Review of Pharmacology - 9E (2015)

Endocrinology
• SERMs are targeted to provide beneficial effect of estrogen as well as to antagonize
its adverse effects. Clomiphene, tamoxifen, doloxifene, toremifene, fulvestrant,
raloxifene, bazedoxifene, ospemifene and ormeloxifene are now classified as
SERMs.
• In humans clomiphene has estrogen antagonistic action in hypothalamus (reduces
feedback inhibition of GnRH secretion). It is used for the treatment of anovulatory
infertility by increasing GnRH release. Major adverse effect is hyperstimulation
syndrome (polycystic ovarian disease) and multiple pregnancy.
• Tamoxifen, doloxifene and toremifene possess estrogen antagonistic activity in
the breast and blood whereas agonistic activity in bone, uterus and liver. Their
major indication is in the treatment of breast carcinoma. These have beneficial
effect on bone and lipid profile but increase the risk of endometrial carcinoma and
thromboembolism.
• Raloxifene and bazedoxifene are used for osteoporosis. Raloxifene also possesses
beneficial effects on lipid profile, breast and endometrium. Major adverse effect is
increased predisposition to thromboembolism.
• Selective tissue estrogen activity regulators (STEAR) are the compounds with
estrogenic activity, tissue-selective mode of action and particular metabolism
that regulates ligand levels. Tibolone belongs to this group. It is considered as a
designer HRT and is used for preventing vasomotor symptoms and osteoporosis
in menopause.
• Centchroman (ormeloxifene) is used as a non hormonal oral contraceptive
(Saheli). It is also approved for the treatment of DUB.
• Fulvestrant is the first FDA approved agent in the new class of drugs that are called
selective estrogen-receptor downregulators (SERDs). These have an improved
safety profile, faster onset, and longer duration of action than the SERMs due to their
pure ER antagonist activity. It was approved for postmenopausal women with
hormone receptor-positive metastatic breast cancer that has progressed despite
antiestrogen therapy. It binds to the estrogen receptor (ER) with an affinity
more than 100 times that of tamoxifen, inhibits its dimerization, and increases
its degradation. As a consequence of this ER “downregulation,” ER-mediated
transcription is abolished, completely suppressing the expression of estrogendependent
genes. This difference in the activity of fulvestrant likely explains why
fulvestrant demonstrates efficacy against tamoxifen-resistant breast cancer.
Fulvestrant is administered intramuscularly at monthly intervals. Most common
adverse effects of this drug include nausea, asthenia, pain, vasodilation (hot flushes),
and headache.
Tamoxifen has
Beneficial effect on three B
Bone (↓ resorption)
Breast (↓ carcinoma)
Blood (↑ HDL & ↓ LDL)
Fulvestrant is a selective estro
gen-receptor downregulator
(SERD). It has improved
safety profile, faster onset, and
longer duration of action than
the SERMs due to its pure ER
antagonist activity.
General Endocrinology Pharmacology
Aromatase Inhibitors
Androgens are converted to estrogen in the peripheral tissue of post-menopausal females
with the help of an enzyme, aromatase. The drugs inhibiting this enzyme will decrease the
formation of estrogen and are beneficial in the treatment of breast carcinoma. Aromatase inhibitors
are divided into first and second generation compounds. First generation drugs include
aminoglutethimide and second generation agents are letrozole, anastrozole, fadrozole,
formestane, vorozole and exemestane. These can also be classified as steroidal or type I
(formestane, exemestane) and nonsteroidal or type II (letrozole, anastrozole, vorozole)
inhibitors. Type I are irreversible (suicide) whereas type II are reversible inhibitors of aromatase.
These are useful for the treatment of tamoxifen resistant breast carcinoma. Common side
effects of these drugs include bone pain, hot flushes and thromboembolism.
Progestins
Progesterone is the most important progestin in humans. It is primarily secreted by corpus
luteum. Synthetic progestins may be classified as:
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