Drugs of Male GU Disorders

Question 1

Where is testosterone synthesized? What other active steroids can it be metabolized to? How is testosterone inactivated?

Answer 1

Synthesized by the testes
Metabolized to DHT (5alpha-reductase) or Estradiol (aromatase)
Inactivated in the liver

Question 2

What are the isoforms and functions of 5alpha-reductase?

Answer 2

5alpha-reductase converts testosterone to DHT

Two isoforms exist:

1) Type 1 - non-gonadal tissue
2) Type 2 - gonadal tissue

Question 3

What is the function of aromatase and where can it be found?

Answer 3

Aromatase converts testosterone to estradiol. It is produced in the liver and adipose tissue.

Note: Responsible for 85% of serum estradiol

Question 4

How does testosterone exert its action directly and indirectly? Describe the difference in efficiency.

Answer 4

Testosterone and DHT both bind to the androgen receptor. However, DHT binds the AR with a much higher affinity.

Question 5

What are the physiologic effects of testosterone?

Answer 5

1. Increased EPO and clotting factors
2. Decreased HDL with increased TG lipase
3. Maintenance of sexual function
4. Tissue growth (includes skeletal) and epiphysial closure
5. Hair, just not on your head
6. Increased sebaceous glands
7. Thicker vocal cords and laryngeal growth

Question 6

Describe the differences in administration routes of androgens?

Answer 6

Orally they are absorbed rapidly, but largely inactivated at the liver. Parenteral preparations are absorbed slower and have a longer duration of action.

Question 7

What are the uses of androgens?

Answer 7

1. Prevent protein loss following trauma
2. Hypogonadism
3. Delayed puberty
4. Abuse in sports
5. Aging - reduces osteoporosis and increases lean mm. mass and hematocrit

Question 8

What are the ADRs of androgens with respect to general use and use in HRT?

Answer 8

General

1. Sodium retention –> edema (esp.ly heart/kidney disease)
2. Synthetics –> reversible cholestatic jaundice
3. BPH - older pt.s
4. Psychosis and psychological dependance

HRT

1. Azoospermia - supraphysiologic doses as well
2. Gynecomastia
3. Acne
4. Sleep Apnea
5. Erythrocytosis

Question 9

What are the CIs of androgens?

Answer 9

1. Children
2. Men with prostate CA
3. Pregnant women

Question 10

Describe GnRH analogs with respect to prototype, MOA, pulsatile versus continuous administration, and uses?

Answer 10

Prototype - Leuprolide
MOA - stimulates the production of FSH and LH
Pulsatile Admin - Every 4 hours to increase FSH and LH
Continuous Admin - Gonadotropins rise for the first 7-10 days, then negative feedback response overrides
Uses - suppression of gonadotropins (prostate CA) or stimulation of gonadotropins (infertility)

Question 11

Describe GnRHR antagonists with respect to prototype, MOA, use, and benefit.

Answer 11

Prototype - Abarelix or degarelix (RELIX)
MOA - binds GnRHR inhibiting the production of LH and FSH
Use - Advanced prostate CA
Benefit - No testosterone spike, like with GnRH agonists

Question 12

Describe 5alpha-reductase inhibitors with respect to prototypes, MOA, effects, ADR and CIs.

Answer 12

Protoypes - finasteride and dutasteride
MOA - inhibits 5-alpha reductase
effects - decreased prostate volume, increase urine flow
ADRs - decreased libido and impotence
CI - women and children

Question 13

What is finasteride?

Answer 13

A Type II 5alpha-reductase inhibitor for male pattern baldness or hirsutism

Question 14

What is dutasteride?

Answer 14

A Type I and II 5alpha-reductase inhibitor for prostate cancer and BPH

Note: longer duration

Question 15

What type of drug is cyproterone and what is it used for?

Answer 15

Cyproterone is an AR blocker used for advanced prostate CA and possibly hirsutism

Question 16

What is flutamide, bicalutamide, and nilutamide? What are there uses?

Answer 16

These are all nonsteroidal AR blockers which are used for metastatic prostate CA. Can also be used to inhibit the tumor surge in GnRH agonist Tx.y. May cause gynecomastia

Question 17

What is spironolactone? What is it commonly used for?

Answer 17

Spironolactone is an inhibitor of AR, aldosterone receptors, and synthesis of testosterone/androstenedione. Commonly used for heart failure and hirsutism

Question 18

Describe the approach to treating BPH.

Answer 18

Tx doesn’t begin until Mx.s significantly impact quality of life.

5alpha-reductase inhibitors - excellent for long-term use; reduced prostate volume and need for surgery

Alpha-adrenergic antagonists - excellent for short-term use; Less side effects when specific for alpha1A

Question 19

Describe prazosin, terazosin, doxazosin, alfuzosin, and tamsulosin with respect to receptor selectivity, half-life, and ADRs.

Answer 19

Prazosin - short half-life with selectivity for alpha1, but no subtypes; ADRs are orthostatic hypotension

Terazosin and doxazosin - both are similar to prazosin but each with a longer half-life and less side effects

Alfuzosin - this is similar in profile to those above, but the half-life is between that of prazosin and terazosin

Tamsulosin - selective for alpha1A receptors; may experience abnormal ejaculation; half-life is similar to terazosin

Question 20

Is saw palmetto effective?

Answer 20

Probably not

Question 21

Describe PDE-5 inhibitors with respect to prototypes, effects, duration, CIs, ADRs.

Answer 21

Prototypes - tadalfil, sildenafil, and vardenafil
Effects - normal doses due not cause erection without sexual stimulation
Duration - most last 4 hours; tadalfil can have effects up to 36 hours
CI - alpha-antagonists and nitrates
ADRs - hypotension, syncope, visual changes, and hearing loss

Question 22

What would you use if patients were refractory to PDE-5 inhibitors?

Answer 22

Alprostadil, a PGE1 which relaxes cavernosal smooth muscle. Direct injection.

Question 23

What is oxybutynin?

Answer 23

Somewhat selective M3 antagonist used in the treatment of urinary urgency. ADRs include opposite dumbbels.