receptor cross-linking) werewashed with either R- or S-albuterol. Cellstreated with S-albuterol secreted almost 20%more histamine than untreated cells. Cellstreated with R-albuterol and untreated cellssecreted approximately the same amount ofhistamine. Treatment with S-albuterol alsosignificantly increased interleukin 4 protein andthe message for its production. R-albuterol didnot affect mast cell mediator release. These resultssuggest that S-albuterol has proinflammatoryeffects.

Another study examined the presence ofeosinophils when guinea pigs were exposed to anallergen (ovalbumin as the sensitizing agent).47

After exposure to either sham (placebo), 0.1%albuterol, 1% albuterol, or 0.01% levalbuterol,researchers found that S-albuterol actuallypromoted eosinophilia in the bronchoalveolarlavage of these guinea pigs. Eosinophils are keyinflammatory cells involved in asthma and insome cases of COPD.46

One Institution’s Experience

At Duke University Medical Center, currentpolicy is based on existing literature and an in-house study that compared levalbuterol given 3times/day and albuterol given 4 times/day.48 Thatstudy found the dosing schedules equivalent.

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Duke University Medical Center’s guidelines forlevalbuterol are as follows:

• Patients admitted to either the emergencydepartment or the hospital who are receivinglevalbuterol on an outpatient basis continueto receive levalbuterol; if they are experiencingan exacerbation, the administration frequencymay be increased based on response.

• Patients admitted for respiratory distress(e.g., COPD flare) who show intolerance toalbuterol while in the hospital (excessivetachycardia, tremors, or hyperexcitability)are usually given a trial of levalbuterol.

• Should a patient have severe cardiac disease,clinicians should consider levalbuterolinstead of albuterol; its use is not mandated,but suggested.

• Other patients continue or begin to receivealbuterol (note: most patients receive albuterol).

Based on several studies in an emergencydepartment in which treatment with levalbuterolresulted in a lower hospitalization rate forpatients with asthma flares compared withalbuterol, it is reasonable to postulate that one oflevalbuterol’s niches may be in the emergencydepartment setting. Studies that demonstratelevalbuterol’s superiority in terms of patientsrequiring hospitalization are described in Table2.49–53

If this observation ultimately proves correct,the emergency department might be a particu-larly cost-effective setting in which to uselevalbuterol. Additional randomized, double-blind studies would be useful to validate thesestudies. Emergency department costs can beconsiderable, and treating a patient in thehospital for an asthma flare can cost severalthousand dollars, with prolonged stays costing$7000. Subsequently, a small change in the rateof hospitalization from the emergency depart-ment for patients with asthma can save consider-able money.

Patient Preferences

Any agent’s ultimate role in the treatment of adisease is substantially influenced by patients’perceptions of their disease and the role of thatagent. Two large, relatively recent surveys ofpatients with asthma provide significant insightinto the b2-agonists’ role.54, 55 A survey of membersof the Allergy and Asthma Network–Mothers ofAsthmatics documented that 99% of pediatricrespondents were taking a bronchodilator, oftenby nebulizer.53 Side effects were reported in 63%of patients receiving nebulized drug, 57% ofthose using MDI, and 79% of those taking oraldrugs. Only 13–14% of these patients felt thatthe side effects were due to their antiinflammatory

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Table 2. Comparative Studies of Levalbuterol versus Albuterol by Nebulization in the Emergency Department Setting

Study Design Patient Population Hospitalization Rate CommentsProspective, randomized, Asthmatic children aged 1–18 yrs Levalbuterol 37% Projected annual costdouble-blind comparison of (mean age 7.4 yrs) with acute albuterol 45% savings $270,000levalbuterol vs albuterol asthma flares (p=0.047)by nebulization49 Levalbuterol: 282 patients

Albuterol: 274 patients

Prospective, open-label Asthmatic patients aged > 12 yrs Levalbuterol 12%,comparison of levalbuterol with acute asthma flares albuterol 20%vs albuterol50 Levalbuterol: 24 patients (p value NR)


Prospective, open-label Asthmatic patients aged > 6 yrs NR Greater improvement incomparison of levalbuterol with acute asthma flares FEV1 with levalbuterolvs albuterol51 Levalbuterol: 57 patients 0.63 and 1.25 mg than

Albuterol: 47 patients with albuterol 2.5 mg

Retrospective study of Asthmatic patients aged > 1 yr Levalbuterol 4.7%,levalbuterol vs albuterol with acute asthma flares albuterol 15.1%in 736 consecutive cases52 Levalbuterol: 128 patients (p=0.00016)


Prospective, open label study Asthmatic patients aged > 17 yrs NR Greater improvement inwith dose-escalated with acute asthma FEV1 for levalbuterollevalbuterol vs set dose 1.25 mg vs albuterolof albuterol53 2.5 mg (p<0.05)

NR = not reported; FEV1 = forced expiratory volume in 1 second.


drug. The most common bronchodilator sideeffects were jitteriness and restlessness. Most ofthe patients with asthma indicated that theirasthma was under control. This may partially berelated to disease denial as well as adjustments oflifestyle to a chronic disease.

In the Asthma in America survey of approxi-mately 2500 adults with asthma or parents ofchildren with asthma, 25% of patients withasthma took quick relief (likely short-acting b2-agonists) at least 3 times/day.54 Eighty percent ofpatients took a short-acting b2-agonist. Patientspreferred their short-acting b2-agonists to inhaledcorticosteroids. The number of b2-agonistcanisters used each year ranged from 4.9–11.4depending on asthma severity. Patients alsoindicated that they needed more educationconcerning their disease and its treatment, thusidentifying an opportunity for pharmacists.Patients’ perceptions of their disease and theeffectiveness of short-acting b2-agonists likelywere key reasons for these findings.

Conclusion

The clinical efficacy and favorable safety profileof inhaled short-acting b2-agonists have madethese agents a standard therapy for many patientswith obstructive lung diseases. A relatively newagent, levalbuterol, is the R-isomer of albuteroland may be superior to the racemic mixturealbuterol in the management of acute asthmaflare in the emergency department setting, whererelatively high doses of these agents are oftenadministered. Formoterol is a a new long-actinginhaled b2-agonist. With all the different agentsavailable, opportunities exist for pharmacists tointervene and make a difference for patients withobstructive lung disease. Understanding theoptions available and those preferred by patientsis a start.

References1. Knoell DL, Pierson JF, Marsh CB, Allen JN, Pathak DS.

Measurement of outcomes in adults receiving pharmaceuticalcare in a comprehensive asthma outpatient clinic.Pharmacotherapy 1998;18:1365–74.

2. Munzenberger PJ, Vinuya RZ. Impact of an asthma program onthe quality of life of children in an urban setting.Pharmacotherapy 2002;22:1055–62.

3. Stiegler KA, Yunker M, Crouch MA. Effect of pharmacistcounseling in patients hospitalized with acute exacerbations ofasthma. Am J Health-System Pharm 2003;60:433–6.

4. Anonymous. Physicians’ desk reference, 58th ed. Montvale, NJ:Thomson PDR, 2004.

5. Devalia JL, Sapsford RJ, Rusznak C, Thoumbis RJ, Davies RJ.The effects of salmeterol and salbutamol on ciliary beatfrequency of cultured human bronchial epithelial cells in vitro.Pulm Pharmacol 1992;5:257–63.

6. Reid DW, Ward C, Wang N, et al. Possible anti-inflammatoryeffect of salmeterol against interleukin-8 and neutrophilactivation in asthma in vivo. Eur Respir J. 2003;21:994–9.

7. Jeffery PK, Venge P, Gizycki MJ, Egerod I, Dahl R, FaurschouP. Effects of salmeterol on mucosal inflammation in asthma: aplacebo-controlled study. Eur Respir J 2002;20:1378–85.

8. Lazarus SC, Boushey HA, Fahy JV, et al. Long-acting b2-agonist monotherapy vs continued therapy with inhaledcorticosteroids. JAMA 2001;285:2583–93.

9. Taylor DR, Hancox RJ, McRae W, et al. The influence ofpolymorphism at position 16 of the b2-adrenoceptor on thedevelopment of tolerance to b-agonist. J Asthma 2000;37:691–700.

10. Fink JB. Metered-dose inhalers, dry powder inhalers, andtransitions. Respir Care 2000;45:623–35.

11. Wraight JM, Hancox RJ, Herbison GP, Cowan JO, FlanneryEM, Taylor DR. Bronchodilator tolerance: the impact ofincreasing bronchoconstriction. Eur Respir J 2003;21:810–15.

12. Georgopoulos D, Wong D, Anthionsen NR. Tolerance to b2-agonists in patients with chronic obstructive pulmonarydisease. Chest 1990;97:280–4.

13. Repsher LH, Anderson JA, Bush RK . Assessment oftachyphylaxis following prolonged therapy of asthma withinhaled albuterol aerosol. Chest 1984;85:34–8.

14. Edelman JM, Turpin JA, Bronsky EA, et al. Oral montelukastcompared with salmeterol to prevent exercise-inducedbronchoconstriction: a randomized, double-blind trial. AnnIntern Med 2000;132:97–104.

15. Cockcroft DW. Functional antagonism: tolerance produced byinhaled beta2-agonists. Thorax 1996;51:1051–6.

16. Cockcroft DW, Davis BE, Swystun VA, Marciniuk DD.Tolerance to the bronchoprotective effect of b2-agonists: com-parison of the enantiomers of salbutamol with racemic salbu-tamol and placebo. J Allergy Clin Immunol 1999;103:1049–53.

17. Pauwels RA, Buist AS, Ma P, Jenkins CR, Hurd SS, for theGOLD Scientific Committee. Global strategy for the diagnosis,management, and prevention of chronic obstructive pulmonarydisease: National Heart, Lung, and Blood Institute and WorldHealth Organization global initiative for chronic obstructivelung disease (GOLD): executive summary. Respir Care2001;46:798–825.

18. Kercsmar CM. Current trends in management of pediatricasthma. Respir Care 2003;48:194–208.

19. Walters EH, Walters JA, Gibson PW. Regular treatment withlong-acting b-agonists versus daily regular treatment withshort-acting b-agonists in adults and children with stableasthma. Cochrane Database Syst Rev 2002;4:CD003901.

20. Peters JI, Shelledy DC, Jones AP Jr, Lawson RW, Davis CP,LeGrand TS. A randomized, placebo-controlled study toevaluate the role of salmeterol in the in-hospital management ofasthma. Chest 2000;118:313–20.

21. Pharma-Help.com. Salmeterol multi-center asthma researchtrial (SMART) information. Available from http://pharma–help.com/smart. Accessed January 15, 2004.

22. Newman KB, Milne S, Hamilton C, Hall K. A comparison ofalbuterol administered by metered-dose inhaler and spacer withalbuterol by nebulizer in adults presenting to an urbanemergency department with acute asthma. Chest 2002;121:1036–41.

23. Marik P, Hogan J, Krikorian J. A comparison of bronchodilatortherapy delivered by nebulization and metered-dose inhaler inmechanically ventilated patients. Chest 1999;115:1653–7.

24. Rodrigo C, Rodrigo G. Salbutamol treatment of acute severeasthma in the ED: MDI versus hand-held nebulizer. Am JEmerg Med 1998;16:637–42.

25. Williams JR, Bothner JP, Swanton RD. Delivery of albuterol ina pediatric emergency department. Pediatr Emerg Care1996;12:263–7.

26. Turner MO, Patel A, Ginsburg S, FitzGerald JM .Bronchodilator delivery in acute airflow obstruction: a meta-analysis. Arch Intern Med 1997;157:1736–44.

27. Shrestha M, Bidadi K, Gourlay S, Hayes J. Continuous vsintermittent albuterol, at high and low doses, in the treatment

53S


of severe acute asthma in adults. Chest 1996;110:42–7.28. Reisner C, Kotch A, Dworkin G. Continuous versus frequent

intermittent nebulization of albuterol in acute asthma: arandomized, prospective study. Ann Allergy Asthma Immunol1995;75:41–7.

29. Besbes-Ouanes L, Nouira S, Elatrous S, Knani J, BoussarsarM, Abroug F. Continuous versus intermittent nebulization ofsalbutamol in acute severe asthma: a randomized, controlledtrial. Ann Emerg Med 2000;36:198–203.

30. Rodrigo GJ, Rodrigo C. Continuous vs intermittent b-agonistsin the treatment of acute adult asthma: a systematic review withmeta-analysis. Chest 2002;122:160–5.

31. Hess DR, Acosta FL, Ritz RH, Kacmarek RM, Camargo CA.The effect of heliox on nebulizer function using a b-agonistbronchodilator. Chest 1999;115:184–9.

32. Kress JP, Noth I, Gehlbach BK, et al. The utility of albuterolnebulized with heliox during acute asthma exacerbations. Am JResp Crit Care Med 2002;165:1317–21.

33. Corcoran TE, Shortall BP, Kim IK, Meza MP, Chigier N.Aerosol drug delivery using heliox and nebulizer reservoirs:results from an MRI-based pediatric model. J Aerosol Med2003;16:263–71.

34. Viau CJ, Kern T, Handley DA. Acute IV and oral toxicology of(S)-albuterol in rats. Presented at the American College ofAllergy, Asthma, and Immunology annual meeting,Philadelphia, PA, November, 6, 1998.

35. Gumbhir-Shah K, Kellerman DJ, DeGraw S, Koch P, Jusko WJ.Pharmacokinetics and pharmacodynamics of cumulative singledoses of inhaled salbutamol enantiomers in asthmatic subjects.Pulm Pharmacol Ther 1999;12:353–62.

36. Maier G, Henry A, Baumgartner RA, Rubino C, Cirincione B.The effect of the d-isomer, (S)-albuterol, is not throughalteration of the pharmacokinetics of (R)-albuterol: apopulation PK analysis [abstr]. J Allergy Clin Immunol2002;109:S237.

37. Gawchik SM, Saccar CL, Noonan M, Reasner DS, DeGraw SS.The safety and efficacy of nebulized levalbuterol compared withracemic albuterol and placebo in the treatment of asthma inpediatric patients. J Allergy Clin Immunol 1999;103:615–21.

38. Nelson HS, Bensch G, Pleskow WW, et al. Improvedbronchodilation with levalbuterol compared with racemicalbuterol in patients with asthma. J Allergy Clin Immunol1998;102(6 pt 1):943–52.

39. Devalia JL, Sapsford RJ, Rusznak C, Toumbis MJ, Davies RJ.The effects of salmeterol and salbutamol on ciliary beatfrequency of cultured human bronchial epithelial cells in vitro.Pulm Pharmacol 1992;5:257–63.

40. Davis B, Marin MG, Yee JW, Nadel JA. Effect of terbutaline on

movement of Cl- and Na+ across the trachea of the dog in vitro.Am Rev Respir Dis 1979;120:547–52.

41. Sepracor Inc. Data on file. Study 051-516. Marlborough, MA;2000.

42. Au DH, Lemaitre RN, Curtis JR, Smith NL, Psaty BM. Therisk of myocardial infarction associated with inhaled b-adreno-receptor agonists. Am J Respir Crit Care Med 2000;161:827–30.

43. Spitzer WO, Suissa S, Ernst P, et al. The use of beta-agonistsand the risk of death from asthma. N Engl J Med 1992;326:501–6.

44. Datta D, Vitale A, Lahiri B, ZuWallack R. An evaluation ofnebulized levalbuterol in stable COPD. Chest 2003;124:844–9.

45. Templeton AG, Chapman ID, Chilvers ER, Morley J, HandleyDA. Effects of S–salbutamol on human isolated bronchus. PulmPharmacol Ther 1998;11:1–6.

46. Cho SH, Hartleroad JY, Oh CK. (S)-albuterol increases theproduction of histamine and IL-4 in mast cells. Int Arch AllergyImmunol 2001;124:478–84.

47. Agrawal DK, Clark KC, Townley RG. Differential effects ofalbuterol enantiomers on pulmonary functions and broncho-alveolar lavage (BAL) eosinophilia [abstr]. Am J Respir CritCare Med 2000;163:A590.

48. Davies J, MacIntyre N, Ahearn G, Hudson B, Webb B. Acomparison of the use of levalbuterol compared to racemicalbuterol in the pulmonary stepdown population [abstr]. RespirCare 2001;46:1083.

49. Carl JC, Myers TR, Kirchner L, Kercsmar CM. Comparison ofracemic albuterol and levalbuterol for the treatment of acuteasthma. J Pediatr 2003;143:731–6.

50. Haider D. Breathing easier: highlighting new asthmamedications. AARC Times 2000;Nov:38–42.

51. Ford D, Dilley S, Handley D. Levalbuterol use in theemergency department increases PEF over racemic albuterol[abstr]. Respir Care 2000;45(suppl):980.

52. Schreck DM, Brotea C, Shah SP. Comparison of racemicalbuterol and levalbuterol in the treatment of acute asthma[abstr]. Ann Emerg Med 2001;38(pt 2). Available fromhttp://www2.us.elsevierhealth.com/scripts/om.dll/serve?action=searchDB&searchDBfor=art&artType=misc&id=jem384bab003025. Accessed January 15, 2004.

53. Nowak RM, Emerman CL, Schaefer K, Disantostefano RL,Vaickus L, Roach JM. Levalbuterol compared with racemicalbuterol in the treatment of acute asthma: results of a pilotstudy. Am J Emerg Med 2004;22:29–36.

54. GlaxoSmithKline. Asthma in America, a landmark survey.Available from www.AsthmainAmerica.com. Accessed January15, 2004.

55. White MV, Sander N. Asthma from the perspective of thepatient. J Allergy Clin Immunol 1999;103:S47–52.

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Focus on Inhaled β 2 -Agonists: Efficacy, Safety, and Patient Preference