Phosphodiesterase 5 Inhibitors - Drug Design and Differentiation Based on Selectivity, Pharmacokinetic and Efficacy Profiles

Abstract

The discovery that inhibition of phosphodiesterase-5 (PDE5) reduces the degradation of cGMP, allowing erectile function to occur by relaxation of penile smooth muscle, represents a revolutionary approach or the treatment of erectile dysfunction (ED). Three PDE5 inhibitors (sildenafil, tadalafil, and vardenafil) are clinically available at this time, and extensive drug design efforts are registered for finding agents with a better activity, enhanced selectivity and reduced side effects. Many classes of such compounds have been reported, belonging to diverse chemical entities. The drug design has been very much facilitated after the report of the X-ray crystal structure of the PDE5 catalytic domain in complex with the three clinically used derivatives. PDE5 inhibitor therapy, has been found to be effective in special clinical populations, such as those with prostate cancer, diabetes, and cardiovascular disease. The duration of action of sildenafil and vardenafil is of about 4 hours, whereas that of tadalafil is of about 36 hours, and the overall safety of the treatments is good. There is a risk of hypotension if nitrates are given concurrently with the PDE5 inhibitors. Common side-effects include headache, facial flushing, nasal congestion, dyspepsia and transient visual impairment. There are pharmacological interactions between these drugs and other medications metabolized by the cytochrome P450 (P3A4 isoform), such as the azole antifungals, erythromycin and the HIV protease inhibitors.

Tadalafil rehabilitation therapy preserves penile size after bilateral nerve sparing radical retropubic prostatectomy

“…However it was reported in a recent study that * mean p < 0.05 the duration of action of sildenafil and vardenafil is about 4 hours, whereas Tadalafil action is approximately 36 hours, and the overall safety of the treatment is good (23). In another study by Doggrell S (24) it was concluded that Tadalafil is similarly effective as Sildenafil in the treatment of ED and in comparison studies; Tadalafil is preferred to Sildenafil (50/100mg) by men with ED, possibly because of its longer duration of action.…”

Phosphodiesterase inhibition with tadalafil provides longer and sustained protection of stem cells

“…Although having selective inhibitory effects on PDE5 activity, sildenafil and vardenafil differ from tadalafil in their interaction with the catalytic domain of PDE5, which forms the basis of their difference in affinity and effectiveness (25). Moreover, unlike sildenafil and vardenafil with 4 h biological half-life, tadalafil is a long-acting PDE5A inhibitor with 17.5 h biological half-life.…”

High Doses of PDE5 inhibitors and tramadol reversibly alters haematological parameters in rats

“…PDE5i are also used in the treatment of pulmonary hypertension (Supuran et al, 2006;Aversa et al, 2006).These drugs act selectively in the smooth muscle of the lungs and penis because their receptors are primarily distributed within these areas (Oka et al, 2015). PDE5i are so called because they selectively inhibit the action of phosphodiesterase type 5, an enzyme which promotes the degradation of cyclic guanosine monophosphate (cGMP) (Salam et al, 2015).Thus, erection is prolonged as long ascGMP is not degraded.…”