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Hypo-pit.-gonads
Drugs
| Question | Answer |
|---|---|
| Gonadorelin. | GnRH agonist. mimics effects of GnRH |
| Leuprolide | GnRH agonist. Used to induce chemical castration (for treatment of breast cancer, prostate cancer, endometriosis) Inhibits effects of GnRH |
| Goserelin | GnRH agonist. Used to induce chemical castration (for treatment of breast cancer, prostate cancer, endometriosis) Inhibits effects of GnRH |
| Abarelix | GnRH antagonist. Specifically inhibits axis for treatment of endometriosis, breat cancer, prostate cancer. |
| Estradiol, progesterone, testosterone (function) | secondary sexual characerisitcs and for gametogensis |
| Ethinyl estradiol | natural estrogen. Used in contraceptive pill. Hormone replacement therapy. |
| Estrone sulfate | synthetic estrogen. Contraceptive pill. Hormone replacement therapy. |
| Clomiphene | Antiestrogen. for assisted fertility |
| Tamoxifen | Antiestrogen. For treatment of breast cancer. |
| Aminoglutethimide | Aromatase inhibitior. Second line treatment of Breat cancer after Tamoxifen therapy. |
| Anastrozole | New aramatase inhibitor. Far more potent and specific |
| Mifepristone | RU 486. Progestin receptor antagonist. Terminates pregnancy |
| Norgestrel | Progestin agonist. Used alone or combined with estrogens for contraceptive pills. Used together with estrogens for hormone replacement. |
| Medroxyprogesterone acetate | Progestin agonist. Used alone or combined with estrogens for contraceptive pills. Used together with estrogens for hormone replacement. |
| Norethindrone | Progestin agonist. Used alone or combined with estrogens for contraceptive pills. Used together with estrogens for hormone replacement. |
| Testosterone (transdermal patch) | Treats hypogonadism, delayed puberty |
| Testosterone enanthate | Treats hypogonadism, delayed puberty |
| flutamide | androgen receptor antagonist. Used with GnRH analogs to treat prostate cancer. |
| Ketoconazole | Blocks testicular production of testosterone. Treats prostatic hyperplasia |
| Finasteride | Inhibits conversion of testosterone to more active 5-a-dihydroxy metabolite. Treats prostatic hyperplasia. |
| Raloxifene | SERM. prevents osteoporosis. Improves lipoprotein profiles in postmenopausal women. |
| Natural estrogens | estradiol, estrone, estriol |
| synthetic steroidal estrogens | estradiol esters, conjugated estrogens, alkyl estrogens |
| Estradiol esters | Estradiol valerate, estradiol cypionate |
| Conjugated estrogens | estrone sulfate, equilin sulfate |
| Synthesis inhibitors | aminoflutethimide, anastrozole |
| Selective Estrogen Receptor Modulators | Raloxifene |
| Natural Progestins | progesterone |
| Synthetic Progestins (C21) | Medroxyprogesterone acetate |
| Synthetic Progestins (C19) | Norethindrone |
| Gonanes (progestrins) | Norgestrel, Norgestimate, desorgestrel |
| Antiprogestins | Mifepristone |
| Synthetic Androgens | unmodified 17B-esters, modified 17B-esters, 17a-alkyl compounds |
| Natural Androgens | Testosterone, 5-a-dihydrotestosterone |
| unmodified 17B esters(synthetic andro.) | testosterone enanthate |
| 17a-alkyl compounds (synthetic andro.) | Danazol |
| Antiandrogens | receptor antagonists, synthesis inhibitors, 5a reductase inhibitor |
| receptor antagonists (antiandro.) | Cyproterone acetate, flutamide |
| Synthesis inhibitor | ketocanazole, spironolactone |
| 5a-reductase inhibitor | finasteride |
| GnRH (molecule) | 10 amino acid peptide form 92 amino acid precursor |
| GnRH pulses | one per hour |
| GnRH release control | anterior mediobasal hypothalamus |
| GnRH synthetic analogs | substitute hydophobic D-amino acid for glycine at position 6 and replace glycine-amide with N-ethylamide at position 10. Slower clearance, increased potency (increased affinity for GnRH receptors, greater binding to plasma proteins, reduced poteolytic cl |
| Leuprolide | GnRH AGONIST. Suppressrs gonadotorpin secretion, sc once daily, im (monthly) |
| Abarelix | GnRH antagonist. Supresses gonadotropin secretion. Chemical castration |
| Advantages of GnRH antagonists over agonists are: | 1. Rapid suppression of gonadotropin secretion & sex hormone level, avoidace of flare up, no need for concurrent treatment with steroid receptor antagonists |
| Bromocriptine | dopamine agonist. Treats hyperprolactimemia and resulting infertility |
| Menotropins | Human menopausal gonadotropins. Obtained from urine of postmenopausal women. Contains FSH and LH in equal amounts |
| Urofollitropin (uFSH) | Menotropin cleared of LH, mostly FSH |
| HumanChorionic Gonadotropin (hCG) | From urine of pregnant women. LH like activity. T1/2 of hCG is 8-23 hrs while T1/2 of LH is only 1-4hrs. (longer half life: presence of O-linked sugars on carboxy terminal extension of hCG) |
| Menotropin use (concerns) | Ovarian overstimulation, higher incidence fo multiple births, slightly increased incidence of spontaneous abortions |
| Menotropin uses | for female infertility, to stimulate spermatogenisis (first hCG, then hMG treatment), cryptochordism) |
| Treatment of Chryptochordism | hCG injections (IM) in one to four yr old boys. May require surgery when hormone therapy stopped. hCG may cause precocious puberty |
| Synthetic Steroidal Estrogens | Estradiol esters, conjugated estrogens, alkyl estrogens |
| Estradiol Esters (syn steroidal estrogens) | Estradiol Valerate, estradiol cypionate. Intramuscular injectio. C17 short chain fatty acid. not orally active |
| Conjugated estrogens (syn steriodal estrogens) | estrone sulfate and equilin sulfate. Active orally, parentarally, topically. Oral route is for replacement therapy. The IV route for emergency treatment of dysfunctional uterine bleeding |
| Alkyl Estrogens (syn steroidal estrogens) | Most potent because bypasses 1st pass metabolism (alkyl substition at c17) ex: Mestranol, ethinyl estradiol. |
| Prodrug to Ethinyl estradiol (alkyl estrogen) | Mestranol (removal of C3 methyl group). Both mestranol and ethinyl estradiol used as oral contraceptives. |
| Syn. Non-steroidal Estrogens | Not widely used in therapy. Examples include pestisides (DDT) and Deithylstilbestrol (orally active for endocrine therapy) |
| Therapeutic uses of estrogens | Replacement therapy (postmenopause, hypogonadotropic females, dysfunctional uterine bleeding), inhibiting postpartum lactation, treatment of prostatic carcinoma, last line treatment for breast cancer |
| Side effects of estrogen replacement therapy | endometrial carcinoma (unopposed), 26% increased risk of breast cancer (>5yr use), heart attacks (29%), strokes (41%), leg blood clots (100%), 34% fewer hip fractures, reduced colorectal cancer (37%), gall bladder disease, cholestatic jaundice |
| Strong Contraindications of estrogen replacement | people with breast, endometrial cancer; endometriosis; undiagnosed vaginal bleeding. |
| Relative Contraindications of Hormone replacement | People with hypercalcemia, pregnancy, thromoboembolic disease, hypertension, hepatic disease. Family history of breast/uterine cancer |
| Clomiphene citrate | Antiestrogene activity in trans isomer. Racemic mixture. Long T1/2(5-7 days) because of plasma protein binding, hepatic recycling, accumulation in fatty tissue. Inhibits feedback inhibition by estrogen receptor in pit. Less active in periphery |
| Tamoxifen Citrate | antiestrogen in trans isomer. Long T1/2 (4-11). Blocks estrogen dep. proliferation of breast cancer cells |
| Aminoglutethimide | Aromatase inhibitor, blocks estrogen synthesis. Inhibits conversion of cholesterol to pregnenolone, interferes with adrenal steroids, including androgenic precursors of estrogen in periphery. |
| What drug is given with aminoglutethimide to maintain adrenocortical function | Hydrocortisone |
| Anastrozole | more potent, specific aromatase inhibitor |
| Letrozole | more potent, specific aromatase inhibitor |
| Exemestane | more potent, specific aromatase inhibitor |
| Side effects of Clomiphene treatment | Teratogen, menopause-like symptoms (hot flashes, vaginal dryness, blurred vision), ovarian overstimulation, ovarian cysts. |
| Side effects of Tamoxifen treatment | (antagonist to inhibit proliferation of breast cancer cells, agonist like activity on bone density and lipoprotein profiles) Menopause, vaginal bleeding, menstrual irregularities, skin rashes, increased risk of endo. cancer. |
| Beneficial effects of Tamoxifen | Slowing of osteoporosis, lowering of cholesterol and LDL levels |
| Selective estrogen Receptor modulators | raloxifene |
| Raloxifene actions on breast and uterus | full antagonist rather than partial agonist |
| Raloxifene pharmacology | Tissue specificity may have something to do with ERa and ERB. Raloxifene is a benzothiophene. Well absorbed orally. Not potent. Extensive first pass metabolism (glucoronide conjugation, enterohepatic recycling). Fecal excretion |
| Therapeutic uses of SERMS | HRT in postmenopausal women. Safely prevents postmenopausal osteoporosis and heart disease without increasing risk for breast cancer and uterine cancer, without inconvenience of withdrawal bleeding. Doesn't reduce hot flashes |
| Cholesterol side chain cleavage enzyme complex, 3Beta-hydroxysteroid dehydrogenase | Progesterone synthesized in all steriodogenic tissues (ovary, testis , adrenal cortex, placenta) from cholesterol by sequential action of these enzymes |
| Medroxyprogesterone acetate | C21 derived progestin. Methyl subsitution at C6, which reduces first pass hepatic met. Can be taken orally and via IM injection. |
| Synthetic C19-Derived Progestins | More androgenic activity than C 21. Included in this class are norethindorone, and Gonanes (norgesterl, norgestimate, desogesterl) Commonly included in oral contracepive formulations |
| Therapuetic uses of Progestins | Birth control in Oral Contraceptives, Replacement Therapy, Suppression of Estrogen Function, treatment of endometriosis, treatment of estrogen-dependent cancers |
| Progesterone Replacement therapy side effects | Weight gain, acne, hirsutism, libido changes, adverse lipoprotein profiles, menstrual irregularities, glucose tolerance, fluid retention, mood lability, depression, nausea, vomiting, breast discomfort, migraine headaches |
| Strong Contraindications of Progesterone therapy | People with hepatic disease, dysfunction, incomplete abortion, suspected pregnancy, undiagnosed vaginal bleeding |
| Relative Contraindicatoins of Progesterone therapy | Hyperlipidemia, thromboembolic disease (smokers). Caution in patietns with heart disease due to fluid retention |
| Progesterone Receptor antagonist | Mifepristone (RU 486). |
| Mifepristone | Competitive Progesterone receptor antagonist. derived from 19-nor compund, norethindrone. Terminates pregnancy. |
| Mifepristone Mechanism of action in pregnancy termination | Decidual breakdown, blastocyst detachment. Blastocyst detachment leads to decreased Cg production and decreased progesterone synthesis, further decidual breakdown. Decrease in progesterone increases prostaglandin secretion. |
| What is give 48-72 hrs after mifepristone to increase contractions | Misoprostol |
| Oral Contraception | Combination preparation ( Fixed formulation, multiphasic) |
| Combination preparation | Block ovulation. Both steroids can decrease GnRH release from hypothalamus. Decreases gonadotope repsonsiveness to GnRH. Estrogens decrease FSH secretion from gonadotropes. |
| Fixed forumulation of Oral contraception | Same amt. of estrogen and progestin provided in each of 21 pills that are taken daily. Either no pills or 7 blank pills taken. |
| Multiphasic preparation | Bi- and Triphasic. Contain two or three different pills with varying doses of estrogen and progestins. Taken at different times over 21 day cycle. Lowers total amt of hormone administered, provide ratios of E and P that more closely match menst. cycle |
| Multiphasic preparation components | estrogen (ethynyl estradiol, mestranol) at 20-5 ug/day. dose of progestin more variable, less than 1 mg/day |
| Oral contraceptive side effects | cardiovascular effects, cancer, metabolic and miscellaneous. Beneficial include reduced risk of endometrial and ovarian cancer. |
| Progestrin-Only Preperations | "Minipill" low doses of oral progestins daily. Subdermal implants (norgestrel) slow release and long term use. Other options: MPA im injeciton, intrauterine device that releases progesterone locally |
| Progesterone only mechanism of action | Decreases GnRH pulse frequency and blunts LH surge. Thickens cervical mucus, dev. of endometrium that doesnt support implantation |
| Progesterone-only side effects | Break through beeding, edema, weight gain, depression, headache, potential change in lipoprotein profiles |
| Post-Coital | Early regimens: High concentration of estrogens taken with 72 hrs. Includes the Yuzpe regimen and the Plan B regimen. Efficacy greatest when taken within 24 hrs. |
| Yuzpe regimen | Post-coital. lower dose of ethinyl estradiol combined with progestin, levonorgestrel. Taken twice, 12 h apart. |
| Plan B regimen | only a high dose of levonorgestrel. Taken twice, 12 h apart. lower incidence, severity of side effects |
| Contraindications of Oral contraceptive use | thromboembolic disease, cerebrovascular disease,MI, coronary a. disease, hyperlipidemia, breast/reproductive tract carcinoma, other hormone dep. neoplasias,undiagnosed vaginal bleeding, pregancy, liver tumors/impaired liver functions,smoking (35 yrs old) |
| Action of 5-a-reductase on Testosterone | Production of 5-a-dihydrotestosterone |
| 10 fold higher affintiy for androgen receptor | Dihydrotestosterone |
| Action of 17B-hydroxysteriod dehydrogenase on androstenedione | Production of testosterone |
| Action 3B-hydroxysteriod dehydrogenase on androstendiol | Production of testosterone |
| Major physiological effects of androgens | Promote development of male reporductive organs and stimulation of development of secondary sexual characterisitcs and general growth |
| Does Testosterone have a long or short half life? | Short. metabolized in liver |
| Natural Androgens | Testosterone. Not orally active. Transdermal Patch |
| 17 B- Testosterone Esters | unmodified and modified. length, hydrophobicity of ester group determines rate of release. |
| Unmodified testosterone esters | Testosterone enanthate |
| Modified testosterone esters | orally available, limited potency |
| 17 a-Testosterone alkyls | Greatly reduced hepatic metabilsm. Orally available. hepatotoxicity with long term use. Short term use in patients with serious illness or with hereditary agnioneurotic edema. |
| Danazol | 17-a-testosterone. Treats angioneurotic edema. Used together with GnRH to treat endometriosis |
| Mechanism of Action of Testosterone | Genomic, acts as a transcription factor |
| Binding proteins | SHBG in plasma, albumin, CBG, and ABP in semineferous tubules. ABP identical to SHBG |
| Therapeutic Uses of Androgens | Androgen Replacement Therapy, treatment of short stature |
| Hereditary Angioneurotic Edema | Autosomaul dominant disorder. Decreased acitvity or loss of inhibitor of first component of complement. Unopposed activation of complement cascade, enhanced vascular permeability. Angioedema. |
| Treatment of hereditary angioneurotic edema | 17 a-alkylated androgens increases activity of inhibitor and restores secondarily depleted plasma levels. Week androgens,like danazol work too. indep. of androgenic activity |
| Treatment for Endometriosis | Danazol inhibits hypothalamo-pituatary funtion, decreases ovarian function and estro production |
| Other uses of Androgens | for anemia, breast cancer (2nd, 3rd line therapy), positive nitrogen balance in catabolic states (reduces excretion of Na, Cl, K, nitrogen), athletic performance |
| Side effects of Androgen therapy (women) | Virilizing effects (acne, hirsutism, voice changes, male pattern baldness, increased body hair, clitoral enlargement...may be irreversible. |
| Side effects of Androgen therapy (children) | growth disturbances, premature closure of epiphysial plates |
| Side effects of Androgen therapy (men) | decreased gonadotropin release, inhibition of spermatogensis. Gynecomastia |
| Toxic effects of Androgen Therapy | Edema, liver disease. 17 a-alkyl substitutions can cause cholestatic hepatitis, jaundice. Long term treatment with alkyl androgens may cause hepatic carcnoma. Rarely, peliosis hepatitis. |
| Antiandrogens | receptor antagonists that intefere with synthesis of testosterone or dihydrotestosterone. (most effective inhibition of testosterone uses GnRH analogs. |
| Flutamide | Orally active, non steroidal component. Increases LH secretion and secondary elevations in testosterone levels, secondary elevations in testosterone levels. Given with GnRH analogs when used to treat metastatic prostate carcinoma and benign hyperplasia. |
| What is used to treat hyperandrogenism in women | Flutamide |
| Cyproterone acetate | Orally active anrogen receptor antagonist. Treats precocious puberty, acne, male pattern baldness, inhibits libido in sexual deviants. Potent progestational activity |
| Inhibitors of androgen synthesis and 5-a-reductase | ketocanazole, spironolactone, finasteride |
| Ketoconazole | synthetic imidazole, oral, antifungal agent. Used to treat prostate cancer. inhibits C7,20 Lyase activity. |
| Spironolactone | Aldosterone antagonist. Also androgen antagonist and cytochrome P450. lower test. levels. Treatment for Hirsutism, flutamide better though. |
| Finasteride | 5-a-reductase inhibitor. blocks androgen actions in target tissues that rely on conversion of test. to DHT. Reduces prostate size, treats benign prostatic hyperplasia. |
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