PHRM 825 Lecture 14- Progestins

where is progesterone synthesized

corpus luteum in the ovary and the placenta during pregnancy

what is progesterone converted to to be excreted and where is it excreted from

pregnanediol and excreted in the urine

physiologic effects of progesterone

-menstruation cycle

-metabolic effects (increase insulin levels and promote glycogen storage)

-interference with aldosterone (causes decrease in Na+ reabsorption)

-depressant and hypnotic effects on the brain

clinical uses of progesterone

-hormonal contraception

-hormone replacement therapy in combination with estrogens

-endometriosis (suppress growth of endometrial cells)

-dysmenorrhea

-bleeding disorders

how does the native acetyl moiety affect progestins in the body

it has poor oral bioavailability

19-nor, 17-ethynyl steroids: explain the significance

oral contraception

-17-ethynyl group increases oral bioavailability

-19-methyl group is not necessary for progestenic activity, replacing with H enhances the activity

1st generation progestin

replacement of acetyl group with OH increases bioavailability

norethindrone

1st generation progestin

ethynodiol diacetate

2nd generation progestin

only levo form is active

high oral availability

used in IUDs and Mirena

levonorgestrel

prodrug

converted to levonorgestrel

norgestimate

3rd generation progestin

prodrug

high oral availability

metabolized to etonogestrel

desogestrel

active form of desogestrel

structurally analogous to levonorgestrel

used in the implant or the vaginal ring

etonogestrel

4th generation progestin

weak progestognenic activity

antimineralocorticoid activity

negates side effects of ethynyl estradiol in combo therapy

drospirenone

1st generation progestin

used for depot injection as progesterone only

medroxyprogesterone acetate

which hormonal contraception has the least androgen and anti estrogen effects

drospirenone

continuous progestin therapy without estrogen

minipill

pharmacological effects of oral contraceptives

-inhibition of ovulation (inhibit pituitary function)

-effects on the ovary (suppression of ovarian function)

-effects on the uterus (change in cervical mucus)

-effects on the breast (enlargement)

mild adverse effects of oral contraceptives

-nausea, hypertension, edema, breast fullness- estrogens

-increased appetite, fatigue, breast regression- progestins

moderate adverse effects of oral contraceptives

-irregularities in menstruation, weight gain, acne, hirsutism, amenorrhea

severe adverse effects of oral contraceptives

venous thromboembolic disease-estrogens

myocardial infarction- due to androgenic activity of progestins

dangerous in women over 35 who smoke

what interactions do progestins have with other steroids and an example

may increase the blood levels by interfering with their metabolism, glucocorticoids

what interactions do progestins have with anticonvulsants

phenytoin- induces drug metabolizing enzymes in the liver

what interactions do progestins have with antibiotics

Rifampin- induces drug metabolizing enzymes in the liver, increases rate of metabolism of many other drugs

Tetracyclines- suppresses gut flora that participate in enterohepatic recycling

types of emergency contraceptives

combination (oral, preven- ethinyl estradiol + norgesterel)

progestin only (plan B- levonorgestrel)

selective progesterone receptor modulator (SPRM)

emergency contraceptive

ulipristal acetate

RU-486

progesterone antagonist

abortifacient (in combination with misoprostol)

mifepristone

weak androgen, weak progestin, and antiestrogen

effective for endometriosis (inhibit surge of LH and FSH, atrophy of endometrium)

weight gain, decreased breast size, acne, oily skin

contraindications: hepatic dysfunction, pregnancy + breastfeeding

danazol