Pharm of Male Disorders

Question 1

In treating erectile dysfunction, sildenafil, vardenafil and tadalafil all work to inhibit what enzyme?

Answer 1

Phosphodiesterase 5 (PDE5)

Question 2

Benign prostatic hyperplasia (BPH) can be treated with what general class of drugs?

Answer 2

Alpha 1 adrenergic receptors antagonists. Provides rapid relief of symptoms (within days)

Question 3

What are the two targets of therapy for BPH?

Answer 3

1. Relax the smooth muscle of prostate

2. Reverse androgen outflow

Question 4

In rational drug design of alpha 1 adrenoreceptors antagonist works to treat BPH due to the different subclasses. Explain the specificity of the following:
A. alpha1B
B. alpha1A
C. Alpha1D

Answer 4

A. blood vessels (vascular resistance)
B. Prostate (smooth muscle contraction)
C. Detrusor (instability)

Question 5

alpha1D receptors + NE leads to _ 1_

Alpha1A receptors +NE leads to _ 2_

Answer 5

1. detrusor instability

2. muscle contraction

Question 6

Of the following drugs (a. terazosin; b.doxazosin; c. alfuzosin; d. tamsulosin; e. silodosin) indicate:

1. which ones are specific for alpha 1 and alpha 2
2. Non specific for alpha 1 subtypes
3. sub-type specific for alpha1A and alpha1D.

Answer 6

1. a, b and c
2. c
3. d and e

Question 7

which drugs used for BPH are known to causes postural hypotension, vascular dilation.

A. Terazosin
B. Doxazosin
C. tamsulosin
D. Silodosin
E. A and B
F. C and D

Answer 7

E. A and B both are nonselective alpha 1 antagonists and thus causes systemic side effects.

Question 8

_ is a drug used for LUTS which has some uroselectivity but is known to cause QT prolongation and interacts with CYp450.

Answer 8

Alfuzosin

Question 9

What are the common AE associated with Tamsulosin and Sildosin?

Answer 9

• reduced ejaculation

- intraoperative floppy iris syndrome (IFIS)

Question 10

Pt comes in complaining of LUTS. Pt has a history of episodic hemodynamic insufficiency which are controlled most of the time, but does have episodes here and there. Which drugs used to treat LUTS are preferred for this patient?

Answer 10

Tamsulosin and silodosin since these are selective for A1A and A1D.

Question 11

Alfuzosin is not selective for a1A or a1D like tamsulosin or silodosin. However, it is considered an uroselective drug, why?

Answer 11

Alfuzosin is an alpha 1 receptor antagonist generally. It’s uroselective becuase it tends to concentrate in the prostate and does not stay in the general circulation. It’s an accident of design.

Question 12

Which drug treatment for BPH provides an structural remedy? 
A. Alfuzosin
B. Finasteride
C. Tamsulosin
D. Silodosin
E. Doxazosin

Answer 12

B. Finasteride. these are steroid 5-a reductase inhibitors which work to shrink the prostate.

Question 13

As part of normal aging, what enzymes are expressed with a higher amounts associated with hypertrophic prostate?

Answer 13

Steroid-5a reductase II which converte serum testosterone to DHT in the cells which are 10x more potent than T.

Question 14

Explain how an SAR II inhibitor would work to treat BPH.

Answer 14

Normally T from testes gets taken up into prostate cells where they are converted to DHT by SAR II. The potent DHT then binds to AR and dimerize and this causes nuclear uptake and promotes gene transcription. With an SAR II inhibitor, the conversion of T to DHT is inhibited and thus gene transcription is halted.

Question 15

with a SAR inhibitor therapy, how long it take to see an intermediate shrinkage of the prostate?

Answer 15

about 6-18 months.

Question 16

What are the direct and indirect consequences of SAR inhibition?

Answer 16

Direct: build up of testossterone and depletion of DHT
Indirect: AR receptor less occupied thus less dimerized and thus less nuclear transport and gene transcription

Question 17

what are the two SAR inhibitor used to treat BPH?

Answer 17

Finasteride and Dutasteride

Question 18

Which SAR inhibitor drug is specific for SAR II? SAR I and II?

Answer 18

FInasteride (speciFIc inhibitor) for SAR II

DUtasteride is DUal inhibitor of SAR I and II

Question 19

Compare finasteride and dutasteride in terms of time it takes to show measurable effect, efficiacy, and adverse events

Answer 19

Both takes about 3 months to show measurable effect

Have similar efficacy to improve LUTS, reduce prostate volume, serum PSA and need for surgery.

Have similar AE: ED, gynecomastia, depressed libido, ejaculation disturbances.

Question 20

Explain how Sildenafil, vardenafil and tadalafil work to treat ED

Answer 20

They block PDE-5 which normally breaks down cGMP into GMP. these drugs by blocking PDE5 keeps cGMP around longer and thus allows for action of NO to keep the eraction

Question 21

Which ED drug has the longest half life?

Answer 21

Tadalafil (18 hours). efficacy is about 36 hrs and doesn’t need to be taken on an empty stomach like the other

Question 22

Explain why ED drugs that target PDE5 works where it does and not in other places where these enzymes are also found

Answer 22

PDE5 is almost exclusively found in the corpus cavernosum. PDE6 is found in retina but it’ll take about 10 fold more of the drugs to get any effect.

Question 23

What are some common AE associated with Sildenafil vardenafil and tadalafil?

Answer 23

PDE5:
- headache 15%
-dyspepsia 5-10%
nasal congestion 5%

tadalafil is also known to cause back pain, maylgia and limb pain. Remember taladalfil is also used for other problems like BPH,

Question 24

What is the biggest contraindications for PDE5 inhibitors?

Answer 24

Organic nitrates: use of PDE5 inhibitors concurrently with nitrates (glyceryl trinitrate) may induce extreme hypotension. Combination of PDE5 inhibitors plus organic nitrates is strictly contraindicated. Organic nitrates are commonly used in pts with coronary artery disease, e.g. angina pectoris; they work by releasing NO, powerful systemic vasodilator

Question 25

For patients who are on alpha receptor antagonist, how should pts be dosed for vardenafil, tadalafil and sildenafil?

Answer 25

For vardenafil and sildenafil, start at the LOWEST recommended dose

Tadalafil is NOT recommended concurrently with alpha 1 blocker.

Question 26

Prostaglandins E1 inhibits such as papaverine and phentalamine have also been used for ED. PDE5 inhibitors and PGE1 inhibitors have a similar MOA but their signaling transduction is slightly different. Explain

Answer 26

PDE5 binds to gualyate cyclase and then amplifies cGMP. PGE1 binds to adenylate cyclase and amplify cAMP.