Pharmacokinetic and Pharmacodynamic of

Hormonal Contraception

Hasanul Arifin - Tri Widyawati

Departement of Pharmacology & Therapeutic
School of Medicine
2008
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 INTRAUTERINE SYSTEM

INJECTION HORMONAL CONTRACEPTION ORALLY

IMPLANT

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Siklus Menstruasi

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The Estrogens

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 Natural Estrogens : biosynthesis and metabolism

Follicular Phase Lutheal Phase

Pregnenolone Pregnenolone

17-Hydroxypregnolone Progesterone

Dehydroepiandrosterone 17-Hydroxyprogesterone

Androstenedione Testoterone

Estriol 16-Hydroxyestrone Estrone 17-Estradiol

2-Hydroxyestrone and 2-Hydroxyestradiol and

other metabolites other metabolites 6
 Synthetic Estrogens
Steroidal, natural : estradiol, estrone,
estriol
Steroidal, synthetic : ethynil estradiol,
mestranol, quinestrol
Nonsteroidal, synthetic ;
diethylstilbestrol, chlorotrianisme,
methallenestril

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 Pharmacokinetics
Absorbed : small intestine

Binds : strongly affinity 2-globulin (SHBG)

lower affinity albumin

Liver and other tissues : converted to

- estrone and estriol ( low affinity for the estrogen reseptor )
- 2-hydroxylated derivatives Enterohepatic
- conjugated metabolites circulation

Excreted : the bile

the breast milk (small amounts)

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 Commonly used estrogens
Average replacement dosage
Ethynyl estradiol 0.005 0.02 mg/d
Micronized estradiol 1 2 mg/d
Estradiol cypionate 2 5 mg every 3-4 weeks
Estradiol valerate 2 20 mg every other week
Estropipate 1.25 2.5 mg/d
Conjugated, esterified, or mixed estrogenic
substances :
Oral 0.3 1.25 mg/d
Injectable 0.2 2 mg/d
Transdermal Patch
Diethylstilbestrol 0.1 0.5 mg/d
Quinestrol 0.1 0.2 mg/week
Chlorotrianisene 12 25 mg/d
Methallenestril 3 9 mg/d
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 Physiologic effects
Female maturation
Endometrial :
- growth effects on uterine muscle
- the development of the endometrial lining
Metabolic and cardiovascular :
- maintenace of the normal structure and function of the skin
and blood vessels in women
- decrease the rate of resorption of bone
- stimulated adipose tissue production
- alter the production and activity of many proteins in the
body
Blood coagulation :
- enhance the coagulability of blood
- increased plasminogen levels
- decreased platelet adhesiveness 10
 Clinical Uses
Primary hypogonadism
Postmenopausal hormonal therapy
Other uses : combine with progestin
- to supress ovulation : intractable
dysmenorrhea
- hirsutism
- amenorrhea
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 Adverse Effects
Uterine bleeding

Cancer
Nausea
Breast tenderness
Hyperpigmentation
Others Migraine headache
Cholestasis
Gallbladder diseases
Hypertention

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 Contraindications
Patienst with estrogen dependent
neoplasma
Undiagnosed genital bleeding
Liver disease
History of thromboembolic disorder
Heavy smokers

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 The Progestins

Natural progestins
Progesterone
Primarily produced by the corpus luteum

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 Activities of progestetational agents Activities
Route D oA Est And Anti-E Anti-A Ana

Progesterone & Derivatives

Progesterone IM 1 day - - + - -
Hydroxyprogesterone caproate IM 8-14 days sl sl - - -
Medroxyprogesterone acetate IM, PO Tab : 1-3 - + + - -
days; inj:4-
12 weeks
Megestrol acetate PO 1-3 days - + - + -
17-Ethinyl testosterone derivatives

Dimethisterone PO 1-3 days - - sl - -

19-Nortestosterone derivatives

Desogestrel PO 1-3 days - - - - -

Norethynodrel PO 1-3 days + - - - -
Lynesterol PO 1-3 days + + - - +
Norethindrone PO 1-3 days Sl + + - +
Norethindrone acetate PO 1-3 days Sl + + - +
Ethynodiol diacetate PO 1-3 days sl + + - -
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L-Norgestrel PO 1-3 days - + + - +
 Pharmacoknetic
ORAL
C MAX PLASMA: 2 H AFTER ADMINISTRATION
ABSORBTION
BASELINE-LEVEL : AFTER 24 H

SEX-HORMONE BINDING GLOBULIN

DISTRIBUTIO (SHBG) 90%
N
FIRST-PASS EFFECT PATHWAY
METABOLISM (HEPAR)
SLOW DEGRADATION OF
PROGESTIN
URINE
EXCRETION
FAECAL

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 Clinical Uses
Therapeutic applications :
- hormone replacement therapy
- hormonal contraception
Diagnostic uses : a test of estrogen
secretion

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Contraindications, Cautions & Adverse Effects

BP
Plasma HDL
Breast cancer risk

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Combination of Estrogen and Progesteron

Chemistry structure

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 Pharmacologic effects
The combination :
- selective inhibition of pituitary function
- a change in the cervical mucus, in the uterine
endometrium, and in motility and secretion in the
uterine tubes
Ovary : depresses ovarian function
Uterus : hypertrophy and polyp formation
Breast :
- stimulation of the breast ( estrogen)
- suppress lactation( combinations of estrogen and
progestin) 20
 Pharmacologic Effects

CNS :
- estrogen : * exciteability in the brain
* successfully employed in the therapy of pre
menstrual tention syndrome, post partum
depression, and climacteric depression
- progestin : * exciteability in the brain
* thermogenic action

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 Pharmacologic Effects
Endocrine function:
- estrogen : * alter adrenal structure and function
* at high dose increase plasma
concentration of CBG
* alter RAA system
* T4
Cardiovascular system : CO
Skin : increase pigmentation

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 Pharmacologic Effects
Blood:
- thromboembolic phenomenoral contraceptives
- develop folic acid deficiency anemias
Liver:
- alterations in hepatic drug excretion and metabolism
Lipid metabolism:
- serum TG
Carbohydrate metabolism:
- progesterone : the basal insulin level

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 Contraindications & Cautions
Thrombophlebitis
Thromboembolic phenomena
Cardiovascular disease
Cerebrovascular disorder
Suspected tumor of the breast
Other estrogen dependent neoplasm
Liver disease
Asthma
Eczema
Migraine
Diabetes
Hypertention
Optic neuritis 24
Convulsive disorder