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Erectile Dysfunction

Medical Treatment

Alireza Ghoreifi

Assistant of Urology

Mashhad University of Medical Sciences

March 2012

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Treatment of ED

Unknown cases of ED

Three lines

First-line therapy

Second-line therapy

Third-line therapy

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Treatment of ED

First-line therapy

Oral pharmacotherapy

Topical pharmacotherapy

Vacuum constriction devices “VCD”

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Treatment of EDSecond-line therapy

1. Intracavernous injections

2. Intraurethral alprostadil “PGE1”

Treatment of EDThird-line therapy

Penile prothesis

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First line Treatment of EDOral pharmacotherapy

PDE5 inhibitors

The PDE5 enzyme hydrolyses cyclic

guanosine monophosphate (cGMP) in the

cavernosum tissue of the penis.

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PDE 5 inhibitorsMechanism of action

Inhibition of PDE5 reduce the

degradation of cGMP that effect on nitric oxide

Vasodilatation Smooth muscle relaxation

Penile erection

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PDE 5 inhibitors

- Sildenafil*

- Tadalafil*

- Vardenafil*

* European Medicines Agency “EMEA” Approval

PDE 5 inhibitorsnew generation

Avanafil: currently has no trademarked

Lodenafil: (Helleva), not FDA approved

Mirodenafil: (Mvix), not FDA approved

Udenafil:( Zydena) , not FDA approved

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Sildenafil

Iaunched in 1998

First PDE5 inhibitor erection and rigidity sufficient for

vaginal penetration

Effective: 30-60 min after administration and

T max = 0.8 to 1 hour

Heavy meal prolonged absorption reduce of

efficacy

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Sildenafil

Starting dose = 50 mg and then adapt according

to the:

- Patients response

- Side-effects

Efficacy maintain for up to 12h

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Sildenafil

After 24 weeks of treatment and in a dose-response study

“Pre-market”; improved erections:

1. 25 mg = 56%

2. 50 mg = 77%

3. 100 mg = 84%

4. Placebo = 25%

In diabetics:

- Improved erection= 66.6% / 28.6%

- Successful intercourse= 63% / 33%

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Tadalafil

Licensed for the treatment of ED = Feb 2003

Effective = 30 min with peak efficacy = 2h

Efficacy is maintained for up to 36h and is not

affected by food.

Recommended starting dose = 10 mg and then

adapt

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Tadalafil

After 12 weeks of treatment and in a dose - response

study, ”Pre-market” improved erections:

1- 10 mg = 67%

2- 20 mg = 81%

3- Placebo = 35%

Diabetic = 64% / 25%

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Vardenafil

Commercially available as of March 2003

Effective = 30 min, reduce effect by a heavy fatty meal

(>57%) and Tmax = 0.9h

Recommended starting dose = 10 mg (5-10-20mg)

Improved erections in difficult-to-treat

subgroups.

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Vardenafil

5 mg = 66%

10 mg = 76%

20 mg = 80%

Placebo = 30%

Diabetic patients =72% / 13%

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PDE5 inhibitors : Not 100% effective

to everyone , every time

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Choice or preference between the

different PDE5 inhibitor

To date , no data are available

Choice of drug will depend on:

- The frequency of intercourse (occasional

use or regular therapy, 3-4 times weekly)

- Patients personal experience

Patients need to know whether a drug is short or long-

acting, possible disadvantages and how to use it

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On-demand or continuous therapy (daily)of PDE5 inhibitors?

Tadalafil 5 mg once daily is an alternative to on-demand

for couples who prefer spontaneous rather than

scheduled sexual activities or who anticipate frequent

sexual activity

Tadalafil 2.5 and 5 mg/daily is efficacious and well

tolerate

However, when patients have the choice, it seems that

they prefer on-demand rather than continuous therapy.

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Safety issues for PDE5 inhibitors

In patients receiving PDE5 inhibitors,

myocardial infarction rates does not increase.

PDE5 inhibitors may improve exercise tests,

and dose not alter cardiac contractility, and

cardiac out-put

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Absolute contraindications with the use

of PDE5 inhibitors

Agents used to treat angina:

- Organic nitrates:

nitroglycerine

isosorbide mononitrate

isosorbide dinitrate

- Other nitrate preparations

Agents used for recreation:

- Amyl nitrite or amyl nitrate

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If a PDE5 inhibitors is taken and the patients

develops:

Chest pain = nitroglycerine must be withheld for

at least 24h for use of sildenafil and vardenafil

and 48h for use of tadalafil

Angina = other agents may be given instead of

nitroglycerine until the appropriate time has

(above) passed.

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Alpha-blocker interactions

All PDE5 inhibitors show some interaction

with alpha-blockersorthostatic hypotension.

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Alpha-blocker interactions

Sildenafil (50 or 100mg ) should not

be taken within 4h following treatment

with an alpha-blocker

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Alpha-blocker interactions

Co-administration of vardenafil with

tamsulosin is not associated with

clinically significant hypotension

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Alpha-blocker interactions

In the USA, vardenafil is absolutely

contraindicated with alpha-blocker

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Alpha-blocker interactions

Tadalafil is contraindicated in patients

taking alpha-blockers, except for

tamsulosin, 0/4mg

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Dosage adjustment

Lower doses

Ketoconazole, itraconazole, erythromycine,

clarythromycin increase blood levels of

PDE5 inhibitors so that lower doses of PDE5

inhibitors are necessary.

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Dosage adjustment

higher doses

Rifampin, phenobarbital, phenytoin and

carbamazepine enhance the breakdown

of PDE5 inhibitors so that higher doses

of PDE5 inhibitors are required

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Dosage adjustment

Severe kidney or hepatic dysfunction may

require dose adjustments or warnings

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Ways of improving efficacy

1- Medication of associated risk factors.

2- Treatment of associated hypogonadisem.

3- Changing to another PDE5 inhibitor.

4- Continuous use daily of a PDE5 inhibitor.

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Non-responders to PDE5 inhibitors

Reasons

1- Incorrect drug use= the main reason is

inadequate counseling from his physician.

2- Inefficacy of the drug

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Management of non-responders to PDE5 inhibitors

Check by physician

Using a licensed medication (black market)

The main ways in which a drug may be incorrectly

used are:

- Failure to use adequate sexual stimulation

- Failure to use an adequate dose

- Failure to wait an adequate amount of

time between taking the medication

and attempting sexual intercourse

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PDE5 inhibitorsTime between taking and intercourse

All three drugs have an onset of action in

some patients within 30 min of oral ingestion,

most patients require a longer time with at

least:

60 min for sildenafil and vardenafil

2h for tadalafil

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PDE5 inhibitors

food and delay of absorption

Sildenafil = Heavy meal

Vardenafil = Fatty meal

Tadalafil = Is less affected

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Side effects of PDE5 inhibitors

Flushing and headache (mild to moderate in

severity)

Myalgia, back pain, leg pain, vision disturbances

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ED and dyslipedemia

In hypercholesteromic men with erectile

dysfunction not initially responsive to

sildenafil improves the response to

sildenafil

LDL > 120 mg/100cc

40 mg atorvastatin

100 mg On-demand sildenafil for 12 weeks.

27 Nov 2009

Atorvastatine

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Treatment of EDFirst-line therapy

Apomorphine sublingualis a centrally acting dopamine agonist

Enhancing the natural central erectile signals that occur during sexual stimulation

improve erectile erection

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Apomorphine

Has been approved in several countries

but

not in the USA

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Apomorphine

Dose = 2 or 3 mg sublingually

Efficacy rate = 28.5% to 55%.

Due to rapid absorption, 71% of erections

are achieved within 20 min

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Apomorphine

Most common adverse effects

Nausea 7%

Headache 6.8%

Dizziness 4.4%

Are generally mild in nature and self-limited.

Severe events such as syncope, are

extremely rare = < 0.2%

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Apomorphine

Apomorphine is not contraindicated in

patients that taking nitrates or

antihypertensive drugs (of all classes) and

is a first-line treatment in patients, who use

nitrates.

Does not effect on vital signs.

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Apomorphine

It is use is limited to patients with mild to

moderate ED or psychogenic causes of

sexual dysfunction due to reduce efficacy

rates.

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Treatment of EDOther oral treatment

Yohimbine and Trazodone

Randomized trials have shown that

yohimbine and trazodone have a similar

efficacy to placebo in patients with organic

causes of ED.

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Other oral agents

Red korea ginseng

Is a formulation with an unknown mechanism of

action (though it may possibly act as a nitric oxide

donor)

Efficacy data on red korea ginseng suggested it

might have a role in treatment of ED

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Other oral agents

Phentolamine

Oral formulation of phentolamine (non selective

alpha-adrenergic antagonist) had efficacy rates

(erections sufficient for intercourse) of about

50%, but possible carcinogenesis in animal

models stopped further development.

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Other oral agents

l-argenine is a nitric oxide donor

Nalmefene / naltrexone is an opioid-receptor

antagonist

Limaprost is an alprostadil derivative for oral use

There are no efficacy data on these drugs

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Treatment of EDFirst-line therapy

Topical pharmacotherapy

No topical therapy has been approved and

currently these agents have no role in

treatment of ED.

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Treatment of EDFirst-line therapy

Vacuum therapy

More acceptable to older patients with infrequent

sexual intercourses

Efficacy is as high as 90%

Satisfactory rate range = 27% and 94%

Long-term use decreases to 50% - 64% after

2 years

Most men who discontinue use of VCDs do so

within 3 months

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Vacuum therapyThe commonest adverse events

Occur in less than 30% of patients:

Penis pain, petechiae , bruising,

numbness, inability to ejaculate, and

delayed ejaculation

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Treatment of EDSecond-line therapy

1. Intracavernous injections

- Monotherapy “Alprostadil PGE1”

- Combination therapy:

* Papaverine + Phentolamine

* Papaverine + Phentolamine + PGE1

2. Intraurethral alprostadil “PGE1”

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Treatment of EDSecond-line monotherapy therapy

Alprostadil “PGE1”

Is the first and only approved for

intracavernous ED treatment in general

ED papulation and patients subgroups

“diabetes, cardiovascular disease”.

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Alprostadil

Efficacy rate > 70 %

Satisfaction rate = 87% - 93.5% in patients and 86%

-90.3% in partners

Doses : 5 - 4µg and erection appears after 5 -15 min

Drop-out rate : 41% - 68% particularly within the first

2 - 3 months

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Alprostadil

Complications:

* Pain 50% after 11% of injections

* Prolonged erection 5%

* Priapism 1%

* Fibrosis 2%

* Hypotension is uncommon

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AlprostadilContraindications

History of hypersensitivity to alprostadil

Men at risk of priapism

Men with bleeding disorders

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Intracavernous injectionsCombination therapy

1) Papaverine 7.5 - 45mg + Phentolamine 0.25 -1.5mg

2) Papaverine 8-16mg + Phentolamine 0.2-0.4mg+

Alprostadil 10-20µg

Penile pain due to decrease of dose of Alprostadil

and fibrosis for Phentolamine and mild

hepatotoxicity with Papaverine

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Intracavernous injections

Combination therapy

Efficacy rate = 92%

If not respond to combination therapy

sildenafil + triple combination regimen

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Treatment of EDSecond-line therapyIntraurethral alprostadil

125-1000µg in a medicated pellet

Erection sufficient for intercourse = 30% - 65.9%

Adverse events:

* Local pain 29% - 41%

* Dizziness 1.9% - 14%

* Penile fibrosis and priapism < 1%

* Urethral bleeding 5%

* Urinary tract infections 0.2%

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Third-line therapy

Penile prothesis

Do not respond to pharmacotherapy

Who prefer a permanent solution to their problem

Malleable (semi-rigid) and inflatable:

- Two piece

- Three piece

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Penile prothesis

Complications

Mechanical failures < 5% at 5 years fallow up

Infection = 2-3% but with antibiotic -impregnated

prothesis or hydrophilic – coated prothesis = 1%

In spinal cord injuries : infection and erosions = 9%

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when infection occurred:

1) Removed the prothesis, antibiotic

administration and re-implantation after

6-12 months.

2) Removed and re-implantation at the same

time, after copious irrigation of the

corpora with multi-drug solutions, had

an 82% success rate.

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