Progestins

Question 1

Levonorgestrel

Answer 1

2nd generation progestin
- levo isomer or norgestrel, which is racemic mixture
- only levo form is active
- high bioavailability

Question 2

Norgestimate

Answer 2

• prodrug
• converted to levonorgestrel oxime and then to levonorgestrel in vivo

Question 3

Desogestrel

Answer 3

3rd generation progestin
- prodrug
- rapidly metabolized to etonorgestrel
- high oral bioavailability

Question 4

Etonogestrel

Answer 4

• active form of desogestrel
• structurally analogous to levonorgestrel
  use: subdermal implant of vaginal ring

Question 5

Drospirenone

Answer 5

4th generation progestin
- relatively weak progestogenic activity (10% levonorgestrel)
- antimineralcorticoid activity
- negates side effects of ethynyl estradiol in combo therapy

Question 6

Medroxyprogesterone acetate

Answer 6

1st generation progestin
use: depot injection as a long-acting progesterone only contraceptive

Question 7

Ulipristal acetate

Answer 7

Selective progesterone receptor modulator (SPRM)
use: emergency contraceptive
- can be effective up for 5 days
side effects: nausea, abdominal pain

Question 8

Mifepristone

Answer 8

RU-486
- progesterone antagonist
- abortifacient (used in combo with misoprostol up to 70 days)
side effects: nausea, vomiting, bleeding (5%-requires intervention)

Question 9

Danazol

Answer 9

use: endometriosis
- inhibits surges of LH and FSH and suppresses ovarian function
- causes atrophy of endometrium
adverse effects:
- mostly from weak androgenic activity (weight gain, decreased breast size, acne, oily skin, hirsutism)
contraindications: hepatic dysfunction, pregnancy and breast feeding

Question 10

What are the physiological effects of progesterone? (4)

Answer 10

1) Menstrual Cycle
- causes maturation and secretory changes in the endometrium following ovulation
2) Metabolic Effects
- inc basal insulin levels and insulin response to glucose
3) Interferences with Aldosterone
- competes with aldosterone for mineralocorticoid receptor
- causes decrease in NA reabsorption -> inc aldosterone secretion by adrenal cortex
4) Depressant and hypnotic effects on the brain

Question 11

What are the clinical uses of progestins? (5)

Answer 11

1) Hormonal Contraception
2) Hormone Replacement Therapy in combo with estrogens
- prevents adverse effects of estrogens
3) Endometriosis
- growth of endometrial cells outside uterine cavity
- cells respond to hormonal changes and cause severe pain from inflammation during menstruation
- progestins suppress growth of endometrial cells
4) Dysmenorrhea
5) Bleeding Disorders

Question 12

What are the structural characteristics responsible for changes in drug properties of progestins?

Answer 12

1) 17a-ethynyl = oral activity
2) 3-ketone essential for activity, introduced by in vivo oxidation
3) acetyl moiety = highest activity (poor oral bioavailability)
4) 17B-OH or esters = oral activity
5) 19-methyl with H = enhances activity

Question 13

Explain the MOA of Hormonal Contraceptives (3)

Answer 13

1) Ovulation stops -> hormone levels are steady, no LH surge, no egg release
2) Thicken Cervical Mucus -> progestin makes mucus sticky, hard for sperm to swim through
3) Thin Uterine Lining -> progestin keeps endometrium thin

Question 14

What are the types of hormonal contraceptives?

Answer 14

1) Estrogen combos
- typically 21 days, 7 day placebo
- mono/bi/triphasic
(ex) ethynyl estradiol or mestranol
2) Progestin therapy (no estrogen)
(ex) norethindrone

Question 15

Adverse Effects of hormonal contraceptives (mild/mod/severe)

Answer 15

Mild:
estrogen -> nausea, HTN, edema, breast tenderness
progestin -> inc appetite, fatigue, breast regression
Mod:
progestin only -> irregularities in menstruation
androgen-like progestins -> weight gain, acne, hirsutism
Severe:
estrogens -> venous thromboembolic disease
progestins -> myocardial infarction
can be dangerous in women over 35 who smoke

Question 16

Common drug interactions (3)

Answer 16

1) Other Steroids
- contraceptives inc blood levels of other steroids by interfering with metabolism (glucocorticoids)
2) Anticonvulsants
- Phenytoin (induces drug metabolizing enzymes in liver)
3) Antibiotics
- Rifampin (induces drug metabolizing enzymes, inc rate of metabolism)
- Tetracyclines (suppresses gut flora participating in enterohepatic recycling)