-agonist treatment to inhibit the response to subsequent challenge with exercise, methacholine,or antigen challenge (referred to as a loss of bronchoprotective action). Fears that heavy use of -agonist inhalers could actually increase morbidity and mortality have not been borne out by careful epidemiologic investigations.Heavy use most often indicates that the patient should be receiving more effective prophylactic therapy with corticosteroids. Although it is true that 2-adrenoceptor agonists appear to be safe and effective bronchodilators for most patients,there is some evidence that the risk of adverse effects from chronic treatment with long-acting agonists may be greater for some individuals,possibly as a function of genetic variants for the receptor.Two retrospective and one prospective study have shown differences between patients homozygous for glycine versus arginine at the B-16 locus of the receptor.Among patients homozygous for arginine,a genotype found in 16%of the Caucasian population in the USA,but more commonly in African Americans,asthma control deteriorated with regular use of albuterol or salmeterol,whereas asthma control improved with this treatment among those homozygous for glycine at the same locus. These findings need to be replicated in larger studies,but it is tempting to speculate that a genetic variant may underlie the report of an increase in asthma mortality from regular use of a long-acting agonist in studies involving very large numbers of patients METHYLXANTHINE DRUGS Introduction The three important methylxanthines are theophylline,theobromine,and caffeine. Their major source is beverages(tea,cocoa,and coffee,respectively).The importance of theophylline as a therapeutic agent in the treatment of asthma has waned as the greater effectiveness of inhaled adrenoceptor agents for acute asthma and of inhaled anti-inflammatory agents for chronic asthma has been established,but theophylline's very low cost is an important advantage for economically disadvantaged patients in societies in which health care resources are limited. Chemistry As shown below,theophylline is 1,3-dimethylxanthine;theobromine is 3,7-dimethylxanthine;and caffeine is 1,3,7-trimethylxanthine.A theophylline preparation commonly used for therapeutic purposes is aminophylline,a theophylline-ethylenediamine complex.The pharmacokinetics of theophylline are discussed below.The metabolic products,partially demethylated xanthines(not uric acid),are excreted in the urine.-agonist treatment to inhibit the response to subsequent challenge with exercise, methacholine, or antigen challenge (referred to as a loss of bronchoprotective action). Fears that heavy use of -agonist inhalers could actually increase morbidity and mortality have not been borne out by careful epidemiologic investigations. Heavy use most often indicates that the patient should be receiving more effective prophylactic therapy with corticosteroids. Although it is true that 2-adrenoceptor agonists appear to be safe and effective bronchodilators for most patients, there is some evidence that the risk of adverse effects from chronic treatment with long-acting agonists may be greater for some individuals, possibly as a function of genetic variants for the receptor. Two retrospective and one prospective study have shown differences between patients homozygous for glycine versus arginine at the B-16 locus of the receptor. Among patients homozygous for arginine, a genotype found in 16% of the Caucasian population in the USA, but more commonly in African Americans, asthma control deteriorated with regular use of albuterol or salmeterol, whereas asthma control improved with this treatment among those homozygous for glycine at the same locus. These findings need to be replicated in larger studies, but it is tempting to speculate that a genetic variant may underlie the report of an increase in asthma mortality from regular use of a long-acting agonist in studies involving very large numbers of patients. METHYLXANTHINE DRUGS Introduction The three important methylxanthines are theophylline, theobromine, and caffeine. Their major source is beverages (tea, cocoa, and coffee, respectively). The importance of theophylline as a therapeutic agent in the treatment of asthma has waned as the greater effectiveness of inhaled adrenoceptor agents for acute asthma and of inhaled anti-inflammatory agents for chronic asthma has been established, but theophylline's very low cost is an important advantage for economically disadvantaged patients in societies in which health care resources are limited. Chemistry As shown below, theophylline is 1,3-dimethylxanthine; theobromine is 3,7-dimethylxanthine; and caffeine is 1,3,7-trimethylxanthine. A theophylline preparation commonly used for therapeutic purposes is aminophylline, a theophylline-ethylenediamine complex. The pharmacokinetics of theophylline are discussed below. The metabolic products, partially demethylated xanthines (not uric acid), are excreted in the urine