Reproductive disorders Flashcards
What is benign prostate hyperplasia?
Enlarged prostate
Who is more likely to suffer from BPH?
Majority of men above 50 years old and the frequency of the disease is increased with age
What causes BPH?
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
What is the goal of treatment for BPH?
The goal of treatment is to relieve LUTS and slow the clinical progression of BPH while improving patient QOL.
When to treat or not treat?
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.
Current oral pharmacotherapy options for managing BPH (those in syllabus)
(1) alpha-adrenergic antagonists (α-blockers)
(2) 5α-reductase inhibitors (5ARIs)
What is an example of an alpha-blocker used for BPH?
Tamsulosin
What is the outcome of Tamsulosin?
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
Which type of patients can use Tamsulosin?
Moderate-to-severe symptomatic BPH regardless of prostate size.
Describe the MOA of Tamsulosin
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.
Describe the selectivity of Tamsulosin
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.
What are the PK properties of Tamsulosin?
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
What are the adverse effects of Tamsulosin?
Abnormal ejaculation
Back pain
What is the contraindication of Tamsulosin?
Concurrent use of another α1-adrenoceptor antagonist (eg. Prazosin – non-selective α1
blocker)
What is an example of a 5-alpha-reductase inhibitor?
Finasteride
What is the MOA of Finasteride?
- 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.
How long does it take to see clinical effects for BPH if Finasteride is used?
Up to 6 months (serum prostate specific antigen (PSA) levels decrease with Finasteride)
PK properties of Finasteride
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
What are the adverse effects of Finasteride?
- Loss of libido and sexual potency
- Gynaecomastia (rare)
What is the contraindication of Finasteride?
Women and children, pregnancy
What is erectile dysfunction (ED)?
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.
What are the risk factors for ED?
Alcohol or tobacco use, an enlarged prostate, psychological factors, sleep disorders, and stress
What is a drug used for ED?
Sildenafil
What is the MOA of Sildenafil?
- 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
ADME of Sildenafil
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
What are the adverse effects of Sildenafil?
- Headache
- Flushing
- Dyspepsia
- Dizziness
- Back pain
- Blur vision; blue-green tinting of vision (inhibits retinal PDE6)
- Priapism*
Contraindications of Sildenafil
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!
What is the starting dose for Sildenafil?
Starting dose recommendations vary: patients should start
@ the lowest recommended dose, especially important
>65yr old.
Describe the MOA of Ethinyl estradiol
- 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
What condition is Ethinyl estradiol used to treat?
(a) menopausal symptoms
(b) gynecological disorders
(c) certain hormone-sensitive cancers
ADME of Ethinyl estradiol
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
What are the adverse effects of Ethinyl estradiol?
- Breast tenderness
- Headache
- Fluid retention (bloating)
- Nausea
- Dizziness
- Weight gain
- Venous Thromboembolism (VTE)
- Myocardial infarction/stroke
- Liver damage
What is the contraindication of Ethinyl estradiol?
- 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
Describe the MOA of Norethindrone
- 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
When is Norethindrone indicated?
(a) endometriosis
(b) abnormal periods or bleeding and to bring on a normal menstrual cycle
ADME of Norethindrone
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%)
What are the adverse effects of Norethindrone?
- Headache
- Dizziness
- Bloating
- Weight gain
- Episodes of unpredictable spotting and bleeding (initial)
- Amenorrhea
What is a special note to take for women who wish to get pregnant but are on Norethindrone?
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
What complications can Norethindrone cause?
The partial conversion of norethindrone to EE requires special attention due to the potential cardiovascular related complications (eg. Venous Thromboembolism VTE) of EE.
