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 in vitro to inhibit several members of the phosphodiesterase (PDE)enzyme family (Figure 3). Because the phosphodiesterases hydrolyze cyclic nucleotides,this inhibition results in higher concentrations of intracellular cAMP and,in some tissues,cGMP.Cyclic AMP is responsible for a myriad of 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. Of the various isoforms of phosphodiesterase that have been identified,PDE4 appears to be the most directly involved in actions of methylxanthines on airway smooth muscle and on inflammatory cells.The inhibition of PDE4 in inflammatory cells reduces their release of cytokines and chemokines,which in turn results in a decrease in immune cell migration and activation. In an effort to reduce toxicity while maintaining therapeutic efficacy,more selective inhibitors of different isoforms of PDE4 have been developed,particularly for the treatment of chronic obstructive pulmonary disease (COPD).Several are now in advanced stages of clinical development,(eg,roflumilast,cilomilast,tofimilast),but at the time of writing,none has been approved for clinical use by the FDA.Although several appear promising,none is entirely free of the major adverse effect of this class of drugs,nausea and vomiting. Another proposed mechanism is inhibition of cell surface receptors for adenosine. These receptors modulate adenylyl cyclase activity,and adenosine has been shown to provoke contraction of isolated airway smooth muscle and histamine release from airway mast cells.It has been shown,however,that xanthine derivatives devoid of adenosine antagonism (eg,enprofylline)may be potent in inhibiting bronchoconstriction in asthmatic subjects. Pharmacodynamics of Methylxanthines The methylxanthines have effects on the central nervous system,kidney,and cardiac and skeletal muscle as well as smooth muscle.Of the three agents,theophylline is most selective in its smooth muscle effects,whereas caffeine has the most marked central nervous system effects. A.CENTRAL NERVOUS SYSTEM EFFECTS In low and moderate doses,the methylxanthines especially caffeinecause mildMechanism 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 in vitro to inhibit several members of the phosphodiesterase (PDE) enzyme family (Figure 3). Because the phosphodiesterases hydrolyze cyclic nucleotides, this inhibition results in higher concentrations of intracellular cAMP and, in some tissues, cGMP. Cyclic AMP is responsible for a myriad of 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. Of the various isoforms of phosphodiesterase that have been identified, PDE4 appears to be the most directly involved in actions of methylxanthines on airway smooth muscle and on inflammatory cells. The inhibition of PDE4 in inflammatory cells reduces their release of cytokines and chemokines, which in turn results in a decrease in immune cell migration and activation. In an effort to reduce toxicity while maintaining therapeutic efficacy, more selective inhibitors of different isoforms of PDE4 have been developed, particularly for the treatment of chronic obstructive pulmonary disease (COPD). Several are now in advanced stages of clinical development, (eg, roflumilast, cilomilast, tofimilast), but at the time of writing, none has been approved for clinical use by the FDA. Although several appear promising, none is entirely free of the major adverse effect of this class of drugs, nausea and vomiting. Another proposed mechanism is inhibition of cell surface receptors for adenosine. These receptors modulate adenylyl cyclase activity, and adenosine has been shown to provoke contraction of isolated airway smooth muscle and histamine release from airway mast cells. It has been shown, however, that xanthine derivatives devoid of adenosine antagonism (eg, enprofylline) may be potent in inhibiting bronchoconstriction in asthmatic subjects. Pharmacodynamics of Methylxanthines The methylxanthines have effects on the central nervous system, kidney, and cardiac and skeletal muscle as well as smooth muscle. Of the three agents, theophylline is most selective in its smooth muscle effects, whereas caffeine has the most marked central nervous system effects. A. CENTRAL NERVOUS SYSTEM EFFECTS In low and moderate doses, the methylxanthines especially caffeinecause mild