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International Journal of Clinical and Experimental Medical Sciences
2017; 2(6): 87-94
http://www.sciencepublishinggroup.com/j/ijcems
doi: 10.11648/j.ijcems.20170306.15
ISSN: 2469-8024 (Print); ISSN: 2469-8032 (Online)
Review Article
A Review on Erectile Dysfunction Among Hypertensive
Patients on Pharmacotherapy
Bright Boafo Boamah
1, *
, Edward Kwaku Armah
2
, Gifty Oppong Boakye
3
1
Department of Pharmacology, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana
2
Department of Chemical Engineering, Durban University of Technology, Durban, South Africa
3
Department of Mechanical Engineering, University of Leeds, Leeds, United Kingdom
Email address:
briteboafo@gmail.com (B. B. Boamah)
*
Corresponding author
To cite this article:
Bright Boafo Boamah, Edward Kwaku Armah, Gifty Oppong Boakye. A Review on Erectile Dysfunction Among Hypertensive Patients on
Pharmacotherapy. International Journal of Clinical and Experimental Medical Sciences. Vol. 2, No. 6, 2017, pp. 87-94.
doi: 10.11648/j.ijcems.20170306.15
Received: November 12, 2017; Accepted: November 27, 2017; Published: December 21, 2017
Abstract:
Hypertension and its related disorders have a high mortality as well as morbidity and require strict adherence to
medications in order to mitigate these consequences. Sexual dysfunction is prevalent among patients with hypertension and can
either be attributed to the disease progression or as a result of antihypertensive medications. Most patients report the symptoms
after initiation therapy and sometimes leads to a spurious association with antihypertensive drugs. However, most drugs in the
antihypertensive classes have been associated with sexual dysfunction in both men and women. The most implicated drugs are
diuretics, beta-blockers, and centrally acting agents while angiotensin modulating drugs have proved to improve upon erectile
dysfunction. The older generation of antihypertensive medications tends to have a negative impact on sexual performance.
Females experience sexual dysfunction associated with hypertension and its treatment, but this is grossly under-reported
compared to their male counterparts. The incidence in females is higher compared to men and it is sometimes erroneously
considered as part of the post-menopausal period rather than hypertension. The impact of medications on sexual dysfunction has
somewhat produced contrasting results with some studies showing an association with medications and others proving otherwise.
Clinicians need to be aware of the impact of sexual dysfunction among hypertensive patients in order to make an informed
decision regarding dosage and choice of medications while keeping target blood pressure in mind.
Keywords:
Erectile Dysfunction, Hypertension, Antihypertensive Medications, Sexual Dysfunction
1. Introduction
Erectile dysfunction (ED) among hypertensive patients is a
common disorder
[1]. Sexual dysfunction is defined by World
Health Organization (WHO) as the various ways in which an
individual is unable to participate in a sexual relationship as he
or she would wish. Females encounter the problem of sexual
dysfunction but studies have probed more into the pattern of
male sexual dysfunction [2]. Erectile dysfunction, as defined
in 1992 by the National Institutes of Health Consensus Panel
as the persistence with respect to achievement and/or
maintenance of penile erection in the presence of appropriate
stimuli for sexual intercourse [3]. Females tend to
under-report the symptoms of sexual dysfunction which
includes; lack of desire, arousal, orgasm and increased pain
during intercourse [4]. In men, erectile dysfunction is a hurdle
in the management of hypertension which presents as every
physician’s nightmare in deciphering if its aetiology is due to
the medication taken [5]. Establishing a baseline sexual
function in every patient is therefore imperative [6].
In the second Princeton consensus, knowledge of sexual
function in hypertensive men is imperative in initiating
antihypertensive therapy while planning for treatment of
erectile dysfunction if it presents itself in the course of
treatment [7]. Several studies have tried to mitigate this
confusion by advocating for a thorough sexual history prior to
88 Bright Boafo Boamah et al.: A Review on Erectile Dysfunction Among Hypertensive Patients on Pharmacotherapy
the commencement of antihypertensive therapy [5]. Erectile
dysfunction has been erroneously limited to the shortfall in
sexual function and activity but this stretches beyond this
purview. ED is currently considered as a predictor of
cardiovascular diseases and a premonitory sign to a general
systemic vascular impairment [8]. Erstwhile, sexual
dysfunction was considered more of psychogenic origin rather
than organic but now it has been found to be due to vascular,
neurogenic, drug-induced, metabolic, and hormonal etiologies
[9].
Drug-induced erectile dysfunction can be ascribed to the
increased prevalence of diseases such as obesity, hypertension,
dyslipidemia and diabetes mellitus [10]. Advancing age in
men has been associated with erectile dysfunction even in the
absence of the aforementioned risk factors [11].
The objective of this review is to assess the impact of
hypertension and antihypertensive drugs on erectile function.
2. Prevalence of Erectile Dysfunction in
General Population
The existence of multiple data on the epidemiology of
erectile dysfunction has warranted the need for a critical
consideration in hypertensive patients. The impact of erectile
dysfunction on the control of hypertension has generated a
huge concern among the scientific community [12]. Age has
been a strong predictor of sexual dysfunction in both genders
[13]. In the famous Massachusetts Male Aging Study, a
prevalence of 52% was observed with increasing age which
was directly associated erectile dysfunction. At age 40, 40%
of males had sexual dysfunction which increased to 70% at
age 70. Worsening of erectile dysfunction was consistent with
the presence of co-morbid conditions like diabetes mellitus
and dyslipidemia [14].
In Brazil, a study on the prevalence of erectile dysfunction
observed a prevalence of 45.9% among men which worsened
with increasing age [15]. In the Cologne study, the prevalence
of erectile dysfunction was 19% with a sharp increase from
2.3% to 53.4% associated with aging [16]. Age undoubtedly
proves to be a strong risk factor for erectile dysfunction. The
pathogenesis of erectile dysfunction with aging has been
associated with uncoupling of endothelial nitric oxide
synthase (eNOS) from tetrahydrobiopterin (BH
4
) [17].
Angiotensin-II has been found to reduce BH
4
leading to
oxidative stress and erectile dysfunction [17]. The uncoupling
of eNOS from BH
4
diverts the enzymatic action of eNOS from
nitric oxide to superoxide production [18]. A vicious cycle
occurs as superoxide mediates further uncoupling of nitric
oxide (NO) from eNOS.
Arginase is an enzyme which acts on L-arginine and
converts it into urea and ornithine. L-arginine is a substrate for
eNOS and highly essential in the anabolism of nitric oxide
[19]. Nitric oxide synthase competes with arginase for the
substrate L-arginine leading an eventual reduction in nitric
oxide and hence erectile dysfunction [20]. The substrate,
ornithine has been associated with neurovascular diseases
such as atherosclerosis and erectile dysfunction [21]. A trial
where long-term administration of arginase inhibitor
(2-S-amino-6-boronohexanoic acid) improved erectile
dysfunction in aged rats [22].
A Clinical study in patients unresponsive to sildenafil,
found high levels of plasma arginase. Erectile function was
enhanced in patients who received arginase inhibitors
compared to placebo [23]. These findings support the effects
of disturbed enzymatic pathways on erectile dysfunction.
Further studies are required to determine the possibility of
drugs modulating arginase in managing erectile dysfunction in
humans.
3. Prevalence of Sexual Dysfunction
Among Hypertensives
Hypertension is a disorder with high mortality and
morbidity associated with its progression especially if poorly
managed [24]. The issue of erectile dysfunction cannot be
segregated from hypertension which has raised several
concerns most especially in deciphering where the etiology
lies. Regardless of this conundrum, multiple studies have
confirmed the direct link between the pathogenesis of erectile
dysfunction and hypertension. The prevalence of systolic
hypertension linearizes with increasing age [25].
Diastolic blood pressure, however, decreases with
increasing age [26] as compared to systolic blood pressure.
Sexual dysfunction is now considered a sign of systemic
vasculopathy [27].
A retrospective study done on patients without
atherosclerotic disease prior to the manifestation of erectile
dysfunction were sampled. It was realized that a significant
number of patients developed atherosclerotic plaques after the
manifestation of erectile dysfunction [28]. Several published
studies are advocating for erectile dysfunction to be
considered a premonitory sign to adverse cardiovascular
events such as ischemic heart disease, heart failure and sudden
cardiac death [29]. Erectile dysfunction has been found to be
the highest independent risk factor for cardiovascular diseases
[30].
Experimental follow-up studies found out that cavernous
arteries were susceptible to hypertensive vasculopathy
compared to coronary arteries [31]. This explains why erectile
dysfunction predates angina in coronary artery disease and the
need for total cardiovascular evaluation in hypertensive
patients presenting with erectile dysfunction.
The Treatment of Mild Hypertension Study (TOMHS)
reported a prevalence of erectile dysfunction as 12% of study
participants which was quite low. TOMHS was one of the big
pioneer trials to investigate on erectile dysfunction [32]. In
contrast to these findings, an incidental observation was made
at the end of TOMHS where erectile dysfunction among male
hypertensive patients was associated with polytherapy and
increased systolic blood pressure [33]. A study found out that
the presence of vasculogenic erectile dysfunction among
hypertensive men was associated with subclinical
International Journal of Clinical and Experimental Medical Sciences 2017; 2(6): 87-94 89
atherosclerosis, impaired arterial function as well as
endothelial and systemic inflammation [34].
A study done in hypertensive women of 60 to 80 years
found a significant relationship between antihypertensive
medications and the prevalence of sexual dysfunction. The
antihypertensive drugs implicated were enalapril, atenolol or
isradipine [35]. There were no reference control groups to
compare with but this finding galvanized further studies to
start investigating hypertensive women on treatment for
possible sexual dysfunction.
However, a prospective study by Monowar and colleagues
found out that erectile dysfunction among Blacks was (7.9%),
Hispanics (6.3%) and Caucasians (4.7%) had the least
prevalence. In the study, it was realized that age was the only
significant factor that influenced sexual dysfunction among
the various races [36]. This was supported by the Boston Area
Community Health (BACH) study where no significant
relationship was found between race and erectile dysfunction
[37].
4. Pathophysiology of Sexual Dysfunction
Among Hypertensives
Hypertension and its related disorders have an impact on
various end-organs such as kidney, brain as well as the
vasculature. Hypertension causes erectile dysfunction in men
via endothelial dysfunction and subsequently impairing the
function of nitric oxide [21] Experimental studies have
revealed anatomical aberrations within the penile blood
vessels [38]. Longstanding hypertension leads to oxidative
stress, endothelial injury and subsequently arteries, arterioles
and sinusoids of corpus cavernosum fail to relax [39].
Several studies on the effect of hypertension on ED have
found vasculopathy and higher levels of serum inflammatory
mediators to be a implicated [34]. Nitric oxide is the main
vasodilator involved in the erectile pathway mediated by
cyclic-guanosine monophosphate (C-GMP) although
bradykinin’s effect on activation bradykinin type 2 receptors
from current studies has been implicated [35]. The Enos
activity in several experimental studies have been found to
play a crucial role in the erectile pathway. The intact
endothelium responds adequately to NO and hence any
impairment in endothelium will result in minimal or no
response [18]. Angiotensin-II has been recently been
implicated in erectile dysfunction [36]. Angiotensin-II is
found in both plasma and tissues with variable levels of
concentration with corporal cavernosum containing
angiotensin-II of about 200-fold compared to plasma [37-38].
Angiotensin-converting enzyme inhibitors (ACEIs) reduce the
level of angiotensin-II but less efficacious compared to
Angiotensin-II receptor type-I blockers (ARBs) [39].
Chymase is usually up-regulated with long-term use of ACEIs
[40]. Angiotensin-II receptor type-1 blockers halt the
progression of erectile dysfunction [41]. Bradykinin has been
implicated as a vasodilator involved in erection whose levels
increase with the use of ACEIs [42]. The predominant
bradykinin receptor type in the penile tissues and blood
vessels needs to be investigated upon as bradykinin type-II
receptor activation favors erectile function while type-I
activation inhibits erection. ACEIs’ inferiority to ARBs in
improving erectile function might be from the prevalence of
bradykinin-type-1 receptor in penile tissues.
In a pre-clinical study, Chymase to angiotensin converting
enzyme concentration in the penile tissues was found to be
160-fold to 30-fold respectively [43].
5. Antihypertensive Medications and
Erectile Dysfunction
The role of antihypertensive medications in the
management of hypertension and its related disorders cannot
be understated. Antihypertensive medications from different
classes target specific pathways making combination therapy
an essential aspect of management [43 - 44]. Antihypertensive
drugs can affect the central nervous system by reducing libido
and inducing depression while peripherally by reducing
vasodilators and reducing receptor sensitivity [45]. Although
an advantage of combination therapy is to reduce the
incidence of side effects by reducing dosages while
maintaining efficacy. The older generation of drugs in the
classes of beta-blockers, diuretics and centrally acting agents
have been greatly implicated [32] while newer agents have
neutral (ACEIs and calcium channel blockers, CCBs) or
improved effect (ARBS and Nebivolol) on erectile function
[46]. Most of these drugs has side effects which are
unbearable in patients [5]. Antithetical to this, some
antihypertensive drugs are able to improve erectile function by
donating nitric oxide [47] blocking or reducing angiotensin-II
[46] and aiding in alternate pathways mediating erection.
Nitric oxide is found in the chemical structure of some
antihypertensive drugs [48] but only the modified type is
physiologically active.
5.1. Beta-Blockers (BB)
Beta blockers have been implicated in erectile dysfunction
[49] but this effect has been found to be drug-specific other
than class effect [50]. Decreased sympathetic outflow coupled
with depression and loss of libido (reduced level of
testosterone) are implicated in the pathophysiology of erectile
dysfunction among hypertensive individuals on beta-blockers
[49]. A recent survey, where 199 patients were followed-up
after coronary artery bypass graft. These patients were on two
different beta-blockers, nebivolol and metoprolol. An
increased incidence of erectile dysfunction was observed with
metoprolol and nebivolol but a reduced risk was associated
with nebivolol use [47]. The findings in this study were in line
with several studies which clearly implicated erectile
dysfunction among certain drugs in this class (beta-blockers).
A prospective study in 44 patients on beta-blockers who
presented with erectile dysfunction after initiation of
treatment had nebivolol replacing the other beta-blockers.
After 3 months of therapy, 68% had an appreciable
90 Bright Boafo Boamah et al.: A Review on Erectile Dysfunction Among Hypertensive Patients on Pharmacotherapy
improvement of erectile function [51].
On a large cross-sectional study, hypertensive patients who
reported with erectile dysfunction while on beta-blockers
were recruited. Metoprolol and carvedilol were associated
with the highest prevalence of erectile dysfunction, while
atenolol and bisoprolol had a moderate impact on erectile
dysfunction and nebivolol was associated with the lowest
prevalence of erectile dysfunction [52]. The essential
information is drawn from the fact that various beta blockers
have variable effects on erectile function. Nebivolol has a
good profile with less erectile dysfunction which can be
ascribed to the nitric oxide moiety [53].
Beta-blockers (Nebivolol, bisoprolol, atenolol, and
carvedilol) were given for 12 weeks. At the end of the study,
there was a statistically significant wane in the arterial flow
velocities in participants who were on carvedilol, atenolol, and
bisoprolol while nebivolol had no impact on flow velocity
[54]. Nebivolol is the only beta-blocker shown to have a
favorable impact on erectile function [51]. Boydak and
colleagues in a randomized double-blind study assessed the
influence of beta-blockers (nebivolol and atenolol) and a
diuretic (chlorthalidone) on erectile dysfunction. After a
3-month period of follow-up, it was realized that erectile
dysfunction worsened with atenolol use and this select was
exaggerated when chlorthalidone was added. In contrast to
this, nebivolol did not affect sexual function in these study
subjects [55]. Nebivolol is peno-protective effect compared to
other beta-blockers and its choice is appropriate in patients
requiring beta-blockers as well as maintenance of erectile
function.
In contrast to the aforementioned evidence on beta-blockers,
some studies have implicated the knowledge of side effects of
beta-blockers as the primary psychogenic factors mediating
erectile dysfunction in some hypertensive men [56 - 57].
The findings on the psychogenic etiology implies that fear
of side effects can aggravate the erectile dysfunction caused
by the medications.
5.2. Calcium Channel Blockers (CCBs)
CCBs are essential in the management of hypertension and
its role cannot be underemphasized in black populations and
the aged [58]. Some calcium channel blockers have been
implicated in erectile dysfunction [33]. Calcium channel
blockers are known to have a neutral effect on erectile
function although some reports have been made concerning its
association with erectile dysfunction [59]. The occurrence of
erectile dysfunction with calcium channel blockers can be
possibly ascribed to reduced blood flow especially in patients
with atherosclerotic arteries who have a reduced mean arterial
pressure while on CCBs [60]. Further research will be
required in this area to determine the effect of blood pressure
reduction and erectile dysfunction in patients on CCBs. In a
study, patients taking verapamil developed
hyperprolactinemia which was associated with gynecomastia
and erectile dysfunction as a result of reduced testosterone
[61]. In another study, the dihydropyridine and
benzothiazepines were not involved in serum prolactin
increment while verapamil was still implicated [62]. In
another study involving 134 patients on calcium channel
blockers (diltiazem, verapamil, and nifedipine),
angiotensin-converting enzyme inhibitors (lisinopril) and
diuretics (frusemide and hydrochlorothiazide). Diltiazem and
nifedipine were shown to improve erectile function, while
verapamil, frusemide, and lisinopril exhibited neutral effects.
Hydrochlorothiazide use was associated with reduced libido
and poor erectile function [63]. In contrast to this, a prior
pre-clinical study found out that, the use of amlodipine was
associated with a decline in testosterone levels which was
ascribed to increased prolactin secretion and subsequently
leading to reduced libido and erectile function. Amlodipine's
effect on ED was dependent on dose and duration [64]. The
evidence so far on calcium channel blockers is inconclusive
but a possibility of erectile dysfunction might result from
specific agents increasing serum prolactin. Serum prolactin
should be monitored in suspected patients on calcium channel
blockers exhibiting anti-androgenic symptoms. Further
studies are required in this area to elucidate possible hormonal
imbalances with the use of calcium channel blockers.
5.3. Diuretics (Ds)
Diuretics have been the most implicated antihypertensive
drugs causing erectile dysfunction [65]
followed by centrally
acting agents and beta-blockers. Thiazide mediates the
antihypertensive action through a reduction in effective
plasma volume and vasodilation caused by the release of a
nitric oxide moiety in its chemical architecture [66]. In the
Trial of Antihypertensive Interventions and Management
(TAIM) study, erectile function was assessed among patients
taking atenolol, chlorthalidone, and placebo. At the end of the
study, erectile dysfunction was highest among the group on
chlorthalidone (28%), atenolol (11%) and placebo (3%). Of
note, weight reduction among patients who received
chlorthalidone had an improved sexual Function [67].
Chlorthalidone and hydrochlorothiazide were associated with
worsened erectile dysfunction in a study assessing the impact
of diuretic therapy on erectile function [68]. Hormonal
disturbances are common with spironolactone which causes
loss of libido and gynecomastia leading to erectile dysfunction
[69].
5.4. Angiotensin-Converting Enzyme Inhibitors (ACEIs)
Angiotensin-converting enzyme inhibitors (ACEIs) have a
neutral effect on erectile function similar to calcium channel
blockers. With the recent implication of angiotensin-II in
affecting erectile dysfunction negatively, much focus was
placed on ACEIs [70]. ACEIs play a neutral role or enhances
erectile function but inferior to angiotensin-II receptor-type-I
blockers [39] due owing to the fact that alternate enzymes
such as Chymase mediates conversion of angiotensin-I to
angiotensin-II [72].
5.5. Angiotensin Receptor Type-I Blockers (ARBs)
ARBs have an excellent impact on halting progression or
International Journal of Clinical and Experimental Medical Sciences 2017; 2(6): 87-94 91
reversal of erectile dysfunction. Intracavernosal injection of
angiotensin-II led to reduced erectile function and
detumescence in the erected penis but the injection of losartan
had an antithetical effect [73]. In a robust study by Della and
colleagues, valsartan use was associated with an improved
sexual function among 2202 hypertensive individuals
recruited. In several pre-clinical trials, intracavernous
injection of angiotensin-II led to reduced intracavernosal
pressure and prevented erection as well as aborted erection
already in place [74].
Blockade of angiotensin-II with losartan a led to an increase
in intracavernosal pressure and hence erection [75]. Clinical
trials have affirmed the experimental studies where an
improvement with the use of angiotensin receptor blockers
and angiotensin-converting enzyme inhibitors were associated
with an improved erectile function [38].
5.6. Centrally-Acting Agents (CA)
Centrally-acting agents, methyldopa, and clonidine have
been implicated in erectile dysfunction although the latter drug
has been withdrawn due to multiple side effects. Of note, no
new drugs have been recently produced from this class as a
result of the presence of other effective and beneficial
drug-classes. In the era of clonidine prescription, a pre-clinical
study was set out to determine its effects together with other
medications on erectile function. Propranolol and clonidine
were associated with poor sexual performance in males whereas
captopril was without erectile dysfunction [76]. Multiple
studies have shown methyldopa to aggravate or cause erectile
dysfunction in hypertensive males [77], [78]. This class has all
agents entirely involved in erectile dysfunction.
6. Conclusion
Erectile dysfunction is a challenge to both the physician and
the hypertensive patient as the progression of the disease,
aging, co-morbidities, and medications all affect sexual
function or combination of these factors. Erectile dysfunction
is currently being advocated for as a risk factor in
cardiovascular diseases as evidence shows its occurrence prior
to asymptomatic cardiovascular diseases. Spurious
associations linking erectile dysfunction and antihypertensive
medications, or hypertension can be obviated by assessing the
state of erectile function prior to the commencement of
antihypertensive therapy. The natural progression of
hypertension can invariably lead to erectile dysfunction
through endothelial dysfunction or disturbances in
vasodilation. Undoubtedly, multiple studies on
antihypertensive drugs have proven to have an impact on
erectile function by negatively or positively affecting it. The
diuretics and centrally acting drugs are the class-specific drugs
implicated in erectile dysfunction while the other classes
(beta-blockers, angiotensin converting enzyme inhibitors,
angiotensin receptor blockers, calcium channel blockers) are
drug-specific in causing erectile dysfunction. Erectile
dysfunction among patients with hypertension needs to be
critically evaluated by all physicians treating patients with
hypertension and its related disorders.
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