2402 REPRO(M)

Question 1

Flaccid state

Answer 1

Sympathetic nervous system keeps smooth
muscle in the corpus cavernosa and blood
vessels (arterioles) contracted

Maintains unhindered bidirectional blood
flow –> prevents blood retention

Question 2

Erect state

Answer 2

Sexual stimulation –> release of
neurotransmitters from the cavernous nerve
terminals

Smooth muscle relaxes

Allows more blood in and clamps down on
veins (so blood can’t escape)

Erection results

Question 3

External stimuli (erection)
- Begins with the brain via

Answer 3

• Visual
• Smell
• Imaginary
• Touch

Question 4

NANC nerves:

Answer 4

nor-adrenergic and nor-cholinergic

Question 5

Stimulation pathway:

Answer 5

1. NANC nerve
   - -> Ca+2 influx
   - -> production of nitric oxide (NO)
2. Cholinergic nerve
   - -> Release of Ach
   - -> Activation of muscarinic receptor on endothelial cell
   - -> NO release

Question 6

Nitric Oxide (NO) pathway

Answer 6

1. NO activates guanylate cyclase which converts
   GTP –> cGMP
2. cGMP activates protein kinaseG
3. Phosphorylates certain proteins:
   - -> Opens K channels
   - -> Closes Ca+2 channels
   - -> Ca+2 back into SR
   - -> Reduced intracellular Ca+2

** Smooth muscle relaxation

Question 7

Prostaglandin Pathway

Answer 7

1. PGE1 binds to its receptor (G protein coupled
   receptor) on CC smooth muscle cells
2. Activates adenylate cyclase
3. Converts ATP –> cAMP
4. cAMP activates protein kinaseA
5. Phosphorylates certain proteins to cause **Nitric Oxide Pathway

Question 8

Inhibiting the erect state:

Answer 8

Adrenergic nerve

• -> release of NA
• -> muscle contraction (detumescence)

Question 9

Alprostadil

Answer 9

Incr. PGE1

Injection into CC tissue
Efficient

Question 10

Alprostadil side effects

Answer 10

• Pain (PGE1)
• Painful erection (priapism) lasting
>8h
• Redness/lump
• Rash/Itching
• Trouble urinating
• Feeling faint
• Permanent damage to penis/fibrosi

Question 11

Papaverine

Answer 11

Less commonly used

• Mechanism of action not completely known, but
proposed to inhibit phosphodiesterase 5

• Causes vasodilation
• Only used if alprostadil use is contraindicated
• Does not induce localised pain

Question 12

Phentolamine (Inhibition)

Answer 12

• Mechanism of action is via vasodilation as a
result of potent competitive antagonism of α1
adrenoceptors

• Generally used along with papaverine and/or
alprostadil (Trimix, also available as a gel)

• Trimix has to be formulated by a pharmacist and
used within 1-6 months (>90% effective).

• Dose is 50 to 200 ul depending on severity of problem (increase dose in 25 ul increments)
• Prescribed when single dose therapy has failed

Question 13

Phosphodiesterase 5

(PDE5) inhibitors

Answer 13

• Need to take the pills 1
-2h before intercourse
(time to reach
tmax)

• ~70% effective in healthy patients

• Inhibits hydrolysis of cGMP
–> longer residence of cGMP
–> prolonged smooth
muscle relaxation

• Still need stimulation coming from the NANC
nerves

• The ‘fils’ are eventually metabolised/inactivated
by liver P450 3A4

Question 14

(PDE5) Inhibitors

Side Effects:

Answer 14

• Visual isturbances
• Indigestion
• Headaches and dizziness
• Unstable angina
• Bladder pain

Question 15

ED drugs may be ineffective from:

Answer 15

Diabetes

Veno-occlusive disorders

Hypogonadal patients

Prostate removal

Smoking

Question 16

Explain how diabetes can inhibit effective ED drugs

Answer 16

1. Endothelial dysfunction
2. Increased contractile sensitivity
3. Reduced NO signalling
4. Diabetic neuropathy

Question 17

Explain how veno-occlusive disorders can inhibit effective ED drugs

Answer 17

Simply can’t get enough blood vessel dilation

–> Drug intervention is useless

Question 18

Explain how hypogonodal disorders can inhibit effective ED drugs

Answer 18

Reduced testosterone

–> Testosterone regulates NOS & PDE5

Question 19

Explain how prostate removal can inhibit effective ED drugs

Answer 19

Surgery can damage the penile nerve bundle

• -> No signalling from the brain
• -> Can damage the whole organ

Question 20

The flaccid smoker :(

Answer 20

1. Damages endothelial cells
2. Respond by releasing
   vasoconstrictors
3. Hardens blood vessels
4. Cumulative reduced penile blood flow

Question 21

The prostate

Answer 21

• Doughnut shaped structure sitting just inferior
  to the bladder and anterior to the rectum
• Surrounds proximal end of the urethra (usually
  20-30 cm3
  in size)
• Consists of glandular, connective and smooth
  muscle tissue. Blood is supplied by the
  hypogastric artery
• Its job is to secrete a milky, slightly alkaline
  fluid that contributes ~ 25% of semen volume
• The secreted fluid also contains citrate (to feed
  sperm ATP production) and enzymes that
  liquefy coagulated semen (eg. prostate specific
  antigen or ‘PSA’)

Question 22

Benign Prostatic Hyperplasia

Answer 22

1. Enlargement of the prostate due to nodular prostatic
   remodelling of the stroma and endothelium and inflammation
2. Remodelling and inflammation begin in the transition zone
   usually and is characterised by an increase in cell numbers and
   increase in cell size (advanced)
3. Hyperplasia and hypertrophy are stimulated by androgens
4. Enlargement

Question 23

Benign Prostatic Hyperplasia: Symptoms

Answer 23

**Pushes on bladder and rectum and constructs urethra, leading
to:

• Abdominal pain
• Difficulty urinating and slow urine flow
• Incontinence (by pushing on bladder)
• Feeling of urinary ‘urgency’
• Pain can be worse in the cold or when stressed

Question 24

DHT is…..

Answer 24

• Produced by the enzyme 5α reductase (5AR)
• Important in promoting prostate development, growth and differentiation
• A very potent androgen, 5x more potent than testosterone
• Binds the testosterone receptor with higher affinity than testosterone and binds longer
• The cause of male patterned balding due to high local 5AR levels in the scalp

• BPH pathogenesis results from chronic inflammatory reactions induced by the growing prostate
stromal cells

Question 25

Benign Prostatic Hyperplasia: Treatment

Answer 25

RETURN NORMAL URINARY FUNCTION! 1. Drug treatments to inhibit 5AR (Decr. DHT and reduce prostate size) ``` 2. Drug treatments to inhibit prostate smooth muscle contraction and reduce urinary obstruction (α1 adrenergic antagonists) ``` Final straw: • surgical removal of prostate

Question 26

Benign Prostatic Hyperplasia: Treatment

Answer 26

``` Finastride: Also used for androgenic alopecia • 6 month treatment for men with >30 cm3 prostate • Pharmacokinetics - ~60% bioavailability, t½ ~8h ``` Dutasteride: Pharmacokinetics - ~60% bioavailability, t½ ~ 5 days • better and more consistent therapy than finasteride • Ideally the drug of choice

Question 27

Benign Prostatic Hyperplasia: Treatment Side Effects (Dutasteride, and Finastride)

Answer 27

• ED, ejaculation problems and reduced libido • Male breast enlargement • May increase the chances of male breast cancer, so need to monitor changes in breast tissue

Question 28

A1 Adrenergc Antagonists:

Answer 28

Reduce the degree of smooth muscle contraction in the prostate Reduce pressure on the urethra and increase urinary flow (5AR inhibitors are better if they can be tolerated or are not contraindicated)

Question 29

Alfuzosin and Tamsulosin

Answer 29

Only indication is for BPH • α1A selective (specific for the capsule of the prostate grand and bladder neck) • Little effect on α2 & 1 receptors and therefore less likely to cause cardiac side effects • Less effective against BPH than prazosin and terazosin, but also less hypotension.

Question 30

Prazosin and Terazosin

Answer 30

Can be used as 3rd line drugs in hypertension More effective in BPH treatment than alfuzosin and tamsulosin, but dose titration needed to minimise hypotensive effects

Question 31

A1 Adrenergc Antagonists: Treatment Side Effects (Alfuzosin and Tamsulosin, Prazosin and Terazosin)

Answer 31

``` Common Hypotension, dizziness, fatigue, ‘floppy iris syndrome’, nasal congestion, first dose hypotension ``` Rare Vision disturbances, tachycardia, palpitations