W12 Patho of Erectile dysfunction (RT)

Question 1

Male Reproductive System - overview

Answer 1

Organs
* Testes
* Penis
Ducts
* Epididymis
* Ductus deferens
* Urethra
Glands
* Seminal vesicles
* Prostate

Question 2

Spermatozoa journey

Answer 2

• Seminal vesicles in testis
• Epididymis
• Ductus deferens (vas deferens)
• loops behind the urinary bladder
• peristaltic waves to propel the sperm
  to approach the prostate gland
• Seminal vesicles (semen)
• Prostate (semen – surrounds urethra)
• Urethra

Question 3

Bladder and penis structure

Answer 3

• Dual purpose – urinary and
  reproductive
• Urethra
  -Prostate
  -Base/ root of penis (bulbar)
  -Body / shaft of penis (spongy tissue)

Question 4

Erectile / connective tissue

Answer 4

Corpus Cavernosum
* Become engorged with blood for rigidity
-turgid
* Maintains erection

Corpus Spongiosum
-Remains pliable/soft to allow urethra to remain open

Question 5

Physiology of male reproduction:

Answer 5

• Erection
• Ejaculation
  -Emission - secretion of semen
  -Propulsion of semen

Inputs from
* sympathetic
* parasympathetic
* somatic

Question 6

Physiology of erectile tissue and erection: Parasympathetic stimulation

Answer 6

• smooth muscle of erectile tissues relax
• increased arterial flow
• reduced venous return – causes INC Pressure in sinusoids
• Result: Erectile tissues become turgid

Question 7

Physiology of erectile tissue and erection

Answer 7

• Cavernosal arteries dilate
• Sinusoids fill with blood
• Tissue swells enlarging penis
• This compresses penile veins
• Prevents outflowing of blood
• Maintains erection

Question 8

Physiology of ejaculation
Sympathetic stimulation:

Answer 8

• Smooth muscle in vas/ductus deferens contracts
  -Propels sperm and testicular/epidiymal
  secretions → prostatic urethra
• Smooth muscle in prostate & seminal
  vesicles contracts
  -Release secretions into prostatic urethra
• Accumulation of semen in prostatic
  urethra
  → sensory action potentials ( via pudendal nerve and spinal cord)
  -Constriction of urinary sphincter (bladder
  neck)
  -Retrograde ejaculation

Somatic response (via pudendal nerve)
* Rhythmic contraction of skeletal
muscles of base of penis
* Force semen out of urethra

Question 9

What is Erectile dysfunction?
What drugs can cause this? (3)
Causes?

Answer 9

• Difficulty either initiating or maintaining an erection
• Associated with age (aging not direct cause)
• Drug treatment
  -antipsychotic
  -antidepressant
  -antihypertensive agents
• CV disease
• Diabetes (and other)
  -Neuropathy

Question 10

Erectile dysfunction:
Drug treatment?
(Not expected to know detail in mode of action)

Answer 10

• Intra-cavernosal vasodilators
  -Injecting vasodilator drugs directly into the corpora cavernosa causes penile erection
• PGE1 (prostaglandin E1 alprostadil). *
  -Increase cAMP and reduce Calcium concentrations
  -Alprostadil (available also as cream and pessary)
• Still available as injection and transurethrally
  -Mode of delivery generally not preferable
• Replaced Generally by Pharmacological methods
• These drugs cause vasodilation- when injected/delivered to corpus cavernosa, this causes erections

Question 11

Erection physiology
What is the main mediator of erection

Answer 11

• Nitric oxide, NO (neuronal and endothelium derived) is the main mediator of erection
• Sexual stimulation
  -Nitrergic nerves
  -(release NO)
• (Activates guanylyl cyclase)
• Leads to production of cGMP
  -Reduction in intracellular calcium
  -Smooth muscle relaxation of arteriole
  walls
  -Vasodilation
  -Penile erection

Question 12

Sildenafil – PDE (phosphodiesterase ) V inhibitor
mechanism of action?

Answer 12

• cGMP is inactivated by PDE V
• PDE Reduces cGMP which reduces vasodilation
• PDE V inhibitors prevent activity and increase cGMP
• Potentiate effects of NO
  released by sexual stimulation
  -Enhances response to sexual stimulation
  -Does not cause erection independent of sexual stimulation (needs NO)

see diagram on slide

Question 13

PDE V Inhibitors examples? (2)
When to take them?
Contraindications?

Answer 13

Sildenafil
* Peak plasma concentrations - 30–120 min after oral dose
* taken an hour or more before sexual activity

Tadalafil
* longer half-life than sildenafil
* can be taken longer before sexual activity

Contraindications
* All organic nitrates (GTN), which work through increasing cGMP
* Concurrent use with PDE V inhibitors contraindicated
(enhanced synergistic effects- may result in severe hypotension)

Question 14

Unwanted effects
Effects of PDE V inhibitors?

Answer 14

• Vasodilation in other vascular beds
• Hypotension
• Flushing
• Headache
• Visual effects
  -PDE VI found in retina
  -Some effects on PDEV inhibitors on PDE VI

Question 15

Premature ejaculation:
Drug treatment?

Answer 15

• Little Research on cause
• SSRIs have proved effective
  -Delayed ejaculation has been reported as a common sexual side-effect of selective serotonin reuptake inhibitor (SSRI) antidepressants
• Dapoxetine: selective serotonin reuptake inhibitor (SSRI)
  -Unsuccessful as antidepressant
• Dapoxetine is absorbed and eliminated rapidly in the body

Question 16

Dapoxetine- SSRI
Presumed mode of action?

Answer 16

Ejaculation regulated:
* Various areas of CNS
-Spinal reflex
-Influenced by nuclei in brain – particularly medulla/brain stem
Animal studies shown
* Dopamine inhibits ejaculation reflex by acting at supra spinal level, particularly in the medulla

Question 17

Summary

Answer 17

• Erection maintained by increased and blood flow in corpus cavernosum
  (dilation of arterioles, allows more blood into sinusoids of corpus cavernosum. Pressure on venules, prevents outflow of blood)
• Mediated by NO
• Sildenefil, potentiates action of NO
• Premature ejaculation
  -SSRI has little effect (10%)