Pathophysiology of asthma

Asthma is a chronic inflammatory disorder of the airways. In about 50% of children with asthma and in some adults, airway inflammation results from an immune response to known allergens. In the remaining children and in most adults, the cause of airway inflammation is unknown—although as-yet unidentified allergens are suspected.

Figure 76–1 depicts the events that lead to inflammation and bronchoconstriction in patients whose asthma is caused by specific allergens. Although this model may not apply completely to all asthma patients, it nonetheless provides a basis for understanding the drugs used for treatment. The inflammatory process begins with binding of allergen molecules (eg, house dust mite feces) to immunoglobulin E (IgE) antibodies on mast cells. This causes mast cells to release an assortment of mediators, including histamine, leukotrienes, prostaglandins, and interleukins. These mediators have two effects. They act immediately to cause bronchoconstriction. In addition, they promote infiltration and activation of inflammatory cells (eosinophils, leukocytes, macrophages). These inflammatory cells then release mediators of their own. The end result is airway inflammation, characterized by edema, mucus plugging, and smooth muscle hypertrophy, all of which obstruct airflow. In addition, inflammation produces a state of bronchial hyperreactivity. Because of this state, mild trigger factors (eg, cold air, exercise, tobacco smoke) are able to cause intense bronchoconstriction.

From a therapeutic perspective, the important message here is that symptoms of asthma result from a combination of inflammation and bronchoconstriction. Accordingly, treatment must address both components.

Overview of drugs for asthma

The major drugs for asthma are listed in Table 76–1. As indicated, they fall into two main pharmacologic classes: anti-inflammatory agents and bronchodilators. The principal anti-inflammatory drugs are the glucocorticoids. The principal bronchodilators are the beta₂ agonists. For chronic asthma, glucocorticoids are administered on a fixed schedule, almost always by inhalation. Beta₂ agonists may be administered on a fixed schedule (for long-term control) or PRN (to manage an acute attack). Like the glucocorticoids, beta₂ agonists are usually inhaled. As discussed in Box 76–1, the drugs we use for asthma are also used for chronic obstructive pulmonary disease (COPD).

Administering drugs by inhalation

Most antiasthma drugs can be administered by inhalation, a route with three advantages: (1) therapeutic effects are enhanced (by delivering drugs directly to their site of action), (2) systemic effects are minimized, and (3) relief of acute attacks is rapid. Three types of inhalation devices are employed: metered-dose inhalers, dry-powder inhalers, and nebulizers.

Metered-dose inhalers

Metered-dose inhalers (MDIs) are small, hand-held, pressurized devices that deliver a measured dose of drug with each actuation. Dosing is usually accomplished with 1 or 2 puffs. When 2 puffs are needed, an interval of at least 1 minute should separate the first puff from the second. When using most MDIs, the patient must begin to inhale prior to activating the device. Hence, hand-lung coordination is required. MDIs can be difficult to use correctly. Accordingly, patients will need a demonstration as well as written and verbal instruction. Even with optimal use, only about 10% of the dose reaches the lungs. About 80% impacts the oropharynx and is swallowed, and the remaining 10% is left in the device or exhaled.

Several kinds of spacers are available for use with MDIs. All of these devices, which attach directly to the MDI, serve to increase delivery of drug to the lungs and decrease deposition of drug on the oropharyngeal mucosa (Fig. 76–2). Some spacers contain a one-way valve that activates upon inhalation, thereby obviating the need for good hand-lung coordination. Some spacers also contain an alarm whistle that sounds off when inhalation is too rapid.

In the past, MDIs employed two kinds of propellants: hydrofluoroalkane (HFA) and chlorofluorocarbons (CFCs). Today, however, nearly all MDIs use HFA. Most MDIs made with CFCs have been discontinued. And the two that remain—albuterol/ipratropium [Combivent Inhalation Aerosol] and pirbuterol [Maxair Autohaler]—will be phased out by December 31, 2013. Why are CFCs being phased out? Because they can deplete the Earth’s ozone layer, which protects us from ultraviolet radiation. HFA does not affect ozone.

Dry-powder inhalers

Dry-powder inhalers (DPIs) are used to deliver drugs in the form of a dry, micronized powder directly to the lungs. No propellant is employed. Hence, DPIs pose no environmental risk. Unlike MDIs, DPIs are breath activated. As a result, DPIs don’t require the hand-lung coordination needed with MDIs, and hence DPIs are much easier to use. Compared with MDIs, DPIs deliver more drug to the lungs (20% of the total released vs. 10%) and less to the oropharynx. Also, spacers are not used with DPIs.

Nebulizers

A nebulizer is a small machine used to convert a drug solution into a mist. The droplets in the mist are much finer than those produced by inhalers. Inhalation of the nebulized mist can be done through a face mask or through a mouthpiece held between the teeth. Nebulizers take several minutes to deliver the same amount of drug contained in 1 puff from an inhaler. For some patients, a nebulizer may be more effective than an inhaler. Although nebulizers are usually used at home or in a hospital, these devices, which weigh under 10 pounds, are sufficiently portable for use in other locations.

Glucocorticoids

Glucocorticoids (eg, budesonide, fluticasone) are the most effective antiasthma drugs available. Administration is usually by inhalation, but may also be IV or oral. Adverse reactions to inhaled glucocorticoids are generally minor, as are reactions to systemic glucocorticoids taken acutely. However, when systemic glucocorticoids are used long term, severe adverse effects are likely. The basic pharmacology of the glucocorticoids is presented in Chapter 72. Discussion here is limited to their use in asthma.

Mechanism of antiasthma action

Glucocorticoids reduce asthma symptoms by suppressing inflammation. Specific anti-inflammatory effects include

• Decreased synthesis and release of inflammatory mediators (eg, leukotrienes, histamine, prostaglandins)

• Decreased infiltration and activity of inflammatory cells (eg, eosinophils, leukocytes)

• Decreased edema of the airway mucosa (secondary to a decrease in vascular permeability)

By suppressing inflammation, glucocorticoids reduce bronchial hyperreactivity. In addition to reducing inflammation, glucocorticoids decrease airway mucus production and increase the number of bronchial beta₂ receptors as well as their responsiveness to beta₂ agonists.

Use in asthma

Glucocorticoids are used for prophylaxis of chronic asthma. Accordingly, dosing must be done on a fixed schedule—not PRN. Because beneficial effects develop slowly, these drugs cannot be used to abort an ongoing attack. Glucocorticoids do not alter the natural course of asthma, even when used in young children.

Inhalation use.

Inhaled glucocorticoids are first-line therapy for asthma. All patients with moderate to severe asthma should use these drugs daily. Inhaled glucocorticoids are very effective and very safe.

Oral use.

Oral glucocorticoids are reserved for patients with severe asthma. Because of their potential for toxicity, these drugs are prescribed only when symptoms cannot be controlled with safer medications (inhaled glucocorticoids, inhaled beta₂ agonists). Because the risk of toxicity increases with duration of use, treatment should be as brief as possible.

Adverse effects

Inhaled glucocorticoids.

These preparations are largely devoid of serious toxicity, even when used in high doses. The most serious concern is adrenal suppression.

The most common adverse effects are oropharyngeal candidiasis and dysphonia (hoarseness, speaking difficulty). Both effects result from local deposition of inhaled glucocorticoids. To minimize these effects, patients should gargle after each administration. Using a spacer device can help too. If candidiasis develops, it can be treated with an antifungal drug.

With long-term, high-dose therapy, some adrenal suppression may develop, although the degree of suppression is generally low. In contrast, with prolonged use of oral glucocorticoids, adrenal suppression can be profound. As noted below, patients who have been switched from oral glucocorticoids to inhaled glucocorticoids must be given supplemental oral or IV doses at times of stress. (At times of stress, inhaled glucocorticoids can control symptoms of asthma, but cannot replace the glucocorticoids required to support life.)

Glucocorticoids can slow growth in children and adolescents—but these drugs do not decrease adult height. Short-term studies have shown that inhaled glucocorticoids retard growth. However, long-term studies indicate that adult height is not reduced. Two studies reported in the October 12, 2000, issue of the New England Journal of Medicine demonstrated that inhaled budesonide does indeed slow growth in children—but only temporarily. Despite continued budesonide use, growth rate returns to normal within a year, and children eventually achieve their expected adult height. Moreover, adult height is not affected by either the duration of budesonide use or the total cumulative dose. Unfortunately, these studies focused only on skeletal growth, and hence we still don’t know if glucocorticoids suppress growth and development of the brain, lungs, and other organs. Until more is known about how glucocorticoids affect organs, it would seem prudent to reserve these drugs for older children and for young children whose asthma is relatively severe; young children whose asthma is very mild, and hence can be treated effectively without glucocorticoids, should probably not receive these drugs.

Like oral glucocorticoids, inhaled glucocorticoids can promote bone loss—at least in premenopausal women. Fortunately, the amount of loss is much lower than the amount caused by oral glucocorticoids. To minimize bone loss, patients should (1) use the lowest dose possible, (2) ensure adequate intake of calcium and vitamin D, and (3) participate in weight-bearing exercise.

There has been concern that prolonged therapy might increase the risk of cataracts and glaucoma. However, a study reported in 2011 showed no increase in the incidence of cataracts or elevated intraocular pressure in young adults who had been treated with inhaled budesonide for 16 years.

Oral glucocorticoids.

When used acutely (less than 10 days), even in very high doses, oral glucocorticoids do not cause significant adverse effects. However, prolonged therapy, even in moderate doses, can be hazardous. Potential adverse effects include adrenal suppression, osteoporosis, hyperglycemia, peptic ulcer disease, and, in young patients, suppression of growth.

Adrenal suppression is of particular concern. As discussed in Chapter 72, prolonged glucocorticoid use can decrease the ability of the adrenal cortex to produce glucocorticoids of its own. Because high levels of glucocorticoids are required to survive severe stress (eg, surgery, trauma, infection), and because adrenal suppression prevents production of endogenous glucocorticoids, patients must be given increased doses of oral or IV glucocorticoids at times of stress. Failure to do so can prove fatal! Following withdrawal of oral glucocorticoids (or transfer to inhaled glucocorticoids), several months are required for recovery of adrenocortical function. Throughout this time, all patients—including those switched to inhaled glucocorticoids—must be given supplemental oral or IV glucocorticoids at times of severe stress.

A complete list of contraindications to oral glucocorticoids is presented in the Summary of Major Nursing Implications at the end of this chapter.

Preparations, dosage, and administration

Inhaled glucocorticoids.

Six glucocorticoids are available for inhalation (Table 76–2). Four are available in MDIs, three are available in DPIs, and one is available in suspension for nebulization. Inhaled glucocorticoids are administered on a regular schedule—not PRN. Pediatric and adult dosages are summarized in Table 76–2. In all cases, the dosage should be kept as low as possible to minimize adrenal suppression, possible bone loss, and other adverse effects.

TABLE 76–2 

Inhaled Glucocorticoids: Formulations and Dosages

		Dosage
Drug	Formulation	Adults	Children
Beclomethasone dipropionate
[QVAR]	MDI: 40 or 80 mcg/puff	40–320 mcg twice daily	40–80 mcg twice daily (5–11 yr)
Budesonide
[Pulmicort Flexhaler]	DPI: 90 or 180 mcg/inhalation	360–720 mcg twice daily	180–360 mcg twice daily (6–17 yr)
[Pulmicort Respules]	Suspension for nebulization	250–500 mcg once or twice daily or 1000 mcg once daily	500–1000 mcg/day (1–8 yr)
Ciclesonide
[Alvesco]	MDI: 80 or 160 mcg/puff	80–320 mcg twice daily	80–320 mcg twice daily (12 yr and up)
Flunisolide
[AeroSpan]	MDI: 80 mcg/puff	160–320 mcg twice daily	80–320 mcg twice daily (6–11 yr)
Fluticasone propionate
[Flovent HFA]	MDI: 44, 110, or 220 mcg/puff	88–440 mcg twice daily	88 mcg twice daily (4–11 yr)
[Flovent Diskus]	DPI: 50, 100, or 250 mcg/puff	100–1000 mcg twice daily	50–100 mcg twice daily (4–11 yr)
Mometasone furoate
[Asmanex Twisthaler]	DPI: 110 or 220 mcg/puff	220–440 mcg once or twice daily	110 mcg once daily (4–11 yr)

DPI = dry-powder inhaler, MDI = metered-dose inhaler.

Glucocorticoids in mdis.

All of the glucocorticoid MDIs now on the market employ HFA as a propellant. All MDIs that employed a CFC propellant have been withdrawn. With the CFC-powered MDIs, patients needed to use a spacer device to increase drug delivery to the lungs. With the HFA-powered MDIs, no spacer is needed. Why? Because HFA produces smaller droplets than CFCs, and hence delivery of drugs to the lungs is greatly improved. Nonetheless, even with HFA-powered MDIs, drug delivery can be increased by inhaling a short-acting beta₂ agonist 5 minutes prior to inhaling the glucocorticoid.

Nebulized budesonide.

Budesonide suspension [Pulmicort Respules] is the first inhaled glucocorticoid formulated for nebulized dosing. The product is approved for maintenance therapy of persistent asthma in children 1 to 8 years old—that is, children too young to use an MDI or DPI. Improvement should begin in 2 to 8 days; maximal benefits may take 4 to 6 weeks to develop. Budesonide suspension is available in 2-mL ampules containing 250 or 500 mcg of the drug. Administration is done with a jet nebulizer equipped with a mouthpiece or face mask; ultrasonic nebulizers should not be used. Administration takes 5 to 10 minutes. For children who are not taking an oral glucocorticoid, the initial dosage is 500 mcg/day in one or two doses. For children who are taking an oral glucocorticoid, the initial dosage is 1000 mcg/day in one or two doses. After 1 week, dosage of the oral glucocorticoid should be tapered off.

Oral glucocorticoids.

Prednisone and prednisolone are preferred glucocorticoids for oral therapy of asthma. For acute therapy, the usual adult dosage for either drug is 30 to 40 mg twice daily for 5 to 7 days.

For long-term treatment, alternate-day dosing is recommended (to minimize adrenal suppression). The initial adult dosage is 40 to 60 mg (of prednisone or prednisolone) administered every other morning. The initial pediatric dosage is 20 to 40 mg every other morning. After symptoms have been controlled for a month, dosages should be reduced by 5 to 10 mg every 2 weeks to establish the lowest dosage that can keep the patient free of symptoms. As discussed above, supplemental doses are required at times of stress.

Leukotriene modifiers

When they were introduced in the late 1990s, the leukotriene modifiers were the first new drugs for asthma in over 20 years. All of these agents suppress the effects of leukotrienes, compounds that promote bronchoconstriction as well as eosinophil infiltration, mucus production, and airway edema. In patients with asthma, these drugs can decrease inflammation, bronchoconstriction, edema, mucus secretion, and recruitment of eosinophils and other inflammatory cells.

Three leukotriene modifiers are currently available: zileuton, zafirlukast, and montelukast. Zileuton blocks leukotriene synthesis; zafirlukast and montelukast block leukotriene receptors. All three drugs are dosed orally. Current guidelines recommend using these agents as second-line therapy (if an inhaled glucocorticoid cannot be used), and as add-on therapy when an inhaled glucocorticoid alone is inadequate. Although generally well tolerated, all of the leukotriene modifiers can cause adverse neuropsychiatric effects, including depression, suicidal thinking, and suicidal behavior.

Zileuton

Zileuton [Zyflo, Zyflo CR], an inhibitor of leukotriene synthesis, is approved for asthma prophylaxis and maintenance therapy in adults and children age 12 years and older. Benefits derive from inhibiting 5-lipoxygenase, the enzyme that converts arachidonic acid into leukotrienes. Symptomatic improvement can be seen within 1 to 2 hours of dosing. Because effects are not immediate, zileuton cannot be used to abort an ongoing attack. Zileuton is less effective than an inhaled glucocorticoid alone, and appears to be less effective than a long-acting inhaled beta₂ agonist as adjunctive therapy in patients not adequately controlled with an inhaled glucocorticoid.

Zileuton is given orally and undergoes rapid absorption, both in the presence and absence of food. Plasma levels peak 2 to 3 hours after dosing. Zileuton is rapidly metabolized by the liver, and the metabolites are excreted in the urine. Its plasma half-life is 2.5 hours.

Zileuton can injure the liver, as evidenced by increased plasma levels of alanine aminotransferase (ALT) activity. A few patients have developed symptomatic hepatitis, which reversed following drug withdrawal. To reduce the risk of serious liver injury, ALT activity should be monitored. The recommended schedule is once a month for 3 months, then every 2 to 3 months for the remainder of the first year, and periodically thereafter.

Postmarketing reports indicate that zileuton and the other leukotriene modifiers can cause adverse neuropsychiatric effects, including depression, anxiety, agitation, abnormal dreams, hallucinations, insomnia, irritability, restlessness, and suicidal thinking and behavior. If these develop, switching to a different medication should be considered.

Zileuton is metabolized by cytochrome P450, and hence can compete with other drugs for metabolism, thereby increasing their levels. Combined use with theophylline can markedly increase theophylline levels. Accordingly, dosage of theophylline should be reduced. Zileuton can also increase levels of warfarin and propranolol.

Zileuton is available in 600-mg immediate-release (IR) tablets, sold as Zyflo, and 600-mg extended-release (ER) tablets sold as Zyflo CR. With the IR tablets, the recommended dosage is 600 mg 4 times a day. With the ER tablets, the recommended dosage is 600 mg twice a day, taken within 1 hour of the morning and evening meals.

Zafirlukast

Zafirlukast [Accolate], approved in 1996, was the first representative of a unique group of anti-inflammatory agents, the leukotriene receptor antagonists. The drug is approved for maintenance therapy of chronic asthma in adults and children 5 years of age and older. Benefits derive in part from reduced infiltration of inflammatory cells and decreased bronchoconstriction. According to a recent trial reported in the New England Journal of Medicine (May 21, 2011), zafirlukast, when used short term (2 months), is equivalent to an inhaled glucocorticoid as first-line therapy of asthma, and equivalent to an inhaled long-acting beta₂ agonist as add-on therapy in patients not controlled adequately with an inhaled glucocorticoid alone. However, benefits with long-term use (2 years) are less impressive.

Zafirlukast is administered orally, and absorption is rapid. Food reduces absorption by 40%. Hence, the drug should be administered at least 1 hour before meals or 2 hours after. Zafirlukast undergoes hepatic metabolism followed by fecal excretion. The half-life is about 10 hours, but may be as long as 20 hours in the elderly.

Zafirlukast causes few adverse effects—although there is concern about neuropsychiatric effects, liver injury, and Churg-Strauss syndrome. The most common side effects are headache and GI disturbances, both of which are infrequent. Arthralgia and myalgia may also occur. Like zileuton, zafirlukast can cause depression, suicidal thinking, hallucinations, and other neuropsychiatric effects. A few patients have developed Churg-Strauss syndrome, a potentially fatal disorder characterized by weight loss, flu-like symptoms, and pulmonary vasculitis (blood vessel inflammation). However, in all cases, symptoms developed when glucocorticoids were being withdrawn, suggesting that glucocorticoid withdrawal—and not zafirlukast—may be the underlying cause.

Rarely, patients develop clinical signs of liver injury (eg, abdominal pain, jaundice, fatigue). If these occur, zafirlukast should be discontinued, and liver function tests (especially serum ALT) should be performed immediately. If test results are consistent with liver injury, zafirlukast should not be resumed. Curiously, signs of liver injury have developed mainly in females.

Zafirlukast inhibits two isozymes of cytochrome P450, and hence can suppress metabolism of other drugs, thereby causing their levels to rise. Concurrent use can raise serum theophylline to toxic levels. Accordingly, serum theophylline should be closely monitored, especially when zafirlukast is started or stopped. Zafirlukast can also raise levels of warfarin (an anticoagulant), and may thereby cause bleeding.

Zafirlukast is available in 10- and 20-mg tablets. The dosage for adults and children age 12 and older is 20 mg twice a day. The dosage for children 5 to 11 years old is 10 mg twice a day. Zafirlukast should not be administered with food.

Montelukast

Montelukast [Singulair], a leukotriene receptor blocker, is the most commonly used leukotriene modulator. The drug has three approved indications: (1) prophylaxis and maintenance therapy of asthma in patients at least 1 year old; (2) prevention of exercise-induced bronchospasm (EIB) in patients at least 15 years old; and (3) relief of allergic rhinitis (see Chapter 77). Montelukast cannot be used for quick relief of an asthma attack because effects develop too slowly. For prophylaxis and maintenance therapy of asthma, maximal effects develop within 24 hours of the first dose, and are maintained with once-daily dosing in the evening. In clinical trials, montelukast decreased asthma-related nocturnal awakening, improved morning lung function, and decreased the need for a short-acting inhaled beta₂ agonist throughout the day. In the trial cited in the section on Zafirlukast above, montelukast, when used short-term, was equivalent to an inhaled glucocorticoid as first-line therapy, and equivalent to an inhaled long-acting beta₂ agonist as add-on therapy (in patients not adequately controlled with an inhaled glucocorticoid alone). Although montelukast is approved for preventing EIB, a short-acting beta₂ agonist is preferred.

Montelukast is rapidly absorbed following oral administration. Bioavailability is about 64%. Blood levels peak 3 to 4 hours after ingestion. The drug is highly bound (over 99%) to plasma proteins. Montelukast undergoes extensive metabolism by hepatic P450 enzymes followed by excretion in the bile. The plasma half-life ranges from 2.7 to 5.5 hours.

Montelukast is generally well tolerated. In clinical trials, adverse effects were equivalent to those of placebo. In contrast to zileuton and zafirlukast, montelukast does not seem to cause liver injury. As with zafirlukast, Churg-Strauss syndrome has occurred when glucocorticoid dosage was reduced. Postmarketing reports suggest a link between montelukast and neuropsychiatric effects, especially mood changes and suicidality. Fortunately, these effects are rare.

Montelukast appears devoid of serious drug interactions. Unlike zileuton and zafirlukast, it does not increase levels of theophylline or warfarin. Concurrent use of phenytoin (an anticonvulsant that induces P450 enzymes) can decrease levels of montelukast.

Montelukast is available in three formulations: standard tablets (10 mg), chewable tablets (4 and 5 mg), and oral granules (4 mg/packet). The oral granules may be put directly in the mouth or may be mixed with one spoonful of either applesauce, carrots, rice, or ice cream. For prophylaxis or chronic treatment of asthma, dosing is done once a day in the evening, with or without food. Dosage is based on patient age as follows:

• Age 15 years and older—one 10-mg tablet daily

• Age 6 to 14 years—one 5-mg chewable tablet daily

• Age 2 to 5 years—one 4-mg chewable tablet or 4 mg of oral granules daily

• Age 12 to 23 months—4 mg of oral granules daily

To prevent EIB, patients should take one 10-mg tablet at least 2 hours before exercising. No additional dose should be taken for at least 24 hours. Patients already taking montelukast daily should not take any more to prevent EIB.

Cromolyn

Cromolyn [Intal] is an inhalational agent that suppresses bronchial inflammation. The drug is used for prophylaxis—not quick relief—in patients with mild to moderate asthma. Anti-inflammatory effects are less than with glucocorticoids.

Effects on the lung.

Cromolyn suppresses inflammation; it does not cause bronchodilation. The drug acts in part by stabilizing the cytoplasmic membrane of mast cells, thereby preventing release of histamine and other mediators. In addition, cromolyn inhibits eosinophils, macrophages, and other inflammatory cells.

Pharmacokinetics.

Cromolyn is administered by inhalation. The fraction absorbed from the lungs is small (about 8%) and produces no systemic effects. Absorbed cromolyn is excreted unchanged in the urine.

Therapeutic uses. 

Chronic asthma.

Cromolyn is an alternative to inhaled glucocorticoids for prophylactic therapy of mild persistent asthma. The drug produces adequate control in 60% to 70% of patients. When administered on a fixed schedule, cromolyn reduces both the frequency and intensity of attacks. No tolerance to effects is seen with long-term use. To be of benefit, cromolyn must be administered prior to the onset of an attack; the drug is without benefit if taken after an episode has begun. In patients with chronic asthma, maximal effects may take several weeks to develop. Cromolyn is especially effective for prophylaxis of seasonal allergic attacks and for acute prophylaxis immediately prior to allergen exposure (eg, before mowing the lawn).

Exercise-induced bronchospasm.

Cromolyn can prevent bronchospasm in patients at risk for EIB. For best results, cromolyn should be administered 15 minutes prior to anticipated exertion.

Allergic rhinitis.

Intranasal cromolyn [NasalCrom] can relieve symptoms of allergic rhinitis, as discussed in Chapter 77.

Adverse effects.

Cromolyn is the safest of all antiasthma medications. Significant adverse effects occur in fewer than 1 of every 10,000 patients. Occasionally, cough or bronchospasm occurs in response to cromolyn inhalation.

Preparations, dosage, and administration.

Cromolyn for inhalation [Intal] can be administered with two devices: (1) a power-driven nebulizer and (2) an MDI. Patients will need instruction on using both. With the nebulizer, the initial dosage for adults and children is 20 mg 4 times a day. With the MDI, the initial dosage for adults and children is 2 to 4 puffs (1.6 to 3.2 mg) 4 times a day. For maintenance therapy with either device, the lowest effective dosage should be established. For therapy of chronic asthma, cromolyn must be administered on a fixed schedule.

Omalizumab

Omalizumab [Xolair] is a monoclonal antibody with a unique mechanism of action: antagonism of IgE. The drug is a second-line agent indicated only for allergy-related asthma and only when preferred options have failed. Omalizumab offers modest benefits and has significant drawbacks: The drug poses a small risk of anaphylaxis and cancer, must be given subQ, and costs over $10,000 a year. Furthermore, its long-term safety is unknown. Use of omalizumab for seasonal allergic rhinitis and other allergic disorders is under investigation.

Mechanism of action.

Omalizumab forms complexes with free IgE in the blood and thereby reduces the amount of IgE available to bind with its receptors on mast cells. This greatly reduces the number of IgE molecules on the mast cell surface, and hence limits the ability of allergens to trigger release of histamine, leukotrienes, and other mediators that promote bronchospasm and airway inflammation. At recommended doses, omalizumab decreases free IgE in serum by 96%. When treatment stops, about 1 year is required for free IgE to return to its pretreatment level.

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