Erectile Dysfunction

Treatment options
Tarek Anis
Prof. of Andrology, Cairo University
PASSM President
Incidence of Erectile
Dysfunction
Prevalence of erectile dysfunction
Prevalence of erectile dysfunction
18! of all men above 20 years
80% 77.6%

60.2%
60%

43.7%
40%

23.9%
20%

6.5% 8.2%
3.8%
0%

20-29 30-39 40-49 50-59 60-69 70-74 >75

 International Index of Erectile Function
IIEF Score
Over the past 6 months:
1 How do you rate your confidence that you could get an erection?
1 Very Low 2 Low 3 Moderate 4 High 5 Very High

When you had erections with sexual stimulation, how often were your erections hard enough for
2 penetration?
0 No sexual activity 1 Almost never or 2 A few times 3 Sometimes 4 Most times 5 Almost always or
never always

During sexual intercourse, how often were you able to maintain your erection after you had
3 penetrated (entered) your partner?
0 Did not attempt 1 Almost never or 2 A few times 3 Sometimes 4 Most times 5 Almost always or
never always

During sexual intercourse, how difficult was it to maintain your erection to completion of
4 intercourse?

0 Did not attempt 1 Extremely difficult 2 Very difficult 3 Difficult 4 Slightly difficult 5 Not difficult

5 When you attempted sexual intercourse, how often was it satisfactory to you?
0 Did not attempt 1 Almost never or 2 A few times 3 Sometimes 4 Most times 5 Almost always or
never always
 Erection Hardness Score

Severe ED Moderate ED Mild ED No ED

(IIEF5: ! 10) (IIEF5: 11–15) (IIEF5: 16–20) (IIEF5: >20)

GRADE 1 GRADE 2 GRADE 3 GRADE 4

Penis is hard
Penis is hard enough for
Penis is
Penis is larger but not hard penetration completely
but not hard enough but not hard and
for penetration completely
hard fully rigid

Goldstein I et al. N Engl J Med 1998;338:1397–1404.

Rosen RC et al. Int J Impot Res 1999; 319–26.
Major Risk Factors of
Erectile dysfunction
Major Risk Factors of Erectile
dysfunction
Aging
Chronic disease
Cardiovascular disease, hypertension, diabetes, lower
urinary tract symptoms, and depression
Medications
Thiazide diuretics, beta"blockers, selective serotonin
reuptake inhibitors
Lifestyle
Stress, alcohol and drug abuse, smoking, obesity, and
sedentary lifestyle
WHO Treatment Recommendation
1 2 3
Lifestyle Modification

Stop smoking
Limit or avoid alcohol
Follow healthy diet
Exercise regularly
Reduce weight
Get adequate sleep
WHO Treatment Recommendation
1 2 3
Lifestyle Modification
Drug Therapy Modifications

Antihypertensives/diuretics
Selective serotonin"reuptake inhibitors
Hormonal agents #eg, anti"androgens$
H2"receptor
WHO Treatment Recommendation
1 2 3
Lifestyle Modification
Drug Therapy Modifications
Psychosocial Counseling

Anxiety reduction/desensitization
Cognitive"behavioral interventions
Sexual stimulation techniques
Interpersonal assertiveness/couples’ communication
training
WHO Treatment Recommendation
1 2 3
Lifestyle Modification
Drug Therapy Modifications
Psychosocial Counseling
Androgen Replacement

Transdermal testosterone
Gel or scrotal, buccal, and non"scrotal patches
Intramuscular #IM$ injection
Subcutaneous implant
Oral testosterone
WHO Treatment Recommendation
1 2 3
Lifestyle Modification
Drug Therapy Modifications
Psychosocial Counseling
Androgen Replacement
Oral PDE5 Inhibitors

Sildenafil #Viagra®$
Tadalafil #Cialis®$
Vardenafil #Levitra®$
WHO Treatment Recommendation
1 2 3
Lifestyle Modification Intracavernosal
Drug Therapy Modifications injection
Psychosocial Counseling
Androgen Replacement
Oral PDE5 Inhibitors
WHO Treatment Recommendation
1 2 3
Lifestyle Modification Intracavernosal
Drug Therapy Modifications injection
Psychosocial Counseling
MUSE
Androgen Replacement
Oral PDE5 Inhibitors
WHO Treatment Recommendation
1 2 3
Lifestyle Modification Intracavernosal
Drug Therapy Modifications injection
Psychosocial Counseling
MUSE
Androgen Replacement
Oral PDE5 Inhibitors Vacuum device
WHO Treatment Recommendation
1 2 3
Lifestyle Modification Intracavernosal Penile prosthesis
Drug Therapy Modifications injection
Revascularization
Psychosocial Counseling
MUSE
Androgen Replacement
Oral PDE5 Inhibitors Vacuum device
First"Line Therapy for
Management of ED
 Approved and emerging
PDE5 inhibitors
Sildenafil Pfizer Approved for ED and
PAH
Vardenafil Bayer Approved for ED

Tadalafil Eli Lilly Approved for ED

Udenafil Dong Pharmaceutical Co Ltd Approved for ED in

Korea, Phase 3 in US
Avanafil Vivus Phase 2

SLX"2101 Surface Logics Phase 2

Tadalafil

Vardenafil

Sildenafil
 Mechanism of action
Sexual
Stimulation Endothelial cell Stimulation
Inhibition

Cavernous Smooth muscle cell

nerve Ca2+
Endoplasmic Decreased
reticulum Ca2+
Nitric cGMP!specific
Guanylate
oxide protein Kinase
cyclase
Smooth muscle
cGMP K+ relaxation
GTP
PDE5
Ca2+
5’ GMP K+
PDE5 inhibitor
site of action

Image by Christine Kenney, from “Erectile dysfunction: management update,” Reprinted from CMAJ ; 170#9$, page#s$ 1429%1437,
Chemical Structure

O O O O
H
HN N O N
O HN N HN
N N
N N N
N N H 2N N N
O O

O S O 0H
O S O O
N O O O
N P
O
0H
N N

Sildenafil Vardenafil Tadalafil cGMP

Tadalafil: a new agent for erectile dysfunction.

Brock, G. (2003).
Can J Urol, 10 Suppl 1, 17-22.
 Pharmacokinetic Profile

Viagra Cialis Levitra

& C max with food 29! no change 20!
t max #h$ 1 2 1
t 1/2 #h$ 3"5 17.5 ~4
Presence in the body #h$ 24 72 24
Therapeutic window #h$ 4 24 4
 Metabolism
The 3 drugs are metabolized by CYP3A4, a
member of the Cytochrome P450 family

Several drugs are known to inhibit this

enzyme, such as the ketoconazole,
erythromycin

Any of these drug can result in elevated

maximum plasma concentrations #Cmax$ of
PDE5 inhibitors.

Dose reduction of the PDE5 inhibitors is

mandatory when they are being taken
concomitantly with these drugs.
E'cacy of PDE5
inhibitors
 Number of erections / month

VIAGRA 50 mg Placebo

1. Goldstein I, Lue TF, Padma-Nathan H, Rosen RC, Steers WD, Wicker PA for the Sildenafil Study Group. Oral sildenafil in the treatment of erectile
dysfunction. N Engl J Med. 1998;338:1397-1404.
 Erection time in Time of Strong Erection
minutes

VIAGRA 100 mg Placebo

1. Goldstein I, Lue TF, Padma-Nathan H, Rosen RC, Steers WD, Wicker PA for the Sildenafil Study Group. Oral sildenafil in the treatment of erectile
dysfunction. N Engl J Med. 1998;338:1397-1404.
 ! increase Ability to penetrate

VIAGRA Placebo

1. Goldstein I, Lue TF, Padma-Nathan H, Rosen RC, Steers WD, Wicker PA for the Sildenafil Study Group. Oral sildenafil in the treatment of erectile
dysfunction. N Engl J Med. 1998;338:1397-1404.
Time of maintenance of erection
! increase

VIAGRA Placebo

Reference: 1. Data on file. Pfizer Inc., New York, NY.

 Successful intercourse
completion
! increase

VIAGRA Placebo

Pooled data from Protocols 148-106 and 148-364 (12-week fixed dose studies) that included 370 patients. Patients responded to Event Log Question 3: Did you
have successful sexual intercourse?
 Reliability to have & Maintain
Erection
! increase

VIAGRA Placebo

Data pooled from flexible-dose, placebo-controlled, parallel-group studies with 6129 patients
! increase
Total satisfaction

VIAGRA Placebo

Data pooled from flexible-dose, placebo-controlled, parallel-group studies with 6129 patients
 Total Satisfaction

1 year 2 years 3 years 4 years

McMurray JG, Feldman RA, Auerbach SM, deRiesthal H, Wilson N. Long-term effectiveness and tolerability of Viagra ® (sildenafil citrate) in men with erectile
dysfunction. Int J Impot Res. 2002;14(suppl 3):S104.
Side e(ects of PDE5
inhibitors
Phosphdiestrase Families
Family Conserved Catalytic
Regulatory Regions
Domain Calmodulin-stimulated
Calmodulin-binding sites cAMP/cGMP PDE
1 P
cGMP-stimulated
cGMP-binding sites cAMP/cGMP PDE
2
Membrane association cGMP-inhibited
region cAMP/cGMP PDE
3 P
URC sites
cAMP-specific
4 P Rollpram-inhibited PDE
cGMP-binding sites
cGMP-binding
5 P
cGMP-specific PDE
cGMP-binding sites
Photoreceptor
6 cGMP-specific PDE

cAMP-specific
7
Rollpram-insensitive PDE

8 cAMP-specific PDE
IBMX-insensitive
High affinity
9
cAMP/cGMP PDE
cGMP-binding sites?
10 cGMP-binding
cAMP/cGMP PDE
cGMP-binding site?
11 cAMP/cGMP PDE
 Selectivity

Potency against PDE5

Selectivity Ratio =
Potency against other PDEs

IC50 for PDE5

=
IC50 for other PDEs

The smaller the number the less

selective the drug is for PDE5
compared with the other isoenzyme
 Selectivity of PDE5 inhibitors

IC50(nM) PDE5A PDE1 PDE2A PDE3B PDE4B PDE6 PDE7B PDE8 PDE9A PDE10A PDE11A

Vardenafil 0.89 121 >10000 2400 2055 11 4600 >10000 3370 1000 308

RatioX/5 1 136 >10000 2696 2308 15 5168 >100000 3786 1123 346

Sildenafil 8.5 350 >10000 >10000 3190 49 >10000 >1000 >10000 3800 1725

RatioX/5 1 41 >1000 >1000 375 7.4 >1000 >1000 >1000 447 203

Tadalafil 9.4 >10000 >10000 >10000 >10000 n.d. >10000 >10000 >10000 >10000 67

RatioX/5 1 >1000 >1000 >1000 >1000 780 >1000 >1000 >1000 >1000 7.1

E Bischo", Potency, selectivity, and consequences of nonselectivity of PDE inhibition. International Journal of Impotence Research #2004$ 16, S11"S14.
Important PDE families
 E(ect on PDE 6
Sildenafil is about 10 times more selective
for PDE5 than for PDE6.
Tadalafil is more selective for PDE5 than
PDE6 compared with Sildenafil and
Vardinafil.
Sildenafil may be associated with visual
disturbances "" blue hue, brightness, and
blurring of vision.
Infrequent reports of mild haziness,
increased brightness of light, and color
abnormalities have been reported with
Vardenafil. Rods sense brightness
Cones sense color
Visual abnormalities have been rarely
reported with Tadalafil
 PDE11 Localization in Human
Tissues
PDE11 occurs at highest levels in skeletal muscle, the testis,
pituitary, pancreas, heart, prostate and salivary glands

Testis : Germinal epithelium, i.e., spermatogonia, spermatocytes

and spermatids, and interstitial #Leydig$ cells

Pituitary : acidophils #somatotrophs and lactotrophs$ of the

anterior pituitary

SG=spermatogonia
ST=spermatid
IC=interstitial cells

AF B SG ST SG ST IC
 E(ects on Skeletal Muscles
In tadalafil clinical trials, back pain or
myalgia occurred 12 to 24 hours after
dosing and typically resolved within
48 hours

Back pain/myalgia associated with

tadalafil treatment was characterized Nucleus

Endomysium
by bilateral lower lumbar, gluteal,
Striation
thigh, or thoracolumbar muscular
discomfort and was exacerbated by
recumbency
 E(ect on spermatogenesis
AUA Clinical Guidelines
PDE11 is present in the anterior pituitary
and the testes. While studies, to date, have
demonstrated no e(ect on spermatogenesis
when PDE5 inhibitors are administered
daily for 6 months in healthy individuals,
further assessment of the e(ect of PDE5
inhibitors that cross react with PDE11 in
patients with abnormal spermatogenesis is
needed.

2005! "American Urological Association Education and Research!, "Chapter 1-p 28

PDE5 Inhibition Related
Adverse Events
Headache Dyspepsia Flushing
 Adverse E(ects Related to
PDE6 and PDE11 Inhibition

Abnormal Myalgia & Abnormal

Vision back pain Spermatogenesis

Sildenafil 3% -ve -ve

Vardenafil 2% -ve -ve

Tadalafil 0.1% 5-12% ?

PDE"5 Inhibitors and
NAION
In March 2005, a series of 7 patients, who had
typical features of nonarteritic anterior
ischemic optic neuropathy within 36 hours
after ingestion of PDE5 inhibitors s was
reported

Two months later, the FDA advised healthcare

professionals of a potential risk of sudden vision
loss that may be attributed to use of PDE5
inhibitors.

As of May, 2005, the FDA had received a total

of 43 post"marketing reports of NAION in
patients using PDE5 inhibitors
PDE"5 Inhibitors and NAION
On July, 2005, the FDA approved updated labeling for sildenafil,
tadalafil, and vardenafil to reflect a small number of
postmarketing NAION cases

FDA advises patients to stop taking these medicines, and call a

doctor right away if they experience sudden decreased vision in
one or both eyes.

Patients considering taking these products should inform their

doctors if they have ever had severe loss of vision, which might
reflect a prior episode of NAION. Such patients are at an
increased risk of recurrance
 Pathogenesis
NAION appears to be a multifactorial disease.

Numerous risk factors, both systemic and local to the

optic nerve, have been reported in association with the
development of NAION.

It has been suggested some of these risk factors

#Cardiovascular and ocular$ predispose a patient to the
development of NAION, while other risk factors
#Nocturnal Hypotension and Sleep Apnea$ precipitate
NAION in at"risk patients.
 Risk Factors
Systemic Factors Ocular/optic nerve factors Drugs

Aging Vasospasm and impaired Angiotensin-converting

Hypertension autoregulation of the optic enzyme (ACE) inhibitors
Diabetes mellitus nerve vasculature Alpha-blockers
Hyperlipidemia Beta-blockers, including
Smoking Rise in intraocular pressure eyedrops
Cerebrovascular disease Calcium-channel blockers
Ischemic heart disease Crowded optic disc ("disc- Interferon-alpha
Systemic atherosclerosis at-risk") Nasal decongestants
Nocturnal hypotension Amiodarone
Gastrointestinal ulcers Amitriptyline
Anemia Phentermine
Hypercoagulable state Sumatriptan
Thyroid disease PDE5 inhibitors
Chronic obstructive
pulmonary disease
Surgery
Sleep apnea
Embolic disease

Dimitris Hatzichristou, Phosphodiesterase 5 Inhibitors and Nonarteritic Anterior Ischemic Optic Neuropathy #NAION$: Coincidence or
Causality?
Journal of Sexual Medicine, Volume 2 Issue 6 Page 751 " November 2005
 Number of Reported
NAION Cases
Viagra Cialis Levitra

4 1 3
5

38 27

Number of reported NAION Number of PDE5 inhibitors

Cases users in Millions
Nocturnal systemic hypotension
The relative hypotension that normally occurs with sleep may
chronically compromise optic disc circulation, in patients with
heightened nocturnal drops in blood pressure or with hypertension,
where optic disc circulation autoregulatory mechanisms are
impaired.

This e(ect could be heightened with antihypertensive or other

medications #especially if administered at night$ that further
exacerbate the nocturnal drop in blood pressure.

This combination of hypertension during the day and hypotension

during sleep could play a role in either the development or
progression of NAION
 PDE"5 Inhibitors and
NAION

The FDA statement concluded, "At this

time, it is not possible to determine
whether these oral medicines for ED were
the cause of the loss of eyesight or whether
the problem is related to other factors such
as high blood pressure or diabetes, or to a
combination of these problems."
Optimizing PDE5 Inhibitor Therapy
Correct Use ! Treatment Success
Patients should be advised that
Sexual stimulation is needed
Multiple attempts or dosage adjustments may be
required
Start with recommended dose, then increase or decrease
dependent on e(ectiveness and tolerability
• Sildenafil recommended dose is 50 mg, then increase
to 100 mg or decrease to 25 mg
• Tadalafil and vardenafil recommended dose is 10 mg;
increase to 20 mg or decrease to 5 mg as needed
Optimizing PDE5 Inhibitor Therapy
Correct Use ! Treatment Success
Food interactions
• Sildenafil and vardenafil may be taken with food but the
rate and extent of absorption may be reduced by high"fat
foods
• Tadalafil may be taken with or without food and the rate
and extent of absorption is una(ected by high"fat foods
Testosterone augmentation should be prescribed for those
with documented hypogonadism
Risk"factor modification may improve treatment outcomes
Patient education improves success
Follow"up visits are essential
Management of ED in
Cardiovascular patients
 High prevalence of ED in patients with
vascular disorders
No ED ED

49!
75! 68!

Chronic stable Acute chest pain Elevated blood

CAD pressure
Kloner RA, Mullin SH, Shook T, et al. Erectile dysfunction in the cardiac patient:how common and should we treat? J
Urol. 2003;170#suppl$:S46"S50.

Montorsi F, Briganti A, Salonia A, et al. Erectile dysfunction prevalence, time of onset and association with risk factors in
300 consecutive patients with acute chest pain and angiographically documented coronary artery disease. Eur Urol.
2003;44:360"365.
Risk Factors of CAD
Age
Dyslipidemia
Smoking
Obesity and Sedentary Lifestyle
Diabetes mellitus
Hypertension
Depression
Medication
Risk Factors of ED
Age
Dyslipidemia
Smoking
Obesity and Sedentary Lifestyle
Diabetes mellitus
Hypertension
Depression
Medication
 Endothelial Dysfunction is
the common dominator

Endothelial Dysfunction
Erectile
dysfunction

Risk
Factors

Cardiovascular
disease
 Princeton Consensus Panel
Cardiovascular risk in patients with erectile dysfunction

Low risk
Asymptomatic; < 3 coronary artery disease risk factors, excluding gender
Controlled hypertension Mild, stable angina
Has had successful coronary revascularization
Uncomplicated past myocardial infarction #> 6%8 weeks$
Mild valvular disease Intermediate risk
Left ventricular dysfunction/congestive heart failure #NYHA class I*$
) 3 major coronary artery disease risk factors,
excluding gender
Moderate, stable angina
High risk Recent myocardial infarction #> 2 but < 6 weeks$
Left ventricular dysfunction/congestive heart failure
Unstable or refractory angina Uncontrolled #NYHA class II$
hypertension Non"cardiac sequelae of atherosclerotic diseases such
Left ventricular dysfunction/congestive heart failure as stroke or peripheral vascular disease
#NYHA class III or IV$
Recent myocardial infarction #< 2 weeks$, stroke
High"risk arrhythmias
Hypertrophic obstructive and other cardiomyopathies
Moderate or severe valvular disease

*New York Heart Association functional class

 Low risk
Asymptomatic and <3 major risk factors
Controlled hypertension
Mild, stable angina pectoris
After revascularization and without significant
residual ischemia
Post"myocardial infarction #MI$ #>6%8 weeks$, but
asymptomatic.
Mild valvular disease
Left ventricular dysfunction/congestive heart failure
#NYHA class I*$

The Second Princeton Consensus on Sexual Dysfunction and Cardiac Risk: New Guidelines for Sexual Medicine
Graham Jackson, Raymond C. Rosen, Robert A. Kloner, John B. Kostis, Journal of Sexual Medicine, Volume 3 Page 28 " January 2006
Intermediate or indeterminate risk
Asymptomatic and )3 CAD risk factors
#excluding gender$
Moderate, stable angina pectoris
MI >2 weeks but <6 weeks
LVD/congestive heart failure #NYHA class II$
Non cardiac atherosclerotic sequelae #peripheral
arterial disease, history of stroke, or transient
ischemic attacks$
 High risk
Unstable or refractory angina
Uncontrolled hypertension
CHF #NYHA class III, IV$
Recent MI #<2 weeks$
High"risk arrhythmia
Obstructive hypertrophic cardiomyopathy
Moderate to severe valve disease
 Management of ED in
Cardiovascular patients
Princeton Consensus Panel
Sexual activity deferred
High
until stabilization of
Risk cardiac condition

Clinical Cardiovascular
Sexual
Evaluation Indeterminate assessment and
Inquiry
Risk re-stratification

Initiate or resume
Low sexual activity or
Risk treatment for sexual
dysfunction
 Management Recommendations Based on
Graded Cardiovascular Risk Assessment

Grade of Risk Management Recommendations

Low risk Primary care management
Consider all first"line therapies
(60% to 70%) Reassess at regular intervals #6"12 m$

Priority referral for specialized cardiovascular management

High Risk Treatment for sexual dysfunction to be deferred until cardiac
(10% to 15%) condition stabilized; dependent on specialist recommendations

Specialized cardiovascular testing

#eg, Exercise tolerance testing, echo cardiography$
Intermediate Risk Re"stratification into high risk or low risk based on the results of
(15% to 30%) cardiovascular assessment

Kostis JB, Jackson G, Rosen R, et al. Sexual dysfunction and cardiac risk #the Second Princeton Consensus Conference$. Am J Cardiol.
2005;96:313"321
PDE5 Inhibitors Daily
use for Erectile
Dysfunction
 Daily tadalafil Intake
Ability to penetrate partner
Vaginal Penetration#SEP2$

12 weeks of treatment

Chris McMahon,The Journal of Sexual Medicine. Volume 1 Issue 3 Page 292 " November 2004
SEP = Sexual Encounter Profile diary
 Daily tadalafil intake
Intercourse Completion #SEP3$
Intercourse completion

Tadalafil 5 mg and 10 mg taken once a day for 12 weeks for the

treatment of erectile dysfunction improves patient ability to
maintain erection
Buvat et al. ESSM. 4"7 December 2005.
 Daily tadalafil Intake
Satisfaction with
Satisfaction with hardness
hardness#SEP4$

Tadalafil 5 mg and 10 mg taken once a day for the treatment

of erectile dysfunction improves patient sexual satisfaction
Buvat et al. ESSM. 4"7 December 2005.
 Daily tadalafil intake
Overall Satisfaction #SEP5$ Overall Sexual Satisfaction

Tadalafil 5 mg and 10 mg taken once a day for the treatment of

erectile dysfunction improves patient sexual satisfaction
Buvat et al. ESSM. 4"7 December 2005.
 Improved spontaneous erectile function in
men with arteriogenic ED treated with a
nightly dose of sildenafil for one year

Group 1 50 mg sildenafil nightly

112 ED Patients

One Year 1 m 6 months

Group 2
50 " 100 mg sildenafil Follow Follow
on demand up up

Sommer F, Klotz T, Engelmann U. Asian J Androl 2007; 9 #1$: 134"141

Improved spontaneous erectile function in
men with arteriogenic ED treated with a
nightly dose of sildenafil for one year
Nightly On demand

! of patients with normal EF domain

Sommer F, Klotz T, Engelmann U. Asian J Androl 2007; 9 #1$: 134"141
Improved spontaneous erectile function in
men with arteriogenic ED treated with a
nightly dose of sildenafil for one year
PSV cm/sec

Patients who maintained normal EF for 6 months

Sommer F, Klotz T, Engelmann U. Asian J Androl 2007; 9 #1$: 134"141
Indications for PDE5 Inhibitors
daily use

Failed on demand use

Di'cult to treat Erectile dysfunction

#diabetes, after radical prostatectomy$

Honeymoon impotence

Rehabilitation after radical prostatectomy

 Long"Term Continuous Treatment with
Sildenafil Ameliorates Aging"Related
Erectile Dysfunction
• Aging"related erectile dysfunction is characterized by a
loss of smooth muscle cells and fibrosis in the corpora
cavernosa, and functionally by veno"occlusive
dysfunction manifested by inability to maintain rigid
erection.

• PDE5 inhibitors, via upregulating inducible nitric oxide

synthase #iNOS$, have anti"fibrotic properties in penile
tissues.

Ferrini et al. Published on February 14, 2007 as DOI:10.1095/biolreprod.106.059642

 Long"Term Continuous Treatment with
Sildenafil Ameliorates Aging"Related
Erectile Dysfunction

Aged male rats Aged male rats Untreated young rats

#20 month old$ #20 month old$ #5 months old$ served
received sildenafil in received plain water for as controls.
their drinking water 45 days
for 45 days
 Long"Term Continuous Treatment with
Sildenafil Ameliorates Aging"Related
Erectile Dysfunction
Response to ICI #mmHg$

Ferrini et al. Published on February 14, 2007 as DOI:10.1095/biolreprod.106.059642

 Long"Term Continuous Treatment with
Sildenafil Ameliorates Aging"Related
Erectile Dysfunction
Drop rate #mmHg/1st min$

Ferrini et al. Published on February 14, 2007 as DOI:10.1095/biolreprod.106.059642

 Long"Term Continuous Treatment with
Sildenafil Ameliorates Aging"Related
Erectile Dysfunction
Young Old Old + Sildenafil

Reduced smooth muscle/collagen ratio and increased

collagen content in the aged rat corpora cavernosa
 Endothelial Repair

Endothelial Neovascularization
Progenitor Cells

Endothelial Regeneration

Urbich C, Dimmeler S : Endothelial Progenitor Cells Characterization and Role in Vascular

Biology. Circ Res. 2004;95:343"353.
Circulating endothelial progenitor cells
in subjects with erectile dysfunction
EPCs numbers #PC/ml$

Foresta et al... Int J Impot Res. 2005 May"Jun;17#3$:288"90.

Circulating endothelial progenitor cells
in subjects with erectile dysfunction
EPCs numbers #PC/ml$

Foresta et al. Eur Urol. 2007 May;51#5$:1411"9.

 E(ect of single vardenafil
Administration
Base line Vardenafil
EPCs numbers #PC/ml$

Foresta et al. Eur Urol. 2007 May;51#5$:1411"9.

 E(ect of Chronic Tadalafil
Administration
EPCs numbers #PC/ml$

Controls
ED

20 mg/3 times/W
for 3 months

Foresta et al Int J Impot Res. 2006 Sep"Oct;18#5$:484"8.

New PDE5 Inhibitors
Udenafil #Zydena$

A newly developed, potent, selective PDE5 inhibitor

Pharmacokinetic profiles include a Tmax of 1.0%1.5 hours

and a T1/2 of 11% 13 hours, i.e. relatively rapid onset and
long duration of action.

Selectivity profile of udenafil is similar to that of

sildenafil, it does not inhibit PDE11
Avanafil : The Ultra"Short
PDE5 Inhibitor

Greatest selectivity for PDE5, when compared to other PDE5 inhibitors

Avanafil is rapidly absorbed after oral administration, with T max of 35
minutes.
A short plasma T 1/2 < than 1.5 hours.
• Shorter side e(ects
• Twice / day
• Shorter duration of drug drug interaction
Avanafil plus nitroglycerin resulted in smaller changes in blood pressure
and heart rate, a shorter duration of interaction with nitroglycerin, and
fewer subjects with clinically significant hypotension than did combined
treatment with other PDE5 inhibitors and nitroglycerin.
SLx"2101: The Ultra"Long
PDE5 Inhibitor
SLx"2101 is a, long acting PDE"5 inhibitor for disorders
associated with endothelial dysfunction, including ED

Phase IIa study shows that this drug is working at 48

hours after a single dose of 10 mg

Unlike the currently approved PDE"5 inhibitors,

SLx"2101 is two drugs in one. When first taken, SLx"2101
has a fast action #15 min$. While it is still working, the
body metabolize it into a second drug, SLx"2101m1#v
long acting 48 hours$.
Second"Line Therapy
for Management of ED
 Second"Line Therapy for
Management of ED

Vacuum constriction devices

Intracavernosal injection
• Alprostadil
• Drug mixture #trimix: papaverine, phentolamine,
alprostadil$
Transurethral alprostadil #MUSE®$

MUSE®=Medicated Urethral System for Erection.

Second"Line Therapy: VCDs
Lack of interest in drug therapy

Specific contraindications to drug therapy

#e.g. nitrate intake$

Patient preference

Vacuum
 Second"Line Therapy:
Intracavernosal Injection
Lack of response to oral therapy
Contraindications to specific oral
drugs
Adverse reactions/intolerance to oral
drugs
More reliable, instant, predictable
erection
Patient preference
 Second"Line Therapy:
Medicated Urethral System for
Erection #MUSE$

Lack of response to oral therapy

Contraindications to specific oral

drugs

Adverse reactions/intolerance to oral

drugs

Rapid, predictable erection

Third"Line Therapy for
Management of ED
 Third"Line Therapy: Penile
Prostheses
Intolerance or lack of response to
other treatment modalities

Irreparably damaged erectile tissue

Specific concomitant medical

conditions such as vascular or
neurologic disease, chronic renal
disease, and genital trauma #eg,
Peyronie’s disease$
 Third"Line Therapy:
Penile Revascularization
Only performed in carefully selected
patients
• Young men with traumatic pelvic
injury or congenital ED
• Poor response in men with diabetes,
neurologic disorders, nicotine abuse
Data over a 10"y period showed an
overall long"term success rate of 48!
• Another 29! reported successful
intercourse aided by oral or
intracavernosal injection therapy
 Combination Therapy for
Monotherapy Nonresponders
Sildenafil + transurethral alprostadil

Sildenafil + triple"agent intracavernosal injection

Transurethral alprostadil + VCD or penile prosthesis

Sildenafil + psychosocial counseling

Sildenafil + testosterone replacement therapy

 Advantages of Therapeutic
Options
Noninvasive, involves partner, may be
Psychosexual therapy
curative

PDE5 inhibitors Oral therapy, e(ective

Transurethral alprostadil Local therapy, few systemic side e(ects

Intracavernosal alprostadil Highly e(ective, few systemic side

or drug mixtures e(ects
Least expensive over time, no systemic
VCDs
side e(ects

Penile prostheses Highly e(ective

 Disadvantages of Therapeutic
Options
Time"consuming; patient resistance;
Psychosexual therapy variable e'cacy; cost; availability of
qualified providers
Contraindicated in patients receiving
nitrates; interactions with alpha
PDE5 inhibitors blockers need to be considered;
potential for drug" food interactions
may delay onset and reduce e'cacy
Moderately e(ective; requires o'ce
Transurethral alprostadil training; causes penile pain; relative
cost; partner"related vaginal irritation
 Disadvantages of Therapeutic
Options
Requires injection; high dropout rate;
Intracavernosal alprostadil
can cause priapism, penile fibrosis, or
or drug mixtures
penile pain

Unnatural erection; causes petechiae,

VCDs
numbness #20!$, trapped ejaculation

Unnatural erection #semi"rigid device$;

Penile prostheses risk of infection; requires anesthesia/
surgery; replacement in 5"10 years