drugs for female reproductive systems (dr.edy)

7/31/2019 Drugs for Female Reproductive Systems (Dr.edy)

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Drugs for Female Reproductive

Systems

Edy Junaidi


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Neuroendocrine Control

Neuronal oscillatoror clock in the hypothalamus fires at intervals bursts of GnRH release into the hypothalamic-pituitary portal vasculature

GnRH release isintermittent LH and FSH secretion ispulsatile

Thepulse frequencyis determined by the hypothalamic GnRH pulsegenerator

The amount of gonadotropin released in each pulse (i.e., the pulse amplitude) is

largely controlled by the actions of estrogens and progesterone on the pituitary

Ovarian steroids, primarilyprogesterone, regulate the frequency of GnRHrelease by direct and indirect effects on GnRH neurons


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Progesterone decreases the frequency of GnRHpulsesand also exerts a

direct pituitary effect to oppose the inhibitory actions of estrogens and

thus enhance the amount of LH released.

steroid feedback effects, coupled with the intrinsic activity of the GnRH

neurons, lead to relatively frequent LH pulses of small amplitude in the

follicular phase, and less frequent pulses of larger amplitude in the luteal

phase

The ovarian peptide also exerts a negative feedback to selectively

decrease serum FSH


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Role of PGs

PTGES is 150-fold more efficient at converting PGH2 to PGE2 compared with

its conversion to PGF2 by PGFS

PGE2 luteotropic factor

Expression increase during early midluteal cycle

PGF2luteolytic factor

Level increases during late luteal cycle

PG reductase convert PGE2 into PGF2a (increase during late cycle)

HPGD metabolize PGE & PGF2a into inactive metabolites; HPGD level highat mid-late cycle, but reaching lowest level at very late luteal cycle

hCG inhibit the role of PGF2 on Corpus luteum regression

Bogan, et al, 2008


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Estrogens & Progestins

Developmental effects

Control of ovulation

Cyclical preparation of the reproductive tractfor fertilization and implantation

Metabolic actions


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Estrogens

Naturally occuring estrogens : Estradiol, Estriol, Estrone

Secreted by ovarian follicles

Responsible for :

maturation of sex organs

secondary female sex characteristics

Estrogen receptors :

ESR1 encodes ER,

ESR2 encodes ER

Estrogens receptors differ in their ligand-binding, transactivation domain, receptor

distributions, biological effects, & its responds to various estrogenic compounds


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is expressed most abundantly in the female reproductivetractespecially the uterus, vagina, and ovariesas well as in

the mammary gland, hypothalamus, endothelial cells, and

vascular smooth muscle

is expressed most highly in the prostate and ovaries, withlower expression in lung, brain, bone, and vasculature

Both ERs are increase

or decrease the transcription of target genes


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Estrogens available in various preparations : oral, parenteral, transdermal,

or topical administration

Transdermal administration of estradiol provides slow,sustained release

of the hormone, systemic distribution, and more constant blood levels

than oral dosing

The transdermal route does not lead to the high level of the drug

that enters the livervia the portal circulation after oral administration

and is thus may decrease estrogen effects on hepatic protein

synthesis, lipoprotein profiles, and triglyceride levels

Topical preparations (creams or gels) also has lower effects on lipid

profiles compare to oral preps.


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Estrogens are extensively bound to plasma proteins & undergo rapid

biotransformations

Ethinyl estradiol is cleared more slowly than is estradiol due to decreased hepatic

metabolism

Estrogens increase high-density lipoprotein (HDL) levels and decrease the levels of

low-density lipoprotein (LDL) and Lp(a)

Estrogens increase biliary cholesterol secretion and decrease bile acid secretion

increased saturation of bile with cholesterol gallstone formation in some women

receiving estrogens

Estrogen induce NO synthaseand increased production of NOand prostacyclin

promote vasodilation

Estrogens decrease bone resorption


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Therapeutic Uses

Menopausal Hormone Therapy

Vasomotor Symptoms

Osteoporosis

Vaginal Dryness and Urogenital Atrophy

Cardiovascular Disease

Estrogen Treatment In The Failure Of Ovarian Development

Contraceptions


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SELECTIVE ESTROGEN RECEPTOR

MODULATORS AND ANTIESTROGENS

SERMs: TAMOXIFEN, RALOXIFENE, AND TOREMIFENE

ANTIESTROGENS: CLOMIPHENE AND FULVESTRANTpure

antagonistsin all tissues

SERMs effects tissue selective, produce beneficial estrogenic actions incertain tissues (e.g., bone, brain, and liver) but antagonist activity in others

All of these agents bind to the ligand-binding pockets of both ER and ERand competitively block estradiol binding

The distinct ER-ligand conformations recruit different coactivators

and corepressors onto the promoter of a target gene


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Tamoxifen inhibits the proliferation of cultured human breast cancer

cells and reduces tumor size and number in women, yet it stimulates

proliferation of endometrial cells

Tamoxifen has an antiresorptive effect on bone and decreases totalcholesterol, LDL, and Lp(a) but does not increase HDL and triglycerides

Tamoxifen approximately doubles the relative risk of DVT and

pulmonary embolism and endometrial carcinoma

Tamoxifen produces hot flashes and other adverse effects, including

cataracts, nausea, and hepatic steatosis


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Raloxifene :

estrogen agonist in bone and reduces the number of vertebral fractures by up

to 50% in a dose-dependent manner

acts as an estrogen agonist in reducing total cholesterol and LDL but does not

increase HDL or normalize plasminogen-activator inhibitor 1 in

postmenopausal women.

does not cause proliferation of the endometrium.

antiproliferative effect on ER-positive breast tumors and on proliferation of ER

positive breast cancer cell lines and significantly reduces the risk of ER-positive

breast cancer. does not alleviate the vasomotor symptoms associated with menopause

Adverse effects include hot flashes and leg cramps and a threefold increase in

deep vein thrombosis and pulmonary embolism


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Therapeutic Uses

Breast Cancer

Osteoporosis

Infertility


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Estrogen-Synthesis Inhibitors

only prevents ovarian estrogens syntesis

but does not influence adrenal estrogen synthesis development of: steroidal( formestane and exemestane) and

nonsteroidal agents(anastrozole , letrozole, and vorozole) Steroidal agents are substrate analogs that act as suicide inhibitors to

irreversibly inactivate aromatase

Nonsteroidal agents works as reversible aromatase inhibitors

These agents may be used as first-line treatment of breast cancer or as

second-line drugs after tamoxifen


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They are highly efficacious and actually superior to tamoxifen

in some adjuvant settings; unlike tamoxifen, they do not

increase the risk of uterine cancer or venous

thromboembolism

The marked decreases in estrogen levels are likely to be

associated with significant bone loss, but long-term studies are

needed


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PROGESTINS

Progesterone produced in the luteal phase of the cycle decreases the

frequency of GnRH pulses one mechanism of action of progestin-containing contraceptives

Progesterone decreases estrogen-driven endometrial proliferation andinduces a secretory endometrium

Progesterone also influences the endocervical glands, changing the

abundant watery secretion of the estrogen-stimulated to a scant, viscidmaterial sperm difficult to penetrates into cervix

Progesterone and analogs (e.g., MPA) increase LDL and cause either no

effect or modest reduction in serum HDL levels


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Progesterone receptor, PRA and PRB are distinct and vary for

different target genes

In most cells, PRB mediates the stimulatory activities of

progesterone; PRA inhibits this action of PRB and is also a

transcriptional inhibitor of other steroid receptors

Progesterone undergoes rapid first-pass metabolism

Highly bound to protein plasma

Progestins available in various preps.


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Therapeutic Uses

Contraceptions

Hormone replacement therapy

secondary amenorrhea Dysfunctional uterine bleeding

Infertility

premature labor

Diagnostic test for estrogen secretion and endometrium

response


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Progestins for endometrial protection (Oral Cyclic Administrati


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ANTIPROGESTINS AND PROGESTERONE-RECEPTOR

MODULATORS

Mifepristone, Onapristone

Mifepristone effectively competes with both progesterone and

glucocorticoids for binding to their respective receptors

Mifepristone is considered a PR modulator (PRM) due to its context-

dependent antagonist/agonist activity

In the presence of progestins, mifepristone is a competitive antagonist

of both PRs and, in certain contexts, may also be an agonist

In contrast, Onapristone appears to be apure progesterone antagonist


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Therapeutic Uses

Terminate early pregnancy

Contraceptives

Induce labor, To treat uterine leiomyomas, endometriosis, meningiomas,

and breast cancer


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Uterine Stimulants and Relaxants

OXYTOCIN

Natural hormones secreted by posterior pituitary

Stimulate uterine contractions to induce labor

Suckling stimulates release of oxytocin Causes more milk ejection

to induce labor by increasing frequency and force of uterine

contractions

as drug of choice for inducing labor

complications in fetus include dysrhythmias or intracranial hemorrhage

Serious complications in mother may include uterine rupture, seizures, coma


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TOCOLYTICS

Slow uterine contractions to delay labor

Tocolysis may be considered for women with suspected preterm labour who

have had an otherwise uncomplicated pregnancy. It is reasonable not to use anytocolytic drug. B

Women most likely to benefit from use of a tocolytic drug are those who are in

very preterm labour, those needing transfer to a hospital which can provide

neonatal intensive care and those who have not yet completed a full course of

corticosteroids

Tocolysis should not be used where there is a contraindication to prolonging

pregnancy


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TOCOLYTICS

NSAIDs

Beta agonist

Calcium channel Blockers (Nifedipin)

Mg Sulfat

Oxytocin antagonist (Atosiban)


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Nifedipine and atosiban have comparable effectiveness in delaying birth for up

to seven days.

Compared with beta-agonists, nifedipine is associated with improvement in

neonatal outcome, although there are no long-term data

Beta-agonists have a high frequency of adverse effects. Nifedipine, atosiban and

the COX inhibitors have fewer types of adverse effects, and they occur less

frequently than for beta-agonists but how they compare with each other is

unclear.

Using multiple tocolytic drugs appears to be associated with a higher risk of

adverse effects and so should be avoided


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The suggested dose of nifedipine is an initial oral dose of 20 mg followed by

1020 mg three to four times daily, adjusted according to uterine activity for up

to 48 hours. A total dose above 60 mg appears to be associated with a three- to

four-fold increase in adverse events.

A suggested dose of atosiban of an initial bolus dose of 6.75 mg over 1 minute,

followed by an infusion of 18 mg/hour for 3 hours, then 6 mg/hour for up to

45 hours (to a maximum of 330 mg).

There is insufficient evidence for any firm conclusions about whether or notmaintenance tocolytic therapy following threatened preterm labour is

worthwhile. Thus, maintenance therapy is not recommended

drugs for female reproductive systems (dr.edy)

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