100 %
0 %
Information about Serm

Published on March 11, 2014

Author: sohinthaim


SELECTIVE ESTROGEN RECEPTOR MODULATORS Dr. SOHIN THAIM Date : 11/03/2014 Dept. of Pharmacology JNMC, Sawangi (W)

ESTROGEN • History : • Greek word ‘oistros’ meaning ‘gadfly’ or ‘mad impulse’-sexual passion or desire ‘gens’ meaning ‘producer of’  1900 – Knauer and Halban established that Ovaries control female reproductive function  1923 – Allen and Doisy found that alcoholic extract of Ovaries was capable of producing Estrus  1928 - Zondek reported excretion of estrogen in Urine  1929 – Butendant and Doisy isolated principle Estradiol in pure form

Physiology • Synthesized from Cholestrol in Graffian follicle, Corpus Luteum and Placenta • Natural Estrogens : Estradiol Estrone Estriol • Synthetic Estrogens : Ethinylestradiol, Mestranol, Tibolone Diethylstilbestrol • Regulation : • Estrogen after Ovulation produces negative feedback inhibition of FSH by direct action on Pituitary

• Normally : Daily secretion-10-100 µg in menstruating women Depends on the phase of the cycle. • During pregnancy : Placenta secrets Estrogen Peak up to 30mg/day • Postmenopausal women : Daily production – 2- 10 µg From Extra glandular size

Chemical Structure Phenolic A ring – Principal Structure Hydroxyl Group at Carbon 3 ß – OH or Ketone at Carbon 17

Actions of Estrogen 1. Sex Organs : Pubertal changes in female Growth of - Uterus - Fallopian tubes - Vagina • Estrogen augments rhythmic contractions of fallopian tube and uterus • Induce watery alkaline secretion from cervix making sperm penetration favorable

2. Secondary Sex Characters : - Growth of Breast Proliferation of ducts and stroma Accumulation of fat - Pubic and Axillary Hair - Feminine Body Contour and behaviour

3. Metabolic Effects : Bone : maintains bone mass Inhibits Osteoclast formation Promotes positive calcium balance Fluid Balance : mild salt and water retention Edema and mild rise in BP after prolonged use Lipid Profile : Increase in HDL Increase in Triglycerides Decrease in LDL

Molecular Action

What is SERM ? • SERM is a group of drugs which are - Synthetic - Non Steroidal - Tissue selective Estrogenic and Anti Estrogenic actions • So SERM may have one or combination of - Full agonist such as the natural endogenous estrogen - Mixed agonist /antagonist such as tamoxifen - Full antagonist such as Fulvestrant

Ideal SERM • The ideal SERM is one that - Prevents bone loss - No risk of uterine or breast cancer - + ve effect on lipids & cardiovascular system - Relieves PMS - Maintains cognitive function of the brain

• Examples : Tamoxifen Citrate Tamoxifen Analogue Toremifene Droloxifene Idoxifene Raloxifene Lasofoxifene Arzoxifene

TAMOXIFEN CITRATE • History :  The first true SERM  In use since 1966 for Breast cancer  Developed as an Oral Contraceptive but was found to induce ovulation  Approved for Prophylactic use in Breast cancer since 1997

Chemical Structure l Trans Clomiphene or Enclomiphene Trans conformation –Anti- estrogenic Cis conformation- Estrogenic Tamoxifen is marketed as Trans isomer

Molecular Action

• Potent Estrogen Receptor Antagonist at : - Breast - Blood vessels - Peripheral sites • Potent Estrogen Receptor Agonist at : - Uterus - Bone - Pituitary - Liver

• Mechanism of Action :  Competitive inhibitor of estradiol binding to the ER  Binding of Estradiol and SERM to Estrogen binding sites of ER.  Initiate a change in conformation of ER  Dissociation of ER from Heat Shock Protein  Inhibition of ER Dimiresation

• Pharmacological Actions : • Anti estrogenic effects : Inhibition human breast cancer cells Hot flushes • Estrogenic effects : Endometrial Proliferation Improvement in Bone density Decrease in total and LDL cholesterol No change in HDL and Triglyceride Increase in Thromboembolism

• Pharmacokinetics : - effective orally - biphasic half life – 10hrs and 7days - major metabolite 4 hydroxytamoxifen - long duration of action - excreted in bile and stool • Side effects : - Hot flushes - Vaginal bleeding - Vaginal discharge - Menstrual irregularities

- Increased risk of thromboembolism - Dermatitis - Anorexia - Depression - Mild Leucopenia

• Therapeutic Uses : - Pre and Postmenopausal breast cancer - Primary prophylaxis of Breast cancer in High risk women - Post menopausal Osteoporosis - Male infertility – alternative to Clomiphene • Dose : - 20mg/day in 1 or 2 doses - maximum 40mg/day.

TOREMIFENE • Triphenylethylene derivative of Tamoxifen • Chemical structure same as Tamoxifen with Chlorine substitution as R2 position • Similar pharmacological profile • Used to treat ER positive breast cancer

RALOXIFENE • Developed in 1998 for treatment and prevention of Postmenopausal Osteoporosis. • 1999 approved for prophylaxis of breast cancer • Partial Estrogenic effects : Bone CVS • Antiestrogenic Effects : Breast Endometrium • Has distinct DNA target ‘raloxifene response element’

Chemical Structure Polyhydroxylated nonsteroidal compound

• Pharmacological Actions : - Improves Bone Mineral Density, prevents bone loss - Reduces incidence of Compression vertebral fractures - Decreases LDL, No increase in HDL and Triglycerides - Does not stimulate Endometrial Proliferation • Pharmacokinetics : - Absorbed orally - Has low oral bioavailability – only 2% - Half life 28 hrs - Excreted in faeces

• Side effects : - Hot flushes - Leg cramps - Deep vein thrombosis - Pulmonary embolism • Uses : - Second line drug for Osteoporosis - Secondary prevention and treatment of vertebral fractures - Prevention of Breast cancer - alternative to Hormone replacement therapy

ORMELOXIFENE • Estrogen antagonist at breast and uterus • Has anti estrogenic as well as anti progestogenic action. • Uses :  Dysfunctional Uterine Bleeding  Non Hormonal Oral Contraceptive Under Investigation for USE in :  Osteoporosis  Breast cancer  Endometrial Cancer

• Adverse Effects :  Nausea  Headache  Weight gain  Fluid retention

CLOMIPHENE CITRATE • Competitive antagonist of ER at Hypothalamus • Inhibits negative feedback effects on the release of GnRH • Release of FSH/LH at each secretory pulse is enhanced  Pharmacokinetics : • Well absorbed orally • Long plasma half life - 5 to 7 days • Highly plasma protein binding, undergoes enterohepatic circulation • Excreted in Urine and Faeces

 Adverse Effects : • Polycystic Ovarian Disease • Multiple Pregnancy • Risk of Ovarian Cancer • Hot flushes  Uses : • Infertility due to anovulation • Male infertility due to Oligozoospermia • In vitro fertilization

FULVESTRANT 7 α Alkylamide derivative of Estradiol

Molecular Action

• First member of – SERD ‘ Selective Estrogen Receptor Down-regulators’ • Pure estrogen antagonist • Introduced for treatment of metastatic ER positive breast cancer in postmenopausal women • Inhibits ER Dimerisation-ER interaction with DNA is prevented • Receptor degradation is enhanced

• More complete suppression of ER responsive gene function • Slowly eliminated, half life more than a month • Elimination in faeces  Adverse Effects : • Nausea, Headache, Asthma, Vasodilatation  Dose : 250mg monthly i.m. injections in buttocks  Use : Tamoxifen Resistant Breast Cancer

Recent Advances Lasofoxifene :  Investigated for the treatment of Post menopausal Osteoporosis and Vaginal Atrophy  Not approved by FDA for the treatment of vaginal atrophy Osmepifene :  Similar effects on bone as like Raloxifene- Increase BMD  Does not induce vasomotor symptoms in Post menopausal women  Increases endometrial thickness

 Arzoxifene : • Prevention and treatment of Breast cancer • Reduction in Vertebral Fractures • Failed to meet secondary endpoints of reduction in non vertebral fractures and cardiovascular events and cognitive function  Bazedoxifene : • Prevention and treatment of Post menopausal Osteoporosis • Favorable effects on Lipid profile


Add a comment

Related pages

Herz-Jesu-Kirche, Duisburg-Serm

Herzlich Willkommen! Adventssammlung der Caritas: Advent in unserer Pfarrei: letzte Änderung dieser Seite: Dienstag, 29. November 2016
Read more

SERM – Wikipedia

Die Abkürzung SERM steht für: Selektive Estrogenrezeptormodulatoren, eine Klasse von Arzneistoffen; Structured-Entity-Relationship-Modell, eine ...
Read more -

Am Samstag findet in Serm, rund um der Sermer Kirche, der Kappesmarkt statt. Programm für Groß und Klein entnehmen Sie bitte den Plakaten:
Read more

Serm (Duisburg) – Wikipedia

Serm ist ein Ortsteil des Duisburger Stadtteils Mündelheim im Stadtbezirk Duisburg-Süd. Der Ort besitzt ca. 3.500 Einwohner.
Read more

Selective estrogen receptor modulator - Wikipedia

Selective estrogen receptor modulator Selective estrogen receptor modulators ... SERM act on the estrogen receptor (ER), which is an intracellular, ...
Read more

Wetter Serm (Duisburg) |

Wie wird das Wetter heute in Serm? Temperatur-, Wind- und Regenvorhersage, sowie aktuelle Wetterwarnungen finden Sie auf für 47259 Serm ...
Read more - Prinz Frank I.

Wenn Sie gerne Mitglied der KG Südstern Serm e.V. werden wollen, können Sie sich gerne den Aufnahmeantrag als PDF-Format herunterladen.
Read more - Startseite

Das kommende Oktoberfest findet am 7. Oktober 2017 statt. Auch im nächsten Jahr möchten wir Sie wieder zu unserem. 18. Oktoberfest in Serm. herzlich ...
Read more

Wetter Serm (Duisburg) morgen |

Regen oder Sonne? So wird das Wetter morgen in 47259 Serm. Temperatur-, Wind- und Regenvorhersage auf
Read more

SCHERM Gruppe - the value of better logistics.

SCHERM Gruppe - the value of better logistics. Die SCHERM Gruppe ist ein international tätiger Systemdienstleister aus Karlskron bei Ingolstadt.
Read more