Metabolic and Endocrine Pharmacology

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,

methallenestril & chlorotrianisene

Tibolone has estrogenic, progestogenic & weak androgenic activity

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

circulation. This ensures high ratio of hepatic to peripheral effects

of orally administered estrogen Estrogen freely filtered by kidney but are readily reabsorbed Estrogens are also excreted in small amounts in the breast milk

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

liver disease Hx of thromboembolic disorder. heavy smokers. Caution

Surgery (HRT stopped 4-6wks before)

Side effects
Feminising effect on men (diethyl stilboestrol) Uterine bleeding. The smallest amount of estrogen dose

should be used (however rule out endometrium cancer)

Breast cancer- with long term use ( & no protective effect with progestogen adenocarcinoma of the vagina in young women whose mothers were large doses of diethyl stilboestrol)

PROGESTINS

 Progesterone & analogues (dydrogesterone, Hydroxyprogesterone, Megestrol & medroxyprosgesterone Testosterone analogues (norethisterone & norgesterel (levonogestrel is the active isomer)

Newer progestogens ( desogestrel, norgestimate & gestodene are

derivatives of norgesterel, & have no androgenic activity Lynestreno

Pharmaceuticals: Available as tablets, & long acting IM depot

Pharmacokinetics
Progesterone is rapidly absorbed following administration by any route.

tin the plasma is 5 min, and small amounts are stored

temporarily in body fat. The bioavailablity of natural progesterone is poor orally due hepatic metabolism. However, high-dose oral micronized progesterone preps have been developed that

provide adequate progestational effect

Synthetic progesterone have good oral bioavailability

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

atropy of endometrial glands, thicken cervical mucus, decrease tubal

molitity thus decrease fertility when used with estrogen, the dose required for above is low ( increase tissue sensitivity) Estrogen suppresses FSH to a greater extent than progesterone ( additional ovarian suppression) Estrogen also reduce incidence of break thro menstrual bleeding

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.

monophasic (constant dosage of both components during the cycle)

Biphasic or triphasic forms (dosage of one or both components is changed once or twice during the cycle).

Oral preps are all adequately absorbed, & the pharmacokinetics of neither drug is
significantly altered by the other.

Some oral and implantable contraceptive agents in use

NB: The estrogen-containing compounds are arranged in order of increasing content of estrogen. (Ethinyl estradiol and mestranol have similar potencies.)

Some oral and implantable contraceptive agents in use

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)

3. Breast enlargement; only small & negligible amount is secreted

to the milk

Pharmacological effects
4. thromboembolic phenomena on blood. Factors VII, VIII, IX, and X are increased and a decrease in antithrombin III. Increased amounts of

coumarin anticoagulants may be required to prolong prothrombin time in

patients taking oral contraceptives. (drug interactions) 5. 6. Altered lipid metabolism Increased cardiac output associated with higher systolic and diastolic BP & HR (normalizes on discontinuation) 7. Increased pigmentation of the skin (chloasma) Enhanced in dark complexion skin & UV exposure. Androgen-like progestins might may increase the production of sebum (acne)

Indication 1. 2. Contraception Endometriosis Drug Interactions Drugs that stimulate cytochrome enzymes phenytoin, carbamazepine, phenobarbitone & rifampicin- alternative methods may be desired C/I

The same as estrogen & progestins

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

Headache is mild and often transient. However, migraine is often made

worse and has been reported to be ass with an increased freq of CVA Withdrawal bleeding may fail to occur esp with COC

Moderate ADE ( may require discontinuation)

Breakthrough bleeding (more common with progestins) . Biphasic and triphasic oral contraceptives decrease the incidences Weight gain ( more common with COC with andogen like progestins

Moderate ADE ( may require discontinuation)

Hirsutism (aggravated by the "19-nortestosterone" derivatives ) Ureteral dilation similar to that observed in pregnancy has been reported, and bacteriuria is more frequent. Vaginal infections is difficult to trear Amenorrhea

Severe ADE
Vascular disorders
Myocardial infarcts (esp obese, hx of eclampsia, HT, DM venous thromboembolism ( 3 fold increase in risk)), CVA (35yrs)

Git disorders - cholestatic jaundice (esp due to progestin) , gallbladder disease

(cholecystitis & cholangitis Depression occur in 6% & require cessation

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.

Schedules for use of postcoital contraceptives. 1) Combined

Estrogen Ethyl estradiol 50g Ethyl estradiol 30g Ethyl estradiol 30g Ethyl estradiol 30g Progestin Norgestrel 0.5mg Norgestrel 0.3mg Levonogestrel 150g Levonogestrel 125g No. of pill per dose 2 4 4 4

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

Estrogen & Progesterone Inhibitors & Antagonists

1. Estrogens partial agonist
2. Gonadotropin releasing hormone agonist (leuprolide, gonadorelin, goserelin 3. Aromatase inhibitors 4. Progestin antagonist

Tamoxifen & related partial agonist estrogens

Tamoxifen , Toremifene, Raloxifene & Clomiphene

Chemistry & MOA

Demonstrate as selective estrogen receptor modulator i.e., Level of estrogenic or anti-estrogenic activity depends on endogenous estrogen & organ affected However, pharmacologically, they are competitive partial agonist inhibitor of estradiol at the estrogen receptor Are antiestrogenic in treatment of infertility & breast cancer

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

In estrogen deficit post-menopausal period, it displays agonist effect

e.g. increased bone resorption & plasma protein, endometrial proliferation

Tamoxifen/Toremifene / Clomiphene
MOA In both pre & post menopausal women, it displays antiestrogenic

effects on the breast cancer

Raloxifene
A benzothiophene with a pattern of agonist/antagonist different from triphenylethylene

Has similar effects on lipids & bone but appears not to

stimulate the endometrium or breast. (lack agonist effect on

reproductive tissues)

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

estrogen receptor + early breast cancer ( Primary therapy

for metastatic breast ca) in doses 20-40mg/day.

1. Tamoxifen: Mastalgia (useful adjunct though not licensed indication 2. Toremifene: breast ca in post menopausal women 3. Clomiphene

Partial agonist at estrogen receptors.

Clomiphene has also been shown to effectively inhibit the action of stronger estrogens. In humans it leads to an increase in the secretion of gonadotropins and estrogens by inhibiting estradiol's -ve feedback effect on the gonadotropins Indication:1st line treatment of female infertility (not due to hypopituitarism or hyperprolactemia.

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

enlarged ovaries (more sensitive hence small doses. Max

enlargement occurs after the 5-day course

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

ca in post menopausal women

C/I : pregnancy S/E: hot flashes, venous thromboembolism, GIT (nausea)

Aromatase inhibitors
1. Highly specific non steriodal inhibitors include ; Anastrozole, Letrozole , Exemestane & Fadrozole (a newer oral nonsteroidal (triazole)

2.

Others weak aromatase inhibitor: aminoglutethimide, testolactone, 4-OH

androstenedione MOA

Inhibit both adrenal & gonadol androgens

Provide alternative pharmacological avenue of inhibiting estrogen action

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

S/E : GIT (nausea, Vomiting, Abd pain, constipation)

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

Progestin antagonist Danazol

isoxazole derivative of ethisterone (17-ethinyltestosterone)

It binds to androgen, progesterone, and glucocorticoid receptors

Weak progestational, androgenic, and glucocorticoid activities, is used to suppress ovarian function does not bind to estrogen receptors nor does it inhibit aromatase

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