The first‐generation phosphodiesterase 5 inhibitors and their pharmacokinetic issue

Abstract

Background Erectile dysfunction (ED) is a relatively frequent disease that negatively impacts the overall quality of life, well‐being, and relationships. Although the use of phosphodiesterase 5 inhibitors (PDE5is) has revolutionized the treatment of ED, a high percentage of ED patients discontinue PDE5i treatment. Objectives (i) To analyze the reasons for patient dissatisfaction leading to PDE5i discontinuation; (ii) analyze the pharmacokinetics of new formulations focusing on the time needed to reach an effective plasma concentration of PDE5is (Tonset) following drug intake; and (iii) summarize the physicochemical properties of sildenafil to understand which excipients may increase the absorption rate. Material and methods An online PubMed literature search was conducted to identify English language publications from inception to January 2019. Results The main reasons for patient dissatisfaction when using PDE5is on demand are the relatively long Tonset after taking vardenafil and sildenafil, including formulations such as film‐coated tablets, fine granules, orally disintegrating tablets (ODTs), and oral thin films (ODFs). The relatively long Tonset, further worsened when accompanied by eating, highlights the following: (i) the need for planning intercourse, determining partner‐related issues; (ii) issues when having sex before the maximum effect of the drug; and (iii) lower drug‐related placebo effects. Some data suggest that sildenafil is a ‘difficult’ molecule, but Tonset can be improved following absorption by buccal mucosa using appropriate excipients. Conclusions We conclude that several ODT and ODF formulations can improve the ‘discretion’ issue because they are taken without water, but they have similar pharmacokinetics to corresponding film‐coated tablet formulations. One ODF formulation of sildenafil was characterized by a shorter Tonset and could potentially increase patient satisfaction following treatment. However, more clinical studies are needed to confirm the findings. Surfactants and ascorbic acid appear to be crucial excipients for achieving a high absorption rate, but more studies are needed.

Effects of shRNA‑mediated silencing of PDE5A3 on intracellular cGMP and free Ca2+ levels and human prostate smooth muscle cell proliferation from benign prostatic hyperplasia

“…This suggests that PDE5 may serve as a potentially promising target for the treatment of BPH/LUTS ( 13 , 14 ). However, since PDE5 is ubiquitously expressed in the human body and participates in a number of physiological and pathological processes in numerous tissues or organs, inhibition of PDE5 using traditional inhibitors may induce various adverse side effects ( 15 , 16 ). Therefore, an effective inhibitor targeting PDE5 that causes fewer adverse side effects is required.…”

The Use of Vasoactive Drugs in the Treatment of Male Erectile Dysfunction: Current Concepts

“…Pharmacological intervention into intracellular pathways regulating smooth muscle tone has become a common strategy in urology for relief of symptoms caused by dysfunctions of the urogenital tract. Based on the physiological mechanisms regulating the male genital tract, vasoactive drugs (such as selective PDE5 inhibitors or prostaglandin E1) modulating signal transduction cascades represent a straightforward logical approach for effectively treating ED of various origins (vasculogenic/neurogenic/psychogenic) in a significant number of patients [62]. While some strategies of treatment target the cyclic GMP system, other approaches take into account the cyclic AMP system.…”

Visual Side Effects Linked to Sildenafil Consumption: An Update

“…Nonetheless, despite this high selectivity, each of these drugs inhibits other PDE isoenzymes to some extent. Sildenafil and vardenafil, for example, have shown only 10 and 15 times lower specificity for PDE6 than for PDE5, respectively (reviewed in [ 14 ]), which could be explained by the fact that the kinetic and catalytic properties of PDE6 are very similar to those of PDE5 [ 15 , 16 , 17 ].…”

“…In addition to the three drugs mentioned above, the second-generation inhibitor avanafil (Stendra ® ) became internationally available in 2013. Avanafil exhibited 100 times lower specificity for PDE6 than for PDE5, presumably reducing the potential side effects derived from the nonselective inhibition of PDE6 by sildenafil and vardenafil (reviewed in [ 14 ]). Other second-generation (udenafil and mirodenafil) or third-generation (lodenafil, SLX-2101, JNJ-10280205, and JNJ-10287069) PDE5 inhibitors have been either approved and introduced into the market in some parts of the world or are at the final stages of their clinical development.…”