L 14 progestins Flashcards
progesterone
-Most important progestin in human
-Functions as a hormone and also a precursor to the estrogens, androgens, and corticosteroids.
-Binds to the progesterone receptor and alters rate of transcription
-Synthesized in the ovary, testis, and the adrenal glands.
-A large quantity of progesterone is synthesized by the corpus luteum in the ovary in the luteal phase and by the placenta during pregnancy
metabolism
-Rapidly absorbed following administration by any route.
-Half-life in the plasma ~5 min
-Synthetic progestins are used clinically.
-Almost completely metabolized in one passage through the liver.
-Converted to pregnanediol and conjugated with glucuronic acid.
-Excreted into the urine
physiological effects
menstruation cycle,
metabolic effect
interference with aldosterone
depressant and hypnotic effets on the brain
menstruation cycle physiological effects
causes the maturation and secretory changes in the endometrium following ovulation
metabolic effect physiological effects
-increases basal insulin levels and the insulin response to gluscose
-promotes glycogen storage in the liver
interference with aldosterone physiological effects
-completes with aldosterone for the mineralocorticoid receptor
-causes a decrease in Na+ reabsorption –> increase in aldosterone secretion by the adrenal cortex (in pregnancy)
clinical uses
-hormonal contraception
-hormone replacement therapy in combination with estrogens
-endometriosis
-dysmenorrhea
-bleeding disorders
hormonal replacement therapy in combination with estrogen
Prevents some adverse effects of estrogens (uterine bleeding and endometrial carcinoma).
endometriosis
-Growth of endometrial cells outside the uterine cavity
-The cells respond to the hormonal changes and cause severe pain from inflammation during menstruation.
-Progestins suppress the growth of endometrial cells
19 nor, 17 ethynyl steroids (oral contraceptives)
-1 st generation progestins
-17-ethynyl group increases oral bioavailability.
-19-methyl group is not necessary for progestenic activity.
-Replacement of 19-methyl with H enhances the activity.
-Replacement of 17-acetyl with OH increases oral bioavailability.
-Ester groups are rapidly hydrolyzed in vivo.
levonorgestrel
-2 nd generation progestin
-Levo isomer of norgestrel, which is a racemic mixture.
-Only levo form is active.
-High oral bioavailability
-Used in intrauterine devices (IUDs) also (Mirena ®)
etonogestel
-The active form of desogestrel
-Structurally analogous to levonorgestrel
-Used in the subdermal implant (Nexplanon ®) or the vaginal ring (Nuvaring ®).
drospirenone
-4 th generation progestin
-Relatively weak progestogenic activity (10% of levonorgestrel)
-Antimineralocorticoid activity
-Negates side effects of ethynyl estradiol in combination therapy.
medroxyprogesterone acetate
-1 st generation progestin
-Used for depot injection (Depo- Provera ®) as a long-acting progesterone-only contraceptive.
hormonal activites of progestins
-Progestins frequently have hormonal activities other than progestonic effects due to their interaction with other steroid receptors.
-Minimizing androgenic and antiestrogenic activities are desirable
types of hormonal contrception
-Combinations of estrogens (ex. ethynyl estradiol or mestranol) and progestins
=Typically 21 days on active compounds and 7 days on placebo (à withdrawal bleeding)
=Monophasic, biphasic, or triphasic according to the dose variation
-Continuous progestin therapy without estrogen (“minipill”, ex. norethindrone)
delivery of hormonal contraception
-Mostly oral administration
=Adherence to the administration schedule is more critical for progestin-only therapies.
-Implantable (etonogestrel), IUD (levonogestrel), or depot injection (medroxyprogesterone acetate)
pharmacologial effects of oral contraceptives: inhibition of ovulation
-Combinations of estrogens and progestins selectively inhibit pituitary function.
-Progestin-only contraceptives do not always inhibit ovulation
pharmacologial effects of oral contraceptives: effects of ovarian functions
-Suppression of ovarian function
-When discontinued, a majority of patients return to the normal cycle in 1-2 months
pharmacologial effects of oral contraceptives: effect on the uterus
Change in the cervical mucus and in the uterine endometrium à decrease in the likelihood of conception and implantation
pharacological effects of oral contraceptives: effects on the breasts
-combination only
-Stimulation of the breasts à enlargement
-Suppression of lactation
mild adverse effects of oral contraceptives
-Nausea, hypertension, edema, breast fullness – due to estrogens
-Increased appetite, fatigue, breast regression – due to progestins
moderate adverse effects of oral contraceptives
-Irregularities in menstruation (breakthrough bleeding) – more common in progestin-only contraceptives
-Weight gain, acne, hirsutism – more common with the combinations containing androgen-like progestins
-Amenorrhea
severe adverse effects of oral contraceptives
-Venous thromboembolic disease – due to estrogens
-Myocardial infarction – due to androgenic activity of progestins
-Can be dangerous in women over 35 who smoke
drug interactions: other steroids
-Oral contraceptives may increase the blood levels of other steroids by interfering their metabolism.
-Ex. glucocorticoids
drug interactions: anticonvulsants
Phenytoin; Induces drug-metabolizing enzymes in the liver
drug interactions: antibiotics
-Rifampin
-Induces drug metabolizing enzymes in the liver.
-Increases the rate of metabolism of many other drugs.
-Tetracyclines
-Suppresses gut flora that participate in enterohepatic recycling.
emergency contraceptives
-Postcoital (“morning-after”) contraception
-Effective 99% of the time, when the treatment is begun in 72 hrs.
-Similar to oral contraceptives, but with much higher doses.
-Types
=Combination (originated from the Yuzpe regimen)
=Ex. Ovral ®, Preven ® (ethinyl estradiol 50 μg + norgestrel 500 μg)
=Progestin only
=Ex. Plan B ® (levonorgestrel 750 μg)
-Side effects
=Nausea, vomiting – more common in combinations
ulipristal acetate
-Selective progesterone receptor modulator (SPRM)
-Used as an emergency contraceptive
-Can be effective up to 5 days after an unprotected sex
-Side effects: Nausea, Abdominal pain
mifepristone
-RU-486
-Progesterone antagonist
-Abortifacient: Used in combination with misoprostol (PGE 1derivative, oral prostaglandin) up to 70 days.
-Side effects:
=Nausea, vomiting,
=Bleeding (5%) (Requires intervention, Administered only by physicians)
danazol
-weak androgen, weak progestin, and antiestrogen
-effective for endometriosis
danazol: effective for endometriosis
-Inhibits the surges of LH and FSH and suppress
ovarian function.
-Causes atrophy of the endometrium.
adverse effects of danazol
-Mostly from weak androgenic activity
-Weight gain, decreased breast size, acne, oily skin,
hirsutism
danazol contraindications
-hepatic dysfunction
-pregnancy and breast feeding
progestins
-Norethindrone
-Ethynodiol diacetate
-Levonorgestrel
-Norgestimate
-Desogestrel
- Etonogestrel
-Drospirenone
-Medroxyprogesterone acetate
selective progesterone receptor modulators
Ulipristal acetate (Ella ®)
progesterone antagonist
Mifepristone (Mifeprex)
atypical drugs
Danazol (Danocrine ®)
