Lesson 3 Gonadol Pharmacology

8/13/2019 Lesson 3 Gonadol Pharmacology

1/38

Gonadol Drugs

Metabolic and Endocrine

Pharmacology


2/38

THE ESTROGENS


3/38

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


4/38

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 a 2 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


5/38

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


6/38

Indication

1. Primary hypogonadism- esp in estrogen-deficient patients due to premature menopause, castration, or menopause or failure ofovary

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 breastcancer

Pharmaceuticals: Available as tablets, transdermal patches


7/38

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)


8/38

Side effectsFeminising 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)


9/38

PROGESTINS


10/38

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


11/38

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


12/38

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


13/38

C/I

Hormone dependent neoplastic dx severe liver impairment

&tumors, genital/breast caUndiagnosed vaginal bleeding

Pregnancy

Side effectsMenstrual disturbance

Prementrual like syndrome-bloating, breast tenderness, fluid

retention

Wt gain

CNS-depression, hdx, insomnia


14/38

Oral, parenteral, & implanted contraceptives

HORMONAL CONTRACEPTION


15/38

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


16/38

IntroductionTypes of oral contraception;

i. combinations of estrogens and progestins

ii. continuous progestin therapy without concomitant administration of

estrogens.

The combination agents are further divided into 2 forms ;

i. monophasic (constant dosage of both components during the cycle)

ii. 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.


17/38

Some oral and implantable contraceptive agents in use

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


18/38

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

Some oral and implantable contraceptive agents in use


19/38

Pharmacological effects

1. Depresses ovarian function. A greater majority returns to

normal after discontinuation; 75% will ovulate in the 1 st

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


20/38


21/38

Indication

1. Contraception

2. EndometriosisDrug 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


22/38

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) . B iphasic and

triphasic oral contraceptives decrease the incidences

Weight gain ( more common with COC with andogen like progestins


23/38

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


24/38

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 3 rd & mifepristone on 1 st 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 anti-

emetics)

Other adverse effects include headache, dizziness, breast tenderness,

and abdominal and leg cramps.


25/38

Estrogen Progestin No. of pill

per doseEthyl estradiol 50g Norgestrel 0.5mg 2

Ethyl estradiol 30g Norgestrel 0.3mg 4

Ethyl estradiol 30g Levonogestrel 150g 4

Ethyl estradiol 30g Levonogestrel 125g 4

Schedules for use of postcoital contraceptives.1) Combined

2) Estrogen alone : Ethinyl estradiol: 2.5 mg twice daily for

5 days3) Progestin alone : L-Norgestrel: 0.75 mg twice daily for 1

day4) Other : Mifepristone, 600 mg once with misoprostol, 400

mcg once1


26/38

1. Estrogens partial agonist2. Gonadotropin releasing hormone agonist (leuprolide,

gonadorelin, goserelin3. Aromatase inhibitors4. Progestin antagonist

Estrogen & Progesterone Inhibitors &Antagonists


27/38

Tamoxifen & related partial agonistestrogens

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


28/38

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


29/38

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 tostimulate the endometrium or breast. (lack agonist effect on

reproductive tissues)


30/38

Raloxifene

Has a high 1 st -pass effect, a very large V D & 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.


31/38

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.


32/38

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


33/38

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)


34/38

Aromatase inhibitors1. Highly specific non steriodal inhibitors include ; Anastr ozole, 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 Estradioltestosterone

5 reductaseinhibitors

Aromatase inhibitors


35/38

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)


36/38

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


37/38


38/38

Progestin antagonistIndication

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

Documents

Lesson 3 Gonadol Pharmacology