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SERM & SERD

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SERM & SERD

  1. 1. SERM & SERD Tulasi Raman P
  2. 2. ESTROGEN – PHYSIOLOGICAL EFFECTS On blood: Decreased antithrombin III Increased Factor II, VII, IX, X Thrombolic predisposition Lipid profile: Increase in HDL Decrease in LDL Increase in triglycerides
  3. 3. Uterine endometrium Induction of secretory phase Mammary glands Development of alveo-lobular system Cervix Viscous, scanty mucus secretion Bones: Maintains bone mass Decrease in bone resorption
  4. 4. FSH / LH secretion Feedback control Carbohydrate metabolism Increases basal insulin levels Insulin response to glucose Fat deposition Increased Increased appetite
  5. 5. WHAT IS SERM ?  Selective Estrogen Receptor Modulator (SERM) are non steroidal synthetic agents whose agonist or antagonist activities on estrogen receptor (ER) are tissue selective.
  6. 6. SERM - DRUGS  Prototype : Tamoxifen  Tamoxifen analogs : Toremifine, Droloxifene, Idoxifene  Fixed ring compounds : Raloxifene, Lasofoxifene, Arzoxifene, Miproxifene, Levormeloxifene, EM652
  7. 7. CLOMIPHENE Orally active SERM Acts as competitive antagonist of ER in hypothalamus Inhibits negative feedback effects on the release of GnRH Increases the pulse frequency of GnRH
  8. 8. CLOMIPHENE - USES  Infertility due to anovulation  Male infertility due to oligozoospermia  In vitro fertilization
  9. 9. CLOMIPHENE – ADVERSE EFFECTS  Twins / Multiple pregnancy  Ovarian enlargement  Polycystic ovaries (can rupture leading to internal hemorrhage)  Hot flushes  Weight gain  Reversible alopecia  Vertigo
  10. 10. TAMOXIFEN  Potent ER antagonist at: Breast Blood vessel Peripheral sites  ER agonist at: Uterus Bone Liver Pitutary
  11. 11. TAMOXIFEN - MOA Competitive inhibitor of estradiol binding to the ER Binding of estradiol & SERM to the estrogen binding sites of the ER’s initiate a change in conformation of the ER, dissociates the ER form heat-shock proteins and inhibition of ER dimerisation
  12. 12. TAMOXIFEN - MOA Up regulates Transforming Growth Factor β (TGF- β) Decreases total serum cholesterol Decreases LDL cholesterol Increases apolipoprotein A1
  13. 13. TAMOXIFEN - PHARMACOKINETICS Readily absorbed on oral administration Peak concentration – 3-7 hours Steady state – 4-6 weeks Oral dose 20mg/day At high doses 200mg/day can cause retinal degeneration
  14. 14. TAMOXIFEN - PHARMACOKINETICS Metabolites CYP3A4/5  N desmethyl tamoxifen CYP2D6  4 hydroxytamoxifen 4 hydroxy N desmethyltamoxifen (Retains affinity) T ½ Parent drug – 7days Metabolites – 14 days Enterohepatic circulation Excreted in stool
  15. 15. TAMOXIFEN – USES Breast Carcinoma – Pre & Postmenopausal Prevents post-menopausal osteoporosis Improves bone density Decreases incidences of Coronary Artery Disease (CAD) Improves lipid profile
  16. 16. TAMOXIFEN – ADVERSE EFFECTS Hot flushes Menstrual irregularities Nausea Vomiting Anorexia Hair loss Vaginal bleeding and discharge Pruritis vulvae and dermatitis Atrophy of lining of vagina
  17. 17. TAMOXIFEN RESISTANCE Polymorphism of CYP2D6 Cross talk between ER & HER2/neu pathway Interaction between PAX2 and the ER coactivator AIB-1 / SRC-3 determine tamoxifen response in breast cancer cells
  18. 18. TOREMFINE Triphenylethylene derivative of Tamoxifen Similar pharmacological profile Used to treat Brest cancer with ER+ or unknown receptor states Not hepatocarcinogenic in experimental animals
  19. 19. WHAT IS SERD ? Selective Estrogen Receptor Down regulator (SERD) are pure anti- estrogens. Paradoxically SERM down-regulates ER’s and also promotes degradation of ER’s by proteosomal enzymes
  20. 20. SERD - DRUGS Fulvestrant – Prototype SR16234 ZK191703 RU58668 ZK191703
  21. 21. FULVESTRANT Steroidal anti-estrogen that binds to the ER with an affinity >100 times that of tamoxifen Pure anti-estrogen
  22. 22. FULVESTRANT - MOA  Inhibits binding of estrogen  Alters the receptor structure such that the receptor is targeted for proteosomal degradation  Inhibits receptor dimerisation  Decreases number of ER molecules in cells  ER downregulation  abolishes ER mediated transcription of estrogen dependant genes
  23. 23. FULVESTRANT - PHARMACOKINETICS Given i.m. Max plasma concentration: 7 days t ½: 40 days Steady state 3-6 months Dosing Loading dose 500mg on day 0 250 mg on 14th & 28th day 250 mg every month
  24. 24. FULVESTRANT - PHARMACOKINETICS Extensive, rapid distribution & extensive protein binding CYP3A4  metabolites <1% of drug is excreted intact in urine
  25. 25. FULVESTRANT - USES Tamoxifen resistant Breast Cancer
  26. 26. FULVESTRANT – ADVERSE EFFECTS Nausea Asthma Pain Vasodilation Headache
  27. 27. RALOXIFENE Antiestrogen effect at: Breast Endometrial tissue Estrogenic effect at: Bone Lipid metabolism Blood coagulation
  28. 28. RALOXIFENE Dose dependant increase in osteoblast activity and decreased osteoclast action Increases Bone density Maintains favorable lipid profile Does not stimulate endometrial carcinoma No risk of endometrial cancer
  29. 29. RALOXIFENE - PHARMACOKINETICS Orally absorbed Poor bioavailability Extensive first pass metabolism in liver Large aVd & longer t ½ Hence once a day administration 60mg/day
  30. 30. RALOXIFENE - USES Prevention of osteoporosis in post- menopausal women Decrease risk of Breast cancer (ER positive) Decreases risk of vertebral compression fracture Alternative for Hormone Replacement Therapy
  31. 31. RALOXIFENE – ADVERSE EFFECTS Hot flushes Leg cramps Increased risk of Deep Vein Thrombosis Pulmonary embolism Estrogenic effect on blood coagulation
  32. 32. ORMELOXIFENE Estrogen antagonist at breast and uterus Has anti-estrogen activity as well as anti-progestogenic action
  33. 33. ORMELOXIFENE - USES Dysfunctional Uterine Bleeding (DUB) Non-hormonal oral contraceptive Investigated for Osteoporosis Breast cancer Endometrial cancer
  34. 34. ORMELOXIFENE - USES Nausea Headache Fluid retention Weight gain
  35. 35. RECENT ADVANCES
  36. 36. LASOFOXIFENE Investigated for the prevention and treatment of osteoporosis and for the treatment of vaginal atrophy in postmenopausal women. Increased endometrial thickness. Lasofoxifene was not approved by the US FDA for the treatment of vaginal atrophy.
  37. 37. OSPEMIFENE Similar effect on most markers of bone resorption and bone formation compared with raloxifene Does not induce vasomotor symptoms in postmenopausal women Increased endometrial thickness and uterine volume
  38. 38. ARZOXIFENE  Treatment and prevention of breast cancer  Reduction in vertebral fractures and breast cancer in postmenopausal women  Failed to meet secondary endpoints of reduction in non-vertebral fractures and cardiovascular events and improvements in cognitive function  The drug company announced they are discontinuing further development of the drug and would not seek regulatory approval
  39. 39. BAZEDOXIFENE Prevention and treatment of postmenopausal osteoporosis Favorable effects on lipid parameters total cholesterol low-density lipoprotein cholesterol high-density lipoprotein cholesterol
  40. 40. THANK YOU !

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