Pharmacology for reproductive disorders

Question 1

MOA of Tamsulosin

Answer 1

*REVERSIBLE alpha1 receptor ANTAGONIST
-> INHIBITS vasoconstriction induced by endogenous catecholamines
-> blocks alpha-adrenoreceptors on smooth muscle on prostate, prostatic urethra & bladder neck -> decreased muscle tone & reduction in bladder obstruction; relaxation of prostate smooth muscle, then improvements in urodynamics (increased max urinary flow rate by reducing smooth muscle tension in prostate & urethra -> RELIEVE OBSTRUCTION); also improves symptoms related to bladder instability & tension of smooth muscle of lower urinary tract

** SELECTIVE for alpha1A (in blood vessels & prostate) [alpha1B in heart] -> little effect on BP

-> Effects on urinary storage & voiding symptoms: maintained during LONG-TERM therapy -> significantly delays need for surgery/ catheterisation
*onset of improved urinary flow rate: few hours/ days after administration

Question 2

PK, AE and CI of Tamsulosin

Answer 2

A: well absorbed orally (0.4mg OD)

D: HIGHLY bound to plasma protein (>90%) -> stays in circulation
- SMALL Vd: 0.2L/kg

M: metabolised by CYPs (eg. 3A4, 2D6) *DDI
- t1/2: ~10-15h

E: ~10% excreted unchanged in urine (metabolites in urine)

AE: abnormal ejaculation, back pain

CI: CONCURRENT USE OF ANOTHER ALPHA1-adrenoreceptor antagonist (eg. Prazosin- non-selective alpha1 blocker)

Question 3

MOA of Finasteride

Answer 3

*5alpha-reductase inhibitor
- 5alpha-reductase converts testosterone to dihydrotestosterone DHT

MOA: inhibits action of 5alpha- reductase -> DECREASES PROSTATE SIZE (prostate growth stimulated by DHT) -> improved urine flow, reduced frequency of acute retention of urine & need for surgical procedures for prostate transurethral resection & prostatectomy)
*also increases hair growth

*COMPETITIVE inhibitor (NO affinity for androgen receptor)

**may take up to 6months to see BPH clinical effect after initiating treatment;
SERUM PROSTATE SPECIFIC ANTIGEN (PSA) levels DECREASES with finasteride

Question 4

PK/AE/CI of Finasteride

Answer 4

A: well absorbed orally (F ~ 0.65)
*NO DOSAGE READJUSTMENT needed for pts with RENAL insufficiency/ LIVER failure/ ELDERLY pts

D: HIGHLY plasma protein bound (~90%)

M: Metabolised by liver (eg. CYP3A4) *DDI
- t1/2 ~6h

E: 50% unchanged excreted in faeces; metabolites excreted in urine & faeces

AE: loss of libido & sexual potency, gynaecomastia *RARE

CI: WOMEN & children, pregnancy

Question 5

MOA of sildenafil

Answer 5

• inhibits phosphodiesterase type-5 (PDE-5) in penis -> INCREASES cGMP levels in response to NO-releasing by sexual stimulation -> smooth muscle relaxation & INCREASED blood flow to corpora cavernosa -> erection

*PDE-5: highly expressed in corpora cavernosa of penis BUT poorly in myocardium -> TISSUE SPECIFICITY

Question 6

PK/AE/ CI of Sildenafil

Answer 6

A: Well absorbed orally (5mg OD) (F ~0.4)
*onset: 30-60mins
*NO DOSAGE READJUSTMENT needed for pts with RENAL insufficiency/ LIVER failure/ ELDERLY pts
- Duration of action (max) ~12h

D: widely distributed (Vd 5-8L)

M: metabolised by liver (3A4: MAJOR, 2C9: minor)
- t1/2: 4h

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

AE: headache, flushing, dyspepsia, dizziness, back pain, blur vision; blue-green tinting of vision (*inhibtion of retinal PDE6), priapism

CI: CARDIAC pts on GTN (nitroglycerin) - POTENTIATES vasodilation effect of GTN via INCREASED cGMP due to concomitant blockage of cGMP degradation by sildenafil -> potential marked vasodilation & hypotension

**STARTING DOSE recommendations vary; pts should start @ LOWEST RECOMMENDED DOSE esp >65y/o

Question 7

MOA, indication of ethinyl estradiol

Answer 7

*synthetic estrogen - estrogen receptor AGONIST
[MOA]: inhibits FSH release from anterior pituitary -> suppresses development of ovarian follicle -> makes endometrium unsuitable for implantation of ovum

Indication:
- Menopausal symptoms
- Gynecological disorders
- Hormone-sensitive cancers

Question 8

PK/AE/CI of ethinyl estradiol

Answer 8

A: well-absorbed orally (OD) (F~0.45)
onset 30-60mins
*may be administered parenteral/ transdermal/ topical

D: VERY HIGHLY plasma protein bound (~98%; albumin)

M: liver
- Phase 1: HYDROXYLATION by CYP3A4 *DDI
- Phase 2: CONJUGATION with glucuronide & sulfation -> hormonally inert ethinylestradiol glucuronides & ethinylestradiol sulfate
**sulfate conjugate: undergoes ENTEROHEPATIC RECIRCULATION
-> t1/2: 13-27h

E: METABOLITES excreted in feces & urine

AE: breast tenderness, headache, fluid retention (bloating), nausea, dizziness, weight gain

*VTE (venous thromboembolism). MI/stroke, LIVER DAMAGE RISK

CI: BREAST CANCER/ BREASTFEEDING postpartum <21d/ Hypertension >/=160/100 / History/susceptibility to ARTERIAL/VENOUS THROMBOSIS / advanced diabetes with VASCULAR disease

Question 9

MOA & indication of norethindrone

Answer 9

*progestin/ SYNTHETIC PROGESTERONE (birth control pill; oral contraceptive)

MOA: INHIBITS LH release -> PREVENTS ovulation -> makes endometrium unsuitable for implantation of ovum
*acts as progesterone receptor AGONIST

Indication:
- endometriosis
- abnormal periods/ bleeding; induce normal menstrual cycle

Question 10

PK/AE/CI of norethindrone

Answer 10

A: well absorbed orally (OD) (F ~0.64)

D: HIGHLY plasma protein bound (eg. albumin)

M: Liver by REDUCTION followed by GLUCURONIDATION & SULFATION
- t1/2 ~8h
*some evidence that some % of norethindrone can be metabolised in liver to ethinylestradiol

E: METABOLITES excreted in urine (~50%) & faeces (~40%)

AE: headache, dizziness, bloating, weight gain, episodes of unpredictable spotting & bleeding (initial), amenorrhea

**may not be desirable for women planning pregnancy soon after cessation of therapy because ovulation suppression can persist as long as 1.5yrs
***partial conversion of norethindrone to EE requires special attention: potential CV related complications eg. VTE of EE