FARMAKOTERAPI:

ERECTILE
Rudy Salam
DYSFUNCTION Jurusan Farmasi FKUB
 01
An erection is a physiological
phenomenon during which the
penis becomes engorged with
blood, causing it to become
enlarged and more firm
ERECTION
02
a complex interaction between
psychological, neurological,
endocrine and vascular factors
that are associated with sexual
arousal
ANATOMY AND MECHANISM OF PENILE ERECTION

regulate penile blood primarily

flow during erection responsible for
and detumescence penile sensation

Sexual stimulation à nerve impulses à

release of neurotransmitters (cavernous
nerve) and relaxing factors (endothelial
cells) in the penis à relaxation of smooth
muscle in the arteries and arterioles
supplying the erectile tissue and a
severalfold increase in penile blood flow à
facilitating rapid filling and expansion of
the sinusoidal system à resulting in almost
total occlusion of venous outflow à trap
the blood within the corpora cavernosa
and raise the penis from a dependent
position to an erect position
THE ROLE OF THE PARASYMPATHETIC & SYMPATHETIC NERVOUS SYSTEM

• male erection is triggered by

the parasympathetic nervous
system à NO release
• NO is neither an adrenergic, nor a
cholinergic neurotransmitter -->
NANC
• NO can also be produced and
released by endothelial cells of
the corpus cavernosum in
response to chemical and
physical stimuli
THE ROLE OF TESTOSTERONE
 ERECTILE
• Erectile function is about performance
DYSFUNCTION IS
• ED is defined as the consistent inability to acquire or
sustain an erection sufficient for sexual intercourse COMMON
 Negative effects of ed on men’s quality of life
70

60

50

40 worry/anxiety
lack of confidence
negative feeling toward impotence
30 feel depressed
feel unattractive

20

10

0
worry/anxiety lack of negative feel feel
confidence feeling toward depressed unattractive
impotence

Massachusetts Male Aging Study longitudinal data

 The incidence of ED,
calculated from A large European A UK study of men
longitudinal data in the study of men aged 30- aged 18-75 showed a
MMAS (Massachusetts 80 reported a rate of 39% for lifetime
Male Aging Study), prevalence of 19% ED
was 26 new cases per
1000 per year

EPIDEMIOLOGY
 Jenis-jenis Disfungsi Klinik Andrologi JUMLAH KASUS/
Klinik Andrologi Y
Seksual Rumah Sakit X Persentase
Gang.Hasrat Seksual 3 4 7 (2,7%)
Disfungsi Ereksi 119 78 197 (77,2%)
Disfungsi Orgasme 0 0 0 (0%)
Ejakulasi Dini 23 21 44 (17,2%)
Dispareunia 3 4 7 (2,7%)
JUMLAH PASIEN/
148 107 255 (100%)
Persentase

EPIDEMIOLOGI DI INDONESIA
Faktor Internal
Jumlah/
Disfungsi Seksual Kelainan
Neuro Genik Endokrin Vaskuler Sistemik Penuaan Persentase
Anatomi
Gang.Hasrat Seksual - 1 - - - 1 2 (1,3%)
Disfungsi Ereksi 1 53 8 18 - 3 83 (56%)
Disfungsi Orgasme - - - - - - 0 (0%)
Ejakulasi Dini - 3 1 - - - 4 (2,7%)
Dispareunia - - - - 2 - 2 (1,3%)

Pradana, G. F. (2015). Profil disfungsi seksual pria di Klinik Andrologi Rumah Sakit Kharitas Bhakti dan Klinik Andrologi Yu Tee di Kalimantan Barat Tahun 2009-2014. Jurnal
Mahasiswa PSPD FK Universitas Tanjungpura, 3(1).
ETIOLOGY

Organic traditionally Non-Organic

refers to vascular or traditionally refers to
neurogenic (nerve “Psychogenic”
damage) causes
PATHOHYSIOLOGICAL CAUSE OF ED

Performance Heart and

anxiety Vascular disease

Depression Diabetes

Drugs
 CATEGORY OF function.21 Veno-occlusive dysfunction may be ca
ERECTILE DYSFUNCTION COMMON DISORDERS PATHOPHYSIOLOGY
by the formation of large venous channels drainin
Psychogenic Performance anxiety
Relationship problems
Loss of libido, overinhi-
bition, or impaired
PATHOHYSIOLOGICAL CAUSE OF ED
corpora cavernosa, degenerative changes to the tu
albuginea (due to Peyronie’s disease, old age, o
Psychological stress nitric oxide release
Depression abetes mellitus) or traumatic injury (penile fract
•structural
Anticholinergic agents
alterations ofà antihistamin,
the TCA,
cavernous smooth
Neurogenic Stroke or Alzheimer’s Failure to initiate nerve
antiparkinson
disease impulse or interrupt- cle and endothelium, poor relaxation of trabe
Spinal cord injury ed neural transmis- •smooth
Dopamine antagonis
muscle (metoclopramide)
(in anxious à
men with excessive
Radical pelvic surgery sion
Diabetic neuropathy
inhibittone
nergic prolactin inhibitory
22), and shuntsfactorà
acquired as a result o
Pelvic injury increasing
erative prolactin
correction of levels à inhibit
priapism.
Hormonal Hypogonadism Loss of libido and inad- testosterone à decreased libido
Hyperprolactinemia equate nitric oxide re- •Drug-Induced
Estrogen, antiErectile Dysfunction
androgens (spironolactone,
lease
Vasculogenic (arterial Atherosclerosis Inadequate arterial flow
Many drugs
digoxin, have been
ketoconazole, reportedàto cause ere
cimetidine)
or cavernosal) Hypertension or impaired veno- dysfunction. Central neurotransmitter
suppress testosterone mediated stimulation pathway
Diabetes mellitus occlusion cluding
of libidoserotonergic, noradrenergic, and dopa
Trauma
Peyronie’s disease •ergic
CNS pathways involved
depressants, in sexual
large doses function, ma
of alcohol,
Drug-induced Antihypertensive and Central suppression disturbed by antipsychotic,
anticonvulsant à suppress antidepressant,
perception of and
antidepressant drugs trally acting antihypertensive
psychogenic stimuli drugs.
Antiandrogens Decreased libido
Alcohol abuse Alcoholic neuropathy
• Agents
b-Adrenergic–blocking
that decrease penile drugs
bloodmayflowcause ere
Cigarette smoking Vascular insufficiency dysfunction by potentiating
(diuretics, β-blocker, 1-adrenergic activi
central asympatholytics
Caused by other sys- Old age Usually multifactorial, the penis. Thiazide
à methyldopa, diuretics
clonidine) have been
à reduce reporte
arterial
temic diseases and Diabetes mellitus resulting in neural produce erectile dysfunction, but the cause is
flow to corpora
aging Chronic renal failure and vascular dysfunc-
Coronary heart disease tion known. Spironolactone can cause erectile failu
CLINICAL PRESENTATION

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
• International Index of Erectile Dysfunction survey --> consistent with low satisfaction with the quality of
erectile function
• Medical history à past surgical procedures that interfere with good vascular flow to the penis or damage
nerve function to the corpora
• Medication history
• Physical examination may reveal signs of hypogonadism
Lab INVESTIGATIONS

Serum lipids

Fasting plasma glucose

Serum testosterone measured on a blood sample taken in the morning between

08.00 and 11.00 (<11 nmol/L à considering testosterone replacement)

FSH, LH and prolactin (>1000 mU/L)

Thyroid

Serum prostate specific antigen (PSA)

INDICATIONS FOR SPECIALIST INVESTIGATIONS

Young patients who have

always had difficulty in Patients with a history of
obtaining and/or trauma
sustaining an erection

Where an abnormality of Patients unresponsive to

the testes or penis is medical therapies that
found on examination. may desire surgical
treatment for ED
Goal of Therapy

Providing
education
and
counselin
Initiating g to
lifestyle patients
change and and their
Identifying risk factor partners
and modification
treating
any
curable
causes of
ED
INDICATIONS FOR SPECIALIST
INVESTIGATIONS

Young patients who have

always had difficulty in
obtaining and/or
sustaining an erection

Patients with a history of

trauma

Where an abnormality of
the testes or penis is
found on examination.

Patients unresponsive to
medical therapies that
may desire surgical
treatment for ED
DIAGNOSIS AND
TREATMENT OF
ERECTILE
DYSFUNCTION
ALGORITHM FOR
SELECTING TREATMENT
FOR ERECTILE
DYSFUNCTION.
MANAGEMENT OF
ERECTILE DYSFUNCTION
LIFESTYLE MODIFICATIONS

psychosocial issues adverse side effects of

non-prescription drugs

the influence of any co-

morbidities, including weight loss
those in the partner

exercise activity
1 st LINE TREATMENT

Oral Tx Inhibit PDE5 à ↑ arterial blood flow à smooth

(PDE5 muscle relaxation à vasodilation à penile erection
Inhibitor)
NOT initiators of erection! Require sexual
stimulation in order to facilitate an erection

Patients should receive 8 doses of a PDE5 inhibitor

at maximum dose with sexual stimulation before
classifying a patient as a non-responder
Patients followed up within 6 weeks of commencing
therapy (ideally)
PDE5 INHIBITORS CONTRAINDICATION

Unstable Uncontrolled High risk Unstable HF

angina hypertension arrhythmias (NYHA clas
III & IV)

Less than 2 Obstructive Moderate to

weeks previous hypertrophic severe valve
of myocardial cardiomyopathy disease
infarction
 RECOMMENDED
STANDARD TIME BETWEEN ONSET OF
DRUG DURATION†
DOSE* DOSING AND ACTION
INTERCOURSE

Sildenafil (Viagra) 50 to 100 mg One hour 14 to 60 minutes Up to four hours

Tadalafil (Cialis) 10 to 20 mg One to 12 hours 16 to 45 minutes Up to 36 hours

Vardenafil
10 to 20 mg One hour 25 minutes Up to four hours
(Levitra)
The most common adverse effects of PDE-5 inhibitors

Adverse
Sildenafil Tadalafil Wardenafil Avanafil Udenafil
effect (%)
Headache 12.8% 14.5% 16% 9.3% 1.7%
Flushing 10.4% 4.1% 12% 3.7% 8.3%
Dyspepsia 4.6% 12.3% 4% 1.4% -
Nasal
1.1% 4.3% 10% 1.9% -
congestion
Dizziness 1.2% 2.3% 2% 0.6% 1%
Abnormal
1.9% - - - -
vision
Backache - 6.5% - 1.1% -
Myalgia - 5.7% - - -
PDE5 INHIBITORS DRUG INTERACTIONS

Absolute • Organic nitrates (e.g., nitroglycerine, isosorbide

mononitrate, isosorbide dinitrate), recreational drugs such
contraindication as amyl nitrate (poppers)
due to • Result in cGMP accumulation and unpredictable falls in
interaction blood pressure and, potentially, catastrophic hypotension

• Sildenafil or Vardenafil are taken and the patient develops

Separate chest pain, nitroglycerine must be withheld for at least 24
administration hours
between drug • Tadalafil à nitroglycerine must be withheld for at least 48
hours

Co- • Alpha-blockers antihypertensive

administration • result in a small additive drop in the blood pressure (NO
significant orthostatic hypotension)
need dose
adjustment
RECOMMENDATIONS FOR USE OF SILDENAFIL BY MEN
WITH CARDIAC DISEASE.

has stable coronary disease and does

not need nitrates regularly, the risks of
Sildenafil is absolutely contraindicated in sildenafil should be carefully discussed
men taking long-acting or short-acting with him. If the man requires nitrates
nitrate drugs because of mild-to-moderate exercise
limitation due to coronary disease,
sildenafil should not be given.

All men taking an organic nitrate Men must be warned of the danger of
(including amyl nitrate) should be taking sildenafil 24 hours before or after
informed about the nitrate–sildenafil taking a nitrate preparation.
hypotensive interaction.

Initial monitoring of blood pressure after

Before sildenafil is prescribed, treadmill the administration of sildenafil may be
testing may be indicated in some men indicated in men with congestive heart
with cardiac disease to assess the risk of failure who have borderline low blood
cardiac ischemia during sexual pressure and low volume status and men
intercourse. being treated with complicated,
multidrug antihypertensive regimens.
4), orgasmic function, and overall sexual sat- March to mid-November 1998, more than 6 million
n were significantly higher with sildenafil than outpatient prescriptions of sildenafil were dispensed

TABLE 4. EFFICACY OF SILDENAFIL IN MEN WITH ERECTILE DYSFUNCTION.*

RESPONSE CAUSE OF ERECTILE DYSFUNCTION

DIABETES SPINAL CORD RADICAL PSYCHOGENIC
MELLITUS INJURY PROSTATECTOMY CAUSE DEPRESSION
(N=268) (N=178) (N =198) (N=179) (N=151)

percentage of patients

Improved erection
Placebo 10 12 15 26 18
Sildenafil 57 83 43 84 76
Successful intercourse
Placebo 12 13 NA 29 Not measured
Sildenafil 48 59 26 (at 0–6 mo), 70 Not measured
60 (at 18–24 mo)†

*Most data are from the sildenafil package insert (Viagra, Pfizer, New York, 1998). The dose is 50 to 100 mg. NA
denotes not applicable.
†The data are from a non–placebo-controlled trial.35 The rate of satisfaction with treatment was higher in men who
underwent bilateral nerve-sparing prostatectomy.
 1 ST LINE TREATMENTS

Highly effective in inducing

erections regardless of the
etiology of the ED

Adverse effects include bruising,

local pain, and failure to ejaculate
Vacuum Implant devices
erection devices

Vacuum devices are

Reported satisfaction rates vary contraindicated in men with
considerably from 35% to 84% bleeding disorders or those taking
anticoagulant therapy
 Intracavernous
injection therapy Intraurethral alprostadil 2ND LINE
• Alprostadil • The pellet is inserted
(prostaglandin
analogue) à 5-40 μg
into the urethra via a
small applicator and TREATMENTS
à erection occurs 5- the penis massaged
15 minutes after à absorbed through
injection à frequently the epithelium into the
last 30-40 minutes venous channels of
(duration can be dose the corpus
dependent) spongiosum.
• Adverse effects: post- • In clinical practice
injection penile pain only the higher
• Phentolamine dosages of 500 μg
mesilate (short-acting and 1000 μg are
alpha-adrenoreceptor effective
antagonist) à direct
effect on smooth
muscle, causing
relaxation
3 rd line TREATMENTS

• Particularly suitable for whose

severe ED, especially if the cause
is Peyronie’s disease
Penile • Patients must be medically fit for
surgery
prosthesis • Potential complications of
infection, erosion and mechanical
failure which may need re-
operation.

• Yohombine, Delaquamine,
Trazodone, L-arginine, Red Korea,
Other Ginseng, Oral limaprost, Oral
phentolamine and nitroglycerine,
treatments Papaverine, Minoxidil topically
• None this products is licensed for
the treatment of ED and they
should not be used routinely
ONCE ORAL TREATMENT PER WEEK
WILL BE APPROPRIATE FOR MOST
PATIENTS
ED SEVERITY DETERMINATION
THE INTERNATIONAL INDEX OF ERECTILE FUNCTION

à Related to satisfaction with intercourse

THE INTERNATIONAL INDEX OF ERECTILE FUNCTION

à Related to orgasm
THE INTERNATIONAL INDEX OF ERECTILE FUNCTION

à Related to sexual
desire
THE INTERNATIONAL INDEX OF ERECTILE FUNCTION

à Related to overall
satisfaction
 vidual man’s health status and goals, is outlined in mal range in over 90 percent of men. The most com-
Figure 4. mon adverse effects are skin irritation and contact
TREATMENT OPTIONS FOR MEN WITH ERECTILE DYSFUNCTION
TABLE 3. TREATMENT OPTIONS FOR MEN WITH ERECTILE DYSFUNCTION.

TREATMENT COST ADVANTAGES DISADVANTAGES RECOMMENDATION

Psychosexual therapy $50–$150/session Noninvasive Time-consuming First-line treatment

Partner involved Patient resistance May be combined with other treat-
Curative ments
Oral sildenafil $10/dose Oral dosage Cardiovascular disease a contra- First-line treatment
Effective indication in some men Contraindicated with nitrates
1-Hr wait
Transurethral alprostadil $25/dose Local therapy Moderately effective (43–60% Second-line treatment
Few systemic side effects with Actis*)
Requires office training
Causes penile pain
Intracavernous alprostadil $5–$25/dose Highly effective (up to 90%) Requires injection Second-line treatment
or drug mixtures† Few systemic side effects High dropout rate
Can cause priapism or fibrosis
Causes penile pain
Vacuum constriction $150–$450/device Least expensive Unnatural erection Second-line treatment
device No systemic side effects Causes petechiae
Causes numbness (20%)
Trapped ejaculation
Surgical treatment
Prosthesis (all types) $8,000–$15,000 Highly effective Unnatural erection (semirigid For men not satisfied with medical
device) treatment
Infection
Requires replacement in 5–10 yr
Requires anesthesia and surgery
Vascular surgery $10,000–$15,000 Curative Poor results in older men with For young men with congenital or
generalized disease traumatic erectile dysfunction
Requires anesthesia and surgery

*Actis is an adjustable penile-constriction device.

†Drug mixtures contain two or three of the following drugs: papaverine, phentolamine, and alprostadil.
 Schematic diagram summarizing the use of regenerative technology
(pharmacotherapy, protein therapy, gene therapy, and cell therapy) to
treat erectile dysfunction

Ryu, J.K., & Suh, J.K. (2012). Regenerative technology for future therapy of erectile dysfunction. Translational andrology and urology.
Schematic diagram depicting the
concept of combination therapy
for erectile dysfunction

Ryu, J.K., & Suh,

Schematic diagram
J.K. (2012). illustrating the concept of
Regenerative
technology for targeted therapy based
future therapy of on molecular
erectile
dysfunction. Tran pathophysiology to treat
slational
andrology and
erectile dysfunction
urology.
RISK FACTOR
MANAGEMENT
Potential drug side effects PATIENT EDUCATION
Potential drug interaction

Support to solve psychosocial issues

Support exercise activity

Life style modification

Reduce body weight

Check therapy efficacy

 IS VIAGRA EFFECTIVE
IN MEN WITHOUT ED?

Online sales:
Definitely safe
• Little info
EAU 2008 Placebo controlled RCT in
men without ED • significant fraud
Men have a “real” benefit in quality • more than 10X prescription sales
and durability of erections
 Daftar Pustaka

1. Pharmacotherapy: A Pathophysiologic Approach, Ninth Edition

2. Traish, A.M., Goldstein, I., & Kim, N.N. (2007). Testosterone and erectile
function: from basic research to a new clinical paradigm for managing men
with androgen insufficiency and erectile dysfunction. European urology, 52 1,
54-70
3. Ryu, J.K., & Suh, J.K. (2012). Regenerative technology for future therapy of
erectile dysfunction. Translational andrology and urology.
4. Isidori, A. M., et al. (2014). "A Critical Analysis of the Role of Testosterone in
Erectile Function: From Pathophysiology to Treatment&#x2014;A Systematic
Review." European Urology 65(1): 99-112.
5. Heidelbaugh, J. J. (2010). "Management of erectile dysfunction." Am Fam
Physician 81(3): 305-312.
 EUROPEAN UROLOGY 65 (2014) 99–112 105
[(Fig._3)TD$IG]
Men of any age complaining of ED
Obtain two separate T and LH measurements

T<12 nmol/L T>12 nmol/L

Discordant results
between the two
measurements

High LH Low/normal LH Low/normal LH High LH

Old men Young men PDE5-I only PDE5-I only

with co- without co- Revaluate T Follow-up for
morbidi!es morbidi!es within 1 mo later T decline

T<12 nmol/L T>12 nmol/L

Start TRT + PDE5-I Consider hCG or Add up TRT If subsequent failure to PDE5-I
“combina!on TRT only clomiphene in men (independently of PDE5-I only consider a short trial of
therapy” desiring children response to PDE5-I) TRT + PDE5 “salvage therapy”

Fig. 3 – Pathophysiology-oriented algorithm for the treatment of erectile dysfunction in men with altered circulating testosterone levels. ED = erectile
dysfunction; hCG = human chorionic gonadotropin; LH = luteinizing hormone; PDE5-I = phosphodiesterase type 5 inhibitor; T = testosterone;
TRT = testosterone replacement therapy.
Table 2 – Available preparations to treat male hypogonadism

PROPOSAL OF A
Compound Dosage Advantages Disadvantages reveals that the discrepancies among studies are related to
inclusion criteria and outcome measures. TRT monother-
Oral agents apy, PDE5-I only, and the combination of the two could all
T undecanoate 120–240 mg -Oral -Variable T levels and clinical responses
be valid options for different cases of ED coexisting with
2–3 times daily -Adjustable dose -Must be taken with meals containing at least 20 g of lipids

TREATMENT ALGORITHM
Intramuscular agents hypogonadism. To support physicians in the selection of the
Testosterone enanthate 250 mg every -Low cost -Wide fluctuations in T levels best treatment strategy, we have developed a multistep
2–3 wk -Multiple injections treatment algorithm presented in Figure 3.
-Relative higher risk of polycythemias
Testosterone cypionate 200 mg every -Low cost -Wide fluctuations in T levels
2–3 wk -Multiple injections
-Relative higher risk of polycythemia Table 3 – Safety monitoring during testosterone replacement
T propionate 100 mg every -Low cost -Wide fluctuations in T levels therapy
2d -Multiple injections
-Relative higher risk of polycythemias Baseline 3–6 mo 12 mo Subsequent
T undecanoate in castor oil 1000 mg every -Efficient T normalization -Pain at injection site screening
periodicity
10–14 wk -Long lasting -Requires injection training
-Better compliance Testosterone + + 6–12 mo
Subcutaneous agents LH/FSH/PRL + –
Surgical implants 4/6 200-mg implants -Treatment only twice per year -Placement is invasive Hematocrit/Hemoglobin + + + 6–12 mo
lasting up to 6 mo -Risk of extrusion and site infections Glycemia/Lipid profile + + 12 mo
-Requires trained operator PSA + + 6–12 mo
Controlled release T buccal formulation agents DRE + + + 12 mo
T buccal 30 mg 2 times daily -Oral -Possible oral irritation Bone densitometry scan + 24 mo
-Twice-daily dosing
-Unpleasant taste DRE = digital rectal examination; FSH = follicular stimulating hormone;
LH = luteinizing hormone; PRL = prolactin; PSA = prostate-specific antigen.
Transdermal agents
T patches 5–10 mg -Mimics circadian rhythm -Skin irritation
1 daily -Simple administration -Daily administration
-Noisy/sport/washing issues
T gel 40–80 mg -Efficient T normalization -Possible transfer during intimate contact
1–2% 1 daily -Flexible doses -Daily administration
-Less skin irritation
Underarm testosterone 60–120 mg -Efficient T normalization -Possible transfer during intimate contact
2% solution 1 daily -Daily administration
T gel 20.25–81 mg -Efficient T normalization -Possible transfer during intimate contact
1.62% 1 daily -Flexible doses -Daily administration
-Less skin irritation
-Lower amount to apply

T = testosterone.
 T h e N e w E n g l a n d Jo u r n a l
FURTHER INVESTIGATIONS

TABLE 2. SPECIALIZED UROLOGIC AND RADIOLOGIC TESTS

FOR MEN WITH ERECTILE DYSFUNCTION.
Androg

TEST INDICATIONS His

male s
Combined penile injection of a Assess penile vascular function
vasodilator and sexual stimu- Therapeutic test in men who choose in-
are av
lation tracavernous therapy courag
Duplex (color) ultrasonography Assess vascular function and evaluate for associ
Peyronie’s disease with n
Cavernosography Young men with congenital or traumat-
ic venous leakage
functi
Pelvic arteriography Young men with traumatic arterial in- behav
sufficiency no eff
Nocturnal penile monitoring Differentiate psychogenic from organic In m
(R igiScan Ambulatory R igid- erectile dysfunction
ity and Tumescence System,
aration
Timm Medical, Minneapolis) derma
totoxi
malign
TERIMA KASIH