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Author: Admin | 2025-04-28
Alan W. Shindel, MD, MAS, presented “Novel Oral Pharmacotherapies for ED: Are PDE5 Inhibitors the Final Answer?” during the Jackson Hole Seminars on January 30, 2019 in Jackson Hole, Wyoming.How to cite: Shindel, Alan W. “Novel Oral Pharmacotherapies for ED: Are PDE5 Inhibitors the Final Answer?” January 30, 2019. Accessed [date today]. https://grandroundsinurology.com/novel-oral-pharmacotherapies-for-ed-are-pde5-inhibitors-the-final-answer/Alan W. Shindel, MD, MAS, discusses the current treatment of erectile dysfunction (ED) with PDE5 inhibitors, as well as the limitations of the currently available drugs for ED patients. He also reviews a number of potential targets for novel ED treatments, including nitric oxide, soluble guanylate cyclase, the RhoA/Rho Kinase/ROCK pathway, and the Sonic Hedgehog protein. Current Treatment of Erectile DysfunctionWhile there is optimism for the future of ED treatment, there are still limitations to current treatment practices and methods. The advent of phosphodiesterase type 5 (PDE5) inhibitors in 1998 revolutionized the management of ED. However, patients with other contributing factors to ED, including the presence of diabetes, vasculopathy, damage from radial pelvic surgery, and central nervous system lesions, may not respond well to these drugs. There is also a significant side effect profile with these drugs. Additionally, the fast-onset nature of PDE5 inhibitors does not always align with individual patient preferences. Certain patients desire a durable-response therapy that will divorce the use of a medication with sexual encounters. This highlights an unmet need in ED management—namely the need to offer a variety of treatment options to patients will optimize individualized outcomes, efficacy, and tolerability. PDE5 Inhibitors – Mechanism of ActionAs of now, PDE5 is the mainstay of treatment in ED management. Although there are many places to intervene in the NO/cGMP pathway, PDE5 is localized largely to the penis, making the PDE5 pathway an available target for ED treatment.PDE5 inhibitors are designed to block the catalytic domain of PDE5. However, the other part of the PDE5 molecule could be another target for ED treatment. On the other hand, there are alternative targets in ED treatment outside of PDE5.Alternatives to PDE5 Inhibitors One alternative target is nitric oxide (NO), which has a critical role in initiation of vasodilation, but has a very short half-life. NO works by activation of guanylate cyclase (GC), which cleaves GTP to cGMP. The NO activation of GC is one of the main steps in the pathway involved in erections. Because of this, soluble guanylate cyclase (sGC) is another enzyme of interest. Targeting sGC bypasses NO and the signal transduction pathway can continue without it. There is a class of drugs called guanylate cyclase activators which may be very useful in patients with neurogenic ED. For example, results of a 2011 animal model study suggest that there may be benefits to use of sGC. The RhoA/Rho Kinase/ROCK pathway is a calcium sensitization pathway. This pathway makes calcium more effective in promoting muscular contraction. Inhibition of the RhoA/ROCK pathway can enhance erectile function. A 2017 study by Uvin et al looked at a potential Rho kinase inhibitor, Y-27632, compared to a non-specific kinase inhibitor and
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