Pharmacokinetic and PharmacodynamicPharmacokinetic and Pharmacodynamic of Hormonal Contraception

Tri Widyawati – Sake Juli MartinaDepartement of Pharmacology & Therapeutic p gy p

School of Medicine2007

INTRAUTERINE SYSTEM

HORMONAL CONTRACEPTIONHORMONAL CONTRACEPTION ORALLYINJECTION

IMPLANT

Siklus Menstruasi

The EstrogensThe Estrogens

Natural Estrogens : biosynthesis and metabolism

Follicular Phase Lutheal Phase

Pregnenolone Pregnenolone

17α-Hydroxypregnolone Progesterone

Dehydroepiandrosterone 17α-Hydroxyprogesterone

Androstenedione Testoterone

Estriol Estrone16α-Hydroxyestrone 17β-Estradiol

2-Hydroxyestrone and other metabolites

2-Hydroxyestradiol and other metabolites

Synthetic EstrogensSynthetic Estrogens

• Steroidal natural : estradiol estroneSteroidal, natural : estradiol, estrone, estriol

• Steroidal synthetic : ethynil estradiol• Steroidal, synthetic : ethynil estradiol, mestranol, quinestrolN t id l th ti di th l tilb t l• Nonsteroidal, synthetic ; diethylstilbestrol, chlorotrianisme, methallenestril

Pharmacokinetics• Absorbed : small intestine

• Binds : strongly affinity ⇒ α2-globulin (SHBG)lower affinity ⇒ albumin

• Liver and other tissues : converted to - estrone and estriol ( low affinity for the estrogen reseptor )- 2-hydroxylated derivatives- conjugated metabolites

Enterohepatic circulation

• Excreted : the bilethe breast milk (small amounts)

Commonly used estrogensAverage replacement dosage

Ethynyl estradiol 0.005 – 0.02 mg/dMicronized estradiol 1 – 2 mg/dEstradiol cypionate 2 – 5 mg every 3-4 weeksEstradiol valerate 2 – 20 mg every other weekEstradiol valerate 2 20 mg every other weekEstropipate 1.25 – 2.5 mg/dConjugated, esterified, or mixed estrogenic substances :

Oral 0.3 – 1.25 mg/dInjectable 0.2 – 2 mg/dTransdermal PatchTransdermal Patch

Diethylstilbestrol 0.1 – 0.5 mg/dQuinestrol 0.1 – 0.2 mg/weekChl t i i 12 25 /dChlorotrianisene 12 – 25 mg/dMethallenestril 3 – 9 mg/d

Physiologic effects• Female maturationFemale 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- 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 bodyy

• Blood coagulation : - enhance the coagulability of blood

i d l i l l- increased plasminogen levels- decreased platelet adhesiveness

Clinical UsesClinical Uses

• Primary hypogonadismPrimary hypogonadism• Postmenopausal hormonal therapy

Oth bi ith ti• Other uses : combine with progestin- to supress ovulation : intractable dysmenorrhea- hirsutism- amenorrhea

Adverse EffectsAdverse EffectsUterine bleedingUterine bleeding

Cancer• Nausea• Breast tenderness

H i t ti• Hyperpigmentation• Migraine headache• Cholestasis

Others

Cholestasis• Gallbladder diseases• Hypertention

ContraindicationsContraindications

• Patienst with estrogen dependentPatienst with estrogen dependent neoplasma

• Undiagnosed genital bleeding• Undiagnosed genital bleeding• Liver disease• History of thromboembolic disorder• Heavy smokersy

The ProgestinsThe Progestins

Natural progestinsNatural progestins

• ProgesteroneProgesterone• Primarily produced by the corpus luteum

Activities of progestetational agentsRoute D o A Est And Anti-E Anti-A Ana

Activities

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 + +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 + + +Norethindrone acetate PO 1-3 days Sl + + - +Ethynodiol diacetate PO 1-3 days sl + + - -L-Norgestrel PO 1-3 days - + + - +

PharmacokneticPharmacoknetic•ORAL

ABSORBTION

ORAL

• C MAX PLASMA: 2 H AFTER ADMINISTRATION

• BASELINE-LEVEL : AFTER 24 H

DISTRIBUTION• SEX-HORMONE BINDING GLOBULIN (SHBG) 90%

METABOLISM•FIRST-PASS EFFECT PATHWAY (HEPAR)

• SLOW DEGRADATION OF PROGESTIN

EXCRETION•URINE

•FAECAL

Clinical UsesClinical Uses

• Therapeutic applications :Therapeutic applications :- hormone replacement therapy

h l t ti- hormonal contraception• Diagnostic uses : a test of estrogen

secretion

Contraindications, Cautions & Adverse Effects

• BP ↑Pl HDL ↓• Plasma HDL ↓

• Breast cancer risk ↑

METABOLISMEMetabolisme Metabolisme

Efektifitas Efektifitas Induksi

Cytochrome P450

Metabolisme

Efek toksik (+)Inhibisi

Efek toksik (+)

EE dan Progestogen: * 60% melalui first pass metabolism di mukosa usus halus dan hatidi mukosa usus halus dan hati dalam bentuk Sulphate dan glucoronida terkonjugasi

*Bioavaibilitas 40%

In Bowel Non-liverenzymey

inducing antibiotics

Colonic Bacteri (+) Colonic Bacteri

Hydrolytic Enzyme Hydrolytic Enzymey y yto Conjugate EE (+)

y y yto Conjugate EE (-)

Reabsorption Reabsorption

EHC

Pharmacokinetic

Adverse EffectsMildMild

• nausea, mastalgia, breakthrough bleeding, edema

• changes in serum protein and other effects on endocrine function

• headache is mild and often transient

• withdrawal bleeding

Moderate

• breakthrough, weight gain, skin pigmentation, acne, hirsutism, ureteralbreakthrough, weight gain, skin pigmentation, acne, hirsutism, ureteral dilation, vaginal infections, amenorrhea

Adverse Effects

Severe Adverse Effects

• vascular disorders: venous thromboembolic diseasevascular disorders: venous thromboembolic disease

myocardial infarction

cerebrovascular disease

• gastrointestinal disorders: cholestatin jaundice (progestin)

• depression

• cancer

• others : alopecia, erythema multiform, other skin disorders

Combination of Estrogen and ProgesteronCombination of Estrogen and Progesterong gg g

Chemistry structure

Pharmacologic effectsPharmacologic effects• The combination :

- selective inhibition of pituitary function- a change in the cervical mucus, in the uterine endometrium and in motility and secretion in theendometrium, and in motility and secretion in the uterine tubes

• Ovary : depresses ovarian functiony p• Uterus : hypertrophy and polyp formation• Breast :

i l i f h b ( )- stimulation of the breast ( estrogen)- suppress lactation( combinations of estrogen and progestin)progestin)

Pharmacologic Effects• CNS :

- estrogen : * ↑ exciteability in the brainestrogen : ↑ exciteability in the brain* successfully employed in the therapy of pre menstrual tention syndrome, post partumy p pdepression, and climacteric depression

- progestin : * ↓ exciteability in the brain* thermogenic action

Pharmacologic Effects• Endocrine function:

estrogen : * alter adrenal structure and function- estrogen : * alter adrenal structure and function* at high dose increase plasma

t ti f CBGconcentration of CBG * alter RAA system * ↑* T4 ↑

• Cardiovascular system : CO ↑• Skin : increase pigmentation

Pharmacologic Effects• Blood:

- thromboembolic phenomenoral contraceptivesp p- develop folic acid deficiency anemias

• Liver:- alterations in hepatic drug excretion and metabolism

• Lipid metabolism:- ↑ serum TG

• Carbohydrate metabolism:- progesterone : ↑ the basal insulin level

Contraindications & CautionsContraindications & Cautions• Thrombophlebitis• Thromboembolic phenomena• Cardiovascular disease• Cerebrovascular disorder

Suspected tumor of the breast• Suspected tumor of the breast• Other estrogen dependent neoplasm• Liver disease• AsthmaAsthma• Eczema• Migraine• Diabetes• Hypertention• Optic neuritis• Convulsive disorder