madman
Super Moderator
Abstract: It is widely accepted that disorders of the male (uro) genital tract, such as erectile dysfunction (ED) and benign diseases of the prostate (lower urinary tract symptomatology or benign prostatic hyperplasia), can be approached therapeutically by influencing the function of both the vascular and non-vascular smooth muscle of the penile erectile tissue or the transition zone/periurethral region of the prostate, respectively. As a result of the discovery of nitric oxide (NO) and cyclic guanosine monophosphate (GMP) as central mediators of penile smooth muscle relaxation, the use of drugs known to increase the local production of NO and/or elevate the intracellular level of the second messenger cyclic GMP have attracted broad attention in the treatment of ED of various etiologies. Specifically, the introduction of vasoactive drugs, including orally active inhibitors of the cyclic GMP-specific phosphodiesterase (PDE) 5, has offered a great advantage in the pharmacotherapy of ED and other diseases of the genitourinary tract. These drugs have been proven efficacious with a fast onset of action and an improved profile of side-effects. This review summarizes current strategies for the treatment of ED utilizing the application of vasoactive drugs via the oral, transurethral, topical, or self-injection route.
1. Introduction
Erectile dysfunction (ED) is defined as the consistent inability to attain or maintain penile erection sufficient for conducting sexual intercourse [1]. According to data from worldwide epidemiological surveys, the prevalence of ED is 20–40% at 40 years of age and an overall 70% in the decade from 70 years to 80 years. It is estimated that approximately 150 million men suffer from ED [2,3]. The vascular system provides adequate blood supply to the corpora cavernosa of the penis, thus facilitating the so-called Veno-occlusive mechanism required for inducing and maintaining an erection. Since pathological alterations of the vascular system can significantly compromise erectile function, diseases such as atherosclerosis/vascular ischemia, hypertension, lipidemia/hypercholesterolemia, diabetes mellitus (known to promote peripheral neuropathies and, eventually, vascular deteriorations) and generalized endothelial dysfunction can cause erectile dysfunction. ED has been shown to be associated with an increased risk of developing severe coronary heart disease or a stroke event within a time interval of 10 years [4]. Thus, there is a high prevalence of ED in patients sharing risk factors known to contribute to the onset of endothelial dysfunction, characterized by an impairment in the endothelium-dependent vasodilation triggered by NO (FMD = flow-mediated vasodilation brought about by sheer stress) [5–7]. To date, extensive coverage has been made on the NO/cyclic guanosine monophosphate (cGMP) pathway in penile erectile tissue [8]. This landmark discovery has enabled the development of drugs enhancing the intracellular levels of cyclic GMP, in particular, the phosphodiesterase (PDE)5 inhibitors sildenafil, tadalafil, vardenafil, and avanafil. In addition, compounds acting via cyclic adenosine monophosphates (cyclic AMP), such as prostaglandin E1 (PGE1) and vasoactive intestinal polypeptide (VIP), are used in self-injection or topical regimens for the management of ED [9,10]. Via binding to specific receptors located in the outer membrane said compounds can stimulate the activity of the cyclic AMP producing enzyme adenylyl cyclase (AC). Cyclic AMP stimulates the activity of cyclic AMP-dependent protein kinases which, in turn, interact with Ca2+-channels, thereby antagonizing contraction responses of smooth muscle cells. In human corpus cavernosum tissue, the intracellular level of cyclic AMP is under the control of the cyclic AMP-degrading PDE isoenzymes type 3 and 4 [11].
2. Recent PDE5 Inhibitors in the Treatment of Erectile Dysfunction
2.1 Sildenafil
2.2 Vardenafil
2.3 Tadalafil
2.4 Avanafil
2.5 Udenafil
2.6 Mirodenafil
2.7 Lodenafil
3. Intra-Cavernous, Transurethral or Topical Administration of Vasoactive Drugs: Alprostadil
4. Conclusions
Pharmacological intervention into intracellular pathways regulating smooth muscle tone has become a common strategy in urology for the 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 a treatment target the cyclic GMP system, other approaches take into account the cyclic AMP system. The combination of active agents in order to affect multiple intracellular targets is also being considered. In order to ensure a pharmacological effect without significant adverse events, especially on the cardiovascular system, drug action should be limited to the target tissue (the erectile vascular and non-vascular smooth musculature). This can be contracted either by a certain degree of tissue selectivity of orally available drugs or the local application of active compounds via suitable routes [63,64]. An improved bioavailability, faster onset, and sustained duration of drug action, in combination with a high response rate and the advantage of an on-demand application, might be associated with more spontaneous sexual activity for ED patients. The development of first-line oral treatments demonstrating advanced efficacy over the previous options will remain an important topic.
1. Introduction
Erectile dysfunction (ED) is defined as the consistent inability to attain or maintain penile erection sufficient for conducting sexual intercourse [1]. According to data from worldwide epidemiological surveys, the prevalence of ED is 20–40% at 40 years of age and an overall 70% in the decade from 70 years to 80 years. It is estimated that approximately 150 million men suffer from ED [2,3]. The vascular system provides adequate blood supply to the corpora cavernosa of the penis, thus facilitating the so-called Veno-occlusive mechanism required for inducing and maintaining an erection. Since pathological alterations of the vascular system can significantly compromise erectile function, diseases such as atherosclerosis/vascular ischemia, hypertension, lipidemia/hypercholesterolemia, diabetes mellitus (known to promote peripheral neuropathies and, eventually, vascular deteriorations) and generalized endothelial dysfunction can cause erectile dysfunction. ED has been shown to be associated with an increased risk of developing severe coronary heart disease or a stroke event within a time interval of 10 years [4]. Thus, there is a high prevalence of ED in patients sharing risk factors known to contribute to the onset of endothelial dysfunction, characterized by an impairment in the endothelium-dependent vasodilation triggered by NO (FMD = flow-mediated vasodilation brought about by sheer stress) [5–7]. To date, extensive coverage has been made on the NO/cyclic guanosine monophosphate (cGMP) pathway in penile erectile tissue [8]. This landmark discovery has enabled the development of drugs enhancing the intracellular levels of cyclic GMP, in particular, the phosphodiesterase (PDE)5 inhibitors sildenafil, tadalafil, vardenafil, and avanafil. In addition, compounds acting via cyclic adenosine monophosphates (cyclic AMP), such as prostaglandin E1 (PGE1) and vasoactive intestinal polypeptide (VIP), are used in self-injection or topical regimens for the management of ED [9,10]. Via binding to specific receptors located in the outer membrane said compounds can stimulate the activity of the cyclic AMP producing enzyme adenylyl cyclase (AC). Cyclic AMP stimulates the activity of cyclic AMP-dependent protein kinases which, in turn, interact with Ca2+-channels, thereby antagonizing contraction responses of smooth muscle cells. In human corpus cavernosum tissue, the intracellular level of cyclic AMP is under the control of the cyclic AMP-degrading PDE isoenzymes type 3 and 4 [11].
2. Recent PDE5 Inhibitors in the Treatment of Erectile Dysfunction
2.1 Sildenafil
2.2 Vardenafil
2.3 Tadalafil
2.4 Avanafil
2.5 Udenafil
2.6 Mirodenafil
2.7 Lodenafil
3. Intra-Cavernous, Transurethral or Topical Administration of Vasoactive Drugs: Alprostadil
4. Conclusions
Pharmacological intervention into intracellular pathways regulating smooth muscle tone has become a common strategy in urology for the 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 a treatment target the cyclic GMP system, other approaches take into account the cyclic AMP system. The combination of active agents in order to affect multiple intracellular targets is also being considered. In order to ensure a pharmacological effect without significant adverse events, especially on the cardiovascular system, drug action should be limited to the target tissue (the erectile vascular and non-vascular smooth musculature). This can be contracted either by a certain degree of tissue selectivity of orally available drugs or the local application of active compounds via suitable routes [63,64]. An improved bioavailability, faster onset, and sustained duration of drug action, in combination with a high response rate and the advantage of an on-demand application, might be associated with more spontaneous sexual activity for ED patients. The development of first-line oral treatments demonstrating advanced efficacy over the previous options will remain an important topic.
