BMS207, BMS305

UroGenital tract diseases

Faculty of Medicine, Spring

2024
Galala University

gu.edu.eg
 G A L A L A U N I V E R S I T YT H E F U T U R E S T A R T S H E R E

Lec 2.
BMS207, BMS305
Erectile dysfunction

Dr.Amany Nasr Ahmed

Galala University

T H E F U T U R E S T A R T 3/31/2024
S
H E R E
Intended Learning Outcomes
By the end of this lecture, you should be
able to:

1) Know the meaning of erectile dysfunction

2) Revise the possible drugs that could cause this
condition
3) Discuss the available different lines of therapy
4) Know mechanism, adverse effects of mentioned drug
 Pathophysiology
Mechanism of an erection
*An erection occurs when the amount of blood rushing to
the penis is greater than the amount of blood flowing
from it.
* A massive influx of blood accumulates in the sinusoidal
spaces(erection chamber) due to relaxation of smooth
muscle & dilatation of cavernosal arteries → corpora
cavernosa to swell (tumescence)
* Tumescence compresses the veins that normally drain
the penis → reduces venous outflow &
maintains penile rigidity
• somatic and autonomic pathways.
• Sensory receptors
• thalamus and sensory cortex.

• Activation of parasympathetic pathways prompts release of nitric oxide

(NO) from cavernous nerves and endothelial cells, resulting in penile
cavernosal smooth muscle relaxation, reducing peripheral arteriolar
resistance and permitting blood inflow.

• On a molecular level, NO release ++++ guanylyl cyclase+++= (cGMP),

+++ protein kinase G and leads to phosphorylation of potassium and calcium
channels : hyperpolarization, reduced intracellular calcium, dissociation of
myosin from actin, and subsequent smooth muscle relaxation.

• Cyclic adenosine monophosphate (cAMP) is a functionally similar

mediator of smooth muscle relaxation activated by adenosine, calcitonin
gene-related peptides, and prostaglandins.
Peripheral HAEMODYNAMIC CHANGES inducing ERECTION

FLACCID State ERECT State

 ERECTILE DYSFUNCTION
Persistent or recurrent inability to attain (acquire) & maintain (sustain)
an erection (rigidity) sufficient for satisfactory sexual performance
“Impotent" is reserved for those men who experience erectile failure
during attempted intercourse more than 75 % of the time.
Risk factors for erectile dysfunction

• Advanced age
• Atherosclerosis-related risk factors (e.g. cardiovascular disease, cigarette smoking,
hypertension, dyslipidaemia, diabetes mellitus)
• Pelvic surgery (e.g. radical prostatectomy), radiation, trauma
• Endocrinological conditions (e.g. hypogonadism, hyperprolactinaemia, thyroid disorder)
• Obesity and metabolic syndrome
• Substance abuse – alcohol, illicit drugs (e.g. cannabis, barbiturates, cocaine, heroin,
methamphetamine)
• Psychological (partner-related, stress, guilt, situational anxiety, self-image problems, low self-
esteem, history of sexual abuse, highly restricted sexual upbringing, generalised anxiety
disorder, depression, psychosis)
• Erectile dysfunction associated with other sexual dysfunction(s) (e.g. premature ejaculation,
sexual aversion disorder, anorgasmia)
• Medicines: – antihypertensives (e.g. diuretics, alpha and beta blockers) – psychotropics (e.g.
selective serotonin reuptake inhibitors and other antidepressants, antipsychotics, anxiolytics) –
anticonvulsants, anti-Parkinson’s drugs – hormone-affecting drugs – antiandrogens,
corticosteroids, chronic opioid use
• Neurological conditions (Alzheimer’s disease, multiple sclerosis, Parkinson’s disease, stroke),
spinal cord and peripheral nerve disorders (diabetic neuropathy)
• Penile abnormalities (e.g. Peyronie’s disease, venous leak)
Medicines:
– antihypertensives (e.g. diuretics, alpha and beta
blockers)
– psychotropics (e.g. selective serotonin reuptake
inhibitors and other antidepressants, antipsychotics,
anxiolytics)
– anticonvulsants, anti-Parkinson’s drugs
– hormone-affecting drugs
– antiandrogens, corticosteroids, chronic opioid use

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 Management
• Penile implants
• Intrapenile injection of alprostadil
• Intra-Urethral suppositories of alprastadil
• PDE-5 Inhibitors: First line therapy

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 Desire Androgens
DRUGS TREATING ED
CENTRALLY
Arousal Apomorphine
PERIPHERALLY
ORAL Transurethral Intracavernosal
Inj.

Nitrates !!! + + Prostaglandin Analogues

PDE5 Inhibitors
•Sildenafil cGMP cAMP
•Vardenafil - PDE5 - Papaverine
•Tadalafil PDE2,3,4
•Avanafil a1
AMP - Phentolamine
SELECTIVE PDE-5 INHIBITORS:(oral)
Sildenafil, Vardenafil, Tadalafil, Avanafil
(differ in duration of action and effect of food on drug absorption)

Mechanism of action:
Inhibit PDE5  prevent breakdown of cGMP  vasodilatation 
erection.
Have no action in absence of sexual stimulation( is essential)

Pharmacodynamic action of PDE5 inhibition ►

• VSMCs of Erectile Tissue of Penis (vascular smooth muscle cells (VSMCs)
• Other VSMCs ( lung, brain….) / heart
• Other non-VSMCs (prostate, bladder, seminal vesicle, GIT….)
• Platelets
• Other tissues; testis, sk. muscles, liver, kidney, pancreas, …..

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Indications

1. Erectile dysfunction; 1st line therapy. All types have similar efficacy

2. Pulmonary hypertension
3. BPH & premature ejaculation
 Pharmacokinetic profile difference of PDE5 inhibitors

• Should be taken 1 hour prior to anticipated sexual activity.

1- Sildenafil & Vardenafil:
• enhance Erection up to 4 hours after adminstiration.
• Must be timed as regard anticipated sexual activity.
• Fatty food interferes with their absorption → so taken on empty
stomach / at least 2 hr.s after food
2-Tadalafil & Avanafil are not affected by food
3- Avanafil: quickest onset of action Should be taken 30 minutes
prior to sexual activity.
4- Tadafil: slower onset, longer half life 18 hours, enhance Erection
up to 36 hours, once daily, No need for timing.

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• All metabolized by CYP3A4:
Tadalafil > the rest thus;
ADRs with enzyme inhibitors; erythro & clarithromycin, ketoconazole,
cimetidine, tacrolimus, fluvoxamine, amiodarone…etc.
 efficacy with enzyme inducers; rifampicin, carbamazipine, phenytoin
• Dose adjustment in hepatic patient and sever renal dysfunction
• Shouldn’t be used more than once/day
• Used with percuation in patient wit history or even risk of CVS
Contraidication:
1-Not Not use PDE-5 Inhibitors with organic nitrate(Nitroglycerine,
isosorbide dinitrate, isosorbide mononitrate)
Potentiate of their hypotensive effect (life threating condition)
2-Take care while using a blockers [except tamsulosin] →orthostatic hypotension
Additive blood pressure lowering effect
Reduce the dose of ά blocker
Start with low dose of PDE-5 Inhibitors
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1- Most frequents side effects:
• Headache
• Flushing
• Nasal
• Dyspepsia
2- Inhibition of PDE-6 in retina (color vision):
• Disturbance in color vision: loss of blue/green
discrimination
• Not occur with tadalafil
• Dose dependant

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3-Sudden hearing loss:
due to V.D & change in sinus pressure
4- Tadalafil: --- PDE-11 in skeletal
Myalgia & Back pain
5-have potential to cause priapism
(a painful, prolonged erection), rare but medical emergency
6- IHD & AMI > patients on big dose or on nirates
7- Hypotension > patients on a-blockers than other
antihypertensives
8- Bleeding; epistaxis…..etc

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Hypogonadism and ED—
• Intracavernosal pressure and PDE5 activity are
androgen-dependent.
• The prevalence of hypogonadism (defined as a
morning serum total testosterone level less than 300
ng per dL in men with ED is estimated to be 5 to 10
percent.
• Testosterone monotherapy in men with ED show an
improvement in erectile function in as well as
improvements in sexual performance, desire, and
motivation
Testosterone supplementation may result in
• erythrocytosis,
• elevated serum trans-aminase levels,
• exacerbation of untreated sleep apnea,
• benign prostatic hyperplasia,
• an increased risk of adenocarcinoma of the prostate.

Men receiving testosterone supplementation require more

frequent monitoring of hemoglobin, serum transaminase,
and prostate-specific antigen levels, and prostate
examinations.
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Alprostadil
 Alprostadil; PG E1 → cAMP TRANSURETHRAL
Synthetic + more stable
Applied by a special applicator into penile urethra
& acts on corpora cavernousa →Erection
Low - Intermediate Efficacy
Minimal systemic effects / Rarity of drug interactions.
ADRs 1. Variable penile pain
2. Urethral bleeding / Urethral tract
infection
3. Vasovagal reflex / Hypotension
Topical 4. Priapism or Fibrosis →rare
20% Papaverine; cAMP + cGMP
2% Minoxidil; NO donner + K channel opener
2% Nitroglycerine
+ a drug absorption enhancers
Low efficacy / No FDA approval
Female Partner can develop → hypotension, headache → vaginal absorption.
1. Alprostadil; PG E1 → cAMP Intracavernosal Inj.
Needs training → Erection → after 5-15 min
lasts according to dose injected →
May develop fear of self injury / Discontinuation
ADRs 1. Pain or bleeding at injection site
2. Cavernosal fibrosis
3. Priapism
2. Papaverine; It is a direct-acting smooth
muscle relaxant 3 combined in severe cases
3. Phentolamine; a1 blocker

Treatment of Priapism

1. A medical emergency
2. Aspirate blood to decrease intracavernous pressure.
3. Intracavernous injection of Phenylephrine → a1 agonist
→ detumescence
Stem cell injection therapy
• injection of neural embryonic stem cells into the corpus cavernosa in
neurogenic impotence could improve the erectile function
• enhance the ratio of smooth muscle over collagen content, and
promote the neuronal nitric oxide synthase-positive nerve regeneration

Low-intensity extracorporeal shock wave:(Li-ESW)

❖ A physical shock wave that emits energy density lower than
0.1mj/mm2.
❖ A non-invasive treatment technology, Li-ESW focuses on the
target tissue area through the sound wave passing through the
tissue structure
❖ can stimulate the expression of eNOS, VEGF and other
vascular growth factors in the corpora cavernosa, expand
blood vessels, induce neovascularization, promote blood flow,
and improve erectile function .
Function & problems of prostate
• It produces fluid which forms the part of semen.
• THREE main problems
Benign prostate hyperplasia
Prostatitis
Prostate cancer

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The dynamic component of benign prostatic hyperplasia. The bladder outlet and
prostate are richly supplied with alpha-1 receptors (their distribution represented by
blue dots), which increase smooth muscle tone, promoting obstruction to the flow
of urine. Alpha-1 adrenergic blockers counteract this effect.

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1-adrenergic blockers
Dynamic component
2-5 α-reductase inhibitors
Anatomic component
3-Anticholinergic Therapy

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1- Alpha-blockers
• minimize muscle tone in prostate stromal smooth muscle and bladder
neck tissue.
• results in smooth muscle relaxation, thus improving flow and urinary
symptoms.
• Examples: selective alpha-blockers tamsulosin, alfuzosin, and
silodosin
• Their effect maximizes in about 72 hours.
• These medications are associated with floppy iris syndrome and
should be used cautiously in patients requiring cataract or glaucoma
surgery.
• Ejaculatory issues are a common side effect of alpha-blocker
• dizziness
• low blood pressure.
• Other alpha-blockers, such as terazosin and doxazosin, are equally
effective in relieving prostatic issues but are much more generalized
side effects such as orthostatic hypotension.
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 Comparison of a-Adrenergic Blockers
Agent Uroselective
Terazosin NO

Doxazosin NO

Tamsulosin YES
(Relative affinity for a1A
receptors over a1B )
Alfuzosin YES
(Highly diffused in prostatic
tissue vs serum)
1. HytrinR (terazosin hydrochloride) Prescribing information, Abbott Laboratories.
2. CarduraR (doxazosin mesylate tablets) Prescribing Information, Pfizer Inc.
3. FlomaxR (tamsulosin hydrochloride) Prescribing Information, Boehringer Ingelheim Pharmaceuticals Inc.
4. UroxatralR (alfuzosin HCl extended release tablets) Prescribing Information, Sanofi-Synthelabo Inc.
2-Tadalafil is a phosphodiesterase type 5 inhibitor roughly equivalent
in efficacy to tamsulosin 0.4 mg. Since it can treat both ED and BPH

3- 5- alpha-reductase inhibitors,
finasteride and dutasteride,
Block the intraprostatic conversion of testosterone to DHT(an androgen
stimulate prostate growth)
This causes a reduction in individual cell volume and an increase in
cellular apoptosis
significantly reduce the incidence of bladder cancer
The overall effect is a reduction in prostatic tissue volume, takes several
months to show noticeable improvement, with 6 months needed for
maximal effectiveness.

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 Adverse effects
● Erectile dysfunction
● Aletred libido
● Ejaculatory disorder
● Gynecomastia and breast tenderness

The new 5 alpha-reductase inhibitor Dutasteride has been shown to be of

similar efficacy as Finasteride in terms of symptom score and flow-rate
improvement, as well as in the prevention of disease progression, while
having a comparable safety profile.3
*Not from a comparative trial.
1. McConnell JD et al. NEJM. 1998;338:557-563. 2. Roehrborn C et al. Urology. 2002;60:434-441.
3. American Urological Association Research and Education Inc. BPH Guidelines April 2003: page 33
● Antimuscarinics
● commonly used for urinary frequency, urgency, and bladder
overactivity symptoms.
● symptomatic management of detrusor instability due to bladder
outlet obstruction from BPH, which can result in increased urgency
(overactive bladder) and frequency.
● by blocking muscarinic receptors in the detrusor muscle. This
reduces smooth muscle tone and can improve irritative symptoms in
those with bladder overactivity.
● Examples include solifenacin, tolterodine, trospium, and
oxybutynin.

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 Rationale for
Combination Therapy

Alpha-
5a-Reductase Blockers:
Inhibitors:
Relieve
Arrest Disease Symptoms
Progression Rapidly

Combination Therapy: Arrest Disease Progression

and Rapidly Relieve Symptoms
1-Which of the following statements is correct regarding the mechanism of action of
phosphodiasterase-5(PDE-5) inhibitors?
a. PDE-5) inhibitors increase prostaglandin production
b. PDE-5) inhibitors enhance the effect of nitric oxide
c. PDE-5) inhibitors cause vasoconstriction of the erection chamber
d. PDE-5) inhibitors antagonize cyclic GMP
e. PDE-5) inhibitors antagonize cylclic AMP

2-A patient who is taking a PDE-5 inhibitor for erectile dysfunction is diagnosed with
angina which of the following antianginal medication would cause life threating
hypotension?
a. Metoprolol
b. Diltiazm
c. Amlodipine
d. Nitroglycerin
e. Verapamil

List side effect of tadalfil?

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