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Pharmacologic Therapy: Managing Asthma Long Term
The management of asthma therapy is based on a stepwise approach as outlined in the Expert Panel Report 2 of the National Institutes of Health (Table 1).1 The stepwise approach provides guidelines to assist the clinician in decision making. The goal of the guidelines is to gain control of asthma as quickly as possible and then decrease the treatment to the least amount of medication necessary to maintain control.
The goals of asthma therapy are to 1) prevent chronic and troublesome symptoms such as coughing or breathlessness in the night, in the early morning, or after exertion, 2) maintain "normal" pulmonary function, 3) maintain normal activity levels such as exercise and other physical activity, 4) prevent recurrent exacerbations of asthma and minimize the need for emergency department visits or hospitalizations, 5) provide optimal pharmacotherapy with minimal or no adverse effects, and 6) meet patient's and families' expectations of and satisfaction with asthma care.1 The medications used in the treatment of asthma are categorized into two general classes: long-term control medications and quick-relief medications. The long-term control medications are used to achieve and maintain control of persistent asthma. The quick-relief medications are used to treat acute symptoms and exacerbations.1
Long-term control medications are used to maintain control of asthma symptoms on a daily basis (Table 2).1 The most effective and potent anti-inflammatory medication currently available are the corticosteroids.1 The inhaled form is used in the long-term control of asthma (Table 3).1 Systemic corticosteroids are used in long-term therapy to gain control of asthma and can be used to manage all but mild intermittent asthma. Persistent asthma is most effectively controlled with daily anti-inflammatory therapy.
Mechanism of Action: Corticosteroids are produced endogenously by the adrenal cortex. They are anti-inflammatory agents which inhibit the production of cytokines, an effect which reduces eosinophil infiltration, inhibits macrophage and eosinophil function, decreases mediator cells in the epithelium, reduces vascular permeability, and reduces the production of leukotrienes.
Indications and Usage: The inhaled corticosteroids are indicated for the long-term prevention of asthma symptoms, suppression, control, and reversal of inflammation. Regular use will reduce the need for oral corticosteroids.
Adverse Effects: The main adverse effects of inhaled steroids are caused by the deposition of the drug in the upper airways, resulting in dysphonia, oropharyngeal candidiasis, and cough. These effects may be reduced by rinsing the mouth and use of a spacer device. Systemic adverse effects include adrenal suppression, osteoporosis, growth suppression, skin thinning, and easy bruising. Cumming, et al have suggested that inhaled corticosteroids use is associated with the development of posterior subcapsular and nuclear cataracts.2
Indications and Usage: The oral corticosteroids are usually used for short-term (3-10 days) "burst" to gain prompt control of inadequately controlled persistent asthma. They are also used for long-term prevention of symptoms in severe persistent asthma to suppress, control and reverse inflammation.
Adverse Effects: The short term use of the oral corticosteroids are associated with reversible abnormalities in glucose metabolism, increased appetite, weight gain, mood alteration, fluid retention, hypertension, peptic ulcer, and rarely aseptic necrosis. The long term use is associated with adrenal axis suppression, skin thinning, diabetes, hypertension, Cushing's syndrome, cataracts, muscle weakness, and, rarely, immune function impairment. Precautions should be given to patients with coexisting conditions that could be worsened by systemic corticosteroids, such as herpes virus infections, varicella, tuberculosis, hypertension, peptic ulcer, and Strongyloides.
The lowest effective dose of oral corticosteroids should be used in order to minimize associated adverse effects. For long-term use, alternate day morning dosing produces the least toxicity. Beam, et al showed improved efficacy with no increase in adrenal suppression when daily dosages were given at 3 p.m. rather than in the morning.3
Mechanism of Action: Cromolyn and nedocromil are mast-cell stabilizers. They prevent the release of the mediators of type I allergic reactions, including histamine and slow-reacting substance of anaphylaxis, from sensitized mast cells. They also inhibit type III reactions to a lesser extent. It has been suggested that the drugs may block calcium channels in mast cell membranes. The specific mechanism(s) of action of the drug on mast cells remains to be established.
Indications and Usage: Cromolyn or nedocromil is recommended for prophylaxis of exercised induced bronchospasm or exposure to a known allergen. They are also recommended as anti-inflammatory long-term control medications in patients with mild persistent asthma.
Adverse Effects: Adverse effects reported with the use of the aerosol inhalation include irritation or dryness of the throat, bad taste, cough, wheezing, and nausea. Up to twenty percent of patients may complain of an unpleasant taste from nedocromil.
The therapeutic response may occur within the first two weeks of therapy, but may take up to six weeks to determine the maximum benefit. The primary advantage of these agents is safety.
Mechanism of Action: Long-acting beta-2 agonists are bronchodilator medications. They stimulate intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate to cyclic-3',5'-adenosine monophosphate (cAMP). Increased cAMP levels cause relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells.
Indications and Usage: Salmeterol is indicated for the long-term prevention of asthma symptoms. It is added to anti-inflammatory therapy. Studies have shown the addition of salmeterol to standard dose of inhaled corticosteroids may provide more effective symptom control as compared to increasing the inhaled corticosteroid dosage.4,5 It is especially useful in the prevention of nocturnal symptoms. It is also used to prevent exercise-induced bronchospasm. It is not to be used to treat acute symptoms or exacerbations of asthma. The inhaled long-acting beta-2 agonists are preferred over oral sustained release products because they are longer acting and have fewer side effects than the oral sustained-release agents.
Adverse Effects: Some of the adverse effects of long-acting beta-2 agonists include tachycardia, palpitations, skeletal muscle tremor, and headache. Overdosage with salmeterol can lead to clinically significant prolongation of the QTc interval.
Mechanism of Action: The methylxanthines directly relax the smooth muscle of the bronchi and pulmonary blood vessels. The exact mode of action is unknown. The proposed mechanism of action was inhibition of phosphodiesterase, which results in an increase in cAMP. However, this effect is negligible at therapeutic concentrations.
Indications and Usage: Sustained release theophylline is indicated for the long-term control and prevention of symptoms, especially nocturnal symptoms. The use of theophylline requires careful prescribing, serum concentration monitoring, and patient education.
Adverse Effects: The dose related acute toxicities include tachycardia, nausea and vomiting, tachyarrhythmias (SVT), central nervous system stimulation, headache, seizures, hematemesis, hyperglycemia, and hypokalemia. Adverse effects which occur at usual therapeutic dosages include gastric upset, aggravation of ulcer or reflux, insomnia, hyperactivity in some children, and difficult urination in elderly males with prostatism.
Routine serum theophylline concentration monitoring is necessary due to significant toxicities, narrow therapeutic range, and inter-individual differences in metabolic clearance. The steady state serum concentrations should be between 5 and 15 mcg/ml. There are many factors which can alter the absorption and metabolism of theophylline.1 These can produce significant changes in the steady state serum theophylline level.
Mechanism of Action: The leukotriene receptor antagonists are selective and competitive antagonists of the cysteinyl leukotriene (Cys LT1) receptor. Cysteinyl leukotriene (LTC4, LTD4 and LTE4) production and receptor occupation have been correlated with the pathophysiology of asthma, including airway edema, smooth muscle constriction, and altered cellular activity associated with the inflammatory process. Zafirlukast is the first Cys LT1 receptor antagonist to be released. Montelukast has recently been released and pranlukast is undergoing clinical trial.
Indications and Usage: Zafirlukast is indicated for the long-term control and prevention of symptoms in mild persistent asthma for patients twelve years of age or greater. Montelukast is indicated for the long-term control and prevention of symptoms in mild persistent asthma for patients six years of age and older.
Adverse Effects: The most frequent adverse effects noted in clinical trials were headache, gastritis, pharyngitis and rhinitis. These adverse effects were not significantly different from placebo. In some patients on zafirlukast, the reduction of oral steroid doses resulted in the occurrence of eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting as Churg-Strauss syndrome (CSS). Causal relationship with zafirlukast has not been established.
Other Considerations: Zafirlukast should be taken one hour before meals or two hours after meals because food can decrease the bioavail-ability. Montelukast should be taken in the evening and may be taken without regard to food.
Coadministration of zafirlukast with warfarin increases the half-life of warfarin by approximately 36%, thereby significantly increasing prothrombin time by approximately 35%. Co-administration of zafir-lukast with theophylline may reduce zafirlukast plasma concentrations by approximately 30%, but without an effect on plasma theophylline concentrations. Coadministration of zafirlukast with aspirin may result in an approximately 45% increase in plasma zafirlukast concentrations. Coadministration of zafirulkast with erythromycin will result in a decrease of plasma zafirlukast concentrations by approximately forty percent. Montelukast, at recommended clinical dosages, did not have clinically important effects on the pharmacokinetics of theophylline, prednisone, prednisolone, oral contraceptives, terfenadine, digoxin and warfarin. Phenobarbital decreased the area under the curve (AUC) of montelukast approximately forty percent folowing a single 10 mg dose of monterlukast. No dosage adjustment for montelukast is recommended.
Mechanism of Action: Zileuton is a 5-lipoxygenase inhibitor which inhibits leukotriene (LTC4, LTD4, LTE4) formation. Leukotrienes are substances that induce numerous biological effects including augmentation of neutrophil and eosinophil migration, neutrophil and monocyte aggregation, leukocyte adhesion, increased capillary permeability and smooth muscle contraction. These effects contribute to inflammation, edema, mucus secretion and bronchoconstriction in the airways of asthmatic patients.
Indications and Usage: Zileuton is indicated for the long-term control and prevention of symptoms in mild persistent asthma for patients twelve years of age or greater.
Adverse Effects: Zileuton has been associated with elevation of liver enzymes. Hepatic transaminases must be evaluated at initiation of and during therapy with zileuton. Monitor before treatment begins, once a month for the first 3 months, every 2 to 3 months for the remainder of the first year and periodically thereafter. There may be some dyspepsia associated with the use of zileuton.
Other Considerations: Zileuton decreases the metabolism of warfarin, theophylline, and terfenadine. Coadministration of zileuton and theophylline results in an approximate doubling of serum theophylline concentrations. Coadministration of zileuton and warfarin results in a clinically significant increase in prothrombin time. Coadministration of zileuton with terfenadine results in a decrease in clearance of terfenadine by 22%. Coadministration of zileuton with propranolol affects a doubling of the propranolol area under the curve and consequent increased beta-blocker activity. Use caution when prescribing a medication that inhibits cytochrome P450 isoenzymes 1A2, 2C9, and 3A4.
The quick-relief medications are used to treat acute symptoms of asthma and exacerbations (Table 4).1 The quick-relief medications include the short-acting inhaled beta-2 agonists, anticholinergics, and systemic corticosteroids.
Mechanism of Action: Short-acting beta-2 agonists are bronchodilator medications. They stimulate intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate to cyclic-3',5'-adenosine monophosphate (cAMP). Increased cAMP levels cause relaxation of bronchial smooth muscle.
Indications and Usage: The short acting inhaled beta-2 agonists are used for the relief of acute symptoms of asthma. They are used on an as needed basis. A second indication is for the prevention of exercise-induced bronchospasm used prior to exercise.
Adverse Effects: The usage of the short-acting inhaled beta-2 agonists may be associated with tachycardia, skeletal muscle tremor, headache, hypokalemia, and hyperglycemia. The inhaled route generally causes fewer adverse effects than the oral route.
These agents are the drugs of choice for acute bronchospasm. The inhaled route is preferred over the systemic route as the inhaled route has a faster onset and fewer adverse effects. Oral albuterol liquid is not recommended.
Increasing use or lack of expected effect indicates inadequate asthma control. Patients using more than one canister per month may indicate overreliance on this drug. Patients using two or more inhalers per month may also have additional problems. Anti-inflammatory medication should be initiated or intensified for patients frequently using beta-2 agonists.
Mechanism of Action: Ipratropium is a bronchodilator which is a competitive inhibitor of muscarinic cholinergic receptors. In asthma, inhaled anticholinergics are less potent bronchodilators than inhaled beta-2 agonists and are of unclear benefit.
Indications and Usage: Ipratropium may be used for the relief of acute bronchospasm. It may provide additive effects to beta-2 agonist, but it has a slower onset of action. It may be considered for patients who are intolerant of beta-2 agonists. It is not to be used to block exercise-induced bronchospasm.
Adverse Effects: Ipratropium has been associated with drying of the mouth and respiratory secretions. It may increase wheezing.
The stepwise approach to asthma therapy emphasizes initiating higher level therapy at the onset to establish prompt control and then stepping down. The medications are classified as long-term control medications and quick-relief medications. The most effective medications for long-term control are those with anti-inflammatory effects.
References
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