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Dúvidas
Arquivo
Medicamentos atuantes no sistema reprodutivo feminino - Anticoncepcionais
Site
www.gdenucci.com
Dúvidas
Arquivo
Medicamentos atuantes no sistema reprodutivo feminino - Anticoncepcionais
Site
www.gdenucci.com
Walter F. Boron/ Emile L. Boulpaep – Medical Physiology – Fig 54-1
The anatomy of the female internal genitalia and accessory sex organs
Walter F. Boron/ Emile L. Boulpaep – Medical Physiology – Fig 54-1
The anatomy of the female internal genitalia and accessory sex organs
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
800
600
400
200
0800
600
400
200
0
8
6
4
2
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28
Est
radi
ol (
pg/m
l)F
SH
and
LH
(n
g/m
l)
Days of female sexual cycle
FSH
LHEs
trad
iol
Ovu
lati
onO
vula
tion
Progesterone
Pro
gest
eron
e (n
g/m
l)
Men
stru
atio
n
Approximate plasma concentrations of the gonadotropins and ovarian hormones during the normal female sexual cycle
Guyton & Hall – Textbook of Medical Physiology – fig 81.3
Pu
ber
ty
Men
opau
se400
300
200
100
00-----12 13------40 50 60
Age (yr)
Est
roge
ns
excr
eted
in u
rin
e(µ
g/24
hr)
Estrogen secretion throughout the sexual life of the female human being
Guyton & Hall – Textbook of Medical Physiology – fig 81.10
Walter F. Boron/ Emile L. Boulpaep – Medical Physiology – Fig 54-1
6 mo 10-14 yr 50 yr1st2nd
3rdBirth
Trimesters
100
70
10
Plasma gonadotropins (um/M)
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
Hours
Hours
GnRH
GnRH
GnRH
Estrogen
Estrogen
Estrogen
GnRH
GnRH
GnRH
FSH
LH
FSH
LH
FSH
LH
FSH
LH
FSH
LH
FSH
LH
Hypothalamus GnRH
(pulses /hr)
PituitaryLH-FSH
Ovary Estrogen
Progesterone
Correlation of serum gonadotrophic and ovarian hormone levels and feedback mechanisms
Follicular phaseFSH-LH
(pulses/hr)
2 4 6 8 10 12 14 16 18 20 22 24 26 28Days
500
400
300
200
100
50
40
30
20
10
Menses
Serum levels
LHmlUml
pgml
ngml
Progesterone
10987654321
EstrogenFSH
Luteinizing hormone
Folicular steroid hormones (progesterone)
Proteolytic enzymes (collagenase)
Follicular hyperemia and
prostaglandin secretion
Weakened follicle wallPlasma 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
HO
OH
Estradiol
Foyes Principles of Medicinal Chemistry – pag 685
RO
X
OHCCH
RO
OR1
Ethinyl estradiol: R = X = H
Mestranol: R = CH3; X = X
2-Hydroxyethinylestradiol: R = H; X = OH
Estradiol 17β-valerate: R = H: R1 = CH3(CH2)3CO
Estradiol 17β-cyclopentylpropionate
R = HR1 = CH2CH2CO
17α-Ethinyl estrogens, and Estradiol Esters
Foyes Principles of Medicinal Chemistry – fig. 29.6
O
O
Progesterone
Foyes Principles of Medicinal Chemistry – pag 685
O
OHC CH C CCH3
OH
O
OO
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. 29.16
H3C-C-O
O
O
OC-CH3
C≡CH
O
O O O
O
O
OH
OH
OH OH OH
OH
C≡CH
C≡CH C≡CH C≡CH
C≡CHC≡CHC≡CH
OC-CH3
HON
3-Ketodesogestrel (etonogestrel) Ethynodiol diacetate
Desogestrel Norgestimate Norgestrel
NorethindroneNorethynodrelNorethisterone
Foyes Principles of Medicinal Chemistry – fig. 29.17
19-Norandrostanes used clinically in oral
contraceptives
Estrógenos
• Síntese de DNA e RNA hepático,
• Enzimas hepáticas
• Enzimas séricas formadas no fígado
• Proteínas plasmáticas
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
Estrogen and progesterone
GnRH
Hypothalamus
Anterior pituitary
Combination oral contraceptives (estrogen and
progestin)
FSH LH
Granulosa cellsOvary
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
OHOHOH
HO HO HO
O
Testosterone
Co
mb
inat
ion
Ora
l Co
ntr
acep
tive
s
Pílula de Primeira Geração
• Etinilestradiol - doses altas (50mcg ou maior)
• Progestágeno - Levonorgestrel, noretisterona ou etinodiol diacetato.
Pílula de segunda geração
•Etinilestradiol (dose até 30 mcg)
•Progestágeno - levonorgestrel ou noretisterona
Pílula de Terceira Geração
• Etinilestradiol (20-30 mcg)
• Progestágeno - desogestrel, gestodeno ou norgestimato
ETINILESTRADIOL + GESTODENO
etinilestradiol 15 mcg + gestodeno 60 mcg etinilestradiol 20 mcg + gestodeno 75 mcg etinilestradiol 30 mcg + gestodeno75 mcg
MINESSEMIRELLE
DIMINUTFEMIANEGINESSEHARMONETMICROPIL R21TÂMISA 20
CICLO 21GESTINOL 28GYNERAMINULETTÂMISA 30
ETINILESTRADIOL + DESOGESTREL
etinilestradiol 20 mcg + desogestrel 150 mcg etinilestradiol 30 mcg + desogestrel 150 mcg)
FEMINAMERCILONMINIANPRIMERA
MICRODIOL
ETINILESTRADIOL+DROSPERINONA
etinilestradiol 20 mcg + drosperinona 3 mg etinilestradiol 30 mcg + drosperinona 3 mg
Yaz YASMIN
ETINILESTRADIOL+CLORMADINONA
etinilestradiol 30 mcg + clormadinona 2mg
BELARA
ETINILESTRADIOL E OUTROS
etinilestradiol 30 mcg + levonorgestrel 150 mcg etinilestradiol 20 mcg + levonorgestrel 150 mcgComp. azul: Desogestrel 0,025 mg + Etinilestradiol 0,04
mg; Comp. branco: Desogestrel 0,125 mg + Etinilestradiol 0,03 mg
CICLONGESTRELANNOCICLINMICROVLARNORDETTE
LEVEL GRACIAL
etinilestradiol 50 mcg + levonorgestrel 250 mcg
EVANORNEOVLAR
Progestin-Only Contraceptives
Mechanism – Altered GnRH release leads to ↓ ovulation
Drug Summary Table – Pharmacology of Reproduction
Norgestrel Norethindrone
Contraception Breakthrough Sporting Norgestrel 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
Contraceptive use in the United States, 1995.
Essential of Reproductive Medicine – Fig. 26.2
26%24%
19%
7% 6%
3%1% 1% 1%
30
25
20
15
10
5
0
Percentage of Women Ages 15-50
Pill Sterilization Condom Withdrawa/ Rhythm
Hysterectomy/ Menopause
Injectable Spermicide IUD Implants
Method
Noncontraceptive Health Benefits of Oral Contraceptives
Percent Reduction/ Protection
(%)Minium Use
RequiredDuration of
EffectOCP
Formulation CommentsDefinitive evidence
Ovarian cancer 40 3-6 months At least 15 >20 µg EE Also protective against years hereditary ovarian cancer
Endometrial cancer 50 12-months 15 years All monophasic No data on multiphasic or progestin-only forms
Benign breast disease 30 12-24 months 1 year >20 µg EE Effect consistent across all age groups
Pelvic inflamatory 50 12 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
Noncontraceptive Health Benefits of Oral Contraceptives
Percent Reduction/ Protection
(%)Minium Use
RequiredDuration of
EffectOCP
Formulation CommentsConflicting evidence, favor beneficial effect
Bone mineral density 60 Unknown Unknown >35 µg EE Decreased incidence of hip fractures with higher doses
Colorectal cancer 40 96 months Unknown >50 µg EE Increasing protection with increased duration
Uterine leiomyomas 30, 50 10 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
Noncontraceptive Health Benefits of Oral Contraceptives
Percent Reduction/ Protection
(%)Minium Use
RequiredDuration of
EffectOCP
Formulation CommentsConflicting 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
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
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.
250
200
150
100
50
020-24 25-29 30-34 35-39 40-44
0 0 0
Age group (years)
Dea
ths
/ 100
,000
wom
en nonuser, nonsmokeruser, nonsmokernonuser, heavy smokeruser, 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
Relative Risk and Actual Incidence of Venous Thromboembolism
Population Relative Risk Incidence
Young women-general population 1 4-5 per 100,000 per year
Pregnant women 12 48-60
High-dose oral contraceptives 6-10 24-50
Low dose oral contraceptives 3-4 12-20
Leiden mutation carrier 6-8 24-40
Leiden carrier and oral contraceptives 10-15 40-75
Leiden mutation – homozygous 80 320-400
A Clinical Guide for Contraception – tab. Pag 53
The carrier frequencies of the Leiden mutation in American population (the percentages are similar in men and women) are as
follows
Caucasian Americans 5.27%
Hispanic Americans 2.21%
Native Americans 1.25%
Black Americans 1.23%
Asian Americans 0.45%
A Clinical Guide for Contraception – tab. Pag 53
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
ConfidenceCases Controls Odds Ratio Interval
Any OC use 57 156 2.35 1.42-3.89
50 µg estrogen OCs 14 22 4.32 1.59-11.74
Old progestin OCs 28 71 2.96 1.54-5.66
New progestin OCs 7 49 0.82 0.29-2.31
A Clinical Guide for Contraception – tab. Pag 55
Incidence of Myocardial Infarction in Reproductive Age Women
Overall incidence 5 per 100,000 per year
Women less than age 35
Nonsmokers 4
Nonsmokers & OCs 4
Smokers 8
Smokers & OCs 43
Women 35 years old and older
Nonsmokers 10
Nonsmokers & OCs 40
Smokers 88
Smokers & OCs 485
A Clinical Guide for Contraception – tab. Pag 57
Incidence of Stroke in Reproductive Age Women
Incidence of
ischemic stroke 5 per 100,000 per year
1-3 per year in women under age 35
10 per 100,000 per year in women over age 35
Incidence of
hemorrhagic stroke 6 per 100,000 per year
Excess cases 2 per 100,000 per year in low-dose OC users
per year due to 1 per 100,000 per year in low-dose OC users under age 35
OCs, including 8 per 100,000 per year in high-dose users
smokers and
hypertensives
A Clinical Guide for Contraception – tab. Pag 61
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
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
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 (Gilbert’s 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
AOC e Fígado
Transporte ativo de componentes biliares é inibido por estrógenos e progestágenos.
Contraindicado formalmente em doença colestática aguda ou crônica
Importante
Não há evidências de aumento de incidência de doença hepática séria causado por uso de ACO
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.
Anel Vaginal (RING)
Emplastro dérmico (patch)
40 mm
2 mm
Rate-controlling membrane: (.06 mm) 100% EVA
Core: 40% Ethylene vinyl acetate (EVA)
60% Etogestrel (68 mg)
Required Equipment for Implanon Insertion
Implantation technique
Technique for the Tcu-380A
Progesterone Receptor Antagonists
Mechanism – Inhibit progesterone binding to receptor
Drug Summary Table – Pharmacology of Reproduction
Mifepristone Medical abortion Bleeding 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
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
Mixed Estrogen / Progestin Oral ContraceptivesMechanism – 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
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
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
Testosterone
O
OH
Foyes Principles of Medicinal Chemistry – pag 685
O
OH
H
5α-Dihydrotestosterone
Foyes Principles of Medicinal Chemistry – pag 685
HO
O
Estrone
Foyes Principles of Medicinal Chemistry – pag. 686
Estriol
HO
OH
OH
Foyes Principles of Medicinal Chemistry – pag. 686
Foy
es P
rinc
iple
s of
Med
icin
al C
hem
istr
y –
fig.
29.
3
HOCholesterol
O
HO
HO
OH
O O
O
Pregnenolone
17α-Hydroxypregnenolone Progesterone
a
b c,d
HO
O O O
O
O
HO
c,d g
OH
O
OOH
HO
OH
OH
i g
f h
e
Dehydroepiandrosterone Androstenedione Estrone
5α-Dihydrotestosterone Testosterone Estradiol
Biosynthesis of sex steroid hormones
Estrogen metabolism
Foy
es P
r inc
i ple
s of
Med
ici n
al C
hem
i str
y –
fig.
29.
5
HO
O O
O
RO
RO
EquilinEquilin sodium sulfate
EstroneEstrone sodium sulfate
Piperazine estrone sulfate
R = HR = SO3 –Na+
R = HR = SO3 –Na+
R = SO3 + N NHH
H
Conjugated and esterified estrogens
Foyes Principles of Medicinal Chemistry – fig. 29.7
O
O
O
O OOH
OH
HOH
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. 29.14
OH
HO
OH
O HOH
O
OHOH
OH
HO
OH
HH
O
OO
O
Testosterone
Epi-testosterone AndrosteroneEstradiol
6α-Hydroxytestostenore
5α-Dihydrotestosterone etiocholanolone
O
OH
H
H
HO
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
Foy
es P
rinc
iple
s of
Med
icin
al C
hem
istr
y –
fig.
29.
18
CH3CH3
H3C N H3CN
O O
OH OHCH2-CH2CH2OHC ≡ CCH3
Mifepristrone Onapristrone
Foyes Principles of Medicinal Chemistry – pag. 703
The tetracyclic ring system characteristic of steroids
Organic Chemistry – fig. 26.9