Page 752 - Basic _ Clinical Pharmacology ( PDFDrive )

738 SECTION VII Endocrine Drugs

Prevention of the expected loss of lumbar spine bone density Mifepristone’s major use thus far has been to terminate early
and plasma lipid changes consistent with a reduction in the risk pregnancies. Doses of 400–600 mg/d for 4 days or 800 mg/d for
for atherosclerosis have also been reported in tamoxifen-treated 2 days successfully terminated pregnancy in >85% of the women
patients following spontaneous or surgical menopause. However, studied. The major adverse effect was prolonged bleeding that
this agonist activity also affects the uterus and may increase the on most occasions did not require treatment. The combination
risk of endometrial cancer. of a single oral dose of 600 mg of mifepristone and a vaginal
Raloxifene is another partial estrogen agonist-antagonist at pessary containing 1 mg of prostaglandin E or oral misoprostol
1
some but not all target tissues. It has estrogenic effects on lipids has been found to effectively terminate pregnancy in over 95%
and bone but appears not to stimulate the endometrium or breast. of patients treated during the first 7 weeks after conception. The
Although subject to a high first-pass effect, raloxifene has a very adverse effects of the medications included vomiting, diarrhea,
large volume of distribution and a long half-life (>24 hours), so and abdominal or pelvic pain. As many as 5% of patients have
it can be taken once a day. Raloxifene has been approved in the vaginal bleeding requiring intervention. Because of these adverse
United States for the prevention of postmenopausal osteoporosis effects, mifepristone is administered only by physicians at family
and prophylaxis of breast cancer in women with risk factors. planning centers. Note: In a very small number of cases, use of a
Newer SERMs have been developed and one, bazedoxifene, in vaginal tablet for the prostaglandin dose has been associated with
combination with conjugated estrogens, is approved for treatment sepsis, so it is recommended that both drugs be given by mouth
of menopausal symptoms and prophylaxis of postmenopausal in all patients.
osteoporosis. ZK 98734 (lilopristone) is a potent experimental progester-
Clomiphene is an older partial agonist, a weak estrogen that one inhibitor and abortifacient in doses of 25 mg twice daily.
also acts as a competitive inhibitor of endogenous estrogens Like mifepristone, it also appears to have antiglucocorticoid
(Figure 40–5). It has found use as an ovulation-inducing agent activity.
(see below).
DANAZOL
MIFEPRISTONE (RU-486)
Danazol, an isoxazole derivative of ethisterone (17α-ethinyl-
Mifepristone is a “19-norsteroid” that binds strongly to the pro- testosterone) with weak progestational, androgenic, and gluco-
gesterone and glucocorticoid receptors and inhibits the activity of corticoid activities, is used to suppress ovarian function. Danazol
progesterone and that of glucocorticoids (see Chapter 39). The inhibits the midcycle surge of LH and FSH and can prevent
drug has luteolytic properties in 80% of women when given in the the compensatory increase in LH and FSH following castration
midluteal period. The mechanism of this effect is unknown, but in animals, but it does not significantly lower or suppress basal
it may provide the basis for using mifepristone as a contraceptive LH or FSH levels in normal women (Figure 40–5). Danazol
(as opposed to an abortifacient). However, because the compound binds to androgen, progesterone, and glucocorticoid receptors
has a long half-life of 20–40 hours, large doses may prolong the and can translocate the androgen receptor into the nucleus to
follicular phase of the subsequent cycle and so make it difficult initiate androgen-specific RNA synthesis. It does not bind to
to use continuously for this purpose. A single dose of 600 mg is intracellular estrogen receptors, but it does bind to sex hormone–
an effective emergency postcoital contraceptive, though it may binding and corticosteroid-binding globulins. It inhibits P450scc
result in delayed ovulation in the following cycle. As noted in (the cholesterol side chain–cleaving enzyme), 3β-hydroxysteroid
Chapter 39, the drug also binds to and acts as an antagonist at dehydrogenase, 17α-hydroxysteroid dehydrogenase, P450c17
the glucocorticoid receptor. Limited clinical studies suggest that (17α-hydroxylase), P450c11 (11β-hydroxylase), and P450c21
mifepristone or other analogs with similar properties may be use- (21β-hydroxylase). However, it does not inhibit aromatase, the
ful in the treatment of endometriosis, Cushing’s syndrome, breast enzyme required for estrogen synthesis. It increases the mean
cancer, and possibly other neoplasms such as meningiomas that clearance of progesterone, probably by competing with the
contain glucocorticoid or progesterone receptors. hormone for binding proteins, and may have similar effects on
H C CH 3 other active steroid hormones. Ethisterone, a major metabolite
3
N of danazol, has both progestational and mild androgenic effects.
Danazol is slowly metabolized in humans, having a half-life of
>15 hours. This results in stable circulating levels when the drug
OH is administered twice daily. It is highly concentrated in the liver,
H C C CCH 3 adrenals, and kidneys and is excreted in both feces and urine.
3
Danazol has been employed as an inhibitor of gonadal function
and has found its major use in the treatment of endometriosis.
For this purpose, it can be given in a dosage of 600 mg/d. The
dosage is reduced to 400 mg/d after 1 month and to 200 mg/d
O in 2 months. About 85% of patients show marked improvement
Mifepristone in 3–12 months.