Reproductive disorders

Question 1

What is benign prostate hyperplasia?

Answer 1

Enlarged prostate

Question 2

Who is more likely to suffer from BPH?

Answer 2

Majority of men above 50 years old and the frequency of the disease is increased with age

Question 3

What causes BPH?

Answer 3

BPH is dependent on the androgen 5-alpha dihydrotestosterone (5α-DHT)

Testosterone secreted by the testicles and the adrenal glands, is quickly metabolized into DHT by the enzyme 5α-reductase at the prostate gland

Question 4

What is the goal of treatment for BPH?

Answer 4

The goal of treatment is to relieve LUTS and slow the clinical progression of BPH while improving patient QOL.

Question 5

When to treat or not treat?

Answer 5

If the patient presents with LUTS, with or without uncomplicated prostate enlargement, and the symptoms are not affecting his QOL, then no further evaluation
or treatment is recommended.

Question 6

Current oral pharmacotherapy options for managing BPH (those in syllabus)

Answer 6

(1) alpha-adrenergic antagonists (α-blockers)
(2) 5α-reductase inhibitors (5ARIs)

Question 7

What is an example of an alpha-blocker used for BPH?

Answer 7

Tamsulosin

Question 8

What is the outcome of Tamsulosin?

Answer 8

Relaxes smooth muscle of bladder and urethra to improve urine flow

The effects on urinary storage and voiding symptoms are maintained during long-term therapy. The need for surgery or catheterization is significantly delayed; help to improve urinary flow rate after a few hours or days after administration

Question 9

Which type of patients can use Tamsulosin?

Answer 9

Moderate-to-severe symptomatic BPH regardless of prostate size.

Question 10

Describe the MOA of Tamsulosin

Answer 10

Reversible α1 receptor antagonist
* Inhibits vasoconstriction induced by endogenous catecholamines
* Blocking the α-adrenoceptors on the smooth muscle of the prostate, prostatic urethra, and bladder neck, leading
to ↓ muscle tone and reduction in bladder obstruction; relaxation of prostate smooth muscle followed by
improvements in urodynamics (increases maximum urinary flow rate by reducing smooth muscle tension in the
prostate and urethra and thereby relieving obstruction); also improves the symptoms related to bladder instability and tension of the smooth muscle of the lower urinary tract.

Question 11

Describe the selectivity of Tamsulosin

Answer 11

Has greater selectivity for α1A – favours blockade of α1A (blood vessels and prostate) over α1B (blood
vessels and heart) receptors –> may explain why little effect on blood pressure but particularly useful in BPH.

Question 12

What are the PK properties of Tamsulosin?

Answer 12

A: well absorbed orally (0.4mg once a day)

D: highly bound to plasma proteins (>90%)
small Vd (0.2L/kg)

M: metabolized by CYPs (eg. CYP3A4 (inhibited by pomelo and grapefruit), CYP2D6)
T1/2 ~10 - 15h

E: ~10% excreted unchanged in urine

Question 13

What are the adverse effects of Tamsulosin?

Answer 13

Abnormal ejaculation
Back pain

Question 14

What is the contraindication of Tamsulosin?

Answer 14

Concurrent use of another α1-adrenoceptor antagonist (eg. Prazosin – non-selective α1
blocker)

Question 15

What is an example of a 5-alpha-reductase inhibitor?

Answer 15

Finasteride

Question 16

What is the MOA of Finasteride?

Answer 16

• 5α-reductase converts testosterone to another hormone
  (dihydrotestosterone, DHT) that causes the prostate to grow or hair loss in
  males.
• ⊗ the action of 5α-reductase.
• Overall effect: decreases prostate size (increases hair growth)

A competitive, 5α-reductase inhibitor (no affinity for androgen receptor)
* the conversion of testosterone to dihydrotestosterone, esp. in male external
genitalia
* ↓ prostate size leading to improved urine flow, reduces frequency of acute
retention of urine and the need to surgical procedures for prostate transurethral
resection and prostatectomy.

Question 17

How long does it take to see clinical effects for BPH if Finasteride is used?

Answer 17

Up to 6 months (serum prostate specific antigen (PSA) levels decrease with Finasteride)

Question 18

PK properties of Finasteride

Answer 18

A: well absorbed orally (5mg once a day)
F ~ 0.65
No dosage readjustment needed for patients
with renal insufficiency, liver failure and
elderly patients

D: high plasma protein bound (~90%)

M: metabolized by liver (eg. CYP3A4)
T1/2 ~6h

E: 50% unchanged drug excreted in feces;
metabolites excreted in urine & feces

Question 19

What are the adverse effects of Finasteride?

Answer 19

• Loss of libido and sexual potency
• Gynaecomastia (rare)

Question 20

What is the contraindication of Finasteride?

Answer 20

Women and children, pregnancy

Question 21

What is erectile dysfunction (ED)?

Answer 21

Erectile dysfunction (ED), the inability to develop or keep an erection, often occurs when blood flow to the penis is limited or nerves are damaged, often by consistent hyperglycemia in diabetes. About 95% of ED cases are
treatable.

Question 22

What are the risk factors for ED?

Answer 22

Alcohol or tobacco use, an enlarged prostate, psychological factors, sleep disorders, and stress

Question 23

What is a drug used for ED?

Answer 23

Sildenafil

Question 24

What is the MOA of Sildenafil?

Answer 24

• Specifically inhibits phosphodiesterase type-5 (PDE5) in penis
• Outcome: Sildenafil increases cGMP levels in response to NO-releasing by sexual stimulation, which results in smooth muscle relaxation and ↑ blood flow to the
  corpora cavernosa, producing an erection.
• Physiology: PDE5, highly expressed in the corpora
  cavernosa of the penis and its vasculature, but poorly in the myocardium, which provides tissue specificity to the compound

Question 25

ADME of Sildenafil

Answer 25

A: well absorbed orally (5mg once a day)
onset 30-60min
F ~ 0.4
No dosage readjustment needed for patients
with renal insufficiency, liver failure and
elderly patients
Duration of action (max) ~ 12h

D: widely distributed

M: metabolized by liver
(CYP3A4 – major; CYP2C9 – minor)
T1/2 ~4h

E: Metabolites largely excreted in feces (80% of
oral dose); to a lesser extent in urine (13%);
remaining excreted unchanged in urine

Question 26

What are the adverse effects of Sildenafil?

Answer 26

• Headache
• Flushing
• Dyspepsia
• Dizziness
• Back pain
• Blur vision; blue-green tinting of vision (inhibits retinal PDE6)
• Priapism*

Question 27

Contraindications of Sildenafil

Answer 27

Cardiac patients on GTN (nitroglycerin) – potentiates
vasodilation effect of GTN via ↑ cGMP due to concomitant
blockade of cGMP degradation by sildenafil…potential
marked vasodilation and hypotension. CONSULT DOCTOR!

Question 28

What is the starting dose for Sildenafil?

Answer 28

Starting dose recommendations vary: patients should start
@ the lowest recommended dose, especially important
>65yr old.

Question 29

Describe the MOA of Ethinyl estradiol

Answer 29

• A synthetic estrogen (birth control pill; oral contraceptive)
• An estrogen receptor agonist
• Inhibits follicle-stimulating hormone (FSH) release from anterior
  pituitary –> suppresses the development of ovarian follicle –> make endometrium unsuitable for implantation of the ovum

Question 30

What condition is Ethinyl estradiol used to treat?

Answer 30

(a) menopausal symptoms
(b) gynecological disorders
(c) certain hormone-sensitive cancers

Question 31

ADME of Ethinyl estradiol

Answer 31

A: well absorbed orally (once a day)
onset 30-60min
F ~ 0.45
May be administered parenteral, transdermal or topical

D: very highly plasma protein bound (~98%; albumin)

M: metabolized by liver via
Phase I – EE undergoes hydroxylation by CYP3A4
Phase II – conjugation with glucuronide and sulfation
into hormonally inert ethinylestradiol glucuronides and ethinylestradiol sulfate
due to the formation of EE sulfate, enterohepatic
recirculation* is involved in the pharmacokinetics of EE
T1/2 ~ 13-27hrs

E: metabolites excreted in feces and urine

Question 32

What are the adverse effects of Ethinyl estradiol?

Answer 32

• Breast tenderness
• Headache
• Fluid retention (bloating)
• Nausea
• Dizziness
• Weight gain
• Venous Thromboembolism (VTE)
• Myocardial infarction/stroke
• Liver damage

Question 33

What is the contraindication of Ethinyl estradiol?

Answer 33

• Patients have known history or susceptibility
  to arterial or venous thrombosis
• Advanced diabetes with vascular disease
• Hypertension ≥160/100
• Avoid in breastfeeding (<21 days postpartum) and breast cancer women

Question 34

Describe the MOA of Norethindrone

Answer 34

• A synthetic progestogen (birth control pill; oral contraceptive)
• Inhibits luteinizing hormone (LH) release –> prevents ovulation –> make endometrium unsuitable for implantation of the ovum
• Act as a progesterone receptor agonist

Question 35

When is Norethindrone indicated?

Answer 35

(a) endometriosis
(b) abnormal periods or bleeding and to bring on a normal menstrual cycle

Question 36

ADME of Norethindrone

Answer 36

A: well absorbed orally (once a day)
onset
F ~ 64%

D: Highly plasma protein bound (eg. albumin)

M: Metabolized in liver by reduction follow by
glucuronidation and sulfation
T1/2 ~ 8h
some evidence suggest some % norethindrone
can be metabolized in liver to EE* (ethinyl
estradiol)

E: metabolites excreted in urine (~50%) and feces (~40%)

Question 37

What are the adverse effects of Norethindrone?

Answer 37

• Headache
• Dizziness
• Bloating
• Weight gain
• Episodes of unpredictable spotting and bleeding (initial)
• Amenorrhea

Question 38

What is a special note to take for women who wish to get pregnant but are on Norethindrone?

Answer 38

May not be desirable for women planning a pregnancy soon after cessation of therapy because ovulation
suppression can sometimes persist for as long as 1.5yrs

Question 39

What complications can Norethindrone cause?

Answer 39

The partial conversion of norethindrone to EE requires special attention due to the potential cardiovascular related complications (eg. Venous Thromboembolism VTE) of EE.