The demonstration of genetic variations in the β receptor raised the possibility that the risks of adverse effects might not be uniformly distributed among asthmatic patients. Attention first focused on a single nucleotide polymorphism (SNP) that changes the amino acid code at position 16 from glycine to arginine (Gly16Arg). Retrospective analyses of studies of regular β-agonist treatment suggested that asthma control deteriorated among patients homozygous for arginine at this locus, prompting speculation that a genetic variant may underlie the controversial reports of increased asthma mortality in studies of very large numbers of patients treated with an LABA (see below). Studies of LABA treatment have since shown, however, that differences in multiple measures of asthma control are negligible in patient groups with different genotypes at that locus. Nonetheless, it is certain that pharmacogenetic studies of asthma treatment will continue to be an active focus of research, as an approach to the development of “personalized therapy.”
The three important methylxanthines are theophylline, theobromine, and caffeine. Their major source is beverages (tea, cocoa, and coffee, respectively). The use of theophylline, once a mainstay of asthma treatment, has almost ceased with demonstration of the greater efficacy of inhaled adrenoceptor agonists for acute asthma and of inhaled anti-inflammatory agents for chronic asthma. Accelerating this decline in theophylline’s use are its toxicities (nausea, vomiting, tremulousness, arrhythmias) and the requirement for monitoring serum levels because of its narrow therapeutic index. This monitoring is made all the more necessary by individual differences in theophylline metabolism and frequent drug-drug interactions. Despite these disadvantages of theophylline, it is still used in some countries because of its low cost.
As shown below (Figure 20–5), 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 theophyllineethylenediamine complex. The pharmacokinetics of theophylline are discussed below (see Clinical Uses of Methylxanthines). Its metabolic products, partially demethylated xanthines (not uric acid), are excreted in the urine.
FIGURE 20–5 Structures of theophylline and other methylxanthines.
Mechanism of Action
Several mechanisms have been proposed for the actions of methylxanthines, but none has been firmly established. At high concentrations, they can be shown to inhibit several members of the phosphodiesterase (PDE) enzyme family in vitro, thereby increasing concentrations of intracellular cAMP and, in some tissues, cGMP (Figure 20–3). Cyclic AMP regulates many cellular functions including, but not limited to, stimulation of cardiac function, relaxation of smooth muscle, and reduction in the immune and inflammatory activity of specific cells.
Another proposed mechanism for the bronchodilating action of this class of drugs is inhibition of cell surface receptors for adenosine. Adenosine has been shown to provoke contraction of isolated airway smooth muscle and release of histamine from airway mast cells. It has been shown, however, that xanthine derivatives devoid of adenosine antagonism (eg, enprofylline) can inhibit bronchoconstriction in asthmatic subjects.