pharm_repro_ms2.txt

• ESTRADIOL
• CONJUGATED ESTROGENS
• ETHINYL ESTRADIOL
• DIETHYLSTILBESTROL (DES)

Natural steroidal estrogen

ALL estrogens interact w/ intracellular receptors to alter gene tsc & thus protein synth

Composed of phytoestrogen

Contains same 3 major & 6 minor estrogens as Premarin

Synthetic steroidal estrogens

Ethinyl group added to 17 position of steroid ring →rev 1st pass metab → incr:

• --bioavailability
• --potency
• --t1/2

Synthetic non-steroidal estrogen

• teratogenic (1st trimester)
• --♀ fetus: clear cell adenocarc of vagina in late teens-20s
• --♂ fetus: undesc testes, epidydymal cysts &
• azoospermia

Nl sexual maturation of ♀

Dev of 2o sex char

Distrb fat to hips & breasts

Accel growth phase & epiphyseal closure at puberty

Maintenance of nL struct of skin, mucosa & blood vessels

• Stim hepatic synth of:
• --TBG, SHBG, transcortin, transferrin, renin substrate & fibrinogen →
• --incr circ levels (thyroxine, estrogen, testosterone, Fe, Cu, etc.) but free conc ≤
• nL

Stim synth clotting factors 2, 7, 9, 10 → incr likelihood of thromboembolic disease

• Antag PTH → decr rate of bone resorption by osteoclasts
• --reason for postmenopausal bone loss

Incr HDL & TG

Decr LDL & total chol

Facilitate mov of fluid from plasma to ECF → edema (Kidney has compensatory salt/H2O retention)

Pharmacokinetics (of estrogens):

1. Enterohepatic recirc → greater effect on liver than periphery

2. Apply drugs topically (cream) for periph action to minimize hepatic effects

Primary hypogonadism

• Post-menopausal HRT
• --> dec LDL & ­HDL & TGs
• --> “Perfect” HRT:
• ----Agonistic (+) at bone, skin & mucous membranes, CNS & plasma lipid profile.
• ----Antagonistic or no effect at breast, uterus & liver

• Contraception (***combo w/ progestin to prevent endometrial hyperplasia caused by
• estrogen)

“Morning after” contraception

Dysmenorrhea

Dysfunctional uterine bleeding

OCP’s decr Sx of benign breast dz

• Hirsuitism
• --Combo w/ finasteride, flutamide & spironolactone may prevent
• --Eflornithine applied topically → irrev inhb ornithine decarboxylase → prevent hair growth

1. n/v

2. Diarrhea

3. Breast tenderness

• 4. Endometrial hyperplasia
• (post-meno dec via co-admin progestin)

5. Salt & H2O retention

6. HTN

7. Gallbladder disease

8. Chol jaundice (very rare)

9. Thromboembolic disease

10. Post-meno bleeding

11. Headache

• 12. Hyperpigmentation
• (Chloasma or melasma)

• DES:
• teratogenic (1st trimester)
• --♀ fetus: clear cell adenocarc of vagina in late teens-20s
• --♂ fetus: undesc testes, epididymal cysts &
• azoospermia

• Relative:
• 1. Fam hx of breast or uterine malign
• 2. Severe varicose veins
• 3. Hx of hepatic dz
• 4. HTN

• Absolute:
• 1. Estgn-dep breast or uterine cancer
• 2. UnDx abnl genital bleeding
• 3. Hx of severe thromboembo dz
• 4. Acute hepatic dz

CLOMIPHENE

TAMOXIFEN

RALOXIFEN

• Acts as estrogen agonist (+) in some tissues
• & estrogen antagonist (-) in other tissues

SERM

Orally active non-steroidal

• 1. BLOCKS estgn rec in hypothal → interrupts nl feedback inhb of GnRH &
• gonadotropin secretn

2. Incr GnRH secrtn → incr FSH & LH

• 3. Incr FSH & LH → gametogenesis & estgn
• --------------------------

Induce ovulation in ♀ w/ amenorrhea or anovulatory cycles

(-) CNS (nl sleep & temp regltn)

(+) liver: protein synth

SERM

Orally active non-steroid comptv estgn receptor antag (-) w/ partial agon (+) in some pts

1. Estgn receptor antag (-) in BREAST

• 2. Agonist (+) in liver & uterus*** → S/E
• --DVT or PE in high risk pts
• --Prolonged tx: endometrial hyperplasia → endometrial cancer

• Pre-meno ♀: Tamox antag (-)
• estgn receptors in hypothal & pit
• → incr GnRH → incr LH → incr estgn → (-) tamox effects.
• ----Prev the incr estgn w/ GnRH analog

Post-meno ♀: Same as pre-meno but ovaries quit making estgn → doesn’t matter

-----------------------------------------------

• (-) breast
• (-) CNS (nl sleep & temp regltn)
• (-) skin/mucous membr

• (+) bone density
• (+) plasma lipids
• (+) liver: protein synth
• (+) uterus: hyperplasia***

SERM

Estrogen receptor AGONIST (+) on:

• 1. Bone: decr bone resorption by osteoclasts
• 2. Plasma lipid profile
• 3. Hepatic protein syn

• ANTAGONIST (-) on:
• 1. Uterus***
• 2. Breast
• -------------------------------------

• (-) breast
• (-) CNS (nl sleep & temp reg)
• (-) skin/mucous membr
• (-) uterus: hyperplasia***

• (+) bone density
• (+) plasma lipids
• (+) liver: protein synth

SERM

Want to be pregnant!!!!

Induce ovulation in ♀ w/ amenorrhea or anovulatory

• Poss:
• 1. Multiple births
• 2. Stillbirths
• 3. Ovarian enlargement
• ------------------------------------

ADVERSE

• 1. Ovarian enlargement
• 2. Temp scintillating scotomata
• (blurred spots or flashes)
• 3. Sx of menopause (hot flashes, etc.)

• Contraindicated in pts w/ thromboembo
• d/o b/c acts as an estrogen receptor (+) in liver → incr clot factor synth

SERM

1. Tx E(+) breast cancer

2. Breast cancer prophylaxis in high risk ♀

• 3. Post-meno ♀: same (+) agonistic
• (good) effect on bone density & lipids as estrogen
• ----------------------------------

ADVERSE

• 1. n/v
• 2. Hot flashes
• 3. Less freq vag bleeding & menstrual irreg
• 4. Comp prevents metab of warfarin → incr PT

1. Decr size of uterine leiomyomas in post-meno ♀

2. Maint post-meno bone density

3. Decr incid of vertb fractures by 30-40% (but effctv < HRT w/ conjugated estrogens)

4. Decr breast cancer in high risk ♀

• 5. Decr Tc & LDL. No incr HDL
• (like HRT w/ estgn)
• ------------------------------------

• ADVERSE
• 1. Hot flashes
• 2. Flu-like sx
• 3. Arthralgia
• 4. Thromboembo (inc hep clot factor synth)
• 5. p.o. → prev bene of topical estradiol in post-meno ♀ w/ atropic vaginitis
• (dec estrogen → vaginal itching & dryness)

ANASTROZOLE

LETROZOLE

(Block synth of ALL estrogen in body)

Prevents conversion of androgens to estrogens

• LH → thecal cells make Androstenedione (ASDN) →
• granulosa cells take up ASDN → testn → [aromatase (fat cells)] → estradiol

• Aromatase (CYP450 enz) converts andgns → estgns (testn → estradiol & DHEA → estrone)
• --------------------

• ANASTROZOLE
• LETROZOLE

Tx breast cancer in post-meno ♀:

• 1. Estro receptor (+) cancer
• 2. Advanced or metastatic breast cancer
• 3. NOT responded to tamoxifen
• 4. Been on tamoxifen for 5 years
• ----------------------------

ADVERSE:

• 1. MENOPAUSAL Sx
• 2. MSK PROBS

PROGESTERONE

NORETHINDRONE

NORGESTIMATE

NORELGESTROMIN

DROSPIRENONE

MEDROXYPROGESTERONE

PROGESTIN

ANTI-MINERALOCORTICOID

ANTI-ANDROGENIC

PROGESTIN

FAMILY OF DERIVATIVES OF 19-MORTESTOSTERONE

SOME ANDROGENIC EFFECTS

LACK ANTI-MINERALOCORTICOID ACTIVITY

PROGESTINS

• Norelgestromin = 17-deacylated norgestimate
• = actv metabolite of norgestimate

• 1. Does NOT stim androgen receptors
• → NOT (-) antagonize estrogen effect on plasma HDL conc
• ---- NO stim of sebum prodn → good skin (No acne)

2. Combo w/ ethinyl estradiol (OCP) → 3x incr serum conc of SHBG → 50% decr in serum free testosterone conc

PROGESTINS

Spironolactone derivative

1. Stim (+) progesterone rec

2. Blocks (-) androgen & mineralocorticoid rec

3. Block mineralocorticoid rec → CV benefits ♥

PROGESTIN

I.M. DEPO PROVERA

COMPLETE AMENORRHEA --> CONTRACEPTION LASTING 3 MONTHS

Uses of OCPs

1. Contraception: combo w/ ethinyl estradiol

• 2. Acne
• --Estgn inhb hypothal & pit → decr LH → decr testn
• prodn by ovaries

--Incr hepatic synth of SHBG → decr free testn conc

--Decr free testn → decr sebum prodn in skin

• 3. HRT for post-meno (esp drospirenone***)
• --Constant estgn w/ cyclic or intermittent progestin
• --Const estgn & progestin
• --Ethinyl estradiol + drospirenone: Drospirenone has
• anti-androgenic and anti-mineralocorticoid effects

• NORETHINDRONE
• --LOW ANDROGENIC ACT --> INC SEVUM PROD --> ACNE
• --Tx w SPIRONOLACTONE

• MEDROXYPROGESTERONE
• --NO RISK OF THROMBOEMBOLIC Dz BUT UNPREDICTABLE MENSTRUAL BLEEDING

MIFEPROSTONE (RU-486)

ULIPRISTAL

PROGESTIN ANTAG

GLUCOCORTICOID REC ANTAG

OUTPATIENT ABORTION OF FETUS < 49 DAYS

• INTERRUPTS PREG
• --2 DAYS LATER GIVE SYNTH PG DINOPROSTONE --> CONTRACTS UTERINE SMOOTH MUSC
• ---------------------------------------

THERA

1. Prevent implantation of fertilized egg

2. Alleviate sx of endometriosis

3. Tx non-resectable meningiomas

4. Tx uterine leiomyomas

5. Tx Cushing’s syndrome (b/c also glucocorticoid receptor antag)

BISPHOSPHONATES

INH BONE REABS BY STIM OSTEOBLASTS

• BINDS TO REMODELING BONE SURFACES
• --> INH OSTEOCLASTS

• PREVENT POST-MENO BONE LOSS
• -------------------------------------

ADVERSE

• Esophagitis:
• --Pts should take drug w/ 8 oz of H2O & remain upright for 30 min.

• --If drink too much or lie down (before 1st
• meal of the day) → level of drug reaches LES → damage

Osteonecrosis of the jaw (mostly w/i.v.)