Pharmacokinetic and PharmacodynamicPharmacokinetic ocw.usu.ac.id/course/download/1110000106-reproductive-system/rps...Pharmacokinetic and PharmacodynamicPharmacokinetic and Pharmacodynamic

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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

  • INTRAUTERINE SYSTEM

    HORMONAL CONTRACEPTIONHORMONAL CONTRACEPTION ORALLYINJECTION

    IMPLANT

  • Siklus Menstruasi

  • The EstrogensThe Estrogens

  • Natural Estrogens : biosynthesis and metabolism

    Follicular Phase Lutheal Phase

    Pregnenolone Pregnenolone

    17-Hydroxypregnolone Progesterone

    Dehydroepiandrosterone 17-Hydroxyprogesterone

    Androstenedione Testoterone

    Estriol Estrone16-Hydroxyestrone 17-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 2-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 - + + - +

  • PharmacokneticPharmacokneticORAL

    ABSORBTION

    ORAL

    C MAX PLASMA: 2 H AFTER ADMINISTRATION

    BASELINE-LEVEL : AFTER 24 H

    DISTRIBUTION SEX-HORMONE BINDING GLOBULIN (SHBG) 90%

    METABOLISMFIRST-PASS EFFECT PATHWAY (HEPAR)

    SLOW DEGRADATION OF PROGESTIN

    EXCRETIONURINE

    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