Review

Journal of Cardiovascular
Pharmacology and Therapeutics
Antihypertensive Drugs and Male 2016, Vol. 21(3) 233-244
ª The Author(s) 2015
Reprints and permission:
Sexual Dysfunction: A Review of Adult sagepub.com/journalsPermissions.nav
DOI: 10.1177/1074248415598321
Hypertension Guideline Recommendations cpt.sagepub.com

Khalid A. J. Al Khaja, PhD1, Reginald P. Sequeira, PhD, FCP1,

Alwaleed K. Alkhaja, PhD2, and Awatif H. H. Damanhori, MBBCh, FP3

Abstract
Background: Published clinical practice guidelines have addressed antihypertensive therapy and sexual dysfunction (SD) in many
different ways. Objective: In this systematic review, we evaluated guidelines that address antihypertensive drug-associated SD,
guideline recommendations, and recent guideline trends. Methods: Thirty sets of guidelines for hypertension management in
adults that had been published in the English language since 2000 were reviewed. The primary outcome measure was
antihypertensive-associated SD potential, which was independently evaluated using specific questions by 2 authors in a nonblinded
standardized manner. Results: Sexual dysfunctions associated with thiazide-class diuretics, b-blockers, and centrally acting
sympathoplegics were addressed by half of the guidelines reviewed. There is no clarity on b-blockers and thiazide-class diuretics
because one-third of the guidelines are vague about individual b-blockers and diuretics, and there is no statement on third-
generation b-blockers and thiazide-like diuretics that can improve erectile function. The revised guidelines never use terms
such as loss of libido, ejaculatory dysfunction, lack of orgasm, and priapism. Summary versions of guidelines are inadequate to
reflect the key interpretation of the primary guidelines on SD associated with antihypertensives, even in the major guidelines that
were updated recently. Therapeutic issues such as exploring SD in clinical history, assessing SD prior to and during treatment with
antihypertensives, substituting the offending agents with alternatives that possess a better safety profile, intervening with
phosphodiesterase-5 inhibitors, and avoiding the concomitant use of nitrovasodilators are superficially addressed by most
guidelines, with the exception of 2013 European Society of Hypertension/European Society of Cardiology and Seventh Joint
National Committee recommendations. Conclusion: Future guideline revisions, including both full and summary reports, should
provide a balanced perspective on antihypertensive-related SD issues to improve the impact of hypertension treatment guidelines
on patient care and quality of life.

Keywords
hypertension, guidelines, antihypertensive drugs, sexual dysfunctions, treatment, revisions, adult male

Introduction is higher in hypertensive men than in normotensives6-10 and

Cardiovascular disease is the leading cause of death, and pub-
lic health efforts to improve lifestyles and risk factors can
contribute to cardiovascular disease prevention.1 Despite the
significant progress made in improving drug therapies for
hypertension and the promulgation of treatment guidelines
over the past 2 decades, only a small proportion of patients
with documented hypertension have had their condition con-
trolled to target levels. Moreover, the complex interrelation-
ship among hypertension, erectile dysfunction (ED), and
antihypertensive drug therapy has become better understood
in recent years. Erectile dysfunction has a high prevalence
in individuals with multiple cardiovascular risk factors and
patients with cardiovascular diseases.2-4 Hypertension is con-
sidered one of the most hazardous risk factors and is a fre-
quent comorbidity in men with ED.5 The prevalence of ED
is exacerbated by many older antihypertensive drugs.10-12 The
deterioration of sexual function due to antihypertensive drug
therapy can contribute to a poor quality of life (QOL) and,
consequently, noncompliance with the therapy.5,13-16
1
Department of Pharmacology & Therapeutics, College of Medicine & Medical
Sciences, Arabian Gulf University, Manama, Kingdom of Bahrain
2
Qatar Foundation, Doha, Qatar
3
Primary Care, Ministry of Health, Manama, Kingdom of Bahrain
Manuscript submitted: January 15, 2015; accepted: June 21, 2015.
Corresponding Author:
Khalid A. J. Al Khaja, Department of Pharmacology & Therapeutics, Arabian
Gulf University, PO Box 22979, Kingdom of Bahrain.
Email: khlidj@agu.edu.bh
234
Most of the recently revised guidelines for managing hyper-
tension in adults, both comprehensive and abridged versions,
do not satisfactorily address the complexity of hypertension
and sexual dysfunction (SD).17-21 Only a minority of clinical
practice guidelines stress the importance of ED or other
sexual-related issues either as adverse outcomes or as factors
to be considered when making treatment decisions.22
The purpose of this systematic review is to critically evalu-
ate how comprehensively ED associated with antihypertensive
drug therapy is addressed by various national and international
guidelines that were developed for managing arterial hyperten-
sion in adults, with reference to (1) recognizing antihyperten-
sive drug-associated SD; (2) the potential differences in the
guideline recommendations that were presented as complete
or summary versions of international reports; and (3) compar-
isons between the guideline recommendations published at the
end of the second millennium and those developed at the begin-
ning of the third millennium.
Methods
The general methodology (literature search, inclusion/exclu-
sion criteria, outcome measures, validity assessment, and defi-
nitions) used in this review has been described previously.22,23
Literature Search
National and international guidelines for hypertension manage-
ment were identified by searching for the following PubMed
Medical Subject Heading terms: ‘‘guidelines’’ and ‘‘hyperten-
sion.’’ The World Wide Web via Google search engine and
other effective search approaches were used with the following
title: Guidelines on management of hypertension followed by
name of countries (eg, Bahrain and Taiwan) or organizations
(eg, National Institute for Health and Clinical Excellence
[NICE], European Society of Hypertension [ESH], and
National Heart, Lung, and Blood Institute [NHLBI]). The
search was limited to studies that were published from Janu-
ary 2000 through January 2014. Based on the contact details
retrieved from the International Society of Hypertension
(ISH) Web site, e-mails were sent to several ISH-affiliated
societies of Middle East, South East Asia, and Africa and
requested these societies to provide the Web sites of their
national guidelines for the management of arterial hyperten-
sion in adults, if available, in English.
Inclusion and Exclusion Criteria
Guidelines written in English and published from 2000 onward
were included. However, guidelines written in languages other
than English and those published prior to 2000 were excluded.
Outcome Measures
The primary outcome measures were the potential antihyper-
tensives associated with SD. The guidelines were evaluated
with research questions adapted from Karavitakis et al.22
Journal of Cardiovascular Pharmacology and Therapeutics 21(3)
1. Does the guideline recognize the importance of SD as a
component of patients’ clinical history?
2. Does the guideline emphasize assessing sexual function
prior to initiating or during treatment with antihyperten-
sive drugs?
3. Does the guideline specify antihypertensive drugs with
potential sexual adverse effects?
4. Does the guideline recommend that antihypertensive
therapy in sexually active males be initiated with those
drugs that are unlikely to affect sexual function (if the
indication of the unlikely antihypertensive(s) associated
with SD is/are not compelling) and to substitute the
offending agent(s) with one(s) that possess a better
safety profile?
5. Does the guideline recommend intervention with
phosphodiesterase-5 (PDE-5) inhibitors for antihyperten-
sive-induced SD?
6. Does the guideline specify that the use of PDE-5 inhibi-
tors is contraindicated in patients with hypertension hav-
ing ischemic heart disease who are on nitrovasodilators?
7. Does the guideline recommend screening and treatment
of hypertensive men with ED for low testosterone
levels?
Validity Assessment
Assessment of outcome measures was independently carried
out by the first 2 authors of this review in a nonblinded standar-
dized manner. Any discrepancy between the reviewers was
resolved by the fourth author based on consensus.
Operational Definitions
In the tables, the guidelines’ recommendations pertaining to the
adverse effects of antihypertensives on sexual function in male
patients are identified as (þ) if they are available or addressed
and as () if they are not available or not addressed. A superfi-
cially addressed guideline (SAG) means that data pertaining to
hypertension- and antihypertensive-related ED were primarily
derived from tables that list compelling and possible indications,
contraindications, and cautions for major classes of antihyper-
tensive drugs. A comprehensively addressed guideline (CAG)
means that hypertension and antihypertensive-induced SD as a
category has been explicitly addressed as one of the various
headings under hypertension in special patient groups.
Results
A total of 30 national and international guidelines fulfilled
the inclusion criteria used in this review for outcome measures,
as summarized in Table 1. The recommendations related to
the antihypertensive-associated SD (thiazide-class diuretics,
b-blockers, and centrally acting sympathoplegics) were not
addressed in 46.7% (14 of 30), superficially addressed in
43.3% (13 of 30), and comprehensively addressed in 10%
(3 of 30) of the reviewed guidelines. Thiazide-class diuretics
 Table 1. Antihypertensives With Predictable Sexual Dysfunction Addressed by National and International Guidelines.
Predictable Antihypertensives
Associated With Sexual Dysfunction
Guidelines’
Organizations Acronym Presentation Year Ref # Diuretics b-Blockers CASDs

Africa
24
Egyptian Hypertension Society EHS SAG 2004 þa,I þa,I,NS þa,b,I
25
Southern African Hypertension Society SAHS NA 2011   
Asia
26
Gulf Heart Association GHA NA 2010   
27
Ministry of Health, Bahrain MOH, Bahrain SAG 2008 þc,I þc,I,NS 
28
Ministry of Health, Malaysia MOH, Malaysia SAG 2008 þa,ED þa,ED,NS 
29
Ministry of Health, Singapore MOH, Singapore NA 2005   
30
Saudi Hypertension Management Society SHMS SAG 2011 þd  
31
Taiwan Society of Cardiology TSC NA 2010   
32
The Korean Society of Circulation KSC NA 2006   
33
The Task Force on Conceptual and Preventive Protocols (Hong Kong) TFCPP-HK NA 2010   
Australia
34
Heart Foundation HF SAG 2008 þc,ED þc,ED,NS 
Caribbean and Latin America
35
Latin America Society of Hypertension LASH NA 2009   
36
Pan America Health Organization/Caribbean Health Research Council PAHO/CHRC SAG 2007 þd  þa,e,I
Europe
37
British Hypertension Society BHS SAG 2004 þa,ED þa,ED,NS 
15
European Society of Hypertension-reappraisal ESH CAG 2009 þa,ED þa,ED,f þa,g,ED
16 g,h,SD
European Society of Hypertension/European Society of Cardiology ESH/ESC CAG 2013 þh,SD þh,SD,f þ
18
National Institute of Health and Clinical Excellence (United Kingdom) NICE NA 2011   
19
Scottish Intercollegiate Guidelines Network SIGN NA 2007   
International
38
American Society of Hypertension/International Society of Hypertension ASH/ISH SAG 2014  þa,SD,NS 
20
World Health Organization/International Society of Hypertension WHO/ISH NA 2003   
39
World Health Organization WHO SAG 2007 þi,I þi,I,NS þg,i,SD
North America
40
American Association of Clinical Endocrinologist Hypertension Task Force AACE SAG 2006  þa,ED,j 
41
American College of Cardiology Foundation/American Heart Association ACCF/AHA SAG 2011 þk,SD þa,SD,f 
21
Canadian Cardiovascular Society CCS NA 2011   
42
Dept of Veterans Administration/Dept of Defense (United States) DVA/DoD NA 2004   
43 c,ED,NS
Institute of Clinical Systems Improvement (United States) ICSI SAG 2010 þc,ED þ 
44
International Society on Hypertension in Blacks ISHIB NA 2010   
45
National Heart, Lung, Blood Institute (United States) NHLBI CAG 2003 þa,SD þa,ED,NS þa,g,ED
46
National Heart, Lung, Blood Institute (United States) NHLBI NA 2014   
47
Registered Nurses Association of Ontario RNAO SAG 2005 þa,ED þa,ED,j 

Abbreviations: CAG, comprehensively addressed guideline; CASDs, centrally acting sympathoplegic drugs; NA, not addressed; SAG, superficially addressed guideline; þ, data are available; , no data are
available; ED, erectile dysfunction; I, impotence; NS, not specified; SD, sexual dysfunction; S, specified.
a
Side effect/adverse effect.
b
Clonidine þ methyldopa.
c
Potential adverse effect.
d
Possible contraindication in sexually active males.
e
Methyldopa.
f
More prominent with old generations and not with new one such as nebivolol.
g
Nonspecified drug.
h
Adverse effects were more prominent with old antihypertensive drugs, however in 2009 Guidelines15 old antihypertensives were defined as diuretics, b-blockers, and centrally acting drugs.
i
Major adverse effects.
j
Old generations of b-blockers.

235
k
Spironolactone.
236 Journal of Cardiovascular Pharmacology and Therapeutics 21(3)

Table 2. Antihypertensive-Induced Sexual Dysfunction as Presented by Full and Summary Reports.

Antihypertensive-Induced
Sexual Dysfunction
Organizations Guidelines
(Publication Year) Guideline format (Reference No.) Presentation No. of Pages Diuretics b-Blockers CASDs
37 a,ED a,ED,NS
BHS-IV (2004) Full Report SAG 46 þ þ 
Summary Version48 NA 7   
HF (2008) Full Report34 SAG 38 þb,ED þb,ED,NS 
Quick Reference Guide49 NA 18   
NHLBI (2003) Full Report, 200345 CAG 48 þa,SD þa,ED,NS þa,c,ED
JNC-7 Express, 200350 NA 12   
WHO (2007) Full Report39 SAG 92 þd,I þd,I,NS þc,d,SD
Pocket Guidelines51 NA 20   
Abbreviations: CAG, comprehensively addressed guideline; CASDs, centrally acting sympathoplegic drugs; NA, not addressed; SAG, superficially addressed
guideline; þ, data are available; , no data are available; ED, erectile dysfunction; I, impotence; NS, not specified; SD, sexual dysfunction; BHS-IV, 2004 Fourth
Working Party of British Hypertension Society; HF, Heart Foundation; NHLBI, National Heart, Lung, Blood Institute; WHO, World Health Organization.
a
Side effect/adverse effect.
b
Potential adverse effect.
c
Nonspecified drug.
d
Major adverse effects.

Table 3. Comparison Between Old and Updated Full Guideline Reports.

Predictable Antihypertensive-Induced Sexual Dysfunction

Organizations Publication Guideline
(Reference #) Year Presentation Diuretics b-Blockers CASDs

BHS-III52 1999 NA   
BHS-IV37 2004 SAG þa,ED þa,ED,NS 
NHLBI-VI53 1997 NA   
NHLBI-VII45 2003 CAG þa,SD þa,ED,NS þa,b,ED
WHO/ISH54 1999 SAG þa,I  
WHO/ISH20 2003 NA   
Abbreviations: CAG, comprehensively addressed guideline; CASDs, centrally acting sympathoplegic drugs; NA, not addressed; SAG, superficially addressed
guideline; þ, data are available; , no data are available; ED, erectile dysfunction; I, impotence; NS, not specified; SD, sexual dysfunction; BHS, Working Party of
British Hypertension Society; NHLBI, National Heart, Lung, Blood Institute; WHO, World Health Organization; ISH, International Society of Hypertension.
a
Side effect/adverse effect.
b
Nonspecified drug.

and b-blockers were identified as offending agents in 46.7% of
the guidelines (14 of 30) each, whereas centrally acting sym-
pathoplegics were identified in 20% (6 of 30). Sexual dysfunction
induced by antihypertensives was recognized as an adverse effect,
a major adverse effect and as a possible or absolute contraindica-
tion. Individual members of b-blockers and centrally acting
agents that are associated with SD were not specified in 30% (9
of 30) and 13.3% (4 of 30) of the guidelines, respectively.
The differences between the primary full reports and sec-
ondary summary publications pertaining to antihypertensive-
related SD (either as a potential adverse effect or as a major
adverse effect) are shown in Table 2. The issue of SD (as a
potential adverse effect) has been overlooked completely in
summary or quick reference guide compared with primary full
report publications. This clinical issue has been inconsistently
recognized by guidelines and recommendations that were
updated in the third millennium compared with those pub-
lished at the end of second millennium. It was only superfi-
cially updated by the 2004 Fourth Working Party of British
Hypertension Society (BHS-IV), fully ignored by 2003 World
Health Organization (WHO)/ISH, and comprehensively
addressed by the 2003 Seventh Joint National Committee
(JNC-7; Table 3).
In this review, the guidelines were evaluated based on 7
author-specified research questions. The rate of addressing
these questions by practice guidelines was as follows: 30%
(9 of 30) considered SD to be a component of a patient’s
clinical history; 10% (3 of 30) emphasized the assessment
of SD prior to initiating or during treatment with antihyperten-
sive drugs; 53.3% (16 of 30) specified antihypertensives with
potential SD; 10% (3 of 30) recommended the importance of
initiating treatment with an antihypertensive that is unlikely
to cause SD (if the antihypertensive indication is not compel-
ling) or substituting the offending agent with better alternatives;
10% (3 of 30) recommended an intervention with PDE-5 inhi-
bitors to treat SD due to antihypertensive medications; 6.7%
(2 of 30) specified that the use of PDE-5 inhibitors with vaso-
dilators is contraindicated; and finally, none of these guidelines
Al Khaja et al 237

Table 4. Guideline Profile in Terms of Research Questions.a

Research Questions

Organizationsb Year Ref # Q1 Q2 Q3 Q4 Q5 Q6 Q7

Africa
24
EHS 2004 þ  þ    
25
SAHS 2011       
Asia
26
GHA 2010       
27
MOH, Bahrain 2008 þ  þ    
28
MOH, Malaysia 2008   þ    
29
MOH, Singapore 2005       
30
SHMS 2011   þ    
31
TSC 2010       
32
KSC 2006       
33
TFCPP-HK 2010       
Australia
34
HF 2008 þ  þ    
Caribbean and Latin America
35
LASH 2009       
36
PAHO/CHRC 2006   þ    
Europe
37
BHS 2004   þ    
15
ESH 2009 þc þ þ þ þ  
16
ESH/ESC 2013 þ þ þ þ þ þ 
18
NICE 2011       
19
SIGN 2007       
International
38
ASH/ISH 2014   þ    
20
WHO/ISH 2003       
39
WHO 2007 þ  þ    
North America
40
AACE 2006   þ    
41
ACCF/AHA 2011   þ    
21
CCS 2011       
42
DVA/DoD 2004 þ      
43
ICSI 2010   þ    
44
ISHIB 2010 þ      
45
NHLBI 2004 þc þ þ þ þ þ 
46
NHLBI 2014       
47
RNAO 2005   þ    
Rate of addressing each research questions, % 30 10 53.3 10 10 6.7 0
Abbreviations: þ, data are available; , no data are available.
a
Q1, Does the guideline recognize the importance of sexual dysfunction as a component of patients’ clinical history? Q2, Does the guideline emphasize on
assessment of sexual function prior to initiating or during any antihypertensive drug treatment? Q3, Does the guideline specify antihypertensive drugs with
predictable sexual adverse effects? Q4, Does the guideline recommend when commencing antihypertensive therapy in sexually active males to initiate erectile
dysfunction-free agent(s) (if the indication of unlikely antihypertensive is not compelling)? and to substitute the offending agent(s) with one(s) that possess a better
safety profile? Q5, Does the guideline recommend a special drug management as administration of phosphodiesterase-5-inhibitors in case of antihypertensive-
induced sexual dysfunction? Q6, Does the guideline contraindicate the use of phosphodiesterase-5-inhibitors in patients with hypertension having ischemic heart
disease receiving nitrates? Q7, Does the guideline recommend screening and treatment men with ED for low testosterone levels?
b
See Table 1 for details of organizations’ acronym.
c
Was not absolutely specified under clinical ‘‘medical’’ history.

recommended screening and treatment of hypertensive men
with ED for low testosterone levels (Table 4).
Discussion
Thiazide-class diuretics are one of the most widely used
class of antihypertensives. They are used both as fixed-dose
formulations and as individual agents in complementary
combination therapy and can be further classified into
thiazide-type diuretics (ie, hydrochlorothiazide) and thiazide-
like diuretics (ie, chlorthalidone and indapamide). Some of
thiazide-class diuretics have been reported to be associated with
potentially detrimental adverse effects on male sexual func-
tion.10-12,16,55-59 Nonetheless, SD induced by this class of anti-
hypertensives has not been addressed by several clinical
practice guidelines,18-21,25,26,29,31-33,35,38,42,44,46 either as an
238
adverse effect or as a factor to be considered by physicians
when prescribing antihypertensive agents. However, ED and
SD were deemed to be potential adverse effects,27,34,43 defi-
nite side effects,15,16,24,28,37,45,47 and major adverse effects39
on male sexual function by some sets of guidelines. Some
treatment guidelines such as Saudi Hypertension Manage-
ment Society30 and Pan America Health Organization36 con-
sidered thiazide-class diuretics to be possibly or absolutely
contraindicated in sexually active hypertensive males, respec-
tively. Of note, the term ‘‘thiazide-class diuretics’’60 has
never been used by any of the guidelines reviewed. Instead,
the term ‘‘thiazide diuretics’’ has been commonly used by
most guidelines,27,30,34,36,43,45,47 whereas thiazide and
thiazide-like diuretics have been used in other guidelines.24,28,37
Diuretics, as a generic term, has been used by the ESH.15 We sug-
gest that an explicit categorical term such as thiazide-class diure-
tics60 be used in future guideline revisions to avoid ambiguity.
It has been reported that thiazide-like diuretics, such as
indapamide, decrease the risk of worsening of sexual function
by lowering blood pressure in men61 and that switching to
indapamide-based therapy improves SD due to other antihyper-
tensives.62,63 Indapamide is rarely associated with an adverse
effect on male sexual function,61-64 and indapamide-related
SD has been addressed only by the Registered Nurses Associ-
ation of Ontario (RNAO).47
Although b-blockers are one of the most widely used antihy-
pertensive classes of drugs for the prevention and treatment
of cardiovascular diseases, the use of some first-generation
b-blockers has occasionally been associated with SD in
males.59 b-Blockers are distinguished based on several proper-
ties, such as their relative affinity to b1 and b2 receptors, differ-
ence in lipid solubility, capacity to induce vasodilatation, and
pharmacodynamic and pharmacokinetic parameters.65 Some
of these characteristics are clinically relevant for selecting the
appropriate b-blocker for individual patients with hyperten-
sion.65 Propranolol, a first-generation nonsubtype selective
b-blocker, has the potential to impair sexual function in males;
this adverse effect appears to be dose related and often occurs
at doses in excess of 120 mg/d.66,67 Second-generation
b1-selective blockers such as atenolol have less of a tendency
to produce ED than do nonsubtype selective b-blockers.68,69
However, b1-selectivity is dose related66,67 and tends to dimin-
ish at higher drug concentration69,70; thus, the incidence of SD
may rise.69 Nebivolol, a third-generation b1-blocker, has the
highest cardioselectivity of any of the currently available
b-blockers.71 Additionally, nebivolol produces an endothelium-
derived nitric oxide-dependent vasodilatation that results in the
reduction of systemic vascular resistance and facilitates penile
erection. Hence, nebivolol may offer the additional benefit of pre-
cluding ED in male patients with hypertension.72-74 Of note, the
Hawthorne effect of ED with b-blockers should also be consid-
ered; knowledge and prejudice about ED as a side effect of
b-blockers can produce anxiety, which may adversely influence
erectile function in hypertensive men.75 Because the etiology of
the ED is largely psychological, it is not surprising that placebo
is as effective as PDE-5 inhibitors in reversing this side effect.75,76
Journal of Cardiovascular Pharmacology and Therapeutics 21(3)
Of the 30 reviewed national and international guidelines,
46.7% (14 of 30) focused on the potential implications of
b-blockers on impairing male sexual function (Table 1).
b-Blocker-associated SD has been deemed as a potential adverse
effect by some of these guidelines27,34,43 as either a major side
effect39 or a definite adverse effect.15,16,24,28,37,38,40,41,45,47 Indi-
vidual b-blockers were not specified by approximately 30%
(9 of 30) of guidelines,24,27,28,34,37-39,43,45 though they were
specified by a mere 16.7% (5 of 30) of the treatment guide-
lines.15,16,40,41,47 The ESH guidelines state that ‘‘older b-blockers
exert negative effects on ED, whereas newer drugs such as nebi-
volol have neutral or beneficial effects.’’15(p2146) The SD as an
adverse effect of b-blockers was more commonly associated
with other b-blockers.16 Moreover, atenolol-related ED, based
on the outcomes of United Kingdom Prospective Diabetic
Study,77 has been addressed as a prototype for b-blockers by the
American Association of Clinical Endocrinologists.40 The
American College of Cardiology Foundation/American Heart
Association41 state that ‘‘older b-blockers have been associated
with depression, SD, dyslipidemia, and glucose intolerance, and
these side effects are less severe or unlikely with newer agents.’’
The RNAO47(p2439) precisely specified that first-generation
nonsubtype-selective b-blockers (nadolol, pindolol, proprano-
lol, and timolol), second-generation selective b1-blockers
(acebutolol, atenolol, bisoprolol, and metoprolol), and third-
generation labetalol are all associated with ED.
The relation between centrally acting sympathoplegic drugs,
such as a-methyldopa and clonidine, and the incidence of SD
has been noted by only 20% (6 of 30) of the reviewed guide-
lines.15,16,24,36,39,45 The plausible explanation for paying less
attention to these antihypertensive agents may be attributed
to several reasons: (1) a-methyldopa is reserved as the drug
of choice for nonsevere hypertension in pregnancy25,35-37,45;
(2) a-methyldopa is no longer recommended for the treatment
of uncomplicated hypertension and has been superseded by
newer antihypertensive classes; and (3) in addition to SD, cen-
trally acting antihypertensives are associated with numerous
unpleasant adverse effects.48,54
Clinical practice guidelines are systematically developed
statements that assist clinicians, consumers, and policy makers
in making appropriate health-related decisions. Potential guide-
line deficits and the need for guideline appraisal tools have been
proposed by Siering et al.78 To reach the widest possible audi-
ence, these guidelines are developed as primary ‘‘full reports’’
and as ‘‘secondary summary’’ publications in a prearranged pro-
cess that is accepted by both authors and the editors of journals.79
A full report is deemed as an evidence-based approach that pro-
vides a broader and more detailed review of recommendations
and is based on observational studies and major clinical
trials.18,45 However, secondary publications such as the sum-
mary version,48 quick reference guide,49 express report,50 and
pocket guide51 are abridged versions that are intended to provide
recommendations for busy primary care physicians and should
be used for educational purposes. Secondary publications are
considered justifiable if their contents are sufficiently abbre-
viated and faithfully reflect the data and interpretation of the
Al Khaja et al
primary version.79 As a recommendation, SD associated with
hypertension per se and the use of antihypertensive medications
have been completely excluded from the summary versions of
several full report guidelines48-51 (Table 2). The omission of
such pivotal recommendations may lead to undesired conse-
quences: (1) inappropriate attention to SD as an adverse effect
may result in a negative impact on patients’ QOL, compliance
with drug therapy and discontinuation of the antihypertensive
medications58,66; (2) an inadvertent departure from the
evidence-based approach recommended by full report clinical
guidelines; and (3) confusion and misleading of practicing phy-
sicians and researchers.79 For instance, Viigimaa and his col-
leagues3 (the ESH Working Group on SD) inadvertently cited
the JNC-7 full report that comprehensively addressed the SD
issue instead of the JNC-7 Express Report as a reference for
guidelines that ignore or superficially address the important
association between cardiovascular risk factors and SD. We
opine that despite their usefulness, guideline summary versions
should faithfully reflect the data and interpretations of the
primary full report versions. We suggest that the issue of
antihypertensive-related SD should be prudently addressed and
appropriately considered in future guideline revisions.
Some of the widespread guideline recommendations devel-
oped at the end of the second millennium52-54 were compared
with those updated at the third millennium20,37,45 to identify the
scope of the changes and updates that have occurred in pub-
lished clinical guidelines on antihypertensive-associated SD
(Table 3). From this perspective, the importance of iatrogenic
SD due to antihypertensives has been rather superficially
updated by the report of the BHS-IV37 compared with BHS-
III.52 This issue has been completely overlooked by WHO/ISH
updated clinical practice guidelines.20 However, the recognition
of antihypertensive-induced SD and its management in patients
with hypertension has been comprehensively addressed by the
updated complete report of the JNC-7—NHLBI45 (Tables 3 and
4). Our observations suggest that antihypertensive-related SD is
inconsistently recognized by clinical practice guidelines that
were developed for managing primary hypertension in adults,
even among those that were published more recently. We
believe that this clinical issue is an area that needs further atten-
tion to improve the quality and impact of the guidelines and, ulti-
mately, patient care and QOL.
Of note, an association has been documented between
arterial hypertension and SD5,12,80 and other cardiovascular
risk factors.2-4,80,81 Recently, the revised appraisal of Eur-
opean guidelines on hypertension management stressed that
ED is a prevalent condition in patients with hypertension and
is a predictor of future cardiovascular diseases; the screening
and treatment of ED, therefore, improve the management of
cardiovascular risk factors.15 Thus, SD should be explored
while taking the clinical history from patients with arterial
hypertension. Such an approach has been recommended by
30% (9 of 30) of the treatment guidelines15,16,24,27,34,39,42,44,45
(Table 4). Nonetheless, SD has not been explicitly specified
under patients’ clinical history by ESH15 or NHLBI.45 The ESH
is implicit that screening and treatment of ED improve the
239
management of cardiovascular risk factors, whereas NHLBI
recommends that a clinician be willing to discuss SD problems.
Although SD is frequently encountered in patients with cardio-
vascular diseases82 and in cardiology practice, there may be an
overall lack of attention to exploring sexual problems (Table 4).
It should be noted that sexual function in male patients with
hypertension may be impaired by hypertension per se5,12 and
by the use of some older antihypertensives as a drug-related
side effect.10-12 The practicing physicians should therefore
carefully explore and assess the sexual sequelae in patients
with hypertension. The typical initial evaluation of a man com-
plaining of ED is conducted in person and includes sexual,
medical, and psychosocial histories as well as laboratory tests
that are sufficiently thorough to identify comorbid conditions
that may predispose the patient to ED or contraindicate certain
drug therapies. History may reveal causes or comorbidities
such as cardiovascular disease (including hypertension, athero-
sclerosis, or dyslipidemia), diabetes mellitus, depression, and
alcoholism.83 Emphasis on the assessment of sexual function
prior to initiating or during antihypertensive drug treatment has
been stressed only by ESH,15 ESH/European Society of Cardi-
ology [ESC]16 and NHLBI,45 which represent a mere 10% (3 of
30) of all national and international guidelines.
Antihypertensive drug regimens should be tailored to the
age and gender of individual patients and should consider SD
as a potential adverse effect.16,66 Such a therapeutic strategy
is necessary to achieve the objectives of treatment of hyperten-
sion: ensuring good compliance and QOL, achieving optimal
control of blood pressure, and reducing the risk of cardiovascu-
lar events.66 It is extremely important to take a complete drug
history, particularly with regard to antihypertensives and other
offending medications. Antihypertensive drugs, such as diure-
tics, first- and second-generation b-blockers, and centrally act-
ing drugs can be discontinued or switched (if the indication is
not compelling) to alternatives with a better sexual safety pro-
file, such as angiotensin-converting enzyme inhibitors, angioten-
sin II receptor blockers, and calcium channel blockers.59 Despite
its importance, such a recommendation has been stressed by only
NHBLI,45(p1236) which states ‘‘if SD appears after institution of
antihypertensive drug therapy, the offending agent should be dis-
continued and treatment restored with another agent.’’
Sexual dysfunctions associated with antihypertensives
(diuretics or b-blockers or centrally acting medications) have
been addressed by approximately half (16 of 30) of the revised
guidelines15,16,24,27,28,30,34,36-41,43,45,47 (Tables 1 and 4). Over-
all, 10% (3 of 30) and 43.3% (13 of 30) of the guidelines have
presented data pertaining to antihypertensive-related SD in
CAG and SAG, respectively (Table 1). Male SD refers to a
problem during any phase of the sexual response cycle that pre-
vents achieving satisfaction from sexual activity. The most
common problems related to male SD include ED (impotence),
loss of libido (loss of sexual interest or desire), ejaculatory dys-
function, and priapism. Other than ED, none of the above-
mentioned terms have been stated in the revised guidelines.
It is well known that SD compromises the QOL of both
the patient and the partner. Management of ED thus not only
240
improves QOL but also substantially enhances adherence
to antihypertensive drug therapy.3,4 Oral PDE-5 inhibitors are
generally effective and safe as a first-line treatment of patients
with hypertension having SD, unless contraindicated.12,83
In addition to the potential blood pressure lowering effect,
which does not appear to be a major problem,12,84 PDE-5 inhi-
bitors improve patients’ adherence to antihypertensive drug
therapy3,4,85 and allow the implementation of antihypertensive
add-on approach to the existing antihypertensive therapy.12,86
It should be noted that PDE-5 inhibitors are absolutely contra-
indicated in patients on short- and long-acting nitrovasodilators
because of an unpredictable synergistic decline in blood pres-
sure.3,4,12 In patients with hypertension having lower urinary
tract symptoms, a-blocker and PDE-5 inhibitor therapy should
be cautiously used, and the lowest effective dose of these
medications should be considered.83,87 The role of PDE-5
inhibitors in ameliorating SD induced by either hypertension
or certain antihypertensive drugs has been emphasized by the
ESH,15 ESH/ESC,16 and NHLBI45 guidelines. However, the
life-threatening symptomatic hypotension in some patients
that results from the concurrent use of PDE-5 inhibitors and
nitrovasodilators has been addressed only by ESH/ESC16 and
NHLBI.45 According to the ESH/ESC guidelines, PDE-5 inhi-
bitors may be safely administered to hypertensive, even to
those who are on multiple drug regimens (with the possible
exception of a-blockers and nitrovasodilators). The NHLBI
declared that sildenafil or other PDE-5 inhibitors may be pre-
scribed, without a significant likelihood of adverse reactions,
to those with concomitant antihypertensive therapy, provided
that nitrovasodilators are avoided.
Low testosterone levels may contribute to ED88 and are
prevalent in men with hypertension,89-91 diabetes mellitus,92
and metabolic syndrome.93 Men with ED should, therefore, be
screened for testosterone because hypotestosteronemia-related
dysfunction can be improved by exogenous testosterone ther-
apy.94-96 It is evident that none of the revised guidelines have
recommended the importance of testosterone screening and sup-
plementation in hypogonadal men with hypertension (Table 4).
The combination of testosterone therapy, unless contraindicated,
with PDE-5 inhibitors may be beneficial for treating ED in men
with a low level of total testosterone (<8 nmol/L) or in those with
borderline levels (8-12 nmol/L), who did not adequately respond
to prior treatment with PDE-5 inhibitors alone.94-97
A strong link between ED and endothelial dysfunction has
been postulated.98-100 Moreover, there is an emerging body
of evidence that endothelial dysfunction due to gene poly-
morphisms may be linked with hypertension. A recent study
has identified a single-nucleotide polymorphism of the human
calcium/calmodulin-dependent protein kinase type 4 gene,
which plays a role in blood pressure regulation by controlling
endothelial nitric oxide synthase activity.101 Given the wide
array of G-protein-coupled receptors (GPCRs), it is reasonable
to speculate that gene polymorphism related to GPCRs may
play a critical role in regulating vascular smooth muscle func-
tion.102 In view of these findings, it is imperative that the
choice of antihypertensive drug should also consider the
Journal of Cardiovascular Pharmacology and Therapeutics 21(3)
pivotal role of endothelial function as an important target.
There is also a need to understand whether gene polymorph-
isms determine the susceptibility of patients to the adverse
effects of antihypertensive medications, which may result in
ED.
Conclusion
In this systematic review, there may be a discrimination bias
because only English-language guidelines were included in the
analysis. Notwithstanding this limitation, hypertension treat-
ment guidelines have placed less emphasis on the issue of anti-
hypertensive drug-associated SD. Most of the national or
international guidelines are less explicit concerning preexisting
or treatment-induced SD in patients with hypertension, with the
exception of the 2003 NHLBI, 2009 ESH and the more recently
revised 2013 ESH/ESC guidelines. The future guideline revi-
sions, including both full and summary report versions, should
provide a balanced perspective on antihypertensive-related SD
issues to improve the QOL of patients with hypertension, bear-
ing in mind that QOL is a more serious issue than hypertension
for many men during midlife.
Acknowledgments
We acknowledge the assistance given to us by Ina D’Souza in prepar-
ing this manuscript.
Authors’ Contribution
K. A. J. Al Khaja contributed to conception and design; acquisition,
analysis, and interpretation; drafted the manuscript; critically revised
the manuscript; gave final approval; and agrees to be accountable for
all aspects of work ensuring integrity and accuracy. R. P. Sequeira, A.
K. Alkhaja contributed to acquisition, analysis, and interpretation; cri-
tically revised the manuscript; gave final approval; and agree to be
accountable for all aspects of work ensuring integrity and accuracy.
A. H. H. Damanhori contributed to analysis and interpretation, criti-
cally revised the manuscript, gave final approval, and agrees to be
accountable for all aspects of work ensuring integrity and accuracy.
Authors’ Note
This article has not been submitted or presented elsewhere. In prepar-
ing this manuscript, the authors have not received financial support
from any drug companies or organizations.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to
the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, author-
ship, and/or publication of this article.
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