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Asthma Management: Long-Term Control Medications

A number of agents are used in the long-term control of asthma. These agents are taken on a daily basis for an extended period of time to treat persistent asthma. Medications used for this purpose include inhaled and systemic corticosteroids, cromolyn sodium and nedocromil; long-acting beta2-agonists; methylxanthines; and leukotriene modifiers. TABLE 3 lists the advantages and disadvantages of the long-term control medications.

Among the anti-inflammatory medications, corticosteroids are the most effective due to their broad range of anti-inflammatory effects. This includes reduction of airway hyperresponsiveness, lessening of symptom severity, and improvement in peak expiratory flow and spirometry.

Cromolyn sodium and nedocromil are controller medications with similar mechanisms. While both effectively treat allergen-induced asthma, nedocromil is more effective in inhibiting exercise-induced bronchospasm, and has greater efficacy for nonallergic patients taking inhaled corticosteroids. The agents may be equally effective for reducing asthma symptoms, improving morning peak flow, and alleviating the need for quick-relief beta2-agonists.

Asthma Management: Long-Term Control Medications

Long-acting beta2-agonists are bronchodilators that can provide effective symptom relief for up to 12 hours. These bronchodilators are especially beneficial for protection against nocturnal and exercise-induced bronchoconstriction. The inhaled formulations should not be used as quick-relief medication; they should be used in conjunction with anti-inflammatory agents for chronic disease management.The duration of bronchodilation is approximately 12 hours after a dose of inhaled agent. Inhaled long-acting beta2-agonists are preferred over oral sustained-release formulations due to their longer duration of action, greater bronchial protection during exercise, and a lower incidence of adverse events.

Methylxanthines are bronchodilators that provide long-term control of symptoms. The sustained-release formulations are useful as adjunctive therapy and can be beneficial for the control of nocturnal symptoms. These agents are not recommended for the treatment of exacerbations. Serum concentrations must be monitored periodically to avoid toxicity. Signs and symptoms of toxicity include headache, nausea, vomiting, and, at high levels, possible seizures. Factors that can increase serum theophylline levels leading to possible toxicity include fever, influenza, and medications requiring hepatic metabolism through the cytochrome p450 system (e.g., oral antifungal medications and macrolide antibiotics).

Leukotriene modifiers improve lung function and reduce symptoms by modifying the effects of leukotrienes, which are mediators released from mast cells, eosinophils, and basophils. Leukotrienes are associated with airway mucosal inflammation, smooth muscle contraction, and mucus secretion. Currently available leukotriene modifiers include zileuton, which works by inhibiting the action of lipoxygenase, the essential enzyme in leukotriene production; and the direct leukotriene receptor antagonists, montelukast and zafirlukast. Hepatic enzyme monitoring is recommended during the administration of the lipoxygenase inhibitor, zileuton, and if signs of hepatic toxicity occur during treatment with the leukotriene receptor antagonists, montelukast or zafirlukast. Warfarin levels may also be affected by zafirlukast or zileuton, and should also be monitored in patients requiring such therapy.

Table 3. Long-Term Control Medications
Corticosteroids
1. Inhaled Agents
Beclomethasone dipropionate
Budesonide
Flunisolide
Fluticasone propionate
Triamcinolone acetonide
Mechanism
Anti-inflammatory
Pros
Reduce airway hyperresponsiveness, suppress and reverse inflammation
Reduction of bronchial hyperreactivity
Cons
Cough, oral candidiasis, dysphonia
Possible HPA (hypothalamic-pituitary-adrenal) axis suppression
Possible transient growth effect in pediatric patients
Possible contribution to osteoporosis at high doses long-term
Possible cataracts, glaucoma
Possible immunosuppression, especially against varicella, fungal infections
 
2. Systemic Agents
Methylprednisolone
Prednisone
Prednisolone
Pros
Long-term use in persistent asthma to reduce inflammation and control symptoms
Most effective and most potent anti-inflammatory medication available
Cons
Short-term
Weight gain
Fluid retention
Altered mood
Glucose intolerance
Hypokalemia
Long-term
Adrenal axis suppression
Cushing’s syndrome
Glucose intolerance
Gastritis, ulcer
Diabetes
Osteoporosis
Cataracts
Glaucoma
Myopathies
Immunosuppression (especially in fungal and varicella viral infections)
Possible growth suppression in children
Cromolyn Sodium and Nedocromil Agents
Cromolyn sodium
Nedocromil sodium
Mechanism
Anti-inflammatory (stabilize mast cell membrane to reduce mediator release)
Pros
Provide long-term prevention of symptoms
Can be used prophylactically, prior to allergen or exercise exposure
Strong safety profile
Cons
Unpleasant taste from nedocromil perceived in some patients
Minimal protection from infection-induced exacerbations
Long-Acting Beta2-Agonists
Inhaled Agents
Formoterol
Salmeterol
Oral Agents
Albuterol: sustained-release
Mechanism
Bronchodilator
Pros
Relax smooth muscles to antagonize bronchoconstriction
Provide long-term symptom prevention
Prevent exercise-induced bronchospasm
Are used with anti-inflammatory therapy for effective relief of symptoms, especially nocturnal symptoms
Cons
Tachycardia
Tremor
Possible hypokalemia, hyperglycemia
Not approved for treatment of acute symptoms
Methylxanthines
Agents
Aminophylline dihydrate
Oxtriphylline
Theophylline anhydrous, immediate-release
Theophylline anhydrous, sustained-release
Mechanism
Bronchodilator
Pros
Relax airway smooth muscle to control symptoms
Cons
Insomnia
Gastritis, gastroesophageal reflux
Hyperactivity in children
Low therapeutic index; serious toxicity (possible seizures) at high blood levels
Drug interactions (cytochrome p450 metabolism)
Not recommended for exacerbations
Leukotriene Modifiers
Agents
Montelukast
Zafirlukast
Zileuton
Mechanism
Leukotriene receptor antagonist — zafirlukast and montelukast
5-lipoxygenase inhibitor — zileuton
Pros
Control and prevent symptoms in persistent asthma
Reduce need for short-acting, inhaled beta2-agonists
Cons
Possible elevation of hepatic enzymes associated with zileuton (liver function monitoring is recommended) and, in rare cases, zafirlukast or montelukast
Zileuton and zafirlukast may inhibit metabolism of warfarin
Rare association with Churg-Strauss systemic vasculitis
Combination Therapies
Agent
Ipratropium bromide/Albuterol sulfate (via metered-dose inhaler or inhalant solution for nebulizer)
Pros
Beneficial for patients being treated with regular inhaled bronchodilator who may benefit from additional bronchodilation
Cons
Same as for individual agents
Agent
Salmeterol xinafoate/Fluticasone propionate
Pros
Addresses both the inflammation and bronchoconstriction associated with asthma with one device
Combination dosing of both agents increases convenience and potential adherence to the treatment program
Cons
Same as for individual agents

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