Toxicity

Cromolyn and nedocromil generally are well tolerated by patients. Adverse reactions are infrequent and minor and include bronchospasm, cough or wheezing, laryngeal edema, joint swelling and pain, angioedema, headache, rash, and nausea. Such reactions have been reported at a frequency of <1 in 10,000 patients. Very rare instances of anaphylaxis also have been documented.

USE IN ASTHMA The main use of cromolyn (intal) and nedocromil (tilade) is to prevent asthmatic attacks in individuals with mild- to-moderate bronchial asthma. These agents are ineffective in treating ongoing bronchoconstriction. When inhaled several times daily, cromolyn inhibits both the immediate and the late asthmatic responses to antigenic challenge or to exercise. With regular use for >2-3 months, bronchial hyperreactivity is reduced, as measured by response to challenge with histamine or methacholine. Nedocromil is approved for use in asthmatic patients 12 years of age and older; cromolyn is approved for all ages.

Theophylline

Theophylline, a methylxanthine, still is commonly used for asthma pharmacotherapy in many countries. In developed countries, the advent of inhaled glucocorticoids, b adrenergic receptor agonists, and leukotriene-modifying drugs has diminished theophylline use significantly, and it has been relegated to a third- or fourth-line treatment in patients whose asthma is otherwise difficult to control.

MECHANISM OF ACTION Theophylline inhibits cyclic nucleotide phosphodiesterases (PDEs), thereby preventing hydrolysis of cyclic AMP and cyclic GMP to 5'-AMp and 5'-GMP. Inhibition of PDEs leads to an accumulation of cyclic AMP and cyclic GMP, thereby increasing signal transduction through these pathways. Theophylline and related methylxanthines are relatively nonselective in PDE inhibition. Cyclic nucleotide production is regulated by endogenous receptor-ligand interactions leading to activation of adenylyl cyclase and guanylyl cyclase. Inhibitors of PDEs therefore can be thought of as drugs that enhance the activity of endogenous autacoids, hormones, and neurotransmitters that signal via cyclic nucleotides.

Theophylline is also a competitive antagonist at adenosine receptors (see Chapter 12). Adeno-sine can act as an autacoid and transmitter with myriad biological actions. Of particular relevance to asthma are the observations that adenosine can cause bronchoconstriction in asthmatics and potentiate immunologically induced mediator release from lung mast cells. Inhibition of the actions of adenosine therefore also must be considered when attempting to explain the mechanism of action of theophylline.

Theophylline also may owe part of its anti-inflammatory action to its ability to activate histone deacetylases in the nucleus. In theory, the deacetylation of histones could decrease the transcription of several proinflammatory genes and potentiate the effect of corticosteroids.

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CH:i

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