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Home , Bronchodilator, Salbutamol, Vilanterol

Clinical of

Dennis M Williams PharmD BCPS AE-C and Bruce K Rubin MEngr MD MBA FAARC

Introduction ␤ 2 Receptors History Structure and Function Chemistry Selectivity and Specificity ␤ and of 2 Adrenergic Agonists Desensitization and Tolerance Adverse and Off-Target Effects Interactions ␤ Safety of Inhaled 2 Agonists Cholinergic (Muscarinic) Receptors History Structure and Function Pharmacodynamics and Pharmacokinetics Adverse and Off-Target Effects Drug Interactions Therapeutic Administration of Bronchodilator Medications Bronchodilator Therapy for Airways Diseases COPD Research and Development of Summary

Obstructive diseases, including asthma and COPD, are characterized by air-flow limitation. Bronchodilator therapy can often decrease symptoms of air-flow obstruction by relaxing airway (bronchodilation), decreasing dyspnea, and improving quality of life. In this review, we discuss the pharmacology of the ␤ agonist and bronchodilators and their use, particularly in asthma and COPD. Expanding knowledge of receptor subtypes and G-protein signaling, agonist and antagonist specificity, and drug delivery have led to the introduction of safer medications with fewer off-target effects, medications with longer duration of action that may improve adherence, and more effective and efficient aerosol delivery devices. Key words: beta agonists; anticholinergic medications; muscarinic antagonists; aerosol delivery; clinical pharmacology; asthma. [Respir Care 2018;63(6):641–654. © 2018 Daedalus Enterprises]

Introduction targets for bronchodilator therapy. Bronchodilation can be achieved through 2 primary and complementary mech- ␤ The bronchial smooth muscle of the airways is di- anisms. The activation of 2 receptors results directly in rectly innervated by the parasympathetic nervous sys- relaxation of smooth muscle. Muscarinic receptor an- tem where cholinergic receptors control bronchomotor tagonists, or anticholinergic therapies, are competitive tone.1 There is no direct sympathetic innervation of the antagonists of acetylcholine (ACH) at postganglionic ␤ airways, although they are rich in 2 adrenergic recep- nerve receptors, resulting in smooth muscle relaxation tors. Cholinergic and adrenergic receptors are major and bronchodilation.2

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␤ 2 Adrenergic Receptors Table 1. Systemic Effects of Inhaled Beta Agonists

History Organ System Observed Adverse Effect Cardiovascular and As far back as 3000 BCE, the Chinese used , Central , insomnia, nervousness, dizziness from the plant Ephedra vulgaris, to make ma huang to Gastrointestinal Nausea, vomiting treat dyspnea.3 In the 1800s, research focused on adrenal Musculoskeletal , leg gland extracts. By 1903, was being adminis- Biochemical , hyperglycemia tered subcutaneously for treating asthma, although it was Reproductive Uterine relaxation not until 1907 that its bronchodilation properties were ap- preciated.4,5 Injectable aqueous epinephrine, in conjunc- ␤ tion with an epinephrine suspension, was commonly used intestinal smooth muscle, and 2 receptors in bronchial, ␤ in the emergency management of until the uterine, and vascular smooth muscle. A third subtype, 3, early 1980s. Epinephrine has also been administered as an is present in adipose tissue. aerosol for more than a century.6 The ␤ receptor is a classic G-protein-coupled receptor In the 1950s, the first ␤-selective (but ␤-subtype non- (GPCR) with an extracellular N-terminus, traversing the selective) inhaled agents, isoproterenol and isoetharine, membrane 7 times (transmembrane domains) to form 3 ex- were developed as aerosol therapies for asthma.7 Synthetic tracellular and 3 intracellular loops, as well as an intracel- analogues of naturally occurring were sub- lular C-terminus10 (Fig. 1). The loops of the receptor that sequently developed, and these had greater selectivity for transverse the lipid bilayer of the membrane comprise a ␤ the 2 subtype receptor and, in some cases, extended du- cylindrical structure. The G-protein-coupled receptor reg- rations of effect. These emerged in the early 1980s, with ulates various effector proteins.12 Each G protein is a het- the introduction of metaproterenol and albuterol (salbuta- erotrimer consisting of ␣, ␤, and ␥ subunits, and is clas- mol) as rapid- and short-acting therapy for acute asthma. sified by its distinctive ␣ subunits. Among the various ␤ By the mid-1990s, long-acting agonists were introduced, forms, the Gs protein acts as a stimulatory protein of ad- which allowed for once or twice daily dosing. enyl cyclase; Gi and Go, as inhibitory proteins of adenyl ␣ cyclase; and Gq and G11 act to couple receptors to phos- Structure and Function pholipase C. In the resting state, the Gs protein is com- plexed with guanosine diphosphate. The activation of these Although adrenergic receptors are present throughout receptors by catecholamines or agonists promotes the dis- the body, the most clinically relevant ␤-mediated effects sociation of guanosine diphosphate from the ␣ subunit of occur in cardiac muscle, bronchial and uterine smooth the associated protein. This allows guanosine triphosphate muscle, and (Table 1). The ␣ and ␤ (GTP) to bind to this G protein, and the ␣ subunit disso- receptor subtypes were first described 70 years ago.8 The ciates from the ␤ unit. The activated GTP-bound ␣ subunit ␣ receptors were thought primarily to have excitatory func- acts to regulate the activity of its effector. When activated, tions, and ␤ receptors inhibitory function, except in the the conversion of GDT to GTP occurs. GTP can then myocardium. ␤ receptors subtypes 1 and 2 were identi- activate the adenyl cyclase enzyme, as well as activating 9 ␤ fied, with 1 receptors present in cardiac muscle and cyclic guanosine monophosphate phosphodiesterase, phos- pholipase C, and ion channels. Receptor agonists bind to one or more of the transmem- Dr Williams is affiliated with the University of North Carolina Eshelman brane loops. The primary neurotransmitters at adrenergic School of Pharmacy, Chapel Hill, North Carolina. Dr Rubin is affiliated receptors are and epinephrine. Adenyl cy- with The Children’s Hospital of Richmond at Virginia Commonwealth clase stimulates conversion of adenosine triphosphate to University, Richmond, Virginia. cyclic adenosine monophosphate, which activates a pro-

Dr Rubin presented a version of this paper at the 56th RESPIRATORY CARE tein kinase. The kinase phosphorylates a calcium channel, Journal Conference, Respiratory Medications for COPD and Adult Asth- which promotes calcium influx and thus activates contrac- ma: Pharmacologic Actions to Clinical Applications, held June 22–23, tile proteins, increasing inotropic and chronotropic action 2017, in St Petersburg, Florida. in cardiac muscle. In bronchial smooth muscle, the in- The authors have disclosed no conflicts of interest. crease in protein kinases and phosphorylation lead to bronchial smooth muscle relaxation because of decreased Correspondence: Bruce K Rubin MEngr MD MBA FAARC, Children’s calcium influx and increased calcium uptake in the sar- Hospital of Richmond at Virginia Commonwealth University, 1000 East Broad St, Richmond, VA 23298. E-mail: [email protected]. coplasmic reticulum. ␤ 2 adrenergic receptors are also present in submucosal DOI: 10.4187/respcare.06051 glands, endothelium of vessels, mast cells, and white

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D Extracellular r Beta receptor u g

NH2

Cell membrane III- -VI IV- -V

COOH Intracellular Gs βαγ ATP cAMP

G Protein -Inactivates myosin light chain kinase GDP GTP -Decreased intracellular calcium

Smooth muscle relaxation

Fig. 1. Structure of ␤ . GDP ϭ guanosine 5Ј; GTP ϭ guanosine 5Ј-triphosphate; ATP ϭ adenosine 5Ј-triphosphate; cAMP ϭ cyclic adenosine monophosphate. From Reference 11.

Table 2. Effects of Inhaled Beta Agonists in the Lung β-OH phenylethylamine

Relaxes bronchial smooth muscle (bronchodilation) β α α β HC HC Inhibits mediator release CH CH22NH 22HN Inhibits airway edema and plasma exudation OH HO Increases mucociliary clearance I- or R-isomer d- or S-isomer Increases secretion ␤ Decreases parasympathetic transmission Fig. 2. Isomer chemistry showing the hydroxyl group on the Reduces carbon. From Reference 11.

actions and activities. In the case of epinephrine, the R blood cells involved in inflammatory responses, including isomer alone is responsible for activation of the ␤ adren- and lymphocytes. This explains the various ergic receptor and the resultant effects. effects beyond bronchodilation that are exhibited in vitro Albuterol, the most commonly used ␤ agonist therapy (Table 2).13 for relief of acute asthma, is a of the R and S enantiomers. As is the case with epinephrine, the Isomer Chemistry pharmacologic effects are due to the R isomer, whose affinity for the ␤-adrenergic receptor is 110 times greater The carbons in the center of the phenylethylamine struc- than the S isomer.14 Whether the S isomer is inert or ture of ␤ adrenergic agents produce , or asymme- contributes to adverse effects through inhibition of the R try, of the compound. Depending on the position of the isomer is a controversy with no clear evidence of adverse carbon (Fig. 2), the molecule appears as chiral mirror im- effects shown in humans. High doses of ␤ agonists can lead ages that are not superimposable, like gloves for the right to tachycardia, tremor, hypokalemia, and hyperglycemia. The and left hand. These configurations, called enantiomers, pharmacodynamics of these suggests that optimal bron- rotate light in different directions, and thus are described chodilation is achieved far below dosages that can cause these as dextrorotary or levorotary, or as S enantiomers or R adverse effects. It had been postulated that the single R en- enantiomers, respectively, when described by their spe- antiomer levalbuterol may cause less tachycardia and tremor cific spatial configuration. From a chemical perspective, based on studies in animals demonstrating that the R enan- enantiomers exhibit similar properties. However, their in- tiomer appeared to be responsible for bronchodilation, while teraction with the receptor can vary, resulting in different the S enantiomer with no bronchodilator effects could in-

RESPIRATORY CARE • JUNE 2018 VOL 63 NO 6 643 BRONCHODILATOR MEDICATIONS crease rate and tremor. In humans, the dose-related Table 3. Characteristics of Beta Agonist Medications increase in heart rate and tremor are identical for racemic Available albuterol as for levalbuterol.14 Duration of Inhalational Lipophilicity Molecule Action/Dosing Routes (in the (Log P) Frequency Selectivity and Specificity United States) Albuterol pMDI, DPI, 1.4 4–6 h Agonists and antagonists of the ␤ receptor may exhibit Nebulizer 2.2 12 h receptor selectivity but not specificity. This suggests that pMDI, nebulizer 2.2 12 h some molecular configurations fit one subtype of a ␤ re- Levalbuterol pMDI, nebulizer 1.4 4–6 h ceptor better than other, but that off-target effects are pos- DPI 3.9 24 h sible, especially when higher or more frequent dosing is Soft mist NA 24 h used. These effects also occur because most tissues ex- DPI 4.2 12 h press multiple subtypes of receptor; eg, cardiac muscle DPI 3.8 24 h ␤ does not exclusively express 1, and the bronchial smooth Data from Reference 16. ␤ Log P describes the partition between lipid and aqueous phases, thus higher lipophilicity is muscle does not express only 2. ␤ indicated by larger number. Improved selectivity for the 2 receptor can be achieved pMDI ϭ pressurized metered-dose inhaler by increasing the size of the molecule on the amine.7,15 DPI ϭ dry powder inhaler ϭ Modifications to the aromatic ring can also prolong the NA not applicable duration of action; however, the more recent strategy used to develop long-acting and ultra long-acting therapies has been to elongate the ethylamine side chain of the structure. formoterol is less lipophilic than salmeterol, it attaches to the ␤ receptor more quickly and its onset is more rapid Pharmacodynamics and Pharmacokinetics of than salmeterol. On the other hand, a partial agonist is ␤ ␤ 2 Adrenergic Agonists expected to produce less desensitization and fewer ad- renergic-associated . Despite the differences in ␤ As catecholamines, 2 agonists exhibit low bioavail- these 2 agents, clinical efficacy and safety appear to be ability, and the therapeutic benefit of oral administration is similar. The drugs also differ in intrinsic activity and se- ␤ limited. These agents are absorbed in the gastrointestinal lectivity at the 2 receptor, although the clinical impor- tract but undergo significant first-pass , which tance of these differences is unproven.17 Indacaterol was limits their true bioavailability. To overcome this, higher the first cleared ULABA with a 24-h duration of action, doses are required for oral therapy, which can result in which allows for once-daily administration. Other new unacceptable side effects. agents, including olodaterol and vilanterol, are single en- ␤ Short-acting 2 agonists (SABAs) have an onset of ef- antiomer products that exert full agonist activity sustained fect within minutes, which is the basis for their role as for 24 h. rescue treatment for acute symptoms associated with bron- chospasm. The duration of effect of SABA therapy is 3–6 h, Desensitization and Tolerance which limits their role in chronic management. The first ␤ ␤ long-acting 2 agonists (LABAs) exhibited prolonged bron- With chronic stimulation by 2 agonists, adrenergic re- chodilation, which allowed for 12-h dosing; now ultra- ceptors have decreased intensity of response and duration long acting agents (ULABAs) have been developed that of effect, known as tolerance. Tolerance is exhibited with can be dosed every 24 h (Table 3). LABAs generally have both SABAs and LABAs, and it is characterized more by ␤ greater specificity for the 2 receptor compared to short- a loss of bronchoprotective effect rather than the broncho- acting agents. The extended effectiveness of these agents dilator effect. The activity of adrenergic receptors are in- is attributed to various factors, including the presence of fluenced by several factors, including hormones, cat- large side chains on the molecular structure. In general, echolamines, and medications. Changes in the number and these side chains increase the lipophilicity of the molecule, function of receptors on the cell surface will change the which allows their retention in the lipid bilayer of the cell magnitude and duration of response.12 These changes can membrane. This is in contrast to albuterol, which is a more be clinically relevant as they may limit the therapeutic hydrophilic molecule that diffuses out of the membrane response to treatment with prolonged high-dose adminis- quickly. tration, while adverse effects such as tachycardia and hy- LABAs differ in their pharmacologic properties, al- pokalemia are not generally susceptible to receptor toler- though the clinical relevance of these differences is un- ance. Desensitization can be homologous or heterologous. clear. For example, formoterol is more potent than salme- Homologous desensitization occurs directly at a receptor terol, which is a partial agonist at the receptor. Although activated by an agonist, whereas a heterologous change

644 RESPIRATORY CARE • JUNE 2018 VOL 63 NO 6 BRONCHODILATOR MEDICATIONS refers to another receptor in the same region but is not COPD.19 There are no data demonstrating that this improves directly involved in agonist activation. mucus clearance in individuals with asthma.20 Several mechanisms contribute to receptor desensitiza- Adverse or unwanted effects can occur due to excessive tion, including changes in protein transcription or transla- receptor activation or actions at off-target sites. Off-target tion that develop over several days, while desensitization effects are reduced with the use of the inhaled route as due to phosphorylation of amino acids, or changes in re- well as more selective therapies, but they are not elimi- ceptor cellular location, can occur in hours. Prolonged nated. Commonly observed side effects or adverse reac- phosphorylation of the receptor through activity of protein tions are summarized in Table 3. Fortunately, tolerance to kinases as a result of repeated or prolonged use leads to these effects usually develops with regular use. ␤ internalization of the receptor. Once phosphorylated, the 2 agonists have been associated with an increased risk ␤ receptor has an increased affinity for arrestins, which at- of adverse cardiovascular events due to actions at the 1 ␤ tenuates the ability to activate G proteins due to steric receptor. All 2 agonists can cause tachycardia and palpi- hindrance. Arrestin then interacts with clathrin, leading to tations.21 Activation can increase the risk of , endocytosis of the receptor. The development of tolerance especially in patients with underlying cardiovascular dis- ␤ to 2 agonists can be attenuated by therapy. ease. Data regarding risk are conflicting, but caution is advised when using these agents in patients with preexist- Adverse and Off-Target Effects ing cardiovascular disease.22 Tal et al23 were among the first to report that the ad- ␤ ␤ The primary and clinically relevant effect of inhaled 2 ministration of agonists could acutely worsen hypox- agonists is bronchodilation.12 However, in vitro studies emia in children with asthma. The presumed mechanism suggest that ␤ agonists may have nonbronchodilator ef- was vasodilatation with improvement of to un- fects, such as decreasing production and activity of leu- derventilated portions of the lung, leading to an increased kotrienes and histamine from mast cells, reducing micro- mismatch of ventilation and perfusion. It is recommended vascular permeability, inhibiting phospholipases A2, and patients who are hypoxemic and are receiving a ␤ agonist increasing ciliary beat frequency (Table 2). The anti-in- should also receive supplemental oxygen to minimize this flammatory effects are thought to be due to functional risk. antagonism by inhibiting smooth muscle contraction, rather Investigators in the 1980s showed that the of than direct anti-inflammatory effects. Although ␤ agonists ␤ agonists worsened air flow in infants with tracheoma- appear to reduce some aspects of inflammation in vitro, lacia. It was postulated that, with poor cartilage develop- there are data suggesting that the chronic use of ␤ agonist ment, airway patency was being maintained by intrinsic bronchodilators may be pro-inflammatory, which may be airway muscle tone, and that the administration of a ␤ one of the reasons that chronic use of inhaled ␤ agonists agonist would lead to bronchial relaxation and worsening perpetuates asthmatic airway inflammation. These obser- of the airway malacia. They further showed that the ad- vations remain speculative. ministration of bethanechol, a cholinergic agent, improved Off-target effects can present as side effects or adverse air flow.24 Many children who have airway malacia also ␤ drug reactions, and they occur due to 2 receptor stimu- have wheeze, which can be confused for asthma. For these ␤ lation of cardiac and peripheral muscle, or 1 adrenergic reasons, it is recommended that neonates or infants with ␤ effects. At the 2 receptor, similar events occur with stim- tracheomalacia not receive bronchodilators. ulation and result in activation of protein kinase. In this instance, protein kinase promotes calcium influx and ac- Drug Interactions tivates contractile proteins. Protein kinase also phosphor- ylates troponin and G*, which activates a calcium channel Although the inhaled route of administration can dra- resulting in positive inotropy and chronotropy in cardiac matically reduce side effects, there are pharmacokinetic tissue and blood vessel . considerations with some ␤ agonists. Sal- Albuterol has been reported to help clear pulmonary meterol is metabolized by cytochrome (CYP) p450 3A4, edema fluid from the alveolus by accelerating the resorp- and formoterol is a substrate for several CYP enzymes, tion of alveolar fluid. This effect has been demonstrated in including 2D6, 2C9, and 2C19. The product labeling for patients with fluid overload of cardiogenic pulmonary ede- salmeterol suggests caution when using with strong 3A4 ma; however, the clinical implications are modest.18 It has inhibitors, including ritonavir or ketoconazole, because of also been suggested that the inhalation of a ␤ agonist bron- the increased risk for adverse effects from higher salmet- chodilator will improve the effectiveness of airway clearance erol concentrations. The product label for formoterol does maneuvers, and so albuterol is often inhaled before chest not mention CYP-related drug interactions, but there is a physical therapy or airway clearance maneuvers. Beneficial statement cautioning use with other agents that can pro- effects on mucociliary clearance have been demonstrated in longed the QT interval of cardiac rhythm.

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␤ 33 Safety of Inhaled 2 Agonists pending on the preparation. Nicotinic receptors are lo- cated mainly on autonomic ganglia and skeletal muscle. ␤ The clinical safety of inhaled 2 agonists has been a These receptors are ligand-gated ion channels, and activa- source of controversy for decades. In the 1990s, an in- tion results in an increase in permeability to sodium and creased risk for asthma deaths was attributed to SABA calcium, leading to depolarization and excitation.34 Mus- use, including albuterol. In 2006, the post-marketing carinic receptors are G-protein-coupled receptors, and they SMART study25 reported an increased risk of fatal or near- are found in the central nervous system and the periphery fatal asthma associated with salmeterol compared to usual on autonomic effector cells innervated by postganglionic therapy. These data, along with additional small studies parasympathetic nerves, including smooth and cardiac mus- and a meta-analysis, resulted in an FDA black box warn- cle.31 ing in 2010 that is included on all products containing a ACH is the primary neurotransmitter at receptors LABA in the United States. The FDA also required man- throughout the body, and it activates both nicotinic and ufacturers of LABA-containing products to conduct safety muscarinic receptors. ACH is an excitatory neurotransmit- studies. The results of those long-term studies are now ter that requires an energy-dependent pump for uptake into published and support the safety of LABA therapy when the synaptic vesicle, where it is stored in the neuron. Dur- used in combination with inhaled in chil- ing neurotransmission, ACH is released into the synaptic dren, adolescents, and adults.26-28 In November 2017, the cleft.35 The enzyme acetylcholinesterase is also found at FDA removed the black box warning from products con- the postsynaptic membrane and inactivates ACH through taining a combination of a LABA and inhaled corticoste- hydrolysis. Choline liberated by hydrolysis is taken up roid. again by the nerve, and new ACH is synthesized and stored (Fig. 3). Cholinergic (Muscarinic) Receptors Nicotinic receptor antagonists are used clinically as an- esthetics, skeletal muscle relaxants, and central and adre- History nal-active therapies. Muscarinic receptor antagonists are agents include naturally occurring bel- more relevant for this review as they are present on airway ladonna alkaloids (atropine, scopolamine). For centuries, smooth muscle. In clinical practice, the terms anticholin- Ayurvedic healers in India burned leaves from Datura ergic and antimuscarinic are often used interchangeably, species (jimson weed, thorn apple, moonflowers) and in- although in the airway the action occurs at the muscarinic haled the vapors for relief of asthma. This practice was receptor. Parasympathetic innervation of airway smooth muscle is provided by the tenth cranial nerve, the vagus. brought to England by General Gent,29 and cigarettes con- taining Datura alkaloids were sold as asthma therapy as Antagonists of muscarinic receptors exhibit both or- late as the 1970s. These alkaloid compounds have been thosteric binding at the active site and allosteric binding modified to create synthetic derivatives with improved clin- elsewhere, which changes the conformation of the protein- ical applications, including inhaled ipratropium and tiotro- binding site. There are 5 subtypes of muscarinic receptors, pium, which are quaternary ammonium compounds with and 3 of them, M1–M3, are located on airway smooth limited systemic absorption and blood–brain barrier trans- muscle, on the nerves that control smooth muscle, and on location. In clinical studies, the other anticholinergic ef- glands. Muscarinic receptors control basal airway smooth 36 fects of these inhaled therapies are not significant, includ- muscle tone, which is increased in COPD. M1 and M3 ing effects on sputum volume or viscosity. are excitatory and promote ACH release and coupling Ipratropium was the first commercially available inhaled through Gq/G11 to activate phospholipase C, which results in phosphatidylinositol turnover. Calcium is released, re- anticholinergic agent, cleared in 1987.30 It is short-acting and nonselective in that it blocks all 3 muscarinic recep- sulting in an increase in intracellular calcium and receptor activation. M2 receptors inhibit adenylyl cyclase activity tors (M1,M2,M3). Tiotropium, a long-acting agent, selec- through another G-protein (Gi/Go), which results in pro- tively blocks M1 and M3 receptors. Antagonism at the M3 receptor appears to be the most clinically relevant for bron- longed opening of ion channels and flow of calcium and potassium. Activation of potassium channels leads to hy- chodilation31 and for decreasing mucin hypersecretion perpolarization of the cell membrane. In addition, ACH driven by neutrophil elastase.32 Other long-acting agents activation of M2 receptors reduces ACH release from the that are now available are selective for the M3 receptor as well. vesicle. The summative effect of muscarinic receptor an- tagonists is decreased airway tone with improvement in Structure and Function expiratory air flow.37 M3 receptors appear to be most clinically important in A report published in 1914 described choline ester re- mediating smooth muscle contraction. This is also true in sponses that were similar to nicotine or muscarine, de- bladder smooth muscle, which may partially explain the

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Airway

Parasympathetic nerve

M2 receptor

M3 receptor M1 receptor ACH ACH

Preganglionic Postganglionic Submucosal Ganglionic gland

synapse M3 receptor

Smooth muscle

Anticholinergic drug

Epithelium

Fig. 3. Identification and location of muscarinic receptor subtypes M1,M2, and M3 in the vagal nerve, submucosal gland, and bronchial smooth muscle in the airway, showing nonspecific blockade by anticholinergic drugs. ACH ϭ acetylcholine. From Reference 30, with permission. potential side effect of urinary retention.38 The structure of cause the main benefit of these therapies is a prolonged the M3 receptor has intracellular and extracellular loops duration of effect (Table 4). In late 2017, glycopyrrolate and a large extracellular vestibule within a hydrophilic was cleared as the first nebulized formulation of a LAMA channel, which is where the orthosteric binding site resides therapy. (eg, for tiotropium). Studies show that selective antago- nists (eg, tiotropium) bind to M2 receptors as well as M3 Adverse and Off-Target Effects receptors, but they dissociate from M3 receptors much more slowly.38 The most common side effects from inhaled anticholin- ergics is dry mouth and, with aerosol administration using Pharmacodynamics and Pharmacokinetics a poorly fitting mask, mydriasis. These agents have no adverse effects on mucus clearance or viscosity.39 In- Bronchodilation from ipratropium is evident in 15 min, haled anticholinergics have negligible effects on heart with a maximum effect at 1.5 h. Receptor binding is esti- rate and blood pressure (Table 5). Some observational mated at 3 h, and the duration of effect lasts for up to 6 h. studies have implicated that inhaled anticholinergic ther- Serum concentrations are undetectable with usual doses. apies relate to an increased risk of stroke and myocar- The duration of bronchodilation from short-acting inhaled dial infarction.40 The basis for this increased risk is anticholinergics is longer compared to SABAs, and toler- unclear, but it may be due to the anticholinergic effect ance does not appear to occur in response to the anticho- on cardiac muscle. Findings in observational studies linergic effects. differ from those of randomized clinical trials; however, ␤ Tiotropium was developed as a structural analogue of as with precautions for 2 agonists, caution is prudent glycopyrrolate. This agent binds the M3 receptor for 36 h, when initiating therapy in patients with preexisting car- and bronchodilation persists for 24 h. After inhalation of diovascular disease. tiotropium as a dry powder, about 14% of the drug appears in the urine. Newer long-acting Drug Interactions (LAMA) therapies (eg, aclidinium, glycopyrrolate, and umeclidinium) exhibit a faster onset of action compared to Inhaled anticholinergic therapies rarely cause side ef- tiotropium, although the clinical relevance is unclear be- fects related to the blockage of cholinergic receptors. The

RESPIRATORY CARE • JUNE 2018 VOL 63 NO 6 647 4 R 648 Table 4. Available Products Containing Inhaled Bronchodilator

Class Indication Brand Name Device Dosing SABA SAMA ICS LABA LAMA COPD Asthma

SABA, SAMA, and SABA/ SAMA Combinations ProAir, Ventolin, Proventil pMDI Albuterol (90 ␮g) 1–2 puffs every XX ProAir RespiClick DPI Albuterol (90 ␮g) 4–6 h as needed XX Albuterol (generic) Nebulizer Albuterol (various) XX Xopenex (also generic) pMDI Levalbuterol (45 ␮g) 1–2 puffs every XX Nebulizer Levalbuterol (various) 4–6 h as needed XX Combivent Respimat Albuterol (100 ␮g) Ipratropium (20 ␮g) 1 puff every 6 h X Albuterol and ipratropium Nebulizer Albuterol (2.5 mg) Ipratropium (500 ␮g) X combination (generic) Atrovent pMDI Ipratropium (17 ␮g) 2 puffs every 6 h X Ipratropium (generic) Nebulizer Ipratropium (500 ␮g) X ICS and LABA Combinations Symbicort pMDI (80, 160 ␮g) Formoterol (4.5 ␮g) 2 puffs twice daily X (160 ␮g only) X B Advair pMDI (45, 115, 230 ␮g) Salmeterol (21 ␮g) 2 puffs twice daily X RONCHODILATOR Diskus Fluticasone (100, 250, 500 ␮g) Salmeterol (50 ␮g) 1 puff twice daily X (250 ␮g only) X AirDuo RespiClick DPI Fluticasone (55, 113, 232 ␮g) Salmeterol (14 ␮g) 1 puff twice daily X Breo Ellipta Fluticasone (100, 200 ␮g) Vilanterol (25 ␮g) 1 puff once daily X (100 ␮g only) X Dulera pMDI (100, 200 ␮g) Formoterol (5 ␮g) 2 puffs twice daily X LABA Brovana Nebulizer Arformoterol (15 ␮g) 15 ␮g twice daily X Perforomist Nebulizer Formoterol (20 ␮g) 20 ␮g twice daily X

Arcapta Neohaler Indacaterol (75 ␮g) 1 puff once daily X M

Striverdi Respimat Olodaterol (2.5 ␮g) 2 puffs once daily X EDICATIONS Serevent Diskus Salmeterol (50 ␮g) 1 puff twice daily X LABA and LAMA Combinations ESPIRATORY Bevespi Aerosphere Formoterol (4.8 ␮g) Glycopyrrolate (9 ␮g) 1 puff twice daily X Utibron Neohaler Indacaterol (27.5 ␮g) Glycopyrrolate (15.6 ␮g) 1 puff twice daily X Stiolto Respimat Olodaterol (2.5 ␮g) Tiotropium (2.5 ␮g) 2 puffs once daily X Anoro Ellipta Vilanterol (25 ␮g) Umeclidinium (62.5 ␮g) 1 puff once daily X LAMA

C Tudorza Pressair Aclidinium (400 ␮g) 1 puff twice daily X ARE Seebri Neohaler Glycopyrrolate (15.6 ␮g) 1 puff twice daily X Lonhala Magnair Nebulizer Glycopyrrolate (25 ␮g) 25 ␮g twice daily X • Spiriva Handihaler Tiotropium (18 ␮g) 1 puff once daily X J

UNE Respimat Tiotropium (1.25 ␮g and 2 puffs once daily X (5 ␮g) X (2.5 ␮g) 2.5 ␮g) Incruse Ellipta Umeclidinium (62.5 ␮g) 1 puff once daily X 08V 2018 LABA, LAMA and ICS Combinations Trelegy Ellipta Fluticasone (100 ␮g) Vilanterol (25 ␮g) Umeclidinium (62.5 ␮g) 1 puff once daily X OL SAMA ϭ short-acting muscarinic antagonist 3N 63 SABA ϭ short-acting ␤2 agonist ICS ϭ inhaled corticosteroids LABA ϭ long-acting ␤2 agonist O LAMA ϭ long-acting muscarinic antagonist 6 BRONCHODILATOR MEDICATIONS

Table 5. Possible Adverse Effects Reported for Inhaled chamber that allows the aerosol cloud to mature (ie, larger Anticholinergics particles are removed) and thus reduces oropharyngeal de- position, swallowing, and systemic side effects. Many stud- Organ System Observed Adverse Effect ies have shown that, when used appropriately, Otolaryngology Dry mouth, blurred vision, taste disturbances delivered by either pMDI or DPI is equivalent or superior Genitourinary Urinary retention to that delivered by jet nebulization, often at a lower dose. Gastrointestinal Constipation DPIs are generally breath-activated and therefore can be Cardiovascular Tachycardia (rare) ideal for delivery of medication to the older child and adult. They do require significant inspiratory flow to dis- aggregate the particles, although active-dispersal DPIs have quaternary structure also limits central nervous system pen- been developed. In all cases, whether using a nebulizer, a etration and avoids the side effects, including delirium, pMDI, a holding chamber, or DPI, dosages should never associated with atropine. As a result, there are no clinically be adjusted based on the patient’s age or weight. For any relevant drug interactions associated with these therapies. child old enough (generally 3 y and older), the use of a mouthpiece will effectively double the amount of medica- Therapeutic Administration of Bronchodilator tion delivered to the airways compared to the same num- Medications ber of delivered using a masked interface.42 Regardless of the device chosen for aerosol delivery, The ␤ agonist and the anticholinergic bronchodilator education and appropriate use is important to ensure suc- medications are effective when administered systemically cessful outcomes. It is recommended that patients bring by mouth or intravenously, or when delivered topically as their aerosol device to clinic at each visit and demonstrate an aerosol deposited on the airway. Inhalational therapy is appropriate use. In that , it does not matter how ef- generally preferred. Systemic administration requires a fective the medication is because it will not work if it is higher dosage with greater systemic side effects and no not inhaled using appropriate technique as prescribed.44 therapeutic advantage.41 This is true even for the critically ill patient. Both anticholinergics and ␤ agonists have an Bronchodilator Therapy for Airway Diseases extremely broad therapeutic window when given by aero- sol. Asthma Aerosols can be delivered as wet aerosols via traditional Venturi , vibrating mesh nebulizers, dry powder (DPI), slow mist inhalers, or pressurized metered- The benefits of using ␤ agonist bronchodilators to re- dose inhalers (pMDI). Under most circumstances, the use lieve smooth muscle spasm are well established as a hall- of either a DPI or a pMDI is preferred to nebulization.42 mark of therapy for acute asthma. However, the chronic Nebulizers used for aerosol administration vary greatly in use of ␤ agonists is thought to worsen asthma control. This their respirable mass output, or the amount of particles in may be due to decrease in ␤ receptor expression on the the aerosol of the appropriate size for inhalation. Further- target cells, a decreased rate of adherence to inhaled cor- more, nebulization is generally a longer and more complex ticosteroids and other controller medications, and the pos- procedure than using a pMDI or DPI. Nebulization entails sibility that chronic ␤ agonist use might worsen inflam- measuring the medication into the nebulizer cup, having mation. the patient breathe consistently and deeply during the pe- When the LABA salmeterol was introduced, a large riod of nebulization (generally about 5 min), and then study evaluating its use as monotherapy for chronic asthma cleaning the nebulizer before it is put away. For these (the SMART study) showed excess mortality leading to an reasons nebulization has the lowest adherence rate of any FDA black box warning about the use of this medication form of aerosol medication delivery.43 alone.25 Because this excess mortality was primarily noted The pMDI has been a standard for aerosol delivery for among African-American subjects, and this group has a Ͼ 50 y. Recent changes from the chlorofluorocarbon greater prevalence of homozygous Arg/Arg polymorphism (CFC-9 and CFC-11) carrier to a more environmentally at locus 16 of the ␤ agonist receptor (the normal receptor friendly hydrofluoroalkane (HFA-134a) carrier, in response type is Arg/Gly), this Arg/Arg polymorphism was thought to the Montreal protocol to protect the ozone layer, does to lead to an ineffective response to inhaled bronchodila- not lead to a change in either aerosol size or output from tors. Reanalysis of the data and a subsequent study the pMDI. Because aerosols from the pMDI are delivered (BARGE)45 have failed to confirm this, and it is now at a high velocity and require significant coordination be- thought that this excess of death in patients receiving sal- tween actuation and inhalation, it is recommended that meterol monotherapy was primarily due to inadequate use these be used either with a spacer or with a valved holding of inhaled corticosteroids rather than due to the drug itself.

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The duration of action of inhaled albuterol is 4–6 h. been clearly demonstrated that this improves airway clear- Nevertheless, it is common practice to give large amounts ance.51 Patients with CF more frequently have bronchial of albuterol over a fairly short period of time when treating hyper-responsiveness than those who do not have CF, but acute asthma. While administering albuterol every 1–2 h bronchial hyper-responsiveness is variable and is not al- for the first 12 h may be effective therapy, particularly in ways responsive to inhaled bronchodilators. It is also un- airways that are obstructed, once the airway ␤ receptors clear if there is increased bronchial hyper-responsiveness are saturated, more frequent use of these drugs adds little during a CF exacerbation of pulmonary disease, which is benefit while increasing adverse effects. A large prospec- when these drugs are often administered. The one docu- tive trial46 did not demonstrate clinical worsening of asthma mented benefit of inhaled albuterol in CF is use before when albuterol was dosed at regular intervals was com- administration of an osmotic agent, such as hypertonic pared to albuterol administration as needed. In another saline or mannitol, which can produce bronchospasm in a study47 in adults with asthma exacerbations, the as-needed subset of patients with underlying airway hyper-respon- administration of albuterol was as effective as regularly siveness. scheduled administration of this drug, but the former strat- egy led to a shorter length of hospital stay and a lower total Research and Development of Bronchodilators dose of ␤ agonist used. ␤ The choices among long-acting inhaled 2 agonists and COPD anticholinergic therapies have improved in recent years. Currently, there are a variety of products and inhalational Bronchodilator use is common in patients with COPD, forms for these products. Newer combination inhalers, con- although the response is variable. Those patients who dem- taining both a LABA and a LAMA, also represent a sig- onstrate elements of fixed air-flow obstruction and revers- nificant advance for treatment of COPD. The newest agents ible air-flow obstruction with triggering factors may have include bifunctional molecules that exhibit both musca- 48 ␤ the asthma-COPD overlap syndrome. It is likely that rinic antagonism and 2 agonism. These agents are re- these patients will be more responsive to bronchodilators ferred to as MABAs or LAMA/LABAs. One challenge in than those with so-called pure COPD. Nonetheless, one the development of these agents is determining the optimal study demonstrated that Ͼ 50% of COPD subjects (with- ratio of each activity in the therapeutic entity. Nonetheless, out an asthma component) demonstrated a significant bron- with the development of new medications and new aerosol chodilator response on .49 devices, the key to optimizing outcomes from therapy is identifying the right drug and delivery device, for the right Bronchiolitis patient, at the right time.52

For many years, it was assumed that bronchiolitis was Summary an infantile form of asthma, and thus the use of a ␤ agonist bronchodilator was routinely recommended. Accumulat- Adrenergic and cholinergic and receptors are major tar- ing evidence demonstrating a clear lack of effectiveness of gets for bronchodilator therapy. Expanding knowledge of inhaled ␤ agonists in the treatment of this disease has receptor subtypes and G-protein signaling, agonist and an- finally led to consensus among published guidelines that tagonist specificity, and drug delivery have led to the in- there is no value to administering albuterol to infants with troduction of safer medications with fewer adverse effects, bronchiolitis; in addition, because of the known side ef- medications with longer duration of action, and more ef- fects of this medication, it should not be administered to fective and efficient aerosol delivery devices. There are a infants with bronchiolitis.50 There is also no role for the variety of products and inhalational forms for these bron- use of inhaled albuterol in premature newborns with re- chodilators. Combination inhalers, containing a LABA and spiratory distress syndrome of the newborn. With increased a LAMA, are a significant advance for treatment of COPD. drug absorption from the newborn lung, this poses a risk of systemic adverse effects. REFERENCES 1. Cazzola M, Page C, Matera MG. Long-acting muscarinic receptor Cystic Fibrosis antagonists for the treatment of . Pulm Pharmacol Ther 2013;26(3):307–317. There is controversy related to the effectiveness of ␤ 2. Greenblatt DJ, Shader RI. Drug therapy. Anticholinergics. N Engl agonist bronchodilators in patients with cystic fibrosis (CF). J Med 1973;288(23):1215–1219. 3. Chen KK, Schmidt CF. The action and clinical use of ephedrinean Guidelines from the Cystic Fibrosis Foundation recom- alkaloid isolated from the Chinese drug, ma huang. J Am Med Assoc mend the use of albuterol before administering chest phys- 1926;87(11):836–842. ical therapy or mucoactive medications, although it has not 4. Kahn R. Zur physiologie der trachea. Arch Physiol 1907;398–426.

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5. Bullowa JGM, Kaplan DM. On the hyperdermatic use of adrenalin 27. Stempel DA, Raphiou IH, Kral KM, Yeakey AM, Emmett AH, chloride in the treatment of asthmatic attacks. Med News 1903;83: Prazma CM, Buaron KS, Pascoe SJ; AUSTRI Investigators. Serious 787. asthma events with fluticasone plus salmeterol versus fluticasone 6. Barger G, Dale HH. Chemical structure and sympathomimetic action alone. N Engl J Med 2016;374(19):1822–1830. of amines. J Physiol 1910;41:19. 28. Wechsler ME, Kunselman SJ, Chinchilli VM, Bleecker E, Boushey 7. Leifer KN, Wittig HJ. The beta-2 sympathomimetic aerosols in the HA, Calhoun WJ, et al.; National Heart, Lung and Blood Institute’s treatment of asthma. Ann Allergy 1975;35(2):69–80. Asthma Clinical Research Network. Effect of beta2-adrenergic re- 8. Ahlquist RP. A study of the adrenotropic receptors. 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Brittain RT, Jack D, Ritchie AC. Recent beta-adrenoceptor stimu- Lefkowitz RJ, et al. G protein-coupled receptor kinase 5 regulates lants. Adv Drug Res 1970;5:197–253. airway responses induced by muscarinic receptor activation. Am J 16. Antus B. Pharmacotherapy of chronic obstructive pulmonary dis- Physiol Lung Cell Mol Physiol 2004;286(2):L312-L319. ease: a clinical review. ISRN 2013;2013:1–11. 35. Fagerlund MJ, Eriksson LI. Current concepts in neuromuscular trans- 17. Woo AY, Song Y, Zhu W, Xiao RP. Advances in receptor confor- mission. Br J Anaesth 2009;103(1):108–114. mation research: the quest for functionally selective conformations 36. Fryer AD, Jacoby DB. Muscarinic receptors and control of airway focusing on the ␤2-adrenoceptor. Br J Pharmacol 2015;172(23): smooth muscle. Am J Respir Crit Care Med 1998;158(5 Pt 3):S154- 5477–5488. S160. 18. Mutlu GM, Koch WJ, Factor P. Alveolar epithelial beta 2-adrenergic 37. Ferrando M, Bagnasco D, Braido F, et al. Umeclidinium for the receptors: their role in regulation of alveolar active sodium transport. treatment of uncontrolled asthma. Expert Opin Invest Drugs 2017; Am J Respir Crit Care Med 2004;170(12):1270–1275. 26(6):761–766. 19. Bennett WD, Almond MA, Zeman KL, Johnson JG, Donohue JF. 38. Kruse AC1, Li J, Hu J, Kobilka BK, Wess J. Novel insights into M3 Effect of salmeterol on mucociliary and cough clearance in chronic muscarinic acetylcholine receptor physiology and structure. J Mol . Pulmon Pharmacol Ther 2006;19:96–100. Neurosci 2014;53(3):316–323. 20. Daviskas E, Anderson SD, Shaw J, Eberl S, Seale JP, Yang IA, 39. Kishioka C, Cheng PW, Seftor RE, Lartey PA, Rubin BK. Regula- Young IH. Mucociliary clearance in patients with chronic asthma: tion of mucin secretion in the ferret trachea. Otolaryngol Head Neck effects of beta agonists. Respirology 2005;10(4):426–435. Surg 1997;117(5):480–486. ␤ 21. Cazzola M, Page CP, Rogliani P, Matera MG. 2-agonist therapy in 40. Suissa S, Dell’Aniello S, Ernst P. Concurrent use of long-acting lung disease. Am J Respir Crit Care Med 2013;187(7):690–696. bronchodilators in COPD and the risk of adverse cardiovascular 22. Maak CA, Tabas JA, McClintock DE. Should acute treatment with events. Eur Respir J 2017;49(5):1602245. inhaled beta agonists be withheld from patients with dyspnea who 41. Rubin BK. Air and soul: the science and application of aerosol may have ? J Emerg Med 2011;40(2):135–145. therapy. Respir Care 2010;55(7):911–921. 23. Tal A, Pasterkamp H, Leahy F. Arterial oxygen desaturation follow- 42. Rubin BK, Fink JB. Optimizing aerosol delivery by pressurized me- ing inhalation in acute asthma. Chest 1984;86(6):868– 869. tered-dose inhalers. Respir Care 2005;50(9):1191–1200. 24. Panitch HB, Keklikian EN, Motley RA, Wolfson MR, Schidlow DV. 43. Rubin BK. What does it mean when a patient says, “my asthma Effect of altering smooth muscle tone on maximal expiratory flows medication is not working?” Chest 2004;126(3):972–981. in patients with tracheomalacia. Pediatr Pulmonol 1990;9(3):170– 44. Fink JB, Rubin BK. Problems with inhaler use: a call for improved 176. clinician and patient education. Respir Care 2005;50(10):1360–1374. 25. Nelson HS, Weiss ST, Bleecker ER, Yancey SW, Dorinsky PM; 45. Israel E, Chinchilli VM, Ford JG, Boushey HA, Cherniack R, Craig SMART Study Group. The Salmeterol Multicenter Asthma Research TJ, et al. Use of regularly scheduled albuterol treatment in asthma: Trial: a comparison of usual pharmacotherapy for asthma or usual genotype-stratified, randomised, placebo-controlled cross-over trial. pharmacotherapy plus salmeterol. Chest. 2006;129(1):15–26. Lancet 2004;364(9444):1505–1512. 26. Chauhan BF, Chartrand C, Ni Chroinin M, Milan SJ, Ducharme FM. 46. 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Discussion Williams: The issue is that func- responsiveness to ␤ agonists in gen- tionally in the pharmacy to prepare eral. MacIntyre: Let me start off. I find the solution for continuous nebuliza- continuous aerosols to be a very con- tion would require opening a lot of Rubin: Fantastic. Really glad to fusing area. You pointed out that high- single-use vials or ampules. There’s have that update. One of the criticisms dose ␤ agonists from continuous aero- been this trend toward using the multi- of the findings of the SMART trial3 sol therapy likely saturate ␤ receptors, dose systems that contain benzalko- was that a larger proportion of the sub- and thus may only promote toxicities. nium chloride. The interesting thing is jects who had very bad outcomes were On the other hand, in the patient who that we knew 12 years ago that ben- not on an inhaled corticosteroid. So is on a ventilator with an endotracheal zalkonium chloride, if used in large the question is if you use a concomi- tube full of mucus, delivery of a drug enough doses, is a functional antago- tant inhaled corticosteroid, will you may be really compromised. The ar- nist. There are reports of problems us- abrogate some of the phenomenon that gument might be to use continuous ing multi-dose containers with ben- you see with the genotyping? aerosols there because it’s so doggone zalkonium where patients looked difficult to get it down into the . resistant or didn’t do well with ther- Wechsler: More recently there were Does that make sense to you? apy, and it was attributed to the pre- a few different reports on different servative. LABAs.4,5 Rubin: You could make the same statement for giving systemic bron- Wechsler: Just a comment regard- Rubin: This is highly charged. As I ␤ recall, when all this was coming out chodilators, because if the airway is ing the pharmacogenetics of ago- nists. You showed the LARGE study2 there was a commentary by Salpeter blocked, don’t you want to get medi- that we published as part of the Asthma et al6 who made the statement that cation to the airway by blood flow? Clinical Research Network and more people had died from taking And yes, that makes sense but you showed the global results. While sub- LABAs than had died from their balance it with having a really sick jects who had the Arg/Arg genotype asthma. That was much more inflam- patient on a mechanical ventilator who had no significant improvement in matory than any allergen I’ve seen. may be on neuromuscular blockade, peak flow with salmeterol in com- who may have some cardiac abnor- bination with inhaled corticoste- Wise: You mentioned one of the bar- malities as well. These patients are of- roids, in the subset of African- riers to using pressurized metered-dose ten elderly, they’re your COPDers, and American subjects, there was a inhalers (pMDIs) in the hospital com- are you willing to risk cardiovascular difference in ␤ agonist response pared to nebulizers is the cost. Some adverse effects? I don’t think I’ve seen based on genotype, and in the global hospital are using single shared pMDIs a formal risk-benefit study done. population there were differences in between patients. The question I have There’s something else, since you airway hyper-responsiveness based is, what is the status of that, and is there brought up continuous nebulizations: on genotype. With regard to the Af- any concern about cross-contamination? Leslie Hendeles, who’s a clinical phar- rican-American population, there were macist in Gainesville, has been inter- also differences in airway hyper-re- Rubin: Yes, that’s known as com- ested in benzalkonium as a preserva- sponsiveness. We just this week com- mon canister. The concern with com- tive for albuterol in multi-dose form.1 pleted an AsthmaNet study of Ͼ 500 mon canister usage is cross-contami- And it is a bronchoconstrictor. So, if subjects looking at inhaled steroids and nation. There are disposable holding you were using continuous nebuliz- LABAs in African-Americans. The chambers that are fairly inexpensive ers with a ␤ agonist like albuterol, last person finished their last visit this that have been used under those cir- you need to go preservative-free or week, and we expect it will be ana- cumstances for common canister use. you may be worsening bronchocon- lyzed and published next year. We are I am not familiar with the latest rul- striction. looking at genetic factors in terms of ing; I know the Commission has

652 RESPIRATORY CARE • JUNE 2018 VOL 63 NO 6 BRONCHODILATOR MEDICATIONS been concerned about possible cross- go home. I wonder if you have any have all of these new drugs, none of contamination with that. We are not a comments as to the payer side of this? which are being studied in the hospi- common-canister institution, although tal setting. We’re not studying the tran- we do not use nebulizers once patients Rubin: We rarely encounter that. sition to home, and all of these are are admitted to the hospital. The response would be that we want obviously important for long-term patients out faster and we want them care. I don’t know how we break that Peters: So I can’t tell you the reg- to do better, and for that reason we’re barrier and get some of these studies ulations, but in almost every hospital, using pMDIs. actually funded and done. Do you have the control committee will any observations? Our observers say not allow you to use common canis- George: Is it possible that it’s re- these are really hard studies to do. Sub- ters. Yet, as has been mentioned, we gional or payer-specific? jects get enrolled and leave the hos- commonly use—in both the PFT lab pital quickly. You don’t have the time as well as on the wards—the dispos- Rubin: I can’t understand why one to capture the important primary out- able cardboard holding chambers that would assume nebulizers are given to come measures. have been cleared by all of our infec- sicker patients. Unless you assume tion control committees. they’re also receiving O2, but you Rubin: Again, I’m sure this will could give O2 to someone with a pMDI come up again later when we talk about Rubin: We’re the same. as well. My suspicion is that it’s the clinical applications. insurance company trying to find a George: Going back to the SMART way to not pay for something. *Newhouse: I would like to com- trial,3 I think we have to remember ment on the issue of the cost of ad- that there were other unique features MacIntyre: Let me go back to that. ministering a pMDI and a valved hold- in the African-American subjects who We have a protocol at Duke where ing chamber in the emergency were enrolled in that study. They had patients come in and get assessed by department in the United States. I’ll lower FEV1, and they had more acute an RT to see if they can even use a preface my remarks with the fact that health care utilization. There were pMDI properly. You know as well as nowhere else in the world are small- probably some things about the sub- anybody, it does require a certain volume nebulizers used for broncho- jects they recruited that had more to amount of skill and coordination to dilation in the . do with their disease severity or psy- properly use a pMDI. Somebody like And virtually every guideline, includ- chosocial factors that may have also a tight asthmatic or with a COPD ex- ing that of the National Institutes of contributed to the higher death rates. acerbation, you’ll have a devil of a Health,7 says that the first-line treat- Having been on the receiving side of time properly using the pMDI. Our ment should be pMDI with a valved all of that coming out, working pre- protocol allows you to switch to a neb- holding chamber. The issue about cost dominantly in an African-American ulizer for those kinds of patients until has been raised because there’s this patient population, when all of this they are able to recover. Does that make strange idea in the United States that, news started to hit and all of these sense? if you use a pMDI and a valved hold- patients started coming back and say- ing chamber, somehow contamination ing, “I’m going to stop taking the med- Rubin: Anything you say makes can occur from the boot of that device icine you have me on,” it really forced sense. Well, I’m trying to avoid talk- so that one pMDI cannot be used se- us to look deeply into the attributes of ing about my favorite subject, which quentially for several patients. Profes- the subjects enrolled. And how to fig- is aerosol delivery clinically, because sor Leslie Hendeles at the University ure out the right messaging to encour- I know that will be covered. Maybe of Florida, Gainesville, showed me an age patients to continue on a therapy these questions can come up again for excellent protocol that they have de- that we thought was really needed to that presentation and discussion. veloped in which they can repeatedly control their asthma. I haven’t worked use a pMDI and the boot is cleaned in an acute care setting in a while, but Strange: My observation is that off appropriately with a cloth contain- I know that when we tried to transi- we’ve done a really poor job of ac- ing an antibacterial agent between in- tion away from nebulizer therapy in tually studying delivery of both ␤ sertions into the pMDI. Furthermore, the hospital to a pMDI with a spacer, agonists and anticholinergics in the because patients usually use a valved we got pushback from the payers, that hospital setting. You showed the meta- holding chamber, there is no contact if a patient was well enough to be analysis showing no difference be- between the pMDI mouthpiece and the treated in-patient with a pMDI and a tween intermittent albuterol and con- patient. There’s a study not yet pub- valved holding chamber, then they tinuous nebulization, which just can’t lished that has shown that, because of were well enough to be discharged and be true in all subsets of patients. We the more rapid response to multi-dose

RESPIRATORY CARE • JUNE 2018 VOL 63 NO 6 653 BRONCHODILATOR MEDICATIONS bronchodilators given by pMDI with my view, is much better patient edu- crossover trial. Lancet 2009;374(9703): a valved holding chamber, fewer pa- cation based on the overwhelming ev- 1754–1764. tients are admitted to the hospital be- idence of therapeutic equivalence or 3. Nelson HS, Weiss ST, Bleecker ER, Yancey SW, Dorinsky PM; SMART Study Group. cause they improve more quickly and superiority of the pMDI with a valved The Salmeterol Multicenter Asthma Re- more of them are sent home earlier. holding chamber, assuming that suf- search Trial: a comparison of usual pharma- So if you take the cost of that into ficient doses of the latter are admin- cotherapy for asthma or usual pharmacother- effect, it isn’t more expensive to use a istered-dose equivalents of about half apy plus salmeterol. Chest 2006;129(1): pMDI with a valved holding chamber, of that given by nebulizer (ie, 500– 15–26. ␮ 4. Stempel DA, Raphiou IH, Kral KM, Yeakey and indeed it’s a good opportunity to 1,000 g (5–10 puffs) by pMDI with AM, Emmett AH, Prazma CM, et al.; for the teach patients how to use them while a valved holding chamber ϭ approx- AUSTRI Investigators. Serious asthma they’re in the hospital with an exac- imately 1,000–2,500 ␮g by a small- events with fluticasone plus salmeterol ver- erbation that they just recovered from volume nebulizer). sus fluticasone alone. N Engl J Med 2016; and, I would surmise, are particularly 374(19):1822–1830. 5. Peters SP, Bleecker ER, Canonica GW, Park amenable to being educated. Unsur- YB, Ramirez R, Hollis S, et al. Serious prisingly, the reason that so many pa- REFERENCES asthma events with budesonide plus formot- tients still request small-volume neb- erol vs budesonide alone. N Engl J Med 2016; ulizers for use at home is that they 1. Prabhakaran S, Abu-Hasan M, Hendeles L. 375(9):850–860. observe, as soon as they arrive in the Benzalkonium chloride: a bronchoconstrict- 6. Salpeter SR, Wall AJ, Buckley NS. Long- acting beta-agonists with and without in- ambulance or the emergency depart- ing preservative in continuous albuterol neb- ulizer solutions. Pharmacother 2017;37(5): haled corticosteroids and catastrophic ment, someone slaps a mask with aero- 607–610. asthma events. Am J Med 2010;123(4): sol from a nebulizer on their face. They 2. Wechsler ME, Kunselman SJ, Chinchilli 322–328. get the idea that the pMDI with a VM, Bleecker E, Boushey HA, Calhoun WJ, 7. National Heart, Lung and Blood Institute. valved holding chamber that they have et al.; National Heart, Lung and Blood In- Asthma action plan. Publication no. 07-5251, April 2007. at home is the kids’ stuff, and the re- stitute’s Asthma Clinical Research Network Effect of beta2-adrenergic receptor polymor- ally good stuff is in that very obvious phism on response to long-acting beta2 ag- * Michael T Newhouse MD, invited discus- cloud of raindrops pouring out of the onist in asthma (LARGE trial): a genotype- sant. Dr Newhouse is chief medical officer nebulizer. What needs to be done, in stratified, randomized, placebo-controlled, for InspiRx.

This article is approved for Continuing Respiratory Care Education credit. For information and to obtain your CRCE (free to AARC members) visit www.rcjournal.com

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