Selecting the appropriate pharmacologic therapy to achieve and maintain control of asthma involves several considerations: the medications and their routes of administration, a stepwise approach to managing asthma long term as a chronic disorder, and a protocol for managing exacerbations. Each will be discussed in this Unit. In addition, substantial reports in the literature since publication of the 1991 Expert Panel Report have commented on the safety of regular administration of inhaled beta2 -agonists and the potential adverse effects of inhaled corticosteroids. Because of the importance of these two classes of compounds in the treatment of asthma, it is the opinion of the Panel that special emphasis should be given to these issues. A summary is presented in this unit.

The therapeutic strategies provided here should be considered in concert with the clinician-patient partnership strategies provided in the last section of this course. Effective communication with, and education of, patients will increase the benefits of the therapeutic regimen.

Upon successful completion of this course, you should be able to:

• Identify and discuss the long-term and short-acting medications used in the management of asthma.
• Explain the various routes of administration used with medications for asthma
• Discuss special issues regarding asthma-patient medications
• Identify the key factors regarding asthma—patient education
• Identify and discuss the key factors associated with long-term management of asthma
• Explain what is meant by the "step" approach to gaining control of asthma
• Identify and discuss the key points associated with managing exacerbations of asthma

Key Points: The Medications

   Long-term-control medications

• Corticosteroids: Most potent and effective anti-inflammatory medication currently available. Inhaled form is used in the long-term control of asthma. Systemic corticosteroids are often used to gain prompt control of the disease when initiating long-term therapy.
• Cromolyn sodium and nedocromil: Mild-to-moderate anti-inflammatory medications. May be used as initial choice for long-term-control therapy for children. Can also be used as preventive treatment prior to exercise or unavoidable exposure to known allergens.
• Long-acting beta2 -agonists: Long-acting bronchodilator used concomitantly with anti- inflammatory medications for long-term control of symptoms, especially nocturnal symptoms. Also prevents exercise-induced bronchospasm (EIB).
• Leukotriene modifiers: Zafirlukast, a leukotriene receptor antagonist, or zileuton, a 5- lipoxygenase inhibitor, may be considered an alternative therapy to low doses of inhaled corticosteroids or cromolyn or nedocromil for patients 12 years of age with mild persistent asthma, although further clinical experience and study are needed to establish their roles in asthma therapy.

   Quick-relief medications

• Short-acting beta2 -agonists: Therapy of choice for relief of acute symptoms and prevention of EIB.
• Anticholinergics: Ipratropium bromide may provide some additive benefit to inhaled beta2- agonists in severe exacerbations. May be an alternative bronchodilator for patients who do not tolerate inhaled beta2-agonists.
• Systemic corticosteroids: Used for moderate-to-severe exacerbations to speed recovery and prevent recurrence of exacerbations.

Pharmacologic therapy is used to prevent and control asthma symptoms, reduce the frequency and severity of asthma exacerbations, and reverse airflow obstruction. Recommendations in this Unit reflect the scientific concept that asthma is a chronic disorder with recurrent episodes of airflow limitation, mucus production, and cough. Asthma medications are thus categorized into two general classes: long-term-control medications taken daily on a long-term basis to achieve and maintain control of persistent asthma (these medications are also known as long-term preventive, controller, or maintenance medications) and quick-relief medications taken to provide prompt reversal of acute airflow obstruction and relief of accompanying bronchoconstriction (these medications are also known as reliever or acute rescue medications). Patients with persistent asthma require both classes of medication. Figures 3-1 and 3-2 present summaries of the indications, mechanisms, potential adverse effects, and therapeutic issues for currently available long-term-control and quick-relief medications.

Figure 3-1 Long-Term-Control Medications

• Corticosteroids
• Cromolyn Sodium and Nedocromil
• Long-acting beta2-agonists
• Methylxanthines
• Leukotriene modifiers

Figure 3-2 Quick Relief Medications

• Short-acting inhaled beta2-agonists
• Anticholinergics
• Corticosteroids

Long-Term-Control Medications

Long-term-control medications are taken daily on a long-term basis to achieve and maintain control of persistent asthma. They include anti-inflammatory agents, long-acting bronchodilators, and leukotriene modifiers. Because eosinophilic inflammation is a constant feature of the mucosa of the airways in asthma, the most effective long-term-control medications are those that attenuate inflammation (Haahtela et al. 1991; Kerrebijn et al. 1987; van Essen-Zandvliet et al. 1992). The Expert Panel defines anti-inflammatory medications as those that cause a reduction in the markers of airway inflammation in airway tissue or airway secretions (e.g., eosinophils, mast cells, activated lymphocytes, macrophages, and cytokines; or eosinophilic cationic protein and tryptase; or extravascular leakage of albumin, fibrinogen, or other vascular protein) and thus decrease the intensity of airway hyperresponsiveness. Because many factors contribute to the inflammatory response in asthma, many drugs may be considered anti-inflammatory. It is not yet established, however, which anti-inflammatory actions are responsible for therapeutic effects, such as reduction in symptoms, improvement in expiratory flow, reduction in airway hyperresponsiveness, prevention of exacerbations, or prevention of airway wall remodeling.

Corticosteroids

Corticosteroids are the most potent and consistently effective long-term-control medication for asthma. Their broad action on the inflammatory process may account for their efficacy as preventive therapy. Their clinical effects include reduction in severity of symptoms, improvement in peak expiratory flow and spirometry, diminished airway hyperresponsiveness, prevention of exacerbations, and possibly the prevention of airway wall remodeling (Barnes et al. 1993; Jeffery et al. 1992; Dahl et al. 1993; Fabbri et al. 1993; Gustafsson et al. 1993; Haahtela et al. 1991; Kamada et al. 1996; Rafferty et al. 1985; van Essen-Zandvliet et al. 1992). Which of these clinical effects depend on specific anti-inflammatory actions of corticosteroids is not yet clear. Corticosteroids suppress the generation of cytokines, recruitment of airway eosinophils, and release of inflammatory mediators. These anti-inflammatory actions of corticosteroids have been noted in clinical trials and analyses of airway histology (Busse 1993; Booth et al. 1995; Laitinen et al. 1992; Djukanovic et al. 1992; Duddridge et al. 1993; Laitinen et al. 1991; Levy et al. 1995; McGill et al. 1995).

Dosages for inhaled corticosteroids vary depending upon the specific product and delivery devices (see figure 3-5b). For many patients, a twice-a-day dosing schedule maintains control of asthma; even high doses of some preparations are effective when given twice a day (Noonan et al. 1995). Some studies show that once-daily dosing is effective in mild persistent asthma (Jones et al. 1994; Pincus et al. 1995).

Cromolyn Sodium and Nedocromil

Although cromolyn and nedocromil have distinct properties (Clark 1993), they have similar anti-inflammatory actions. Their mechanism appears to involve the blockade of chloride channels (Alton and Norris 1996), and they modulate mast cell mediator release and eosinophil recruitment (Eady 1986). They also inhibit the early and late asthmatic response to allergen challenge and exercise-induced bronchospasm (EIB) (Novembre et al. 1994; Alton and Norris 1996; Thompson 1989; Gonzalez and Brogden 1987).

The two compounds are equally effective against allergen challenge (Gonzalez and Brogden 1987), although nedocromil appears to be more potent than cromolyn in inhibiting bronchospasm provoked by exercise (Novembre et al. 1995; deBenedictis et al. 1995), by cold dry air (Juniper et al. 1987), and by bradykinin aerosol (Dixon and Barnes 1989).

Both compounds have been shown to reduce asthma symptoms, improve morning peak flow, and reduce need for quick-relief beta2 -agonists (Lal et al. 1993; Schwartz et al. 1996). Two large clinical trials comparing nedocromil MDI 4 mg qid to cromolyn MDI 2 mg qid demonstrated that they are generally comparable in mild allergic patients and that nedocromil was more effective than cromolyn in nonallergic patients using inhaled corticosteroids. Furthermore, nedocromil may have a modest effect in helping reduce the dose requirements for inhaled corticosteroids (Lal et al. 1993; O’Hickey and Rees 1994; Svendsen and Jorgensen 1991), although some studies did not demonstrate this effect (Wong et al. 1993). Dosing recommendations for both drugs are for administration four times a day, although nedocromil has been shown to be clinically effective with twice daily dosing (Creticos et al. 1995). The clinical response to cromolyn and nedocromil is less predictable than the response to inhaled corticosteroids. Both compounds have a strong safety profile.

Long-Acting Beta2 -Agonists (Beta2-Adrenergic Agonists)

The principal action of beta2 -agonists is to relax airway smooth muscle by stimulating beta2 - receptors, which increases cyclic AMP and produces functional antagonism to bronchoconstriction. Long-acting inhaled beta2 -agonists have a duration of bronchodilation of at least 12 hours after a single dose (Becker and Simons 1989; D’Alonzo et al. 1994). This class of medication is not to be used for exacerbations. Rather, it is used as an adjunct to anti-inflammatory therapy for providing long-term control of symptoms, especially nocturnal symptoms (Yates et al. 1995) and to prevent exercise-induced bronchospasm. The use and safety of beta2 -agonists are discussed in Special Issues Regarding Safety.

Methylxanthines

Theophylline, the principally used methylxanthine, provides mild-to-moderate bronchodilation in asthma. Although its mechanism of action has yet to be established (Weinberger and Hendeles 1996; Hendeles et al. 1995), recent evidence suggests that low serum concentrations of theophylline are mildly anti-inflammatory (Sullivan et al. 1994; Kidney et al. 1995; Pauwels 1989). Sustained-release theophylline’s main use is as adjuvant therapy, and it is particularly effective for controlling nocturnal asthma symptoms. Sustained-release theophylline may be considered as an alternative, but not preferred, long-term preventive therapy when issues arise concerning cost or adherence to regimens using inhaled medication. Monitoring serum concentration levels is essential to ensure that therapeutic, but not toxic, doses are achieved.

Leukotriene Modifiers

Leukotrienes are potent biochemical mediators released from mast cells, eosinophils, and basophils that contract airway smooth muscle, increase vascular permeability, increase mucus secretions, and attract and activate inflammatory cells in the airways of patients with asthma (Henderson 1994). Two leukotriene modifiers—zafirlukast and zileuton—have recently become available as oral tablets for the treatment of asthma. From the information currently available, it appears that leukotriene modifiers improve lung function (Gaddy et al. 1992) and diminish symptoms and the need for short-acting inhaled beta2 - agonists. The majority of trials have been conducted in mild-to-moderate asthma, and the improvements noted have been modest. Leukotriene modifiers may be considered an alternative to low-dose inhaled corticosteroid therapy for patients with mild persistent asthma, although increased clinical experience and further study in a wide range of patients are needed to determine those patients most likely to benefit from leukotriene modifiers and to establish a more specific role for leukotriene modifiers in asthma therapy.

Zafirlukast, a leukotriene receptor antagonist, has been demonstrated to attenuate the late response to inhaled allergen and post-allergen induced bronchial responsiveness (Dahlen et al. 1994; Taylor et al. 1991). Studies comparing zafirlukast to placebo in patients with mild-to-moderate asthma demonstrated that patients treated with zafirlukast experienced modest improvement in FEV1 (mean improvement of 11 percent above placebo), improved symptom scores, and reduced albuterol use (average decline of 1 puff/day) (Spector et al. 1994). In a small study of healthy males, 60 mg a day of zafirlukast caused a significant increase in the half-life of warfarin. Consequently, for those individuals receiving zafirlukast and warfarin, it will be necessary to closely monitor prothrombin times and adjust doses of warfarin accordingly.

Zileuton, a 5-lipoxygenase inhibitor, has been demonstrated to provide immediate and sustained improvements in FEV1 (mean increase of 15 percent above placebo) in placebo-controlled trials in 1 patients with mild-to-moderate asthma (Israel et al. 1993, 1996). Compared to placebo, the patients with moderate asthma treated with zileuton experienced significantly fewer exacerbations requiring oral corticosteroids (Israel et al. 1996), thus suggesting anti-inflammatory action. Finally, zileuton is capable of attenuating bronchoconstriction from exercise (Meltzer et al. 1996) and from aspirin in aspirin-sensitive individuals (Israel et al. 1993). Because liver toxicity has been found in some subjects receiving zileuton, it is recommended that hepatic enzymes (ALT) be monitored in patients who take this medication. Zilueton is a microsomal CYP3A4 enzyme inhibitor that can inhibit the metabolism of terfenadine, warfarin, and theophylline. Doses of these drugs should be monitored accordingly.

Quick-Relief Medications

Quick-relief medications are used to provide prompt relief of bronchoconstriction and its accompanying acute symptoms such as cough, chest tightness, and wheezing. They include short-acting beta2 -agonists and anticholinergics. Although the onset of action is slow (>4 hours), systemic corticosteroids are important in the treatment of moderate-to-severe exacerbations because they prevent progression of the exacerbation, speed recovery, and prevent early relapses.

Short-Acting Beta2 -Agonists

Short-acting beta -agonists relax airway smooth muscle and cause a prompt (within 30 minutes) increase in airflow. Inhaled short-acting beta2 -agonists are the drug of choice for treating acute asthma 2 symptoms and exacerbations and for preventing EIB. Concerns about the safety of short-acting beta2 - agonists are discussed in another section of this Unit (see Special Issues Regarding Safety).

Anticholinergics

Cholinergic innervation is an important factor in the regulation of airway smooth muscle tone. Ipratropium bromide is a quaternary derivative of atropine that does not have atropine’s side effects. Ipratropium bromide may provide some additive benefit with inhaled beta2 -agonists in severe asthma exacerbations. Its effectiveness in long-term management of asthma has not been demonstrated (Kerstjens et al. 1992; Gross 1988; Storms et al. 1986).

Systemic Corticosteroids

Systemic corticosteroids can speed resolution of airflow obstruction and reduce the rate of relapse (Fanta et al. 1983; Rowe et al. 1992; Scarfone et al. 1993; Connett et al. 1994; Chapman et al. 1991)

Medications To Reduce Oral Systemic Corticosteroid Dependence: Troleandromycin, Cyclosporine, Methotrexate, Gold, Intravenous Immunoglobulin, Dapsone, and Hydroxychloroquine

These regimens to reduce oral systemic corticosteroid dependence should be used only in selected patients who are under the supervision of an asthma specialist. Although some of the compounds have corticosteroid-sparing effects, their use in asthma remains complicated because of highly variable effects, potential toxicity, and limited clinical experience (Bernstein et al. 1996; Jarjour et al. 1996; Mullarkey et al. 1988; Shiner et al. 1990; Erzurum et al. 1991; Muranaka et al. 1978; Klaustermeyer et al. 1987; Kamada et al. 1993; Nelson et al. 1993; Alexander et al. 1992; Mazer and Gelfand 1991). Colchicine is not considered effective in reducing need for oral systemic or high doses of inhaled corticosteroids (Newman et al. 1997).

Complementary Alternative Medicine

Alternative healing methods are not substitutes for recommended pharmacologic therapy. Although alternative healing methods may be popular with selected patients and of some interest to investigators, their scientific basis has not been established.

The most widely known complementary alternative medicine methods are acupuncture, homeopathy, herbal medicine, and Ayurvedic medicine (which includes transcendental meditation, herbs, and yoga). A review of multiple trials on the use of acupuncture in asthma concluded that the trials lacked quality and that the effectiveness of acupuncture in treating asthma has not been established (Kleijnen et al. 1991). One trial, however, demonstrated benefit in EIB (Fung et al. 1986). Homeopathy, based on the "law of similars" and the use of infinitesimally small doses, is as yet unproven for asthma (Reilly et al. 1986); some homeopathic remedies may contain potent unidentified pharmacologic agents (Morice 1986). No controlled clinical trials have been reported on herbal medicines, and the claims of effectiveness of western plant derivatives for asthma remain unsubstantiated (Dorsch and Wagner 1991; Ziment and Stein 1993). Because complementary alternative medicine is reported to be used by as much as one-third of the U.S. population (Eisenberg et al. 1993), it may be important to inquire about all the medications a patient uses and advise the patient accordingly.

Medications for asthma can be administered either by inhaled or systemic routes. Systemic routes are oral (ingested) or parenteral (subcutaneous, intramuscular, or intravenous). The major advantages of delivering drugs directly into the lungs via inhalation are that higher concentrations can be delivered more effectively to the airways and that systemic side effects are avoided or minimized (Newhouse and Dolovich 1986). Furthermore, the onset of action of inhaled bronchodilators is substantially shorter than that of oral bronchodilators.

Inhaled medications, or aerosols, are available in a variety of devices that differ in technique required and quantity of drug delivered to the lung. See figure 3-3 for a summary of issues to consider for different devices. Whatever device is selected, patients should be instructed in its use and their technique checked regularly.

Figure 3-3 Aerosol Delivery Devices

• Metered Dose Inhalers
• Breath actuated MDI
• Dry powder inhale
• Spacer/Holding chamber
• Nebulizer

*See figure 4-3 for description of MDI and DPI techniques.

Sources: Agertoft and Pedersen 1993; Ahrens et al 1995; Brown et al. 1990; Connett et al 1993; Higgins et al. 1987; Crompton and Duncan 1989; Everard et al. 1992; Fuglsang and Pedersen 1986; Goren et al. 1994; Kemp et al. 1989; Kesten et al 1994; Kim et al 1987; Lipworth 1995; Melchor et al 1993; Newman et al. 1981, 1984, 1991; O’Callaghan et al. 1994; Pedersen et al. 1990; Pedersen and Mortensen 1990; Prahl and Jenson 1987; Rossing et al. 1980; Ruggins et al. 1993; Schecker et al. 1993; Selroos and Halme 1991; Selroos et al. 1995; Thorsson et al 1994; Vidgren et al. 1983

Most inhaled medications currently used for asthma are available as metered-dose inhalers (MDIs). Historically, MDI technology has utilized chlorofluorocarbons (CFCs) as propellants. CFCs usually constitute 95 percent or more of the formulation emitted from an MDI; CFCs are metabolically stable and even the portion of an actuation that is systemically absorbed is quickly excreted unchanged via exhalation. However, CFCs have been found to deplete stratospheric ozone and have been banned internationally. Although a temporary medical exemption has been granted, it is expected that CFC-propelled MDIs will eventually be phased out completely. Alternatives include MDIs with other propellants (nonchlorinated propellants such as hydrofluoroalkane [HFA] 134a do not have ozone-depleting properties), multidose dry powder inhalers, and other hand-held devices with convenience and delivery characteristics similar to current MDIs. An MDI for albuterol with HFA 134a has been approved for use; additional non-CFC products and delivery systems are expected in the future. The Food and Drug Administration approval process requires that the replacement products demonstrate comparability to the corresponding CFC products so that clinicians and patients can anticipate similar effectiveness and safety with the new products. During the phaseout of CFC products, clinicians will need to be informed of the alternatives and assist their patients in the transition to non-CFC products (See Unit 4).

Short-Acting Inhaled Beta2 -Agonists

Key Points: Short-Acting Inhaled Beta2 -Agonists

• Short-acting beta -agonists are the most effective medication for relieving acute bronchospasm.
• Increasing use of short-acting beta2 -agonists or the use of more than one canister in 1 month indicates inadequate control of asthma and the need for initiating or intensifying anti-inflammatory therapy.
• Regularly scheduled, daily use of short-acting beta -agonists is generally not recommended.

Short-acting inhaled beta2 -agonists (e.g., albuterol) are the medications of choice for treating exacerbations of asthma and for preventing EIB. Prior to 1990, many clinicians prescribed short-acting beta2 -agonists on a regularly scheduled basis in the belief that this treatment regimen improved overall asthma symptom control. Some recent reports, however, have modified these beliefs. For example, in moderate asthma, regular use of a potent inhaled beta2 -agonist (fenoterol) produced a significant 2 diminution in asthma control and objective measurements of pulmonary function (Sears et al. 1990). In mild asthma, regularly scheduled use of albuterol compared to use on an as-needed basis only resulted in no significant differences in a variety of outcome indices. Although regularly scheduled use of beta2 - agonists in mild asthma produced no harmful effects in a 4-month period, it also produced no demonstrable benefits (Drazen et al. 1996). Similar findings were noted in studies with moderate asthma (D’Alonzo et al. 1994; Pearlman et al. 1992). Based on these and other observations (Cockcroft et al. 1993; van Schayck et al. 1991; O’Connor et al. 1992; Mullen et al. 1993; Ernst et al. 1993; Suissa et al. 1994), the regularly scheduled, daily use of short-acting beta -agonists is not generally 2 recommended.

The frequency of beta2 -agonist use can be clinically useful as a barometer of disease activity because increasing use of beta2 -agonists has been associated with increased risk for death or near death in patients with asthma (Spitzer et al. 1992). The use of more than one beta2 -agonist canister (e.g., albuterol, 200 puffs per canister) predominantly for quick-relief treatment during a 1-month period most likely indicates over-reliance on this drug and suggests inadequate asthma control (Spitzer et al. 1992).

Long-Acting Inhaled Beta2 -Agonists

Key Points: Long-Acting Inhaled Beta2 -Agonists

• Long-acting beta2 -agonists (salmeterol) can be beneficial to patients when added to inhaled corticosteroid therapy, especially to control nighttime symptoms (Greening et al. 1994; Woolcock et al. 1996). Daily use of long-acting beta2 -agonists should generally not exceed 84 mcg (salmeterol; four puffs).

Salmeterol is not to be used for treatment of acute symptoms or exacerbations.

• Patient education regarding correct use of salmeterol is critical.
• Patients should be instructed not to stop anti-inflammatory therapy while taking salmeterol even though their symptoms may significantly improve.

Long-acting beta2 -agonists have several beneficial clinical properties. They attenuate EIB for longer time periods than do short-acting beta2 -agonists (Green and Price 1992; Henriksen et al. 1992) and improve nocturnal asthma symptoms (Fitzpatrick et al. 1990; Maesen et al. 1990). Recent studies suggest that for patients with inadequate symptom control who are receiving low-to-medium doses of inhaled corticosteroids, it may be more beneficial to add salmeterol than to increase the dose of inhaled corticosteroids (Greening et al. 1994; Woolcock et al. 1996). Furthermore, in one study, salmeterol resulted in statistically significant increases in overall quality of life (Juniper et al. 1995) although the clinical significance of the reported differences is not certain.

Several studies report that patients do not appear to develop a tolerance to the bronchodilator action of salmeterol even after months of regular treatment (D’Alonzo et al. 1994; Lotvall et al. 1992; Pearlman et al. 1992; Ullman et al. 1990). In contrast, in bronchoprovocation studies following chronic administration of either short-acting or long-acting beta2 -agonists, a decrease was demonstrated in the bronchoprotective effect against exercise (Ramage et al. 1994), allergen (Cockcroft et al. 1993, 1995; Bhagat et al. 1996), and methacholine (Bhagat et al. 1996; Cheung et al. 1992). However, the bronchoprotective effect over time, although diminished, was still significantly greater than placebo. Thus, the clinical importance of the reported decrease in bronchoprotective effect remains uncertain (McFadden 1995)

Following the introduction of salmeterol into clinical practice, case reports of sudden severe attacks of asthma (Clark et al. 1993) raised concerns that in certain asthma patients, under certain conditions, the use of salmeterol may cause a sudden worsening of symptoms and possibly death. A recent randomized study in England compared more than 16,000 patients who received regular salmeterol for a 16-week period with more than 8,000 patients receiving regular (qid) albuterol therapy. The study found more deaths in the salmeterol group; however, the differences did not reach statistical significance (Castle et al. 1993). Nor did a prescription-event monitoring survey demonstrate a statistically significant difference in deaths (Mann et al. 1996). Several large studies have demonstrated that, overall, patients taking salmeterol do not experience an increase in the frequency of exacerbations (Britton et al. 1992; Lundback et al. 1993; Greening et al. 1994; Pearlman et al. 1992; Woolcock et al. 1996). There are ongoing longitudinal studies to determine if there might be risk for special populations. The potential for patients to incorrectly use salmeterol as a quick-relief medication warrants special attention by the clinician and appropriate patient education. Based on current information, long-acting inhaled beta2 -agonists should be used only in conjunction with anti- inflammatory medication. When added to inhaled corticosteroids, long-acting inhaled beta2 -agonists are helpful long-term-control therapy.

Inhaled Corticosteroids

  Key Points: Inhaled Corticosteroids

  Inhaled corticosteroids are the most effective long-term therapy available for mild, moderate, or severe persistent asthma; in   general, inhaled corticosteroids are well tolerated and safe at the recommended dosages.

  The potential but small risk of adverse events from the use of inhaled corticosteroids is well balanced by their efficacy.

  To reduce the potential for adverse effects, the following measures are recommended:

• Administer inhaled corticosteroids with spacers/holding chambers.
• Advise patients to rinse their mouths (rinse and spit) following inhalation.
• Use the lowest possible dose of inhaled corticosteroid to maintain control.
• To maintain control of asthma (especially for nocturnal symptoms), consider adding a long-acting inhaled beta2 -agonist to a low-to-medium dose of inhaled corticosteroid rather than using a higher dose of inhaled corticosteroid.
• For children, monitor growth (see key points below).
• For postmenopausal women, consider supplements of calcium (1,000 to 1,500 mg per day) and vitamin D (400 units a day). Estrogen replacement therapy, where appropriate, may be considered for patients on doses that exceed 1,000 mcg of inhaled corticosteroid a day.

Inhaled corticosteroids are the most effective long-term therapy available for patients with persistent asthma. In general, inhaled corticosteroids are well tolerated and safe at the recommended dosages (Barnes 1995; van Essen-Zandvliet et al. 1992; Tinkelman et al. 1993). Systemic effects have been identified, particularly at high doses (see figure 3-5b for a definition of high-, medium-, and low-dose inhaled corticosteroids), but their clinical significance remains unclear. Furthermore, there may be interindividual variations in dose-response effects, and thus some patients may experience effects at lower doses. (See key points above for a summary of recommendations to minimize the potential for adverse effects.) In general, the potential for adverse effects must be weighed against the risk of uncontrolled asthma; to date evidence supports the use of inhaled corticosteroids, especially at low and medium doses.

Figure 3-5b Estimated Comparative Daily Dosages for Inhaled Corticosteroid