Brody's Human Pharmacology: With STUDENT CONSULT

Chapter 16 Drugs to Treat Asthma and Chronic Obstructive Pulmonary Disease

MAJOR DRUG CLASSES

Chromones

Glucocorticoids

Leukotriene modulators

Methylxanthines

Adrenergic β2 receptor agonists

Muscarinic receptor antagonists

Therapeutic Overview

Asthma is a chronic inflammatory disorder of the large airways in which many different cellular elements play a role. A characteristic feature of asthma is obstruction of the airways (predominantly in the third to seventh generation of the bronchi) that is reversible with time or in response to treatment. Even when patients have a normal airflow (which for mild asthmatics is much of the time), their lungs are hyper-reactive to a variety of stimuli that occur naturally (e.g., cold air, exercise, chemical fumes) or are used to test pulmonary function (e.g., methacholine, histamine, cold air). Bronchial hyper-reactivitycorrelates with inflammation of the bronchi, which includes damage to the epithelium and eosinophil infiltration. Other characteristics of asthma include airway mucosal edema, mucus hypersecretion, and remodeling of the airways. Symptomatically, patients experience chest tightness, wheezing, shortness of breath, or coughing. Mild forms of the disease occur in up to 10% of the population, but asthma requiring regular treatment affects approximately 2% of the population.

Compared with asthma, chronic obstructive pulmonary disease (COPD) is defined by the Global Initiative on Obstructive Lung Disease as “A disease state characterized by airflow limitation that is not fully reversible. The airflow limitation is usually progressive and associated with an abnormal inflammatory response of the lungs to noxious particles and gases.” COPD includes chronic obstructive bronchiolitis with fibrosis and obstruction of small airways, emphysema with enlargement of airspaces and destruction of lung parenchyma, loss of lung elasticity, and closure of small airways. Most patients with COPD experience a triad of symptoms, including:

• Chronic obstruction

• Emphysema

• Mucus plugging

Abbreviations

ACh

Acetylcholine

BLT

Leukotriene B receptor

cAMP

Cyclic adenosine monophosphate

CNS

Central nervous system

COPD

Chronic obstructive pulmonary disease

CysLT

Cys-leukotriene

Epi

Epinephrine

FEV1

Forced expiratory volume in 1 second (liters)

GCs

Glucocorticoids

GI

Gastrointestinal

IgE

Immunoglobulin type E

IL

Interleukin

IV

Intravenous

LOX

Lipoxygenase

LTs

Leukotrienes

LTMs

Leukotriene modulators

MDI

Metered-dose inhaler

PDE

Phosphodiesterase

PEF

Peak expiratory flow

TNF

Tumor necrosis factor

Smoking is by far the primary cause of COPD; other risk factors include occupational dust and chemical exposures, environmental exposure (second-hand smoke), and genetic predisposition (primarily α1antitrypsin deficiency). Currently, COPD is the fourth leading cause of death in the United States.

Normal bronchial smooth muscle tone is controlled by vagal innervation (see Chapter 9). Cholinergic activity or sensitivity is often increased in asthmatics, and increased cholinergic tone is the primary reversible component of COPD. However, most patients with asthma also have increased adrenergic activity (see Chapter 11), which manifests as increased wheezing if patients are treated with β adrenergic receptor blocking drugs (e.g., propranolol), which are contraindicated in asthma. A variety of agents can contribute to the inflammation of asthma; however, immediate hypersensitivity to common allergens is the most common cause. It is estimated that 80% of children and 50% of adults with asthma are allergic. The common allergens include seasonal outdoor allergens (e.g., ragweed pollen, grass pollen, and mold) or the year-round indoor allergens (dust mites, cockroaches, and domestic animal dander). Allergens cause release of the preformed granule mediator histamine, which can trigger bronchospasm. However, antihistamines (H1 receptor antagonists) are relatively ineffective in the treatment of asthma, demonstrating that other factors are key mediators of the asthma attack. In patients with asthma, in addition to the release of prestored mediators such as histamine from mast cells, other inflammatory mediators are synthesized and released including arachidonic acid, its metabolites, and several cytokines (Fig. 16-1). Leukotrienes (LTs), primarily LTD4, are implicated as major mediators of bronchoconstriction. Agents that inhibit the synthesis or action of the LTs, known as leukotriene modulators (LTMs), are useful for the treatment of asthma.

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FIGURE 16–1 Mast cells release prestored inflammatory mediators such as histamine, which act rapidly. Other mediators such as leukotrienes are newly generated after their precursors are released and act more slowly. Some mediators are also produced by basophils.TNF-α, Tumor necrosis factor-alpha; IL-4, Interleukin-4.

The inflammatory component of COPD differs from that of asthmatics in that patients with COPD demonstrate increased neutrophil as opposed to eosinophil activity. In COPD, macrophage activation, due to exposure to noxious stimuli, releases neutrophil chemotactic factors, including interleukin-8 and LTB4. Protease enzymes are also released that destroy connective tissues in the lung parenchyma, and oxidants capable of direct tissue damage are produced. These events lead to the pathological damage to small airways and increased mucus secretion characteristic of COPD. The resulting chronic inflammation causes fibrosis and a proliferation of smooth muscle. As the airways progressively narrow, airflow is severely limited, and respiratory function declines.

Asthma is treated using three main approaches. The first is avoidance of the causative factors, when possible, particularly for patients sensitive to indoor allergens. The second is the use of antiinflammatory drugs, including cromolyn and related agents, glucocorticoids (GCs) (see Chapter 39), and LTMs. If used regularly, these drugs can reduce the signs and symptoms of bronchial hyperactivity, characteristic of asthma. Third, drugs that can reverse or inhibit the development of bronchoconstriction are important; these compounds include methylxanthines, epinephrine (Epi) and selective adrenergic β2 receptor agonists (see Chapter 11), and the muscarinic receptor antagonists (see Chapter 10).

The current therapeutic approaches for the treatment of COPD are similar to those for asthmatics with three exceptions. First, the cessation of smoking is essential to prevent development of COPD and to slow its progression. Second, of the antiinflammatory drugs, only GCs are currently used in the treatment of acute exacerbations of COPD; long-term use of these compounds for the management of COPD is not recommended. Third, β2 receptor agonists are used as bronchodilators for patients with COPD, and muscarinic antagonists result in further improvement. Therefore the combination of a β2-agonist and a muscarinic receptor antagonist is useful in COPD.

The goals in treatment of pulmonary disease are to reverse acute episodes, control recurrent episodes, and reduce bronchial inflammation and associated hyper-reactivity. Three general considerations must be kept in mind:

• The inhaled route of drug administration is very important and has special requirements.

• The pharmacokinetics of pulmonary drugs are based primarily on lung-function response; blood concentrations can be important for the methylxanthines because of toxicity concerns.

• The most commonly encountered adverse effects of respiratory medications are the short-term side effects of the methylxanthines and the cumulative side effects of orally administered GCs.

Because many patients use inhaled steroids or β2 receptor agonists chronically, the adverse effects of these drugs, which are relatively infrequent when used acutely, become more important. A summary of the therapeutic considerations for the treatment of asthma and COPD is presented in the Therapeutic Overview Box.

Therapeutic Overview

Antiinflammatory Agents

Cromolyn and related agents control mediator release from mast and other cells and for their generalized membrane-stabilizing effects

Glucocorticoids, inhaled or systemic, for controlling transcription of mediator genes, and for controlling edema, mucus production, and eosinophil infiltration

Leukotriene modulators to decrease inflammatory mediator synthesis or antagonize inflammatory mediator receptors

Bronchodilators

Methylxanthines for reducing the frequency of recurrent bronchospasm

Adrenergic β2 receptor agonists for relaxing bronchial smooth muscle and decreasing microvascular permeability

Muscarinic receptor antagonists for inhibiting the bronchoconstrictor effects of endogenous acetylcholine

Mechanisms of Action

Treatment of asthma and COPD involves the use of drugs with mechanisms that affect different aspects of these diseases. Table 16-1 summarizes these drugs and their mechanisms of action.

TABLE 16–1 Mechanisms of Action of Drugs to Treat Asthma and COPD

Beneficial Effect

Drug Class

Cellular Mechanisms

Decreased inflammation

Chromones

Prevent the release of inflammatory mediators

   

Alter chloride ion channel function

 

Glucocorticoids (GCs)

Regulate gene expression

 

Leukotriene modulators (LTMs)

Decrease leukotriene (LT) synthesis or prevent LT receptor activation

 

Antihistamines

Prevent activation of histamine receptors

Bronchodilation

Methylxanthines

Increase cAMP

   

Adenosine receptor antagonist

 

Adrenergic β2 receptor agonists

Increase cAMP

 

Muscarinic antagonists

Block activation of muscarinic receptors by endogenous acetylcholine

Chromones (Cromolyn and Nedocromil)

Cromolyn is a synthetic substance derived from a natural plant product that has several important actions. Cromolyn was originally shown to inhibit the release of histamine from mast cells in vitro. Subsequently, it was demonstrated that inhaled cromolyn could inhibit exercise-induced bronchospasm, progressively decrease bronchial hyperactivity, and inhibit seasonal rises in bronchial hyperactivity in patients allergic to grass pollen. Cromolyn and nedocromil act at the surface of the mast cell and eosinophils to inhibit Ca++ influx, thereby preventing the release of histamine and other inflammatory mediators. Cromolyn and nedocromil are active on the lung only when given by the inhaled route. They have no direct bronchodilator effect and thus are not useful for treating acute asthma attacks.

Glucocorticoids

The GCs have multiple actions that decrease inflammation in asthma, which is key to improving asthmatic symptoms and preventing exacerbations. In controlling the inflammation of asthma, the primary effect of the GCs is to alter gene expression. The GCs, through activation of GC receptors (see Chapter 39), suppress the expression of genes for many inflammatory proteins. Inflammation is mediated by the increased expression of multiple inflammatory proteins including cytokines, chemokines, adhesion molecules, and inflammatory enzymes and receptors. The expression of most of these inflammatory proteins is regulated by increased gene transcription, which is controlled by proinflammatory transcription factors. The GCs are believed to switch off only inflammatory genes and do not suppress all activated genes because of the selective binding to coactivators that are activated by proinflammatory transcription factors.

In addition to suppressing the synthesis of inflammatory mediators, the GCs also induce the transcription of several antiinflammatory proteins, including lipocortin, neural endopeptidase, and inhibitors of plasminogen activator. Lipocortin inhibits the activity of phospholipase A2, thus decreasing the release of free arachidonic acid from phospholipids and reducing the subsequent production of leukotrienes and prostaglandins.

GCs decrease bone marrow production of eosinophils and enhance their removal from the circulation by mediating their adherence to capillary walls (margination). GCs also reduce the local accumulation of eosinophils by inhibiting the release of eosinophil chemotactic factors such as LTB4 and cytokine tumor necrosis factor-α (TNF-α). The effect of the GCs on neutrophils is opposite to that on eosinophils. By inhibiting margination and stimulating bone marrow production, GCs lead to an increase in circulating neutrophils.

Leukotriene Modulators

The LTs are potent inflammatory mediators generated from the metabolism of arachidonic acid through the 5-lipoxygenase (5-LOX) pathway (Fig. 16-2). These compounds, along with prostaglandins and related compounds, belong to a group of substances termed the eicosanoids (see Chapter 15). The LTs are synthesized in many inflammatory cells in the respiratory system including eosinophils, mast cells, macrophages, and basophils and are responsible for mediating numerous asthmatic symptoms via stimulation of specific LT receptors. LTB4 is a potent neutrophil chemotactic agent whose actions result from stimulation of members of the LTB receptor (BLT) family. Similarly, LTC4 and LTD4 cause bronchoconstriction, mucus hypersecretion, and mucosal edema and increase bronchial reactivity through activation of the Cys-leukotriene (CysLT, formerly known as the LTD4) receptor family. The effects of the LTs can be modulated either by inhibiting LT biosynthesis or by blocking activation of CysLT receptors. Zileuton* is an inhibitor of 5-LOX, thereby decreasing LT synthesis, whereas zafirlukast and montelukast are antagonists at Cys-LT1 receptors, thereby blocking receptor activation. These drugs are less effective antiinflammatory agents than the corticosteroids, but are preferable to long-term GC therapy because they have fewer adverse effects (see Chapter 39). They are used prophylactically in combination products.

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FIGURE 16–2 Newly generated lipid mast cell mediators depicting the sites of action of the LTMs. Zileuton* inhibits 5-lipoxygenase, thereby inhibiting the synthesis of the leukotrienes, whereas zafirlukast and montelukast are antagonists at the CysLT1 receptor. The inhibitory actions of the LTMs are shown in red.

Methylxanthines

Theophylline is a methylxanthine, pharmacologically similar to caffeine found in coffee and cola drinks. Theophylline exerts three actions, which may contribute to its usefulness as a bronchodilator. A major action of theophylline is as an adenosine receptor antagonist in bronchial smooth muscle. Adenosine acts as a natural bronchoconstrictor and increases histamine release from lung mast cells. Blocking these actions of endogenous adenosine could contribute to the antiinflammatory action of theophylline. The second action is theophylline inhibition of phosphodiesterase (PDE), increasing levels of cyclic adenosine monophosphate (cAMP), which lead to bronchodilation; however, the clinical significance of this mechanism has been questioned, because concentrations of theophylline required to inhibit this enzyme exceed those achieved with usual doses. The third proposed mechanism of theophylline involves its ability to activate histone deacetylase, an enzyme that functions to inhibit the acetylation of core histones required for the transcription of inflammatory genes. The ability of the methylxanthines to interact with ryanodine receptors to increase Ca++ mobilization is important for the ability of these agents to enhance skeletal muscle strength, but not to their action in asthma.

Adrenergic β2 Receptor Agonists

Stimulation of adrenergic β2 receptors raises cAMP concentrations and inhibits smooth muscle contraction (see Chapter 9). Physiologically, bronchial smooth muscle relaxes, and the release of some mast cell-derived bronchoconstricting substances is inhibited. In addition, these drugs decrease microvascular permeability and suppress parasympathetic ganglionic activity (see Chapter 10). There is no evidence for an antiinflammatory effect of adrenergic agents or for any beneficial effect on bronchial hyperactivity.

Several β2 receptor agonists have been used therapeutically for the treatment of asthma. Epi and isoproterenol are highly effective but are reserved for special circumstances because of their nonselective activity, leading to β1 receptor-mediated cardiac stimulation. Short-acting selective β2 receptor agonists include albuterol,1 terbutaline, metaproterenol, bitolterol, and pirbuterol. Formoterol and salmeterol have been developed as highly lipid-soluble long-acting agents (t1/2 = 12 hours).

Muscarinic Receptor Antagonists

Bronchial smooth muscle is innervated mainly by the parasympathetic nervous system, and its activation causes bronchoconstriction (see Chapter 9). Before the development of modern pharmacology, leaves from the belladonna plant, which contain muscarinic antagonists (atropine and scopolamine) were smoked as a treatment for asthma. Atropine can be used as a bronchodilator and to reduce secretions, but its use is limited by autonomic and central nervous system (CNS) adverse effects. Ipratropium bromide is a quaternary nitrogen derivative of atropine that does not cross the blood-brain barrier but competitively inhibits muscarinic acetylcholine receptors in bronchial smooth muscle (see Chapter 10). Ipratropium is used as an inhaled preparation. Tiotropium is a long-acting muscarinic antagonist used as a bronchodilator that is useful for patients with COPD.

Anti-immunoglobulin Antibody

Omalizumab is a recombinant monoclonal antibody, which binds to and neutralizes human serum immunoglobulin type E (IgE) and prevents allergens from activating mast cells and other cells that release cytokines (see Chapter 6).

Pharmacokinetics

The pharmacokinetics of the drugs used for the treatment of asthma are complicated as a consequence of the routes of absorption and differences in the rates of response. Blood levels are relevant only for theophylline and related methylxanthines because of the relatively low therapeutic index and high incidence of adverse effects of these agents. Therefore mean pulmonary function response times are generally used as an indicator of pharmacokinetic profiles. Response rates vary significantly from patient to patient, presumably reflecting differences in the specific pathological state of the obstruction in the lung.

Chromones

Both cromolyn and nedocromil act on inflammatory cells and neurons in the bronchial epithelium and are active only when inhaled, rendering plasma levels largely irrelevant. Cromolyn is very poorly absorbed from the gastrointestinal (GI) tract and has few systemic side effects because it is rapidly excreted. Although cromolyn has no direct bronchodilator activity and should not be used to treat an acute attack, it can be used to control exercise-induced bronchospasm, if administered 10 to 15 minutes before the onset of physical activity. In contrast to its rapid effect in controlling exercise-induced bronchospasm, long-term treatment with cromolyn or nedocromil requires several days or even weeks to produce an optimal antiinflammatory effect.

Glucocorticoids

The pharmacokinetics for the GCs are presented in Chapter 39. When used for the treatment of asthma or COPD, responses to inhaled or oral steroids can occur within 4 hours but may take as long as 2 weeks, depending on the nature of the underlying lung disorder.

Leukotriene Modulators

The LT receptor antagonists, montelukast and zafirlukast, as well as the 5-LOX inhibitor zileuton* are all orally administered, which is advantageous for treatment of children and other patients who have difficulty with or are noncompliant with inhaled therapies. Zileuton* has the disadvantage of requiring dosing four times per day. Montelukast and zafirlukast have similar pharmacokinetic profiles and may be administered once (montelukast) or twice (zafirlukast) daily. Zileuton* is also an inhibitor of hepatic CYP3A and will lead to increased levels of drugs metabolized by this CYP variant, including theophylline. This drug-drug interaction increases potential toxicity if the two drugs are administered concurrently.

Methylxanthines

Theophylline clearance is influenced by food, smoking, age, disease, and other drugs metabolized by the liver (Table 16-2). Monitoring serum theophylline concentrations is necessary for any patient taking more than a minimal dose orally, especially sustained-release formulations, because of the multiple factors that influence blood concentrations and because the range of safe therapeutic concentrations is narrow. The therapeutic range is 5 to 15 µg/mL, and serious toxicity is increasingly likely at blood concentrations greater than 20 µg/mL, which results in a low therapeutic index.

TABLE 16–2 Factors influencing Blood Concentrations of Theophylline

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When administered intravenously, theophylline can act rapidly on the lungs as a bronchodilator. However, this requires large bolus doses, which are used only occasionally because of toxicity. It is easier to maintain therapeutic blood concentrations by the oral route using sustained-release preparations, but this approach can lead to problems of cumulative toxicity.

Adrenergic β2 Receptor Agonists

A general comparison of the pharmacokinetic profiles for these compounds is presented in Table 16-3. The bronchodilation that occurs in response to inhaled β2 receptor agonists has a fairly consistent onset at 5 to 30 minutes. Tightness of the chest will abate in most patients with asthma within 10 minutes after an injection of Epi. An optimal effect usually occurs within an hour and may last for 2 to 4 hours. In most circumstances β2 receptor agonists are effective for approximately 4 to 6 hours. Prolonged, repeated use of short-acting β2 receptor agonists, however, can cause a significant increase in heart rate in a small proportion of patients as a result of systemic absorption and concomitant stimulation of cardiac β1 receptors. With the development of a longer-acting β2 receptor agonist (salmeterol), which lasts for more than 12 hours, this problem may be partially resolved. However, unlike the short-acting β receptor agonists, salmeterol is not effective in treating acute episodes. Its major uses are in controlling nocturnal asthma and some cases of exercise-induced bronchospasm. The use of salmeterol alone has been associated with an increased risk of severe asthma exacerbations. Therefore it has been recommended that this agent be taken in fixed-dose combinations with an inhaled corticosteroid.

TABLE 16–3 Comparison of the Pharmacokinetics of Adrenergic β2 Receptor Agonists and Muscarinic Receptor Antagonists

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Muscarinic Receptor Antagonists

Inhaled ipratropium bromide is poorly absorbed and has few systemic side effects. The peak bronchodilator effect occurs 1 to 2 hours after inhalation, with a duration of action of 3 to 5 hours (see Table 16-3). Tiotropium, which exhibits selectivity at M1 and M3 receptors (see Chapter 10), has a duration of action of 24 hours. Both of these agents are used for management of the bronchoconstrictive component of COPD.

Relationship of Mechanisms of Action to Clinical Response

The central problem in managing asthma is that the symptoms range from occasional tightness in the chest after exercise (which may require no treatment) to continuous airway obstruction. Assessment of pulmonary function by spirometry (to measure forced expiratory volume [FEV1]) or a portable peak flow meter (to measure peak expiratory flow [PEF]) is essential to monitor baseline pulmonary function, correlate changes in airway obstruction with symptoms, and determine the patient’s response to treatment. The patient should be encouraged to record peak flow values for a 2-week period to establish a baseline, assess the severity of episodes, and determine his or her individual response to treatment. An FEV1 or a PEF less than 80% of the predicted value is considered a mild obstructive episode. The predicted value is determined from the patient’s age, gender, race, and height, based on a healthy population. Alternatively, the patient’s best recorded PEF baseline value can be used as the predicted value. An FEV1 or PEF less than 60% of predicted values indicates moderate obstruction, and an FEV1 or PEF less than 40% of predicted values indicates severe obstruction. Most patients will show a 15% to 20% increase in FEV1 or PEF 15 to 20 minutes after administration by metered dose inhaler (MDI) of a bronchodilator, such as a β2 agonist or a muscarinic antagonist. Less than a 12% increase indicates inadequate acute bronchodilator response, and further treatment will be necessary.

Reduced allergen exposure, inhaled cromolyn Na+ or nedocromil, inhaled GCs, or oral LTMs are antiinflammatory treatments that are each capable of reducing bronchial hyperactivity to help manage the problem. Cromolyn and related agents are used prophylactically only and are most effective for treating extrinsic asthma in children and young adults as well as exercise-induced bronchospasm.

Although the mechanism of the therapeutic effect of the methylxanthines in asthma is not clear, regular treatment can be very effective in controlling symptoms. The methylxanthines prevent episodes of airway obstruction. Theophylline administered IV is active within minutes, but when taken orally, 1 to 2 hours are required before its effects occur. Its duration of action depends on absorption and metabolism but correlates well with blood concentrations.

Systemic GCs are the most effective treatment for both moderately severe and severe asthma and are used for treatment of acute exacerbations of COPD. However, these compounds lead to development of side effects after chronic administration (Chapter 39). The indication for oral corticosteroids is ongoing airway obstruction that is not relieved by other medicines within 1 to 2 days. Only a very small percentage of asthmatics (0.1%) become dependent on steroids, but this may represent as many as 10 patients per 100,000; thus it is a very important cause of iatrogenic disease.

For acute severe episodes, corticosteroids such as methylprednisolone may be administered IV. Although the GCs have no direct bronchodilator effects, and 6 hours are required to achieve maximal effects, peripheral blood eosinophil counts decline within 2 hours, and significant effects on lung function and symptoms can be observed within 4 hours of systemic administration. Thus the early use of systemic steroids has become a mainstay of treatment in the management of acute asthma and COPD, both in outpatient practice and in the hospital. In some cases, high doses of inhaled steroids can be used to abort an attack. However, in severe cases, mucus impaction and poor ventilation of the lungs prevent the effective delivery of inhaled steroids, and, therefore oral or IV administration is urgently required.

Outpatient Treatment of Asthma

In a patient with occasional wheezing, a diagnosis must be established by demonstrating a reversible airway obstruction and having the patient use a peak-flow meter at home for 2 weeks. Treatment involves using a β2 receptor agonist, two puffs by MDI when necessary. In a patient with exercise-induced bronchospasm, it is imperative to show that breathlessness after exercise is associated with airway obstruction. Recommended treatments to prevent exercise-induced bronchospasm are an inhaled β2 receptor agonist, two puffs 5 to 10 minutes before exercise, or two puffs of cromolyn Na+ by MDI 10 to 20 minutes before exercise, or one puff of salmeterol by MDI 30 to 60 minutes before exercise. Inadequate control requires identifying the causes of the bronchial hyperactivity. Leukotriene antagonists are effective as prophylactic agents.

In a patient who is suffering more frequent symptoms, including nocturnal asthma, or who is using a short-acting β2 receptor agonist more than three times per week, documentation of reversible airway obstruction is of paramount importance. This can be achieved by: (a) measuring changes in PEF or FEV1 before and after administration of the bronchodilator; (b) demonstrating a 15% to 20% increase in PEF or FEV1 after bronchodilator administration; or (c) demonstrating hyper-reactivity to inhaled histamine, methacholine, or cold air. Skin tests should be used to identify relevant sensitivities to allergens. If a patient has positive skin test results, then education relevant to decreasing exposure to the specific allergens is a first step in management. These patients may benefit from the combination of a long-acting β2 receptor agonist, in combination with a leukotriene antagonist. Short-acting bronchodilators should be reserved for the reversal of acute episodes.

Inhaled corticosteroids, cromolyn, or nedocromil, taken on a regular basis, should be prescribed for any patient who continues to have symptoms necessitating bronchodilator therapy more than three times weekly. If symptoms persist and spirometry confirms obstruction, the dose of the antiinflammatory agent should be increased, and an oral delayed-release theophylline preparation, 200 to 300 mg two or three times a day, should be considered. After 4 days the theophylline blood concentrations should be from 5 to 14 µg/mL.

For acute asthmatic episodes, doses of inhaled steroids should be increased to four puffs four times a day and theophylline added as needed. A short course of oral steroids (60 mg of prednisone reduced to zero over 6 to 8 days) may also be necessary. In the clinic or emergency room, a nebulized β2 receptor agonist is the first line of treatment, which can be repeated three times at 20-minute intervals, and then hourly thereafter. Patients not responding to nebulizer treatment should receive steroids (60 mg of prednisone or 125 mg of methylprednisolone IV).

Patients with unresponsive persistent symptoms may be treated with regular-dose, inhaled steroids four puffs four times a day, theophylline up to a maximum therapeutic range, and additional drugs, including cromolyn or nedocromil, a β2 receptor agonist delivered by nebulizer, or an LTM. Courses of oral steroids (6 to 30 days) and other agents may also be considered. The physician should reinforce education on allergen avoidance and consider other factors such as diet, fungal infections, drug reactions, sinusitis, and gastroesophageal reflux.

Antihistamines are generally not recommended for treatment of asthma. However, many allergic patients with rhinitis and asthma use antihistamines with no apparent harmful effects. Sedative antihistamines (see Chapter 14) should not be used in patients with acute bronchospasm. Antibiotics are commonly recommended for management of an exacerbation of asthma because of sputum production but should be reserved for those patients with bronchial infiltrates, fever, or sinusitis.

Allergen Avoidance

Exposure to allergens, particularly those found indoors, is well recognized as an important cause of asthma. Identification of sensitivity and education about measures necessary to decrease exposure are an important part of antiinflammatory treatment. For control of dust mites, enclosing the mattress and pillows in dust mite-proof covers, washing all bedding in boiling H2O, removing carpets, and using air filtration systems are important measures. Removing cats or dogs from the environment may be helpful; however, it will take weeks or months for the associated allergen levels to decrease. Cockroach eradication may be important for inner-city homes, in particular, and should involve such measures as enclosing all food, sealing gaps around pipes, and using poisonous bait. Special issues related to asthma are discussed in Box 16-1.

BOX 16–1 Special Issues

Asthma in Young Children

There are special issues concerning side effects and the delivery of antiasthmatic drugs in children. Children can be treated with a nebulizer and face mask from infancy; by age 7, they can usually use an MDI with a spacer. Inhaled cromolyn is the antiinflammatory drug of choice because it has no serious side effects and is available for use in a nebulizer. In young children, total daily doses of inhaled steroids as low as 400 μg have been reported to reduce growth. Long-term oral theophylline treatment (taken as sprinkles on food) is effective and well tolerated in many children. However, hyperactivity and/or learning difficulties are potential problems. Allergen avoidance should be recommended for any child who requires more than occasional treatment and has positive skin test results.

Asthma in Pregnancy

Management of asthma in pregnancy is similar to that for adults. Risks of uncontrolled asthma to the fetus outweigh the possible risks of drug therapy. Inhaled cromolyn and related agents, inhaled steroids, β2 receptor agonists, delayed-release theophylline, antibiotics for sinusitis associated with asthma, and short courses of steroids are given in normal adult doses.

COPD

A reactive airway often develops in patients with COPD as their disease progresses. Although these patients are generally not allergic, drug treatment of this condition has many features in common with asthma treatment in adults. Thus theophylline, β2 receptor agonists, steroids, and nebulized cromolyn are commonly used. Special issues include O2 supplementation and monitoring blood gases in respiratory compromised patients. Responses to muscarinic receptor antagonists in patients with COPD are better than with β2 receptor agonists, whereas the converse is true in asthmatics.

Pharmacovigilance: Side Effects, Clinical Problems, and Toxicity

The side effects of drugs used with asthma are summarized in the Clinical Problems Box.

Chromones

The side effects of cromolyn and nedocromil are restricted to the irritant effects of inhaling the drugs. There is very little convincing evidence for short-term or long-term drug toxicity and no recognized blood concentration that is toxic. Occasional cases of dermatitis, gastroenteritis, and myositis that are apparently associated with cromolyn use have been reported but are very unusual.

Glucocorticoids

The side effects of systemic corticosteroids are discussed in Chapter 39 and are mentioned here briefly in the context of pulmonary disease. The most important issue is the difference between short- and long-term use. Treatment with high-dose steroids, even short-term, can cause hypertension, diabetes, GI bleeding, and CNS disturbances. Elevations in blood glucose concentration and emotional changes are common but are usually easy to manage. Long-term steroid use produces a wide range of severe side effects, including thinning of the skin (striae, bruising), osteoporosis with rib fractures and vertebral compression, aseptic necrosis of the femoral head, which usually presents with pain, diabetes with complications, GI discomfort, ulceration and bleeding, cataract formation, and CNS disturbances, including frank psychosis. Prolonged oral use of steroids causes profound suppression of adrenal function. If patients are taking oral steroids for more than 7 days, the dose should be gradually reduced, because abrupt withdrawal can result in life-threatening adrenal insufficiency. Patients must be made fully aware of the harmful effects of long-term orally administered steroids.

Although there was concern that inhaled steroids would produce serious side effects in the lungs or systemically, this is not the case. The major side effects of inhaled steroids (e.g., beclomethasone dipropionate) have been oral candidiasis and occasionally irritation triggered by the use of an MDI. In all patients, but especially those with COPD, yeast infection of the mouth (thrush) is common and requires local treatment. The efficacy of chronic use of inhaled steroids in patients with COPD is not well established, because the possibility exists that inhaled steroids might encourage fungal colonization in patients with a severe fixed obstruction, that is, FEV1 <40% predicted.

In contrast, large doses of inhaled corticosteroids have significant effects on the adrenal axis and bone growth in children. Inhaled steroids are all active locally, and their systemic side effects depend on both absorption and metabolism. There is some evidence that budesonide and flunisolide have fewer systemic effects because their metabolites are inactive.

Leukotriene Modulators

Adverse effects of the leukotriene antagonists zafirlukast and montelukast are minimal, and generally, the drugs are well tolerated. However, rare cases of hepatotoxicity and eosinophilic vasculitis have occurred. The clinical features of the vasculitis are consistent with Churg-Strauss syndrome, a life-threatening condition typically treated with systemic corticosteroid therapy. The occurrence of the vasculitis syndrome appears to be linked with the decrease or withdrawal of oral corticosteroid therapy. Therefore the patient and the physician need to be acutely aware of symptoms related to eosinophilia, vasculitic rash, worsening of pulmonary symptoms, cardiac complications, and developing neuropathies.

Zileuton* can produce elevated liver enzymes, typically in the first few months of therapy. It also inhibits hepatic CYP3A, which metabolizes many drugs, including theophylline. Considering the correlation of serum levels of theophylline to therapeutic and toxic effects, patient monitoring is necessary if the two drugs are used concurrently.

Methylxanthines

The most common side effects of theophylline that can occur within the normal therapeutic range are either GI upset (e.g., heartburn, abdominal pain, nausea, vomiting) caused by an increase in gastric acidity or CNS effects including headache, anxiety, tremor, and insomnia (similar to those reported with excess use of caffeine). Side effects occur with concentrations as low as 5 µg/mL but increase greatly in frequency and severity when the blood concentrations of theophylline exceed 15 µg/mL (the recommended upper limit). When blood concentrations exceed 20 µg/mL, seizures and cardiac dysrhythmias are possible and become common when blood concentrations exceed 35 µg/mL. Seizures can result in significant mortality; thus elevated theophylline concentrations are treated as an emergency with gastric lavage, oral charcoal, and even dialysis. Considerable attention has been given to CNS symptoms in children receiving methylxanthines, including poor attention and insomnia, with resultant poor school performance.

Adrenergic β2 Receptor Agonists

The primary side effects of adrenergic agonists are cardiac stimulation, hypertension, tremor, and restlessness (see Chapter 11). The use of selective β2 receptor agonists decreases the risk of some of these effects. Inhaled β2 receptor agonists generally produce fewer side effects than oral preparations. Nonetheless, tachycardia and muscle tremor still occur. Continued use of these agents may result in the desensitization of β receptors (see Chapter 1); however, GC therapy can prevent or partially reverse this phenomenon. Epi can ameliorate severe life-threatening asthma attacks when administered subcutaneously. However, there are very few indications for this form of treatment in older patients or in those with underlying cardiovascular disease. Although there was a concern that chronic use of short-acting β2 receptor agonists would worsen asthma, this has not proven to be the case.

Muscarinic Receptor Antagonists

Inhaled ipratropium or tiotropium may give rise to drying of the mouth and upper airways. Because these drugs are administered via inhalation, systemic adverse effects,

CLINICAL PROBLEMS

Cromolyn/Nedocromil

Less potent than steroids; may produce coughing during inhalation

Inhaled Steroids

Low doses induce candidiasis; high doses cause growth retardation and other systemic effects

Oral Steroids

High doses can cause GI problems and CNS disturbances

Leukotriene Antagonists

Rare hepatotoxicity and eosinophilia

Theophylline

Narrow therapeutic index, nausea and vomiting, seizures, cardiac dysrhythmias

Adrenergic β2 Receptor Agonists

Tachycardia, tremors

Muscarinic Antagonists

Dry mouth

such as those associated with atropine, are unusual (see Chapter 10).

New Horizons

Cilomilast is a PDE type 4 antagonist under investigation for the treatment of respiratory inflammatory diseases. PDE-4 regulates cell function by altering intracellular levels of CAMP and cyclic guanine monophosphate, particularly in inflammatory cells associated with asthma and COPD. Cilomilast may be less likely to cause CNS or GI side effects and fewer drug-drug interactions.

Etanercept is a [TNF-α] antagonist, being investigated in asthma treatment. TNF-α is a proinflammatory cytokine that is potentially important in refractory asthma. Etanercept is a fusion protein produced by recombinant DNA technology that is approved by the U.S. Food and Drug administration for the treatment of rheumatoid and psoriatic arthritis and ankylosing spondylitis. Initial studies indicate that enteracept improves lung function and airway hyper-responsiveness in asthma.

LTB4 is a proinflammatory lipid mediator generated from arachidonic acid through the action of 5-LOX that is implicated in many inflammatory disorders including asthma. BLT1, a G-protein-coupled receptor, is specific for LTB4, and the LTB4-BLT1 pathway is a novel future target for the treatment of asthma. Different immunosuppressive treatments, including methotrexate and tacrolimus, have been used in patients with severe or steroid-dependent asthma with variable degrees of success. Epidemiological evidence indicates an association of severity of asthma with fungus infections, and treatment with systemic antifungals (fluconazole or itraconazole, see Chapter 50) may be helpful for asthma in some cases.

TRADE NAMES

(In addition to generic and fixed-combination preparations, the following trade-named materials are some of the important compounds available in the United States.)

Adrenergic β2 Receptor Agonists

Albuterol* (AccuNeb, Proventil, Ventolin)

Bitolterol (Tornalate)

Metaproterenol (Alupent, Metaprel)

Pirbuterol (Maxair)

Terbutaline (Brethine, Brethaire, Bricanyl)

Formoterol (Foradil, Aerolizer, Perforomist)

Salmeterol (Serevent)

Chromones

Cromolyn (Intal, NasalCrom)

Nedocromil (Alocril, Tilade)

Inhaled Glucocorticoids

Beclomethasone (Beclovent, Beconase, Quar, Vancenase, Vanceril)

Budesonide (Entocrot, Rhinocort, Pulmicort)

Flunisolide (AeroBid, Nasalide, Nasarel)

Fluticasone (Cutivate, Flonase, Flovent, Veramyst)

Triamcinolone acetonide (Azmacort)

Leukotriene Modulators

Montelukast (Singulair)

Zafirlukast (Accolate)

Muscarinic Receptor Antagonists

Ipratropium (Atrovent, Atrovent HFA)

Tiotropium (Spiriva)

Methylxanthines

Oxtriphylline (Choledyl)

Theophylline (Slo-bid, Slo-Phyllin, Uniphyl, Theo-24, Theo-Dur)

* In the United Kingdom and Japan the drug name is salbutamol.

 Long-acting agents not suitable for emergency use. The use of these agents has been recommended to be taken only in fixed-dose combinations with an inhaled corticosteroid to avoid increased risk of severe asthma exacerbations with one of these agents alone.

 In the United Kingdom the drug name is sodium cromoglycate; in Japan the drug name is cromoglycate sodium.

Acetylcholine (ACh) is synthesized and secreted by non-neuronal cells and modifies their behavior. This “non-neuronal cholinergic system” is present in airway inflammatory cells where ACh has both proinflammatory and antiinflammatory activity, depending on the cell type. The function of this system can be modified by nicotine in cigarette smoke, the inflammation of asthma and COPD, and the drugs used in treating these diseases.

Certain gene polymorphisms in patients with asthma can influence responses to β2 receptor agonists, GCs, and LTMs. These mutations result in altered responses to therapy, GC resistance, decreased theophylline clearance and toxicity, and increased bronchoconstriction.

FURTHER READING

Anonymous. Drugs for allergic disorders. Treat Guidel Med Lett. 2007;60:71-80.

Anonymous. Drugs for asthma. Treat Guidel Med Lett. 2005;3:33-38.

Morrow T. Implications of pharmacogenomics in the current and future treatment of asthma. J Manag Care Pharm. 2007;13:497-505.

Weiss et al. 2006 Weiss ST, Litonjua AA, Lange C, et al. Overview of the pharmacogenetics of asthma treatment. Pharmacogenomics J. 2006;6:311-326.

SELF-ASSESSMENT QUESTIONS

1. An 11-year-old child experiences wheezing and difficulty breathing when exercising. Which of the following drugs would be recommended to prevent these symptoms?

A. Albuterol

B. Cromolyn

C. Fluticasone

D. Ipratropium

E. Zafirlukast

2. A 74-year-old patient with a 50-year history of smoking presents to the emergency room with an acute exacerbation of his COPD. Which of the following classes of drugs would be most effective at relieving the bronchoconstrictive component of his disease?

A. Muscarinic antagonists

B. Corticosteroids

C. Leukotriene modulators

D. Oxygen

E. Adrenergic β2 receptor agonists

3. An essential component in the treatment and management of pulmonary disease is control of the inflammatory process. Which of the following agents will reduce the recruitment of eosinophils?

A. Albuterol

B. Flunisolide

C. Ipratropium

D. Nedocromil

E. Zafirlukast

4. The short duration of action of inhaled β2 agonists can be problematic, especially for nocturnal asthma. Of the following inhaled β2 agonist bronchodilators, which exhibits a long half-life that can ameliorate the problem?

A. Albuterol

B. Metaproterenol

C. Salmeterol

D. Bitolterol

* This drug is no longer available in the United States.

1 In the United Kingdom and Japan the drug name is salbutamol.