1. Pharmacokinetic and Pharmacodynamic of Hormonal Contraception Tri Widyawati – Sake Juli Martina Departement of Pharmacology & Therapeutic School of Medicine 2007

2. HORMONAL CONTRACEPTION IMPLANT ORALLY INTRAUTERINE SYSTEM INJECTION

4. Siklus Menstruasi

5. The Estrogens

6. Natural Estrogens : biosynthesis and metabolism Follicular PhaseLutheal Phase Pregnenolone 17  -Hydroxypregnolone Progesterone Dehydroepiandrosterone AndrostenedioneTestoterone EstriolEstrone 16  -Hydroxyestrone17  -Estradiol 17  -Hydroxyprogesterone 2-Hydroxyestrone and other metabolites 2-Hydroxyestradiol and other metabolites

7. Synthetic Estrogens Steroidal, natural : estradiol, estrone, estriol Steroidal, synthetic : ethynil estradiol, mestranol, quinestrol Nonsteroidal, synthetic ; diethylstilbestrol, chlorotrianisme, methallenestril

8. 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 Excreted : the bile the breast milk (small amounts) Enterohepatic circulation

9. Commonly used estrogens Average replacement dosage Ethynyl estradiol0.005 – 0.02 mg/d Micronized estradiol1 – 2 mg/d Estradiol cypionate2 – 5 mg every 3-4 weeks Estradiol valerate2 – 20 mg every other week Estropipate1.25 – 2.5 mg/d Conjugated, esterified, or mixed estrogenic substances : Oral0.3 – 1.25 mg/d Injectable0.2 – 2 mg/d TransdermalPatch Diethylstilbestrol0.1 – 0.5 mg/d Quinestrol0.1 – 0.2 mg/week Chlorotrianisene12 – 25 mg/d Methallenestril3 – 9 mg/d

10. 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

11. Clinical Uses Primary hypogonadism Postmenopausal hormonal therapy Other uses : combine with progestin - to supress ovulation : intractable dysmenorrhea - hirsutism - amenorrhea

12. Adverse Effects Uterine bleeding Cancer Nausea Breast tenderness Hyperpigmentation Migraine headache Cholestasis Gallbladder diseases Hypertention Others

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

14. The Progestins

15. Natural progestins Progesterone Primarily produced by the corpus luteum

16. Activities of progestetational agents RouteD o AEstAndAnti-EAnti-AAna Progesterone & Derivatives ProgesteroneIM1 day --+-- Hydroxyprogesterone caproateIM8-14 days sl --- Medroxyprogesterone acetateIM, POTab : 1-3 days; inj:4- 12 weeks -++-- Megestrol acetatePO1-3 days -+-+- 17-Ethinyl testosterone derivatives DimethisteronePO1-3 days --sl-- 19-Nortestosterone derivatives DesogestrelPO1-3 days ----- NorethynodrelPO1-3 days +---- LynesterolPO1-3 days ++--+ NorethindronePO1-3 daysSl ++-+ Norethindrone acetatePO1-3 daysSl ++-+ Ethynodiol diacetatePO1-3 days sl++-- L-NorgestrelPO1-3 days -++-+ Activities

17. Pharmacoknetic 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

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

19. Contraindications, Cautions & Adverse Effects BP  Plasma HDL  Breast cancer risk 

20. Cytochrome P450 Metabolisme  Efektifitas Efektifitas Metabolisme Efek toksik (+) Induksi Inhibisi METABOLISME EE dan Progestogen: * 60% melalui first pass metabolism di mukosa usus halus dan hati dalam bentuk Sulphate dan glucoronida terkonjugasi *Bioavaibilitas  40%

21. In Bowel Colonic Bacteri (+) Hydrolytic Enzyme to Conjugate EE (+) Colonic Bacteri Hydrolytic Enzyme to Conjugate EE (-) Non-liver enzyme inducing antibiotics Reabsorption EHC

22. Pharmacokinetic

23. Adverse Effects Mild Moderate nausea, mastalgia, breakthrough bleeding, edema changes in serum protein and other effects on endocrine function headache is mild and often transient withdrawal bleeding breakthrough, weight gain, skin pigmentation, acne, hirsutism, ureteral dilation, vaginal infections, amenorrhea

24. Adverse Effects Severe Adverse Effects vascular disorders: venous thromboembolic disease myocardial infarction cerebrovascular disease gastrointestinal disorders: cholestatin jaundice (progestin) depression cancer others : alopecia, erythema multiform, other skin disorders

26. Combination of Estrogen and Progesteron Chemistry structure

27. 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)

28. 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

29. 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

30. 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

31. 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 Convulsive disorder