dysfunction (ED) is the inability to achieve or maintain an erection
sufficient for satisfactory sexual performance.1 The prevalence of
ED is estimated at 35% in men over age 60 and in some studies as high as 50%.2,3
It has been estimated that globally, the number of patients with ED will
exceed 300 million by 2025.4 Despite recognition that ED is a
common medical illness and not only psychogenic in origin--as historically
described--patients and physicians alike often have difficulty communicating on
this topic. In an international survey of more than 27,000 men and women, only
9% of respondents reported that their physician had inquired about their
sexual health in the last three years.5
Pharmacists--a trusted source
of objective medical information--are responsible for counseling and routinely
dispensing medications for ED. This affords many opportunities to improve
outcomes as well as provide valuable education on optimization of
treatments--especially when a suboptimal response is experienced with
phosphodiesterase type 5 (PDE-5) inhibitors. ED is an important patient care
topic, as patients may associate sexual health with vitality and overall
well-being. Furthermore, there are several treatment options, making this an
amenable medical condition potentially responsive to both pharmacotherapy and
Etiology of Erectile
A complex sequence
of biochemical steps results in an erection during sexual stimulation.6
The principal mediator is nitric oxide (NO), which activates guanylyl cyclase,
thereby increasing concentrations of cyclic guanosine monophosphate. The
resulting relaxation of smooth muscle allows for engorgement of the penis to
provide rigidity for intercourse.
ED has multiple etiologies
including vascular, neurologic, and endocrine disorders. This highlights the
importance of a proper physical exam and a thorough patient history. Many
patients have specific modifiable vascular risk factors that can impact
erectile function. Patients with vascular risk factors including hypertension,
coronary artery disease (CAD), high cholesterol, and diabetes are at increased
risk for ED compared to patients without these conditions.7,8
Smoking appears to further increase the risk of ED in patients with vascular
risk factors, likely due to direct effects on endothelial function.9
Health care providers should routinely remind current smokers with ED of the
beneficial effects of smoking cessation from both a cardiovascular and sexual
health perspective. In regard to diabetes, poor glycemic control and duration
of disease further increases risk, which highlights the need for prevention
and vigilance in this patient population.10
Obese patients are also at
risk for ED, possibly due to increases in oxidative stress that may render NO
inactive.11 In obese men, lifestyle changes including moderate
weight loss and increased exercise can have a significant impact on retaining
and improving erectile function. Additionally, ED is often the first sign of
underlying, undiagnosed cardiovascular disease.11
It is important that
pharmacists recognize medication classes associated with ED and sexual
dysfunction. For example, incidence of selective serotonin reuptake inhibitor
(SSRI)–induced sexual dysfunction is estimated at 30% to 50%.12
In this situation, as well as in beta-blocker–induced ED, drug holidays to
avoid sexual side effects should not be routinely recommended. Whenever
possible, conversion to another agent within the same therapeutic class with a
lower incidence of sexual side effects should be recommended. PDE-5 inhibitors
may be appropriate and have been studied to improve specific causes of
drug-induced sexual dysfunction.13,14 Other medications commonly
associated with ED include antihypertensive agents such as calcium channel
blockers, beta-blockers, and thiazide diuretics as well as miscellaneous
agents including methotrexate, interferon-alpha, and 5-alpha reductase
reversible causes of ED have been ruled out, PDE-5 inhibitors are considered
first-line therapy unless otherwise contraindicated by patient-specific
comorbidities or concomitant administration with certain medications.16
Three agents are currently available: sildenafil (Viagra), vardenafil
(Levitra), and tadalafil (Cialis). Current guidelines for the management of ED
do not favor one agent over another for initial treatment of ED. Post-hoc
analysis of phosphodiesterase inhibitor– naïve men did not identify specific
patient characteristics predicting patient preference for either sildenafil or
tadalafil.17 Specific differences between the three available
agents are largely based on pharmacokinetics and onset of action (Table 1).18-20
Patients with CAD who are
considered for PDE-5 inhibitor therapy should undergo cardiovascular risk
stratification.21,22 Patients determined to be at low risk may
receive medication for ED and may cautiously resume sexual activity.
Higher-risk patients, including those with unstable angina; untreated, poorly
controlled, accelerated, or malignant hypertension; a recent (within two
weeks) myocardial infarction (MI); or aortic stenosis should be advised to
abstain from sexual activity until stabilization has occurred.22
Due to possible precipitous decreases in blood pressure, PDE-5 inhibitors
should not be used in men taking nitrates.
An additional contraindication
to PDE-5 inhibitor use is prior diagnosis of nonarteritic ischemic optic
neuropathy (NAION), a rare ophthalmologic disorder. Temporal association
between PDE-5 inhibitor use and diagnosis of NAION has been documented;
however, a cause-effect relationship has yet to be fully established.23
Patients with this ophthalmologic disorder often share similar vascular risk
factors including hypertension and smoking--further confounding this
relationship. A case control study examining this issue found no increased
risk of this condition except in patients with a history of MI.24
Overall, the risk of this condition is low, but patients with a history of
NAION should not take PDE-5 inhibitors.
Other rare side effects
reported with tadalafil and sildenafil include sudden loss of hearing;
however, a cause-effect relationship has yet to be fully established.19,25
More commonly reported side effects include changes in blue-green vision with
sildenafil and a higher reported incidence of back pain with tadalafil.18,19
While PDE-5 inhibitors have
revolutionized the management of ED, the remainder of this review will focus
on alternative treatment options and potential treatment strategies in the
setting of failed PDE-5 inhibitor therapy or contraindications.
in three men who suffer from ED will have inadequate response,
contraindications, or side effects to PDE-5 inhibitors.15 The
American Urological Association (AUA) states that for patients who fail an
adequate trial of a PDE-5 inhibitor, a trial of another such agent may be
appropriate. However, no studies have shown benefit for one PDE-5 inhibitor
over another.16 Alternative therapies include intracavernosal
injections, intraurethral therapy, vacuum devices, and penile prostheses (Table
2). Although more invasive than oral medications, these options are
effective for many patients.
One injectable medication used as a second-line therapy in the treatment of ED
is alprostadil. This naturally occurring form of prostaglandin E1
acts to increase cyclic adenosine monophosphate (cAMP), which in turn relaxes
smooth muscle, leading to an erection.26 Phentolamine (an
alpha-adrenergic blocker) and papaverine (a nonspecific phosphodiesterase
inhibitor) both act as vasodilators and may be used in combination with
alprostadil if the patient has an inadequate response to alprostadil alone.
Alprostadil is the most effective monotherapy followed by papaverine;
phentolamine is used only in combination as augmentation. It may be preferable
to use all three medications in combination, as efficacy increases from
approximately 80% to 92% with use of the combination (tri-mix), and side
effects may decrease since lower doses of each agent are used.15,27
When side effects do occur, they may include penile ache (5%) and, in rare
cases, penile fibrosis or priapism.15 Hypotension is also rare.26
injection provides local, rapid response, the invasiveness and requirement for
injection may deter patients or decrease compliance.28 As
previously noted, injection therapies are considered second-line treatment and
are typically offered to patients who have failed or cannot tolerate therapy
with PDE-5 inhibitors. Contraindications to intracavernosal injection therapy
include anatomical deformation of the penis, leukemia, myeloma, sickle cell
disease, predisposition to priapism, or hypersensitivity to the agents.26
Precautions to their use include bleeding disorders or concomitant use of
anticoagulants.26 When this therapy is initiated, the first dose
should be administered under the supervision of a health care provider to
allow teaching of administration technique and titration of dose required to
obtain adequate erection.
Alprostadil may also be administered via urethral suppository. A medicated
pellet more commonly called MUSE (medicated urethral system for erection) is
inserted by the patient into the distal urethra prior to intercourse. This
formulation often provides local, rapid response although efficacy (~67%) may
be less than intracavernosal injection.29 Despite using the same
active medication to achieve an erection, it has been shown that patients who
fail intracavernosal injection therapy may have success with use of
intraurethral alprostadil.29 Engel and McVary reported in a
retrospective review that 58% of men who described intracavernosal injection
as "not effective" were able to achieve an erection with use of intraurethral
alprostadil in the clinic setting.29 It is recommended that
intraurethral suppository be offered to patients who have failed PDE-5
inhibitors.15 It may be an especially useful second-line option for
patients who are deterred by intracavernosal injections due to needle aversion
or pain from injection. Side effects are similar to those of intracavernosal
injection and include local pain (32%) and, in rare cases, persistent penile
pain or priapism.30 Intraurethral administration may also lead to
urethral bleeding (5%) and increased risk of urinary tract infection (0.2%).27
second-line therapies include vacuum constriction devices (VCDs), which use
negative pressure to draw blood into the penis. A band is placed at the base
of the penis to maintain the erection for no longer than 30 minutes. Efficacy
of VCDs is unclear due to the lack of high-quality studies, but it has been
estimated at 35% to 90%.15,27 Low patient acceptability again
limits the use of these devices, but they may be appropriate and effective,
especially when it is necessary to avoid drug therapy and provide a
noninvasive mode of administration. Use of anticoagulants or presence of a
bleeding disorder are considered contraindications to use of VCDs.27
Penile prostheses are considered third-line treatment options due to the need
for surgical implantation of the devices. There are two main types--malleable,
also known as semirigid, and inflatable devices. Despite their
invasiveness, prostheses may be preferred by patients over vacuum devices.
Recent analysis of patient satisfaction and device reliability have yielded
very positive results.15,31 Essentially all patients with proper
device function can achieve an erection. Failure of the device most often
results from infection or mechanical failure. The five-year rate of mechanical
failure is estimated to be 6% to 16% depending on the type of device used.16
Infection can also lead to prosthesis failure, but with appropriate surgical
techniques and antibiotic practices these rates are only 2% to 3% (slightly
higher in diabetics).27 Device manufacturers have also attempted to
decrease rates of infection by use of antibacterial-impregnated prostheses or
hydrophilic coatings.16,27 If infection does occur, the prosthesis
must be removed and infection treated appropriately. Reimplantation is an
option after a period of several months, but is more technically challenging.
Due to the replacement of penile erectile tissue during implantation, PDE-5
inhibitors, intracavernosal injection, and MUSE are not considered options
after implantation and subsequent removal of a prosthesis. In these patients,
the only viable option remains reimplantation. However, a vast majority of
patients have previously failed most other therapies upon arrival to this
being advertised as an herbal alternative for the treatment of ED, yohimbine
is not recommended by the AUA, as safety and efficacy in humans have yet to be
determined. This herbal medication, believed to increase libido in rats, has
alpha2-adrenergic inhibition leading to increased blood pressure,
heart rate, and motor activity in humans.16 Yohimbine may also
cause irritability and tremor.16
Use of trazodone for treatment
of ED is not recommended by the AUA. It has been hypothesized that this
antidepressant, via antagonism of alpha2-adrenergic receptors,
would possibly relax penile smooth muscle and dilate penile arteries, leading
to an erection. Results from clinical trials have been conflicting and,
therefore, its use cannot be recommended.16
It is estimated that
approximately 12% of patients with ED have hypogonadism, and in some cases
this may be a reversible cause of ED through treatment with administration of
exogenous testosterone.32 If symptoms persist beyond three months
of testosterone therapy, dysfunction is most commonly due to or complicated by
the adverse effects of the patient's comorbid conditions, including impaired
penile vasculature.32 Dual treatment with testosterone and a PDE-5
inhibitor may be indicated. As AUA guidelines state, administration of
exogenous testosterone in someone with normal serum testosterone values is not
Subgroup Analysis: Status
Post Radical Prostatectomy
attempt to individualize treatment of ED, unique situations arise. A common
scenario includes treatment of ED post radical retropubic prostatectomy (RRP),
as with the 50-year-old man presented in the case study. Prostate cancer is
the fourth most common cancer in adults, and it is estimated that
approximately 40% of patients with localized disease will undergo radical
prostatectomy.33 Urinary incontinence and ED are the most common
complications from this procedure, with the latter attributed mainly to damage
to nerves regulating erections.33 Advances in surgical techniques,
including nerve-sparing procedures, may reduce ED and subsequently improve
response to PDE-5 inhibitors.
Therapy with PDE-5 inhibitors
may be warranted not only to treat but also to prevent ED in patients who have
undergone RRP. Bannowsky et al conducted a randomized, placebo-controlled
trial (N = 43) comparing sildenafil 25 mg nightly on recovery of erectile
function after nerve-sparing radical prostatectomy (NSRP).34 Their
findings suggest that sildenafil may enhance recovery of erectile function by
supporting cavernosal oxygenation and preventing subsequent fibrosis. One year
postsurgery, 47% of patients randomized to sildenafil were able to achieve and
maintain an erection sufficient for vaginal intercourse, compared to 28% of
controls. When "on-demand" sildenafil 50 to 100 mg as needed was allowed,
potency increased to 86% versus 66%, respectively (P <.001).34
Based on these findings,
Bannowsky et al have proposed a new therapeutic concept, termed the Kiel
concept, for optimum reestablishment of erectile function and satisfying
sexual function after NSRP, which is based on the significant benefit observed
in patients taking sildenafil 25 mg nightly.34 They suggest that
patients with no confirmed erections at one year postsurgery should undergo a
trial of intracavernosal injection therapy, and if no spontaneous erections
occur at two years, more invasive therapy may be required.34 Future
studies are needed to further investigate the theories behind the Kiel
concept, as it remains controversial; however, this study conveys the possible
importance of early therapy to support cavernosal oxygenation after RRP. It
also emphasizes the importance of following up with patients for symptoms of
ED and utilization of alternative therapies to treat this clinical problem.
In summary, pharmacists should be
readily available to counsel patients on the differences not only between
PDE-5 inhibitors but between second-line therapies as well. Because failure of
one PDE-5 inhibitor does not necessarily preclude effectiveness of another
agent, pharmacists should determine if the medication has benefited the
patient. In the setting of failed PDE-5 inhibitors, several alternative
therapies exist, and patients may be considered for second-line treatment
options. Patient specific factors, as well as convenience and patient
adherence, should be considered prior to initiating therapy with any agent.
The authors wish to acknowledge Douglas
Geraets, PharmD, BCPS, for his assistance with editing and revisions.
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