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47 Cards in this Set
- Front
- Back
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Concept
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Estrogenic Activity is commonly encountered and structurally nonspecific of all biological activities. Any molecule with 2 H-bond groups separated by 8.55 A on an inert structural skeleton may display estrogenic activity.
-Removal of 3 or 17 oxygen or epimerization to 17-a-hydroxyl decreases estrogenic activity |
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Estradiol (Estrace)
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-Metabolized extensively on 1st pass through liver
-1 hour half life in parenteral administration -Used primarily as supplement with estradiol esters (superior) |
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Estradiol Cypionate
(Depot Testadiol) |
-Lipophilic Ester
-Administered IM in veggie oil -DOA is 3-8 weeks -Depot form of estradiol |
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Concept
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Dissolution of lipophilic prodrug in oil for parenteral administration is common mechanism for depot formulations
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Polyestradil Phosphate (Estradurin)
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-Estradiol Phosphate Polymer
-Hydrolyzed in body to release estradiol -Depot form of estradiol -Used in prostatic carcinoma -DOA is 2-4 weeks |
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Estrone
(Theelin) |
-Replacement Therapy (Postmenopausal)
-Used in prostatic carcinoma -Mixture of natural estrogen(nonhuman) - used as Phase II sulfate conjugate |
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Conjugated Estrogens
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-Amnestrogen
-Menest -Premarin -Major 2 constituents: Estrone & Equilin -Much more effective orally than unconjugated estrogens -Taken up by enterohepatic circulation and hydrolyzed by liver |
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17-a-Ethinylestradiol
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-Formed when estrone + potassium acetylide in liquid ammonia
-17-a acetylene group protects 17 hydroxyl group from metabolism -Most potent orally active estrogen -Comprises estrogen component of oral contraceptive agents |
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Mestranol
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-Methyl group @ 3-position instead of H like in Ethinylestradiol
-Slightly less active than ethinylestradiol -Comprises estrogen component of oral contraceptive agents |
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Stilbene
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-Nonsteroidal Estrogens derived from Stilbene
-Contraindicated during pregnancy |
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Diethylstilbesterol
(Stilboestroform) |
-Nonsteroidal Estrogen derived from Stilbene
-Contraindicated during pregnancy -2-OH groups separated by same distance as in estradiol -Trans isomer more active -Orally effective -SE=Nausea/Vomiting |
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Dinestreol
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-Similar to Stilbenes
-Potent, topical estrogen -Tx of atrophic vaginitis and Kraurosis vulvae |
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Chlortrianisene
(Tace) |
-Similar to Stilbenes
-Lipophilic; Stored in adipose tissue -Long DOA -Cl (halogens) increases the lipophilicity |
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Clomiphene Citrate
(Clomid) |
-Allows pregnancy in 40-50% infertile women
-Taken for 5 days starting on the 5th day after menstruation -Commonly causes multiple births (twins) -Used in other countries as Tx for disseminated breast cancer |
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Tamoxifen Citrate
(Nolvadex) |
-1st selective estrogen receptor modulator (SERM)
-Estrogen receptors: In 15% of premeno women with breast cancer; In 67% of postmeno women with breast cancer -Effective therapy in breast tumors and reoccurance -2 metabolites form stronger binding to receptors: 1)4-hydroxytamoxifen: formed by hydroxylation by 2D6 2)Endoxifen: formed by N-demethylation by 3A4/3A5 then hydroxylation by 2D6 |
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Raloxifene HCl
(Evista) |
-Different ligand/receptor complex conformations
-Elicits agonist or antagonist activities in different tissues -Antagonist: Mammary and Uterus -Agonist: Cholesterol Metabolism and Bone -Differs from Tamoxifen in that Tamoxifen is an agonist in the uterus and Raloxifene is an antagonist -2nd generation selective receptor modulator -Used to prevent post-menopausal osteoporosis |
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Aminoglutethimide
(Cytadren) |
-Para amino derivative of glutethimide (hypnotic agent)
-Initially used as anticonvulsant; pulled from market -Inhibits several steps in steroidal biosynthesis: 1)conversion of cholesterol to pregnenolone (adrenocorticoid biosynthesis) 2)19-position OH which aromatizes androgens to form estrogens -1st Class of Aromatase Inhibitors |
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Aromatase Inhibitors
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-3 Generations
-Inhibit CYP450-19; inhibits aromatization of A ring which inhibits production of estrogen -Bind covalently/noncovalently -2 classes: Steroidal and Non-steroidal |
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Clinically Utilized Aromatase Inhibitors
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-Fadrozole (Afema)
-Anastrozole (Arimidex) -4-Hydroxyandrostenedione (Formestane, Lenatron) |
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Progesterone
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-Secreted by corpus luteum
-Secreted in high conc during pregnancy in placenta -Physiologic Properties: 1)Modifies uterine tissue to allow transport, implantation and development of fertilized ovum 2)Suppresses further ovulation during pregnancy 3)Decreases uterine motility during pregnancy 4)Proliferation of mammary tissue during pregnancy/luteal phase of menstrual cycle -Formed by oxidation of 3-position hydroxyl group of pregnenolone |
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Progestins Therapeutic Use
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1)Contraception-MAJOR use
2)Dysfunctional uterine bleeding and dysmenorrhea 3)Premenstrual tension 4)Endometriosis 5)Threatened and habitual abortion 6)Suppresses post-partum lactation 7)Endometrial carcinoma |
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Synthetic Progestins
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-Involve derivatives of:
1) 17-a-Hydroxyprogesterone 2) 19-Normethyl-5-a-Androstane |
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Norethynodrel
(Enovid) |
-Combo of Norethynodrel + Mestranol
-1st oral contraceptive used in US |
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Norethindrone
(Norlutin) |
-Isomer of Norethynodrel (Double bond on A ring)
-10x more potent -Greater incidence of androgenic side effects |
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Norgesterol
(Ovrette) |
-Increased progestational activity over Norethindrone (100x)
-Additional methyl group added to methyl group |
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Medroxyprogesterone Acetate
(Provera, DepoProvera) |
-2 Acetate groups added in place of acetylene and hydroxyl groups
-Used to Tx menstrual disorders, luteal infertility, and endometrial carcinoma |
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Testosterone
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-Derivative of 5-a-androstane
-Can be aromatized to estradiol; explains estrogen production in males and postmenopausal women -Reduced at 5-position to form Dihydrotestosterone |
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Dihydrotestosterone
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-Reduced form of Testosterone
-Binds to androgen receptors more tightly and forms more stable complexes -Responsible for many of testosterone's intracellular effects |
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Testosterone Propionate
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-Metabolically activated by hydrolysis to yield testosterone
-Ester derivative |
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Testosterone Enanthate
(Andro LA) |
-Metabolically activated by hydrolysis to yield testosterone
-Ester derivative -More lipophilic = Long Acting |
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Testosterone Cypionate
(Depo Testosterone) |
-Metabolically activated by hydrolysis to yield testosterone
-Ester derivative -More lipophilic = Long Acting |
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Methyltestosterone
(Metandren, Oreton Methyl) |
-17-a-Alkylation (addition of methyl group)
-Slows metabolism and allows oral administration |
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Estratest
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-Combo of Methyltestosterone + Esterified Estrogens
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Premarin w/ Methyltestosterone
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-Combo of Methyltestosterone + Equinine Estrogens
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Fluoxymesterone
(Halotestin, Ora-Testryl) |
-9-a-Fluorination increases activity of androgens
-11-position hydroxylation increases activity as well |
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Methandrostenlone
(Dianabol) |
-1,2 Double bond insertion
-Causes more planar A ring -Increases anabolic activity -Promotes growth in debilitated patients |
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Nandrolone Decanoate
(Deca-Durabolin) |
-19-methyl group removed
-Increases anabolic to androgenic ratio -Used as anabolic steroid every 3-4 weeks in dissolved oil |
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Danazol
(Chronogyn/Danocrine) |
-Addition of 5th ring to system
-Eliminates androgenic activity |
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Stanazol
(Winstrol) |
-Isostere of Danazol
-Addition of 5th ring to system -Eliminates androgenic activity |
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Ways to Improve Activity of Androgens
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1)17-a-alkylation (slows metabolism)
2)9-a-Fluorination/11-postion hydroxylation |
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Ways to Improve Anabolic Activity
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1)1,2 double bond insertion (more planar A ring)
2)Removal of 19-methyl group 3)2-position Oxygen substitution for CH2 (methylene) 4)Addition of 5th ring system |
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Oxymetholone
(Anadrol-50) |
-Derivative of 17-a-methyltestosterone
-3x anabolic activity -1/2 androgenic activity |
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Inhibitors of Androgen Biosynthesis
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-Gonadotropin-releasing hormone
-Leuprolide and Gonadorelin (agonists) -Ketoconazole (inhibits 17-a-hydroxylase which is required for steroidal biosynthesis) so it decreases androgen levels |
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Finasteride
(Proscar) |
-Inhibitor of Dihydrotestosterone Biosynthesis
-Competitive inhibitor of 5a-reductase -Contains lactam in A ring @ 3,4 postions (adjacent to 4,5 position that undergoes reduction to testosterone) -Inhibits 5a-reductase 2 more -Decreases dihydrotestosterone levels in prostate and plasma -Reduces BPH -Also marketed as Propecia to treat baldness |
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Flutamide
(Eulexin) |
-Androgenic Antagonist @ receptor site
-Forms 2-hydroxyflutamide metabolite (more active) -Can be hydrolyzed and N-methylated to form 4-nitro-3-fluoro-methylaniline during prostate cancer Tx-->methemoglobinemia, hemolytic anemia, cholestatic jaundice |
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Biclutamide
(Casodex) |
-Competitive antagonist @ androgen receptors
-Binds more to receptor than Nilutamide and 2-hydroxyflutamide -Used in prostate cancer Tx |
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Nilutamide
(Nilandron) |
-Hydantoin containing competivie antagonist @ androgen receptors
-Similar binding affinity as 2-hydroxyflutamide -Doesn't interact @ other steroidal receptor sites |
