Inhibitors of phosphodiesterases in the treatment of cough

Abstract

A group of 11 enzyme families of metalophosphohydrolases called phosphodiesterases (PDEs) is responsible for a hydrolysis of intracellular cAMP and cGMP. Xanthine derivatives (methylxanthines) inhibit PDEs without selective action on their single isoforms and lead to many pharmacological effects, e.g. bronchodilation, anti-inflammatory and immunomodulating effects, and thus they can modulate the cough reflex. Contrary, selective PDE inhibitors have been developed to inhibit PDE isoforms with different pharmacological effects based on their tissue expression. In this paper, effects of non-selective PDE inhibitors (e.g. theophylline) are discussed, with a description of other putative mechanisms in their effects on cough. Antitussive effects of selective inhibitors of several PDE isoforms are reviewed, focusing on PDE1, PDE3, PDE4, PDE5 and PDE7. The inhibition of PDEs suggests participation of bronchodilation, suppression of TRPV channels and anti-inflammatory action in cough suppression. Selective PDE3, PDE4 and PDE5 inhibitors have demonstrated the most significant cough suppressive effects, confirming their benefits in chronic inflammatory airway diseases associated with bronchoconstriction and cough.