1437
SECTION 10
92
C H AP TER
KEY CONCEPTS
 The incidence of erectile dysfunction is low in men younger
than 40 years of age. The incidence increases as men age,
likely as a result of concurrent medical conditions that impair
the vascular, neurologic, psychogenic, and hormonal systems
necessary for a normal penile erection.
 Many commonly used drugs have sympatholytic, anti-
cholinergic, sedative, or antiandrogenic effects that may
Testosterone supplementation should be reserved for patients
exacerbate or contribute to the development of erectile
dysfunction. Clinicians should be familiar with these agents
and be prepared to make adjustments in drug regimens
to minimize adverse effects of these drugs on a patients
erectile function.
 The first step in clinical management of erectile dysfunction
is to identify and, if possible, reverse the underlying causes.
Risk factors for erectile dysfunction, including hypertension,
diabetes mellitus, smoking, and chronic ethanol abuse, should
be addressed and minimized.
 Specific treatments for erectile dysfunction include vacuum
erection devices, pharmacologic treatments, psychotherapy,
and surgery.
 The ideal treatment of erectile dysfunction should have a fast
onset, be effective, be convenient to administer, be cost effec-
tive, have a low incidence of serious adverse effects, and be
free of serious drug interactions.
 Specific treatment is first initiated with the least invasive forms
of treatment, including vacuum erection devices or oral phos-
phodiesterase inhibitors, followed by intracavernosal injections
or intraurethral inserts, and finally by surgical insertion of a
penile prosthesis.
Learning objectives, review questions,
and other resources can be found at
www.pharmacotherapyonline.com.
UROLOGIC DISORDERS
Erectile Dysfunction
MARY LEE
 Vacuum erection devices can have a slow onset of action
(30 minutes) and are not discreet; therefore, they are most
effective for a couple in a stable relationship.
Although phosphodiesterase inhibitors are convenient and
effective regardless of the etiology of erectile dysfunction,
they fail in 30% to 40% of patients. Also, phosphodiesterase
inhibitors are contraindicated in patients taking any dosage
formulation of nitrate.
with primary or secondary hypogonadism who have erectile dys-
function as a consequence of a decreased libido. Testosterone
supplementation should not be used by patients with erectile
dysfunction who have normal serum testosterone levels.
 Although intracavernosal injections and intraurethral pellets
of alprostadil are effective independent of the etiology of
erectile dysfunction, they fail in one third of patients. To
self-administer medication by these routes, patients require
training to minimize administration-related adverse effects.
The National Institutes of Health Consensus Development Panel
on Impotence defines erectile dysfunction as the failure to achieve a
penile erection to allow for satisfactory sexual intercourse.1 Patients
may refer to it as impotence.
Erectile dysfunction must be distinguished from disorders of
libido, ejaculatory disorders, and infertility, which are caused
by different pathophysiologic mechanisms and are treated with
alternative agents (Table 921). A patient may suffer from one or
more disorders of sexual dysfunction. For example, an elderly man
with primary hypogonadism may suffer from decreased libido and
erectile dysfunction. Diagnosis of the type of sexual disorder that a
patient has is a key to initiating the most appropriate treatment.
EPIDEMIOLOGY
 The incidence of erectile dysfunction is low in men younger
than 40 years of age but increases as men age.24 The Massachusetts
Male Aging Study, a cross-sectional survey of a random sample of
1,290 men in the Boston area, was conducted during the period
1438
TABLE 92-1 Types of Sexual Dysfunction in Men arteriosclerosis, hyperlipidemia, diabetes mellitus, or psychiatric
disorders) or from medications that patients may be taking for these
SECTION 10

Type of Dysfunction Definition

diseases.25 For example, up to 50% of patients with diabetes melli-
Decreased libido Decreased sexual drive or desire tus develop erectile dysfunction, and medications such as -blockers
Increased libido Precocious puberty; inappropriate and excessive sexual
are associated with a high incidence of erectile dysfunction.
drive or desire
Erectile dysfunction Failure to achieve a penile erection suitable for satisfactory
(impotence) sexual intercourse
Delayed ejaculation Commonly referred to as dry sex; ejaculation is PHYSIOLOGY OF A NORMAL
delayed or absent PENILE ERECTION
Retrograde ejaculation Ejaculate passes retrograde into the bladder, instead
Urologic Disorders

of toward the anterior urethra (antegrade) and out
of the penis
Infertility Sperm are insufficient in number, have abnormal
morphology, or have inadequate motility, and fail to
fertilize the ovum
from 1987 to 1989. The study reported an overall prevalence of 52%
for any degree of erectile dysfunction in men aged 40 to 70 years,
with an age-related increase in incidence ranging from 12.4% in
men aged 40 to 49 years, up to 46.4% in men aged 60 to 69 years.1,2
In the more recent Health Professional Follow-Up Study of more
than 31,000 male health professionals aged 53 to 90 years, the preva-
lence of erectile dysfunction was 33%.3 Interestingly, although the
prevalence of erectile dysfunction increases with patient age, many
patients fail to seek medical treatment.4
Erectile dysfunction is sometimes assumed to be a symptom
of the aging process in men. However, more likely it results from
concurrent medical conditions of the patient (e.g., hypertension,
A normal penile erection requires full functioning of several physi-
ologic systems: vascular, nervous, and hormonal. The patient also
must be psychologically receptive to sexual stimuli.
VASCULAR SYSTEM
The penis comprises two corpora cavernosa on the dorsal side and
one corpus spongiosum on the ventral side. The corpus spongiosum
surrounds the urethra and forms the glans penis. The corpora are
composed of multiple interconnected sinuses, which can fill with
blood to produce an erection. The corpora cavernosa are encased
by the tunica albuginea, a fibrous tissue membrane, which has lim-
ited distensibility. In the flaccid state, arterial flow into and venous
outflow from the corpora are balanced. During the erectile phase,
arterial blood flow increases and blood fills the sinusoids within the
corpora, which causes penile swelling and elongation. The erection
is prolonged by a decrease in venous outflow from the corpora,
which is caused by compression of subtunical venules against the
tunica albuginea by the swollen corpora (Fig. 921).

Penile arteries and veins

Corpus cavernosum

Skin

FIGURE 92-1. Microanatomy of and vascular changes in the penis in

flaccid and erect states. In the flaccid state, arterial flow into and venous
Tunica albuginea outflow from the corpora are balanced. During the erectile phase, arte-
rial blood flow increases and blood fills the sinusoids within the corpora,
Erectile tissue causing penile swelling and elongation. The erection is prolonged by
a decrease in venous outflow from the corpora, which is caused by
compression of subtunical venules by the swollen corpora. (From Walsh
Corpus spongiosum PC, ed. Campbells Urology, 8th ed. Philadelphia, PA: WB Saunders,
2002:1595, 1697.)
Urethra

Flaccid State Erectile Phase


Arterial flow into the corpora is enhanced by acetylcholine-
mediated vasodilation. Acetylcholine indirectly enhances arterial
flow to the corpora and increases sinusoidal filling of the corporal
tissue. That is, acetylcholine is a coneurotransmitter, which works
along with other nonpeptidinergic intracellular neurotransmit-
tersincluding cyclic guanosine monophosphate (cGMP), cyclic
adenosine monophosphate (cAMP), or vasoactive intestinal poly-
peptideto produce vasodilation. In effect, cGMP and cAMP are
secondary messengers that direct desired effects in target tissues.6
Acetylcholine produces an erection probably through two
different pathways. Through one pathway, in the presence of
sexual stimulation to genital tissue, acetylcholine enhances the
production of nitric oxide by endothelial cells and nonadrenergic
noncholinergic neurons. Nitric oxide enhances the activity of
guanylate cyclase, which increases the conversion of cyclic guanos-
ine triphosphate to cGMP. cGMP decreases intracellular calcium
concentrations in smooth muscle cells of penile arteries and caver-
nosal sinuses. As a result, smooth muscle relaxation occurs, which
enhances arterial blood flow to and blood filling of the corpora.5
An erection results.
In an alternative pathway, acetylcholine or prostaglandin
E enhances the activity of adenyl cyclase, which increases the
conversion of cyclic adenosine triphosphate to cAMP, a potent
muscle relaxant. Similar to cGMP, cAMP decreases intracellular
calcium concentrations to produce smooth muscle relaxation in
cells of the arteries and cavernosal sinuses. Arterial blood flow
to and blood filling of the corpora are enhanced, and a penile
erection results.5
NERVOUS SYSTEM AND
PSYCHOGENIC STIMULI
Some erections are mediated by a sacral nerve reflex arc (e.g.,
erections can occur while the patient is sleeping). However, in the
conscious patient, sensory sexual stimulation mediates erections via
the central nervous system. That is, when a patient sees an attrac-
tive partner, hears sweet words, smells a particular scent, or tastes
or touches a pleasant object, these situations can result in an erec-
tion. In this case, the patients brain processes this information and
the nervous impulse is carried down the spinal cord to peripheral
cholinergic nerves that innervate the vascular supply to the corpora,
resulting in an erection.
The medial preoptic area of the hypothalamus is thought to be
that portion of the brain responsible for integrating external stim-
uli. Here dopamine exerts a proerectogenic effect, whereas, 2-
adrenergic stimulation causes the penis to become and/or remain
flaccid. After moving down the spinal cord, nerve impulses travel
to the penis by efferent peripheral nerves, including inhibitory
sympathetic neurons (T11L2), proerectogenic parasympathetic
neurons (S2S4), and proerectogenic somatic neurons (S2S4).
In summary, acetylcholine produces an erection by working
along with other coneurotransmitters, including cGMP and cAMP.
Thus, an erection is mediated neurologically, maintained by arterial
blood filling of the corpora, and sustained by occlusion of venous
outflow from the corpora.
Detumescence, or the progression of an erect penis to a flaccid
state, results from the actions of norepinephrine, which contracts
vascular smooth muscle to decrease arterial inflow to the corpora
and contracts sinusoidal tissue in the corpora. As a result, venous
outflow from the corpora increases.
HORMONAL SYSTEM
Testosterone is principally produced by the testes at a daily rate
of 4 to 8 mg. Production follows a circadian pattern with highest
1439
blood levels in the morning and lowest levels in the evening.
Physiologically active (free) testosterone comprises only 2% of
CHAPTER 92
circulating blood levels. About 50% to 60% of testosterone in the
bloodstream is tightly bound to sex hormone-binding globulin and
is inactive. The rest of circulating testosterone is reversibly bound
to albumin; this portion of testosterone is in equilibrium with the
free fraction.
Testosterone stimulates libido (sexual drive) and increases mus-
cle mass in males. In some target cells with 5-alpha reductase, tes-
tosterone is activated to dihydrotestosterone. Dihydrotestosterone,
Erectile Dysfunction
which is more potent than testosterone, stimulates prostate gland
growth, increases facial and body hair, induces baldness, and causes
acne. In adipose tissue, a small portion of testosterone is converted
to estradiol which can lead to gynecomastia.
Beginning at age 40 years, men experience a gradual decrease in
testicular production of testosterone, with an associated decrease in
muscle mass and sexual function.7 The Massachusetts Male Aging
Study reported that 6% to 12% of elderly males had symptoms of
hypogonadism.8
Within the normal physiologic serum total testosterone con-
centration range (normal, 3001,100 ng/dL; 10.438.2 nmol/L),
sexual drive is usually normal. However, because of variability
in circulating levels of sex hormone binding globulin, a patients
serum concentration of testosterone should always be interpreted
in the context of the patients symptoms and physical exam find-
ings. To confirm hypogonadism when the serum total testosterone
concentration is equivocal, the clinician should obtain a serum free
(bioavailable) testosterone level.
The relationship between erectile dysfunction and serum tes-
tosterone levels is complicated. Patients with normal serum tes-
tosterone levels may have erectile dysfunction, and patients with
subnormal serum testosterone levels may have normal sexual func-
tion.5 When a patient has hypogonadism and libido is decreased, a
patient may not develop erections. In this case, erectile dysfunction
is considered secondary to a decreased libido.
PATHOPHYSIOLOGY
Erectile dysfunction can result from any single abnormality or
combination of abnormalities of the four systems necessary for
a normal penile erection. Vascular, neurologic, or hormonal eti-
ologies of erectile dysfunction are collectively referred to as organic
erectile dysfunction. Approximately 80% of patients with erectile
dysfunction have the organic type. Patients who do not respond to
psychogenic stimuli have psychogenic erectile dysfunction.
Diseases that compromise vascular flow to the corpora caverno-
sum (e.g., peripheral vascular disease, arteriosclerosis, and essential
hypertension) are associated with an increased incidence of erectile
dysfunction. Diseases that impair nerve conduction to the brain
(e.g., spinal cord injury or stroke) or conditions that impair periph-
eral nerve conduction to the penile vasculature (e.g., diabetes mel-
litus) can result in erectile dysfunction.
Diseases associated with hypogonadism, primary or second-
ary, result in subphysiologic levels of testosterone, which cause
diminished sexual drive (decreased libido) and secondary erectile
dysfunction. Primary hypogonadism can be associated with the
normal aging process in men or surgical removal of the testes for
treatment of prostate or testicular cancer. Secondary hypogonadism
may result from hypothalamic or pituitary disorders of luteinizing
hormonereleasing hormone or luteinizing hormone, respectively;
or elevated prolactin levels, which can result from pituitary tumors
or can occur in patients with chronic renal failure.
Patients must be in the proper mental frame of mind to be
receptive to sexual stimuli. Patients who suffer from malaise, have
1440
TABLE 92-2 Medication Classes That Can Cause Erectile Dysfunction
SECTION 10

Proposed Mechanism by Which

Drug Class
Anticholinergic agents (antihistamines, antiparkinsonian
agents, tricyclic antidepressants, phenothiazines)
Urologic Disorders
Drug Causes Erectile Dysfunction
Anticholinergic activity
Special Notes
Second-generation nonsedating antihistamines (e.g., loratadine,
fexofenadine, or cetirizine) are associated with less erectile
dysfunction than first-generation agents
Selective serotonin reuptake inhibitor (SSRI) antidepressants cause
less erectile dysfunction than tricyclic antidepressants. Of the SSRIs,
paroxetine, sertraline, and fluoxetine cause erectile dysfunction more
commonly than venlafaxine, nefazodone, trazodone, or mirtazapine.

Phenothiazines with less anticholinergic effect (e.g., chlorpromazine)

can be substituted in some patients if erectile dysfunction is a
problem
Dopamine antagonists (e.g., metoclopramide, phenothiazines) Inhibit prolactin inhibitory factor, Increased prolactin levels inhibit testicular testosterone production;
thereby increasing prolactin levels depressed libido results
Estrogens, antiandrogens (e.g., luteinizing hormonereleasing Suppress testosterone-mediated In the face of a decreased libido, a secondary erectile dysfunction
hormone superagonists, digoxin, spironolactone, stimulation of libido develops because of diminished sexual drive
ketoconazole, cimetidine)
Central nervous system depressants (e.g., barbiturates, Suppress perception of psychogenic
narcotics, benzodiazepines, short-term use of large stimuli
doses of alcohol, anticonvulsants)
Agents that decrease penile blood flow (e.g., diuretics, Reduce arteriolar flow to corpora Any diuretic that produces a significant decrease in intravascular
peripheral -adrenergic antagonists, or central volume can decrease penile arteriolar flow
sympatholytics [methyldopa, clonidine, guanethidine]) Safer antihypertensives include angiotensin-converting enzyme
inhibitors, postsynaptic 1-adrenergic antagonists (terazosin, doxazosin),
calcium channel blockers, and angiotensin II receptor antagonists
Miscellaneous Unknown mechanism
Finsteride, dutasteride
Lithium carbonate
Gemfibrozil
Interferon
Clofibrate
Monoamine oxidase inhibitors

From Thomas et al.9 and Lee and Sharifi.10

reactive depression or performance anxiety, are sedated, have

Alzheimer disease, have hypothyroidism, or have mental disor-
ders, commonly complain of erectile dysfunction. In most studies,
patients with psychogenic erectile dysfunction generally exhibit a
higher response rate to various interventions than do patients with
organic erectile dysfunction because the former have less severe
disease.
Social habits of patients have been linked to erectile dysfunction.
The vasoconstrictor effect of cigarette smoking may compromise
blood flow to the corpora and decrease cavernosal filling. Excessive
ethanol intake may lead to androgen deficiency, peripheral neu-
ropathy, or chronic liver disease, all of which can contribute to
erectile dysfunction.
 Medications may cause erectile dysfunction through similar
pathophysiologic mechanisms (Table 922).911 Medications are
estimated to be responsible for approximately 10% to 25% of cases
of erectile dysfunction.
CLINICAL PRESENTATION: ERECTILE DYSFUNCTION
General
 Men are affected emotionally in many different ways
 Depression
 Performance anxiety
 Marital difficulties and avoidance of sexual intimacy (patients
are often brought to a physician by their partners)
 Nonadherence to medications patient believes are causing
erectile dysfunction
Symptoms
 Erectile dysfunction or inability to have sexual intercourse
Signs
 If completing an International Index of Erectile Dysfunction
survey, results are consistent with low satisfaction with the
quality of erectile function.
 Medical history may identify concurrent medical illnesses,
past surgical procedures that interfere with good vascular
flow to the penis or damage nerve function to the corpora,
or mental disorders associated with decreased reception of
sexual stimuli.
 Medication history may reveal prescription or nonprescrip-
tion medications that could cause erectile dysfunction.
 Physical examination may reveal signs of hypogonadism
(e.g., gynecomastia, small testicles, decreased body hair or
beard, decreased muscle mass), which may contribute to
erectile dysfunction. The patient may have an abnormally
curved penis when erect, decreased pulses in the pelvic
region (suggesting impaired vascular flow to the penis), or
decreased anal sphincter tone (suggesting impaired nerve
function to the corpora). Men older than 50 years should
undergo a digital rectal examination to determine whether
an enlarged prostate is contributing to the patients erectile
dysfunction.
Laboratory Tests
 If patient has signs of hypogonadism and complains of
decreased libido, a serum testosterone concentration may be

below the normal range, which would be consistent with a
hormonal cause of erectile dysfunction.
 If the patient has an enlarged prostate noted on digital rectal
examination, a blood sample for prostate specific antigen
should be obtained. If elevated, the patient should be evalu-
ated for a prostate disorder, which could contribute to erectile
dysfunction.
DIAGNOSIS
With the availability in the late 1990s of effective medications for
erectile dysfunction independent of the etiology, diagnostic evalu-
ation of erectile dysfunction became streamlined.5,12 Key assess-
ments include a description of the severity of erectile dysfunction,
complete medical and surgical histories, review of concurrent
medications, physical examination, and selected clinical labora-
tory tests.12
To assess the severity of erectile dysfunction, the patient should be
asked about the quality of sexual intercourse for the last 4 weeks to
6 months. A self-administered standardized questionnaire, such as
the International Index of Erectile Dysfunction (IIEF), is often used.
It is administered before initiation of any treatment and repeated
at regular intervals during treatment. It includes 15 questions
about the quality of erectile function and satisfactoriness of sexual
intercourse.13 Questions include the following: How often were
you able to maintain an erection? How difficult was it to sustain an
erection? How satisfied are you with your sexual life? The physician
should carefully assess the expectations for erectile function of the
patient and the partner to ensure that expectations are reasonable.
Shorter versions of the IIEF and other self-reporting questionnaires
are also used in clinical practice.
A medical history should be obtained to identify concurrent
medical illnesses (e.g., hypertension, atherosclerosis, hyperlipi-
demia, diabetes mellitus, depression) or surgical procedures (e.g.,
perineal or pelvic) that are risk factors for or are associated with
organic or psychogenic erectile dysfunction. Underlying diseases
that do not optimally respond to treatment should be addressed
before specific treatment for erectile dysfunction is initiated. If the
patient smokes cigarettes, drinks excessive amounts of ethanol, or
uses recreational drugs, these social habits should be discontinued
before specific treatment for erectile dysfunction is started.
A complete listing of the patients prescription and nonprescrip-
tion medications and dietary supplements should be reviewed by
the clinician, who should identify drugs that may be contributing to
erectile dysfunction. If possible, causative agents should be discon-
tinued or the dose should be reduced.
A physical examination of the patient should include a check
for hypogonadism (i.e., signs of gynecomastia, small testicles, and
decreased beard or body hair). The penis should be evaluated for
diseases associated with abnormal penile curvature (e.g., Peyronie
disease), which are associated with erectile dysfunction. Femoral
and lower extremity pulses should be assessed to provide an indi-
cation of vascular supply to the genitals. Anal sphincter tone and
other genital reflexes should be checked for the integrity of the
nerve supply to the penis. A digital rectal examination in patients
50 years or older is needed to rule out benign prostatic hyperplasia,
which may contribute to erectile dysfunction.
Selected laboratory tests should be obtained to identify the pres-
ence of underlying diseases that could cause erectile dysfunction.
They include a fasting serum blood glucose and lipid profile. Serum
testosterone levels should be checked in patients older than 50 years
and in younger patients who complain of decreased libido. At least
1441
two serial early morning serum testosterone levels are needed to
confirm the presence of hypogonadism.14,15
CHAPTER 92
Finally, erectile dysfunction is a potential marker for arterio-
sclerosis. Therefore, patients who present with erectile dysfunction
should undergo a cardiovascular risk assessment to identify treat-
able medical conditions.16,17
TREATMENT
Erectile Dysfunction
Erectile Dysfunction
 DESIRED OUTCOMES
The goal of treatment is improvement in the quantity and quality
of penile erections suitable for satisfactory intercourse. Simple as
this may sound, healthcare providers must ensure that patients
and their partners have reasonable expectations for any therapies
that are initiated. Furthermore, only patients with erectile dysfunc-
tion should be treated. Patients who have normal sexual function
should not seekor be encouraged to seektreatment in an effort
to enhance sexual function or enable increased activity.18
 GENERAL APPROACH TO TREATMENT
 The Second Princeton Consensus Conference is a widely
accepted multidisciplinary approach to managing erectile dysfunc-
tion that maps out a stepwise treatment plan.1921 The first step in
clinical management of erectile dysfunction is to identify and, if
possible, reverse underlying causes. Risk factors for erectile dysfunc-
tion, including hypertension, diabetes mellitus, smoking, or chronic
ethanol abuse, should be addressed and minimized. Patients should
follow a heart-healthy lifestyle, which includes physical fitness,
weight loss to achieve a normal body mass index, low cholesterol
diets, no excessive ethanol intake, and no smoking.22,23 In some
cases, these types of interventions are sufficient to restore erectile
function. However, if erectile dysfunction does not respond to these
measures, specific treatment is indicated.
For patients with psychogenic erectile dysfunction, psychotherapy
can be used as monotherapy or as an adjunct to specific treatments
for the disorder. To enhance the relevance of psychotherapy, both
the patient and the partner should be included in the counseling
sessions. Treatment should be individualized and should address
immediate factors that may be causing performance anxiety or
depression. The effectiveness of psychotherapy is generally low, and
long-term psychotherapy is often necessary.
   Specific treatments of erectile dysfunction include
vacuum erection devices (VEDs), pharmacologic treatments, and
surgery. The ideal treatment of this disorder should have a fast
onset, be effective, be convenient to administer, be cost effective,
have a low incidence of serious adverse effects, and be free of seri-
ous drug interactions (Table 923). Generally, when choosing
from among treatment approaches, those that are least invasive are
selected first; more invasive therapies are reserved for patients who
do not respond to first-line agents.
The American Urological Association Guideline on the Management
of Erectile Dysfunction clearly identifies oral phosphodiesterase
inhibitors for first-line treatment. Vacuum erection devices, intracav-
ernosal injection of erectogenic agents, or intraurethral prostaglandin
inserts are second-line treatments; prescribing of a particular agent
for a patient should be individualized. Surgical intervention should
be reserved for patients who fail to respond to first- and second-line
treatments.24 A sample algorithm that guides selection of treatment is
shown in Figure 922.
1442
TABLE 92-3 Dosing Regimens for Selected Drug Treatments for Erectile Dysfunction
SECTION 10

Route of
Administration Generic Name (Brand Name) Dosage Form Common Dosing Regimen
Oral Yohimbine (Aphrodyne, Yocon, Yohimex) 5.4-mg tablet or capsule 5.4 mg 3 times per day
Sildenafil (Viagra) 25-mg, 50-mg, 100-mg tablet 25100 mg 1 h before intercourse
Apomorphine (Uprima)a 10-mg sublingual tablet, 25-mg tablet and capsule 1040 mg daily
Fluoxymesterone (Halotestin) 2-mg, 5-mg, 10-mg, 50-mg tablet 520 mg daily
Trazodone (Desyrel) 100-mg, 150-mg, 300-mg tablet 50150 mg daily
Vardenafil (Levitra) 2.5-mg, 5-mg, 10-mg, 20-mg tablet 510 mg 1 h before intercourse
Tadalafil (Cialis) 5-mg, 10-mg, 20-mg tablet 520 mg before intercourse or 2.55 mg daily
Urologic Disorders

Topical Testosterone patch (Testoderm) 4 mg/patch, 6 mg/patch 46 mg/day; apply to scrotum

Testosterone patch (Testoderm TTS) 4 mg/patch, 6 mg/patch 46 mg/day; apply to arm, buttock, back
Testosterone patch (Androderm) 2.5 mg/patch 2.55 mg/day; apply to arm, back, abdomen, thigh
Testosterone gel (AndroGel 1%) 5 g/pkt, 10 g/pkt 5 g/activiation 510 g/day; apply to shoulders, upper arms, abdomen
Intramuscular Testosterone cypionate 100 mg/mL, 200 mg/mL 200400 mg every 24 wk
(Depo-Testosterone)
Testosterone enanthate (Delatestryl) 100 mg/mL, 200 mg/mL 200400 mg every 24 wk
Subcutaneous implant Testosterone (Testopel) 75-mg pellet 150450 mg every 34 mo
Intraurethral Alprostadil (MUSE) 125-mcg, 250-mcg, 500-mcg, 1,000-mcg pellet 1251,000 mcg 510 min before intercourse
Intracavernosal Alprostadil (Caverject) 5-mcg, 10-mcg, 20-mcg injection 2.560 mcg 510 min before intercourse
Alprostadil (Edex) 5-mcg, 20-mcg, 40-mcg injection 2.560 mcg 510 min before intercourse
Papaverineb 30 mg/mL injection Variable, usually used in combination with alprostadil
and phentolamine
Phentolamineb 2.5 mg/mL injection Variable, usually used in combination with alprostadil
and papaverine

a
Not commercially available in the United States as a sublingual formulation; only available in United States as subcutaneous injection that is FDA approved for Parkinsons disease.
b
Not FDA approved for this use.

Patient with ED

Drug-induced ED Organic ED Psychogenic ED

1. Discontinue 1. Psychotherapy
offending agent, or Oral Vacuum
2. Behavior Modification
2. Reduce dose of phosphodiesterase erection
offending agent inhibitor device

If ineffective If effective,
If effective, If ineffective continue
continue

Intracavernosal
therapy

If effective, If ineffective
continue

Intraurethral
alprostadil

If effective, If ineffective
continue

Penile prosthesis

FIGURE 92-2. Algorithm for selecting treatment for erectile dysfunction. For organic erectile dysfunction (ED), oral agents are first-line therapy for younger
patients, and vacuum erection devices are generally used first in older patients who are married or otherwise have a stable sexual relationship. These two
approaches are sometimes used together in an effort to avoid surgical implantation of penile prostheses.

c
a penile shaft may feel cold and numb. If the constriction bands are
b
FIGURE 92-3. Technique for using a vacuum erection device with ten-
sion band or rubber constriction ring. The patient inserts his penis into
the cylinder, which is then pushed up flush against his lower abdomen
to create a vacuum chamber. The patient activates the pump to produce
a vacuum pressure, which draws arteriolar blood into the corpora caver-
nosa. To prolong the erection, the patient can use constriction bands or
tension rings, which are placed at the base of the penis, to keep the arte-
riolar blood in and reduce venous outflow from the penis. (From http://
kidney.niddk.nih.gov/kudiseases/pubs/impotence.)
 VACUUM ERECTION DEVICE
A VED has three parts: a pump, which generates a negative vacuum
pressure; a cylinder, which is closed at one end and into which the
penis is inserted; and tubing, which connects the pump to the cylin-
der. The patient inserts his penis into the open end of the cylinder,
which is then pushed up flush against his lower abdomen to create
a vacuum chamber. Then the patient activates the pump to produce
a vacuum pressure, which draws arteriolar blood into the corpora
cavernosa. To prolong the erection, the patient can use constriction
bands or tension rings, which are placed at the base of the penis,
to keep the arteriolar blood in and to reduce venous outflow from
the penis. With the assistance of loading cones to protect the glans,
these bands or rings can be rolled over the glans penis and up the
erect penile shaft. Alternatively, they can be first threaded onto the
plastic cylinder before the penis is inserted. Once the penis is erect,
the band or ring can be rolled off the cylinder onto the base of the
penis (Fig. 923).
 The onset of action of the VED is comparatively slow
(30 minutes), which requires patience from both the patient and
the sexual partner. VEDs are not discreet. That is, a patients use
of a VED is evident to the partner. For this reason, VEDs appear
to work best in older patients who are married or who have stable
sexual relationships. In this group, VEDs could be considered first-
line therapy, and the overall satisfaction rate can be as high as 60%
to 80%.5,18 However, 6% to 11% of partners complain that the penis
is cool to the touch or is discolored (bluish) in appearance, particu-
larly when constriction bands are used.
VEDs may be used as second-line therapy in patients who do not
respond to oral or injectable drug treatments for erectile dysfunc-
tion. The combination of a VED with intracavernosal or intraure-
thral alprostadil is associated with a higher efficacy rate than use
of the VED alone. As a result, combination therapy sometimes
is attempted before penile prosthesis surgery is considered in the
patient who fails VED monotherapy.
VEDs are available with manual or battery-operated pumps.
The latter offer greater convenience, particularly in patients with
arthritis of the hands, who find manual pumps too difficult and
tiring to operate. The American Urological Association recom-
mends the use of commercially available VEDs by prescription
1443
only. These have safety mechanisms that minimize the likelihood
of excessively high vacuum pressures which can cause penile dis-
CHAPTER 92
comfort and injury.24
Pain or injury from VEDs most often is caused by the constric-
tion bands used to sustain an erection. Because these rings trap
blood in the corpora and reduce arteriolar flow into the penis, the
applied for longer than 30 to 60 minutes, the penile shaft may turn
blue and hurt. Patients may complain that a hinge-like erection
is produced in that the penis pivots on the rubber ring or tension
Erectile Dysfunction
band. Patients sometimes fail to ejaculate.
VEDs are contraindicated in patients with sickle cell disease.
These patients are prone to priapism, which can be exacerbated by
the use of constriction bands with VEDs. The devices also should be
used cautiously by patients taking oral anticoagulants because war-
farin, through a poorly understood and idiosyncratic mechanism,
can cause priapism.
 PHOSPHODIESTERASE INHIBITORS
Mechanism
In the presence of sexual stimulation, nitric oxide is released by
neurons or endothelial cells in penile tissue, thereby enhancing
the activity of guanylate cyclase, the enzyme responsible for
conversion of guanylate triphosphate to cGMP (Fig. 924).25
cGMP is a vasodilatory secondary messenger that upregulates
the response to nitric oxide, increases smooth muscle relaxation,
enhances arterial flow to the corpora cavernosa and enhances
blood filling of cavernosal sinuses. Catabolism of cGMP is medi-
ated by phosphodiesterase.
Three competitive, reversible inhibitors of the phosphodiesterase
isoenzyme type 5 found in genital tissue are marketed for erectile
dysfunction in the United States (Table 924). They act by decreas-
ing catabolism of cGMP. However, phosphodiesterase isoenzyme
type 5 is also found in peripheral vascular tissue, tracheal smooth
muscle, and platelets. Inhibition of phosphodiesterase in these non-
genital tissues can produce unwanted effects.
The three marketed phosphodiesterase inhibitors differ in their
degree of selectivity in inhibiting other phosphodiesterase isoen-
zymes, pharmacokinetic profiles, drugfood interactions, and
adverse effects (see Table 924).
Efficacy
Because of their apparent effectiveness, convenient route of admin-
istration, and comparatively low incidence of serious adverse
effects, phosphodiesterase inhibitors are considered first-line ther-
apy for erectile dysfunction, particularly in younger patients. They
allow for discreet use. Although not based on direct comparison
trials, all three commercially available phosphodiesterase inhibitors
are considered to be equally effective.26,27
In the presence of sexual stimulation and in doses of 25 to
100 mg, sildenafil produces satisfactory erections in 56% to
82% of patients, independent of the etiology of erectile dysfunc-
tion. Similar results are documented in the product labeling for
the other two agents in this class (65%80% for vardenafil and
62%77% for tadalafil). Response rates in the lower range for
phosphodiesterase inhibitors have been documented in patients
with diabetes mellitus or in patients after radical prostatectomy,
probably due to neuropathy or surgery-related nerve damage,
respectively.24,25,28 The effectiveness of the drugs appears to be
dose related.
Approximately 30% to 40% of patients do not respond to
phosphodiesterase inhibitors.24 At least half of nonresponders can
1444
SECTION 10

Inhibited by
sildenafil,
vardenafil, and
tadalafil

Sexual Nitric oxide is released Nitric oxide stimulates cGMP is catabolized by

stimulation from NANC nerves and guanylate cyclase, which phosphodiesterase and is
Urologic Disorders

of patient endothelial cells increases tissue converted to GMP which is

concentration of cGMP. inactive
Increased levels of
cGMP produce a penile
erection

FIGURE 92-4. Mechanism of action of phosphodiesterase inhibitors. All inhibit catabolism of cGMP, a vasodilatory secondary messenger. (cGMP, cyclic
guanosine monophosphate; NANC, nonadrenergic noncholinergic.)

benefit from education on proper use of the drugs, and this likely
will prove true for the other agents used for erectile dysfunction.
Education of patients should include the following points: (1)
patients must engage in sexual stimulation (foreplay) for the best
response; (2) sildenafil should be taken on an empty stomach, at
least 2 hours before meals, for the fastest response, but the other two
agents can be taken without regard to meals; (3) taking sildenafil
or vardenafil with a fatty meal can decrease the absorption rate,
but the absorption rate of tadalafil is not affected;26 (4) patients
who do not respond to the first dose should continue with the
phosphodiesterase inhibitor for at least five to eight doses before
failure is declared, as increasing success rates are reported with
sequential dose administration;27 (5) some patients require dosage
titration up to 100 mg sildenafil, 20 mg vardenafil, or 20 mg tadalafil
for a response;27,28 (6) patients should avoid excessive alcohol intake,
which can cause erectile dysfunction; and (7) involvement of the
sexual partner can help improve the patients response to treatment.
In addition, treatment of concomitant medical illnesses which con-
tribute to erectile dysfunction (e.g., diabetes mellitus, hypertension,
hypogonadism) should be optimized.20
The effectiveness of switching from one phosphodiesterase
inhibitor to another when the patient does not respond to an initial
agent is controversial. In two small studies, vardenafil was beneficial
in patients who did not respond to sildenafil.26,29 However, con-
trolled clinical trials in larger patient groups are needed before this
strategy is used as routine treatment.
The phosphodiesterase inhibitors should not be used by patients
with normal erectile function. Also, according to Food and Drug
Administration (FDA)approved labeling, the drugs should not be
used in combination with other forms of therapy for erectile dys-
function because prolonged erections (which may lead to priapism)
may result.30
Long-term use of phosphodiesterase inhibitors is not associated
with tachyphylaxis.31,32

TABLE 92-4 Pharmacodynamics and Pharmacokinetics of Phosphodiesterase Inhibitors

Sildenafil (Viagra)a Vardenafil (Levitra)a Tadalafil (Cialis)a
Inhibits PDE-5 Yes Yes Yes
Inhibits PDE-6 Yes Minimally No
Inhibits PDE-11 No No Yes
Time to peak plasma level (h) 0.51 0.70.9 2
Fatty meal decreases rate of oral absorption? Yes Yes No
Mean plasma half-life (h) 3.7 4.44.8 18
Percentage of dose excreted in feces 80 9195 61
Percentage of dose excreted in urine 13 26 36
Duration (h) 4 4 2436
Usual dose (mg) before intercourse 25100 520 520
Daily dose (mg) Not applicable Not applicable 2.55
Dose (mg) in patients 65 y (mg) 25 5 520
Dose (mg) in moderate renal impairment 25100 520 5
Dose (mg) in severe renal impairment 25 520 5
Dose (mg) in mild hepatic impairment 25100 520 10
Dose (mg) in moderate hepatic impairment 25100 510 10
Dose (mg) in severe hepatic impairment 25 Not evaluated Not recommended
Dose in patients taking cytochrome P450 3A4 inhibitorsa 25 mg 2.55 mg every 2472 h 10 mg every 72 h

a
Sildenafil doses should be decreased when any potent cytochrome P450 3A4 inhibitor (e.g., cimetidine, erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir, and saquinavir) is used. Vardenafil doses
vary according to the agent used (2.5 mg every 72 hours for ritonavir; 2.5 mg every 24 hours for indinavir, ketoconazole 400 mg daily, and itraconazole 400 mg daily; and 5 mg every 24 hours for ketoconazole
200 mg daily, itraconazole 200 mg daily, and erythromycin). Tadalafil doses are reduced only when the drug is used with the most potent cytochrome P450 3A4 inhibitors (e.g., ketoconazole, ritonavir).
PDE, phosphodiesterase.

 SELECTIVITY OF OTHER
PHOSPHODIESTERASE ISOENZYMES
More than 25 different phosphodiesterase isoenzymes have been
identified; however, the physiologic effects of stimulation and
inhibition of some of these isoenzymes remain to be elucidated. Of
note, phosphodiesterase isoenzyme type 6 is localized to the rods
and cones of the eye. Inhibition of this isoenzyme has been associ-
ated with blurred vision and cyanopsia. Sildenafil is the most potent
inhibitor of phosphodiesterase isoenzyme type 6, vardenafil is an
intermediate inhibitor, and tadalafil is the least potent inhibitor.26
Likewise, phosphodiesterase isoenzyme type 11 is localized to stri-
ated muscle. Inhibition of this isoenzyme has been associated with
myalgia and muscle pain. Tadalafil exerts the greatest inhibitory
activity against phosphodiesterase type 11.6
Pharmacokinetics and
DrugFood Interactions
Pharmacokinetic parameters of the phosphodiesterase inhibitors
are listed in Table 924.
Vardenafil and sildenafil have similar pharmacokinetic profiles.
Both drugs have a 1-hour onset of action and short duration of
action. Oral absorption is significantly delayed when either drug
is taken within 2 hours of a fatty meal. In contrast, tadalafil has
a delayed onset of action of 2 hours, has a prolonged duration of
action up to 36 hours, and food does not affect its rate of absorption.
Thus, tadalafil offers greater spontaneity for patients, as one dose
can last through an entire weekend and allow for multiple acts of
sexual intercourse over multiple days with a single dose.32
The onset of action of these agents has undergone reexamination
to assess how soon after drug administration patients can expect
to have an erection suitable for intercourse. Although up to 50%
of patients may develop an erection within 20 to 30 minutes of
sildenafil 100 mg, vardenafil 20 mg, or tadalafil 20 mg, the rest of
the patients may require a full hour to achieve an adequate erec-
tile response.33 Therefore, patients should be instructed to allow
adequate time for the drug to work.
Concomitant ingestion of ethanol with phosphodiesterase inhibi-
tors can result in orthostatic hypotension. Therefore, the manufac-
turer recommends that patients avoid ethanol when taking these
medications.
All three phosphodiesterase inhibitors are hepatically catabolized
principally by the cytochrome P450 3A4 microsomal isoenzyme
and by other P450 isoenzymes (minor routes) and/or other hepatic
enzymes. Sildenafil and vardenafil have active metabolites, which
are excreted primarily in the feces (see Table 924).
Dosing
The usual oral doses of the phosphodiesterase inhibitors are listed in
Table 924. Sildenafil and vardenafil should be taken on demand or
at least 30 to 60 minutes before sexual intercourse. Tadalafil should
be taken at least 2 hours before sexual intercourse. The durations
of action for sildenafil and vardenafil are 4 to 5 hours, whereas the
effects of tadalafil last for 36 hours. The agents vary as to whether
doses must be adjusted for patients 65 years and older and those
with compromised hepatic or renal function. Patients should be
advised to take no more than the amount prescribed and to use
only one dose per day (or less often in the case of some patients
taking tadalafil). Doses greater than those recommended have
been described in the published literature (e.g., tadalafil 100 mg);
however, such dosing regimens have not consistently produced
improved erectile responses.
For patients who do not respond to an adequate course of on-
demand phosphodiesterase inhibitors for erectile dysfunction, daily
1445
low dosing of these agents may improve endothelial function in
cavernosal tissue. That is, regular use of phosphodiesterase inhibi-
CHAPTER 92
tors may increase local concentrations of cGMP, which may lead
to increased oxygen tension, improved blood flow, and reduced
endothelial damage. A preliminary clinical trial of daily use of
tadalafil 2.5 or 5 mg showed a 58% frequency of successful sexual
intercourse compared with conventional on-demand use of tadala-
fil 5 to 20 mg, which produced a 21% frequency of success.34,35 Other
potential advantages of daily low dosing regimens include a lower
potential for dose-related adverse effects, lower cost, and increased
Erectile Dysfunction
spontaneity of sexual intercourse. However, more extensive clinical
study is needed to evaluate the benefit of daily dosing of phospho-
diesterase inhibitors before the approach can be preferred to an
on-demand regimen.
Adverse Effects
Most adverse effects of the phosphodiesterase inhibitors are mild or
moderate and are self-limited, and patients often become tolerant
to them with continued use.36,37 The rates of drug discontinuation
caused by adverse effects are low, ranging from 2.1% to 2.5%, and are
similar for all three agents. In usual doses the most common adverse
effects are headache (11%), facial flushing (12%), dyspepsia (5%),
nasal congestion (3.4%), and dizziness (3%),25 all of which result
from vasodilation or smooth muscle relaxation secondary to inhibi-
tion of phosphodiesterase isoenzyme type 5 in extragenital tissues.18
Sildenafil and vardenafil produce an 8- to 10-mm Hg decrease
in systolic and a 5 to 6 mm Hg decrease in diastolic blood pressure
starting approximately 1 hour after a dose is taken and lasting for
4 hours. Most patients are asymptomatic as a result of these blood
pressure changes, but some patients, particularly those taking mul-
tiple antihypertensives or nitrates or those with baseline hypoten-
sion, may develop clinical symptoms as a consequence of these
peripheral vascular effects. Tadalafil does not produce decreases in
blood pressure, but it must be used with caution in patients with
cardiovascular disease because of the cardiac risk inherent to sexual
activity. A management approach for such patients, developed
based on an analysis of deaths in men who were using sildenafil and
commonly referred to as the recommendations of the Princeton
Consensus Guideline Conference II,19 should be applied to all the
phosphodiesterase inhibitors (Table 925).
Sildenafil and vardenafil cause increased sensitivity to light,
blurred vision, or loss of bluegreen color discrimination in 2%
to 3% of patients. These effects result from inhibition of phospho-
diesterase type 6 in the photoreceptor cells of in retinal rods and
cones, particularly at doses larger than 100 mg. Visual adverse
effects commonly occur at the time of peak serum concentrations.
Although visual adverse effects are mild and reversible, caution
regarding use is recommended for airplane pilots, who rely on
green and blue lights for landing planes. Tadalafil has minimal to no
inhibitory activity against type 6 phosphodiesterase, and no visual
adverse effects have been reported.38 Nevertheless, according to
current product labeling, all phosphodiesterase inhibitors should be
used cautiously in patients at risk for retinitis pigmentosa, a genetic
disease associated with retinal phosphodiesterase deficiency.
Nonarteritic anterior ischemic optic neuropathy (NAION) is a
sudden, unilateral, painless blindness, which may be irreversible.
Isolated cases of NAION have been associated with phosphodi-
esterase inhibitor use.39 Although a cause-and-effect relationship
has not been definitively established, the blood pressurelowering
effects of these medications may decrease blood flow to the optic
nerve and lead to sudden unilateral decrease in vision. Because
NAION may lead to permanent vision loss, the FDA has required
inclusion of warnings on the product labeling of phosphodiesterase
inhibitors. Specifically, before receiving these agents, patients at risk
1446
TABLE 92-5 Recommendations of the Second Princeton Consensus Conference for Cardiovascular Risk Stratification of Patients Being
SECTION 10

Considered for Phosphodiesterase Inhibitor Therapy

Risk Category Description of Patients Condition Management Approach
Low risk Has asymptomatic cardiovascular disease with < 3 risk factors for Patient can be started on phosphodiesterase inhibitor
cardiovascular disease
Has well-controlled hypertension
Has mild, stable angina
Has mild congestive heart failure (NYHA class I)
Has mild valvular heart disease
Had a myocardial infarction >6 weeks ago
Urologic Disorders

Intermediate risk Has 3 risk factors for cardiovascular disease Patient should undergo complete cardiovascular workup and treadmill
Has moderate, stable angina stress test to determine tolerance to increased myocardial energy
Had a recent myocardial infarction or stroke within the past 6 weeks consumption associated with increased sexual activity
Has moderate congestive heart failure (NYHA class II)
High risk Has unstable or symptomatic angina, despite treatment Phosphodiesterase inhibitor is contraindicated; sexual intercourse
Has uncontrolled hypertension should be deferred
Has severe congestive heart failure (NYHA class III or IV)
Had a recent myocardial infarction or stroke within past 2 weeks
Has moderate or severe valvular heart disease
Has high-risk cardiac arrhythmias
Has obstructive hypertrophic cardiomyopathy

NYHA, New York Heart Association.

From Kostis et al.21

for NAION should be evaluated by an ophthalmologist. Patients at
risk include a wide variety of patients: those with glaucoma, macular
degeneration, diabetic retinopathy or hypertension, those who have
undergone eye surgery or have experienced eye trauma, patients
who are age 50 years or more, or smokers. A patient who experi-
ences sudden vision loss while taking a phosphodiesterase inhibitor
should be evaluated for NAION before continuing treatment.40
Tadalafil produces lower back and limb muscle pain, which occur
in a dose-related fashion in 7% to 30% of patients treated with doses
of 10 to 100 mg.41 The mechanism for this is not known. It may be
linked to inhibition of type 11 phosphodiesterase, a unique charac-
teristic of tadalafil.
Vardenafil can cause prolongation of the QT interval. Therefore,
it should be used cautiously in patients with this anomaly or in
patients who are taking medications that prolong the QT interval
(e.g., quinidine).
Priapism is a rare adverse effect of phosphodiesterase inhibitors,
particularly sildenafil and vardenafil, which have shorter plasma
half-lives than tadalafil. Priapism has been associated with excessive
doses of the phosphodiesterase inhibitor or concomitant therapy
involving other erectogenic drugs.
Drug Interactions
Patients taking organic nitrates may develop severe hypotension if
they are taken with phosphodiesterase inhibitors as a result of two
major factors: (1) organic nitrates on their own produce hypoten-
sion, and (2) organic nitrates are nitric oxide donors, which can
stimulate the activity of guanylate cyclase and increase tissue lev-
els of cGMP. For this reason, use of the three phosphodiesterase
inhibitors is contraindicated in patients taking nitrates given by
any route at scheduled times or intermittently.19,42 Furthermore,
nitrates should be withheld for 24 hours after sildenafil or vardenafil
administration and for 48 hours after tadalafil administration.19,42
Finally, if a patient who has taken a phosphodiesterase inhibi-
tor requires medical treatment of angina, nonnitrate-containing
agents (e.g., calcium channel blocker, -adrenergic antagonist,
morphine) should be used.
If severe hypotension occurs after exposure to nitrates and
a phosphodiesterase inhibitor, the patient should be placed
in a Trendelenburg position and aggressive fluid administration
initiated. If severe hypotension continues, parenteral -adrenergic
agonists (e.g., dopamine) should be administered cautiously.
Interestingly, dietary sources of nitrates, nitrites, or l-arginine (a
precursor for nitrates) do not interact with the phosphodiesterase
inhibitors. This is because dietary sources do not increase circulat-
ing levels of nitric oxide in humans.
Sildenafil does not appear to interact with antihypertensive medi-
cations. In retrospective analyses of patients taking sildenafil in com-
bination with -adrenergic antagonists, -adrenergic antagonists,
diuretics, angiotensin-converting enzyme inhibitors, angiotensin
receptor blockers, or calcium channel blockers, the incidence of
hypotension was similar to that reported in patients taking sildenafil
alone.43,44 This finding was confirmed by a retrospective analysis of
pooled data on more than 4,800 patients in 35 clinical trials.30
Small decreases in blood pressure with clinically symptomatic
hypotension have been described in some patients taking sildenafil
and tadalafil and immediate-release formulations of terazosin and
doxazosin.45 In contrast, concurrent administration of extended-
release alfuzosin, silodosin, or tamsulosin, which produce lower
peak serum concentrations than immediate-release formulations
after administration or exhibit 1A-adrenergic selectivity, show
minimal or no decrease in blood pressure.4648 Package labeling for
phosphodiesterase inhibitors include a caution about concomitant
use of phosphodiesterase inhibitors and -adrenergic antagonists.
Hepatic metabolism of all three phosphodiesterase inhibitors can
be inhibited by enzyme inhibitors of CYP 3A4, including cimeti-
dine, erythromycin, clarithromycin, ketoconazole, itraconazole,
ritonavir, saquinavir, and grapefruit juice.4851 Lower starting doses
should be used in these patients (see Table 924).
CLINICAL CONTROVERSY
Some clinicians believe that tachyphylaxis may develop with
continuous use of sildenafil, but others believe that a lack
of responsiveness may be due to worsening of underlying
diseases that may contribute to the development of erectile
dysfunction.18 Positive treatment response despite continuous
use of these agents for up to 6 years suggests that tachyphylaxis
does not occur.26,38
 1447
TABLE 92-6 Comparison of Testosterone Replacement Regimens and Ideal Testosterone Replacement Regimen

CHAPTER 92
Achieves Serum Produces Normal
Testosterone Circadian Pattern of Produces Normal Pattern
Concentrations in Serum Testosterone of Serum Concentrations of
Normal Range? Concentrations? Androgen Metabolites? Adverse Effects
Oral testosterone No No No Hyperlipidemia
Sodium retention
Oral alkylated androgens Yes No No Hyperlipidemia
Sodium retention
Hepatotoxicity

Erectile Dysfunction
Intramuscular testosterone Yes No; produces supraphysiologic No, excess testosterone is Mood swings
cypionate or enanthate serum concentrations for converted to estradiol Gynecomastia
several days after injection Polycythemia
Hyperlipidemia
Transdermal nonscrotal skin patch Yes Yes, provided the patch is Yes Dermatitis due to permeation
placed at night enhancers in formulation
Transdermal scrotal skin patch Yes Yes provided the patch is No; 5-reductase in scrotal skin Dermatitis due to permeation
applied in the morning metabolizes testosterone and enhancers in formulation
increases serum concentrations
of dihydrotestosterone
Transdermal gel Yes Yes Yes May be inadvertently transferred
to others who rub up against
the patients skin treated area
Testosterone subcutaneous implant Yes No No; produces elevated Pellet may be extruded
concentrations of accidentally, resulting in loss
dihydrotestosterone of drug effect
Buccal system Yes No No Gum irritation, bitter taste

Data from Gore JL, Swerdloff RS, Rajfer J. Androgen deficiency in the etiology and treatment of erectile dysfunction. Urol Clin N Am 2005;32:457468.

 TESTOSTERONE REPLACEMENT REGIMENS Testosterone replacement regimens should never be adminis-

tered to men with normal serum testosterone levels.
Mechanism

Testosterone replacement regimens supply exogenous testos- Efficacy

terone and restore serum testosterone levels to the normal range
(3001,100 ng/dL; 10.438.2 nmol/L). In so doing, testosterone
replacement regimens correct symptoms of hypogonadism, which
include malaise, loss of muscle strength, depressed mood, and
decreased libido. Testosterone can directly stimulate androgen
receptors in the central nervous system and is thought to be respon-
sible for maintaining normal sexual drive. In addition, testosterone
may stimulate nitric oxide synthase, thereby increasing cavernosal
concentrations of nitric oxide, and enhancing the effects of phos-
phodiesterase type 5 in cavernosal tissue.52
Indications
Testosterone replacement regimens are indicated in symptomatic
patients with primary or secondary hypogonadism, as confirmed
by both the presence of a decreased libido and low serum con-
centrations of testosterone.18 Serum testosterone concentrations
typically are measured in the early morning because the secretion
pattern of this hormone follows a circadian pattern, with high-
est serum concentrations in the morning hours. Simultaneous
serum luteinizing hormone levels help to distinguish patients
with primary hypogonadism, who have elevated luteinizing hor-
mone levels, from those with secondary hypogonadism, who have
decreased luteinizing hormone levels. Primary hypogonadism
can be a characteristic of aging men who undergo andropause,
in which the Leydig cells of the testes slowly and progres-
sively decrease testosterone production.52 Symptoms, including
decreased libido, erectile dysfunction, gynecomastia, decreased
muscle mass, increased body fat, and osteopenia, develop gradu-
ally over years.
Testosterone replacement regimens restore muscle strength and
sexual drive and improve mood in patients with hypogonadism.
Improvements are generally observed within days or weeks of the
start of testosterone replacement. Administration of testosterone
will correct the serum testosterone level to the normal range. No
additional benefit has been demonstrated for large doses of testos-
terone, which increase the serum testosterone level from the low
end to the upper end of the normal range or to the above-normal
range.53 Testosterone replacement regimens do not directly correct
erectile dysfunction; instead, they improve libido, thereby correct-
ing secondary erectile dysfunction.54
Testosterone replacement regimens can be administered orally,
parenterally, or transdermally (Table 926). Injectable testosterone
replacement regimens are the preferred treatment for symptomatic
patients with primary or secondary hypogonadism because they are
effective, inexpensive, and not associated with the bioavailability prob-
lems or hepatotoxic adverse effects of oral androgens.52 Although con-
venient for the patient, testosterone patches and gels are much more
expensive than other forms of androgen replacement; therefore, they
should be reserved for patients who refuse injectable testosterone.
In the ideal testosterone replacement regimen, the medication
would mimic the normal circadian pattern of serum testosterone
concentrations such that peak and trough concentrations occur in
the early morning and late afternoon, respectively; produce serum
concentrations in the normal range; produce serum concentrations
of dihydrotestosterone and estradiol, which are metabolites of tes-
tosterone that mimic the normal physiologic pattern; and produce
minimal adverse effects.52 Table 926 compares commercially avail-
able testosterone replacement regimens for these characteristics and
shows that an ideal regimen has yet to be identified.
1448
Pharmacokinetics
SECTION 10
Natural testosterone has poor oral bioavailability because of extensive
first-pass hepatic metabolism; therefore, large doses must be taken. To
improve oral bioavailability, alkylated derivatives were formulated. Of
these derivatives, methyltestosterone and fluoxymesterone are more
resistant to hepatic catabolism and can be taken in smaller daily doses,
which are potentially safer. However, oral alkylated derivatives of tes-
tosterone are not metabolized to dihydrotestosterone or estradiol, and
are associated with a higher incidence of serious hepatotoxicity and
therefore are not preferred for management of hypogonadism.
Urologic Disorders
An alternative to oral administration is the testosterone buccal
system (Striant), which is applied to the gum above the upper inci-
sor teeth twice per day. Over time it forms a gel from which testos-
terone is absorbed. One advantage of this route of administration
is that the drug bypasses first-pass hepatic catabolism, which allows
for increased bioavailability of testosterone.
Several testosterone esters have been formulated for intramus-
cular injection, with different durations of action (see Table 923).
The shorter-acting testosterone propionate, which requires dosing
3 times per week, has been replaced with testosterone cypionate or
enanthate, which can be dosed every 2, 4, or 6 weeks in most patients.
An even longer-acting parenteral testosterone is available as a sub-
cutaneous implant for dosing every 3 to 6 months. Although this
schedule minimizes repeat visits to the clinicians office for dosing,
the implant must be administered by a physician, and the implanted
pellet may be extruded after administration. This extrusion has
been reported in up to 8.5% of treated patients and results in loss of
drug effect. These testosterone formulations produce suprapharma-
cologic patterns of serum testosterone during the dosing interval,
which have been linked to mood swings in some patients.
Topical testosterone replacement regimens can be delivered as
once-daily patches or gel. Testosterone patches increase serum testos-
terone levels into the normal range in 2 to 6 hours. Serum testosterone
levels return to baseline 24 hours after patch administration. However,
unlike oral or injectable supplements, transdermal testosterone patches
applied at bedtime or testosterone gel applied each morning produce
physiologic patterns of serum testosterone levels throughout the day.
The clinical importance of this biochemical effect is unknown.52
The original Testoderm brand patch was formulated for scrotal
application. Scrotal skin is thinner and has a richer vascular supply than
does the skin on the arms or thighs. Therefore, application of Testoderm
patches produces excellent absorption of the hormone. However, the
patch can fall off when the scrotum becomes damp or moist, when the
patient exercises, or if the scrotum is excessively hairy.
For improved convenience, Androderm and Testoderm TTS
patches were formulated for application to the arms, buttocks, or
back; Androderm can also be applied to the thighs. The addition
of absorption enhancers and different adhesives has been linked to
a higher incidence of contact dermatitis with Androderm patches
compared with the original Testoderm scrotal patch.55
Testosterone gel 1% formulation (AndroGel) is applied in much
larger doses (5 or 10 g each day) to the skin of the shoulders, upper
arms, or abdomen. The hormone is absorbed quickly, within 30
minutes, but several hours may be required for complete absorption
of the dose. For this reason, the patient should be reminded to wait
at least 5 to 6 hours after application before showering. To prevent
inadvertent transfer of testosterone gel to others, the patient should
thoroughly wash his hands with soap and water after administra-
tion of a dose, and allow the application site to dry undisturbed for
several minutes before dressing or covering it.
Dosing
Table 923 lists the usual doses for testosterone replacement regimens.
Two to 3 months is considered an adequate treatment trial with
a particular dose. Thus, a dose should not be increased until the
patient has used one particular dose for at least this time period.53
The serum testosterone level should return to the normal range and
symptoms of androgen deficiency should be relieved with appropri-
ate dosing.
Before initiating any testosterone replacement regimen in
patients 40 years and older, patients should be screened for benign
prostatic hyperplasia and prostate cancer. Both of these diseases are
testosterone-dependent conditions and theoretically could be wors-
ened by exogenous administration of testosterone. Prostate cancer
is a contraindication to androgen supplementation. To screen for
these conditions, a prostate-specific antigen serum concentration
should be obtained and a digital rectal examination of the prostate
performed. These tests are generally repeated at 1-year intervals
after treatment is started.52
Adverse Effects
Testosterone replacement regimens can cause sodium retention,
which can cause weight gain, or exacerbate hypertension, conges-
tive heart failure, and edema. Gynecomastia can occur as a result
of conversion of testosterone to estrogen in peripheral tissues. This
has been reported most often in patients with liver cirrhosis.
Testosterone replacement regimens are contraindicated in
patients with breast cancer and untreated prostate cancer.
Although serum lipoprotein perturbations may occur, testoster-
one replacement regimens have a neutral effect in that they decrease
both total cholesterol and high-density lipoprotein cholesterol
levels. No cases of cardiovascular disease have been reported with
testosterone replacement regimens.
Large doses of parenteral testosterone can produce adverse meta-
bolic effects. Thus, patients on long-term testosterone replacement
regimens must undergo clinical laboratory testing for a serum tes-
tosterone level and hematocrit before starting treatment and every
6 to 12 months during treatment.54 Repeated serum testosterone
levels that exceed the normal range require a dosage reduction or
increased interval between drug doses. If the hematocrit exceeds
55% (0.55), the testosterone replacement regimen should be with-
held to avoid polycythemia and its consequences.
Oral alkylated testosterone replacement regimens have caused
hepatotoxicity, ranging from mild elevations of hepatic transami-
nases to serious liver diseases, including peliosis hepatis (hemor-
rhagic liver cysts), hepatocellular and intrahepatic cholestasis, and
benign or malignant tumors. For this reason, parenteral testoster-
one replacement regimens are preferred.
Topical testosterone patches may cause contact dermatitis,
which responds well to topical corticosteroids. This adverse effect
has been associated with the presence of permeation enhancers,
which are added to patch formulations. If the dermatitis becomes
problematic, an alternative is testosterone gel formulations, which
are associated with a lower incidence of contact dermatitis compared
with patches.
 ALPROSTADIL
Mechanism
Alprostadil, also known as prostaglandin E1, stimulates adenyl
cyclase, resulting in increased production of cAMP, a secondary
messenger that decreases the intracellular calcium concentration
and causes smooth muscle relaxation of the arterial blood vessels
and sinusoidal tissues in the corpora. This results in enhanced
blood flow to and blood filling of the corpora.
Alprostadil is commercially available as an intracavernosal injec-
tion (Caverject and Edex) and as an intraurethral insert (medicated
urethral system for erection [MUSE]).

Indications
Both commercially available formulations of alprostadil are FDA
approved as monotherapy for management of erectile dysfunction.
Alprostadil is more effective by the intracavernosal route than the
intraurethral route.
The enhanced efficacy of the intracavernosal injection may be
related to the excellent bioavailability of the drug when injected
directly into the corpora cavernosum. In contrast, intraurethral
alprostadil doses generally are several hundred times larger than intra-
cavernosal doses. This is because intraurethral alprostadil must be
absorbed from the urethra, through the corpus spongiosum, and into
the corpus cavernosum, where it exerts its full proerectogenic effect.
Although several other agents, including papaverine, phen-
tolamine, and atropine, have been used off-label for intracavernosal
therapy, alprostadil is preferentially prescribed. This is because
intracavernosal alprostadil has been FDA approved for erectile dys-
function, it does not require extemporaneous compounding, and it
has a low potential for causing prolonged erections and priapism.
Both formulations of alprostadil are considered more invasive
than VEDs or phosphodiesterase inhibitors. For this reason, intra-
cavernosal alprostadil is generally prescribed after patients do not
respond to or cannot use less invasive interventions. Intracavernosal
alprostadil is preferred over intraurethral alprostadil because of
its greater effectiveness. Intracavernosal alprostadil may be pre-
ferred in patients with diabetes mellitus, who are accustomed to
injectable drug therapy and may have peripheral neuropathies,
which decrease the patients perception of pain upon injection.
Intraurethral alprostadil is generally reserved as a treatment of last
resort for patients who do not respond to other less invasive and
more effective forms of therapy and who refuse surgery.
Intracavernosal Alprostadil
Efficacy The overall efficacy of intracavernosal alprostadil is 70%
to 90%.5 Three characteristics of intracavernosal alprostadil include
the following:
1. The effectiveness of alprostadil is dose related over the range of
2.5 to 20 mcg. The mean duration of erection is directly related
to the dose of alprostadil administered and ranges from 12 to
44 minutes.
2. A higher percentage of patients with psychogenic and neuro-
genic erectile dysfunction respond to alprostadil at a lower dose
compared to patients with vasculogenic erectile dysfunction.
3. Tolerance does not appear to develop with continued use of
intracavernosal alprostadil at home.
 Although 70% to 75% of patients respond to intracavernosal
alprostadil, a high proportion of patients elect to discontinue its use
over time. Depending on the study and the length of observation,
30% to 50% of patients voluntarily discontinue therapy, usually dur-
ing the first 6 to 12 months. Common reasons for discontinuation
include lack of perceived effectiveness; inconvenience of adminis-
tration; an unnatural, nonspontaneous erection; needle phobia; loss
of interest; and cost of therapy.5,56
Approximately one third of patients do not respond to usual doses
of intracavernosal alprostadil. In these patients, intracavernosal
alprostadil has been used successfully along with VEDs. Such com-
bination therapy can be attempted by patients before transitioning
to more invasive surgical procedures.57,58 Alternatively, intracavern-
osal injections of synergistic combinations of vasoactive agents that
act by different mechanisms have been used.57 Intracavernosal drug
combinations typically produce an erection that lasts longer than an
erection produced by any one of the agents in the mixture. In addi-
tion, because of the low dosage of each agent in the combination,
1449
fewer systemic and local fibrotic adverse effects develop compared
with high-dose monotherapy. For example, when used in low-dose
CHAPTER 92
combination regimens, papaverine is less likely to induce hypoten-
sion and liver dysfunction, and phentolamine is less likely to induce
tachycardia and hypotension.58 However, as previously mentioned,
such intracavernosal drug combinations are not commercially
available and must be extemporaneously compounded.
Pharmacokinetics Intracavernosal injection should be admin-
istered into only one corpus cavernosum. From this injection site,
the drug will reach the other corpus cavernosum through vascular
Erectile Dysfunction
communications between the two corpora. Alprostadil acts rapidly,
with an onset of 5 to 15 minutes. The duration is directly related to
the dose. Within the usual dosage range of 2.5 to 20 mcg, the dura-
tion of erection is no more than 1 hour. Higher doses are expected
to exhibit a longer duration of action. Local enzymes in the corpora
cavernosum quickly metabolize alprostadil. Any alprostadil that
escapes into the systemic circulation is deactivated on first pass
through the lungs.5 Hence, the plasma half-life of alprostadil is
approximately 1 minute, and the potential for systemic adverse
effects is negligible. Dose modification is not necessary in patients
with renal or hepatic disease.
Dosing The usual dose of intracavernosal alprostadil is 10 to 20 mcg,
with a maximum recommended dose of 60 mcg. Doses greater than
60 mcg have not produced any greater improvement in penile erec-
tion but may cause hypotension or prolonged erections lasting more
than 1 hour.5 The dose should be administered 5 to 10 minutes before
intercourse. The manufacturer recommends that patients be slowly
titrated up to the minimally effective dosage to minimize the likeli-
hood of hypotension. Under a physicians supervision, patients should
be started with a 1.25-mcg dose, which can be increased in increments
of 1.25 to 2.50 mcg at 30-minute intervals up to the lowest dose that
produces a firm erection for 1 hour and does not produce adverse
effects. In clinical practice, this process is rarely done because it is
time consuming. Thus, many physicians start the patient on 10 mcg
and move quickly up the dosage range to identify the best dose for the
patient. To avoid adverse effects, patients should receive no more than
one injection per day and not more than three injections per week.
Intracavernosal injections should be performed using a 0.5-inch,
27- or 30-gauge needle. A tuberculin syringe or a syringe prefilled
with diluent as supplied by the manufacturer should be used to
ensure precise measurement of doses. Patients with needle phobia,
poor vision, or poor manual dexterity can use commercially avail-
able autoinjectors (e.g., PenInject) to facilitate administration of
intracavernosal alprostadil.
Intracavernosal injections require that the patient or the sexual
partner practice good aseptic technique (to avoid infection), have
good manual skills and visual ability, and be comfortable with injec-
tion techniques. When practicing self-injection, the patient should
use one hand to firmly hold the glans penis against his thigh to
expose the lateral surface of the shaft. The injection should be made
at right angles into one of the lateral surfaces of the proximal third
of the penis. The injection should never be made into the dorsal or
ventral surface of the penis. This will prevent inadvertent injection
of the drug into arteries on the dorsal surface or the urethra on the
ventral surface. After the injection, the penis should be massaged
to help distribute the drug into the opposite corpus cavernosum.
Injection sites should be rotated with each dose. Finally, manual
pressure should be applied to the injection site for 5 minutes to
reduce the likelihood of hematoma formation (Fig. 925).
Once the optimal dosage of intracavernosal alprostadil is estab-
lished, the patient should return for routine medical followup every
3 to 6 months. Some patients subsequently require dosage adjust-
ment, largely attributed to worsening of the underlying disease that
is contributing to the erectile dysfunction.
1450
SECTION 10
Urologic Disorders
FIGURE 92-5. Technique for administration of intracavernosal injec-
tions. (From Caverject [package insert]. New York, NY: Pfizer Inc;
1999. Data from http://media.pfizer.com/files/products/uspi_caverject_
powder.pdf.)
Adverse Effects Intracavernosal alprostadil is most commonly
associated with local adverse effects, which occur most often
during the first year of therapy. However, improved administration
technique with continued use is believed to account for the lower
frequency of adverse effects during subsequent treatment periods.
Intracavernosal injections are associated with several local adverse
effects. Cavernosal plaques or areas of fibrosis at injection sites form
in approximately 2% to 12% of patients. When they occur, the
patient should suspend further injections until the plaques resolve.
These plaques may cause penile curvature, similar to Peyronie
disease, which makes sexual intercourse difficult or impossible.
The cause of corporal fibrosis and plaque formation is unknown.
This adverse effect may be caused by poor injection technique or
by alprostadil itself. Although patients have developed corporal
fibrosis, alprostadil may be less likely to cause this adverse effect
compared to other intracavernosal drug combinations, such as
phentolamine or papaverine. Unlike cavernosal fibrosis associated
with large doses and repeated administration of papaverine, penile
scarring secondary to alprostadil appears to be unpredictable.
Alprostadil causes penile pain in approximately 10% to 44%
of patients. The pain has been described as a burning discomfort
or dull pain near the injection site or during the erection, which
generally does not persist after the penis becomes flaccid. The
pain usually is mild, generally does not require discontinuation of
therapy, and often abates even with continued treatment. However,
2% to 5% of patients discontinue taking alprostadil because of
severe pain. The pain can be managed by oral analgesics (e.g.,
acetaminophen), if necessary. One investigator has recommended
adding procaine to intracavernosal alprostadil, but this may mask
the signs of more serious adverse effects of the drug or of penile
injury during intercourse and is not recommended.59 The mecha-
nism of this adverse reaction is poorly understood. Alprostadil may
intrinsically produce pain. Also, the pain may be a result of the
pH of the parenteral solution. Alprostadil is acidic, and the com-
mercially available Caverject formulation is buffered with sodium
citrate, a weak base, to reduce pain on injection.
Priapism, a prolonged, painful erection lasting more than 1 hour,
occurs in 1% to 15% of treated patients. It occurs most often dur-
ing the dose titration period and is rare thereafter. Blood sludging
in the corpora can lead to tissue hypoxia and cavernosal fibrosis
and scarring. The risk for this complication is greatest for erections
that persist beyond 4 hours. Patients are advised to seek medical
attention immediately when drug-induced erections last more than
1 hour, as this is considered a urologic emergency. Its management
includes supportive care, including analgesics for pain and sedatives
for anxiety. In addition, needle aspiration of sludged blood in the
corpora or intracavernosal injection of -adrenergic agonists (e.g.,
phenylephrine) has been used. These procedures facilitate venous
drainage of the corpora, allowing venous outflow to catch up with
arterial inflow.
The likelihood of prolonged erections with intracavernosal
alprostadil is dose related. Therefore, to prevent this adverse effect,
the lowest effective dose should be used, and the dose should be
titrated to ensure that the duration of the erection is no more than
1 hour.
Other local adverse effects include injection site hematomas and
bruising. These effects are largely the result of poor injection tech-
nique. To minimize the risk of injection site hematomas, patients
should be advised to apply pressure to the injection site for 5 min-
utes after each dose. Similarly, infection at the injection site has
been reported. Meticulous aseptic technique is necessary to prevent
this complication.
Intracavernosal alprostadil rarely causes systemic adverse effects,
owing to the agents local catabolism in cavernosal tissue and rapid
deactivation in pulmonary tissue (if any of the drug escapes into the
systemic circulation). However, large doses greater than 20 mcg are
associated with dizziness and hypotension in some patients and is
one reason why such large doses are not commonly used.
Intracavernosal injection therapy should be used cautiously by
patients at risk for priapism, including patients with sickle cell dis-
ease or lymphoproliferative disorders. It should be used cautiously
by patients who may develop bleeding complications secondary
to injections, including patients with thrombocytopenia or those
taking anticoagulants. It also should be used cautiously by patients
who use poor-quality injection technique, including patients with
psychiatric disorders, obese patients (who may not be able to reach
or see the penile injection site), patients who are blind, and patients
with severe arthritis.
Intraurethral Alprostadil
Efficacy  Intraurethral alprostadil inserts are marketed as MUSE,
which contains a medication pellet inside a prefilled urethral appli-
cator. Multiple studies show this product has an overall effectiveness
rate of 43% to 65%5 compared with 70% to 90% for intracavernosal
alprostadil. Its decreased effectiveness and inconvenient adminis-
tration method have resulted in this product being considered a
third-line treatment option for patients with erectile dysfunction.
However, some patients respond to intraurethral alprostadil even
though they did not respond to intracavernosal alprostadil.60
Intraurethral alprostadil has been combined with an adjustable
penile constriction band to improve treatment response.61
Pharmacokinetics Following intraurethral instillation, alpros-
tadil is absorbed quickly through the urethra, into the corpus spon-
giosum, and then into the corpora cavernosum. As much as 90%
of each dose is absorbed by the urethra and corpus spongiosum in
less than 10 minutes, with peak absorption occurring in 20 to 25
minutes. An estimated 20% of each dose is delivered to the corpora
cavernosum. As with intracavernosal injections of alprostadil, any
drug absorbed into the systemic circulation is rapidly metabolized
on first pass through the lungs.
 1451
The onset after intraurethral insertion is similar to that of intra- Plunger
cavernosal injection, 5 to 10 minutes.

CHAPTER 92
Dosing The usual dose of intraurethral alprostadil is 125 to 1,000
mcg. The dose should be administered 5 to 10 minutes before sexual
intercourse. No more than two doses per day are recommended.
Before administration, the patient should be advised to empty his
bladder, voiding completely.
Similar to intracavernosal injection treatments, intraurethral Collar
insertion of alprostadil requires good manual and visual skills to
minimize the risk of urethral injuries. Intraurethral alprostadil is

Erectile Dysfunction
supplied in a prefilled intraurethral applicator. The patient should
void first. With one hand the patient holds the glans penis, and
with the other hand the patient inserts the intraurethral applicator
0.5 inch (1.3 cm) into the urethra. The drug pellet is then pushed
into the urethra. The penis should be massaged to enhance drug Alprostadil pellet
dissolution in the urethral fluids and drug absorption (Fig. 926).
Adverse Effects The urethra can be injured because of improper
administration technique. Injuries can lead to urethral stricture and
difficulty voiding. Patients should receive complete education about
optimal administration procedures before starting treatment.
Urethral pain has been reported in 24% to 32% of patients.
Usually it is mild and does not require discontinuation of treatment.
Female sexual partners may experience vaginal burning, itching, or
pain, which probably is related to transfer of alprostadil from the
mans urethra to the womans vagina during intercourse.
Prolonged painful erections (priapism) have been rarely reported.
Syncope and dizziness have been reported rarely (only 2%3% of
patients) and likely are related to use of excessively large doses.

CLINICAL CONTROVERSY
Although combinations of proerectogenic drugs (e.g., sildenafil
plus alprostadil intracavernosal injection) may be used by some
patients who do not respond to a single agent, such combina-
tions are not recommended by the FDA and may lead to pro-
longed erections and priapism.

 UNAPPROVED AGENTS
FIGURE 92-6. Technique for administration of intraurethral alprostadil with
A variety of other commercially available and investigational agents
a medicated urethral system for erection applicator. (From Muse [package
have been used for management of erectile dysfunction. Although insert]. Mountain View, CA: Vivus, Inc.; 2003. Data from http://www.
it is beyond the scope of this chapter to discuss all of them, some of vivus.com.)
the more commonly used agents are discussed here.

Trazodone
The mechanism by which trazodone produces an erection is not
clear. It likely acts peripherally to antagonize -adrenergic recep-
tors. As a result, a predominant cholinergic effect results, which
causes peripheral arteriolar vasodilation and relaxation of cavern-
osal tissues, enhancing blood filling of the corpora. Intracavernosal
injection of trazodone in experimental studies supports this likely
mechanism.62
Although some clinical trials suggested that trazodone 50 to
200 mg daily by mouth might be effective in the management of
erectile dysfunction, these trials were generally poorly controlled,
were nonrandomized, included small samples treated for short
time periods, and did not include validated objective parameters of
response.62,63
The adverse effects of trazodone, when used for erectile dysfunc-
tion, are similar to those reported with trazodone when used to treat
depression and include dry mouth, sedation, and dizziness.
Yohimbine
Yohimbine, a tree-bark derivative also known as yohimbe, is widely
used as an aphrodisiac. Yohimbine is a central 2-adrenergic
antagonistic that increases catecholamines and improves mood.
Some investigators believe that yohimbine has peripheral proerec-
togenic effects. Yohimbine may reduce peripheral -adrenergic
tone, thereby permitting a predominant cholinergic tone, which
could result in a vasodilatory response.5,64 The usual oral dose is
5.4 mg 3 times per day.
A controlled clinical trial has shown that high-dose yohimbine
(100 mg daily) is no more effective than placebo.65 Based on a
meta-analysis of published studies that came to the same conclu-
sion, the American Urological Association has cautioned against
the use of yohimbine.24 In addition, yohimbine can cause many
systemic adverse effects, including anxiety, insomnia, tachycardia,
and hypertension.
1452
Papaverine
b
SECTION 10

Papaverine is a nonspecific phosphodiesterase inhibitor that

decreases metabolic catabolism of cAMP in cavernosal tissue. As a
result of enhanced tissue levels of cAMP, smooth muscle relaxation
occurs. Cavernosal sinusoids fill with blood, and a penile erection
results.
Papaverine is not FDA approved for erectile dysfunction.
Intracavernosal papaverine alone is not commonly used for man-
agement of erectile dysfunction because the large doses required
produce dose-related adverse effects, such as priapism, corporal
Urologic Disorders

fibrosis, hypotension, and hepatotoxicity.58,66 Papaverine is more

often administered in lower doses combined with phentolamine
and/or alprostadil. A variety of formulas have been used, but
no one mixture has been proven better than other mixtures (see
Table 926). Combination formulations are considered safer and
are associated with the potential for fewer serious adverse effects
than high doses of any one of these agents.
A portion of each papaverine dose is systemically absorbed,
and its prolonged plasma half-life of 1 hour contributes to adverse
effects. The usual dose of papaverine is 7.5 to 60 mg when used as a
single agent for intracavernosal injection. When used in combina-
tion, the dose decreases to 0.5 to 20 mg.
If treated with papaverine, patients with a history of underlying
liver disease or alcohol abuse should undergo liver function testing
at baseline and every 6 to 12 months during continued treatment.
Phentolamine
Phentolamine is a competitive nonselective -adrenergic block-
ing agent. It reduces peripheral adrenergic tone and enhances
cholinergic tone. As a result, it improves cavernosal filling and is
proerectogenic.
Phentolamine has most often been administered as an intracav-
ernosal injection. Monotherapy is avoided because large doses are
required for an erection, and at these large doses systemic hypoten-
sive adverse effects would be prevalent. Most often, phentolamine
has been used in combination with other vasoactive agents for
intracavernosal administration. A ratio of 30 mg papaverine to 0.5
to 1 mg phentolamine is typical, and the usual dose ranges from 0.1
to 1 mL of the mixture. Such a mixture promotes local effects of
phentolamine and minimizes systemic hypotensive adverse effects.
Hypotension is the most common adverse effect of intracavern-
osal phentolamine. It is more common and more severe with large
doses or in patients with poor injection technique who have injected
into a vein (rather than the cavernosa). Prolonged erections have
been reported in patients who used excessive doses of intracavern-
osal medications in combination.
 PENILE PROSTHESES
Surgical insertion of a penile prosthesis is the most invasive treat-
ment of erectile dysfunction. It is reserved for patients who do not
respond to or who are not candidates for less invasive oral or inject-
able treatments.
Prosthesis insertion requires anesthesia and skilled urologists.
Two prostheses are widely used: malleable and inflatable. Malleable
or semirigid prostheses consist of two bendable rods that are
inserted into the corpora cavernosa. The patient appears to have a
permanent erection after the procedure; the patient is able to bend
the penis into position at the time of intercourse.
The inflatable prosthesis has several mechanical parts. The
inflatable prosthesis produces a more natural erection. The patient
develops an erection only when the device is activated. Some
newer advances in inflatable prosthesis technology have resulted in
c
a
FIGURE 92-7. Example of surgically implanted penile prosthesis.
(a, activation mechanism; b, reservoir with fluid for inflating prosthesis; c,
inflatable rods in corpora.) (From http://kidney.niddk.nih.gov/kudiseases/
pubs/impotence.)
devices with fewer mechanical parts. These devices can be placed
during shorter surgical procedures and have a low 5-year mechani-
cal failure rate (6%10%) as compared with the original inflatable
prostheses (Fig. 927).67
Penile prostheses provide penile rigidity suitable for vaginal
intercourse and are associated with a greater than 90% patient
satisfaction rate, which is generally higher than that observed with
any other drug treatment or VED.68 The surgical success rate after
insertion is 82% to 98%.5
Adverse effects of prosthesis insertion can occur early or late
after the surgical procedure. The most common early complica-
tion is infection. Late complications include mechanical failure of
the prosthesis, particularly when an inflatable prosthesis has been
inserted. With improved technology, the mechanical failure rate
has decreased to 5%.5 Other late complications include erosion of
the rods through the penis or late-onset infection. Although some
salvage procedures have been devised, in many cases the prosthesis
requires removal.
EVALUATION OF THERAPEUTIC OUTCOMES
The primary therapeutic outcomes of specific treatments for erectile
dysfunction include (1) improvement in the quantity and quality
of penile erections suitable for intercourse and (2) avoidance of
adverse drug reactions and drug interactions.
At baseline and after the patient has completed a clinical trial
period of 1 to 3 weeks with a specific treatment for erectile dys-
function, the physician should conduct assessments to determine
whether the quality and quantity of penile erections has improved.
A patients level of satisfaction is highly individualized, depending
on his lifestyle and expectations. Therefore, a patient who has suc-
cessful intercourse once per week might be completely satisfied,
whereas another patient might judge this to be unsatisfactory.
Patients with unrealistic expectations in this regard must be identi-
fied and counseled by clinicians to avoid adverse effects of excessive
use of erectogenic agents.
Failure to improve the quality and quantity of penile erections
suitable for intercourse after an appropriate clinical trial period
with a specific treatment for erectile dysfunction occurs in a

significant percentage of patients. In this case, physicians generally
take the following steps in order:
1. Ensure that the patient has been prescribed a maximum toler-
ated dose and has an adequate clinical trial of a specific treat-
ment before discarding it as ineffective.
2. Switch to another drug (see Fig. 924).
3. Reserve surgical treatment for patients who do not respond to
drug treatment.
CONCLUSIONS
Erectile dysfunction is a common disorder of aging men. Its inci-
dence is higher in patients with underlying medical disorders that
compromise the vascular, neurologic, hormonal, or psychogenic
systems necessary for a normal penile erection. Medications are
common causes of erectile dysfunction. By correcting the underly-
ing etiology, erectile dysfunction can often be reversed without the
use of specific treatments.
When treatments of erectile dysfunction are needed, the least
invasive forms of treatment should be used first because they
produce the lowest incidence of serious adverse effects. VEDs or
phosphodiesterase inhibitors are considered first-line treatments. If
these treatments fail, intracavernosal alprostadil injection therapy
can be initiated. If this treatment fails, the patient can attempt a
combination of intracavernosal alprostadil plus VED, combination
intracavernosal therapy, or intraurethral alprostadil. If this treat-
ment fails, the patient may require insertion of a penile prosthesis.
Some insurance companies do not reimburse for drug treatments
for erectile dysfunction, so cost is an important issue for some
patients.
Clinicians should provide clear and simple advice. Patient confi-
dentiality and privacy, which are extremely important to men with
erectile dysfunction, should be maintained at all times.
ABBREVIATIONS
cAMP: cyclic adenosine monophosphate
cGMP: cyclic guanosine monophosphate
VED: vacuum erection device
REFERENCES
1. NIH Consensus Conference. NIH Consensus Development Panel on
Impotence. Impotence. JAMA 1993;270:8390.
2. Johannes CB, Aranjo AB, Feldman HA, et al. Incidence of erectile
dysfunction in men 4069 years old: Longitudinal results from the
Massachusetts Male Aging Study. J Urol 2000;163:460463.
3. Bacon CG, Mittleman MA, Kawach I, et al. Sexual function in men
older than 50 years of age: Results from the Health Professionals
Follow-up Study. Ann Intern Med 2003;139:161168.
4. Lindau ST, Schumm LP, Laumann EO, et al. A study of sexuality
and health among older adults in the United States. N Engl J Med
2007;357:762774.
5. McVary KT. Erectile dysfunction. N Engl J Med 2007;357:24722481.
6. Carrier S. Pharmacology of phosphodiesterase inhibitors. Can J Urol
2003;10(Suppl 1):1216.
7. Araujo AB, Esche GR, Kupelian V, et al. Prevalence of symptom-
atic androgen deficiency in men. J Clin Endocrinol Metab 2007;92:
42414247.
8. Travison TG, Araujo AB, ODonnell AB, et al. A population-level
decline in serum testosterone levels in American men. J Clin Endocrinol
Metab 2007;92:196202.
1453
9. Thomas A, Woodard C, Rovner ES, Wein AJ. Urologic complica-
tions of nonurologic medications. Urol Clin North Am 2003;30:
CHAPTER 92
123131.
10. Lee M, Sharifi R. Sexual dysfunction in males. In Tisdale JE, Miller DA,
eds. Drug-Induced Diseases: Prevention, Detection, and Management.
Bethesda, MD: ASHP, 2005:455467.
11. Balon R. SSRI-associated sexual dysfunction. Am J Psych 2006;163:
15041509.
12. Lobo JR, Nehra A. Clinical evaluation of erectile dysfunction in the era
of PDE-5 inhibitors. Urol Clin North Am 2005;32:447455.
13. Rosen RC, Riley A, Wagner G, et al. The International Index of Erectile
Erectile Dysfunction
Function (IIEF): A multidimensional scale for assessment of erectile
dysfunction. Urology 1997;49:822830.
14. Buvat J, Lemaire A. Endocrine screening in 1,022 men with erectile
dysfunction: Clinical significance and cost-effective strategy. J Urol
1997;158:17641767.
15. Zitzman M, Faber S, Nieschlag E. Association of specific symptoms
and metabolic risks with serum testosterone in older men. J Clin
Endocrinol Metab 2006;91:43354345.
16. Inman BA, St. Souver JL, Jacobson DJ, et al. A population-based
longitudinal study of erectile dysfunction and future coronary artery
disease. Mayo Clin Proceed 2009;84:108113.
17. Nehra A. Erectile dysfunction and cardiovascular disease: efficacy and
safety of phosphodiesterase type 5 inhibitors in men with both condi-
tions. Mayo Clin Proceed 2009;84:139148.
18. Burnett AL. Erectile dysfunction. J Urol 2006;175:S25S31.
19. Rosen RC, Jackson G, Kostis JB. Erectile dysfunction and cardiac
disease: Recommendations of the Second Princeton Conference. Curr
Urol Rep 2006;7:490496.
20. Rosen RC, Friedman M, Kostis JB. Lifestyle management of erectile
dysfunction: The role of cardiovascular and concomitant risk factors.
Am J Cardiol 2005;96(Suppl):76M79M.
21. Kostis JB, Jackson G, Rosen R, et al. Sexual dysfunction and cardiac
risk (the Second Princeton Consensus Conference). Am J Cardiol
2005;96:313321.
22. Bacon CG, Mittleman MA, Kawachi I, et al. A prospective study of risk
factors for erectile dysfunction. J Urol 2006;176:217221.
23. Bacon CG, Mittleman MA, Kawachi I, et al. Sexual function in men
older than 50 years of age: Results from the health professionals
follow-up study. Ann Intern Med 2003;139:161168.
24. American Urological Association Guideline on the Management of
Erectile Dysfunction: Diagnosis and Treatment Recommendations;
updated 2006. http://www.auanet.org/content/guidelines-and-quality-
care/clinical-guidelines.cfm?sub=ed.
25. Jannini EA, Isidori AM, Gravina GL, et al. The Endotrial Study: a
spontaneous, open label, randomized, multicenter cross-over study on
the efficacy of sildenafil, tadalafil, and vardenafil in the treatment of
erectile dysfunction. J Sex Med 2009;6:25472560.
26. Carson CC. PDE5 inhibitors: Are there differences? Can J Urol
2006;13(Suppl 1):3439.
27. McCullough AR, Barada JH, Fawzy A, et al. Achieving treatment
optimization with sildenafil citrate (Viagra) in patients with erectile
dysfunction. Urology 2002;60(2 Suppl 2):2838.
28. Guay AT. Optimizing response to phosphodiesterase therapy: Impact
of risk-factor management. J Androl 2003;24(Suppl):S59S62.
29. Brisson TE, Broderick GA, Thiel DD, et al. Vardenafil rescue rates of
sildenafil nonresponders: Objective assessment of 327 patients with
erectile dysfunction. Urology 2006;68:397401.
30. Padma-Nathan H, Eardley I, Kloner RA, et al. A 4-year update on
the safety of sildenafil citrate (Viagra). Urology 2002;60(Suppl 2B):
6790.
31. Carson CC. Long-term use of sildenafil. Expert Opin Pharmacother
2003;4:397405.
32. Hellstrom WJ, Gittleman M, Karlin G, et al. Sustained efficacy and tol-
erability of vardenafil, a highly potent selective phosphodiesterase type
5 inhibitor in men without erectile dysfunction: results of a random-
ized, double-blind 26 week placebo-controlled pivotal trial. Urology
2003;61(4 suppl 1):814.
33. Shabsigh R, Seftel AD, Rosen RC, et al. Review of time of onset and
duration of clinical efficacy of phosphodiesterase type 5 inhibitors in
treatment of erectile dysfunction. Urology 2006;68:689696.
1454
34. Porst H, Giuliano F, Glina S. et al. Evaluation of the efficacy and safety
of once-a-day dosing of tadalafil 5 mg and 10 mg in the treatment of
SECTION 10
erectile dysfunction: results of a multicenter, randomized, double-
blind, placebo-controlled trial. Eur Urol 2006;50:351359.
35. Donatucci CF, Wong DG, Giuliano F, et al. Efficacy and safety of tada-
lafil once daily: consideration for the practical application of a daily
dosing option. Curr Med Res Opin 2008;24:33833392.
36. Hellstrom WJG, Kendirci M. Type 5 phosphodiesterase inhibitors:
Curing erectile dysfunction. Eur Urol 2006;49:942945.
37. Carson CC. Long-term use of sildenafil. Expert Opin Pharmacother
2003;4:397405.
Urologic Disorders
38. Carson CC, Rajfer J, Eardley I, et al. The efficacy and safety of tadalafil:
an update. BJU Int 2004;93:12761281.
39. Laties A, Sharlip I. Ocular safety in patients using sildenafil citrate
therapy for erectile dysfunction. J Sex Med 2006;3:1227.
40. Wooltorton E. Visual loss with erectile dysfunction medication. CMAJ
2006;175:355
41. Gresser U, Gleiter CH. Erectile dysfunction: comparison of efficacy
and side effects of the PDE-5 inhibitors sildenafil, vardenafil, and
tadalafil-review of the literature. Eur J Med Res 2002;7:435446.
42. Kloner RA, Hutter AM, Emmick JT. Time course of the interaction
between tadalafil and nitrates. J Am Coll Cardiol 2003;42:18551860.
43. Tran D, Howles LG. Cardiovascular safety of sildenafil. Drug Saf
2003;26:453460.
44. Kloner RA. Pharmacology and drug interaction effects of the phos-
phodiesterase 5 inhibitors: Focus on blocker interactions. Am J
Cardiol 2005;96(Suppl):42M-46M.
45. Kloner RA, Jackson G, Emmick JT, et al. Interaction between the phos-
phodiesterase 5 inhibitor, tadalafil, and 2 alpha-blockers, doxazosin
and tamsulosin in healthy normotensive men. J Urol 2004;172:
19351940.
46. Giuliano F, Kaplan SA, Cabanis MJ, Astruc B. Hemodynamic interac-
tion study between the alpha1 blocker alfuzosin and the phosphodi-
esterase-5 inhibitor tadalafil in middle-aged healthy male subjects.
Urology 2006;67:11991204.
47. Carson CC. Combination of phosphodiesterase-5 inhibitors and
blockers in patients with benign prostatic hyperplasia: Treatments of
lower urinary tract symptoms, erectile dysfunction, or both? BJU Int
2006;97(Suppl 2):3943.
48. Ng C-F, Wong A, Cheng C-W, et al. Effect of vardenafil on blood
pressure profile of patients with erectile dysfunction concomitantly
treated with doxazosin gastrointestinal therapeutic system for benign
prostatic hyperplasia. J Urol 2008;180:10421046.
49. Muirhead GJ, Wulff MB, Fielding H, et al. Pharmacokinetic interac-
tions between sildenafil and saquinavir/ritonavir. Br J Clin Pharmacol
2000;50:99107.
50. Sekar V, Lefebvre E, De Marez T, et al. Effect of repeated doses of
darunavir plus low dose ritonavir on the pharmacokinetics of sildenafil
in healthy male subjects: phase I randomized open-label, two way
crossover study. Clin Drug Investig 2008;28:479485.
51. Carson CC. Phosphodiesterase type 5 inhibitors: state of the therapeutic
class. Urol Clin North Am 2007;34:507515.
52. Gore JL, Swerdloff RS, Rajfer J. Androgen deficiency in the etiol-
ogy and treatment of erectile dysfunction. Urol Clin North Am
2005;32:457468.
53. Morales A, Tenover JL. Androgen deficiency in the aging male:
When, who, and how to investigate and treat. Urol Clin North Am
2002;29:975982.
54. Bolona ER, Uraga MV, Haddad RM, et al. Testosterone use in men
with sexual dysfunction: a systematic review and meta-analysis of
randomized placebo-controlled trials. Mayo Clin Proceed 2007;82:
2028.
55. Jordan WP. Allergy and topical irritation associated with transdermal
testosterone administration: A comparison of scrotal and nonscrotal
transdermal systems. Am J Contact Dermatol 1997;8:108113.
56. Kendirci M, Tanriverdi O, Trost L, et al. Management of sildenafil
treatment failures. Curr Opin Urol 2006;16:449459.
57. Nehra A. Oral and non-oral combination therapy for erectile dysfunc-
tion. Rev Urol 2007;9:99105.
58. Chen Y, Dai Y, Wang R. Treatment strategies for diabetic patients
suffering from erectile dysfunction. Expert Opin Pharmacother
2008;9:257260.
59. Albaugh J, Ferrans CE. Patient reported pain with initial intracavern-
osal injection. J Sex Med 2009;6:513519.
60. Engel JD, McVary KT. Transurethral alprostadil as therapy for
patients who withdrew from or failed prior intracavernous injection
therapy. Urology 1998;51:687692.
61. Jaffe JS, Antell MR, Greenstein M, et al. Use of intraurethral alpros-
tadil in patients not responding to sildenafil citrate. Urology 2004;63:
951954.
62. Fink HA, MacDonald R, Rutks IR, Wilt TJ. Trazodone for erectile
dysfunction: A systematic review and meta analysis. BJU Int 2003;92:
441446.
63. Vitezic D, Pelcic JM. Erectile dysfunction: Oral pharmacotherapy
options. Int J Clin Pharmacol Ther 2002;40:393403.
64. Tamier R, Mechanick JI. Dietary supplements and nutraceuticals in
the management of andrologic disorders. Endocrinol Metab Clin
North Am 2007;36:533552.
65. Teloken C, Rhoden EL, Sogari P, et al. Therapeutic effects of high-
dose yohimbine hydrochloride on organic erectile dysfunction. J Urol
1998;159:122124.
66. Brown SL, Haas CA, Koehler M, et al. Hepatotoxicity related to
intracavernous pharmacotherapy with papaverine. Urology 1998;52:
844847.
67. Henry GD, Wilson SK. Updates in inflatable penile prosthesis. Urol
Clin North Am 2007;34:535547.
68. Rajpurkar A, Dhabuwala CB. Comparison of satisfaction rates and
erectile function in patients treated with sildenafil, intracavernous
prostaglandin E1 and penile implant surgery for erectile dysfunction
in urology practice. J Urol 2003;2003;170:159163.