Exam #3 PDF

Hypo F GnRHantagonist SHormones antri...

Hypo F GnRHantagonist SHormones antri s t ↓ um - GnRH agonist He Anteriorj 11 + Clomiphene a Danazol epires , OH Estrogen d S Testosterone d S Progesterone · Of on C3-C17 and aromatic betone at 23 double bond O2 FSH 4 at 23 , ring OH at 217 Ketone No aromatic ring on (17 No aromatic ring CharmacologicalBiological Targets t a T Agents -- A Ketoconazole aromatization of steroid ring Aromatase : enzymatic - S Danazol ↓Aromats to converts androgens · estrogens , Inhibitor = Anastrozole Endogenous agonist Estradio/Estronel Anastrozole Estrogen Receptors - : I Estriol p involved in Female maturation bone density Estradiol * Estrone > Estriol - · , - pregnancy comiphene agonist I [Fuestra Partial : Agonist : ethinglestradis - Anrestrant SelectiveAgonist/Antagonist tagonist tamoxifen : : An Estrogen response Progesterone Receptors Endogenous Agonist progester one - : element & insulin , ventilatory response temperature , NATURAL ESTROGENS a Agonist:Woreindrowetnorgest Antagonist - - : mifepristone H - uni s ↳ cellular response to Estrogen OH · genomic effects will be dominant Estradial > - MB-estradiol; El nuclear receptor predominantly round in nucleus & · Type I isoforms ; BOTH round in tilnes but ratios vary major secretory estrogen of the ovary Two Estrogen receptor (ER) many , tract and mammary grands · ER-a : Female reproductive ↓ · ER-B : bone , vacular endothelial cells , probate isoforms ul equal affinity. Estudiol binds b and binds activation function - 2 domain (AF2 ligand) : OH conformational change + co-repressor (1sp) release ↳ · Estrone -> El - produced in the liver from estradio or androstenedione Ot UHz I H · Tissie specific effects distribution OH · ER/ERB isoform · co-repressors+ co-activators Estrial + E3 - produced in the liver from estradiol or androstenedione  Estrogen Receptor agonist & ESTROGEN ANALOGS HORMONAL CONTRACEPTIVES - ER Agonist MOA 3 SAR & AGONISTS B ANTAGONISTS ECTIVE/ PARTIAL * conjucated Estrogens (Premarin) MOA - ER Selective agonist/antagonist Esterified estrogens (Conestin Enjuvia Menest) · activate estrogen receptors ⑭ activity in reproductive (ER-a) · , , different actions in differenttissues Estradios (Estrace) activity in Druelvascular (ER-B) tissues (a bone density) · AGUNIST · at ERB in bone Estradid Transdermal (Estraderm) · *to conjugated Z estrogens : How release · => (Menest) ANTAGONICE breast (inhibitbreast as · · Estrone recirculation - at ERR in canvy In of · Estropipate (ogen) * Euny / derivatives : prevent oxidation amino ethyl ether is essential 3 to estrone All are indicated to prevent hydroxyl pregnancy Structure Activity Relationship a - - Primary mechanism is by entingorulation · additional effects that reduce - · of · the probability - · aromatic A ring + C3-OH are essential for activity implantation Distance blu (3-OH (17- Oh is important SERMS * Tamoxifen (Nolvadex)selective - + to cervical mucus Uterine changes (rs. Ketone) is · , CIT-OA important for ER activity · endometrium , uterine tubes Modulator - - some have additional indications parent t Tdays * Ethinyl estradiol = N-dealkylation (via CYP3A4) ; metabolite = active - #z(EE/drospirenone) · > 170-alkyl groups Increase stability t 12 14 days · = Indication > premenstrual dysphoric disorder reventsoxidation to estrone & - can proliferation of endometrial tissue = endometriosis · Estrostep (EE/noretwindrome) · cataraus tro-Cyclen (EE/norgestimate) H # Toremifene (Foreston) NOTE:Es · Ortho to ↳. 8 · Yaz + Yasmin (EEldrospirenone) Unlorine Chloro-ethyl substituent replaces ethy/ · Indication : Acne OH PL : metabolized via CYP3A4 ; + 2 Sdays · - = Hormonal contraceptives AES # Conjugated · estrogens · A diaphoresis : , not Flashes waused , too low W: dose-depend QT prolongation Estrogen prodrugs that require hydrolysis of 3 sulfate · charged sulfate ↑ water solubility(half-life (EHR) Breakthrough (early) bleeding light · · menses, requires hydrolysis in Gl by bacteria (DDI w antibiotics) Raloxifene (Evista) f SERM , vaginal dryness · selective ER Erogen too high · - long torm use = Osteoporosis Modulator · bloating breast lenderness housed weight gain, ↳ * Bazedoxifene(Duaree) , ~ , , Fibroid growth Progestin too low core similar to tamoxifen Rigid - b · through (late) bleeding heavy · break menses no reduces proliferation of endometrial tissue , , ~ · withdrawal bleeding Progestin too high T risk for estrogan dependent m cancer ER Partial Agonist * NOTE : Patagonism - un of the endogenous agonist libido , depression , low energy noncyclical weightgain bleeding ↓ uterine in post menopausal Is can be an untagonist in the Clomiphene · · ↑ , * presence of a full agonist ↑ · Androgenic - acre hirsalism , molestatic , jaundice, women increased libido ·↑ dose =↑ risk of endometrial cancer a that also acts as competitive Inhibitor necessestrogen - combining progestin ↓ risk of endogenous estrogen rich for gallbladder disease Little estrogen antagonist · = WA I inclotting Factors = I thromboembolic diseased Cyp inducers cand efficacy no estrogen-agonist block pituitary gonadotrope ER receptors # stimulates orulation · PK : tyz Sdays = ER Antagonist ⑳ blocks normal estrogenic activity compete for ER + have weak estrogenic activity * Fluvestrant · Effective in tamoxifen-resistant breastc ancer · inhibits dimerization of theoccupied estrogen receptor interferes w) its to DNA binding ↳ inhibits both AF2/AFI domains of transcription Factor Las agonistactivity PR t 40 days =  Spartici PROGESTERONE AGONISTS/ANALOGS Progesting PR Leronorgestrel (Norplant) · PR Partial Agonist Antagonist * panazol Mifepristone Medroxy Progester one acetate (Provers) * Emergency contraceptive Megestral acetate (Megace) · · uses endo metriosis Minical : use: steroid structure /D "Im LAR untagonist (Aygestin) : Love Noremindrone acetate SAR: · · 13-Ketone · contains required 4-ring steroid structure Progesterone (generic) true Kelone at C-3 position modifications including balky llBp-aniline · · lacks MOA weak MOA PR receptors partial PR agonist; androgen receptor Antagonist at produces-f inactive MOA activates , confirmation PR + suppress release of LH agonist of suppresses ApOaxis + LH/F2 Secretion; halts prevent binding endogenous progestions prevents follicle development+ orulation E2 synthesis · antagonist at GR (hypothalamus/pirnitary) -> affects CAR Cortisol level) Require 4-ting Scaffold ; A p3-ketone in AE : hirsutism, weight gain , ache hair loss , (androgenic * 11 In PK : long tip = 220 mrs A ring pregnancy metabolized by CYP3A4 remova of 21amethyl ↑ activity (19-mor) DD : ( myopathy) Warfarin (4PT) car baurazepine, statins DD1 : CYP3A4 substrates in hibitors/ inducers strong , · 17 d substituents increase oral - bioavailability , AE ↑ BR + Nat elimination via antagonist at MR stronger androgens may reduce plasma HDL or cause nirsutism AROMATASE INHIBITORS m IrreversibleInhibitors Reversible Inhibitors 3 * Exemestane (Aromasin] * Anastrozole (Arimidex) Pimetabolized via CP1Az 22819, 3A4 *bothpreventteeter , a Androstenedione analogs Dose : log PO QD ↑LetOZOe(Fema 25 Rose : my PO QD LAUSAY De : 2S. mg PO QD SAP Exome stane is structurally similar to and rostenedione Triazole aromstase - inhibitors require free N4 nitrogen for H-bonding ol enzyme · aromatic groups help mimic steroids to facilitate binding MOA Aromataseenzyme that converts androgens into estrogens Androstenedione -> estone testosterone - > estradiol Inhibitors prevent the Final step in biosynthesis to estrogens * used in postmenopausal tamoxifen-resistant breast cancer AE Edema nausea, dizziness sweating + not Fishes , , ↑ molesterol levels (monitor) ↑ rates of fractures myalgia Compareda to tamoxifen 4 long term use can result in osteoporosis ↓ risk of endometrial cancer+ tromboembolic events DDI Letrozole of CIPLAC (few PDI) strong Inhibitor Exemestane is extensively metabolized by CYP3A (inducers) Estrogen agonistantagonist compounds · ↳ eg : tamoxifen  E Important ANDROGENIC conditions Requiring MOLECULES Therapy Testosterone (9 carbons) 3-Sog produced daily in horm males deficiency MMeHormone , brain bone bone marrow low endogenous levels of testosterone (Cow -T) ↑ activity in muscle , , bound Goal Restore normal testosterone s DHT levels free ; remainder (98 %) protein. only 2 - · (SGBG + abumin) Drugs-AR agonist (testosterone analoys) SGBG synthesis * by Th estrogen ; by - GH +androgens Pharmacologic Agents Prostate Hypertrophy Benign of inner prostate tissue hyperplasia Sandrogenogs testosterone - Dihydrotestosterone Androgen Agonist : · Goal : reduce tissue growth to restore urinary of testosterone via Sa-reductase active metabolite methyltestosterone - · function min , hair follicles · activity in genitalis prorate Drugs + Sa reductase inhibitors Anabolic Agonist: Fluoxymesterone , , - OH Nandrolone ↳ Advanced ProstateCarcinoma - Oxandrolone u of superficial prostate cancerous growth Oxy metholone tissue AR Growin reduce androgens biosynthesis/effects 3 : 0 / Antagonist : Flutamide thalt tissue growth Nilmamide Non-steroidal Testosterone inhibitors Bicalutamide Drugs > - AR antagonist; specific betone at testosterone synthesis 23 Apalutamide OH at 217 Reversible Spironolactone 3 Steroidal ⑭ No aromatic ring : Sa reductuse : Finasteride ANDROGEN US. ANABOLIC ANDROGEN inhibitor Dutasteride Androgenic Activity - Inhibit L RECEPTOR Andogen Synthesis : abiraterone GnRH production develop/maintain end male characteristics Inhibitor · 2 AGONISTS GHRH receptor · Body hair; vocal lords thicken ; agonist Semprolide : ↑ subaceous secretions (aune) super aggressive/competitiveness play ; ORAL/Parentes Androgens Antagonist : ganivelix sexual behavior is interest roses maintain spermatogenesis * METhyltestosterone · 10-SOrg PO QD SAR steroid core structure is REQUIRED NOT required Md-methyl analogs ORAL/PARENTAL ANABOLICS Of at C3 + C17 are · · metabolism · small 17 d-alkyl groups prevent bioavailability further modifications ↑ selectivity for anabolic effects ↳ increased - - NOTE : 30 structure ofm e A-ring · Anabolic Activity > decrease protein - changes affect most the has Testosterone breakdown ;& growth-promoting effects * TESTOSTERONE cypionate 1 : / ratio Electrolyse/water retention - Kidney growth androgenic : anaholic * Fluory mesterone Administered IM SAR 02 in A ring anabolic activity - (17 esters 9a-fluoro increases activity (oxymestrone) Testosterone · · esters Formulations for IM - ↳ various lipophilic · 4-OH 20 x anabolic 10 x androgenic vs. 17d-metinyl administration ADS It pass metabolism ; slow hydrolysis Nanavolone 2-CHO (oxymetholone) (Oxandrolone) · releases testosterone and chain that can & lipophilicity · 2-oxa · has a long Fatty EXTENDS duration of action C9 & activity PO QP B-fluto group at 24 + · DOSE : S-LOmg · - 2. & TESTOSTER ONE ENANTHATE analogs ↑ anabolis - · Ratio : Es to lin I · 19- nor & - Administered IM anabolic activity 4x stronger anabolic