Abstract

The present article discusses several aspects of erectile dysfunction (ED), especially what role PDE5 inhibitors can play in enhancing erectile performance and treating the symptoms of ED with much more efficacy and efficiency. Further discussions about the mechanisms of PDE5 inhibitors have occurred in this article, including the various types of PDE5 inhibitors, the results of PDE5 clinical testing, and the proposed methodologies that can be used for future research opportunities on erectile dysfunction.

1. Introduction

The inability to obtain or sustain an erection strong enough for satisfying sexual performance is known as erectile dysfunction (ED), and it can be chronic or recurrent. The severity of erectile dysfunction might vary. Some men with ED may find it impossible or extremely difficult to have an erection at any time.

Currently, PDE5 inhibitors are regarded as the gold standard for treating erectile dysfunction. They generally start acting quickly, have a brief lifespan of up to a day, are highly potent, and typically only have mild, transient negative effects.

With the development of type 5 phosphodiesterase (PDE5) inhibitors over the past 15 years, the treatment of erectile dysfunction (ED) has undergone a revolution. As they were being examined to cure angina and hypertension, PDE5 inhibitors were inadvertently discovered to have a positive impact on erection in men.

The scientists who tested UK-92,480, sometimes known as Sildenafil or Viagra, first considered this to be of little consequence. However, as time went on, the emphasis of the trials shifted from the use of PDE5 inhibitors to treat erectile dysfunction to illnesses including angina and hypertension. In the United States and many other countries, tens of millions of men use PDE5 inhibitors like Sildenafil and other drugs.

1.1 Background of PDE5 inhibitor: ED medication

The relationship between NO and the PDE family led to an increase in drug development in the middle of the 1980s. Numerous physiological effects of NO had significant effects on various disorders. The PDE enzyme is present in all tissues of the body and has 11 different known isoenzymes that are expressed at varying levels. Although it is present everywhere, the PDE5 enzyme is more common in penile tissue. 

Before identifying the connection between NO and PDEs, non-selective PDE inhibitors (such as theophylline) were in use, but selective PDE inhibitors were yet to be created. Since then, several selective PDE inhibitors have been authorized to treat a range of conditions, including ED and pulmonary hypertension.

2. Mechanism of Inhibition: Physiology of Penile Erection

The typical physiology of penile erection, which is a medical condition for which the majority of PDE5 inhibitors are currently prescribed, must first be understood to comprehend the mechanism of PDE5 inhibitors. 

Following sexual stimulation, nerve impulses in the corpora cavernosa release neurotransmitters that cause endothelial cells to produce nitric oxide. This nitric oxide then diffuses into nearby smooth muscle cells and stimulates the formation of cGMP, which causes vasodilation and an increase in penile blood flow. 

ED pills inhibit the production of PDE-5 enzyme in the smooth muscles. 

This buildup of cGMP in the vascular smooth muscle results in dilating blood arteries through the phosphorylation of many downstream effector molecules. As well as improving endothelial function, PDE5 is also reduce the death of smooth muscle cells in the corpus cavernosum.

The most common phosphodiesterase in the corpus cavernosum is PDE5. However, mammalian PDE has been found in at least 11 families. 

There are more than 50 different species of PDE as a result of the association of some PDE types with multiple genes and the presence of two or more splice variants in some mRNAs. 

Some PDE subtypes degrade only cyclic adenosine monophosphate (cAMP) or only cyclic guanosine monophosphate (cGMP), whereas others do both. For instance, PDE11 breaks down both cAMP and cGMP, unlike PDE4 and PDE5, which only break down cAMP. PDE inhibitors’ cross-reactivity can be largely ascribed to similarities in their homologous catalytic domain. 

Human corpus cavernosum tissue contains messenger RNA for the PDE isoforms PDE1A, PDE1B, PDE1C, PDE2A, PDE3A, PDE4A, PDE4B, and PDE4C.

2.1 Physiological mediator of ED

Nitric oxide (NO) is released during sexual arousal by endothelial cells and nerve terminals in the corpus cavernosum. A cGMP-dependent chain of actions is started when NO stimulates guanylate cyclase to change guanosine triphosphate (GTP) into cyclic guanosine monophosphate (cGMP). The buildup of cGMP causes the corpus cavernosum’s smooth muscles to relax and the blood flow to the penis to increase. 

PDE5 is an enzyme that specifically cleaves and degrades cGMP to 5′-GMP in the corpus cavernosum smooth muscle. PDE5 inhibitors have a structure that is comparable to that of cGMP; they bind to PDE5 competitively and prevent cGMP hydrolysis, which improves the effects of NO. Therefore, the lengthening of an erection is caused by an increase in cGMP in smooth muscle cells.

The relaxation of corpus cavernosum smooth muscles is not directly impacted by PDE5 inhibitors. Consequently, for an erection to occur after injection, sufficient sexual excitement is required.

3. Different types of PDE5 inhibitors

There are several PDE5 inhibitors available. Lodenafil, Udenafil, and Mirodenafil are other non-FDA marketed drugs.

3.1 Sildenafil Citrate

Sildenafil was the first PDE5 inhibitor and the first medication of its sort to be sold to the general population. The key advantages of Sildenafil are its availability, low cost, and extensive history. 

It has been used for many years and has been the focus of numerous clinical investigations. 

Sildenafil communicates with the catalytic domain via the L region, Q pocket, and H pocket. It does not interface with the M subsite directly. Sildenafil does not interact with the Zn2+ and Mg2+ metal ions of the M-subsite directly; instead, its pyrazole N2 atom forms a hydrogen bond with a water molecule, which then forms two hydrogen bonds: one with Tyr612 in the Q-pocket and the other with a water molecule that coordinates to the Zn2+ ion. 

Through a bidentate hydrogen connection, the side chain amide group of the conserved Gln817 interacts with the amide group of the pyrazolopyrimidinone moiety of Sildenafil. The connection between Gln817 and the purine ring of cGMP forms a bidentate hydrogen bond, which is like this interaction.

3.2 Vardenafil

Apart from the piperazine ring substitution (methyl in sildenafil vs. ethyl in vardenafil) and the piperazine ring’s position in the active site, vardenafil and sildenafil are structurally quite similar. The heterocyclic ring structure that mimics the purine ring of cGMP is another area where they diverge. 

Similar binding interactions were found to exist between the two inhibitors. 

Despite having identical structural and binding properties to sildenafil, vardenafil is a more effective and focused PDE5 inhibitor. Compared to sildenafil, it has an enzyme affinity that is at least 20 times higher.

3.3 Tadalafil

Tadalafil is more selective than sildenafil or vardenafil because it has 200–600 times greater affinity for PDE5 than PDE6. Tadalafil was said to bind PDE5 differently than sildenafil because it interacts with the L area but forms alternative binding modes with the Q pocket. 

In contrast to a bidentate hydrogen bond, the -amide group of Gln817 forms a solitary hydrogen link with the NH of the indole ring in tadalafil.

4. Clinical Efficacy and Indications in ED treatment

PDE5 inhibitors have been tested for their effectiveness and safety using both objective and patient-reported subjective efficacy measures. Optimal prescribing practices, improved patient-provider communication, and higher pharmacological knowledge are all factors that contribute to improved long-term treatment success.

In men over 50, ED and lower urinary tract symptoms (LUTSs) brought on by benign prostatic hyperplasia (BPH) are prevalent medical conditions. Epidemiological research indicates a significant link between the two. 

It has been demonstrated that lower urinary tract tissue from rats contains PDE5 mRNA. In animal investigations, the dose-dependent effects of sildenafil, tadalafil, and vardenafil on the contraction of isolated urethral and prostatic strips and LUTSs were seen. 

The only medication approved for the treatment of LUTSs secondary to BPH with or without ED is tadalafil 5 mg once daily.

5. The future direction of ED treatment: Pharmacotherapy

• A more recent PDE5 inhibitor called udenafil has the same affinity for PDE5 that sildenafil does. Udenafil was proven to be a safe and effective treatment for ED in a parallel-group Phase three trial conducted in Korea. This trial was multi-center, double-blind, and placebo-controlled, and the volunteers received a fixed dose. Currently, udenafil is offered in various nations under the brand name Zydena, including Korea and Russia (Dong-A PharmTech Co, Seoul, South Korea). One hundred sixty-seven individuals with ED of various origins and severity were randomly selected. They received a placebo or udenafil at fixed doses of 100 or 200 mg as needed for 12 weeks in this parallel-group phase III trial.
• PDE5 inhibitor mirodenafil has been marketed as M-Vix (Korea, 2007). (S. K. Chemicals, Seoul). In Korea, a multi-center, randomized, double-blind, placebo-controlled, parallel-group, fixed-dose research revealed that the medication is efficient and well-tolerated in treating ED caused by a variety of etiologies.
• Since not all patients react favorably to the available PDE5 inhibitors, as was already mentioned, different ED medications are necessary. Phase III clinical studies for Avanafil, one of these novel medications, are now being conducted.
• Avanafil is an oral ED drug that has been developed to be a highly effective and quick-acting PDE5 inhibitor. It is a pyrimidine derivative that has a molecular weight of 483.95 Da.
• For the purpose of treating ED, tissue engineering is being researched. A sural autologous nerve graft was developed as a successful technique for preserving the continuity of the cavernous nerves after radical prostatectomy.

Furthermore, it is shown that endothelial and smooth muscle cells from the human body can create well-vascularized corporal tissue in vivo when they are placed in a mesh of acellular collagen matrix.

To create pure, smooth muscle, we have outlined cell isolation techniques and evaluated their culture compositions, omitting primarily fibroblasts.

6. Conclusion

The PDE5 inhibitors that are now on the market, such as the more recently approved avanafil, offer ED sufferers a secure, practical, and efficient way to enhance erectile function. These medications have replaced other ED treatments as the first-line therapy because of their comfort, quick start-up, and tolerability. However, it is challenging to decide whether an agent is superior to another due to the need for sufficient head-to-head trials.

More research comparing these drugs is needed to determine the potential benefits of each, especially in specific patient subsets. According to each patient’s response and need, prescribing options are available with all PDE5 inhibitors.

Reference

1. Huang SA, Lie JD. Phosphodiesterase-5 (PDE5) Inhibitors In the Management of Erectile Dysfunction. P T. 2013 Jul;38(7):407-19. PMID: 24049429; PMCID: PMC3776492.
2. Wharton, J., Strange, J. W., Møller, G. M., Growcott, E. J., Ren, X., Franklyn, A. P., … & Wilkins, M. R. (2005). Antiproliferative effects of phosphodiesterase type 5 inhibition in human pulmonary artery cells. American journal of respiratory and critical care medicine, 172(1), 105-113.
3. Paick J-S, Kim SW, Yang DY, et al. The efficacy and safety of udenafil, a new selective phosphodiesterase type 5 inhibitor, in patients with erectile dysfunction. J Sex Med. 2008;5(4):946–95.
4. Alwaal, A., Al-Mannie, R., & Carrier, S. (2011). Future prospects in the treatment of erectile dysfunction: focus on avanafil. Drug Design, Development, and Therapy, 5, 435-443.
5. Paick JS, Ahn TY, Choi HK, et al. Efficacy and safety of mirodenafil, a new oral phosphodiesterase type 5 inhibitor, for treatment of erectile dysfunction. J Sex Med. 2008;5(11):2672–2680