management of erectile dysfunction

Erectile DysfunctionTreatment options

Tarek AnisProf. of Andrology, Cairo University

PASSM President

Incidence of Erectile Dysfunction

Prevalence of erectile dysfunction

Prevalence of erectile dysfunction

0%

20%

40%

60%

80%

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

77.6%

60.2%

43.7%

23.9%

8.2%

3.8%6.5%

18! of all men above 20 years

International Index of Erectile FunctionIIEF Score

Over the past 6 months:

1

3

2

5

4

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 penetration?

0 No sexual activity 1 Almost never or never

2 A few times 3 Sometimes 4 Most times 5 Almost always or always

During sexual intercourse, how often were you able to maintain your erection after you had penetrated (entered) your partner?

0 Did not attempt 1 Almost never or never


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

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

When you attempted sexual intercourse, how often was it satisfactory to you?

0 Did not attempt 1 Almost never or never


Goldstein I et al. N Engl J Med 1998;338:1397–1404.Rosen RC et al. Int J Impot Res 1999; 319–26.

Erection Hardness Score

Severe ED(IIEF5: ! 10)

Moderate ED(IIEF5: 11–15)

Mild ED(IIEF5: 16–20)

No ED(IIEF5: >20)

Penis is completely hard and fully rigid

GRADE 4GRADE 3

Penis is hard enough for penetration

but not completely

hard

Penis is hard but not hard

enough for penetration

GRADE 2

Penis is larger but not hard

GRADE 1

Major Risk Factors of Erectile dysfunction

Major Risk Factors of Erectile dysfunction

AgingChronic disease

Cardiovascular disease, hypertension, diabetes, lower urinary tract symptoms, and depression

MedicationsThiazide diuretics, beta"blockers, selective serotonin reuptake inhibitors

LifestyleStress, alcohol and drug abuse, smoking, obesity, and sedentary lifestyle

1 32Lifestyle Modification

Stop smokingLimit or avoid alcoholFollow healthy dietExercise regularlyReduce weightGet adequate sleep

WHO Treatment Recommendation


Drug Therapy Modifications

Antihypertensives/diureticsSelective serotonin"reuptake inhibitorsHormonal agents #eg, anti"androgens$H2"receptor




Psychosocial Counseling

Anxiety reduction/desensitizationCognitive"behavioral interventionsSexual stimulation techniquesInterpersonal assertiveness/couples’ communication training





Androgen Replacement

Transdermal testosteroneGel or scrotal, buccal, and non"scrotal patchesIntramuscular #IM$ injectionSubcutaneous implantOral testosterone





Androgen ReplacementOral PDE5 Inhibitors

Sildenafil #Viagra®$Tadalafil #Cialis®$Vardenafil #Levitra®$






Intracavernosalinjection







MUSE







MUSE

Vacuum device







MUSE

Vacuum device

Penile prosthesis

Revascularization


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

Sildenafil

Tadalafil

Vardenafil

Endothelial cell

Cavernousnerve

SexualStimulation

Endoplasmicreticulum

Nitricoxide

Smooth muscle cell

Smooth muscle relaxation

Ca2+

K+

PDE5 inhibitorsite of action

Ca2+

Ca2+

Decreased

K+

cGMP!specificprotein Kinase

Guanylatecyclase

PDE5

cGMPGTP

5’ GMP

Stimulation

Inhibition

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

Mechanism of action

Chemical Structure

NN

O

N

O

O

O

N

NHN

O

S

O

O O

N

N

NN

NHN

NO

S

O

O O

N

N

O

NH2

N

NH

N

NH

O

O

PO

O0H

0H

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 ~4Presence in the body #h$ 24 72 24Therapeutic 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

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.

Number of erections / month

VIAGRA 100 mg Placebo


Time of Strong ErectionE

rect

ion

tim

e in

m

inut

es

VIAGRA Placebo


Ability to penetrate!

incr

ease

VIAGRA Placebo

Time of maintenance of erection

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

! in

crea

se

VIAGRA Placebo

Successful intercourse completion

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?

! in

crea

se

VIAGRA Placebo

Reliability to have & Maintain Erection

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

! in

crea

se

VIAGRA Placebo

Total satisfaction

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

! in

crea

se

1 year 2 years 3 years 4 years

Total Satisfaction

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

P

P

P

P

Family

1

2

3

4

5

6

7

8

9

10

11

Regulatory Regions

cGMP-binding sites

cGMP-binding sites?

cGMP-binding site?

cGMP-binding sites

URC sites

cGMP-binding sites

Calmodulin-binding sites

Membrane associationregion

Conserved CatalyticDomain Calmodulin-stimulated

cAMP/cGMP PDE

cGMP-binding

cGMP-specific PDE

cGMP-stimulated

cAMP/cGMP PDE

cAMP/cGMP PDE

High affinity

cAMP/cGMP PDE

cAMP-specific PDE

IBMX-insensitive

cAMP-specific

Rollpram-insensitive PDE

Photoreceptor

cGMP-specific PDE

cAMP-specific

Rollpram-inhibited PDE

cGMP-binding

cAMP/cGMP PDE

cGMP-inhibited

cAMP/cGMP PDE

Selectivity

Selectivity Ratio =

Potency against PDE5

Potency against other PDEs

The smaller the number the less selective the drug is for PDE5

compared with the other isoenzyme

=IC50 for PDE5

IC50 for other PDEs

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

Vardenafil

RatioX/5

Sildenafil

RatioX/5

Tadalafil

RatioX/5

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

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

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

1 41 >1000 >1000 375 7.4 >1000 >1000 >1000 447 203

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

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.

Selectivity of PDE5 inhibitors

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.

Visual abnormalities have been rarely reported with Tadalafil

Rods sense brightnessCones sense color

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

SG ST SG ST IC

PDE11 Localization in Human Tissues

AF B

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 by bilateral lower lumbar, gluteal, thigh, or thoracolumbar muscular discomfort and was exacerbated by recumbency

Nucleus

Endomysium

Striation

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 Vision

Myalgia & back pain

Abnormal 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


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 FactorsSystemic Factors

Aging

Hypertension

Diabetes mellitus

Hyperlipidemia

Smoking

Cerebrovascular disease

Ischemic heart disease

Systemic atherosclerosis

Nocturnal hypotension

Gastrointestinal ulcers

Anemia

Hypercoagulable state

Thyroid disease

Chronic obstructive

pulmonary disease

Surgery

Sleep apnea

Embolic disease

Ocular/optic nerve factors

Vasospasm and impaired

autoregulation of the optic

nerve vasculature

Rise in intraocular pressure

Crowded optic disc ("disc-

at-risk")

Drugs

Angiotensin-converting

enzyme (ACE) inhibitors

Alpha-blockers

Beta-blockers, including

eyedrops

Calcium-channel blockers

Interferon-alpha

Nasal decongestants

Amiodarone

Amitriptyline

Phentermine

Sumatriptan

PDE5 inhibitors

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

14

38

3

5

27

Number of reported NAION Cases

Number of PDE5 inhibitors 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


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 SuccessPatients 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

Correct Use ! Treatment SuccessFood 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

Optimizing PDE5 Inhibitor Therapy

Management of ED in Cardiovascular patients

High prevalence of ED in patients with vascular disorders

75!

49!

68!

No ED ED

Chronic stable CAD

Acute chest pain Elevated blood pressure

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.

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.

Risk Factors of CADAge

Dyslipidemia

Smoking

Obesity and Sedentary Lifestyle

Diabetes mellitus

Hypertension

Depression

Medication

Age

Dyslipidemia

Smoking

Obesity and Sedentary Lifestyle

Diabetes mellitus

Hypertension

Depression

Medication

Risk Factors of ED

Endothelial Dysfunction is the common dominator

Erectiledysfunction

Cardiovasculardisease

En

do

thelia

l Dys

fun

ctio

n

RiskFactors

Princeton Consensus PanelCardiovascular risk in patients with erectile dysfunction

Intermediate risk

) 3 major coronary artery disease risk factors, excluding gender

Moderate, stable angina

Recent myocardial infarction #> 2 but < 6 weeks$

Left ventricular dysfunction/congestive heart failure #NYHA class II$

Non"cardiac sequelae of atherosclerotic diseases such as stroke or peripheral vascular disease

Unstable or refractory angina Uncontrolled hypertension

Left ventricular dysfunction/congestive heart failure #NYHA class III or IV$

Recent myocardial infarction #< 2 weeks$, stroke

High"risk arrhythmias

Hypertrophic obstructive and other cardiomyopathies

Moderate or severe valvular disease

High risk

*New York Heart Association functional class

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

Left ventricular dysfunction/congestive heart failure #NYHA class I*$

Low risk

Low riskAsymptomatic 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 riskUnstable 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

SexualInquiry

IndeterminateRisk

Cardiovascularassessment andre-stratification

LowRisk

Initiate or resume sexual activity or

treatment for sexual dysfunction

HighRisk

Sexual activity deferred until stabilization of

cardiac condition

ClinicalEvaluation

Management of ED in Cardiovascular patients

Princeton Consensus Panel

Grade of Risk Management Recommendations

Low risk(60% to 70%)

Primary care managementConsider all first"line therapiesReassess at regular intervals #6"12 m$

High Risk(10% to 15%)

Priority referral for specialized cardiovascular managementTreatment for sexual dysfunction to be deferred until cardiac condition stabilized; dependent on specialist recommendations

Intermediate Risk(15% to 30%)

Specialized cardiovascular testing#eg, Exercise tolerance testing, echo cardiography$ Re"stratification into high risk or low risk based on the results of cardiovascular assessment

Management Recommendations Based on Graded Cardiovascular Risk 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 IntakeAbility to penetrate partner

Chris McMahon,The Journal of Sexual Medicine. Volume 1 Issue 3 Page 292 " November 2004

Vag

inal

Pen

etra

tion#S

EP

2$

SEP = Sexual Encounter Profile diary

12 weeks of treatment

Daily tadalafil intakeIntercourse completion

Buvat et al. ESSM. 4"7 December 2005.

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

Inte

rcou

rse

Com

ple

tion

#SE

P3$

Daily tadalafil IntakeSatisfaction with hardness


Tadalafil 5 mg and 10 mg taken once a day for the treatment of erectile dysfunction improves patient sexual satisfaction

Sati

sfac

tion

wit

h

har

dn

ess#

SEP

4$

Daily tadalafil intakeOverall Sexual Satisfaction


Tadalafil 5 mg and 10 mg taken once a day for the treatment of erectile dysfunction improves patient sexual satisfaction

Ove

rall

Sati

sfac

tion

#SE

P5$

Improved spontaneous erectile function in men with arteriogenic ED treated with a

nightly dose of sildenafil for one year

Group 1

Group 2

50 mg sildenafil nightly

50 " 100 mg sildenafil on demand

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

One Year 6 months1 m

112

ED

Pat

ien

ts

Followup

Followup




Nightly On demand

! o

f p

atie

nts

wit

h n

orm

al E

F d

omai

n




PSV

cm

/sec

Patients who maintained normal EF for 6 months

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



Aged male rats #20 month old$

received sildenafil in their drinking water

for 45 days

Aged male rats #20 month old$

received plain water for 45 days

Untreated young rats#5 months old$ served

as controls.


Erectile DysfunctionR

esp

onse

to

ICI #m

mH

g$



Erectile DysfunctionD

rop

rat

e #m

mH

g/1s

t min$




Young Old Old + Sildenafil

Reduced smooth muscle/collagen ratio and increased collagen content in the aged rat corpora cavernosa

Endothelial Repair

Endothelial Progenitor Cells

Neovascularization

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

EP

Cs

num

ber

s #P

C/m

l$

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

Circulating endothelial progenitor cells in subjects with erectile dysfunction

EP

Cs

num

ber

s #P

C/m

l$

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

E(ect of single vardenafil Administration

EP

Cs

num

ber

s #P

C/m

l$

Base line Vardenafil

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

E(ect of Chronic Tadalafil Administration

EP

Cs

num

ber

s #P

C/m

l$

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

ControlsED

20 mg/3 times/Wfor 3 months

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

Psychosexual therapy Noninvasive, involves partner, may be curative

PDE5 inhibitors Oral therapy, e(ective

Transurethral alprostadil Local therapy, few systemic side e(ects

Intracavernosal alprostadil or drug mixtures

Highly e(ective, few systemic side e(ects

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

Penile prostheses Highly e(ective

Disadvantages of Therapeutic Options

Psychosexual therapyTime"consuming; patient resistance; variable e'cacy; cost; availability of qualified providers

PDE5 inhibitors

Contraindicated in patients receiving nitrates; interactions with alpha blockers need to be considered; potential for drug" food interactions may delay onset and reduce e'cacy

Transurethral alprostadilModerately e(ective; requires o'ce training; causes penile pain; relative cost; partner"related vaginal irritation

Disadvantages of Therapeutic Options

Intracavernosal alprostadil or drug mixtures

Requires injection; high dropout rate; can cause priapism, penile fibrosis, or penile pain

VCDsUnnatural erection; causes petechiae, numbness #20!$, trapped ejaculation

Penile prosthesesUnnatural erection #semi"rigid device$; risk of infection; requires anesthesia/surgery; replacement in 5"10 years

management of erectile dysfunction

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