The drugs most used for asthma management 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.
Adrenoceptor agonists are mainstays in the treatment of asthma. Their binding to β-adrenergic receptors—abundant on airway smooth muscle cells—stimulates adenylyl cyclase and increases the formation of intracellular cAMP (Figure 20–3), 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.
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 now widely used in the treatment of asthma include albuterol and other β2-selective agents (Figure 20–4). The place of epinephrine and isoproterenol has markedly diminished because of their effects on the rate and force of cardiac contraction (mediated mainly by β1 receptors).
In general, β-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 μm, 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 within 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 potentially serious adverse effects. Its current use is thus largely for treatment of the acute vasodilation and bronchospasm of anaphylaxis. Aerosol delivery of other, more β-selective agents has largely displaced its use in asthma (see below).
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. As a result of the availability and efficacy of β2-selective agonists, these have displaced the use of isoproterenol for asthma.
The β2-selective adrenoceptor agonist drugs, particularly albuterol, are now the most widely used sympathomimetics for the treatment of acute bronchoconstriction (Figure 20–4). 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 (levo) and S (dextro) 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). Although this purified isomer is often used in children with asthma, meta-analyses of clinical trials have not shown it to have greater efficacy or lower toxicity than the standard and less expensive racemic mixture of R- and S-albuterol in treating exacerbations of asthma or chronic obstructive pulmonary disease (COPD).
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 produces more pronounced adverse effects and is thus 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.
Long-acting β2-selective agonists (LABA), with 12-hour durations of action, such as salmeterol and formoterol, were developed to facilitate asthma management. These drugs generally achieve their long duration of bronchodilating action 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, such as indacaterol, olodaterol, vilanterol, and bambuterol, need to be taken only once a day, but because their prolonged bronchodilation masks symptoms of bronchial inflammation, they should be used only in combination with an ICS for asthma. However, they may be used as monotherapy for treatment of COPD.
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. Although the vasodilating action of β2-agonist treatment may increase perfusion of poorly ventilated lung units, transiently decreasing arterial oxygen tension (PaO2), this effect is small, is easily overcome by the routine administration of supplemental oxygen, and is made irrelevant after a short period of time 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.
Another concern about the administration of β-agonists is their induction of tachyphylaxis. A reduction in the bronchodilator response to low-dose β-agonist treatment can 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 by 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 first focused on a single nucleotide polymorphism (SNP) that changes the amino acid code at position 16 from glycine to arginine (Gly16Arg). Retrospective analyses of studies of regular β-agonist treatment suggested that asthma control deteriorated among patients homozygous for arginine at this locus, prompting speculation that a genetic variant may underlie the controversial reports of increased asthma mortality in studies of very large numbers of patients treated with an LABA (see below). Studies of LABA treatment have since shown, however, that differences in multiple measures of asthma control are negligible in patient groups with different genotypes at that locus. Nonetheless, it is 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.”
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 almost ceased 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 its narrow therapeutic index. This monitoring is made all the more necessary by individual differences in theophylline metabolism and frequent drug-drug interactions. Despite these disadvantages of theophylline, it is still used in some countries because of its low cost.
As shown below (Figure 20–5), 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.
Several mechanisms have been proposed for the actions of methylxanthines, but none has been firmly established. At high concentrations, they can be shown to inhibit several members of the phosphodiesterase (PDE) enzyme family in vitro, thereby increasing concentrations of intracellular cAMP and, in some tissues, cGMP (Figure 20–3). 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.
Another proposed mechanism for the bronchodilating action of this class of drugs is inhibition of cell surface receptors for adenosine. Adenosine has been shown to provoke contraction of isolated airway smooth muscle and release of histamine 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 proposed mechanism of action for theophylline’s efficacy is 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 deacetylactylases 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, but this approach to treating patients with asthma or COPD uncontrolled by ICS plus LABA therapy has not been widely adopted. 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, thus decreasing 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 they induced unacceptably frequent side effects of nausea, headache, and diarrhea. However, one, roflumilast, has been shown to be effective for reducing the frequency of exacerbations of COPD and is approved by the US Food and Drug Administration (FDA) as a treatment for COPD, although not for asthma.
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, particularly caffeine, cause mild cortical arousal with increased alertness and deferral of fatigue. The caffeine contained in beverages, approximately 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, can 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, potentially 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.
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, although it does counteract some of the cardiovascular effects and limits the degree of hypertension produced.
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.
F. Effects on Skeletal Muscle
The respiratory actions of methylxanthines are not confined to the airways; 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.
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. However, the efficacy and safety of other drugs, especially inhaled β2-agonists and inhaled corticosteroids, and the toxicities and need for monitoring of blood concentration of theophylline have made it almost obsolete in asthma treatment.
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.
Muscarinic antagonists competitively inhibit the action of acetylcholine at muscarinic receptors and are therefore sometimes referred to as “anticholinergic agents” (see Chapter 8). In the airways, acetylcholine is released from efferent endings of the vagus nerve, 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 20–6). This selectivity of muscarinic antagonists accounts for their usefulness as investigative tools to examine the role of parasympathetic reflex 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.
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.
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 with a selective quaternary ammonium derivative of atropine, ipratropium bromide, which can be inhaled in high doses because of its poor absorption into the circulation and poor entry into the central nervous system. Studies with this agent have shown that the degree of involvement of parasympathetic pathways in bronchomotor responses varies among subjects. This variation indicates that other mechanisms in addition to parasympathetic reflex pathways must be involved.
Even though the bronchodilation and inhibition of provoked bronchoconstriction afforded by antimuscarinic agents are incomplete, their use is of clinical value, especially for patients intolerant of inhaled β agonists.
Ipratropium appears to be as effective as albuterol in patients with COPD who have at least partially reversible obstruction. Longer-acting antimuscarinic agents, including tiotropium, aclidinium, and umeclidinium, 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 or 62.5 mcg of umeclidinium 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. These drugs have not yet been approved as maintenance treatment for asthma, but the addition of tiotropium is no less effective than addition of an LABA in asthmatic patients insufficiently controlled by ICS therapy alone.
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 hyperreactivity 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 systemic glucocorticoid treatment for patients with severe asthma have been noted since the 1950s. So too have been its numerous and severe toxicities, 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 could be taken by inhalation 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 treated with “as-needed” use of albuterol alone.
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 high-dose maintenance therapy.
For severe asthma exacerbations, urgent treatment is often begun with an oral dose of 30–60 mg prednisone per day or an intravenous dose of 0.5–1 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 symptoms may worsen in other patients 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 chronic 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 ICS, higher inhaled doses are often effective and enable tapering and discontinuing prednisone treatment. Although these high doses of inhaled steroids may cause mild 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 clotrimazole, and the risk of this complication can be reduced by having patients gargle water and expectorate after each inhaled treatment. Ciclesonide, a prodrug activated by bronchial esterases, is comparably effective to other inhaled corticosteroids and is 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 with persistent asthma 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 nearly 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 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 as asthma treatments. These drugs are thought to act by inhibiting mast cell degranulation and, as such, have no direct bronchodilator action, but inhibit both antigen- and exercise-induced bronchospasm in asthmatic patients.
When taken regularly (2–4 puffs 2–4 times daily), these agents modestly but significantly reduce symptomatic severity and the need for bronchodilator medications, particularly in young patients with allergic asthma. These drugs are poorly absorbed into the systemic circulation and have little toxicity, but are not as potent or as predictably effective as ICS.
The main indication for current use of cromolyn is for reducing symptoms of allergic rhinoconjunctivitis. Applying cromolyn solution by eye drops twice a day is effective in about 75% of patients, even during the peak pollen season. Another indication is the rare disease of systemic mastocytosis for which an oral dose of a solution of 200 mg of cromolyn in water (Gastrocrom) taken four times per day helps control the abdominal cramping and diarrhea caused by activation of overabundant mast cells in the gastrointestinal mucosa.
LEUKOTRIENE PATHWAY INHIBITORS
The involvement of leukotrienes in many inflammatory diseases (see Chapter 18) and in anaphylaxis prompted 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.
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 20–7). All three drugs have been shown to improve asthma control and to reduce the frequency of asthma exacerbations in clinical trials. They are not as effective as even low-dose ICS therapy in inducing and maintaining asthma control, but are preferred by many patients, especially by the parents of asthmatic children, because of often exaggerated concerns over the toxicities of corticosteroids. They have the additional advantage of being effective when taken orally, which is an easier route of administration than aerosol inhalation in young children, and montelukast is approved for children as young as 12 months of age.
Some patients appear to have particularly favorable responses, but apart from the subclass of patients with aspirin-exacerbated respiratory disease (described below), no clinical features 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-exacerbated respiratory disease (AERD), a disease that combines the features of asthma, chronic rhinosinusitis with nasal polyposis, and reactions to aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs) that inhibit cyclooxygenase-1 (COX-1). Aspirin-exacerbated respiratory disease occurs in approximately 5–10% of patients with asthma. In these patients, ingestion of even a very small dose of aspirin causes profound bronchoconstriction, nasal congestion, 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 NSAIDs that target COX-1, AERD 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, because it may be taken without regard to meals, is taken once daily, and does not require periodic monitoring of liver function, as zileuton does. Although not considered first-line therapy, the leukotriene-modifying agents are sometimes given in lieu of inhaled corticosteroids for mild asthma when prescription of an ICS meets patient resistance. The receptor antagonists 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.
TARGETED (MONOCLONAL ANTIBODY) THERAPY
As the pathophysiologic mechanisms responsible for asthma have become better understood, anti-inflammatory therapy targeting specific inflammatory pathways has been developed. Specifically, monoclonal antibodies targeting IgE and IL-5 have been brought to market, and an antibody targeting the receptor for IL-4 and IL-13 is under development (Table 20–1).
TABLE 20–1Monoclonal antibodies for use in asthma.1 ||Download (.pdf) TABLE 20–1 Monoclonal antibodies for use in asthma.1
|Antibody Name ||Isotype ||Target |
|Omalizumab ||Humanized IgG1 ||IgE |
|Mepolizumab ||Humanized IgG1 ||IL-5 |
|Benralizumab ||Humanized IgG1 ||IL-5 receptor |
|Reslizumab ||Humanized IgG4 ||IL-5 |
|Lebrikizumab ||Humanized IgG4 ||IL-13 (IL-4 receptor-binding epitope) |
|GSK679586 ||Humanized IgG1 ||IL-13 receptors α1, α2 |
|Tralokinumab ||Humanized IgG4 ||IL-13 receptors α1, α2 |
|Dupilumab ||Humanized IgG4 ||IL-4 receptor |
Anti-IgE Monoclonal Antibodies
The monoclonal antibody omalizumab was raised in mice and then humanized, making it less likely to cause sensitization when given to human subjects (see Chapter 55). Because its specific target is the portion of IgE that binds to its receptors (Fcε-R1 and Fcε-R2 receptors) on dendritic cells, basophils, mast cells, and other inflammatory cells, omalizumab inhibits the binding of IgE but does not activate IgE already bound to its receptor and thus does not provoke mast cell degranulation.
Omalizumab’s use is restricted to patients with severe asthma and evidence of allergic sensitization, and the dose administered is adjusted for total IgE level and body weight. Administered 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, while enabling a reduction in corticosteroid requirements. 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 often prevented are the most severe; omalizumab treatment reduced exacerbations requiring hospitalization by 88%. Because exacerbations drive so much of the direct and indirect costs of asthma, these benefits can justify omalizumab’s high cost.
The addition of omalizumab to standard, guideline-based therapy for asthmatic inner-city children and adolescents in early summer significantly improved overall asthma control, reduced the need for other medications, and nearly eliminated the autumnal peak in exacerbations. Omalizumab has also been proven effective as a treatment for chronic recurrent urticaria (for which the drug is now approved) and for peanut allergy.
T2 cells secrete IL-5 as a pro-eosinophilic cytokine that results in eosinophilic airway inflammation. Although not central to the mechanisms of asthma in all patients, a substantial proportion of patients with severe asthma have airway and peripheral eosinophilia driven by up-regulation of IL-5-secreting T2 lymphocytes. Two humanized monoclonal antibodies targeting IL-5, mepolizumab and reslizumab, and another targeting the IL-5 receptor, benralizumab, have recently been developed for the treatment of eosinophilic asthma. Clinical trials with these drugs have shown them to be effective in preventing exacerbations in asthmatic patients with peripheral eosinophilia, leading to their approval as add-on, maintenance therapy of severe asthma in patients with an eosinophilic phenotype.
Like omalizumab, reslizumab carries a small (0.3%) risk of anaphylaxis, and a period of observation following infusion is recommended. Mepolizumab, although not associated with anaphylaxis, has resulted in reports of hypersensitivity. In addition, reactivation of herpes zoster has been reported in some patients who received mepolizumab.
Clinical trials of dupilumab (an antibody directed against the IL-4α co-receptor for both IL-4 and IL-13; not yet approved) have shown it to reduce exacerbation frequency and improve measures of asthma control in patients with and without systemic eosinophilia and, further, to markedly reduce the severity of allergic dermatitis.
FUTURE DIRECTIONS OF ASTHMA THERAPY
Ironically, the effectiveness of ICS as a treatment for most patients with asthma, especially 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 implied by the use of modifying terms such as “extrinsic,” “intrinsic,” “aspirin-sensitive,” “adult-onset,” “steroid-dependent,” “exacerbation-prone,” “seasonal,” “postviral,” and “obesity-related” to describe asthma in particular patients. More rigorous description of asthma phenotypes, based on cluster analysis of multiple clinical, physiologic, 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.
Persuasive evidence of the existence of different asthma phenotypes requiring different approaches to therapy is the demonstration of differences in the pattern of gene expression in the airway epithelium of asthmatic and healthy subjects. Compared with healthy controls, half of the asthmatic participants overexpressed genes for periostin, CLCA1, and serpinB2, genes known to be up-regulated in airway epithelial cells by IL-13, a signature cytokine of T2 lymphocytes. The other half of the asthmatic participants did not. These findings suggest that fundamentally different pathophysiologic mechanisms exist even among patients with mild asthma. The participants with overexpression of genes up-regulated by IL-13 are referred to as having a “T2-high molecular phenotype” of asthma. The other subjects, who did not overexpress these genes, are described as having a “non-T2”or “T2-low” molecular phenotype. The T2-high asthmatic subjects on average tended to have more sputum eosinophilia and blood eosinophilia, positive skin test results, higher levels of IgE, and greater expression of certain mucin genes. The response to ICS treatment of these two groups was quite different. Six weeks of treatment with an ICS improved forced expiratory volume in 1 second (FEV1) only in the T2-high subjects. The implications of these findings are far reaching because they indicate that perhaps as many as half of patients with mild to moderate asthma do not respond to ICS therapy. The proportion of non-ICS responders among patients with severe “steroid-resistant” asthma could be much higher.
Current research focuses on further exploring molecular phenotypes in asthma and in finding effective treatments for each group. An investigational IL-13 receptor antagonist, lebrikizumab, for example, has been shown to be more effective in asthmatic subjects with elevated serum levels of periostin (one of the genes up-regulated in the “T2-high molecular phenotype”).
To examine whether tiotropium might be an alternative to ICS therapy for “T2-low” asthma, a NIH–sponsored multicenter trial is embarking on a prospective, double-blind, placebo-controlled trial of ICS versus tiotropium in asthmatic subjects characterized as T2-high or non-T2-high by analysis of their induced sputum samples for eosinophil number and for expression of T2-dependent genes (https://clinicaltrials.gov/ct2/show/NCT02066298).
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. Beyond the monoclonal antibodies directed against cytokines (IL-4, IL-5, IL-13) already reviewed (Table 20–1), these include antagonists of cell adhesion molecules, protease inhibitors, and immunomodulators aimed at shifting CD4 lymphocytes from the TH2 to the TH1 subtype or at selective inhibition of the subset of TH2 lymphocytes directed against particular antigens. As these new therapies are developed, it will become increasingly important to identify biomarkers of specific phenotypes of asthma that are most likely to benefit from specific therapies. This will enable truly personalized asthma therapy.