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DRUGS AFFECTING THE FEMALE REPRODUCTIVE SYSTEM

1. ESTROGENS - used for hormone replacement therapy when ovarian activity is blocked or absent - used less often for palliative and preventive therapy during menopause - systemic effects includes: protecting heart form atherosclerosis retaining calcium in the bones maintaining secondary female characteristics a. estradiol (Estrace, Climara - prototype - widely used b. conjugated estrogens (Premarin) - once one of the most popular drugs for postmenopausal treatment c. estrified estrogen (Menest) d. estropipate (Ortho-Est, Ogen) Therapeutic Actions and Indications - for development of the female reproductive system and secondary sex characteristics - affect the release of pituitary follicle-stimulating hormone(FSH) and luteinizing hormone(LH) - cause capillary dilatation, fluid retention and protein anabolism and thin the cervical mucus - conserve calcium, phosphorus and encourage bone formation - inhibit ovulation - prevent postpartum breast discomfort - for proliferation of the endometrial linin Pharmacokinetics - well-absorbed through GI tract - undergo hepatic metabolism - excreted in urine

cross placenta enters breastmilk

Contraindications and Cautions - allergies to estrogens - pregnancy - idiopathic vaginal bleeding - breast cancer - any estrogen-dependent cancer - history of thromboembolic disorders - hepatic dysfunction - breastfeeding - metabolic bone disease - renal insufficiency Adverse Effects - bleeding - menstrual irregularities - dysmenorrhea - amenorrhea - changes in libido - fluid retention - electrolyte disturbances - headache - dizziness - menstrual changes

edema nausea & vomiting abdominal cramps & bloating colitis acute pancreatitis cholestatic jaundice hepatic adenoma weight changes

Drug-Drug Interactions estrogens + barbiturates,rifampin,tetracyclines,phenytoin

= serum levels smoking + estrogens = risk for devt of thrombi & emboli grapefruit juice= inhibit metabolism of estradiols= serum levels 2. ESTROGEN RECEPTOR MODULATORS - produce positive effects of estrogen replacement a. raloxifene (Evista) - prototype - used to prevent and treat osteoporosis - Therapeutic Actions and Indications; has modulating effects on estrogen receptor sites stimulate specific estrogen receptor sites bone mineral density treatment of postmenopausal osteoporosis Pharmacokinetics : well absorbed from GI tract metabolized in the liver excreted in feces cross placenta enters breastmilk Contraindications and Cautions allergy to raloxifene pregnancy and lactation history of venous thrombosis or smoking Adverse Effects: GI upset nausea & vomiting

headache dizziness visual & mental changes hot flashes skin rash edema vaginal bleeding venous thromboembolism b. toremifene (Fareston) - used as an antineoplastic agent because of its effects on estrogen receptor sites Drug-Drug Interactions raloxifene + cholestyramine = absorption raloxifene diazepam (Valium) ibuprofen (Motrin) indomethacin (Indocin) naproxen (Naprosyn) warfarin + raloxifene = may prothrombin time (PT) interfere with binding sites (highly protein-bound drugs)

3. PROGESTINS - used as contraceptives - most effectively in combination with estrogens - treat amenorrhea and functional uterine bleeding - some are useful for treating specific cancers a. Levonorgestrel - once available as an implant system to prevent pregnancy (Norplant System)

- but now available as uterine insert (Mirena) - used also as morning after pill (Preven, Plan B) b. Medroxyprogesterone (Provera) - for treatment of amenorrhea and by injection for cancer palliation therapy c. Norethindrone (Augestin) - prototype - treatment of amenorrhea d. Norgesterol (Ovrette) - an oral contraceptive e. Progesterone (Progestasert and others) - treatment of amenorrhea, for contraception and in fertility programs Therapeutic Actions and Indications - transform the proliferative endometrium into secretory endometrium - inhibit the secretion of FSH and LH - prevent follicle maturation and ovulation - inhibit uterine contractions - thought that circulating progestins and estrogens trick the hypothalamus and pituitary and prevent the release of gonadotropin-releasing hormone (GnRH), FSH, and LH thus preventing follicle development and ovulation Pharmacokinetics - well-absorbed through GI tract - undergo hepatic metabolism - excreted in urine - cross placenta - enters breastmilk Contraindications and Cautions - allergies to progestins

breastfeding

idiopathic vaginal bleeding breast cancer or genital cancer history of thromboembolic disorders hepatic dysfunction pelvic inflammatory disease (PID) sexually transmitted disease endometriosis or pelvic surgery renal dysfunction

pregnancy epilesy migraine headaches asthma cardiac

Adverse Effects - thromboembolic disorders - abortion - blood pressure - PID - weight gain - bleeding - endometriosis - spotting - local skin irritation - headache - constipation - fluid retention - breast enlargement - thrombophlebitis - perineal pain - changes in mense - abdominal pain Drug-Drug Interactions Progestins + barbiturates, carbamazepine, phenytoin or refampin = effect of progestins

4. FERTILITY DRUGS - act to stimulate follicle development and ovulation in functioning ovaries - combined with human chorionic gonadotropin (HCG) to maintain the follicle once ovulation has occurred a. Cetrorelix(Cetrotide) - inhibits LH surges in woman undergoing controlled ovarian stimulation by acting as a GnRH antagonist

b. Chorionic gonadotropin (Chorex, Profasi, Pregnyl) - used to stimulate ovulation by acting GNRH and affecting FSH and LH release. c. Chorionic goandotropin alpha (Ovidrel) - stimulates final follicular development and ovulation in infertile women d. Clomiphene (Clomid and others) - prototype - used for treatment of male infertility e. Follitropin alfa (Gonal-F) and Follitropin beta (Follistim) - are FSH molecules produces by recombinant DNA technology - stimulate follicular development in infertility and for harvesting of ova for in vitro fertilization f. Ganirelix (Antagon) - inhibits premature LH surges in women undergoing controlled ovarian hyperstimulation g. Menotropins (Pergonal, Humegon) - is a purified gonadotropin - used to stimulate spermatogenesis h. Urofollitropin (Fertinex) - derived form the urine of postmenopausal women i. Urofollitropin purified (Bravelle) - induce ovulation in women with pituitary suppression and to stimulate multiple follicle development in ovulatory patients

Therapeutic Actions and Indications - works either directly or by stimulating the hypothalamus to FSH and LH levels,leading to ovarian follicular development and maturation of ova - used to treat infertility in women Pharmacokinetics - well-absorbed - undergo hepatic metabolism

excreted renally

Contraindications and Cautions - presence of primary ovarian failure - thyroid or adrenal dysfunction - ovarian cysts - preganacy - idiopathic uterine bleeding - breastfeeding - thromboembolic diseases - women with respiratory diseases Adverse Effects - risk for multiple births - birth defects - ovarian overstimulation (abd. pain,distention,ascites,pleural effusion) headache fluid retention nausea bloating uterine bleeding

- ovarian enlargement gynecomastia febrile reactions

5. OXYTOCICS - stimulate contraction of the uterus a. ergonovine (Ergotrate) - used to prevent and treat postpartum and postabortion uterine atony b. methylergonovine (Methegine)

promote uterine involution

c. oxytocin (Pitocin, Syntocinon) induce labor and to promote uterine contractions after labor stimulate milk let down

Therapeutic Actions and Indications - directly affect neuroreceptor sites to stimulate contraction of the uterus - stimulates lacteal glands in the breast to contract - promoting milk ejection in lactating women - indicated for the prevention and treatment of uterine atony after delivery Pharmacokinetics - rapidly absorbed - metabolized in the liver - excreted in urine and feces - cross placenta - enters breastmilk - used in lactation Adverse Effects - excessive effects (uterine hypertonicity and spasm, uterine rapture, postpartum hemorrhage, FHR) GI upset nausea headache dizziness

ergotism ( nausea, blood pressure changes, weak pulse, dyspnea, chest pain, numbness and coldness in extremities, confusion, excitement, delirium, convulsions and even coma) severe water intoxication with coma maternal death

6. ABORTIFACIENTS - used to evacuate the uterus by stimulating intense uterine contractions a. Carboprost - terminate early pregnancy, evacuate a missed abortion or control postpartum hemorrhage b. Dinoprostone - a prostaglandin that stimulates uterine contractions - used to stimulate cervical ripening before labor c. Mifepristone - acts as an antagonist of progesterone sites in the endometrium - allowing local prostaglandins to stimulate uterine contractions and dislodge - prevent the implantation of any fertilized egg Therapeutic Actions and Indications - stimulate uterine activity, dislodging any impimplanted trophoblast and preventing implantation of any fertilized egg - approved for use to terminate pregnancy 12 to 20 weeks from the date of the last menstrual period Pharmacokinetics - well-absorbed - metabolized in the liver - excreted in urine Contraindications and Cautions - allergy to abortifacients or prostaglandins

- after 20 weeks from the last menstrual period - PID - cardiovascular hepatic, renal, or pulmonary disease - history of asthma, HPN, or adrenal disease - acute vaginitis - scarred uterus Adverse Effects - abd. cramping - heavy uterine bleeding - perforated uterus - uterine rapture - headache 6. - nausea and vomiting - diarrhea - diaphoresis - backache - rash

TOCOLYTICS - used to relax the uterine smooth muscle - prevent contractions leading to premature labor and delivery

a. ritodrine (Yutopar) - only one tocolytic agent in the US but b. terbutaline

withdrawn because of its serious adverse effects

- a beta2-selective adrenergic agonist - calms uterine contractions