Chapter: Modern Pharmacology with Clinical Applications: Drugs Used in Asthma

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Alternative Therapies

A number of medications useful in the treatment of asthma are neither strictly bronchodilators nor antiin-flammatory agents.

ALTERNATIVE THERAPIES

A number of medications useful in the treatment of asthma are neither strictly bronchodilators nor antiin-flammatory agents. They are classified as alternative asthma therapies (Table 39.4). These drugs, used pro-phylactically to decrease the frequency and severity of asthma attacks, are not indicated for monotherapy. They are used along with adrenomimetic bronchodilators, corticosteroids, or both.


Leukotriene Modulators

Until the late 1990s, nearly 3 decades had passed since the introduction of a truly new class of antiasthma drugs hav-ing a novel mechanism of action. This situation changed with the introduction of zafirlukast (Accolate) and montelukast (Singulair), cysteinyl leukotriene (CysLT) receptor antagonists, and zileuton (Zyflo), a leukotriene synthesis inhibitor. 

CysLTs include leukotrienes C4, D4, and E4. These mediators are products of arachidonic acid metabolism and make up the components of slow-reacting substance of anaphylaxis.

Basic Pharmacology

The cysteinyl leukotrienes are generated in mast cells, basophils, macrophages, and eosinophils. These media-tors have long been suspected of being key participants in the pathophysiology of asthma. In particular, the powerful bronchoconstrictor activity of these leuko-trienes has implicated them as major contributors to the reversible component of airway obstruction. Additional evidence suggests that their pathophysiologic role ex-tends beyond their ability to elicit bronchoconstriction. Thus, it is now believed that these substances stimulate mucus secretion and microvascular leakage, both of which contribute to airway obstruction. The relative im-portance of the various actions of the cysteinyl leukotrienes in the complex pathophysiology of asthma is not clear.

 

The biological actions of the cysteinyl leukotrienes are mediated via stimulation of CysLT1 receptors. Montelukast and zafirlukast are competitive antagonists of these receptors. In contrast, zileuton suppresses syn-thesis of the leukotrienes by inhibiting 5-lipoxygenase, a key enzyme in the bioconversion of arachidonic acid to the leukotrienes. Zileuton also blocks the production of leukotriene B4, another arachidonic acid metabolite with proinflammatory activity. The CysLT1-receptor an-tagonists alter neither the production nor the actions of leukotriene B4.

Clinical Uses

Montelukast, zafirlukast, and zileuton are indicated for the prophylaxis and chronic treatment of asthma. They should not be used to treat acute asthmatic episodes. All three agents are administered orally.

Adverse Effects, Drug Interactions, and Contraindications

Dyspepsia is the most common side effect of zileuton. Liver transaminase levels are elevated in a small per-centage of patients taking zileuton. Serum liver transaminase levels should be monitored and treatment halted if significant elevations occur. Zileuton inhibits the metabolism of theophylline. Thus, when these agents are used concomitantly, the dose of theophylline should be reduced by approximately one-half, and plasma con-centrations of theophylline should be monitored closely. Caution should also be exercised when using zileuton concomitantly with warfarin, terfenadine, or propranolol, as zileuton inhibits the metabolism of these agents. Zileuton is contraindicated in patients with acute liver disease and should be used with caution in patients who consume substantial quantities of alcohol or have a history of liver disease.

Zafirlukast and montelukast are well tolerated. Zafirlukast increases plasma concentrations of warfarin and decreases the concentrations of theophylline and erythromycin. In rare cases, treatment of patients with CysLT receptor antagonists is associated with the de-velopment of Churg-Strauss syndrome, a condition marked by acute vasculitis, eosinophilia, and a worsen-ing of pulmonary symptoms. Because these symptoms often appear when patients are given the leukotriene receptor antagonists when they are being weaned from oral corticosteroid therapy, it is not clear whether they are related to the action of the antagonists or are due to a sudden reduction in corticosteroid therapy.

Cromolyn Sodium and Nedocromil Sodium

Cromolyn sodium (Intal) and nedocromil sodium (Tilade) are chemically related drugs called chromones that are used for the prophylaxis of mild or moderate asthma. Both are administered by inhalation and have very good safety profiles, making them particularly use-ful in treating children.

Basic Pharmacology

The precise mechanism or mechanisms whereby cro-molyn sodium and nedocromil sodium exert their anti-asthmatic activities is unknown. Early work suggested that these agents act by “stabilizing” mast cells, pre-venting mediator release. However, several other com-pounds exhibit greater potency for stabilization of mast cells yet possess no clinical efficacy in asthma. This sug-gests that the therapeutic activity of cromolyn sodium and nedocromil sodium in asthma is related to one or more other pharmacological mechanisms. Postulates in-clude inhibitory effects on irritant receptors, nerves, plasma exudation, and inflammatory cells in general.

Cromolyn sodium and nedocromil sodium attenuate bronchospasm induced by various stimuli, including antigen, exercise, cold dry air, and sulfur dioxide. They suppress inflammatory cell influx and chemotactic ac-tivity along with antigen-induced bronchial hyperreac-tivity. Also inhibited is C-fiber sensory nerve activation in animal models, which may in turn suppress reflex-induced bronchospasm.

Clinical Uses

Cromolyn sodium and nedocromil sodium are used al-most exclusively for the prophylactic treatment of mild to moderate asthma and should not be used for the con-trol of acute bronchospasm. These agents are effective in about 60 to 70% of children and adolescents with asthma. Unfortunately, there is no reliable means to predict which patients will respond. They are less effec- tive in older patients and in patients with severe asthma. It may take up to 4 to 6 weeks of treatment for cromolyn sodium to be effective in chronic asthma, but it is effective after a single dose in exercise-induced asthma. With respect to clinical efficacy, cromolyn sodium and nedocromil sodium do not differ in a sub-stantial way.

Adverse Effects

Cromolyn sodium and nedocromil sodium are the least toxic of available therapies for asthma. Adverse reac-tions are rare and generally minor. Those occurring in fewer than 1 in 10,000 patients include transient bron-chospasm, cough or wheezing, dryness of throat, laryn-geal edema, swollen parotid gland, angioedema, joint swelling and pain, dizziness, dysuria, nausea, headache, nasal congestion, rash, and urticaria.

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