Physiologic Basis for Bronchodilator Action

Under resting conditions in healthy people, the work of breathing performed by the respiratory muscles is relatively small. Inspiration is an active process, and sufficient flow has to be generated by overcoming respiratory resistive, elastive, and frictional loads to ensure adequate alveolar ventilation. Expiration is passive and ends when the expiratory recoil pressure of the lungs and the chest wall are balanced. There is little expiratory flow resistance within the bronchial tree, and expiratory flow limitation (no increase in flow despite increasing expiratory driving pressure) is detected only during the last part of the maximum forced expiration (Figure 15-3, top). Ventilation increases during exercise but not to the point at which flow limitation significantly limits performance.

Figure 15-3 Expiratory flow limitation in health and disease. Top, The pressure change within and outside the airway in health. Intraluminal driving pressure producing expiratory flow declines owing to frictional resistance. The opposing triangles mark the point at which pressures within and outside the airway are equal (choke point) when expiratory flow limitation is present. This occurs outside of the thorax in healthy people (dotted line) and only during a maximum forced expiration. Bottom, The resistive pressure drop is greater, the choke point is more proximal in the airway, and expiratory flow limitation occurs within the thorax and can be present in tidal breathing. The bronchodilator moves the choke point distally and thus may abolish resting flow limitation altogether or allow more lung emptying to occur before onset of flow limitation.

Airway resistance is influenced significantly by the caliber of the bronchial tree (see Figure 15-2). In health, most of the resistance lies in the region of the larynx, with less than 20% coming from the periphery of the lung. The evidence points to resting airway smooth muscle tone that decreases physiologically during exercise to reduce the resistive work required when ventilation has to increase. Bronchodilator drugs abolish this smooth muscle tone in both healthy persons and patients with disease. In healthy people, the increase in FEV₁ after administration of a β-agonist is between 50 and 120 mL, a value similar to that in patients with COPD, whose baseline FEV₁ usually is much lower. By contrast, in patients with asthma, in which airway smooth muscle bulk is greater and resting muscle tone may be increased by indirect reflex mechanisms, the response to bronchodilator drugs is more dramatic, and substantial increases in lung function occur after the acute administration of a bronchodilator. The improvement in lung emptying that results from bronchodilation has important effects on the operating lung volume and hence on the work of breathing.

In general, wheezing reflects areas of local flow limitation within the airway. Expiratory flow limitation can occur in the absence of audible wheeze and contributes to the slow emptying of the lungs and the higher lung volumes that lead to breathlessness and chest tightness in obstructive lung disease. Expiratory flow limitation may be abolished completely after a bronchodilator drug in asthma (see Figure 15-3), although asthmatic symptoms often will recur when the effects of the bronchodilator wear off (see further on). In COPD, the absolute change in lung function is much smaller than in asthma, and flow limitation often persists, particularly in severe disease, although to a less severe degree. These subtle changes in lung mechanics, however, can produce clinically relevant changes in operating lung volumes, particularly in the end-expiratory lung volume, which is significantly elevated in many patients with COPD and constitutes is a good guide to the degree of exercise impairment experienced by affected persons. A further effect of bronchodilator drugs is to increase the threshold at which symptoms are induced. This increased threshold is important in the prevention of exercise-induced asthma and also in the reduction of symptoms produced more predictably by exercise, as occurs when patients with COPD undertake certain daily activities. This ability to increase baseline lung function and reduce the impact of external stimuli on the airways is likely to be important in explaining why bronchodilator drugs are associated with fewer exacerbations of airways disease when given in effective doses over the long term.

A different situation obtains in patients with restrictive lung function secondary to diffuse pulmonary fibrosis or chest wall disorders, in which the work of breathing is increased because of the greatly increased elastic load on the inspiratory muscles and the airways are largely spared from involvement. In such patients, bronchodilator drugs will have little effect on breathlessness, and their use is associated with unwanted side effects, rather than clinical benefit. Thus, bronchodilators are indicated only for the relief of symptoms that are caused by obstructive lung disease and not when a restrictive disorder is the dominant clinical problem.

Pharmacologic Basis of Bronchodilator Action

Although by definition the focus of action of bronchodilator drugs is the airway smooth muscle, a number of other secondary or incidental effects occur that can be clinically useful. The balance of these nonbronchodilator effects differs significantly between the two main classes of bronchodilator drugs.

β-Agonists

Based on the classical work of Ahlquist in defining different subtypes of adrenoreceptors, a range of relatively specific β-agonist agents were developed. Because β₂-receptors are almost the only subtype expressed on human airway smooth muscle, it makes sense to use highly selective β-agonists and there is no place for nonselective agents in clinical practice today. The chemical structures of the principal β-agonists are shown in Figure 15-4.

Figure 15-4 Chemical structures of commonly used bronchodilator drugs. A, β₂-Agonists. B, Antimuscarinic drugs.

β₂-Agonists produce bronchodilatation by directly stimulating β₂-receptors in airway smooth muscle, which leads to relaxation. This can be demonstrated in vitro by the relaxant effect of β-agonists on human bronchi and small airways—an effect confirmed in humans by a rapid decrease in airway resistance after administration of drug by inhalation. β-Receptors have been demonstrated in airway smooth muscle by direct receptor-binding techniques, and autoradiographic studies indicate that β-receptors are localized to smooth muscle of all airways from the trachea to the terminal bronchioles, although a wide distribution within the lungs as a whole, including the alveoli, is characteristic.

The β-receptor is a seven transmembrane–spanning G protein. Binding of the β₂-agonist to the disulfide bonds on the extracellular surface leads to activation of adenylate cyclase and a consequent increase in intracellular cyclic adenosine-3′,5′-monophosphate (cAMP). This leads in turn to activation of a specific kinase (protein kinase A) that phosphorylates several target proteins within the cell, resulting in several specific effects:

• A fall in the intracellular calcium ion (Ca²⁺) concentration by active removal of Ca²⁺ from the cell into intracellular stores

• Inhibition of phosphoinositide hydrolysis

• Direct inhibition of myosin light chain kinase

• Opening of large-conductance, calcium-activated potassium channels (K_Ca) that repolarize the smooth muscle cell and may stimulate the sequestration of Ca²⁺ into intracellular stores

• β₂-Agonists act as functional antagonists and reverse bronchoconstriction, irrespective of the contractile agent. This is an important property, because multiple bronchoconstrictor mediators (inflammatory mediators and neurotransmitters) are released in asthma.

β₂-Agonists may have other effects on airways, and β₂-receptors are localized to several different airway cells. Thus, additional effects may include the following:

• Inhibition of mediator release from mast cells and other inflammatory cells

• Inhibitory effects on neutrophil migration and activation

• Reduction and prevention of microvascular leakage and, consequently, development of bronchial mucosal edema after exposure to mediators such as histamine and leukotrienes

• Increased mucus secretion from submucosal glands and ion transport across airway epithelium (effects that may enhance mucociliary clearance, thereby reversing the defect in clearance found in asthma)

• Reduction in neurotransmitter release from airway cholinergic nerves, thus reducing cholinergic reflex bronchoconstriction

• Inhibition of the release of bronchoconstrictor and inflammatory peptides, such as substance P, from sensory nerves

How relevant any of these effects are to the observed clinical effects in disease is hard to determine. They may be more important in preventing bronchoconstriction from other stimuli in asthmatic patients than in directly influencing airway dimensions. The immediate impact on airway smooth muscle remains the most important of these various mechanisms, as illustrated in Figure 15-5. Recognized polymorphisms of the β-receptor show variable responses to agonist drugs in vitro. Translation of these observations into clinically noticeable differences in response in the clinical setting has been difficult, however, and at present these observations remain primarily of academic interest.

Figure 15-5 Direct and indirect bronchodilator effects of β₂-agonists. These agents stimulate β₂-receptors throughout the bronchial tree but cause bronchodilatation directly by means of activation of β₂-receptors on airway smooth muscle and also indirectly by inhibition of mediator release from mast cells. The latter mechanism is more likely to operate in allergic asthmatic patients, but its relative significance is unknown. LTD₄, leukotriene D₄.

(From Barnes PJ: β₂-Agonists, anticholinergics, and other nonsteroid drugs. In Albert RK, editor: Clinical respiratory medicine, ed 3, Philadelphia, Mosby, 2008.)

Antiinflammatory Effects of β₂-Agonists

The inhibitory effects of β-agonists on the release of mast cell mediators and on microvascular leakage can be considered to be antiinflammatory effects, although this term is not well defined. Nonetheless, available data suggest that β-agonists may modify acute inflammation. How well sustained such actions are remains unclear. To date, β-agonists have not been shown to modify chronic inflammation, but whether this reflects their basic pharmacology or is simply a result of a limited duration of action is less clear. The advent of very long-acting agents (see below) may resolve this point if any investigators have the courage to test this application in asthmatic patients without a background of other antiinflammatory treatment. Bronchial biopsy specimens in asthmatic patients who regularly take β-agonists show no significant reduction in the number of or activation in inflammatory cells in the airways, in contrast with suppression of inflammation that occurs with inhaled corticosteroids.

Antimuscarinic Agents

Antimuscarinic agents are specific antagonists of muscarinic receptors and inhibit cholinergic nerve–induced bronchoconstriction. Muscarinic receptors bind to acetylcholine released after stimulation of the parasympathetic nerves. These nerves innervate the bronchi and small airways of the human bronchial tree but do not extend to the respiratory bronchioles and alveoli. The receptor has seven membrane-spanning loops, the third of which shows considerable heterogeneity—explaining the existence of several different functional variants. Many of these receptors (M₁ to M₃) occur in different sites and with rather different functions, as shown in Figure 15-6.

Figure 15-6 Distribution of muscarinic receptors in the lung. Note that different receptors have different roles, so their blockade will have different effects. M₁ receptors on the ganglia in the airway wall seem to regulate overall bronchomotor tone. M₂ receptors are involved in the autoregulation of acetylcholine reuptake from the synaptic cleft. M₃ receptors are postsynaptic on airway and pulmonary vascular smooth muscle, and their blockade leads to smooth muscle relaxation.

A small degree of resting bronchomotor tone is caused by tonic cholinergic nerve impulses, which release acetylcholine in the vicinity of airway smooth muscle, and cholinergic reflex bronchoconstriction may be initiated by irritants, cold air, or stress. Although anticholinergics offer some protection against acute challenge by sulfur dioxide, inert dusts, cold air, and emotional factors, they are less effective against antigen challenge, exercise, and fog. This is not surprising, because anticholinergic drugs only inhibit reflex cholinergic bronchoconstriction and have no significant blocking effect on the direct effects of inflammatory mediators, such as histamine and leukotrienes, on bronchial smooth muscle. Furthermore, cholinergic antagonists probably have little or no effect on mast cells, microvascular leak, or the chronic inflammatory response. For these reasons, in patients who have asthma, anticholinergics are less effective as bronchodilators than β₂-agonists. In COPD the drugs appear to be more equivalent, although differences in their duration of action are as likely to explain their relative benefit as are fundamental pharmacologic differences.

β₂-Agonists: Clinical Considerations

Although historically, nonselective adrenaline derivatives such as isoprenaline were used to treat airway disease, cardioselective β₂-agonists are now recognized as being the safest and most effective compounds in this class. The most widely prescribed drug at present is salbutamol (albuterol in the United States), although the closely related compound terbutaline is popular in some parts of Europe. Fenoterol, a more potent β₂-agonist, was widely used in the 1980s, although it was associated with an increased risk of asthma death in New Zealand. Whether this association was causal or coincidental remains a subject of heated debate, which still affects current attitudes toward drugs in this class today. Although oral β-agonists were popular for many years, their slow onset of action and significant side effect profile have led to a decline in their use, and the inhaled route is now preferred, because the effects develop more rapidly and the total dose of drug given is smaller. In general, drugs such as salbutamol and terbutaline are considered short-acting β-agonists (SABAs), to distinguish them from long-acting agents such as salmeterol and formoterol (LABAs), which also are given by inhalation. Once-daily long-acting β-agonists, such as indacaterol and vilanterol, have been developed recently and, in the case of indacaterol, are now licensed for use in certain medical conditions. Intravenous treatment with β-agonist initially was used for emergency care and is still offered to some people in intensive care units; however, this regimen has declined in popularity, and higher doses of these drugs are now given principally by nebulization. The doses, duration of action, and formulations of the most widely used agents are presented in Table 15-1.

The relationship between increases in dose of β₂-agonists and the spirometric response in health and disease is at best a shallow one. This is most easily seen in people with asthma, in whom changes in FEV₁ after administration of these drugs are more dramatic and hence can be defined more reliably. A similar situation, however, applies in patients with COPD. The increase in adverse events is more clearly dose-related, thereby limiting the amount of drug that can be given.

In general, SABA drugs have a duration of action (assessed by a measurable difference in FEV₁ compared with that after administration of placebo) of 4 to 6 hours (Figure 15-7). Although the changes in lung function are statistically significant compared with either baseline or placebo, these effects really are very modest and often below the threshold of a clinically important difference, which for operational purposes is set at around 100 mL from baseline. Some evidence points to a much shorter period of protection against nonspecific challenges (e.g., to methacholine) than the total duration of effect measured in this way. By contrast, long-acting inhaled agents produce more substantial bronchodilation for at least 12 hours relative to their baseline value, and again, the duration of protraction against agonist challenges is much longer (see Figure 15-7). Salmeterol and formoterol are given twice-daily to maintain a bronchodilator effect over the 24-hour day. Salmeterol has a relatively slower onset of action, whereas formoterol, which is a full agonist, induces bronchodilation at a rate similar to that seen with salbutamol. This difference is important only when treatment is given on a maintenance basis, but the fast onset of action of formoterol allows it to be used as a rescue therapy; this has led to the “single inhaler” approach to asthma management. Newer data derived from patients with COPD managed with indacaterol and vilanterol show that these drugs have a rapid onset of action that lasts throughout the day after a single dose.

Figure 15-7 Schematic time course of inhaled bronchodilator action. This usually is expressed in terms of the change in forced expiratory volume in 1 second (FEV₁) from baseline and here is normalized as a percentage of maximum achieved in the disease under treatment. Graph segment A reflects changes in the first 2 hours after inhalation. Red line plots data for short-acting β-agonist (SABA); blue line represents formoterol or indacaterol; purple line represents salmeterol or long-acting muscarinic antagonist (LAMA). Graph segment B depicts action from 4 to 12 hours. Of note, the SABA has already passed its peak effect (orange line). The purple line reflects indacaterol and tiotropium dose profile, whereas the red line reflects both salmeterol and formoterol time courses. Graph segment C extends duration to 24 hours and represents the effect of tiotropium and indacaterol.

Although consideration has been given to the possibility of tachyphylaxis with β₂-agonists, it has been difficult to establish that this occurs in clinical settings. Some data suggest that it may happen to a minor degree with formoterol, but this does not seem to lead to any clinically important difference, and there is certainly no waning of the bronchodilator and clinically relevant actions of any of these drugs when tested in clinical trials. By contrast, an oral agent, viozan, which was developed because of its combination of β₂ and dopaminergic agonist effects, is associated with dramatic tachyphylaxis after several months of use and was never taken forward. Hence, this can be a problem when β-agonists are delivered in certain ways, but it does not seem to be an issue when the inhaled route is adopted.

Antimuscarinic Agents: Clinical Considerations

Antimuscarinic drugs (which also are called anticholinergic agents almost interchangeably, adding an element of confusion to any consideration of this topic) have been developed exclusively for use by the inhaled route. This limited approach reflects the significant side effect profile associated with systemically available drugs such as atropine, which produce a range of pharmacologically predictable adverse events including tachycardia, dry mouth, blurred vision, constipation, and prostatism. The pharmacologic manipulation of the atropine molecule by the addition of an ammonium residue greatly reduces the ability of the drug to cross lipid membranes and hence limits the action of the agent to the airways, rather than allowing systemic absorption. By far the most widely used agent in the past has been ipratropium, which is a short-acting muscarinic antagonist (SAMA) whose duration of effects measured by FEV₁ change is similar to and in general slightly greater than that for SABA drugs (see Figure 15-7). The development of tiotropium, an effective long-acting once-daily inhaled muscarinic antagonist (LAMA), has greatly reduced the use of ipratropium, and newer agents in this class also are being developed. Details of the dose, duration of action, and formulation of these drugs are presented in Table 15-1.

Inhaled antimuscarinic drugs are relatively nonspecific antagonists that block the uptake of acetylcholine at all three clinically relevant muscarinic receptor sites. The main benefit is the result of blockade at the M₃ receptors, but to some extent, blocking the M₂ receptors is a disadvantage because this reduces the reuptake of acetylcholine from the synaptic cleft and antagonizes the blockade of these receptors by the drug. It has been argued that this effect is less important with drugs like tiotropium, but in fact the relative kinetics of receptor occupancy, although longer with tiotropium than with ipratropium, are the same, so any specific advantage for this LAMA, beyond its extended duration of action as a bronchodilator, is unlikely. As with the β-agonists, there is a relatively shallow dose-response relationship with antimuscarinic drugs. These agents do protect against specific agonist challenge, such as with methacholine, and this protective effect has been demonstrated in asthmatic subjects. However, the efficacy of receptor antagonism appears to be less than that seen with agonist drugs, at least in asthma (see earlier), so the major portion of the data on antimuscarinic agents has come from patients with COPD. In this context, high doses of ipratropium (250 to 500 µg administered by nebulizer) have been shown to be more effective in improving lung function (as assessed by changes in FEV₁ and inspiratory capacity) than lower doses of ipratropium (40 µg). Although these differences appear to be small, they may be relevant, particularly when patients have difficulty using inhaled devices and when they are experiencing an acute exacerbation of disease. This explains the popularity of nebulized anticholinergic drugs for use in management of acute exacerbations of airways disease (see later).

As with β-agonists, the duration of effect of SAMA drugs is relatively brief, certainly compared with once-daily agents like tiotropium. And even when ipratropium is taken on a four-times-daily regimen, its clinical effectiveness is significantly less in patients with COPD than once-daily tiotropium, which is associated with better health status, fewer exacerbations, and better-maintained morning lung function. As a result, within the context of COPD, LAMA drug regimens are now the preferred form of maintenance bronchodilator therapy. Other agents in this class are currently being developed, such as glycopyrrolate and aclidinium bromide. The latter drug was believed to have a full 24-hour action, but clinical trials have suggested that it is likely to be more effective if used as a twice-daily inhaled drug. In general, little evidence of tachyphylaxis has been accrued for any of the antimuscarinic agents.

Theophylline

Theophylline drugs have been used for many years in the treatment of airway disease. These drugs were developed after the original observation that xanthine-containing preparations such as coffee and tea had some mild bronchodilator action. Because this group of agents was in use before current drug licensing processes were developed, they have not been subjected to the same rigorous safety and efficacy evaluation required for newer drugs. Direct comparison of theophylline with those inhaled agents already described provides a fairly clear picture of their relative efficacy. Theophylline is the typical example of this class, although it has been modified as aminophylline for intravenous use. These drugs have complex pharmacologic effects, including inhibition of a range of phosphodiesterase enzymes with a rise in intracellular cAMP as a result, as well as adenosine antagonism and a range of potentially antiinflammatory actions. In terms of bronchodilatation, these seem to be associated mainly with antagonism of the phosphodiesterase-3 (PDE3) receptor. This is not necessarily a very potent way to produce bronchodilatation, and these agents are less effective, both in vitro and in vivo, than other, alternative medications.

Theophyllines can be used only by the oral or intravenous route and, for reasons that remain somewhat unclear, appear to be entirely ineffective when given by inhalation. This limitation is unfortunate, because these drugs have a significant adverse event profile, as summarized in Table 15-3. The most dramatic problems are those associated with the unanticipated onset of ventricular tachycardia and of grand mal epileptic convulsions. However, a number of other troublesome side effects are typical of this group and probably are mediated by PDE4 inhibition—namely, headache, nausea, insomnia, vomiting, diarrhea, and poor appetite. These effects occur frequently with theophyllines and are dose-related. Unfortunately, the pharmacokinetics of this class of agents is rather variable, and their absorption is influenced by food and the way in which the drug is presented. Although slow-release preparations have been developed, their use increases the cost of what would otherwise be relatively inexpensive medication. It has been suggested, but not conclusively established, that introducing these drugs in low doses with gradual buildup subsequently is associated with lower incidence of unpleasant adverse events. Nonetheless, it also is a requirement that theophylline levels be monitored to ensure that the patient is not exposed to undue risks of toxicity.

Table 15-3 Factors Affecting Theophylline Metabolism in Chronic Obstructive Pulmonary Disease (COPD)*

* Factors posing particular problems in COPD are indicated by superscript plus signs, the number depending on the likely hazards.

More recently, interesting experimental data have suggested that these agents when given at lower dose have an antiinflammatory effect, and a mechanism has been suggested to explain why this might be important in patients who are smokers, because it would overcome antagonism directly created by the effects of inhaled corticosteroids. This experimental data need to be translated into a clinical setting to ensure that the magnitude of benefit is worth the hazard associated with taking even low doses of these drugs. In most clinical guidelines, theophyllines are now regarded as drugs to be tried in patients where other therapies have not been effective, so their overall use has declined significantly in the past decade.

Drug Delivery

As noted earlier, the most effective bronchodilator drugs are delivered by the inhaled route, which minimizes the dose to the patient while increasing the directly available concentration of the drug at the desired site of action within the airways. Inhalation therapy is more complex than oral treatment, however, and in some settings and cultures, barriers to its uptake remain. As noted in Table 15-1, short-acting inhaled bronchodilators are available both as metered dose inhalers and in dry powder devices. Long-acting inhaled β-agonists also are available in both these forms, but at present tiotropium, the most widely used LAMA drug, is available only as a dry powder. No standardization of inhalation devices used to deliver these drugs has been attempted, but the general requirements for effective inhaler use have been codified and are presented in Table 15-4. An assessment of the effectiveness of the patient’s inhaler technique is one of the most important components of the clinical review on follow-up visits. The ability to use inhalers properly is not related to educational status or age and seems to be somewhat unpredictable. The use of spacer devices can improve the percentage of drug delivered and often can sidestep problems with incoordination. A variety of such devices are available for use with metered dose inhalers. Spacers can be helpful when the need to limit side effects due to inhaled corticosteroids is a primary consideration but also can increase the effectiveness of bronchodilator delivery if the drug is reaching the airway, rather than being swallowed and metabolized. Breath-activated inhalers help some patients who find it hard to coordinate inspiration and device actuation, and often a change to a different delivery system (e.g., switching to a dry powder formulation from a metered dose inhaler) can improve matters significantly. Wet nebulization formulations of both SABA and SAMA drugs are available, but their potential for greater effect reflects the much higher doses given, rather than improvement in the deposition of the drug. These systems are operator-independent and thus well suited for use by distressed patients experiencing exacerbations of symptoms. How much of this acute benefit derives from the drug and how much from the cooling effects on the face of the mist in which it is delivered remain to be quantified.

Table 15-4 Technique for Use of Metered Dose Inhalers in Obstructive Lung Disease

Use of Bronchodilator Drugs in Clinical Practice

The uses of bronchodilators in specific diseases are considered elsewhere in this book. This section presents a brief overview of the main clinical indications for this group of agents at present.

Controversies and Pitfalls with Bronchodilator Drugs

Despite the well-described pharmacologic properties and abundant clinical trial data on the use of bronchodilator drugs, some areas of controversy remain. It is now accepted that inhaled β₂-agonists produce greater degrees of bronchodilatation than those achievable with antimuscarinic agents in the treatment of asthma. This observation probably reflects the additional pharmacologic properties of these drugs as discussed, plus the potential advantages of an agonist over an antagonist agent in inducing smooth muscle relaxation. By contrast, antimuscarinic drugs such as ipratropium and tiotropium have been thought, on balance, to be more effective than inhaled β₂-agonists. As noted, however, this view is now being challenged with the advent of drugs such as indacaterol and oldanterol, which have a truly 24-hour duration of action and, in terms of lung function, appear to be as effective as antimuscarinic drugs in the management of COPD. Almost all available data on the action of bronchodilator drugs in lung disease come from studies in COPD and asthma, and these drugs commonly are used to help airflow obstruction in other settings, such as those of bronchiectasis and obliterative bronchiolitis. Whether these agents have equivalent effects in different disease states remains unclear, although it seems unlikely that their use will be prohibited on these grounds. Most of the data on bronchodilators come from trials of efficacy that established that the treatment is beneficial but have not necessarily studied how effective such treatment is in a “real-world” clinical setting. Here, many other factors come into play, such as adherence to treatment and patient choice, as well as perception and information, and optimizing these aspects of care is as likely to be important as any minor differences in the pharmacology of the agents selected. Finally, a much-needed look at these issues could be realized with good studies of the use of theophylline in stable lung disease on a background of other existing modern treatments. Implementation of such studies would be particularly problematic in the context of bronchial asthma, for which inhaled corticosteroids are seen as first-line therapy but would seem to be possible in COPD, a condition that affects many people, particularly those in the developing economies, who cannot afford more expensive combination treatment.

Concerns about safety of bronchodilator drugs have been present for many years since the first asthma epidemics were associated with excess use of nonspecific adrenergic stimulants such as isoprenaline and the subsequent problems associated with the use of fenoterol. These issues have not been helped by the sometimes overoptimistic promotion of new bronchodilator drugs by their advocates, including the manufacturers. The issues of β₂-agonists and asthma safety have already been considered, but it is unlikely that a clear-cut response to these concerns can be obtained until the large 6-month safety trials being conducted by the U.S. Food and Drug Administration (FDA) have been completed. Inevitably, some clinicians and patients will remain suspicious of the ultimate benefit of these agents in this context. Similar concerns about the cardiovascular safety of antimuscarinic drugs have been raised, although in general it has been possible to offer good clinical trial data that these risks have been exaggerated. The latest concerns, based on a metaanalysis of registration studies for the soft mist form of tiotropium, also have suggested a significant increase in the risk of death for patients who use this agent. A very large prospective clinical trial is now under way that should resolve this issue as well. Nonetheless, the requirement for large numbers of people who have to be studied to exclude a potential risk serves as a brake on development of new drugs in these classes.

Despite the foregoing concerns, bronchodilator drugs remain relatively safe and easy to administer. The pitfalls in their use are practical. In particular, failure to check that the patient is using the inhaler properly remains an issue with both metered dose and dry powder inhalers. Although new devices have been developed, adherence to treatment in a “real-world” setting is likely to be lower than in clinical trials. Use of “reliever” treatment is clearly preferred over maintenance therapy in patient-delivered management of many diseases, and this inclination is a particular concern in patients with asthma, in whom additional use of reliever therapy is a marker for poor asthma control. Understanding the reasons for such patient behaviors is key to effective bronchodilator use. Drugs such as theophyllines are no longer in widespread use, but patients on maintenance treatment, who often are suffering from COPD, are at serious risk for major complications if intravenous aminophylline is added to a regimen associated with already high theophylline levels. In view of the minimal evidence for efficacy of intravenous preparations, these agents are best avoided in the interest of patient safety.

The Future of Bronchodilator Therapy

Although other mechanisms including potassium channel blockade have been explored, the risk of toxicity or lack of clinical effect with alternative approaches has meant that bronchodilator treatment is still focused on the manipulation of the adrenergic and cholinergic systems recognized more than a century ago. In practice, an easier approach has been to modify the duration of drug action rather than its potency, so new treatments are likely to be given once daily. The resulting consistent bronchodilation over the 24-hour day is a particular benefit in patients with COPD and other conditions associated with persistent airflow obstruction, as was seen when tiotropium became available. Indacaterol is the first inhaled once-daily long-acting β-agonist and has been licensed in Europe for treatment of COPD. It produces improvement in lung function comparable with that seen with tiotropium, and more studies are awaited to establish whether it is equivalent to or more effective than this agent. Vilanterol and oldanterol appear to have similar properties when given by inhalation, and clinical data have been presented in abstract, although these drugs are yet to be licensed. Like formoterol, both drugs have a relatively rapid onset of action; the importance of this property when the drug is used as for maintenance therapy remains unclear, however. New LAMA drugs are being developed, and an old agent, glycopyrrolate, has been revived and repackaged as an effective once-daily anticholinergic bronchodilator.

Combining drugs of different classes may potentially achieve greater effect for a given level of adverse effects associated with each agent. This approach proved popular in the 1990s, when the combination of salbutamol and ipratropium was widely used by patients with COPD, and the concept is now being revisited with different combinations of once-daily LAMA and SABA agents. Similarly, new inhaler regimens of once-daily LABA (and potentially LAMA) drugs plus an inhaled corticosteroid are being developed as successors to the single inhaler combinations noted previously. Although the combination of all three agents in a single inhaler is being considered, complex technical issues remain to be solved regarding the simultaneous administration of consistent doses of three chemically different agents.

The limiting factor for dual-agent bronchodilator drugs, and also for new LABA combinations in general, is the concern of the FDA that such treatment might be given to patients with asthma even if that is not the labeled indication. Reflecting FDA concerns already noted that treatment with LABA drugs in patients with asthma may be dangerous, as well as the possible cardiovascular risk associated with anticholinergic agents, large (comprising approximately 11,500 patients) and hence expensive clinical trials are now a regulatory requirement to ensure the safety of such drugs. This requirement can be expected to impede the development of new treatment formulations; accordingly, the agents already discussed in detail are likely to remain the mainstay of clinical management for some time to come.