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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


is exacerbated by many older antihypertensive drugs.10-12 The
Cardiovascular disease is the leading cause of death, and pub-
deterioration of sexual function due to antihypertensive drug
lic health efforts to improve lifestyles and risk factors can
therapy can contribute to a poor quality of life (QOL) and,
contribute to cardiovascular disease prevention.1 Despite the
consequently, noncompliance with the therapy.5,13-16
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
1
with documented hypertension have had their condition con- Department of Pharmacology & Therapeutics, College of Medicine & Medical
trolled to target levels. Moreover, the complex interrelation- Sciences, Arabian Gulf University, Manama, Kingdom of Bahrain
2
Qatar Foundation, Doha, Qatar
ship among hypertension, erectile dysfunction (ED), and 3
Primary Care, Ministry of Health, Manama, Kingdom of Bahrain
antihypertensive drug therapy has become better understood
in recent years. Erectile dysfunction has a high prevalence Manuscript submitted: January 15, 2015; accepted: June 21, 2015.
in individuals with multiple cardiovascular risk factors and
Corresponding Author:
patients with cardiovascular diseases.2-4 Hypertension is con- Khalid A. J. Al Khaja, Department of Pharmacology & Therapeutics, Arabian
sidered one of the most hazardous risk factors and is a fre- Gulf University, PO Box 22979, Kingdom of Bahrain.
quent comorbidity in men with ED.5 The prevalence of ED Email: khlidj@agu.edu.bh
234 Journal of Cardiovascular Pharmacology and Therapeutics 21(3)

Most of the recently revised guidelines for managing hyper- 1. Does the guideline recognize the importance of SD as a
tension in adults, both comprehensive and abridged versions, component of patients’ clinical history?
do not satisfactorily address the complexity of hypertension 2. Does the guideline emphasize assessing sexual function
and sexual dysfunction (SD).17-21 Only a minority of clinical prior to initiating or during treatment with antihyperten-
practice guidelines stress the importance of ED or other sive drugs?
sexual-related issues either as adverse outcomes or as factors 3. Does the guideline specify antihypertensive drugs with
to be considered when making treatment decisions.22 potential sexual adverse effects?
The purpose of this systematic review is to critically evalu- 4. Does the guideline recommend that antihypertensive
ate how comprehensively ED associated with antihypertensive therapy in sexually active males be initiated with those
drug therapy is addressed by various national and international drugs that are unlikely to affect sexual function (if the
guidelines that were developed for managing arterial hyperten- indication of the unlikely antihypertensive(s) associated
sion in adults, with reference to (1) recognizing antihyperten- with SD is/are not compelling) and to substitute the
sive drug-associated SD; (2) the potential differences in the offending agent(s) with one(s) that possess a better
guideline recommendations that were presented as complete safety profile?
or summary versions of international reports; and (3) compar- 5. Does the guideline recommend intervention with
isons between the guideline recommendations published at the phosphodiesterase-5 (PDE-5) inhibitors for antihyperten-
end of the second millennium and those developed at the begin- sive-induced SD?
ning of the third millennium. 6. Does the guideline specify that the use of PDE-5 inhibi-
tors is contraindicated in patients with hypertension hav-
Methods ing ischemic heart disease who are on nitrovasodilators?
7. Does the guideline recommend screening and treatment
The general methodology (literature search, inclusion/exclu- of hypertensive men with ED for low testosterone
sion criteria, outcome measures, validity assessment, and defi- levels?
nitions) used in this review has been described previously.22,23
Validity Assessment
Literature Search
Assessment of outcome measures was independently carried
National and international guidelines for hypertension manage- out by the first 2 authors of this review in a nonblinded standar-
ment were identified by searching for the following PubMed dized manner. Any discrepancy between the reviewers was
Medical Subject Heading terms: ‘‘guidelines’’ and ‘‘hyperten- resolved by the fourth author based on consensus.
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
Operational Definitions
name of countries (eg, Bahrain and Taiwan) or organizations In the tables, the guidelines’ recommendations pertaining to the
(eg, National Institute for Health and Clinical Excellence adverse effects of antihypertensives on sexual function in male
[NICE], European Society of Hypertension [ESH], and patients are identified as (þ) if they are available or addressed
National Heart, Lung, and Blood Institute [NHLBI]). The and as () if they are not available or not addressed. A superfi-
search was limited to studies that were published from Janu- cially addressed guideline (SAG) means that data pertaining to
ary 2000 through January 2014. Based on the contact details hypertension- and antihypertensive-related ED were primarily
retrieved from the International Society of Hypertension derived from tables that list compelling and possible indications,
(ISH) Web site, e-mails were sent to several ISH-affiliated contraindications, and cautions for major classes of antihyper-
societies of Middle East, South East Asia, and Africa and tensive drugs. A comprehensively addressed guideline (CAG)
requested these societies to provide the Web sites of their means that hypertension and antihypertensive-induced SD as a
national guidelines for the management of arterial hyperten- category has been explicitly addressed as one of the various
sion in adults, if available, in English. headings under hypertension in special patient groups.

Inclusion and Exclusion Criteria


Results
Guidelines written in English and published from 2000 onward
were included. However, guidelines written in languages other A total of 30 national and international guidelines fulfilled
than English and those published prior to 2000 were excluded. 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,
Outcome Measures b-blockers, and centrally acting sympathoplegics) were not
The primary outcome measures were the potential antihyper- addressed in 46.7% (14 of 30), superficially addressed in
tensives associated with SD. The guidelines were evaluated 43.3% (13 of 30), and comprehensively addressed in 10%
with research questions adapted from Karavitakis et al.22 (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 Hypertension Society (BHS-IV), fully ignored by 2003 World
the guidelines (14 of 30) each, whereas centrally acting sym- Health Organization (WHO)/ISH, and comprehensively
pathoplegics were identified in 20% (6 of 30). Sexual dysfunction addressed by the 2003 Seventh Joint National Committee
induced by antihypertensives was recognized as an adverse effect, (JNC-7; Table 3).
a major adverse effect and as a possible or absolute contraindica- In this review, the guidelines were evaluated based on 7
tion. Individual members of b-blockers and centrally acting author-specified research questions. The rate of addressing
agents that are associated with SD were not specified in 30% (9 these questions by practice guidelines was as follows: 30%
of 30) and 13.3% (4 of 30) of the guidelines, respectively. (9 of 30) considered SD to be a component of a patient’s
The differences between the primary full reports and sec- clinical history; 10% (3 of 30) emphasized the assessment
ondary summary publications pertaining to antihypertensive- of SD prior to initiating or during treatment with antihyperten-
related SD (either as a potential adverse effect or as a major sive drugs; 53.3% (16 of 30) specified antihypertensives with
adverse effect) are shown in Table 2. The issue of SD (as a potential SD; 10% (3 of 30) recommended the importance of
potential adverse effect) has been overlooked completely in initiating treatment with an antihypertensive that is unlikely
summary or quick reference guide compared with primary full to cause SD (if the antihypertensive indication is not compel-
report publications. This clinical issue has been inconsistently ling) or substituting the offending agent with better alternatives;
recognized by guidelines and recommendations that were 10% (3 of 30) recommended an intervention with PDE-5 inhi-
updated in the third millennium compared with those pub- bitors to treat SD due to antihypertensive medications; 6.7%
lished at the end of second millennium. It was only superfi- (2 of 30) specified that the use of PDE-5 inhibitors with vaso-
cially updated by the 2004 Fourth Working Party of British 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 combination therapy and can be further classified into
with ED for low testosterone levels (Table 4). 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
Discussion potentially detrimental adverse effects on male sexual func-
Thiazide-class diuretics are one of the most widely used tion.10-12,16,55-59 Nonetheless, SD induced by this class of anti-
class of antihypertensives. They are used both as fixed-dose hypertensives has not been addressed by several clinical
formulations and as individual agents in complementary practice guidelines,18-21,25,26,29,31-33,35,38,42,44,46 either as an
238 Journal of Cardiovascular Pharmacology and Therapeutics 21(3)

adverse effect or as a factor to be considered by physicians Of the 30 reviewed national and international guidelines,
when prescribing antihypertensive agents. However, ED and 46.7% (14 of 30) focused on the potential implications of
SD were deemed to be potential adverse effects,27,34,43 defi- b-blockers on impairing male sexual function (Table 1).
nite side effects,15,16,24,28,37,45,47 and major adverse effects39 b-Blocker-associated SD has been deemed as a potential adverse
on male sexual function by some sets of guidelines. Some effect by some of these guidelines27,34,43 as either a major side
treatment guidelines such as Saudi Hypertension Manage- effect39 or a definite adverse effect.15,16,24,28,37,38,40,41,45,47 Indi-
ment Society30 and Pan America Health Organization36 con- vidual b-blockers were not specified by approximately 30%
sidered thiazide-class diuretics to be possibly or absolutely (9 of 30) of guidelines,24,27,28,34,37-39,43,45 though they were
contraindicated in sexually active hypertensive males, respec- specified by a mere 16.7% (5 of 30) of the treatment guide-
tively. Of note, the term ‘‘thiazide-class diuretics’’60 has lines.15,16,40,41,47 The ESH guidelines state that ‘‘older b-blockers
never been used by any of the guidelines reviewed. Instead, exert negative effects on ED, whereas newer drugs such as nebi-
the term ‘‘thiazide diuretics’’ has been commonly used by volol have neutral or beneficial effects.’’15(p2146) The SD as an
most guidelines,27,30,34,36,43,45,47 whereas thiazide and adverse effect of b-blockers was more commonly associated
thiazide-like diuretics have been used in other guidelines.24,28,37 with other b-blockers.16 Moreover, atenolol-related ED, based
Diuretics, as a generic term, has been used by the ESH.15 We sug- on the outcomes of United Kingdom Prospective Diabetic
gest that an explicit categorical term such as thiazide-class diure- Study,77 has been addressed as a prototype for b-blockers by the
tics60 be used in future guideline revisions to avoid ambiguity. American Association of Clinical Endocrinologists.40 The
It has been reported that thiazide-like diuretics, such as American College of Cardiology Foundation/American Heart
indapamide, decrease the risk of worsening of sexual function Association41 state that ‘‘older b-blockers have been associated
by lowering blood pressure in men61 and that switching to with depression, SD, dyslipidemia, and glucose intolerance, and
indapamide-based therapy improves SD due to other antihyper- these side effects are less severe or unlikely with newer agents.’’
tensives.62,63 Indapamide is rarely associated with an adverse The RNAO47(p2439) precisely specified that first-generation
effect on male sexual function,61-64 and indapamide-related nonsubtype-selective b-blockers (nadolol, pindolol, proprano-
SD has been addressed only by the Registered Nurses Associ- lol, and timolol), second-generation selective b1-blockers
ation of Ontario (RNAO).47 (acebutolol, atenolol, bisoprolol, and metoprolol), and third-
Although b-blockers are one of the most widely used antihy- generation labetalol are all associated with ED.
pertensive classes of drugs for the prevention and treatment The relation between centrally acting sympathoplegic drugs,
of cardiovascular diseases, the use of some first-generation such as a-methyldopa and clonidine, and the incidence of SD
b-blockers has occasionally been associated with SD in has been noted by only 20% (6 of 30) of the reviewed guide-
males.59 b-Blockers are distinguished based on several proper- lines.15,16,24,36,39,45 The plausible explanation for paying less
ties, such as their relative affinity to b1 and b2 receptors, differ- attention to these antihypertensive agents may be attributed
ence in lipid solubility, capacity to induce vasodilatation, and to several reasons: (1) a-methyldopa is reserved as the drug
pharmacodynamic and pharmacokinetic parameters.65 Some of choice for nonsevere hypertension in pregnancy25,35-37,45;
of these characteristics are clinically relevant for selecting the (2) a-methyldopa is no longer recommended for the treatment
appropriate b-blocker for individual patients with hyperten- of uncomplicated hypertension and has been superseded by
sion.65 Propranolol, a first-generation nonsubtype selective newer antihypertensive classes; and (3) in addition to SD, cen-
b-blocker, has the potential to impair sexual function in males; trally acting antihypertensives are associated with numerous
this adverse effect appears to be dose related and often occurs unpleasant adverse effects.48,54
at doses in excess of 120 mg/d.66,67 Second-generation Clinical practice guidelines are systematically developed
b1-selective blockers such as atenolol have less of a tendency statements that assist clinicians, consumers, and policy makers
to produce ED than do nonsubtype selective b-blockers.68,69 in making appropriate health-related decisions. Potential guide-
However, b1-selectivity is dose related66,67 and tends to dimin- line deficits and the need for guideline appraisal tools have been
ish at higher drug concentration69,70; thus, the incidence of SD proposed by Siering et al.78 To reach the widest possible audi-
may rise.69 Nebivolol, a third-generation b1-blocker, has the ence, these guidelines are developed as primary ‘‘full reports’’
highest cardioselectivity of any of the currently available and as ‘‘secondary summary’’ publications in a prearranged pro-
b-blockers.71 Additionally, nebivolol produces an endothelium- cess that is accepted by both authors and the editors of journals.79
derived nitric oxide-dependent vasodilatation that results in the A full report is deemed as an evidence-based approach that pro-
reduction of systemic vascular resistance and facilitates penile vides a broader and more detailed review of recommendations
erection. Hence, nebivolol may offer the additional benefit of pre- and is based on observational studies and major clinical
cluding ED in male patients with hypertension.72-74 Of note, the trials.18,45 However, secondary publications such as the sum-
Hawthorne effect of ED with b-blockers should also be consid- mary version,48 quick reference guide,49 express report,50 and
ered; knowledge and prejudice about ED as a side effect of pocket guide51 are abridged versions that are intended to provide
b-blockers can produce anxiety, which may adversely influence recommendations for busy primary care physicians and should
erectile function in hypertensive men.75 Because the etiology of be used for educational purposes. Secondary publications are
the ED is largely psychological, it is not surprising that placebo considered justifiable if their contents are sufficiently abbre-
is as effective as PDE-5 inhibitors in reversing this side effect.75,76 viated and faithfully reflect the data and interpretation of the
Al Khaja et al 239

primary version.79 As a recommendation, SD associated with management of cardiovascular risk factors, whereas NHLBI
hypertension per se and the use of antihypertensive medications recommends that a clinician be willing to discuss SD problems.
have been completely excluded from the summary versions of Although SD is frequently encountered in patients with cardio-
several full report guidelines48-51 (Table 2). The omission of vascular diseases82 and in cardiology practice, there may be an
such pivotal recommendations may lead to undesired conse- overall lack of attention to exploring sexual problems (Table 4).
quences: (1) inappropriate attention to SD as an adverse effect It should be noted that sexual function in male patients with
may result in a negative impact on patients’ QOL, compliance hypertension may be impaired by hypertension per se5,12 and
with drug therapy and discontinuation of the antihypertensive by the use of some older antihypertensives as a drug-related
medications58,66; (2) an inadvertent departure from the side effect.10-12 The practicing physicians should therefore
evidence-based approach recommended by full report clinical carefully explore and assess the sexual sequelae in patients
guidelines; and (3) confusion and misleading of practicing phy- with hypertension. The typical initial evaluation of a man com-
sicians and researchers.79 For instance, Viigimaa and his col- plaining of ED is conducted in person and includes sexual,
leagues3 (the ESH Working Group on SD) inadvertently cited medical, and psychosocial histories as well as laboratory tests
the JNC-7 full report that comprehensively addressed the SD that are sufficiently thorough to identify comorbid conditions
issue instead of the JNC-7 Express Report as a reference for that may predispose the patient to ED or contraindicate certain
guidelines that ignore or superficially address the important drug therapies. History may reveal causes or comorbidities
association between cardiovascular risk factors and SD. We such as cardiovascular disease (including hypertension, athero-
opine that despite their usefulness, guideline summary versions sclerosis, or dyslipidemia), diabetes mellitus, depression, and
should faithfully reflect the data and interpretations of the alcoholism.83 Emphasis on the assessment of sexual function
primary full report versions. We suggest that the issue of prior to initiating or during antihypertensive drug treatment has
antihypertensive-related SD should be prudently addressed and been stressed only by ESH,15 ESH/European Society of Cardi-
appropriately considered in future guideline revisions. ology [ESC]16 and NHLBI,45 which represent a mere 10% (3 of
Some of the widespread guideline recommendations devel- 30) of all national and international guidelines.
oped at the end of the second millennium52-54 were compared Antihypertensive drug regimens should be tailored to the
with those updated at the third millennium20,37,45 to identify the age and gender of individual patients and should consider SD
scope of the changes and updates that have occurred in pub- as a potential adverse effect.16,66 Such a therapeutic strategy
lished clinical guidelines on antihypertensive-associated SD is necessary to achieve the objectives of treatment of hyperten-
(Table 3). From this perspective, the importance of iatrogenic sion: ensuring good compliance and QOL, achieving optimal
SD due to antihypertensives has been rather superficially control of blood pressure, and reducing the risk of cardiovascu-
updated by the report of the BHS-IV37 compared with BHS- lar events.66 It is extremely important to take a complete drug
III.52 This issue has been completely overlooked by WHO/ISH history, particularly with regard to antihypertensives and other
updated clinical practice guidelines.20 However, the recognition offending medications. Antihypertensive drugs, such as diure-
of antihypertensive-induced SD and its management in patients tics, first- and second-generation b-blockers, and centrally act-
with hypertension has been comprehensively addressed by the ing drugs can be discontinued or switched (if the indication is
updated complete report of the JNC-7—NHLBI45 (Tables 3 and not compelling) to alternatives with a better sexual safety pro-
4). Our observations suggest that antihypertensive-related SD is file, such as angiotensin-converting enzyme inhibitors, angioten-
inconsistently recognized by clinical practice guidelines that sin II receptor blockers, and calcium channel blockers.59 Despite
were developed for managing primary hypertension in adults, its importance, such a recommendation has been stressed by only
even among those that were published more recently. We NHBLI,45(p1236) which states ‘‘if SD appears after institution of
believe that this clinical issue is an area that needs further atten- antihypertensive drug therapy, the offending agent should be dis-
tion to improve the quality and impact of the guidelines and, ulti- continued and treatment restored with another agent.’’
mately, patient care and QOL. Sexual dysfunctions associated with antihypertensives
Of note, an association has been documented between (diuretics or b-blockers or centrally acting medications) have
arterial hypertension and SD5,12,80 and other cardiovascular been addressed by approximately half (16 of 30) of the revised
risk factors.2-4,80,81 Recently, the revised appraisal of Eur- guidelines15,16,24,27,28,30,34,36-41,43,45,47 (Tables 1 and 4). Over-
opean guidelines on hypertension management stressed that all, 10% (3 of 30) and 43.3% (13 of 30) of the guidelines have
ED is a prevalent condition in patients with hypertension and presented data pertaining to antihypertensive-related SD in
is a predictor of future cardiovascular diseases; the screening CAG and SAG, respectively (Table 1). Male SD refers to a
and treatment of ED, therefore, improve the management of problem during any phase of the sexual response cycle that pre-
cardiovascular risk factors.15 Thus, SD should be explored vents achieving satisfaction from sexual activity. The most
while taking the clinical history from patients with arterial common problems related to male SD include ED (impotence),
hypertension. Such an approach has been recommended by loss of libido (loss of sexual interest or desire), ejaculatory dys-
30% (9 of 30) of the treatment guidelines15,16,24,27,34,39,42,44,45 function, and priapism. Other than ED, none of the above-
(Table 4). Nonetheless, SD has not been explicitly specified mentioned terms have been stated in the revised guidelines.
under patients’ clinical history by ESH15 or NHLBI.45 The ESH It is well known that SD compromises the QOL of both
is implicit that screening and treatment of ED improve the the patient and the partner. Management of ED thus not only
240 Journal of Cardiovascular Pharmacology and Therapeutics 21(3)

improves QOL but also substantially enhances adherence pivotal role of endothelial function as an important target.
to antihypertensive drug therapy.3,4 Oral PDE-5 inhibitors are There is also a need to understand whether gene polymorph-
generally effective and safe as a first-line treatment of patients isms determine the susceptibility of patients to the adverse
with hypertension having SD, unless contraindicated.12,83 effects of antihypertensive medications, which may result in
In addition to the potential blood pressure lowering effect, ED.
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 Conclusion
add-on approach to the existing antihypertensive therapy.12,86 In this systematic review, there may be a discrimination bias
It should be noted that PDE-5 inhibitors are absolutely contra- because only English-language guidelines were included in the
indicated in patients on short- and long-acting nitrovasodilators analysis. Notwithstanding this limitation, hypertension treat-
because of an unpredictable synergistic decline in blood pres- ment guidelines have placed less emphasis on the issue of anti-
sure.3,4,12 In patients with hypertension having lower urinary hypertensive drug-associated SD. Most of the national or
tract symptoms, a-blocker and PDE-5 inhibitor therapy should international guidelines are less explicit concerning preexisting
be cautiously used, and the lowest effective dose of these or treatment-induced SD in patients with hypertension, with the
medications should be considered.83,87 The role of PDE-5 exception of the 2003 NHLBI, 2009 ESH and the more recently
inhibitors in ameliorating SD induced by either hypertension revised 2013 ESH/ESC guidelines. The future guideline revi-
or certain antihypertensive drugs has been emphasized by the sions, including both full and summary report versions, should
ESH,15 ESH/ESC,16 and NHLBI45 guidelines. However, the provide a balanced perspective on antihypertensive-related SD
life-threatening symptomatic hypotension in some patients issues to improve the QOL of patients with hypertension, bear-
that results from the concurrent use of PDE-5 inhibitors and ing in mind that QOL is a more serious issue than hypertension
nitrovasodilators has been addressed only by ESH/ESC16 and for many men during midlife.
NHLBI.45 According to the ESH/ESC guidelines, PDE-5 inhi-
bitors may be safely administered to hypertensive, even to Acknowledgments
those who are on multiple drug regimens (with the possible We acknowledge the assistance given to us by Ina D’Souza in prepar-
exception of a-blockers and nitrovasodilators). The NHLBI ing this manuscript.
declared that sildenafil or other PDE-5 inhibitors may be pre-
scribed, without a significant likelihood of adverse reactions, Authors’ Contribution
to those with concomitant antihypertensive therapy, provided K. A. J. Al Khaja contributed to conception and design; acquisition,
that nitrovasodilators are avoided. analysis, and interpretation; drafted the manuscript; critically revised
Low testosterone levels may contribute to ED88 and are the manuscript; gave final approval; and agrees to be accountable for
prevalent in men with hypertension,89-91 diabetes mellitus,92 all aspects of work ensuring integrity and accuracy. R. P. Sequeira, A.
and metabolic syndrome.93 Men with ED should, therefore, be K. Alkhaja contributed to acquisition, analysis, and interpretation; cri-
screened for testosterone because hypotestosteronemia-related tically revised the manuscript; gave final approval; and agree to be
dysfunction can be improved by exogenous testosterone ther- accountable for all aspects of work ensuring integrity and accuracy.
apy.94-96 It is evident that none of the revised guidelines have A. H. H. Damanhori contributed to analysis and interpretation, criti-
recommended the importance of testosterone screening and sup- cally revised the manuscript, gave final approval, and agrees to be
accountable for all aspects of work ensuring integrity and accuracy.
plementation in hypogonadal men with hypertension (Table 4).
The combination of testosterone therapy, unless contraindicated,
Authors’ Note
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 This article has not been submitted or presented elsewhere. In prepar-
borderline levels (8-12 nmol/L), who did not adequately respond ing this manuscript, the authors have not received financial support
from any drug companies or organizations.
to prior treatment with PDE-5 inhibitors alone.94-97
A strong link between ED and endothelial dysfunction has
Declaration of Conflicting Interests
been postulated.98-100 Moreover, there is an emerging body
of evidence that endothelial dysfunction due to gene poly- The author(s) declared no potential conflicts of interest with respect to
morphisms may be linked with hypertension. A recent study the research, authorship, and/or publication of this article.
has identified a single-nucleotide polymorphism of the human
calcium/calmodulin-dependent protein kinase type 4 gene, Funding
which plays a role in blood pressure regulation by controlling The author(s) received no financial support for the research, author-
endothelial nitric oxide synthase activity.101 Given the wide ship, and/or publication of this article.
array of G-protein-coupled receptors (GPCRs), it is reasonable
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