94 - Xanthines, Phosphodiesterase Inhibitors, and Chromones

Abstract

Xanthines such as theophylline, doxophylline, and aminophylline have been used for many years as treatments for asthma and chronic obstructive pulmonary disease (COPD). They have both bronchodilator and antiinflammatory actions. Xanthines are usually administered as orally active slow-release preparations for the maintenance treatment to prevent symptoms and for the treatment of nocturnal asthma. Xanthines can also be administered intravenously (IV) for the acute treatment of asthma. However, xanthines have a very narrow therapeutic window with 5 to 15 µg/mL being considered effective, but with serious adverse effects occurring above plasma levels of 20 µg/mL. Side effects of xanthines include nausea and other gastrointestinal disturbances, arrhythmias, and CNS stimulation. Furthermore, xanthines can have interactions when used concomitantly with many other drug classes, which limits the wider use of these drugs, particularly now that safer inhaled medications are available for the treatment of asthma and COPD. The precise mechanism of action of xanthines remains elusive, but they have long been considered to act as nonselective phosphodiesterase (PDE) inhibitors, and theophylline is thought to act as an adenosine receptor antagonist. The ability of xanthines to inhibit PDE3 is thought to contribute to the cardiovascular side effects associated with this drug class, whereas antagonism of adenosine A1 receptors has also been suggested to contribute to the adverse effects of xanthines. The exception is doxophylline, which has a wider therapeutic window than theophylline, perhaps because it lacks significant PDE inhibition and A1 receptor antagonism at therapeutic levels.