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Pharmacokinetic and PharmacodynamicPharmacokinetic and Pharmacodynamic of Hormonal Contraception
Tri Widyawati – Sake Juli MartinaDepartement of Pharmacology & Therapeutic p gy p
School of Medicine2007
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
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
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
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