| The methylxanthines, particularly theophylline, are used as bronchodilators (Table:
Methylxanthine Bronchodilators). Once the mainstay of human asthma therapy, theophylline has a high incidence of side effects, and its use has diminished with the development of local drug delivery by metered dose or disk inhalers. The methylxanthines have a variety of pharmacologic effects on various organ systems, including bronchial smooth muscle relaxation, CNS stimulation, mild diuresis, and mild
cardiac stimulation. |
| The respiratory effects of methylxanthines are due to several cellular mechanisms. Antagonism of adenosine is currently thought to be the most important action. Adenosine induces bronchoconstriction in asthmatic animals and antagonizes adenylate cyclase. Adenylate cyclase is responsible for the synthesis of cAMP, which controls bronchial smooth muscle relaxation and inhibits the release of inflammatory mediators from mast cells. Methylxanthines also inhibit phosphodiesterase, which
further increases intracellular cAMP. They also inhibit calcium mobilization in smooth muscle, inhibit prostaglandin production, augment the release of catecholamines from storage granules, and increase the availability of calcium to contractile proteins of the heart and diaphragm. In addition to promoting bronchial smooth muscle relaxation, methylxanthines decrease the release of inflammatory mediators from mast cells and increase mucociliary transport. |
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Theophylline is available in several formulations including injectable, aqueous solutions, elixirs, tablets, and capsules. Theophylline base is poorly soluble in water and often results in GI irritation when administered PO. Aminophylline is a theophylline salt that is 78-86% theophylline. It is more water soluble and results in less GI irritation. Other theophylline salts, such as oxytriphylline (a choline salt), are available, and their theophylline content must be
considered when developing a drug dosage regimen. Several sustained-release formulations of theophylline are suitable for use in dogs and cats and may be administered less frequently than the regular formulations. After oral administration, theophylline is rapidly and completely absorbed. Therapeutic plasma concentrations, extrapolated from people, are 5-20 µg/mL. Animals are sensitive to high concentrations of theophylline, especially after rapid IV administration, and toxicity may
be seen with concentrations <20 µg/mL. Theophylline tablets may become trapped in bezoars (such as hair balls in cats), and continued absorption can result in toxicity. Cardiac arrhythmias, CNS excitement, tremors, convulsions, and GI irritation may be seen. Theophylline undergoes enterohepatic recirculation, so activated charcoal is recommended if clinical signs are present, no matter how long after the drug was administered. Theophylline metabolism is inhibited by erythromycin,
cimetidine, propranolol, and fluoroquinolones; concomitant therapy can result in theophylline toxicity. Theophylline metabolism is induced by rifampin and phenobarbital, which may necessitate increasing the dose of theophylline. |
| Theophylline is used for the treatment of both cardiac and respiratory diseases in dogs and cats. Theophylline is also used in the management of intrathoracic collapsing trachea and various forms of bronchitis in dogs. Theophylline and aminophylline were used in horses in the management of RAI, but efficacy was often poor and their use has been replaced by β-agonist bronchodilators. There is little clinical experience with the use of theophylline in cattle; experimental evidence
suggests that it is a poor bronchodilator in this species. |
