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Home , Formestane, Mestranol, Nafoxidine, Norgestrel, Oxymesterone

MC: Gonadal & Inhibitors

Required reading W & G 12th Ed, page 819-864 Reference Foye's 7th Ed, Page 1346-1434

PHRM 614-P2

Shengquan Liu Ph. D 12-06-18, Th, AM, Rm 170 File name: EPA_181206aTh/12-03

1 MoA Review (14 Classes & 32 Drugs) Female: Ovary Male: Testis

Antagonist: ganirelix & “-relix” ↓ ovarian hyperstimulation : “-relix” ↓ PC Leuprolide ↓ FSH/LH  ↓ E/A

(-) E®  ↑ FSH/LH  (+) ↓ FSH/LH

(-) P450 & (-) E/A ®

(-) P450  ↓ [EPA]  ↓ PC

(-) P450 & E/A®

↓ BPH/alopecia

↓ E®+ BC 5-1: 5-3:

5-1: ↓ PC ↓ E®+ BC 5-3: (-) A/M®  ↓

2 Learning Objectives: Chemical Structures

1. & metabolism of 3 natural sex hormones (endogenous ligands, E, P & T) – Native hormones are orally inactive & short-lived

rapid metabolism  ↓ F/t1/2/DoA (-) metabolism  ↑ F/t1/2/DoA  new drug designs 2. Metabolism of major drugs & its relations to 1. Bioavailability, DoA & SAR 2. Prodrugs 3. Pharmacophore & SAR related to 1. MoA/site (tissues) of action, indication & SEs 2. Potency/selectivity ( & antagonists) 3. Oral activity & DoA 4. Recognize chemical structures of major drugs – structure ↔ name ↔ drug classification ↔ MoA ↔ indication/SE  drug selection & clinical decision 3 Gonadal Hormones & Inhibitors (32): Outline

1. Ovarian hormones (“female sex hormones”) 1. & ↑ or ↓ E action respectively 1. (E2), ethinyl estradiol & other estrogens (+) E® 2. Antiestrogens (±) or (-) E®; AIs (-) aromatase  ↓ [E] 1. SERMs () (±) E® (±) or (-) E®  ↓ E®+ BC 2. Pure antagonist: (-) E® 3. Aromatase inhibitors (AIs, ) (-) aromatase  ↓ [E]  ↓ E®+ BC 2. Progestins & antiprogestins ↑ or ↓ P action respectively 1. (“pregnancy ”), & its analogs (+) P® 2. Antiprogestins () (-) P®  abortion 2. Testis hormones (“male ”) – & ↑ or ↓ A action respectively 1. (T) & its analogs (+) A®  ↑ A action – 5a- (DHT, a more potent metabolite) 2. Antiandrogens ↓ A action – A® antagonists () (-) A®  ↓ PC – 5a-Reductase inhibitors (*)  ↓ [DHT]  ↓ BPH/hirsutism – Synthesis inhibitors () (-) CYP  ↓ [E, P or A] 4 Biosynthesis of Sex Hormones

Acetate   

What is MoA of: 1. Ketoconazole 2. Anastrozole 3. Finasteride

(DHEA) 5a-reductase DHT Hormonal Control of the Female Reproductive System

6 1. Natural Sex Hormones (Remember)

Steroids that are necessary for reproduction in females & males & affect the development of 2nd sex characteristics – Progesterone (P) precursor to testosterone, estrogens, cortisol & – Testosterone (T) Precursors of estrogens T  5a-Dihydrotestosterone (DHT, 10 X more active than T)

– Estradiol (E2) 7

1. Natural Ovarian (Female) Hormones

Structure 18 Cs 21 Cs 3-,17-di-OH (E2) 17-acetyl Aromatic A ring 3-keto/4-ene A ring Class Estrogens Progestins Released by Follicle in ovary Corpus luteum in ovary Functions 2nd sex characteristics For pregnancy Uses hypoGonad/HRT, OC, osteoporosis HRT/infertility/OC Effects on heart ↓ LDL, ↑ HDL/TG/Thrombosis* ↑ LDL/TG, ↓ HDL, Risk of BC or ↑ ↓ endometrial CA Higher concentration in females * Deep Vein Thrombosis (DVT). 8 1. Ovarian (Female) Hormones: Estrogens

Nature Reviews Endocrinology 7, 715-726 (December 2011) 9 3 Endogenous Estrogens: Ph, 3- & 17-di-O(H)

# of OH FG 1 2 3 Potency 1 10 (most potent) very weak In circulation (%) 60-80 10-20 10-20 In urine Conjugates Uses HRT HRT HRT (rare)

An extract of ovaries can produce estrus (1932) All are 18 Cs, 3-OH & 17-OH (or keto), phenolic A ring (for binding w/ E®) Uses: component in HRT Many phenols are estrogenic 10 1.1. Metabolism in  F-: Major Pathway

16a-hydroxylation & 17-OH oxidation in D ring – Minor pathway: 2-, or 4-hydroxylation  2- or 4-O-methylation (COMT) Metabolism mainly in liver & largely excreted as glucuronide & sulfate conjugates in urine or bile (enterohepatic circulation) SEs: ↑ clotting factor synthesis

To avoid these SEs, use vaginal, transdermal or injection form11 1.1. Steroidal Estrogens: Estradiol (3,17-OH) Uses: hypogonadism/HRT & contraceptives F-/PO+  formulations: – Micronized form (PO) for  ↑ absorption – I.M. injection st – Transdermal patch for menopause No 1 pass metabolism Less DVT risk – Vaginal cream/ring

Lipophilic  high protein binding High affinity for E®s  high potency parenterally, but Poor oral bioavailability (F ≈ 5%) due to: – 3-OH-conjugation in intestine & metabolic oxidation of 17-OH in liver  ↓ oral activity & elimination t1/2 20 min. Can we design longer-acting or more orally active drugs & how ? Think about 3 &17-OH – 3 methods 12

1.1. 17b-Estradiol Esters (IM) ↑ DoA

17-Ester prodrug  IM (in oil) for long-term therapy Slowly hydrolyzed to estradiol in vivo  long-acting – ↑ R size  ↑ log P & more hindered  ↓ absorption rate  ↑ DoA – Tx: hypogonadism in girls or women

13 Ethinyl Estradiol* (EE, 17a-C≡CH  PO, OCs)

(-) metabolic inactivation  ↑ F/t1/2/DoA – 17b-OH metabolism was blocked & permanently protected w/ 17a-ethynyl group – ↑ potency (200 X more potent than estradiol)

Use: Combined oral contraceptive (COC)/HRT14 Ethinyl Estradiol (EE) Metabolism: 2, 3-OMe

Use: COC – Like many other OCs, 3A4 substrate  DDIs – 3-O-glucuronide & -sulfate metabolites (inactive) Why some broad-spectrum antibiotics ↓ OC efficacy? – 3-O-methyl ether of EE = 15 Mestranol (3-OCH3, COC)  Ethinyl Estradiol

A prodrug of EE – Synthetic estrogens, no 3-O-conjugation  ↑ DoA Rapidly bioactived mainly to EE by hepatic O-demethylation following PO

Both mestranol & ethinyl estradiol are used primarily in COC Please compare these 2 drugs Can you use mestranol locally? 16 1.1. : Water-Soluble

Equilin & (equine = horse) – Obtained from Pregnant mares’ urine as “Premarin* or conjugated estrogen for HRT Premarin: a mixture of sodium sulfate, sodium sulfate & sulfate conjugates of some metabolites Excreted in urine as sodium sulfate conjugates – Water-soluble metabolites of natural estrogens Conjugated Estrogens USP is a mixture of sodium salts of sulfate esters of estradiol derived from equine urine or

prepared synthetically from estrone & equilin 17 1.1. Estrogens: Stilbenes

The nucleus is NOT required for activity (B & C rings can open) Some stilbene (diphenylethylene) drugs – trans isomers are more stable & potent than cis isomers

Diethylstilbestrol (DES) – Never used in pregnancy, removed from US, only used in veterinary med now 18 1.1. SAR : General Important FGs

1. Aromatic A ring 1. Planar hydrophobic scaffold 2. w/ an aromatic A ring lack affinity to other steroid hormone ®s 2. 3 & 17b-OH (2 HBDs) 3. Distance between 3-OH & 17-OH groups ≈ 10.3-12.1 Å

19 1.1. Steroid Hormone: MOA

2 HBDs

20 1.1. SAR : Substituents

Aromatic A ring, 3 & 17-OH are important SAR is often in PCOA exam! 21 1.1. Estrogens: Same MoA & Different PK

Uses \ Drugs E2 Estrogen esters EE: Orally active Conjugates (IM) estrogens equine estrogens

PO Poor oral activity ↑ DoA ↑ F/t1/2/DoA /potency Retain some activity Short t1/2/DOA (e.g. equilin sodium sulfate) Metabolism 1st-pass metabolism Slowly hydrolyzed to E2 Resistance to 1st-pass Conjugation hepatic metabolism Metabolic conjugates retain some activity (e.g. equilin sodium sulfate) Hypogonadism + HRT E1, 2 & 3 ++ ++ OC +++ Potency ++ ++++ 200X vs. E2 +

22 Estrogen: Estradiol: MoA Rapid uptake & retained more in breast, & vagina 2 main estrogen ®s – ERa: mainly in female reproductive tract & mammary glands – ERb: mainly in vascular endothelial cells, bone & male prostate tissues – Estradiol has similar affinities for both ERs Certain non-steroidal estrogens & antiestrogens are different ® binding  estradiol-® complex – Conformation change of the ®s  homo or heterodimers – Interacts w/ estrogen response elements (ERE) of cellular DNA  – DNA transcription  mRNA  protein synthesis

Regulation of gene expression & protein synthesis

23 Estrogens: Estradiol & Breast Cancers (FYI) (+) gene expression ↑ production of several proteins – Intracellular proteins important for breast cell function & growth Enzymes needed for DNA synthesis – DNA polymerase, dihydrofolate reductase ……

– Proteins that influence tumor growth & metastasis Transforming growth factor-a (TGFa) & TGFb Insulin-like growth factor I (IGF-I) Cathepsin D protein: (+) cell metastasis So, ↑↑ estrogens can (+) proliferation of breast cells & causes estrogen-dependent breast cancer (ER+ BC) – ↑ growth of hormone-dependent mammary carcinoma

24 2.2. Antiestrogens: BCs & Ovarian Cancers Estrogen is a growth factor for ER+ BC cells (-) estrogen action  ↓ ER+ BC Tx: ER+ BC & infertility 3 groups 1. antiestrogens (±) ERs • Selective modulators (SERMs) • Act as estrogen agonist in some tissues, partial agonists or estrogen antagonists in other tissues  tissue-specific 2. Pure antagonists 3. (-) aromatase  ↓ estrogen (E) biosynthesis  ↓ [E]  ↓ BC

25 SERMs: Antiestrogens

Tamoxifen: High affinity for ERs Produce -® complexes that – Prevent translocation of E-® complex into nucleus of target cells – (-) binding of E-® complex to estrogen response elements (ERE) of cellular DNA (Cl): similar structure/property/indication & toxicity to tamoxifen, but – Beneficial effects on bone, CV & HDL 26

1st G. SERM (Triphenylethylenes): Tamoxifen*

Antagonist on breasts  prevent or treat E®+ BC Antagonist on CNS  hot flash Agonist on bone  prevent osteoporosis in women Weak agonist of endometrial® (↑ risk of endometrium CA) Agonist  ↑ risk N-Demethylated to a major metabolite 4-hydroxytamoxifen is a more active metabolite 27 2nd G. SERMs: & *

Rigid analogs of triphenylethylenes  no problem of geometric isomers 4-hydroxyl-benzothiophene: Raloxifene – Estrogen antagonist at breast  prevent E®+ BC – Estrogen agonist at bone  prevent osteoporosis – No effect on endometrium  no endometrial CA risk – No BC or endometrial CA risk Other drugs for osteoporosis: – Estradiol, conjugated estrogens ↑ endometrial CA risk 28

Nature 1997; 389;753 Estradiol-Bound ERa & Raloxifene-Bound ERa

C  white O  reddish brown N  blue C-terminus S  green C-terminus

H12

H12 H = Helix

N-terminus N-terminus

E2-E® recruits coactivators Reloxifene-E® recruits some coactivators but not others Notes & Questions Why tissue specific?

30 Antagonists: Clomiphene (+) Ovulation

Administered orally as a mixture of 2 geometric isomers – Z (cis: zuclomiphene) has week estrogenic activity – E (trans: enclomiphene) has potent antiestrogenic activity Partial agonist (mixed agonist & antagonist) – Selectively (-) hypothalamus/pituitary E®s  ↓ negative feedback inhibition of estrogens  ↑ FSH/LH  (+) ovulation  treat infertility caused by lack of ovulation – Also used for male infertility due to oligozoospermia? 31 Antiestrogen: Pure Antagonists: Fulvestrant*

Estradiol with a 7a-long alkyl chain (-) E® in all tissues & (-) E® dimerization – No E® agonist activity seen with tamoxifen or raloxifene (+) E® degradation, 1st in a new class of selective ER downregulator (SERDs) Tx: – Pts with breast cancer that has developed resistance to tamoxifen – Alternative to aromatase inhibitors

32 ER Agonists, SERMs & Antagonists: Tissue-Specificity

Class Agonist SERM Antagonist (SERD) E® target organ Estradiol Tamoxifen* Reloxifene Clomiphene Fulvestrant Breast +++ - - - - Endometrium +++ + - (±), partial agonist - Endometrial CA risk No CA risk Bone +++ + or (±) ++ - -

Hypothalamus & +++ - Anterior pituitary Negative - feedback Pharmacology ↑ E action ↓ E®+ BC Good for bone (-) E® in H/P Full antagonist For ≤ 5 years  ↑ FSH/LH Uses HRT, OCs ↓ E®+ BC Osteoporosis (+) ovulation Tamoxifen- or AI- ↓ more cases of BC prevention resistant , or E®+ BC metastatic BC w/ SEs Aromatase Inhibitors:

a, b-unsaturated keto A ring irreversibly (-) aromatase (analog of androstenedione)

– Substrate analogs w/ only small structural changes (D1 & 6 double bonds) (4-OH) (-) conversion of androgens to estrogens  ↓ [estrogens] 34 Competitive Aromatase Inhibitors: Triazoles*

N4 of triazole ring binds to the heme iron atom of aromatase  (-) aromatase (-) conversion of A to T  ↓ [E]  starve E®+ tumor – Tx: E®+ BC for pts who do not tolerate tamoxifen – SEs: bone lose, but no GC or MC SEs 35 Antiestrogens: (FYI)

GnRH agonist → ↓ FSH/LH → ↓ [E2] (-) several P450 enzymes involved in gonadal steroid synthesis a weak partial agonist of G/P/A®s Tx: Endometriosis & fibrocystic breast disease Diverse effects & SEs: hirsutism, hepatic SEs. Rarely used. C/I: pregnancy & breast-feeding. 36 2. Progestins: E2 VS. Progesterone*

37 2. Progestins: Progesterone Progestins are compounds w/ activities similar to those of progesterone (21 Cs) Removal of corpus luteum after conception  pregnancy termination (1903) Major progestin in humans isolated in 1934 Precursor to androgens, estrogens & adrenocorticoids Effects: (+) secretory changes in endometrium Required for maintenance of pregnancy & normal menstrual bleeding Clinical use HRT (PO) & promote/maintain pregnancy Contraceptives 38

2.1. Progestins: 3 Class Contraceptives

39 Progesterone (Hormone of Pregnancy) Synthesized & secreted by corpus luteum (CL) – LH (+) LH® in CL  (+) AC  ↑ cAMP  ↑ cholesterol esterase   ↑ free cholesterol//progesterone Prevent ovulation during pregnancy “natural contraceptive” Drawbacks as a drug – Administered parenterally & injected repeatedly & local irritation & pain

– Rapid metabolism  t1/2 ≤ 10 min. & low oral bioavailability

40 Progesterone: Rapid Metabolism↓F/t1/2/DoA Rapidly metabolized to inactive metabolites by liver 1. 3-one  3a-OH 2. D4 double bond  single bond (5b-H) 3. 6a-hydroxylation (CYP3A4) 4. 20-one  20-OH (20-ketone reduction catalyzed by dehydrogenase)

Block C3 & C20 ketone reduction  ↑ F/t1/2/DoA Block C6 hydroxylation w/ 6-CH3 

41 21 C/17a-OAc: Acetate

17a-acetoxyprogesterone: some oral activity – 17a-acetoxyl FG  ↓ 20-ketone reduction  ↑ F

Medroxyprogesterone acetate* (6a-CH3) for HRT

– 6a-CH3  (-) 6a-hydroxylation & ↓ metabolism of 3-one- 4- ene  ↑ F/t1/2/DoA – Depot Medroxyprogesterone Acetate (DMPA, Depo- Provera®): IM or SC, long-acting every 12 wks – Tx: HRT/dysmenorrhea/uterine bleeding/endometriosis 42 21Cs/17a-OAc: Acetate (D6)

Introduced a D6 double bond  ↑ progestin activity – < 10% of oral dose of megestrol is metabolized Tx: Endometrial cancer

43 19-NorT-Analog: Norethindrone* ( 17a-C≡C T)

Introduce ethinyl (17a-C≡C) to testosterone  – (-) metabolic degradation of 17-OH – 15 X more active than progesterone orally, but androgenic – PO for menstrual dysfunctions Norethindrone* (removal of 19-Me)  ↑ progestin activity – Androgenic SEs – No GC/MC activity – + EE = OC, commonly used – Progestin-only pills (minipills) Norethindrone acetate (prodrug)  norethindrone as OC st – Completely & rapidly deacetylated in hepatic/intestinal 1 -pass metabolism 44

19-NorT-Analog: Norgestrel* ( 13-Ethyl T.)

Norgestrel* (13-ethyl, a racemic mixture) – Some androgenic activity, but no GC/MC action – Orally active – Only levo isomer is active * (a 13-levo isomer) – IUD & OC (F = 95%) – Metabolism: ketone reduction & ester hydroxylation – The most androgenic * (a prodrug) – Converted to 2 active metabolites (norgestrel & norelgestromine)

45

SEs: Progestin vs. Androgenic: “19-Nor, 13-Et/Me”

High Androgenic (A) Moderate A (13-Me) Low A (3rd G, 13-Et) Anti- “Spir”

Levonorgestrel is the most androgenic

↑ & less spotting androgenic SE SEs: ↓ spotting 1. Weight gain ↑ libido 2. Oily skin & scalp “13-Me” 3. 4. Hirsutism 46 2.Progestins: 19-Nortestosterones: Other Forms

47 2.2. Progestin Antagonist: Mifepristone*

Ulipristal: P® modulator, postcoital contraceptive Miferpristone (-) P/G® – Orally active 19- antagonist of progesterone & – Interrupt early stages of implantation & pregnancy – Effective postcoital contraceptive () – Abortifacient in early pregnancy (with misoprostol ↑ contractions) – Also (-) G ®  Tx: Cushing’s disease : less antiglucocorticoid activity 48 OCs: Simple Review (FYI)

49 2.1. Synthetic Progestins: Summary

Structure modifications  ↑ F/t1/2/DoA & ↑ progestin selectivity & ↓ androgenic SEs 2 classes 1. 17a-OAc protect C6 & 20-one metabolism • Medroxyprogesterone acetate (6-Me & 17a-OAc) 2. 19-nortestosterone derivatives differ in their degree of androgenic effects (19-nor & 17a-R) 1. Testosterone 17-ethinyl, methyl or ethyl  ↑ oral bioavailability 2. e.g, ethisterone, Ideally, (+) P® only, but almost all have some androgenic activity Older drugs (eg, L-norgestrel & norethindrone) are more androgenic than newer progestins (eg,

norgestimate & ) 50 TJE Practice Question: Katzung 11e, 10 of 22

OC usually contain lowest doses of E/P components. Margin between effective & ineffective serum concentrations of steroids is narrow, which presents a risk of breakthrough bleeding and also unintended pregnancy resulting from DDIs. Most contraceptives are metabolized by P450.

1. How many drugs ↓ efficacy of contraceptives by ↑ their metabolism? 2. When one of these drugs is prescribed for a woman who already is using a combined contraceptive, what should be done to prevent pregnancy?

1. Gonadal steroids are metabolized primarily by 3A4. Inducers of 3A4 include barbiturates, carbamazepine, corticosteroids, griseofulvin, , pioglitazone, rifampin, and rifabutin. Reduction in contraceptive efficacy of contraceptives by carbamazepine and phenytoin are of particular importance because these drugs are known teratogens. St. John’s wort (+) 3A4 ↓ contraceptive efficacy.

2. To prevent unwanted pregnancy, use a combined contraceptive with a higher dose of 50 mcg of ethinyl estradiol). Alternatively, women may use a barrier form of contraception or switch to an IUD. 51 3. Natural Testis Hormones: T & DHT 3. Natural Testis Hormones: T & DHT

Higher concentration in males; Use: HRT – Androgens 19 Cs, 3-ketone (OH), 17-OH (or ketone) e.g, Testosterone (4-ene) & its more potent metabolite 5a- dihydrotestosterone (DHT, 4-ane) 1. Androgenic (promoting male physical characteristics) 2. Anabolic (muscle building etc.) Nonoral dosage form to bypass 1st pass metabolism – IM, implant, transdermal system, gel, solution, buccal mucosal, but poor F. Why? 53 3. Androgens: Testosterone (T): Metabolism

Rapidly metabolized to inactive 17-keto metabolites Orally inactive  usually injected You can design orally active & long-acting drugs ?

54 3.1 Testosterone (T): 17-Me  Orally Active

Testosterone esters* (IM)  ↓ metabolism  long-acting Must be hydrolyzed to be active 17a-Me (17a-*) & 17a-R  orally active – 4-OH () – 11-OH + 9a-F (): orally active & more potent  D1-double bond (Methandrostenolone): orally active Uses: hypogonadism in boys/men, HRT 55 17a-Methyltestosterone & Fluoxymesterone

T 17a-MeT (17a-methyltestosterone*) – (-) metabolic oxidation of 17b-OH – Androgenic, anabolic activity – Hepatotoxic  used sublingually 9a-F + 11-OH, + 17a-Me (Fluoxymesterone) – ↑ 20 X anabolic VS. 17a-methyltestosterone – ↑ 10 X androgenic

– Hepatotoxic 56 Anabolic T: * & *

Oxandrolone – A lactone in A ring (O bio-isostere of A ring, O insertion ↑ anabolic) – 3 X anabolic activity of 17a-methyltestosterone Stanozolol – Pyrazole ring fused with A ring – 3 X anabolic activity of 17a-methyltestosterone 19Me ↑ androgenic activity  not desirable

– Remove C19  “19-nor-T”  ↓ androgenic activity  anabolics 57

Anabolic Steroids: 19-Nortestosterones

Androgens w/o 19Me (important for androgenic activity) are anabolic – ↓ androgenic activity – ↔ anabolic activity 17a-Et = – Better anabolic selectivity than 19-nortestosterone – 30-50 mg per day orally 17a-Et & 3-Nor = – More potent anabolic drug than norethandrolone – 4 mg per day orally

– See more examples in page 1362 in Foye's textbook 58 Testosterone: Androgenic Hormones Androgenic actions: – Development & maintenance of normal male characteristics

Anabolic (masculinizing) actions – ↑ muscle size & strength/weight – ↑ red blood cell production – ↓ excretion of urea nitrogen & nitrogen balance becomes more positive – helps maintain normal bone density

Separate androgenic & anabolic action 1. ↓ Androgenic (promoting male sex characteristics) 2. ↑ Anabolic activity (muscle-building & masculinizing effects)

59 Modification ↑ Androgenic & Anabolic Activity

B, C, D ring expansion/contraction ↓ activity Esters at 17 b-OH must be hydrolyzed to be active e.g. T-undercanoate, cypionate & enanthate

60 2.2. Antiandrogens & A® Modulators

Nonsteroids competitively (-) prostate A® Flutamide*: Tx: prostate cancer (PC)/hirsutism – ↓ T action  ↓ libido & impotence – Prototype A® antagonist used in PC, but, liver toxicity ↓ liver toxicity – Tx: nonmetastatic PC during its early stages

Nilulutamide, (A® down-regulator) 61

5a-Reductase Inhibitor: Finasteride* ↑ DHT/aging  BPH

IC50 (nM) Type 1 313 3.9

IC50 (nM) Type 2 in prostate 11 1.8 Difference 28 X selective to type 2 More potent F (%) 65 60

Elimination t1/2 5-6 wks Longer Tx: ↓ [DHT]  Tx: BPH/alopecia, interchangeable SEs: Less likely to cause or importance Metabolizing enzyme 3A4, no active metabolite 3A3, active metabolite (6’-OH) 2 azasteroid-17-amides irreversibly (-) 5a-reductase (5aR) 

↓ DHT/BPH/alopecia 62 AR Antagonists: (-) A/M®

Spironolactone (-) A®  Tx: hirsutism/alopecia – SE: gynecomastia, abnormal menstruation, impotence, lethargy (-) M®  ↓ synthesis of Na channels & Na+/K+ ATPase  ↓ Na+ & ↑ K+ (K+ sparing)  ↓ BP – Tx: /HTN. SEs: hyperK+ – Slow onset & offsets of action (24-72 h) (+) P®, (-) A/M®, not (-) E/G® – Uses: 3rd/4th generation progestin OCs. ↓ acne/hirsutism/wt. gain, Na retention 63

Ketoconazole* (-) 17a-hydroxylase (Review)

(-) Ergosterol synthesis  antifungal azole prototype (-) P450c17  ↓ E/P/A/GC/MC synthesis Extensively metabolized & all metabolites are inactive – Substrate & inhibitor of SYP3A4  DDIs Tox – (-) steroid synthesis – (-) CYP450-dependent drug metabolism

– Hepatic dysfunction 64 1.Ovarian (Female) Hormones: Estrogens4e 8: 2 GnRH, 2 EI, 3X2 A/P/E®, 1 A/P® 1. Continuous GnRH suppresses LH/FSH release from pituitary preventing hormone synthesis. 1

2. GnRH antagonists (cetrorelix, ganirelix, 2 degarelix) are also used for this purpose.

3. Exemestane, formestane, anastrozole, (-) aromatase

4. SERM (+/-) E®

3 5. Mifepristone, ulipristal (-) P®

6 6. Finasteride/ (-) 5α-reductase

5 7. Flutamide, bicalutamide, , 7 enzalutamide (-) A® 4

8. Spironolactone* (-) A/P®, 8 65 Summary: Drugs & Classification

* * * Antagonist = fulvestrant * *

Spironolactone (a steroid)

Not covered 66End Applications for Gonadal Hormones & Antagonists (T4, FYI)

Clinical Application Drugs Hypogonadism in girls, women (3) Conjugated estrogens, ethinyl estradiol (EE, PO), estradiol esters (IM) Estrogen component: conjugated estrogens, estradiol, estrone, Hormone replacement therapy (HRT, 6) Progestin component: progesterone, medroxyprogesterone acetate Combined: ethinyl estradiol or mestranol plus a progestin Oral hormonal contraceptive Progestin only: norethindrone or norgestrel Medroxyprogesterone as a depot IM injection Ethinyl estradiol and as a weekly patch Parenteral contraceptive (6) Ethinyl estradiol and as a monthly L-Norgestrel as an (IUD) Etonogestrel as a subcutaneous implant Postcoital contraceptive L-Norgestrel alone, estrogen alone, combined oral contraceptive Conjugated estrogens, ethinyl estradiol, oral contraceptive, GnRH Intractable dysmenorrhea or uterine bleeding agonist, depot injection of medroxyprogesterone acetate Clomiphene; hMG and hCG; GnRH analogs; progesterone; Infertility (5) bromocriptine Abortifacient (2) Mifepristone (RU 486) and misoprostol Oral contraceptive, depot injection of medroxyprogesterone acetate, Endometriosis GnRH agonist, danazol Breast cancer Tamoxifen, aromatase inhibitors (eg, anastrozole) Osteoporosis in postmenopausal women (3) Conjugated estrogens, estradiol, raloxifene or cypionate, methyltestosterone, Hypogonadism in boys, men; replacement therapy fluoxymesterone, testosterone (patch) Anabolic protein synthesis (2) Oxandrolone, stanozolol Benign prostate hyperplasia (BPH), 1) Finasteride GnRH agonist, GnRH , Prostate carcinoma (3) antagonist (eg, flutamide) Hirsutism Combined oral contraceptive, spironolactone, flutamide, GnRH agonist AccessPharmacy > Katzung & Trevor's Pharmacology: Examination & Board Review, 12e > Gonadal Hormones & Inhibitors Bertram G. Katzung, Marieke Kruidering-Hall, Anthony J. Trevor 67