Phosphodiesterase inhibitors

Phosphodiesterases (PDEs) are enzymes responsible for the inactivation of the intracellular second messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). There are many subtypes of phosphodiesterases and many inhibitors which can be either non-specific, or selective in their inhibitory profile.

Methylated xanthine derivatives act as nonselective PDE inhibitors. Examples include the natural product theophylline (aminophylline) which is used for its bronchodilatory effects and pentoxifylline. Xanthine derivatives can also act as nonselective adenosine receptor antagonists. Their combined action on phosphodiesterases and adenosine receptors likely underlies the anti-inflammatory action of pan-phosphodiesterase inhibitors.

Selective phosphodiesterase inhibitors

PDE3 inhibitors: milrinone, enoximone, and inamrinone are cardiotonic agents used to treat congestive heart failure. Cilostazol (used to treat intermittent claudication) and anagrelide (used to treat essential thrombocythaemia) are also PDE3-selective inhibitors.

PDE4 inhibitors: roflumilast and apremilast are used for their anti-inflammatory action, to treat asthma and chronic obstructive pulmonary disease (COPD), and psoriatic arthritis respectively. PDE4 inhibitors suppress the release of cytokines and other inflammatory signals to achieve an anti-inflammatory action.

PDE5 inhibitors: sildenafil, tadalafil, vardenafil, and the newer drug avanafil selectively inhibit PDE5, a cGMP-selective phosphodiesterase expressed in the smooth muscle cells lining the blood vessels of the corpus cavernosum and other tissues. This set of drugs are used primarily to treat erectile dysfunction. Certain of these drugs also show efficacy in treating pulmonary arterial hypertension (PAH) and benign prostatic hyperplasia (BPH).