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Gonadol Drugs
THE ESTROGENS
Natural estrogens
17 estradiol, estrone & estriol- poor oral bioavailabilty hence clinical use limited to HRT when low dose required Synthetic estrogens To overcome poor oral availability Ethyl estradiol, Mestranol & Quinestrol Non steroidal estrogen agonist Diethyl stilboestrol, dienestrol, , benzestrol, hexestrol, methestrol,
Pharmacodynamic, kinetics
Act via 2 estrogen receptors ( & ) Receptor widely distributed resulting in many pharmacological action which
include;
Decrease LDL cholestrol conc, Elevate VLDL & HDL conc, Increase prot synthesis Enhance coagulability of blood thro increase in factor VII, plasminogen activation inhibitor 1 estradiol binds strongly (99% )to an a2 globulin (sex hormone-binding globulin (SHBG) and with lower affinity to albumin. Estradiol is converted by the liver and other tissues to estrone and estriol
Pharmacodynamic, kinetics
Estrogens are metabolised by cytochrome P450 liver enzymes. Drugs such as rifampicin, phenytoin & phenobarbitone may
enhance metabolism
Estrogens & their active metabolites also undergoes enterohepatic
Indication
1. Primary hypogonadism- esp in estrogen-deficient patients due to premature menopause, castration, or menopause or failure of ovary 2. Postmenopausal hormonal therapy ( NB: combined with progestogen in women with intact uterus: 3. Suppression of ovulation ( in conjunction with progestogen) 4. Diethyl stilboestrol
Men : hormonal therapy in prostate cancer & Palliation in metastatic breast cancer Pharmaceuticals: Available as tablets, transdermal patches
C/I
estrogen-dependent neoplasms such as carcinoma of the endometrium, at high risk for carcinoma of the breast. undiagnosed genital bleeding
Side effects
Feminising effect on men (diethyl stilboestrol) Uterine bleeding. The smallest amount of estrogen dose
PROGESTINS
Progesterone & analogues (dydrogesterone, Hydroxyprogesterone, Megestrol & medroxyprosgesterone Testosterone analogues (norethisterone & norgesterel (levonogestrel is the active isomer)
Pharmacokinetics
Progesterone is rapidly absorbed following administration by any route.
MOA
Similar to other steroidal hormones. Act thro progesterone receptors
Indication
1. hormone replacement therapy ( for women with uterus to prevent cystic endometrial hyperplasia 2. hormonal contraception ( Either alone or in combination with estrogens 3. Endometriosis, dysmenorrhea, & bleeding disorders when estrogen is C/I
C/I
Hormone dependent neoplastic dx severe liver impairment &tumors, genital/breast ca Undiagnosed vaginal bleeding Pregnancy Side effects Menstrual disturbance Prementrual like syndrome-bloating, breast tenderness, fluid retention Wt gain CNS-depression, hdx, insomnia
HORMONAL CONTRACEPTION
Oral, parenteral, & implanted contraceptives
MOA
Progestins alone are effective contraceptives: suppress gonadotropin secretion, inhibit mid LH surge & block ovulation, also induce
Introduction
Types of oral contraception; i. ii. combinations of estrogens and progestins continuous progestin therapy without concomitant administration of estrogens. The combination agents are further divided into 2 forms ;
i.
ii.
Oral preps are all adequately absorbed, & the pharmacokinetics of neither drug is
significantly altered by the other.
NB: The estrogen-containing compounds are arranged in order of increasing content of estrogen. (Ethinyl estradiol and mestranol have similar potencies.)
NB: The estrogen-containing compounds are arranged in order of increasing content of estrogen. (Ethinyl estradiol and mestranol have similar potencies.)
Pharmacological effects 1. Depresses ovarian function. A greater majority returns to normal after discontinuation; 75% will ovulate in the 1st post-treatment cycle & 97% by the third3rd cycle. 2% of patients remain amenorrheic for periods of up to several years after administration is stopped 2. hypertrophy and polyp formation of uterus (result in thicker and less copious mucus)
Pharmacological effects
4. thromboembolic phenomena on blood. Factors VII, VIII, IX, and X are increased and a decrease in antithrombin III. Increased amounts of
Indication 1. 2. Contraception Endometriosis Drug Interactions Drugs that stimulate cytochrome enzymes phenytoin, carbamazepine, phenobarbitone & rifampicin- alternative methods may be desired C/I
Side effects
The incidence of serious known toxicities associated with the use COC is
low (far lower than the risks associated with pregnancy) Multiphasic minimize drugs doses hence low incidence of S/E
Mild ADE
Nausea, mastalgia, breakthrough bleeding, & edema are related to the amount of estrogen in the preps
Severe ADE
Vascular disorders
Myocardial infarcts (esp obese, hx of eclampsia, HT, DM venous thromboembolism ( 3 fold increase in risk)), CVA (35yrs)
Postcoital Contraceptives
Pregnancy can be prevented following coitus by the admin of estrogens alone or in combination with progestins ("morning after" contraception). Prostaglandin misoprostol on 3rd & mifepristone on 1st day are also effective When treatment is begun within 72 hours, it is effective 99% of the time
40% of the patients have nausea or vomiting (may require antiemetics) Other adverse effects include headache, dizziness, breast tenderness, and abdominal and leg cramps.
2) Estrogen alone: Ethinyl estradiol: 2.5 mg twice daily for 5 days 3) Progestin alone : L-Norgestrel: 0.75 mg twice daily for 1 day 4) Other: Mifepristone, 600 mg once with misoprostol, 400 mcg once1
Tamoxifen/Toremifene / Clomiphene
Is a triphenylethylene derivatives & structurally similar to diethyl stilboestrol
MOA
In estrogen replete pre-menopausal period, the agents display antiestrogenic effects ( increase folliculogenesis, inhibition of endometrial proliferation, vasodilation (hot flashes) & increased bone resorption
Tamoxifen/Toremifene / Clomiphene
MOA In both pre & post menopausal women, it displays antiestrogenic
Raloxifene
A benzothiophene with a pattern of agonist/antagonist different from triphenylethylene
Raloxifene
Has a high 1st -pass effect, a very large VD & long t (> 24 hrs), so it can be taken once a day.
Indication
1. Raloxifene :Approved in the USA for the prevention of postmenopausal osteoporosis 2. Tamoxifen :
Anovulatory infertility
1. Tamoxifen: Mastalgia (useful adjunct though not licensed indication 2. Toremifene: breast ca in post menopausal women 3. Clomiphene
ADE (clomephene)
hot flushes (resemble those experienced by menopausal patients) eye symptoms due to intensification and prolongation of afterimages Headache, constipation, allergic skin reactions, and reversible hair loss C/I & cautions
Estrogen antagonist
Fulvestrant (pure estrogen receptor antagonist) MOA- it inhibits dimerization of the occupied estrogen receptor and interferes with its binding to DNA Indication: estrogen receptor + metastatic or advanced breast
Aromatase inhibitors
1. Highly specific non steriodal inhibitors include ; Anastrozole, Letrozole , Exemestane & Fadrozole (a newer oral nonsteroidal (triazole)
2.
Dihydrotestosterone
testosterone
Estradiol
5 reductase inhibitors
Aromatase inhibitors
Aromatase inhibitors
Indication Adjuvant Rx of oestrogen receptor + breast tumors resistant to tamoxifen C/I: Pregnancy, breast feeding, premenopausal women
Progestin antagonist
Mifepristone :
binds strongly to the progesterone receptor and inhibits the activity of
progesterone
Has luteolytic properties in 80% of women when given in the midluteal period (mechanism not known).
Has long t
Indication : Postcoital contraceptive (single dose of 600mg), endometriosis, Cushing's syndrome & reast cancer C/I: uncontrolled asthma
Pharmacokinetics Slowly metabolized by liver, ( t 15hrs) Ethisterone, a major metabolite of danazol, has both progestational and mild androgenic effects.
Progestin antagonist
Indication
An inhibitor of gonadal function 1. Endometriosis. 85% of patients show marked improvement in 3-12 months 2. Fibrocystic disease of the breast and hematologic or allergic disorders, including hemophilia, Christmas disease, idiopathic thrombocytopenic purpura, and angioneurotic edema. ADE 3. Wt gain, edema, decreased breast size, acne & oily skin, hirsutism, deepening of the voice, headache, hot flushes, changes in libido, and muscle cramps