Anti-Hypertensive Drugs and Sexual Dysfunction in Men

One of the risk factors associated with the incidence of sexual dysfunction in men is antihypertensive drugs. Anti-hypertensive drugs which have the effect of causing sexual dysfunction in men include; diuretics, clonidine, and β-blockers (except nebivolol), but there are some anti-hypertensive drugs that have a neutral effect, even have a positive effect which in this case can improve sexual function in men. Anti-hypertensive drugs that have a neutral effect on male sexual function include; Calcium Channel Blockers (CCBs)and Angiotensin Converting Enzyme Inhibitors (ACE-Inhibitors) and those that have the effect of increasing sexual function in men include; Angiotensin Receptor Blockers (ARBs) and β-blockers namely nebivolol. The use of anti-hypertensive drugs can affect sexual function in men through different mechanisms. Anti-hypertensive drugs such as diuretics, β-blockers, and clonidine can cause sexual dysfunction in men through the mechanism of changes in the sympathetic outflow, the effect on contractions of corporal smooth muscle, and through the influence on androgen hormone levels. ARBs and Nebivolol can improve sexual function through inhibition mechanism on Angiotensin II and increase the bioavailability of Nitric Oxide (NO).


INTRODUCTION
According to World Health Organization (WHO, 1975) sexual dysfunction is a condition where an individual cannot participate in a sexual intercourse as desired. Sexual dysfunction that occurs in men can be a decrease in libido, erectile dysfunction (ED), and problems with ejaculation. Epidemiological data indicate that erectile dysfunction has a high prevalence and incidence throughout the world. [1] It is estimated that more than 152 million men worldwide experienced erectile dysfunction in 1995, and this number will increase by 170 million, which is estimated to reach 322 million by 2025. [2] The study conducted by The National Social Life, Health and Aging Project (NSHAP) by taking subjects for men aged 57-85 years, the results of the incidence rate of erectile dysfunction were found to be 37% with an incidence rate of 26 new cases per 1000 men. Some risk factors associated with ED include; history of heart disease, hypertension, diabetes mellitus, smoking history, psychological conditions, hormone levels, especially testosterone, and drugs. [3] Many drugs are known to affect sexual function in men, such as; anti-cholinergic, psychotropic, and anti-hypertensive drugs. [2] Anti-hypertension therapy has been associated to the incidence of ED, [4,5] from a study conducted by Doumas et al. (2013) found that the prevalence of ED is more common in hypertensive patients who are treated compared to hypertensive patients who are not treated and normotensive patients, this indicates that therapy for hypertension itself contributes to the occurrence of sexual dysfunction. [4,6] The incidence rate of ED in patients taking anti-hypertensive drugs is 14%. [2] One reason for the non-compliance with the use of anti-hypertensive drugs is because of the side effects which raisedthe occurrence of sexual dysfunction.The use of antihypertensive drugs can affect each sexual function with different mechanisms. [4] It has been proven that some antihypertensive drugs have the effect of causing sexual dysfunction such as diuretics, clonidine, and β-blockers especially those that are non-selective (except nebivolol), [1]

PHYSIOLOGY
OF SEXUAL

FUNCTION IN MEN
The mechanism of erection in male sexual function includes 2 processes namely; the occurrence of dilatation of the arteriolar and the occurrence of increased blood flow to the tissues and blood vessels of the penis, where the innervation system that plays a role is the autonomic innervation system and the somatic innervation system. [2,24] The mechanism of erection is also influenced by androgen hormones which are steroid hormones that play a role in controlling and maintaining erectile function in men. [25] 1. Structure and innervation of male

Mechanisms
The erection begins with stimulation of the arousal center in the brain which will cause inhibition of the release of norepinephrine, parasympathetic stimulation which will induce the production and release of nitric oxide (NO), and stimulation of somatic nerves which will induce the production and release of acetylcholine. [11,21] [13,15,21,28] The cGMP level will be modulated by the Phosphodiesterase (PDE) enzyme, which will break down cGMP into an inactive form of 5GMP. [15] The occurrence of a flaccid state of oxidase. [15,28] Norepinephrine is responsible for regulating smooth muscle tone of the corpus cavernosum through interactions with α-1 receptors and α-2 receptors. [2] Reactive Oxygen Specieswill activate Rho-kinase pathway, which will prevent the dephosphorylation of miofilament which will cause contraction of smooth muscle, causing a flaccid state of the penis. [11,15,28]  (TNF-α) and increased tone of blood vessels. [21] PATHOGENESIS OF SEXUAL

DYSFUNCTION IN MEN
The pathogenesis of the occurrence of sexual dysfunction is classified into several mechanisms, namely: Psychogenic, neurogenic, hormonal, vasculogenic, cellular, and iatrogenic mechanisms. [20]

Hormonal Mechanism
Testosterone hormone has a very important role in sexual function in men, a decrease in the level of androgen testosterone hormone will cause a decrease and loss of libido and ED. [3,20] Circumstances

Vasculogenic Mechanism
Impaired blood vessels can cause sexual dysfunction, through a reduction in arterial inflow that will cause a relative hypoxic state in the penis, which will cause an increase of transforming growth factor beta, that will induce changes in the smooth cavernosum muscle of the penis. [20] Some conditions that can cause a decrease in arterial supply and venous drainage of the penis are shown in Table3. [2,20]

Cellular Mechanism
There are

Angiotensin Receptor Blockers
Some studies state that ARBs can improve sexual function in men. [4,7,9,15]  inhibiting Angiotensin II. [14] Studies show that anti-hypertension ARBs improve endothelial function in the cavernosum network, [10,14,15] this is based on the role of angiotensin II which is known to induce contraction of the penile corpus cavernosum smooth muscle and induce endothelial dysfunction through activation and increase in reactive oxygen species through bonding AT I receptor, so there is a decrease in NO synthesis, ROS will also react with NO and form ONOO -, so there is a decrease in the effectiveness of NO. [7,14]

ACE-Inhibitors
Some studies say that ACEinhibitors do not cause sexual dysfunction and can even improve sexual function in men. [10,12] The association between ACEinhibitors drug use in the absence of complications of sexual dysfunction has been demonstrated in some study. [5] One explanation that can explain this situation is that ACE inhibitors will inhibit ACE, resulting in decreased levels of angiotensin II so that the role of angiotensin II in the renin-aldosterone system that induced vascular remodeling process will be inhibited and will also increase the erectile response. [5,16]

Clonidine
Anti-hypertension drugs α2adrenergic agonist namely Clonidine, are reported to cause ED. [2,8,13,14] Dong Wang et al (2015) reported that the use of clonidine in addition to causing ED can even reduce the level of conception. [16] The use of Clonidine can cause ED through mechanism that reduce the sympathetic outflow and induce the contraction of the corporal smooth muscle. [14]

Calcium Channel Blockers
The calcium channel blockers (CCBs) from several studies have been shown not causing sexual dysfunction and even have a positive effect on sexual function. [6,10,12] Several studies report that

Diuretics
Diuretic groups have side effects that can cause sexual dysfunction. [9,10,12] Erectile dysfunction is a common side effect, either as a single or combination therapy where diuretics are additional therapy. [13]