Pharmacology of antigonadal hormones along with indicaitons and adverse effect.

1. Tamoxifen, clomiphene,
Flutamide , Finasteride
Pharmacology II

2. Tamoxifen
• Tamoxifen citrate belong to drug class: selective estrogen receptor
modulator (SERM)
• Estrogen receptor are present in different part such as breast, brain, lungs,
liver, bone , uterus.
• Mechanismof action: Tamoxifen is prodrug which undergoeshepatic
metabolization intoactive form N-desmethyl tamoxifen and endoxifen.
Now these active metabolitescompete with estrogenfor binding with
estrogenreceptor.In breast and brain they acts as estrogenantagonist
hence no gene transcription and inhibitcellulargrowth & proliferation.
• Tamoxifen is cystostaticrather and cytocidal.
• In uterus, bone and liverit act as estrogenreceptoragonist.

3. M.O.A of tamoxifen

4. Pharmacokinetics
• Half-Life: 7-14 hr
• Peak Plasma Time: 3-6 hr
• Plasma protein bind: 99%
• Metabolism: by hepatic P450 enzyme CYP2C9, CYP2D6, CYP3A4
• Metabolites: N-desmethyl tamoxifen, endoxifen
• Excretion: Feces (65%), urine (9%)

5. Uses and dosage
• Dosage form: Tablet (10mg, 20 mg), solution (10mg/5ml)
• Normal dose: 10 mg BD.
1) Metastatic Breast cancer: It is widely used for breast cancer.
Dose: 20 daily in divided doses.(FDA have approved 20-40 mg daily)
2) Prevention of breast cancer: 20 mg daily in divided dose for 5 yr
3) Gynecomastia
4)Infertility
5) Premature puberty

6. Side effect
• Hot flashes (64%)
• Vaginal discharge (30%)
• Amenorrhea (16%)
• Menstrual changes (13%)
• Oligomenorrhea (9%)
• Cataracts (8%)
• Bone pain (6%)
• Nausea (5%)
• Cough (4%)
• Edema (4%)

7. Contraindications:
• It is contraindicated in uterine malignancies and thromboembolic
event. (Black box warning)
• Hypersensitivity
• Pregnancy
• Undiagnosed vaginal bleeding

8. Drug-drug interaction
• Co administration with warfarin may cause warfarin toxicity.
• Rifampicin might decrease bioavailability of tamoxifen

9. Clomiphene citrate
• It also belong to selective estrogen receptor modulator.
• It is mixture of enclomiphene (more potent) and zuclomiphene
• Clomiphene is a prodrug and its most active metabolite are 4-
hydroxyclomifene and 4-hydroxy-N-desmethylclomifene,
• It is generally use to induce ovulation in women.
• Mechanism of action: It shows both estrogenic and anitestrogenic effect. It
bind to estrogen receptor and induces ovulation by increase output of
pituitary gonadotropins.
• Similarly it also shows antiestrogenic effectin endometrium and cervical
mucus. Hence decrease endometrial thicknes (<5-6mm) and changes
quality and quantity of mucus.

10. Pharmacokinetics
• It is readily absorbed from GI tract
• Half life= 5-7 days
• Metabolisim in liver and form active metabolite 4-hydroxyclomifene
and 4-hydroxy-N-desmethylclomifene,
• Excretion: Faeces: 37-51%, minimally in urine.

11. Pre requisites for Clomiphene citrate therapy
• Evaluation of male partner
• History and physical examination
• Age and duration of infertility
• Cause of infertility
• Prolactin levels.
• Thyroid function
• Pituitary function by baseline hormonal evaluation.

12. Uses and dose
• Dosage form: tablet 50mg
• Treatment of ovulatory disorder(anovulation, polycysticovarian
disorder(PCOS), oligoovulation)
• Luetal phase defect
• 50 mg PO qDay initially for 5 days.
• If no ovulation, treatment can be repeated as early as 30 days after previous therapy
• Dosage can be increased to 100 mg only in patients who do not respond to first
course;
• lower doses of 12.5-25 mg qDay may be administered in women sensitive to the
drug or who consistently develop large ovarian cysts
• Recent guideline suggest use of clomiphene for 12 month in a life time and
maximum for 6 month continuously as it is linked to ovarian cancer

14. Monitoring of clomiphene therapy
• Transvaginal ultrasound shows follicle growth and maturation
• Serum Estrogen level

15. Side Effect
• Ovarian enlargement (14%)
• flushing (10%
• Abdominal discomfort (6%)
• Blurred vision (1.5%)
• Breast discomfort (2%)
• Nausea/vomiting (2%)
Recent guideline suggest use of clomiphene for 12 month in a life time
and maximum for 6 month continuously as it is linked to ovarian cancer

16. Contraindication
• Pregnancy
• Liver disease or history of liver disease
• Undiagnosed abnormal uterine bleeding
• Uncontrolled thyroid or adrenal dysfunction
• Endometrial cancer

17. Clomiphene Resistance
• It is define as failure to ovulate within 3 month of therapy use at
150mg/day for 5 days.
• Most common cause is PCOS.

18. Conception failure
• These are patients who ovulate but failure to conceive.
• If patient has 3 ovulatory cycle but fail to conceive then she is labelled
as conception failure and should started alternative therapy.
• The cause of infertility should be ruled out.
• Sometime it might be due to antiestrogenic effect of clomiphene in
endometrium and cervical mucous.

19. Other estrogen inhibitors
• Aromatose inhibitors: These class of drug inhibit peripheral
conversion of androgen to estrogen.
• Eg.
• 1st generation: Aminogluthemide
• 2nd generation:Fadrazole
• 3rd generation.: Anastrazole, letrozole.

20. Finasteride
• It is one of the common androgen antagonist drug .
• M.O.A: It inhibit enzyme 5 alpha reductase and hence block the
conversion of testosterone to dihydrotestosterone.
• Bioavialability: 65%
• Half life: 6hr
• Metabolism: Liver enzyme
• Excretion: Urine

21. Indication and dose
• Dosage form: Tablet, capsule
• Benign prostatic hyperplasia (BPH) : 5mg daily
• Androgenic Alopecia in male: 1mg daily
• Female hirsutism: 5mg daily

22. Adverse effect
• Erectile dysfunction
• Decrease libido
• Breast enlargement/tenderness
• Rashes

23. Precaution and contradindication
• Hypersensitivity
• Pregnancy
• Precaution; obstructive uropathy, prostate cancer, liver diseases

24. Flutamide
• It is non steroidal antiandrogen drug.
• It is mainly use in androgen dependent tumor (prostatecancer) and
condition associatewith hyper gonadism (Polycysticovarian syndrome).
• M.O.A: Flutamide is a nonsteroidal antiandrogen that competitively binds
androgen receptors throughout the body and inhibit testosterone
stimulation of cell growth in prostate cancer.
• Half-Life: 6 hr
• Peak Plasma Time: 6 hr
• Protein Bound: 94-96%
• Metabolism: Liver
• Excretion: Primarily urine; <5% in feces

25. Indication and Dose
• Dosage form: Capsule 125 mg
• Prostate Cancer: 250 mg TDS

26. Adverse Effect
• Hot flashes
• Decreased libido
• Impotence
• Diarrhea
• Nausea/vomiting
• Gynecomastia
• Anorexia
• Edema
• Leukopenia
• Rash

27. Precaution and Contraindication
• Hypersensitivity
• severe hepatic failure,
• pregnancy
• Cautiously use in Cardiovascular disease, anemia.

28. Thank you