Long-term control therapy focuses on treating the underlying inflammatory process.
Inhaled corticosteroids are the most effective agents for long-term control and are agents of choice for all patients who progress to persistent asthma. Different potencies, durations of activity, delivery mechanisms and dosing schedules are available. The NAEPP has provided a comparison of inhaled corticosteroid dosing based on topical potencies. The newer, more potent agents can achieve the same degree of anti-inflammatory activity with fewer puffs per day. In patients requiring moderate to high doses, one of these agents may greatly improve compliance.
Adverse effects are mostly local, due to deposition of the drug in the oropharynx. Hoarseness and oral candidiasis are most common and can be minimized by rinsing the mouth with water after each inhaler use. Systemic side effects may also occur, especially with the higher-dose regimens. Hypothalamic-pituitary-adrenal (HPA) axis suppression, osteoporosis, and cataract formation are concerns.
Patients receiving high doses of inhaled corticosteroids for long periods of time should be monitored closely for systemic side effects. Higher potency, longer half-life agents may increase the likelihood of systemic side effects. Fluticasone has been associated with a higher degree of HPA axis suppression compared to budesonide. Patients receiving high doses of potent inhaled corticosteroids should be monitored for signs of adrenal insufficiency during periods of physiologic stress and supplemented systemically if necessary.
Mast Cell Stabilizing Agents
The mast cell stabilizing agents (MCSA) are inhaled anti-inflammatory drugs with a complex and not fully understood mechanism of action. Currently, two agents are available — cromolyn and nedocromil. Both are only effective when inhaled and should be given up to four times daily. The higher potency of nedocromil may allow twice-daily administration in certain patients. These agents are effective as prophylaxis against bronchospasm in known allergen exposure.
They are also effective for exercise-induced asthma, although probably not as effective as beta-agonists. Not being bronchodilators, they are not effective for acute asthma. They may require up to four weeks of therapy before maximal benefit is realized. NAEPP guidelines recommend these agents as alternatives to low-dose inhaled corticosteroids for patients with mild persistent asthma. As the disease progresses, patients will likely require a change to moderate- to high-dose inhaled corticosteroids. The potential for systemic side effects is very low with the MCSAs. Because they do not suppress growth, they are recommended in children with mild persistent asthma.
Theophylline is a methylxanthine long used to treat asthma. Inhibition of phosphodiesterase, immunomodulation, and effects on diaphragmatic contractility have all been proposed as mechanisms of action. Although classified as a bronchodilator, theophylline probably has more consistent effects as an anti-inflammatory agent affecting the late-phase response. NAEPP recommends that theophylline may be used as an alternative to low-dose inhaled corticosteroids in mild persistent asthma, but it is not preferred. It may also be used as an adjunct to inhaled corticosteroids in moderate or severe persistent disease, and may be useful for nocturnal symptoms.
Theophylline is available in immediate-release, twice-daily, or once-daily oral dosage forms. For long-term control of asthma, a sustained release formulation is preferred to minimize variability in serum concentrations and maximize compliance. If theophylline is used, the clinician should be aware of several important pharmacologic issues. Theophylline has a very narrow therapeutic window (between 5 mcg/mL and 15 mcg/mL). Concentrations higher than 15 mcg/mL may be associated with additional benefit in some patients, but the risk of adverse effects increases substantially. These include nausea, diarrhea, vomiting, headache, irritability, and insomnia.
More severe side effects that are more likely to occur with serum concentrations in excess of 20 mcg/mL include seizures, hyperthermia, and cardiac dysrhythmias. To minimize the risk of theophylline toxicity, monitoring of serum concentrations is mandatory. Levels should be drawn at least 48 hours after a dosage change to allow adequate time to reach steady state, and the level should be timed so as to approximate a peak concentration as closely as possible. If a twice-daily preparation is selected, the level should be drawn 3–7 hours after the morning dose. For a once-daily preparation, levels should be drawn 8–12 hours after a dose.
Theophylline is metabolized by the hepatic cytochrome (CYP)P450 system. Plasma elimination occurs linearly within the therapeutic range. CYP isoforms responsible for theophylline metabolism are primarily CYP1A2 and also CYP3A3 and CYP2E1. Theophylline is particularly susceptible to drug interactions. For a patient receiving theophylline, an alternative agent that does not interact should be considered. If no alternative exists, the patient must be monitored closely for signs of toxicity and increased serum theophylline.
A new class of anti-inflammatory agents are the antileukotrienes. Leukotrienes, prostaglandins, thromboxanes, and eicosanoids are inflammatory end products of the arachidonic acid cascade. Various triggers affect inflammatory cells, causing them to compromise the integrity of the phospholipid membrane of the epithelial lining of the airway. The phospholipids are deconstructed by phospholipase A2 to liberate arachidonic acid. The leukotrienes produced by this cascade cause bronchoconstriction, eosinophil migration, and neutrophil adhesion to the airway endothelium. Affecting this pathway are the 5-lipoxygenase (5-LO) inhibitor zileuton (Zyflo) and the cysteinyl leukotriene receptor antagonists zafirlukast (Accolate) and montelukast (Singulair).
Zileuton blocks the enzyme 5-LO, preventing leukotriene formation. It is available as a 600 mg tablet, to be given four times daily. It is indicated for long-term control in patients over 12 years of age with mild to moderate asthma. Compared to placebo, zileuton is effective at reducing asthma symptoms and beta-agonist use, improving PFTs, and decreasing the need for systemic steroids in patients with mild to moderate asthma.
Zileuton has also been compared to theophylline in patients with moderate asthma (FEV1 40%–80% of predicted). There was no significant difference in any outcomes measured. The most serious side effect of zileuton is elevation of hepatic transaminases. Liver enzymes were elevated to greater than 3 times normal in approximately 2% of patients during clinical trials. Two-thirds of the cases occurred in the first two months of therapy. The manufacturer recommends that all patients started on zileuton have liver enzymes checked at baseline every month for the first 3 months, every 2–3 months for the first year, and then periodically.
Zileuton is also susceptible to drug interactions: it is known to inhibit CYP3A4 in vitro and is itself metabolized by the cytochrome P450 system. Table 5 lists the known significant drug interactions with antileukotrienes.
|Table 5. Drug Interactions with the Antileukotriene Agents|
|Interacting Agent||Antileukotriene Agent|
|Terfenadine||decreases Zafirlukast||increases Terfenadine|
|Theophylline||decreases Zafirlukast||increases Theophylline|
|Warfarin||increases Warfarin||increases Warfarin|
Zafirlukast and montelukast are the two cysteinyl leukotriene antagonists available in the U.S. The first agent available, zifirlukast, is indicated for long-term control of asthma in patients over 12 years of age. It is available as 20 mg tablets, to be given twice daily on an empty stomach. It is involved in several drug interactions (Table 5).
Zafirlukast is a known inhibitor of CYP2C9 and CYP3A4. Therefore, patients receiving medications metabolized by these isoforms should be monitored closely when zafirlukast is added. The efficacy of zafirlukast has been established in mild to moderate asthma. Compared to placebo, zafirlukast significantly decreased asthma symptoms (first morning symptoms and days with symptoms), nighttime awakenings, and beta-agonist requirements. It also significantly improved objective measures of lung function (FEV1 and PEFR).
Adverse effects were generally not different than placebo. In a small number of patients there was an increase in liver transaminases, which disappeared upon discontinuation. Routine measurement of liver enzymes is not recommended; however, if a patient develops symptoms of hepatitis, hepatic profile should be checked. A rare disorder has been associated with the initiation of zafirlukast in patients receiving oral corticosteroids. When zafirlukast was added and steroids withdrawn, a form of systemic necrotizing vasculitis with prominent lung involvement (Churg-Strauss syndrome) was precipitated in some patients. A definite causal relationship has not been established.
Montelukast is the second leukotriene antagonist to become available in the U.S. It also is approved for long-term management of asthma and may be used in children as young as six years of age. It is available as a 5 mg chewable tablet and a 10 mg tablet. Children 6–14 years of age should receive 5 mg once daily, while patients 15 years and older should be given 10 mg once daily. The drug can be given without regard to meals. Montelukast is metabolized by the cytochrome P450 system but does not appear to inhibit any of the CYP isoforms.
Like the other antileukotriene agents, montelukast is effective in mild to moderate asthma compared to placebo. It has been compared to low-dose inhaled beclomethasone (200 mcg twice daily). Over a 12-week period, inhaled beclomethasone had significantly greater improvements in FEV1 and asthma symptom scores vs. montelukast.
The NAEPP recommends antileukotriene agents as alternatives to low-dose inhaled corticosteroids in mild persistent asthma. Recent data suggest that these agents may have limited efficacy as monotherapy, especially compared to inhaled corticosteroids. They may be especially useful as monotherapy in the mild to moderate asthmatic patient, in whom compliance with inhalers is an issue. They could also prove useful as additional anti-inflammatory therapy in patients receiving inhaled corticosteroids. Clinicians must also monitor for drug interactions and systemic toxicity when the antileukotriene agents are used. Patients should be made aware that, as with inhaled corticosteroids, they are not useful for acute exacerbations, and must be taken regularly to derive benefit.
Long-acting inhaled beta-agonists are indicated as adjunctive long-term control therapy in patients with moderate persistent asthma also receiving inhaled corticosteroids. Salmeterol (Serevent), the only long-acting agent available in the U.S., has an onset of action of approximately 30–60 minutes, and a duration of action of 12 hours. It is administered as two puffs every 12 hours. Salmeterol has been studied in patients with a suboptimal response to low-dose inhaled corticosteroids. In this study, patients were given either salmeterol or increased inhaled corticosteroid. The addition of salmeterol was shown to be superior.
Salmeterol is also effective for exercise-induced asthma, offering a longer duration of protection than short-acting agents. It may be especially useful against nocturnal symptoms. It should always be used as an adjunct to anti-inflammatory therapy, since it does not affect the underlying disease process. Salmeterol should never be used for rescue therapy, since it has a delayed onset of action. Patients must be educated on the use of a short-acting agent for acute exacerbation while using salmeterol.
Anticholinergics, such as atropine and ipratropium, are effective bronchodilators; however, their effect in asthma is delayed and inconsistent. Original asthma therapy guidelines published in 1991 listed inhaled ipratropium as a consideration for step 3 therapy. The NAEPP, however, does not include anticholinergics in its recommendations for the management of asthma. Inhaled ipratropium is not absorbed systemically and results in no systemic anticholinergic effects. Its onset of action is 30–90 minutes, but this is highly variable. Ipratropium may be useful in patients with asthma who have coexistent chronic obstructive pulmonary disease.
Finally, systemic steroids may be necessary to control asthma in severe persistent disease. Ideally, systemic steroid therapy should be limited to short courses for acute exacerbations. Patients who cannot be weaned from steroid therapy without disease exacerbation are at risk of developing long-term sequelae of steroid therapy. Hyperglycemia, HPA axis suppression, immunosuppression, osteoporosis, dermatologic changes, and psychological effects are the most common problems. Steroid-dependent patients should be identified, and measures taken to prevent or minimize the risk from steroid side effects.
Home Monitoring with Peak Flow Meter
The use of peak flow meters is essential to managing asthma (see patient teaching aid in this issue). Normal ranges for PEFR are based upon the patient’s gender, height, and age. Patients should establish a “personal best peak flow” by measuring PEFR daily for two to three weeks when the asthma is under good control. The highest measurement is the “personal best,” against which other measurements are compared.
The Role of the Pharmacist
Pharmacists should monitor patients for appropriate therapy, appropriate technique (including spacers with inhalers), drug interactions, level of understanding, and compliance. Increased beta-agonist use is a marker for disease control and progression. The pharmacist in the community may be the first healthcare professional to recognize increased use of short-acting beta-agonists by attention to the frequency of refills. The pharmacist can then take action to ensure that anti-inflammatory therapy is initiated or intensified if deemed appropriate.
A patient receiving a long-acting inhaled beta-agonist without a concomitant short-acting agent as needed should be questioned about the use of the long-acting agent. Misunderstanding about the use of long-acting beta-agonists for rescue therapy has resulted in death. Patients should be counseled how to use inhaled medications. Those receiving inhaled beta-agonists and corticosteroids chronically should use the beta-agonist before the corticosteroid. This will allow for increased airway penetration of the corticosteroid. Patients should be instructed to rinse their mouths with water after each use. Corticosteroid deposition in the oropharynx can also be minimized by the use of spacer devices. Spacer devices can be used with other inhalers to facilitate the coordination of canister actuation and inhalation.
Dry powder inhaler devices introduce a completely different technique for inhalational therapy. Pharmacists should counsel patients on proper use and storage of these devices, as well as monitor patients for drug interactions. Many of the anti-asthma medications used have drug interaction potential, particularly theophylline and also the new, systemically administered, antileukotriene agents. Not only are they affected by other drugs, but they may also affect the activity of other drugs.
Finally, the pharmacist is in a key position to educate patients on the use of their asthma medications. Patients should understand the purpose of each medication, proper inhaler technique, which drugs are used for rescue therapy, and when to contact their physician for emergency treatment. Patients must be made aware that frequent communication with their healthcare providers is necessary to optimally manage this disease.