Basic and Clinical Pharmacology, 13th Ed.

Drugs Used in Asthma

Joshua M. Galanter, MD, & Homer A. Boushey, MD

CASE STUDY

A 10-year-old girl with a history of poorly controlled asthma presents to the emergency department with severe shortness of breath and audible inspiratory and expiratory wheezing. She is pale, refuses to lie down, and appears extremely frightened. Her pulse is 120 bpm and respirations 32/min. Her mother states that the girl has just recovered from a mild case of flu and had seemed comfortable until this afternoon. The girl uses an inhaler (albuterol) but “only when really needed” because her parents are afraid that she will become too dependent on medication. She administered two puffs from her inhaler just before coming to the hospital, but “the inhaler doesn’t seem to have helped.” What emergency measures are indicated? How should her long-term management be altered?

A consistent increase in the prevalence of asthma over the past 60 years has made it an extraordinarily common disease. The reasons for this increase—shared across all modern, “westernized” societies—are poorly understood, but in the United States alone, 18.9 million adults and 7.1 million children currently have asthma. The condition accounts for 15 million outpatient visits, 1.8 million emergency department visits, and 440,000 hospitalizations each year. Despite substantial improvements in the treatment for the disease, asthma still accounts for 3400 deaths per year in the USA.

The clinical features of asthma are recurrent bouts of shortness of breath, chest tightness, and wheezing, often associated with coughing. Its hallmark physiologic features are widespread, reversible narrowing of the bronchial airways and a marked increase in bronchial responsiveness to inhaled stimuli; and its pathologic features are lymphocytic, eosinophilic inflammation of the bronchial mucosa. These changes are accompanied by “remodeling” of the bronchial wall, with thickening of the lamina reticularis beneath the epithelium and hyperplasia of the bronchial vasculature, smooth muscle, secretory glands, and goblet cells.

In mild asthma, symptoms occur only intermittently, as on exposure to allergens or air pollutants, on exercise, or after viral upper respiratory infection. More severe forms of asthma are associated with more frequent and severe symptoms, especially at night. Chronic airway constriction causes persistent respiratory impairment, punctuated by frequent acute asthmatic attacks, or “asthma exacerbations.” These attacks are most often associated with viral respiratory infections and are characterized by severe airflow obstruction from intense contraction of airway smooth muscle, inspissation of mucus plugs in the airway lumen, and thickening of the bronchial mucosa from edema and inflammatory cell infiltration. The spectrum of asthma’s severity is wide, and patients are classified as having “mild intermittent,” “mild persistent,” “moderate persistent,” and “severe persistent,” either based on the frequency and severity of symptoms and the severity of airflow obstruction on pulmonary function testing or by the minimal medical therapy required to keep their asthma well-controlled, and as “exacerbation-prone” or “exacerbation-resistant” based on the frequency of asthma exacerbations.

Until recently, the entire range of asthma severity was regarded as eminently treatable, because treatments for quick relief of symptoms of acute bronchoconstriction (“short-term relievers”) and treatments for reduction in symptoms and prevention of attacks (“long-term controllers”) have been shown effective in many large, well-designed clinical trials, case-control studies, and evidence-based reviews. The persistence of high medical costs for asthma, driven largely by the costs of emergency department and hospital treatment of asthma exacerbations, was thus believed to reflect underutilization of the treatments available. Reconsideration of this view was driven by recognition that the term “asthma” is applied to a variety of different disorders sharing common clinical features but fundamentally different pathophysiologic mechanisms. Attention has thus turned to the possibility that there are different asthma forms or phenotypes, some of which are less responsive to the current mainstays of asthma controller therapy. The current view of asthma treatment may be summarized as follows: that the treatments commonly used at present are indeed effective for the most common form of the disease, as it presents in children and young adults with allergic asthma, but that there are other phenotypes of asthma for which these therapies are less effective, and that represent an unmet medical need. Accordingly, this chapter first reviews the pathophysiology of the most common form of asthma and the basic pharmacology of the agents used in its treatment. It will then turn to discussion of different forms or phenotypes of asthma and the efforts to develop effective therapies for them.

PATHOGENESIS OF ASTHMA

Classic allergic asthma is regarded as mediated by immune globulin (IgE), produced in response to exposure to foreign proteins, like those from house dust mite, cockroach, animal danders, molds, and pollens. These qualify as allergens on the basis of their induction of IgE antibody production in people exposed to them. The tendency to produce IgE is at least in part genetically determined, and asthma clusters with other allergic diseases (allergic rhinitis, eczema) in family groups. Once produced, IgE binds to high-affinity receptors (FcεR-1) on mast cells in the airway mucosa (Figure 20–1), so that re-exposure to the allergen triggers the release of mediators stored in the mast cells’ granules and the synthesis and release of other mediators. The histamine, tryptase, leukotrienes C4 and D4, and prostaglandin D2 released cause the smooth muscle contraction and vascular leakage responsible for the acute bronchoconstriction of the “early asthmatic response.” This response is often followed in 3–6 hours by a second, more sustained phase of bronchoconstriction, the “late asthmatic response,” associated with an influx of inflammatory cells into the bronchial mucosa and with an increase in bronchial reactivity. This late response is thought to be due to cytokines characteristically produced by TH2 lymphocytes, especially interleukins 5, 9, and 13. These cytokines are thought to attract and activate eosinophils, stimulate IgE production by B lymphocytes, and stimulate mucus production by bronchial epithelial cells. It is not clear whether lymphocytes or mast cells in the airway mucosa are the primary source of the mediators responsible for the late inflammatory response, but the benefits of corticosteroid therapy are attributed to their inhibition of the production of pro-inflammatory cytokines in the airways.

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FIGURE 20–1 Conceptual model for the immunopathogenesis of asthma. Exposure to allergen causes synthesis of IgE, which binds to mast cells in the airway mucosa. On re-exposure to allergen, antigen-antibody interaction on mast cell surfaces triggers release of mediators of anaphylaxis: histamine, tryptase, prostaglandin D2 (PGD2), leukotriene (LT) C4, and platelet-activating factor (PAF). These agents provoke contraction of airway smooth muscle, causing the immediate fall in forced expiratory volume in 1 sec (FEV1). Re-exposure to allergen also causes the synthesis and release of a variety of cytokines: interleukins (IL) 4 and 5, granulocyte-macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor (TNF), and tissue growth factor (TGF) from T cells and mast cells. These cytokines in turn attract and activate eosinophils and neutrophils, whose products include eosinophil cationic protein (ECP), major basic protein (MBP), proteases, and platelet-activating factor. These mediators cause the edema, mucus hypersecretion, smooth muscle contraction, and increase in bronchial reactivity associated with the late asthmatic response, indicated by a second fall in FEV1 3–6 hours after the exposure.

The allergen challenge model does not reproduce all the features of asthma. Most asthma attacks are not triggered by inhalation of allergens, but instead by viral respiratory infections. Some adults with asthma have no evidence of allergic sensitivity to allergens, and bronchospasm can be provoked by nonallergenic stimuli such as distilled water aerosol, exercise, cold air, cigarette smoke, and sulfur dioxide. This tendency to develop bronchospasm on encountering nonallergenic stimuli—assessed by measuring the fall in maximal expiratory flow provoked by inhaling serially increasing concentrations of the aerosolized cholinergic agonist methacholine—is described as “bronchial hyper-reactivity.” It is considered fundamental to asthma’s pathogenesis because it is nearly ubiquitous in patients with asthma, and its degree roughly correlates with the clinical severity of the disease.

The mechanisms underlying bronchial hyper-reactivity are incompletely understood but appear to be related to inflammation of the airway mucosa. The anti-inflammatory activity of inhaled corticosteroid (ICS) treatment is credited with preventing the increase in reactivity associated with the late asthmatic response (Figure 20–1).

Whatever the mechanisms responsible for bronchial hyper-reactivity, bronchoconstriction itself results not simply from the direct effect of the released mediators but also from their activation of neural pathways. This is suggested by the effectiveness of muscarinic receptor antagonists, which have no direct effect on smooth muscle contractility, in inhibiting the bronchoconstriction caused by inhalation of allergens and airway irritants.

The hypothesis suggested by this conceptual model—that asthmatic bronchospasm results from a combination of release of mediators and an exaggeration of responsiveness to their effects—predicts that drugs with different modes of action may effectively treat asthma. Asthmatic bronchospasm might be reversed or prevented, for example, by drugs that reduce the amount of IgE bound to mast cells (anti-IgE antibody), prevent mast cell degranulation (cromolyn or nedocromil, sympathomimetic agents, calcium channel blockers), block the action of the products released (antihistamines and leukotriene receptor antagonists), inhibit the effect of acetylcholine released from vagal motor nerves (muscarinic antagonists), or directly relax airway smooth muscle (sympathomimetic agents, theophylline).

The second approach to the treatment of asthma is aimed at reducing the level of bronchial responsiveness. Because increased responsiveness appears to be linked to airway inflammation and because airway inflammation is a feature of late asthmatic responses, this strategy is implemented both by reducing exposure to the allergens that provoke inflammation and by prolonged therapy with anti-inflammatory agents, especially inhaled corticosteroids (ICS).

image BASIC PHARMACOLOGY OF AGENTS USED IN THE TREATMENT OF ASTHMA

The drugs most used for management of asthma are adrenoceptor agonists, or sympathomimetic agents (used as “relievers” or bronchodilators) and inhaled corticosteroids (used as “controllers” or anti-inflammatory agents). Their basic pharmacology is presented elsewhere (see Chapters 9 and 39). In this chapter, we review their pharmacology relevant to asthma.

SYMPATHOMIMETIC AGENTS

Adrenoceptor agonists are mainstays in the treatment of asthma. Their binding to β receptors—abundant on airway smooth muscle cells—stimulates adenylyl cyclase and increases the formation of intracellular cAMP (Figure 20–2), thereby relaxing airway smooth muscle and inhibiting release of bronchoconstricting mediators from mast cells. They may also inhibit microvascular leakage and increase mucociliary transport. Adverse effects, especially of adrenoceptor agonists that activate β1 as well as β2 receptors, include tachycardia, skeletal muscle tremor, and decreases in serum potassium levels.

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FIGURE 20–2 Bronchodilation is promoted by cAMP. Intracellular levels of cAMP can be increased by β-adrenoceptor agonists, which increase the rate of its synthesis by adenylyl cyclase (AC); or by phosphodiesterase (PDE) inhibitors such as theophylline, which slow the rate of its degradation. Bronchoconstriction can be inhibited by muscarinic antagonists and possibly by adenosine antagonists.

Sympathomimetic agents that have been widely used in the treatment of asthma include epinephrine, ephedrine, isoproterenol, and albuterol and other β2-selective agents (Figure 20–3). Because epinephrine and isoproterenol increase the rate and force of cardiac contraction (mediated mainly by β1 receptors), they are reserved for special situations (see below).

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FIGURE 20–3 Structures of isoproterenol and several β2-selective analogs.

In general, adrenoceptor agonists are best delivered by inhalation. This results in the greatest local effect on airway smooth muscle with the least systemic toxicity. Aerosol deposition depends on the particle size, the pattern of breathing, and the geometry of the airways. Even with particles in the optimal size range of 2–5 mm, 80–90% of the total dose of aerosol is deposited in the mouth or pharynx. Particles under 1–2 μm remain suspended and may be exhaled. Bronchial deposition of an aerosol is increased by slow inhalation of a nearly full breath and by 5 or more seconds of breath-holding at the end of inspiration.

Epinephrine is an effective, rapidly acting bronchodilator when injected subcutaneously (0.4 mL of 1:1000 solution) or inhaled as a microaerosol from a pressurized canister (320 mcg per puff). Maximal bronchodilation is achieved 15 minutes after inhalation and lasts 60–90 minutes. Because epinephrine stimulates α and β1 as well as β2 receptors, tachycardia, arrhythmias, and worsening of angina pectoris are troublesome adverse effects. The cardiovascular effects of epinephrine are of value for treating the acute vasodilation and shock as well as the bronchospasm of anaphylaxis, but other, more β2-selective agents have displaced its use in asthma.

Ephedrine was used in China for more than 2000 years before its introduction into Western medicine in 1924. Compared with epinephrine, ephedrine has a longer duration, oral activity, more pronounced central effects, and much lower potency. Because of the development of more efficacious and β2-selective agonists, ephedrine is now used infrequently in treating asthma.

Isoproterenol is a potent nonselective β1 and β2 bronchodilator. When inhaled as a microaerosol from a pressurized canister, 80–120 mcg isoproterenol causes maximal bronchodilation within 5 minutes and has a 60- to 90-minute duration of action. An increase in asthma mortality in the United Kingdom in the mid-1960s was attributed to cardiac arrhythmias resulting from the use of high doses of inhaled isoproterenol. It is now rarely used for asthma.

Beta2-Selective Drugs

The β2-selective adrenoceptor agonist drugs, particularly albuterol, are now the most widely used sympathomimetics for the treatment of the bronchoconstriction of asthma (Figure 20–3). These agents differ structurally from epinephrine in having a larger substitution on the amino group and in the position of the hydroxyl groups on the aromatic ring. They are effective after inhaled or oral administration and have a longer duration of action than epinephrine or isoproterenol.

Albuterol, terbutaline, metaproterenol, and pirbuterol are available as metered-dose inhalers. Given by inhalation, these agents cause bronchodilation equivalent to that produced by isoproterenol. Bronchodilation is maximal within 15 minutes and persists for 3–4 hours. All can be diluted in saline for administration from a hand-held nebulizer. Because the particles generated by a nebulizer are much larger than those from a metered-dose inhaler, much higher doses must be given (2.5–5.0 mg vs 100–400 mcg) but are no more effective. Nebulized therapy should thus be reserved for patients unable to coordinate inhalation from a metered-dose inhaler.

Most preparations of β2-selective drugs are a mixture of R and S isomers. Only the R isomer activates the β-agonist receptor. Reasoning that the S isomer may promote inflammation, a purified preparation of the R isomer of albuterol has been developed (levalbuterol). Whether this actually presents significant advantages in clinical use is still unproven.

Albuterol and terbutaline are also available in oral form. One tablet two or three times daily is the usual regimen; the principal adverse effects are skeletal muscle tremor, nervousness, and occasional weakness. This route of administration presents no advantage over inhaled treatment and is rarely prescribed.

Of these agents, only terbutaline is available for subcutaneous injection (0.25 mg). The indications for this route are similar to those for subcutaneous epinephrine—severe asthma requiring emergency treatment when aerosolized therapy is not available or has been ineffective—but it should be remembered that terbutaline’s longer duration of action means that cumulative effects may be seen after repeated injections. Large doses of parenteral terbutaline are sometimes used to inhibit the uterine contractions associated with premature labor.

A newer generation of long-acting β2-selective agonists includes salmeterol (a partial agonist) and formoterol (a full agonist). These long-acting β agonists (LABA) are potent selective β2 agonists that achieve their long duration of action (12 hours or more) as a result of high lipid solubility. This permits them to dissolve in the smooth muscle cell membrane in high concentrations or, possibly, attach to “mooring” molecules in the vicinity of the adrenoceptor. These drugs appear to interact with inhaled corticosteroids to improve asthma control. Because they have no anti-inflammatory action, they should not be used as monotherapy for asthma. Ultra-long-acting β agonists, indacaterol, olodaterol, and vilanterol, need to be taken only once a day but are currently FDA-approved only for the treatment of chronic obstructive pulmonary disease (COPD). Other long-acting β agonists approved in Europe, but not yet in the United States include bambuterol.

Toxicities

Concerns over the potential toxicities of acute treatment of asthma with inhaled sympathomimetic agents—worsened hypoxemia and cardiac arrhythmia—have been largely put to rest. It is true that the vasodilating action of β2-agonist treatment may increase perfusion of poorly ventilated lung units, transiently decreasing arterial oxygen tension (PaO2), but this effect is small, is easily overcome by the routine administration of supplemental oxygen in the treatment of severe attacks of asthma, and is soon made irrelevant by the increase in oxygen tension that follows β-agonist-induced bronchodilation. The other concern, precipitation of cardiac arrhythmias, appears unsubstantiated. In patients presenting for emergency treatment of severe asthma, irregularities in cardiac rhythm improve with the improvements in gas exchange effected by bronchodilator treatment and oxygen administration.

Not all of the concerns over the potential toxicities of chronic treatment with an inhaled β agonist—made easy by the introduction of long-acting β agonists—have been as easily resolved. One that has been resolved is the induction of tachyphylaxis to their bronchodilator action. A reduction in the bronchodilator response to low-dose β-agonist treatment can indeed be shown after several days of regular β-agonist use, but maximal bronchodilation is still achieved well within the range of doses usually given. Tachyphylaxis is more clearly reflected in a loss of the protection afforded by acute treatment with a β agonist against a later challenge by exercise or inhalation of allergen or an airway irritant. It remains to be demonstrated in a clinical trial, however, whether this loss of bronchoprotective efficacy is associated with adverse outcomes.

The demonstration of genetic variations in the β receptor raised the possibility that the risks of adverse effects might not be uniformly distributed among asthmatic patients. Attention has focused on the receptor’s B16 locus. Retrospective analyses of studies of regular β-agonist treatment suggested that asthma control deteriorated among patients homozygous for arginine at this locus, a genotype found in 16% of the Caucasian population but more commonly in African Americans. It was thus tempting to speculate that a genetic variant may underlie the report of an increase in asthma mortality from regular use of a long-acting β agonist in studies involving very large numbers of patients (see below), but several studies of LABA treatment have since shown the differences in multiple measures of asthma control to be nil or very small in asthmatics with different Arg/Gly variations at the B16 locus. One large study of COPD patients has even suggested that regular use of salmeterol reduced the risk of exacerbations in patients homozygous for arginine at the B16 locus. The importance of genetic variants in the gene for the B16 locus in the β receptor is thus uncertain. It is nonetheless certain that pharmacogenetic studies of asthma treatment will continue to be an active focus of research, as an approach to the development of “personalized therapy.”

METHYLXANTHINE DRUGS

The three important methylxanthines are theophylline, theobromine, and caffeine. Their major source is beverages (tea, cocoa, and coffee, respectively). The use of theophylline, once a mainstay of asthma treatment, has waned with demonstration of the greater efficacy of inhaled adrenoceptor agonists for acute asthma and of inhaled anti-inflammatory agents for chronic asthma. Accelerating this decline in theophylline’s use are its toxicities (nausea, vomiting, tremulousness, arrhythmias) and the requirement for monitoring serum levels because of the narrowness of its therapeutic index. This monitoring is made all the more necessary by individual and drug-associated differences in theopylline metabolism.

Chemistry

As shown below (Figure 20–4), theophylline is 1,3-dimethylxanthine; theobromine is 3,7-dimethylxanthine; and caffeine is 1,3,7-trimethylxanthine. A theophylline preparation commonly used for therapeutic purposes is aminophylline, a theophylline-ethylenediamine complex. The pharmacokinetics of theophylline are discussed below (see Clinical Uses of Methylxanthines). Its metabolic products, partially demethylated xanthines (not uric acid), are excreted in the urine.

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FIGURE 20–4 Structures of theophylline and other methylxanthines.

Mechanism of Action

Several mechanisms have been proposed for the actions of methylxanthines, but none has been firmly established. At high concentrations, they can be shown in vitro to inhibit several members of the phosphodiesterase (PDE) enzyme family thereby increasing concentrations of intracellular cAMP and, in some tissues, cGMP (Figure 20–2). Cyclic AMP regulates many cellular functions including, but not limited to, stimulation of cardiac function, relaxation of smooth muscle, and reduction in the immune and inflammatory activity of specific cells.

Of the various isoforms of PDE identified, inhibition of PDE3 appears to be the most involved in relaxing airway smooth muscle and inhibition of PDE4 in inhibiting release of cytokines and chemokines, which in turn results in a decrease in immune cell migration and activation. This anti-inflammatory effect is achieved at doses lower than those necessary for bronchodilation.

In an effort to reduce toxicity while maintaining therapeutic efficacy, selective inhibitors of PDE4 have been developed. Many were abandoned after clinical trials showed that their toxicities of nausea, headache, and diarrhea restricted dosing to subtherapeutic levels, but one, roflumilast, has been approved by the FDA as a treatment for COPD, though not for asthma.

Another proposed mechanism is inhibition of cell surface receptors for adenosine. These receptors modulate adenylyl cyclase activity, and adenosine has been shown to provoke contraction of isolated airway smooth muscle and histamine release from airway mast cells. It has been shown, however, that xanthine derivatives devoid of adenosine antagonism (eg, enprofylline) can inhibit bronchoconstriction in asthmatic subjects.

A third mechanism of action may underlie theophylline’s efficacy: enhancement of histone deacetylation. Acetylation of core histones is necessary for activation of inflammatory gene transcription. Corticosteroids act, at least in part, by recruiting histone deacetylases to the site of inflammatory gene transcription, an action enhanced by low-dose theophylline. This interaction should predict that low-dose theophylline treatment would enhance the effectiveness of corticosteroid treatment, and some clinical trials indeed support the idea that theophylline treatment is effective as add-on therapy in patients with asthma or COPD uncontrolled by ICS plus LABA therapy.

Pharmacodynamics

The methylxanthines have effects on the central nervous system, kidney, and cardiac and skeletal muscle as well as smooth muscle. Of the three agents, theophylline is most selective in its smooth muscle effects, whereas caffeine has the most marked central nervous system effects.

A. Central Nervous System Effects

All methylxanthines—but especially caffeine—cause mild cortical arousal with increased alertness and deferral of fatigue. The caffeine contained in beverages—eg, 100 mg in a cup of coffee—is sufficient to cause nervousness and insomnia in sensitive individuals and slight bronchodilation in patients with asthma. The larger doses necessary for more effective bronchodilation cause nervousness and tremor. Very high doses, from accidental or suicidal overdose, cause medullary stimulation, convulsions, and even death.

B. Cardiovascular Effects

Methylxanthines have positive chronotropic and inotropic effects on the heart. At low concentrations, these effects result from inhibition of presynaptic adenosine receptors in sympathetic nerves, increasing catecholamine release at nerve endings. The higher concentrations (> 10 μmol/L, 2 mg/L) associated with inhibition of phosphodiesterase and increases in cAMP may result in increased influx of calcium. At much higher concentrations (> 100 μmol/L), sequestration of calcium by the sarcoplasmic reticulum is impaired.

The clinical expression of these effects on cardiovascular function varies among individuals. Ordinary consumption of methylxanthine-containing beverages usually produces slight tachycardia, an increase in cardiac output, and an increase in peripheral resistance, raising blood pressure slightly. In sensitive individuals, consumption of a few cups of coffee may result in arrhythmias. High doses of these agents relax vascular smooth muscle except in cerebral blood vessels, where they cause contraction.

Methylxanthines decrease blood viscosity and may improve blood flow under certain conditions. The mechanism of this action is not well defined, but the effect is exploited in the treatment of intermittent claudication with pentoxifylline, a dimethylxanthine agent.

C. Effects on Gastrointestinal Tract

The methylxanthines stimulate secretion of both gastric acid and digestive enzymes. However, even decaffeinated coffee has a potent stimulant effect on secretion, which means that the primary secretagogue in coffee is not caffeine.

D. Effects on Kidney

The methylxanthines—especially theophylline—are weak diuretics. This effect may involve both increased glomerular filtration and reduced tubular sodium reabsorption. The diuresis is not of sufficient magnitude to be therapeutically useful.

E. Effects on Smooth Muscle

The bronchodilation produced by the methylxanthines is the major therapeutic action in asthma. Tolerance does not develop, but adverse effects, especially in the central nervous system, limit the dose (see below). In addition to their effect on airway smooth muscle, these agents—in sufficient concentration—inhibit antigen-induced release of histamine from lung tissue; their effect on mucociliary transport is unknown.

F. Effects on Skeletal Muscle

The respiratory actions of methylxanthines are not confined to the airways, for they also improve contractility of skeletal muscle and reverse fatigue of the diaphragm in patients with COPD. This effect—rather than an effect on the respiratory center—may account for theophylline’s ability to improve the ventilatory response to hypoxia and to diminish dyspnea even in patients with irreversible airflow obstruction.

Clinical Uses

Of the xanthines, theophylline is the most effective bronchodilator. It relieves airflow obstruction in acute asthma and reduces the severity of symptoms in patients with chronic asthma. Theophylline base is only slightly soluble in water, so it is administered as several salts containing varying amounts of theophylline base. Most preparations are well absorbed from the gastrointestinal tract; absorption of rectal suppositories is unreliable. Numerous sustained-release preparations are available and can produce therapeutic blood levels for 12 hours or more. These preparations offer the advantages of less frequent drug administration, less fluctuation of theophylline blood levels, and more effective treatment of nocturnal bronchospasm.

Theophylline should be used only where methods to measure blood levels are available. Improvement in pulmonary function is correlated with plasma concentrations in the range of 5–20 mg/L. Anorexia, nausea, vomiting, abdominal discomfort, headache, and anxiety may occur at concentrations of 15 mg/L and become common at concentrations more than 20 mg/L. Higher levels (> 40 mg/L) may cause seizures or arrhythmias; these may not be preceded by gastrointestinal or neurologic warning symptoms.

The plasma clearance of theophylline varies widely. It is metabolized by the liver, so usual doses may lead to toxic concentrations in patients with liver disease. Conversely, clearance may be increased through the induction of hepatic enzymes by cigarette smoking or by changes in diet. In normal adults, the mean plasma clearance is 0.69 mL/kg/min. Children clear theophylline faster than adults (1–1.5 mL/kg/min). Neonates and young infants have the slowest clearance (see Chapter 60). Even when maintenance doses are altered to correct for the above factors, plasma concentrations vary widely.

Theophylline improves long-term control of asthma when taken as the sole maintenance treatment or when added to inhaled corticosteroids. It is inexpensive, and it can be taken orally. Its use, however, also requires occasional measurement of plasma levels; it often causes unpleasant minor side effects (especially insomnia); and accidental or intentional overdose can result in severe toxicity or death. For oral therapy with the prompt-release formulation, the usual dose is 3–4 mg/kg of theophylline every 6 hours. Changes in dosage result in a new steady-state concentration of theophylline in 1–2 days, so the dosage may be increased at intervals of 2–3 days until therapeutic plasma concentrations are achieved (10–20 mg/L) or until adverse effects develop.

The development of more effective bronchodilators (β2-selective adrenergic agonists) and more effective anti-inflammatory agents (ICS) with fewer adverse effects has resulted in the decline in the clinical use of theophylline. Typically, theophylline is rarely used as monotherapy and, when prescribed, is most commonly used as add-on therapy when treatment with other agents, principally ICS, is inadequate.

ANTIMUSCARINIC AGENTS

Observation of the use of leaves from Datura stramonium for asthma treatment in India led to the discovery of atropine, a potent competitive inhibitor of acetylcholine at postganglionic muscarinic receptors, as a bronchodilator. Interest in the potential value of antimuscarinic agents increased with demonstration of the importance of the vagus nerves in bronchospastic responses of laboratory animals and with the development of ipratropium, a potent atropine analog that is poorly absorbed after aerosol administration and is therefore relatively free of systemic atropine-like effects.

Mechanism of Action

Muscarinic antagonists competitively inhibit the action of acetylcholine at muscarinic receptors (see Chapter 8). In the airways, acetylcholine is released from efferent endings of the vagus nerves, and muscarinic antagonists block the contraction of airway smooth muscle and the increase in secretion of mucus that occurs in response to vagal activity (Figure 20–5). Very high concentrations—well above those achieved even with maximal therapy—are required to inhibit the response of airway smooth muscle to nonmuscarinic stimulation. This selectivity of muscarinic antagonists accounts for their usefulness as investigative tools to examine the role of parasympathetic pathways in bronchomotor responses but limits their usefulness in preventing bronchospasm. In the doses given, antimuscarinic agents inhibit only that portion of the response mediated by muscarinic receptors, which varies by stimulus, and which further appears to vary among individual responses to the same stimulus.

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FIGURE 20–5 Mechanisms of response to inhaled irritants. The airway is represented microscopically by a cross-section of the wall with branching vagal sensory endings lying adjacent to the lumen. Afferent pathways in the vagus nerves travel to the central nervous system; efferent pathways from the central nervous system travel to efferent ganglia. Postganglionic fibers release acetylcholine (ACh), which binds to muscarinic receptors on airway smooth muscle. Inhaled materials may provoke bronchoconstriction by several possible mechanisms. First, they may trigger the release of chemical mediators from mast cells. Second, they may stimulate afferent receptors to initiate reflex bronchoconstriction or to release tachykinins (eg, substance P) that directly stimulate smooth muscle contraction.

Clinical Uses

Antimuscarinic agents are effective bronchodilators. Even when administered by aerosol, the bronchodilation achievable with atropine, the prototypic muscarinic antagonist, is limited by absorption into the circulation and across the blood-brain barrier. Greater bronchodilation, with less toxicity from systemic absorption, is achieved by treatment with a selective quaternary ammonium derivative of atropine, ipratropium bromide. Ipratropium can be delivered in high doses by this route because it is poorly absorbed into the circulation and does not readily enter the central nervous system. Studies with this agent have shown that the degree of involvement of parasympathetic pathways in bronchomotor responses varies among subjects. In some, bronchoconstriction is inhibited effectively; in others, only modestly. The failure of higher doses of the muscarinic antagonist to further inhibit the response in these individuals indicates that mechanisms other than parasympathetic reflex pathways must be involved.

Even in the subjects least protected by this antimuscarinic agent, however, the bronchodilation and partial inhibition of provoked bronchoconstriction are of clinical value, and antimuscarinic agents are especially useful for patients intolerant of inhaled β-agonist agents. Although antimuscarinic drugs appear to be slightly less effective in reversing asthmatic bronchospasm, the addition of ipratropium enhances the bronchodilation produced by nebulized albuterol in acute severe asthma.

Ipratropium appears to be as effective as albuterol in patients with COPD who have at least partially reversible obstruction. Longer-acting antimuscarinic agents, tiotropium and aclidinium, are approved for maintenance therapy of COPD. These drugs bind to M1, M2, and M3 receptors with equal affinity, but dissociate most rapidly from M2 receptors, expressed on the efferent nerve ending. This means that they do not inhibit the M2-receptor-mediated inhibition of acetylcholine release and thus benefit from a degree of receptor selectivity. They are taken by inhalation. A single dose of 18 mcg of tiotropium has a 24-hour duration of action, whereas inhalation of 400 mcg of aclidinium has a 12-hour duration of action and is thus taken twice daily. Daily inhalation of tiotropium has been shown not only to improve functional capacity of patients with COPD, but also to reduce the frequency of exacerbations of their condition. Neither drug has been approved as maintenance treatment for asthma, but the addition of tiotropium has recently been shown to be no less effective than addition of a long-acting β agonist in asthmatic patients insufficiently controlled by ICS therapy alone.

CORTICOSTEROIDS

Mechanism of Action

Corticosteroids (specifically, glucocorticoids) have long been used in the treatment of asthma and are presumed to act by their broad anti-inflammatory efficacy, mediated in part by inhibition of production of inflammatory cytokines (see Chapter 39). They do not relax airway smooth muscle directly but reduce bronchial hyper-reactivity and reduce the frequency of asthma exacerbations if taken regularly. Their effect on airway obstruction is due in part to their contraction of engorged vessels in the bronchial mucosa and their potentiation of the effects of β-receptor agonists, but their most important action is inhibition of the infiltration of asthmatic airways by lymphocytes, eosinophils, and mast cells. The remarkable benefits of glucocorticoid treatment for patients with severe asthma have been noted since the 1950s. So too, unfortunately, have been the numerous and severe toxicities of systemic glucocorticoid treatment, especially when given repeatedly, as is necessary for a chronic disease like asthma. The development of beclomethasone in the 1970s as a topically active glucocorticoid preparation that can be taken by inhalation was thus a landmark development. It enabled delivery of high doses of a glucocorticoid to the target tissue—the bronchial mucosa—with little absorption into the systemic circulation. The development of ICS has transformed the treatment of all but mild, intermittent asthma, which can be controlled by “as-needed” use of albuterol alone.

Clinical Uses

Clinical studies of corticosteroids consistently show them to be effective in improving all indices of asthma control: severity of symptoms, tests of airway caliber and bronchial reactivity, frequency of exacerbations, and quality of life. Because of severe adverse effects when given chronically, oral and parenteral corticosteroids are reserved for patients who require urgent treatment, ie, those who have not improved adequately with bronchodilators or who experience worsening symptoms despite maintenance therapy. Regular or “controller” therapy is maintained with ICS in all but the most severely affected individuals.

Urgent treatment is often begun with an oral dose of 30–60 mg prednisone per day or an intravenous dose of 1 mg/kg methylprednisolone every 6–12 hours; the dose is decreased after airway obstruction has improved. In most patients, systemic corticosteroid therapy can be discontinued in 5–10 days, but in other patients symptoms may worsen as the dose is decreased to lower levels.

Inhalational treatment is the most effective way to avoid the systemic adverse effects of corticosteroid therapy. The introduction of ICS such as beclomethasone, budesonide, ciclesonide, flunisolide, fluticasone, mometasone,and triamcinolone has made it possible to deliver corticosteroids to the airways with minimal systemic absorption. An average daily dose of 800 mcg of inhaled beclomethasone is equivalent to about 10–15 mg/d of oral prednisone for the control of asthma, with far fewer systemic effects. Indeed, one of the cautions in switching patients from oral to ICS therapy is to taper oral therapy slowly to avoid precipitation of adrenal insufficiency. In patients requiring continued prednisone treatment despite standard doses of an inhaled corticosteroid, higher inhaled doses are often effective and enable tapering and discontinuing prednisone treatment. Although these high doses of inhaled steroids may cause adrenal suppression, the risks of systemic toxicity from their chronic use are negligible compared with those of the oral corticosteroid therapy they replace.

A special problem caused by inhaled topical corticosteroids is the occurrence of oropharyngeal candidiasis. This is easily treated with topical cotrimazole, and the risk of this complication can be reduced by having patients gargle water and expectorate after each inhaled treatment. Ciclesonide, the most recently approved ICS, is a prodrug activated by bronchial esterases, and though no more effective in the treatment of asthma, has been associated with less frequent candidiasis. Hoarseness can also result from a direct local effect of ICS on the vocal cords. Although a majority of the inhaled dose is deposited in the oropharynx and swallowed, inhaled corticosteroids are subject to first-pass metabolism in the liver and thus are remarkably free of other short-term complications in adults. Nonetheless, chronic use may increase the risks of osteoporosis and cataracts. In children, ICS therapy has been shown to slow the rate of growth by about 1 cm over the first year of treatment, but not the rate of growth thereafter, so that the effect on adult height is minimal.

Because of the efficacy and safety of inhaled corticosteroids, national and international guidelines for asthma management recommend their prescription for patients who require more than occasional inhalations of a β agonist for relief of symptoms. This therapy is continued for 10–12 weeks and then withdrawn to determine whether more prolonged therapy is needed. Inhaled corticosteroids are not curative. In most patients, the manifestations of asthma return within a few weeks after stopping therapy even if they have been taken in high doses for 2 or more years. A prospective, placebo-controlled study of the early, sustained use of inhaled corticosteroids in young children with asthma showed significantly greater improvement in asthma symptoms, pulmonary function, and frequency of asthma exacerbations over the 2 years of treatment, but no difference in overall asthma control 3 months after the end of the trial. Inhaled corticosteroids are thus properly labeled as “controllers.” They are effective only so long as they are taken.

Another approach to reducing the risk of long-term, twice-daily use of ICS is to administer them only intermittently, when symptoms of asthma flare. Taking a single inhalation of an ICS with each inhalation of a short-acting β-agonist reliever (eg, an inhalation of beclomethasone for each inhalation of albuterol) or taking a 5- to 10-day course of twice-daily high-dose budesonide or beclomethasone when asthma symptoms worsen has been found to be as effective as regular daily therapy in adults and children with mild to moderate asthma, although these approaches to treatment are neither endorsed by guidelines for asthma management nor approved by the FDA.

CROMOLYN & NEDOCROMIL

Cromolyn sodium (disodium cromoglycate) and nedocromil sodium were once widely used for asthma management, especially in children, but have now been supplanted so completely by other therapies that they are mostly of historic interest. Both have low solubility, are poorly absorbed from the gastrointestinal tract, and must be inhaled as a microfine powder or microfine suspension. These drugs have no effect on airway smooth muscle tone and are ineffective in reversing asthmatic bronchospasm but effectively inhibit both antigen- and exercise-induced asthma.

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Mechanism of Action

Cromolyn and nedocromil are thought to alter the function of delayed chloride channels in cell membranes, inhibiting cell activation. This action on airway nerves is thought to mediate inhibition of cough; on mast cells and eosinophils, the drugs inhibit the early and the late response to antigen challenge.

Clinical Uses

In short-term clinical trials, pretreatment with cromolyn or nedocromil blocks the bronchoconstriction caused by allergen inhalation, exercise, sulfur dioxide, and a variety of causes of occupational asthma. This acute protective effect of a single treatment makes cromolyn useful for administration shortly before exercise or before unavoidable exposure to an allergen.

When taken regularly (2-4 puffs 2-4 times daily) both agents modestly but significantly reduce symptomatic severity and the need for bronchodilator medications, particularly in young patients with allergic asthma. These drugs are not as potent or as predictably effective as ICS, and the only way of determining whether a patient will respond is by a therapeutic trial of 4 weeks’ duration.

Cromolyn and nedocromil solutions are also useful in reducing symptoms of allergic rhinoconjunctivitis. Applying the solution by nasal spray or eye drops several times a day is effective in about 75% of patients, even during the peak pollen season.

Because the drugs are so poorly absorbed, adverse effects of cromolyn and nedocromil are minor and are localized to the sites of deposition. These include throat irritation, cough, and mouth dryness, and, rarely, chest tightness and wheezing. Inhalation of a β2-adrenoceptor agonist before cromolyn or nedocromil treatment can prevent some of these symptoms. Serious adverse effects are rare. Reversible dermatitis, myositis, or gastroenteritis occurs in less than 2% of patients, and a very few cases of pulmonary infiltration with eosinophilia and anaphylaxis have been reported. This lack of toxicity accounts for cromolyn’s formerly widespread use in children, especially during ages of rapid growth. Its place in treatment of childhood asthma has lately diminished, however, because of the significantly greater efficacy of even low-dose corticosteroid treatment and because of the availability of an alternate nonsteroidal controller class of medication, the leukotriene pathway inhibitors (see below).

LEUKOTRIENE PATHWAY INHIBITORS

Because of the evidence of leukotriene involvement in many inflammatory diseases (see Chapter 18) and in anaphylaxis, considerable effort has been expended on the development of drugs that block their synthesis or interaction with their receptors. Leukotrienes result from the action of 5-lipoxygenase on arachidonic acid and are synthesized by a variety of inflammatory cells in the airways, including eosinophils, mast cells, macrophages, and basophils. Leukotriene B4 (LTB4) is a potent neutrophil chemoattractant, and LTC4 and LTD4 exert many effects known to occur in asthma, including bronchoconstriction, increased bronchial reactivity, mucosal edema, and mucus hypersecretion. Antigen challenge of sensitized human lung tissue in vitro results in the generation of leukotrienes. Inhalation of leukotrienes by volunteers with asthma results not only in bronchoconstriction but also in an increase in bronchial reactivity.

Two approaches to interrupting the leukotriene pathway have been pursued: inhibition of 5-lipoxygenase, thereby preventing leukotriene synthesis; and inhibition of the binding of LTD4 to its receptor on target tissues, thereby preventing its action. Efficacy in blocking airway responses to exercise and to antigen challenge has been shown for drugs in both categories: zileuton, a 5-lipoxygenase inhibitor, and zafirlukast and montelukast, LTD4-receptor antagonists (Figure 20–6). All have been shown to improve asthma control and to reduce the frequency of asthma exacerbations in clinical trials. Their effects on symptoms, airway caliber, bronchial reactivity, and airway inflammation are less marked than the effects of ICS, but they are more nearly equal in reducing the frequency of exacerbations. Their principal advantage is that they are taken orally; some patients—especially children—comply poorly with inhaled therapies. Montelukast is approved for children as young as 12 months.

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FIGURE 20–6 Structures of leukotriene receptor antagonists (montelukast, zafirlukast) and of the 5-lipoxygenase inhibitor (zileuton).

Some patients appear to have particularly favorable responses, but no clinical features aside from the subclass of patients with aspirin-sensitive asthma described below allow identification of “responders” before a trial of therapy. In the USA, zileuton is approved for use in an oral dosage of 1200 mg of the sustained-release form twice daily; zafirlukast, 20 mg twice daily; and montelukast, 10 mg (for adults) or 4 mg (for children) once daily.

Trials with leukotriene inhibitors have demonstrated an important role for leukotrienes in aspirin-induced asthma. It has long been known that in 5–10% of patients with asthma, ingestion of even a very small dose of aspirin causes profound bronchoconstriction and symptoms of systemic release of histamine, such as flushing and abdominal cramping. Because this reaction to aspirin is not associated with any evidence of allergic sensitization to aspirin or its metabolites and because it is produced by any of the nonsteroidal anti-inflammatory agents, it is thought to result from inhibition of prostaglandin synthetase (cyclooxygenase), shifting arachidonic acid metabolism from the prostaglandin to the leukotriene pathway, especially in platelets adherent to circulating neutrophils. Support for this idea was provided by the demonstration that leukotriene pathway inhibitors impressively reduce the response to aspirin challenge and improve overall control of asthma on a day-to-day basis.

Of these agents, montelukast is by far the most prescribed, probably because it can be taken without regard to meals, because of the convenience of once-daily treatment, and because of patient fear of inhaled corticosteroids. Zileuton is the least prescribed because of reports of liver toxicity. The receptor antagonists appear to have little toxicity. Early reports of Churg-Strauss syndrome (a systemic vasculitis accompanied by worsening asthma, pulmonary infiltrates, and eosinophilia) appear to have been coincidental, with the syndrome unmasked by the reduction in prednisone dosage made possible by the addition of zafirlukast or montelukast.

OTHER DRUGS IN THE TREATMENT OF ASTHMA

Anti-IgE Monoclonal Antibodies

The development of a monoclonal antibody that targets IgE antibody itself was a novel approach to the treatment of asthma. The monoclonal antibody-developed omalizumab was raised in mice and then “humanized,” making it less likely to cause sensitization when given to human subjects. Because its specific target is the portion of IgE that binds to its receptors (Fcε-R1 and Fcε-R2 receptors) on mast cells and other inflammatory cells, omalizumab inhibits the binding of IgE but does not activate IgE already bound to mast cells and thus does not provoke mast cell degranulation.

Omalizumab’s use is restricted to patients with evidence of allergic sensitization, and the dose administered is adjusted for total IgE level and body weight. Given by subcutaneous injection every 2–4 weeks to asthmatic patients, it lowers free plasma IgE to undetectable levels and significantly reduces the magnitude of both early and late bronchospastic responses to antigen challenge. Omalizumab’s most important clinical effect is reduction in the frequency and severity of asthma exacerbations, even while enabling a reduction in corticosteroid requirements. It also lessens asthma severity and improves coincident nasal and conjunctival symptoms of allergic rhinitis. Combined analysis of several clinical trials has shown that the patients most likely to respond are those with a history of repeated exacerbations, a high requirement for corticosteroid treatment, and poor pulmonary function. Similarly, the exacerbations most prevented are the ones most important to prevent: omalizumab treatment reduced exacerbations requiring hospitalization by 88%. These benefits justify the high cost of this treatment in selected individuals with severe disease characterized by frequent exacerbations.

The addition of omalizumab to standard, guidelines-based therapy for asthmatic inner-city children and adolescents has been shown to significantly improve overall asthma control, reduce the need for other medications, and nearly eliminate the seasonal peaks in exacerbations attributed to viral respiratory infections. This last, unexpected, finding will likely encourage further development of IgE-targeted therapies. There is also evidence of effectiveness of omalizumab treatment for chronic urticaria (for which the drug is now approved) and peanut allergy.

FUTURE DIRECTIONS OF ASTHMA THERAPY

Ironically, the effectiveness of ICS as a treatment for most patients with asthma, especially for young adults with allergic asthma, may have retarded recognition that the term “asthma” encompasses a heterogeneous collection of disorders, many of which are poorly responsive to corticosteroid treatment. The existence of different forms or subtypes of asthma has actually long been recognized, as is implied by the use of modifying terms such as “extrinsic” versus “intrinsic,” “aspirin-sensitive,” “adult onset,” “steroid-dependent,” “exacerbation-prone,” “seasonal,” “post-viral,” and “obesity-related” to describe asthma in particular patients. More rigorous description of asthma phenotypes, based on cluster analysis of multiple clinical, physiological, and laboratory features, including analysis of blood and sputum inflammatory cell assessments, has identified as many as five different asthma phenotypes. The key question raised by this approach is whether the phenotypes respond differently to available asthma treatments.

The most persuasive evidence of the existence of different asthma phenotypes is the demonstration of differences in the pattern of gene expression in the airway epithelium among asthmatic and healthy subjects (Figure 20–7). Compared with healthy controls, half of the asthmatic participants overexpressed three genes up-regulated in airway epithelial cells by IL-13, a signature cytokine of TH2 lymphocytes. These genes express the proteins periostin, CLCA1, and serpinB2. The other half of the population did not, with some (but not all) having a pattern of airway epithelial cell gene expression suggesting exposure to IL-17. These findings suggest that fundamentally different pathophysiologic mechanisms may underlie the clinical expression of asthma even among patients with mild forms of the disease. The participants with overexpression of genes up-regulated by IL-13 are referred to as having a “TH2 molecular phenotype” (or “endotype”) of asthma. The other subjects, who did not overexpress these genes, are described as having a “non-TH2 molecular phenotype.” The TH2-type asthmatic subjects on average had more sputum and blood eosinophilia, positive skin test results, higher levels of IgE, and greater expression of certain mucin genes, but there was overlap between the groups. Though subjects in both groups showed improvement in their FEV1after treatment with albuterol, their response to treatment with 6 weeks of ICS was quite different; FEV1 improved only in the TH2-type subjects. If these findings are valid—and they have held up well so far—the implications are far-reaching; they would mean that many, perhaps as many as half of, patients with mild-moderate asthma do not respond to inhaled corticosteroid therapy. The proportion of non-inhaled corticosteroid responders among severe “steroid-resistant” asthma could be much higher.

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FIGURE 20–7 Cluster analysis of subjects according to their expression of periostin, chloride channel regulator 1 (CLCA1), and serpinB2 in bronchial epithelium. Note that cluster 1, including all subjects with high expression of these genes, contains only asthmatic subjects (A; n = 22). These are referred to as having TH2-high asthma, because the three genes are known to be up-regulated in epithelial cells by IL-13, a prototypic TH2-cytokine. Cluster 2 includes all subjects with lower levels of expression and contains all healthy control subjects (H; n = 28) and approximately half of the subjects with asthma (n = 20) now referred to as having TH2-low asthma. (B) Responsiveness of TH2-high vs TH2-low asthmatic subjects to inhaled steroids and to placebo in a randomized controlled trial. FEV1 measured at baseline (week 0), after 4 and 8 weeks on daily fluticasone (500 mcg twice daily), and 1 week after the cessation of fluticasone (week 9). (Reproduced, with permission, of the American Thoracic Society. Copyright © 2014 American Thoracic Society. Woodruff PG et al: T-helper type 2-driven inflammation defines major subphenotypes of asthma. Am J Respir Crit Care Med 2009;180:388. Official Journal of the American Thoracic Society.)

Current research has focused on further exploring molecular phenotypes in asthma and in finding effective treatments for each group. An investigational IL-13 receptor antagonist, lebrikizumab, was tested in patients with moderately severe asthma. Though its effects fell short of significance in the study as a whole, when investigators stratified the subjects based on serum levels of periostin (one of the genes up-regulated in the “TH2 molecular phenotype”), the drug was found to be effective in participants with high levels of periostin but not in those with lower levels.

A multicenter trial is embarking on a prospective double-blind, placebo-controlled trial of ICS versus tiotropium in asthmatic subjects characterized as TH2 or non-TH2 by analysis of their induced sputum samples for eosinophil number and for expression of TH2-dependent genes, with the hope of identifying patients that are optimally treated by one or the other medications.

The pace of advance in the scientific description of the immunopathogenesis of asthma has spurred the development of many new therapies that target different sites in the immune cascade. These include monoclonal antibodies directed against cytokines (IL-4, IL-5, IL-13), antagonists of cell adhesion molecules, protease inhibitors, and immunomodulators aimed at shifting CD4 lymphocytes from the TH2 to the TH1 phenotype or at selective inhibition of the subset of TH2 lymphocytes directed against particular antigens. As with the development of the IL-13 receptor antagonist, the identification of subgroups of asthma that are most likely to benefit from therapy may finally herald the advent of truly personalized asthma therapy.

image CLINICAL PHARMACOLOGY OF DRUGS USED IN THE TREATMENT OF ASTHMA

Asthma is best thought of as a disease in two time domains. In the present domain, it is important for the distress it causes—cough, nocturnal awakenings, and shortness of breath that interferes with the ability to exercise or to pursue desired activities. For mild asthma, occasional inhalation of a bronchodilator may be all that is needed. For more severe asthma, treatment with a long-term controller, like an inhaled corticosteroid, is necessary to relieve symptoms and restore function. The second domain of asthma is the risk it presents of future events, such as exacerbations, or of progressive loss of pulmonary function. Satisfaction with the ability to control symptoms and maintain function by frequent use of an inhaled β2 agonist does not mean that the risk of future events is also controlled. In fact, use of two or more canisters of an inhaled β agonist per month is a marker of increased risk of asthma fatality.

The challenges of assessing severity and adjusting therapy for these two domains of asthma are different. For relief of distress in the present domain, the key information is obtained by asking specific questions about the frequency and severity of symptoms, the frequency of rescue use of an inhaled β2 agonist, the frequency of nocturnal awakenings, and the ability to exercise. The best predictor of the risk for future exacerbations is the frequency of their occurrence in the past. Without such a history, estimation of risk is more difficult. In general, patients with poorly controlled symptoms have a heightened risk of exacerbations in the future, but some patients seem unaware of the severity of their airflow obstruction (sometimes described as “poor perceivers”) and can be identified only by measurement of pulmonary function, as by spirometry. Reductions in the FEV1 correlate with heightened risk of future attacks of asthma. Other possible markers of heightened risk are unstable pulmonary function (large variations in FEV1 from visit to visit, large change with bronchodilator treatment), extreme bronchial reactivity, or high numbers of eosinophils in sputum or of nitric oxide in exhaled air. Assessment of these features may identify patients who need increases in therapy for protection against exacerbations.

BRONCHODILATORS

Bronchodilators, such as inhaled albuterol, are rapidly effective, safe, and inexpensive. Patients with only occasional symptoms of asthma require no more than an inhaled bronchodilator taken on an as-needed basis. If symptoms require this “rescue” therapy more than twice a week, if nocturnal symptoms occur more than twice a month, or if the FEV1 is less than 80% predicted, additional treatment is needed. The treatment first recommended is a low dose of an inhaled corticosteroid, although treatment with a leukotriene receptor antagonist or with cromolyn may be used. Theophylline is now largely reserved for patients in whom symptoms remain poorly controlled despite the combination of regular treatment with an inhaled anti-inflammatory agent and as-needed use of a β2 agonist. If the addition of theophylline fails to improve symptoms or if adverse effects become bothersome, it is important to check the plasma level of theophylline to be sure it is in the therapeutic range (10–20 mg/L).

An important caveat for patients with mild asthma is that although the risk of a severe, life-threatening attack is lower than in patients with severe asthma, it is not zero. All patients with asthma should be instructed in a simple action plan for severe, frightening attacks: to take up to four puffs of albuterol every 20 minutes over 1 hour. If they do not note clear improvement after the first four puffs, they should take the additional treatments while on their way to an emergency department or other higher level of care.

MUSCARINIC ANTAGONISTS

Inhaled muscarinic antagonists have so far earned a limited place in the treatment of asthma. The effects of short-acting agents (eg, ipratropium bromide) on baseline airway resistance is nearly as great as, but no greater than, those of the sympathomimetic drugs, so they are used largely as alternative therapies for patients intolerant of β2-adrenoceptor agonists. The airway effects of antimuscarinic and sympathomimetic drugs given in full doses have been shown to be additive only in patients with severe airflow obstruction who present for emergency care.

The long-acting antimuscarinic agents tiotropium and aclidinium have not yet earned a place in the treatment for asthma, although tiotropium has been shown to be as effective as a long-acting β2 agonist when used in addition to an inhaled corticosteroid. As a treatment for COPD, these agents improve functional capacity, presumably through their action as bronchodilators, and reduce the frequency of exacerbations, through mechanisms not yet defined.

Although it was predicted that muscarinic antagonists would dry airway secretions and interfere with mucociliary clearance, direct measurements of fluid volume secretion from airway submucosal glands in animals show that atropine decreases baseline secretory rates only slightly. The drugs do, however, inhibit the increase in mucus secretion caused by vagal stimulation. No cases of inspissation of mucus have been reported following administration of these drugs.

CORTICOSTEROIDS

If asthmatic symptoms occur frequently, or if significant airflow obstruction persists despite bronchodilator therapy, inhaled corticosteroids should be started. For patients with severe symptoms or severe airflow obstruction (eg, FEV1 < 50% predicted), initial treatment with a combination of inhaled and oral corticosteroid (eg, 30 mg/d of prednisone for 10 days) is appropriate. Once clinical improvement is noted, usually after 7–10 days, the ICS should be continued, but the oral dose should be tapered to the minimum necessary to control symptoms.

An issue for inhaled corticosteroid treatment is patient adherence. Analysis of prescription renewals shows that only a minority of patients take corticosteroids regularly. This may be a function of a general “steroid phobia” fostered by emphasis in the lay press on the hazards of long-term oral corticosteroid therapy and by ignorance of the difference between corticosteroids and anabolic steroids, taken to enhance muscle strength by now-infamous athletes. This fear of corticosteroid toxicity makes it hard to persuade patients whose symptoms have improved after starting treatment that they should continue it for protection against attacks. This context accounts for the interest in reports that instructing patients with mild but persistent asthma to take inhaled corticosteroid therapy only when their symptoms worsen is as effective in maintaining pulmonary function and preventing attacks as is taking the inhaled corticosteroid twice each day (see above).

In patients with more severe asthma whose symptoms are inadequately controlled by a standard dose of an inhaled corticosteroid, two options may be considered: to double the dose of inhaled corticosteroid or to combine it with another drug. The addition of theophylline or a leukotriene-receptor antagonist modestly increases asthma control, but the most impressive benefits are afforded by addition of a long-actinginhaled β2-receptor agonist (LABA, eg, salmeterol or formoterol). Many studies have shown this combination therapy to be more effective than doubling the dose of the inhaled corticosteroid for improving asthma control. Combinations of an inhaled corticosteroid and a LABA in a single inhaler are now commonly available in fixed-dose combinations (eg, fluticasone and salmeterol [Advair]; budesonide and formoterol [Symbicort]; and mometasone and formoterol [Dulera]). The rapid onset of action of formoterol enables novel use of the combination of an inhaled corticosteroid with this long-acting β agonist. Several studies have confirmed that twice-daily plus as-needed inhalation of budesonide and formoterol is as effective in preventing asthma exacerbations as twice-daily inhalation of a four-times-higher dose of budesonide with only albuterol for relief of symptoms. Use of this flexible dosing strategy is widespread in Europe but is not approved in the USA.

Offsetting the clear benefits is evidence of a statistically significant increase in the very low risk of fatal or near-fatal asthma attacks from use of a long-acting β agonist, perhaps even when taken in combination with an inhaled corticosteroid. This evidence prompted the FDA to issue a “black box” warning of this risk, especially in African Americans. The FDA did not withdraw approval of these drugs, for it recognizes that they are clinically effective. The major implications of the black box warning for the practitioner are that: (1) patients with mild to moderate asthma should be treated with a low-dose inhaled corticosteroid alone, and additional therapy considered only if their asthma is not well controlled; and, (2) if their asthma is not well controlled, the possible increase in risk of a rare event, asthma fatality, should be discussed in presenting the options for treatment—an increase to a higher dose of the inhaled corticosteroid versus addition of a long-acting β agonist.

The FDA’s warning has not so far had much effect on prescriptions for inhaled corticosteroid/long-acting β-agonist combinations, probably because their combination in a single inhaler offers several advantages. Combination inhalers are convenient; they ensure that the long-acting β agonist will not be taken as monotherapy (known not to protect against attacks); and they produce prompt, sustained improvements in clinical symptoms and pulmonary function and reduce the frequency of exacerbations. In patients prescribed such combination treatment, it is important to provide explicit instructions that a rapid-acting inhaled β2 agonist, such as albuterol, should still be used as needed for relief of acute symptoms.

LEUKOTRIENE ANTAGONISTS; CROMOLYN & NEDOCROMIL

A leukotriene receptor antagonist taken as an oral tablet is an alternative to inhaled corticosteroid treatment in patients with symptoms occurring more than twice a week or those who are awakened from sleep by asthma more than twice a month. This place in asthma therapy was once held by cromolyn and nedocromil, but neither is now available in the USA. Although these treatments are not as effective as even a low dose of an inhaled corticosteroid, both avoid the issue of “steroid phobia” described above and are commonly used in the treatment of children.

The leukotriene receptor antagonist montelukast (Singulair) is widely prescribed, especially by primary care providers. This drug, taken orally, is easy to administer and appears to be used more regularly than ICS. Leukotriene receptor antagonists are rarely associated with troublesome side effects. Because of concerns over the possible long-term toxicity of systemic absorption of ICS, this maintenance therapy is widely used for treating children in the USA, particularly those who have concurrent symptomatic allergic rhinitis, which is also effectively treated by montelukast.

ANTI-IGE MONOCLONAL ANTIBODY

Treatment with omalizumab, the monoclonal humanized anti-IgE antibody, is reserved for patients with chronic severe asthma inadequately controlled by high-dose inhaled corticosteroid plus long-acting β-agonist combination treatment. Omalizumab reduces lymphocytic, eosinophilic bronchial inflammation, oral and inhaled corticosteroid dose requirements, and the frequency and severity of exacerbations. It is reserved for patients with demonstrated IgE-mediated sensitivity (by positive skin test or radioallergosorbent test [RAST] to common allergens) and an IgE level within a range that can be reduced sufficiently by twice-weekly subcutaneous injection.

In addition to its high cost, several factors have limited the use of omalizumab. First, it must be given as a subcutaneous injection every 2–4 weeks. Although the antibody has been humanized, it nonetheless can cause anaphylactic reactions in 0.1–0.2% of patients taking the drug. For this reason, it cannot be self-administered but must be given in a physician’s office or infusion center equipped to manage an anaphylactic reaction. Furthermore, patients receiving omalizumab must be monitored for a period of time after the injection. Even then, anaphylactic reactions have been reported over 24 hours after the injection, even in patients who had safely received the drug before. Finally, in clinical trials, a slight excess of malignancies was observed in patients receiving omalizumab compared with those assigned to the placebo group.

OTHER ANTI-INFLAMMATORY THERAPIES

For the 5–10% of the asthmatic population with severe asthma inadequately controlled by standard therapies, including high-dose inhaled corticosteroid treatment, the development of an alternative treatment is an important unmet medical need. The initial promise of oral methotrexate or gold salt injections has not been fulfilled. While the benefit from treatment with cyclosporine seems real, this drug’s toxicity makes this finding only a source of hope that other immunomodulatory therapies will ultimately emerge. Advances in understanding the immunopathogenesis of asthma may permit the identification of specific phenotypes of asthma and identification of biomarkers of their importance in particular patients. In this respect, asthma may benefit from the rapid advances in treatments developed for other chronic inflammatory conditions such as rheumatoid arthritis, ankylosing spondylitis, and inflammatory bowel disease.

MANAGEMENT OF ACUTE ASTHMA

The treatment of acute attacks of asthma in patients reporting to the hospital requires close, continuous clinical assessment and repeated objective measurement of lung function. For patients with mild attacks, inhalation of a β2-receptor agonist is as effective as subcutaneous injection of epinephrine. Both of these treatments are more effective than intravenous administration of aminophylline (a soluble salt of theophylline). Severe attacks require treatment with oxygen, frequent or continuous administration of aerosolized albuterol, and systemic treatment with prednisone or methylprednisolone (0.5 mg/kg every 6–12 hours). Even this aggressive treatment is not invariably effective, and patients must be watched closely for signs of deterioration. General anesthesia, intubation, and mechanical ventilation of asthmatic patients cannot be undertaken lightly but may be lifesaving if respiratory failure supervenes.

PROSPECTS FOR PREVENTION

The high prevalence of asthma in the developed world and its rapid increases in the developing world call for a strategy for primary prevention. Strict antigen avoidance during infancy, once thought to be sensible, has now been shown to be ineffective. In fact, growing up from birth on a farm with domestic animals or in a household where cats or dogs are kept as pets appears to protect against developing asthma. The best hope seems to lie in understanding the mechanisms by which microbial exposures during infancy foster development of a balanced immune response and then mimicking the effects of natural environmental exposures through administration of harmless microbial commensals (probiotics) or of nutrients that foster their growth (prebiotics) in the intestinal tract during the critical period of immune development in early infancy.

TREATMENT OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)

COPD is characterized by airflow limitation that is not fully reversible with bronchodilator treatment. The airflow limitation is usually progressive and is believed to reflect an abnormal inflammatory response of the lung to noxious particles or gases. The condition is most often a consequence of prolonged habitual cigarette smoking, but approximately 15% of cases occur in nonsmokers. Although COPD is different from asthma, some of the same drugs are used in its treatment. This section discusses the drugs that are useful in both conditions.

Although asthma and COPD are both characterized by airway inflammation, reduction in maximum expiratory flow, and episodic exacerbations of airflow obstruction, most often triggered by viral respiratory infection, they differ in many important respects. Most important among them are differences in the populations affected, characteristics of airway inflammation, reversibility of airflow obstruction, responsiveness to corticosteroid treatment, and course and prognosis. Compared to asthma, COPD occurs in older patients, is associated with neutrophilic rather than eosinophilic inflammation, is poorly responsive even to high-dose inhaled corticosteroid therapy, and is associated with progressive, inexorable loss of pulmonary function over time, especially with continued cigarette smoking.

Despite these differences, the approaches to treatment are similar, although the benefits expected (and achieved) are less for COPD than for asthma. For relief of acute symptoms, inhalation of a short-acting β agonist (eg, albuterol), of an anticholinergic drug (eg, ipratropium bromide), or of the two in combination is usually effective. For patients with persistent symptoms of exertional dyspnea and limitation of activities, regular use of a long-acting bronchodilator, whether a long-acting β agonist such as salmeterol or a long-acting anticholinergic (eg, tiotropium) is indicated. For patients with severe airflow obstruction or with a history of prior exacerbations, regular use of an inhaled corticosteroid reduces the frequency of exacerbations. Theophylline may have a particular place in the treatment of COPD, as it may improve contractile function of the diaphragm, thus improving ventilatory capacity. The major difference in treatment of these conditions centers on management of exacerbations. The use of antibiotics in this context is routine in COPD, because such exacerbations involve bacterial infection of the lower airways far more often in COPD than in asthma.

SUMMARY Drugs Used in Asthma

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PREPARATIONS AVAILABLE

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Beta Agonists

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Methylxanthines & Roflumilast

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Cromolyn & Nedocromil

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Corticosteroids

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Antimuscarinic Drugs

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CASE STUDY ANSWER

This patient demonstrates the destabilizing effects of a respiratory infection on asthma, and the parents demonstrate the common (and dangerous) phobia about “overuse” of bronchodilator or steroid inhalers. The patient has signs of imminent respiratory failure, including her refusal to lie down, her fear, and her tachycardia—which cannot be attributed to her minimal treatment with albuterol. Critically important immediate steps are to administer high-flow oxygen and to start albuterol by nebulization. Adding ipratropium (Atrovent) to the nebulized solution is recommended. A corticosteroid (0.5–1.0 mg/kg of methylprednisolone) should be administered intravenously. It is also advisable to alert the intensive care unit, because a patient with severe bronchospasm who tires can slip into respiratory failure quickly, and intubation can be difficult.

Fortunately, most patients treated in hospital emergency departments do well. Asthma mortality is rare (fewer than 5000 deaths per year among a population of 20 million asthmatics in the USA), and when it occurs, it is often out of hospital. Presuming this patient recovers, she needs adjustments to her therapy before discharge. The strongest predictor of severe attacks of asthma is their occurrence in the past. Thus, this patient needs to be started on a long-term controller, especially an inhaled corticosteroid, and needs instruction in an action plan for managing severe symptoms. This can be as simple as advising her and her parents that if she has a severe attack that frightens her, she can take up to four puffs of albuterol every 15 minutes, but if the first treatment does not bring significant relief, she should take the next four puffs while on her way to an emergency department or urgent care clinic. She should also be given a prescription for prednisone, with instructions to take 40–60 mg orally for severe attacks, but not to wait for it to take effect if she remains severely short of breath even after albuterol inhalations. Asthma is a chronic disease, and good care requires close follow-up and creation of a provider-patient partnership for optimal management.