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Dúvidas Arquivo Medicamentos atuantes no sistema reprodutivo feminino - Anticoncepcionais Site Dúvidas

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Dúvidas Arquivo Medicamentos atuantes no sistema reprodutivo feminino - Anticoncepcionais Site Dúvidas

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1 Dúvidas Arquivo Medicamentos atuantes no sistema reprodutivo feminino - Anticoncepcionais Site Dúvidas Arquivo Medicamentos atuantes no sistema reprodutivo feminino - Anticoncepcionais Site

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3 Walter F. Boron/ Emile L. Boulpaep – Medical Physiology – Fig 54-1 The anatomy of the female internal genitalia and accessory sex organs

4 Walter F. Boron/ Emile L. Boulpaep – Medical Physiology – Fig 54-1 The anatomy of the female internal genitalia and accessory sex organs

5 Ovarian cycle Rupture of mature follice and release of ovum (ovulatory phase) Corpus luteum formation (luteal phase) Growth and development of the follice (follicular phase) Corpus luteum degeneration Foyes Principles of Medicinal Chemistry – Fig. 29.2

6 Estradiol (pg/ml) FSH and LH (ng/ml) Days of female sexual cycle FSH LH Estradiol Ovulation Progesterone Progesterone (ng/ml) Menstruation Approximate plasma concentrations of the gonadotropins and ovarian hormones during the normal female sexual cycle Guyton & Hall – Textbook of Medical Physiology – fig 81.3

7 Puberty Menopause Age (yr) Estrogens excreted in urine (µg/24 hr) Estrogen secretion throughout the sexual life of the female human being Guyton & Hall – Textbook of Medical Physiology – fig 81.10

8 Walter F. Boron/ Emile L. Boulpaep – Medical Physiology – Fig mo10-14 yr50 yr 1st2nd 3rd Birth Trimesters Plasma gonadotropins (um/M)

9 Hypothalamic regulation of pituitary gonadotrophin production and release Ovarian feedback modulation of pituitary gonadotropin production and release Pulsed release of GnRH by hypothalamus (1 pulse/ 1-2 hr) permits anterior pitutary production and release of FSH and LH (normal) Presence of pulsed GnRH and low estrogen and progesterone levels result in increased levels of pulsed LH and FSH (negative feedback) Continuos, excessive, absent or more frequent GnRH release inhibits FSH and LH production and release (downloading) Presence of pulsed GnRH, rapidly increasing levels of estrogen, and small amounts of progesterone result in hight pulsed LH and moderately increased pulsed FSH levels (positive feedback) Decreased pulsed release of GnRH decreases LH secretion but increases FSH secretion (slow-pulsing model) Presence of pulsed GnRH and high levels of estrogen and progesterone result in decreased LH and FSH levels (negative feedback) Neuroendocrine Regulation of Menstrual Cycle Hours GnRH Estrogen GnRH FSH LH FSH LH FSH LH FSH LH FSH LH FSH LH

10 Hypothalamus GnRH (pulses /hr) Pituitary LH-FSH Ovary Estrogen Progesterone Correlation of serum gonadotrophic and ovarian hormone levels and feedback mechanisms Follicular phase FSH-LH (pulses/hr) Days Menses Serum levels LH mlU ml pg ml ng ml Progesterone Estrogen FSH

11 Luteinizing hormone Folicular steroid hormones (progesterone) Proteolytic enzymes (collagenase) Follicular hyperemia and prostaglandin secretion Weakened follicle wall Plasma transudation into follicle Degeneration of stigma Follicle swelling Follicle rupture Evagination of ovum Postulated mechanism of ovulation Guyton & Hall – Textbook of Medical Physiology – fig 81.5

12 HO OH Estradiol Foyes Principles of Medicinal Chemistry – pag 685

13 RO X OH C CH RO OR 1 Ethinyl estradiol: R = X = H Mestranol: R = CH 3 ; X = X 2-Hydroxyethinylestradiol: R = H; X = OH Estradiol 17β-valerate: R = H: R1 = CH 3 (CH 2 ) 3 CO Estradiol 17β-cyclopentylpropionate R = H R1 = CH 2 CH 2 CO 17α-Ethinyl estrogens, and Estradiol Esters Foyes Principles of Medicinal Chemistry – fig. 29.6

14 O O Progesterone Foyes Principles of Medicinal Chemistry – pag 685

15 O OH C CHC CCH 3 OH O O O O O H Ethisterone Dimethisterone 19-Nor-14β, 17α-preg- 4-ene-3,20-dione 19-Norprogesterone Progestins and 19-norandrostane Foyes Principles of Medicinal Chemistry – fig

16 H 3 C-C-O O O O C-CH 3 CCH O OO O O O OH CCH O C-CH 3 HO N 3-Ketodesogestrel (etonogestrel)Ethynodiol diacetate DesogestrelNorgestimateNorgestrel Norethindrone NorethynodrelNorethisterone Foyes Principles of Medicinal Chemistry – fig Norandrostanes used clinically in oral contraceptives

17 Estrógenos Síntese de DNA e RNA hepático, Enzimas hepáticas Enzimas séricas formadas no fígado Proteínas plasmáticas

18 Mechanism of Action of Estrogen/Progestin Contraceptives Inhibition of ovulation by suppression of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) Alteration of cervical mucus to inhibit sperm transport Interference with ovum transport Inhibition of implantation by suppression of normal endometrial development Essential of Reproductive Medicine – Tab. 26.1

19 Estrogen and progesterone GnRH Hypothalamus Anterior pituitary Combination oral contraceptives (estrogen and progestin) FSHLH Granulosa cells Ovary Theca cells Unfavorable endometrial environment Altered transportation of sperm, egg, fertilized ovum Changes cervix environment Uterus Normal cervix Cholesterol Pregnenolone Progesterone Androstenedione EstroneEstriol Estradiol O O O HO O O O OH HO O Testosterone Combination Oral Contraceptives

20 Pílula de Primeira Geração Etinilestradiol - doses altas (50mcg ou maior) Progestágeno - Levonorgestrel, noretisterona ou etinodiol diacetato.

21 Pílula de segunda geração Etinilestradiol (dose até 30 mcg) Progestágeno - levonorgestrel ou noretisterona

22 Pílula de Terceira Geração Etinilestradiol (20-30 mcg) Progestágeno - desogestrel, gestodeno ou norgestimato

23 ETINILESTRADIOL + GESTODENO etinilestradiol 15 mcg + gestodeno 60 mcgetinilestradiol 20 mcg + gestodeno 75 mcgetinilestradiol 30 mcg + gestodeno75 mcg MINESSE MIRELLE DIMINUT FEMIANE GINESSE HARMONET MICROPIL R21 TÂMISA 20 CICLO 21 GESTINOL 28 GYNERA MINULET TÂMISA 30 ETINILESTRADIOL + DESOGESTREL etinilestradiol 20 mcg + desogestrel 150 mcgetinilestradiol 30 mcg + desogestrel 150 mcg) FEMINA MERCILON MINIAN PRIMERA MICRODIOL ETINILESTRADIOL+DROSPERINONA etinilestradiol 20 mcg + drosperinona 3 mgetinilestradiol 30 mcg + drosperinona 3 mg Yaz YASMIN ETINILESTRADIOL+CLORMADINONA etinilestradiol 30 mcg + clormadinona 2mg BELARA ETINILESTRADIOL E OUTROS etinilestradiol 30 mcg + levonorgestrel 150 mcgetinilestradiol 20 mcg + levonorgestrel 150 mcg Comp. azul: Desogestrel 0,025 mg + Etinilestradiol 0,04 mg; Comp. branco: Desogestrel 0,125 mg + Etinilestradiol 0,03 mg CICLON GESTRELAN NOCICLIN MICROVLAR NORDETTE LEVEL GRACIAL etinilestradiol 50 mcg + levonorgestrel 250 mcg EVANOR NEOVLAR

24 Progestin-Only Contraceptives Mechanism – Altered GnRH release leads to ovulation Drug Summary Table – Pharmacology of Reproduction Norgestrel Norethindrone ContraceptionBreakthrough SportingNorgestrel also available as subdermal implant Less effective than estrogen/progestin combination Drug Clinical Uses Side Effects/Toxicities Notes Principles of pharmacology – the Pathophysiologyc Basis of Drug Therapy – pag.454

25 Contraceptive use in the United States, Essential of Reproductive Medicine – Fig % 24% 19% 7% 6% 3% 1% Percentage of Women Ages PillSterilizationCondomWithdrawa/ Rhythm Hysterectomy/ Menopause InjectableSpermicideIUDImplants Method

26 Noncontraceptive Health Benefits of Oral Contraceptives Percent Reduction/ Protection (%) Minium Use Required Duration of Effect OCP Formulation Comments Definitive evidence Ovarian cancer months At least 15 >20 µg EE Also protective against years hereditary ovarian cancer Endometrial cancer months 15 years All monophasic No data on multiphasic or progestin-only forms Benign breast disease months 1 year >20 µg EE Effect consistent across all age groups Pelvic inflamatory months Current use >20 µg EE ? Effect on outpatient disease cases of PID Ectopic pregnancy 90 Current use Current use >20 µg EE No increased risk for ectopic pregnancy in women who become pregnant with OCP use Essential of Reproductive Medicine – Tab. 26.2

27 Noncontraceptive Health Benefits of Oral Contraceptives Percent Reduction/ Protection (%) Minium Use Required Duration of Effect OCP Formulation Comments Conflicting evidence, favor beneficial effect Bone mineral density 60 Unknown Unknown >35 µg EE Decreased incidence of hip fractures with higher doses Colorectal cancer months Unknown >50 µg EE Increasing protection with increased duration Uterine leiomyomas 30, years; Unknown Unclear If used in setting of fibroids no 7 years clinically significant uterine growth Toxic shock syndrome 50 Current use Current use Unclear May be influenced by change in tampon composition/absorbency Essential of Reproductive Medicine – Tab. 26.2

28 Noncontraceptive Health Benefits of Oral Contraceptives Percent Reduction/ Protection (%) Minium Use Required Duration of Effect OCP Formulation Comments Conflicting evidence, favor no effect Functional ovarian cysts 80, 48, 8 Current use Current use Monophasic No statistically significant effect >35 µg EE; Monophasic <35 mcg EE triphasic all types Rheumatoid arthritis 40 Current use Current use Unclear May alter severity and clinical course rather development Essential of Reproductive Medicine – Tab. 26.2

29 Benefícios dos AOC Menor risco de câncer endometrial e ovariano. Menor risco de prenhez ectópica Menstruação mais regular (menor fluxo, menor dismenorréia, menor anemia) Menor incidência de salpingite Aumento da densidade óssea

30 AOC e câncer Redução de 50% do risco de câncer de endométrico Redução de 40% do risco de câncer de ovário Sem efeito no câncer de cérvix uterina ou no câncer de mama.

31 Age group (years) Deaths / 100,000 women nonuser, nonsmoker user, nonsmoker nonuser, heavy smoker user, heavy smoker Number of deaths from cardiovascular diseases per 100,000 women by smoking status or nonuse of oral contraceptives. Essential of Reproductive Medicine – Fig. 26.4

32 Relative Risk and Actual Incidence of Venous Thromboembolism Population Relative RiskIncidence Young women-general population14-5 per 100,000 per year Pregnant women High-dose oral contraceptives Low dose oral contraceptives Leiden mutation carrier Leiden carrier and oral contraceptives Leiden mutation – homozygous A Clinical Guide for Contraception – tab. Pag 53

33 The carrier frequencies of the Leiden mutation in American population (the percentages are similar in men and women) are as follows Caucasian Americans5.27% Hispanic Americans2.21% Native Americans1.25% Black Americans1.23% Asian Americans0.45% A Clinical Guide for Contraception – tab. Pag 53

34 In the Transnational case-control study of myocardial infarctions collected from 16 centers in Austria, France, Germany, Switzerland, and United Kingdom, the results were as follows Confidence Cases ControlsOdds Ratio Interval Any OC use µg estrogen OCs Old progestin OCs New progestin OCs A Clinical Guide for Contraception – tab. Pag 55

35 Incidence of Myocardial Infarction in Reproductive Age Women Overall incidence5 per 100,000 per year Women less than age 35 Nonsmokers4 Nonsmokers & OCs4 Smokers8 Smokers & OCs43 Women 35 years old and older Nonsmokers10 Nonsmokers & OCs40 Smokers88 Smokers & OCs485 A Clinical Guide for Contraception – tab. Pag 57

36 Incidence of Stroke in Reproductive Age Women Incidence of ischemic stroke5 per 100,000 per year 1-3 per year in women under age per 100,000 per year in women over age 35 Incidence of hemorrhagic stroke6 per 100,000 per year Excess cases2 per 100,000 per year in low-dose OC users per year due to1 per 100,000 per year in low-dose OC users under age 35 OCs, including8 per 100,000 per year in high-dose users smokers and hypertensives A Clinical Guide for Contraception – tab. Pag 61

37 Possible Contradications to Use of Combined Oral Contraceptive Pills Absolute Contraindications 1. Thrombophlebitis or Thromboembolic disorders 2. Past history of deep vein thrombophlebitis or thromboembolic disorders 3. Cerebrovascular or coronary artery disease 4. Known or suspected breast carcinoma 5. Known or suspected estrogen-dependent neoplasia 6. Pregnancy 7. Benign or malignant liver tumor 8. Known impaired liver function 9. Previous cholestasis during pregnancy or with prior pill use Essential of Reproductive Medicine – Tab. 26.6

38 Possible Contradications to Used of Combined Oral Contraceptive Pills (cont) Strong Relative Contraindications 10. Severe headaches, particularly vascular or migraine headaches, that start after initiation of oral contraceptives 11. Hypertension with resting diastolic BP of 140 mmHg or greater on three or more separate visits or an accurate measurement of 110 mmHg diastolic or more on single visit 12. Mononucleosis, acute phase 13. Elective major surgery or major surgery requiring immobilization planned in next 4 week 14. Long-leg cast or major injury to lower leg 15. Over 40 years old, accompanied by a second risk factor for the development of cardiovascular disease (such as diabetes or hypertension) 16. Over 35 years old and currently a heavy smoker (15 or more cigarettes/day) 17. Abnormal genital bleeding Essential of Reproductive Medicine – Tab. 26.6

39 Possible Contradications to Used of Combined Oral Contraceptive Pills (cont) Other Considerations Diabetes, prediabetes, or a strong family history of diabetes Sickle cell disease or sickle C disease Active gallbladder disease Congenital hyperbilirubinemia (Gilberts disease) Undiagnosed abnormal genital bleeding Over 50 years old Completion of term pregnancy within past 10 to 14 days Weight gain of 10 lb or more while on the pill Cardiac renal disease (or history thereof) Conditions likely to make patient unreliable at following pill instructions (mental retardation, major psychiatric illness, alcoholism, or other chemical abuse, history of repeatedly taking oral contraceptives or other medication incorrectly) Lactation Family history of death of a parent or sibling due to myocardial infarction before age 50; myocardial infarction in a mother or sister is especially significant and indicates a need for lipid evaluation Family history of hyperlipidemia Essential of Reproductive Medicine – Tab. 26.6

40 AOC e Fígado Transporte ativo de componentes biliares é inibido por estrógenos e progestágenos. Contraindicado formalmente em doença colestática aguda ou crônica

41 Importante Não há evidências de aumento de incidência de doença hepática séria causado por uso de ACO

42 Contraceptivo Oral e Trombose Estrógenos, mas não progestágenos, aumentam a produção de fatores de coagulação. Tabagismo e uso de estrógenos apresentam efeito aditivo no risco de trombose arterial. Contraceptivos de dose baixa de estrógeno (< 50 microg EE) não aumentam o risco de IM ou AVC em mulheres saudáveis, não fumantes, independente da idade. IM e AVC podem ocorrer em mulheres que usam contraceptivos de alta dose, ou que apresentam fatores de risco cardiovascular acima da idade de 35 anos.

43 Anel Vaginal (RING)

44 Emplastro dérmico (patch)

45

46 40 mm 2 mm Rate-controlling membrane: (.06 mm) 100% EVA Core: 40% Ethylene vinyl acetate (EVA) 60% Etogestrel (68 mg)

47 Required Equipment for Implanon Insertion

48 Implantation technique

49 Technique for the Tcu-380A

50 Progesterone Receptor Antagonists Mechanism – Inhibit progesterone binding to receptor Drug Summary Table – Pharmacology of Reproduction Mifepristone Medical abortionBleeding Must be able to verify age of fetus Coadministered with misoprostol (causes ulterine contractions, nausea) Antagonist at glucocorticoid receptor as well as progesterone receptor Drug Clinical Uses Side Effects/Toxicities Notes Principles of pharmacology – the Pathophysiologyc Basis of Drug Therapy – pag.454

51 Progesterone Receptor Antagonists (Cont.) Mechanism – Inhibit progesterone binding to receptor Drug Summary Table – Pharmacology of Reproduction Mifepristone Pregnancy >49 days Principles of pharmacology – the Pathophysiologyc Basis of Drug Therapy – pag.454 Drug Interactions / Contraindications

52 Mixed Estrogen / Progestin Oral Contraceptives Mechanism – Suppres follicular development; inhibit midcycle surge of LH and FSH, inhibit ovulation Drug Summary Table – Pharmacology of Reproduction Estrogens Ethinyl Estradiol Mestranol Progestins Norgestrel, levonorgestrel Norethindrome Ethynodiol, norgestimate Desogestrel Prevention of pregnancy Postcoital contraception Slightly risk stroke Triglyceride levels Risk DVT Drug Clinical Uses Side Effects/Toxicities Notes Principles of pharmacology – the Pathophysiologyc Basis of Drug Therapy – pag.454 Breakthrough bleeding Blood pressure Formulation exist as monophasic, biphasic, triphasic dosage forms Monofasic: Constant estrogen and progestin Biphasic: Higher progestin in second half of cycle + midcycle estrogen Triphasic: higher progestin in second half of cycle + midcycle estrogen No Clinical differences in efficacy or side effects among monophasic, biphasic or triphasic

53 Mixed Estrogen / Progestin Oral Contraceptives (Cont.) Mechanism – Suppres follicular development; inhibit midcycle surge of LH and FSH, inhibit ovulation Drug Summary Table – Pharmacology of Reproduction Estrogens Ethinyl Estradiol Mestranol Progestins Norgestrel, levonorgestrel Norethindrome Ethynodiol, norgestimate Desogestrel Contraindications: Previous DVT or stroke History of strogen-dependent tumor Liver Disease Pregnancy Hypertriglyceridemia Women > 35 y/o who smoke Drug Interactions: Rifampin, phenytoin, and phenobarbital all metabolism of OCPs Drug Interactions/Contraindications Principles of pharmacology – the Pathophysiologyc Basis of Drug Therapy – pag.454

54 Progestins Used in Breast Cancer Mechanism – Unknown Drug Summary Table – Pharmacology of Reproduction Megestrol acetate Medroxyprogesterone acetate Advanced breast cancer Risk DVT Hot flashes Drug Clinical Uses Side Effects/Toxicities Principles of pharmacology – the Pathophysiologyc Basis of Drug Therapy – pag.454

55 Testosterone O OH Foyes Principles of Medicinal Chemistry – pag 685

56 O OH H 5α-Dihydrotestosterone Foyes Principles of Medicinal Chemistry – pag 685

57 HO O Estrone Foyes Principles of Medicinal Chemistry – pag. 686

58 Estriol HO OH Foyes Principles of Medicinal Chemistry – pag. 686

59 Foyes Principles of Medicinal Chemistry – fig HO Cholesterol O HO OH O O O Pregnenolone 17α-HydroxypregnenoloneProgesterone a b c,d HO O OO O O c,d g OH O O HO OH O H i g f h e DehydroepiandrosteroneAndrostenedioneEstrone 5α-Dihydrotestosterone TestosteroneEstradiol Biosynthesis of sex steroid hormones

60 Estrogen metabolism Foyes Principles of Medicinal Chemistry – fig. 29.5

61 HO O O O RO Equilin Equilin sodium sulfate Estrone Estrone sodium sulfate Piperazine estrone sulfate R = H R = SO 3 – Na + R = H R = SO 3 – Na + R = SO 3 + N NH H H Conjugated and esterified estrogens Foyes Principles of Medicinal Chemistry – fig. 29.7

62 O O O O O OH HO H CH 5β-Pregnanediol 6α-Hydroxyprogesterone 20α/β-Hydroxyprogesterone OH H H Conformation of rings A and B for 5β-preganediol Progesterone Conformation of rings A and B for progesterones Metabolism of progesterone Foyes Principles of Medicinal Chemistry – fig

63 OH HO OH O HO H O OH HO OH H H O O O O Testosterone Epi-testosteroneAndrosterone Estradiol 6α-Hydroxytestostenore 5α-Dihydrotestosterone etiocholanolone O OH H H H O Conformation of rings A and B for 5α-dihydrotestosterone Conformation of rings A and B for testosterone Conformation of rings A and B for etiocholanolone Metabolism of testosterone Foyes Principles of Medicinal Chemistry – fig

64 CH 3 H3CH3C N H3CH3C N O O OH CH 2 -CH 2 CH 2 OHC CCH 3 MifepristroneOnapristrone Foyes Principles of Medicinal Chemistry – pag. 703

65 The tetracyclic ring system characteristic of steroids Organic Chemistry – fig. 26.9


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