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Similar to Pharmacology of reproductive system (1).pptx
Pharmacology of reproductive system (1).pptx
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- 2. 2 Learning objective At theend of this chapter the student will be able to: Recognize drugs used as oxytocic agents Describe types of sexual hormones, their pharmacologic and physiological effects Differentiate types of hormonal contraception with their uses and adverse effects including preparations
- 3. 3 OXYTOCICS These aregroup of drugs that cause contraction of the uterus They include Oxytocin Prostaglandins Ergometrine Oxytocin • Oxytocin is a peptide hormone secreted by the posterior pituitary Actions: 1. Oxytocin stimulates the uterus and cause physiologic type of contraction 2. It also causes ejection of milk through contraction of the myo- epithelial cells around the alveoli of the mammary gland
- 4. 4 Pharmacokinetics: It isinactivated orally and absorbed rapidly after intramuscular administration It can also be absorbed from the nasal and buccal membranes Oxytocin is administered intravenously for initiation and augmentation of labor It also can be administered intramuscularly for control of postpartum bleeding Use: Induction of labor in women with uterine inertia relief of breast engorgement during lactation (few minutes before breast feeding) as nasal spray; and, postpartum hemorrhage
- 5. 5 Side effect: Oxytocinmay cause over stimulation and leads to rupture of the uterus in the presence of cephalo- pelvic disproportion Therefore it’s contraindicated in woman with a uterine scar High concentrations can cause excessive fluid retention, or water intoxication, leading to hyponatremia, heart failure, seizures, and death
- 6. 6 Prostaglandins They inducelabor at anytime during pregnancy but are most effective at the third trimester In female reproductive system: prostaglandin E & F are found in ovaries, endometrium and menstrual fluid which are responsible for initiating and maintaining the normal birth process PGF2ά, and PGE stimulate both the tone and amplitude of the uterine contraction
- 7. 7 dinoprostone (PGE2)has been used as an alternative to oxytocin for the induction of labor misoprostol (PGE1)is an effective agent for both cervical ripening and labor induction Adverse reaction: nausa; vomiting; headache; diarrhea; and, fever etc. PGs should be used cautiously in the presence of hypo/hypertension, angina, and diabetes They are contraindicated in the presence of cardiac, pulmonary (PGF2ά,) or hepatic disease
- 8. 8 Ergometrine • This isone of the ergot alkaloids which has the ability to cause contraction of the uterine smooth muscle • It causes sustained uterine contraction • It is completely absorbed after subcutaneous, and intravenous administration. • It is metabolized in the liver and eliminated in the urine • Liver damage enhances the toxicity of ergot alkaloid
- 9. 9 Use: After deliveryof placenta if bleeding is severe (prevent postpartum bleeding) Adverse effect: • Nausea and vomiting • hypertension, headache, and possible seizures Contraindications • pregnancy, and a history of a cerebrovascular accident or hypertension
- 10. 10 Sexual Hormones FemaleSex Hormones Estrogens Progestrones • Male Sex Hormones (Reading assignment) Testosterone 5α-dihydrotestosterone
- 11. 11 Female Sex Hormones ESTROGENS: canbe classified into: 1. Natural – estradiol, esterone, estriol 2. Synthetic – Ethnylestradiol, mestranol, stilbestrol, diethylstilbestrol, Methallenestril, etc Ovary is the major site of estrogen synthesis in non pregnant & premenopausal women • Gonadotrophin-releasing hormone, released from the hypothalamus, acts on the anterior pituitary to release FSH and LH • FSH and LH stimulate follicle development in the ovary FSH is the main hormone stimulating estrogen release
- 12. 12 ESTROGENS….. In pregnantwomen, the feto-placental unit is the major source of estrogens Peripheral sites of estrogen synthesis includes: - Liver, kidney, brain, adipose tissue, testis - Accounts for estrogen in postmenopausal women In postmenopausal women, ovarian steroid synthesis declines and peripheral estrogen biosynthesis accounts for all estrogen produced both in postmenopausal women and in males The starting substance for estrogen synthesis is cholesterol The reaction is catalyzed by a cytochrome P450 monooxygenase enzyme complex (aromatase / CYP19)
- 13. 13 Pharmacokinetics Naturally occurringestrogens: are readily absorbed through the GIT, skin, and mucous membranes Taken orally, estradiol is rapidly metabolized (and partially inactivated) by the liver o Although there is some first-pass metabolism, it is not sufficient to lessen the effectiveness when taken orally Synthetic estrogen analogs: such as ethinyl estradiol and mestranol, are well absorbed after oral administration or through the skin or mucous membranes They have a prolonged action and a higher potency compared to those of natural estrogens
- 14. 14 MOA & PhysiologicEffects of Estrogen Binding to nuclear receptors and cause subsequent genomic effects-either gene transcription (i.e. DNA- directed RNA and protein synthesis) or gene repression This results in the synthesis of specific proteins that mediate a number of physiologic functions: Physiologic Effects Stimulate the development of the vagina, uterus, and uterine tubes as well as the secondary sex characteristics Ovary: estrogen affects the ovary through indirectly influencing the secretion of gonadotrophin Uterus: it affects the ‘proliferative phase’ of the endometrium and also increases the growth and sensitivity of myometrium for oxytocin
- 15. 15 Physiologic Effects ……. When used with progesterone, it causes regular periodic bleeding and shedding of the endometrial lining Cervix: it makes cervical mucus thin and alkaline Breast: estrogen causes the growth of gland and duct system Anterior pituitary: estrogen inhibit release of gonadotropins (FSH, LH) Others Retention of salt and water & increases Catt bone deposition Increase blood coagulation They are responsible for estrous behavior in animals and may influence behavior and libido in humans stimulate development of pigmentation in the skin ( nipples and areolae and in the genital region)
- 16. 16 Therapeutic use: • Contraceptivein combination with progestogens • Functional uterine bleeding • Dysmenorrhea • Alleviation of menopausal disorder • Osteoporosis • Replacement therapy in ovarian failure • Prevents atrophic vaginitis Side effect: Thromboembolism, sodium and water retention, withdrawal bleeding, nausea, endometrial carcinoma Contraindication: History of thromboembolism, indiagnosed uterine bleeding, endometrial carcinoma, liver disease
- 17. 17 SELECTIVE ESTROGEN RECEPTORMODULATORS (SERMS) SERMs: Tamoxifen, Raloxifene, and Toremifene are compounds with tissue-selective actions These drugs are to produce: beneficial estrogenic actions in certain tissues (e.g., bone, brain, and liver) during postmenopausal hormone therapy but antagonist activity in tissues such as breast and endometrium, where estrogenic actions (e.g., carcinogenesis) might be deleterious Tamoxifen and toremifene are used for treatment of breast cancer Both approved for t/t of metastatic breast cancer in postmenopausal women Raloxifene is used primarily for prevention and treatment of osteoporosis
- 18. 18 Anti-Estrogens: Clomiphene Byinterfering with the negative feedback effect of estrogens on the hypothalamus, clomiphene increases the secretion of gonadotropin- releasing hormone and gonadotropins (FSH & LH), →stimulation of ovulation The drug has been used successfully to treat infertility associated with anovulatory cycles, but it is not effective in women with ovulatory dysfunction due to pituitary or ovarian failure Adverse headache, nausea, vasomotor flushes, visual disturbances, and ovarian enlargement
- 19. 19 The natural progestationalhormone (progestogen) is progesterone This is secreted by the corpus luteum in the second part of the menstrual cycle, and by the placenta during pregnancy. Small amounts are also secreted by testis and adrenal cortex There are two main groups of progestogens The naturally occurring hormone and its derivatives e.g. hydroxyprogesterone, medroxyprogesterone Testosterone derivatives (e.g. Norethindrone, norgestrel and ethynodiol) can be given orally Newer progestogens used in contraception include desogestrel and gestodene PROGESTRONES
- 20. 20 Pharmacokinetics Progesterone israpidly absorbed following administration by any route Its half-life in the plasma is approximately 5 minutes It is almost completely metabolized in one passage through the liver, and for that reason it is quite ineffective when given orally Synthetic progestins are less rapidly metabolized Medroxyprogesterone acetate IM has a duration of action of 3 months The other progestins last from 1 to 3 days MOA Progestins enter the cell and bind to progesterone receptors that are distributed between the nucleus and the cytoplasm → activate gene transcription
- 21. 21 Physiological and PharmacologicalActions Ovary: inhibition of ovulation has negative feedback effects on both hypothalamus and anterior pituitary Uterus: decrease estrogen-driven endometrial proliferation and leads to the development of a secretory endometrium and makes the myometrum less sensitive to oxytocin Cervix- cause the endocervical glands secrete a scant viscid (thick) mucus progesterone, acting with estrogen, brings about a proliferation of the acini(clusters) of the mammary gland Progesterone suppresses menstruation and uterine contractility
- 22. 22 Physiological and PharmacologicalActions…. Progesterone has depressant and hypnotic effects on the brain Metabolic actions: Thermogenic action, inhibits sodium reabsorption Therapeutic use: Hormonal contraception Combined with estrogen for estrogen replacement therapy in women with an intact uterus, to prevent endometrial hyperplasia and carcinoma Premenustral tension unwanted effects acne, fluid retention, weight change, depression, change in libido, breast discomfort, irregular menstrual cycles and breakthrough bleeding, thromboembolism
- 23. 23 ANTIPROGESTOGENS Mifepristone is apartial agonist at progesterone receptors It sensitizes the uterus to the action of prostaglandins It is given orally and has a plasma half-life of 21 hours Mifepristone is used, in combination with a prostaglandin (e.g. gemeprost (PGE1)), as a medical alternative to surgical termination of pregnancy
- 24. 24 ORAL CONTRACEPTIVEs Theseare drugs taken orally to prevent conception Types of hormonal contraceptives include: 1. Combination Oral Contraceptives (combinations of estrogens and progestins) a. monophasic forms (constant dosage of both components during the cycle) b. biphasic or triphasic forms (dosage of one or both components is changed once or twice during the cycle) 2. Progestin-Only Contraceptives 3. Postcoital or Emergency Contraceptives
- 25. 25 1. Combination OralContraceptives (COCs) COCs are available in many formulations. Monophasic contains fixed amounts of the estrogen and progestin, which is taken daily for 21 days, followed by a 7-day "pill-free" period The biphasic and triphasic preparations provide 2 or 3 different pills containing varying amounts of active ingredients, to be taken at different times during the 21-day cycle Withdrawal bleeding occurs 2 to 3 days after discontinuation of this regimen (during the 7-day "off" period each month) The use of sequential and triphasic oral contraceptives Minimizes the overall dose of hormone delivered Closely simulate estrogen-to-progestin ratios that occur physiologically during the menstrual cycle The estrogen in most combined preparations is ethinylestradiol The progestin may be norethindrone, levonorgestrel, ethynodiol, desogestrel or gestodene
- 26. 26 COCs-------- Levonorgestrel andnorethindrone are the most potent synthetic progestins in oral contraceptive preparations E.g. of formulations available: a) low estrogen, low progesterone (0.03mg ethinylestradiol + 0.15 mg norgestril) b) Low esterogen, high progestogen (0.03 mg ethinylestradiol + 1.5 mg norethindrone) c) High estrogen, high progesterone (0.05 mg ethinylestradiol + 0.5 mg norgestril)
- 27. 27 COCs-------- Their mode ofaction is as follows: Estrogen inhibits secretion of FSH via negative feedback on the anterior pituitary and thus suppresses development of the ovarian follicle Progestins inhibits secretion of LH and thus prevents ovulation it also makes the cervical mucus less suitable for the passage of sperm Estrogen and progestins act in concert to alter the endometrium in such a way as to discourage implantation
- 28. 28 COCs-------- Common adverse effectsinclude: Increased incidence of thrombosis and embolism, attributed to the estrogen component in particular Weight gain, owing to fluid retention or an anabolic effect or both mild nausea, flushing, dizziness, depression or irritability Skin changes (e.g. acne and/or an increase in pigmentation) Amenorrhea of variable duration on cessation of taking the pill Contraindications: Oral contraceptives are C/I in the presence of cerebrovascular and thromboembolic disease, estrogen-dependent neoplasms, liver disease, and pregnancy
- 29. 29 2.The progestogen-only contraceptives ("minipills") •administered orally or by implantation under the skin • suited for use in patients for whom estrogen administration is undesirable Specific preparations include Low doses of progestins (e.g. 350 mg of norethindrone or 75 mg of norgestrel) taken po daily without interruption Subdermal implants of levonorgestrel 216 mg (Norplant II) for slow release and resultant long-term contraceptive action (e.g., up to 5 years) Crystalline suspensions of medroxyprogesterone acetate (Depo- provera®) for IM injection of 150 mg of drug, which provides effective contraception for 3 months Side effects irregular bleeding episodes, headache, weight gain, and mood changes
- 30. 30 3. Postcoital orEmergency Contraceptives ("morning after" pill) Pregnancy can be prevented following unprotected coitus by the administration of high dose of estrogens alone or in combination with progestins Plan B is an emergency contraceptive consisting of two tablets of the progestin levonorgestrel (0.75 mg) Preven is two 2 pill doses of a high-dose oral contraceptive (0.25mg of levonorgestrel and 0.05 mg of ethinyl estradiol per pill) separated by 12 hours The first dose of Plan B and Preven should be taken anytime within 72 hours after intercourse, and this should be followed 12 hours later by a second dose. This t/t reduces the risk of px approximately 60% for Preven and 80% for levonorgestrel alone (Plan B).
- 31. 31 Postcoital or EmergencyContraceptives ("morning after" pill)……. Multiple mechanisms are likely to contribute to the efficacy of these agents • Some studies have shown that ovulation is inhibited or delayed, but additional mechanisms thought to play a role include: alterations in endometrial receptivity for implantation interference with functions of the corpus luteum that maintain pregnancy Production of cervical mucus that decreases sperm penetration Adverse effects nausea or vomiting, headache, dizziness, breast tenderness, irregular bleeding and abdominal and leg cramps