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1. DRUGS in Obstetrics & Gynecology

2. Oxytocin Cyclic nonapeptide synthesized in the supraoptic and paraventricular nuclei of the hypothalamus ,stored in posterior pituitary Secretion of oxytocin is controlled by a  positive feedback  mechanism, where its initial release stimulates production and release of further oxytocin

3. OXYTOCIN ( i ) Synthetic oxytocin ( Syntocinon or Pitocin ) has only got oxytocic effect without any vasopressor action. Available in ampoules containing 5 IU/mL (ii) Syntometrine —A combination of syntocinon 5 units and ergometrine 0.5 mg. (iii) Desamino -oxytocin—It is not inactivated by oxytocinase and is 50–100 more effective than oxytocin. It is used as buccal tablets containing 50 IU. (iv) Oxytocin nasal solution contains 40 units/mL . Oxytocin loses its effectiveness unless preserved at the correct temperature ( between 2°C and 8°C ).

4. OXYTOCIN Its action is noted at approximately 1 minute Half-life of 3–4 minutes Duration of action of approximately 20 minutes. Plasma steady state is reached in 40 minutes Metabolized and degraded by oxytocinase . When given as a bolus, oxytocin can cause profound hypotension Uterine response to oxytocin increases from 20 to 30 weeks’ gestation and rises rapidly at term

5. USES Ripening of cervix, Induction of labor, Augmentation of labor Active management of third stage of labor- Prevention and treatment of PPH Puerperium: To minimize blood loss and to control postpartum hemorrhage. To accelerate abortion—inevitable or missed and to expedite expulsion of hydatidiform mole — To stop bleeding following evacuation of the uterus — Used as an adjunct to induction of abortion along with other abortifacient agents (PGE1 or PGE2 ). Diagnostic tests- CST or Oxytocin challenge test Milk ejection

6. Contraindications of Oxytocin CPD/contracted pelvis Uterine scar Malpresentations Fetal distress Grand multipara Cardiac disease

7. Risks MATERNAL Uterine hyperstimulation . Uterine rupture Water intoxication is due to its antidiuretic function when used in high dose (30–40 mIU /min), manifested by hyponatremia, confusion, coma, convulsions, congestive cardiac failure and death. It is prevented by strict fluid intake and output record, use of crystalloid solution and by avoiding high dose oxytocin for a long time. Hypotension: Bolus IV injections of oxytocin cause hypotension especially when patient is hypovolemic or with a heart disease. Anginal pain. Tachycardia and bradycardia FETAL: Fetal distress, fetal hypoxia or even fetal death

8. Induction /acceleration Many different protocols Low dose regimen starts with 1-2mu/min with increment of 1-2mu/min every 30min maximum up to 32mu/min (RCOG) or 42mu/min (ACOG) High dose regimen starts with 4-6 mu/min with increment of 4-6 mu/min every 30min maximum up to 32mu/min. (  maximum dose of 92 mu/min in some trials) – used mainly for augmentation

9. High dose oxytocin has high risk of excessive uterine contraction or tachysystole (more than or equal to 5 contractions in 10 minutes) Maternal adverse effects : hyponatremia, hypotension, arrhythmia, tachysystole Neonatal adverse effects such as seizures, hyperbilirubinemia, retinal haemorrhages , fetal distress. Low dose regimen has prolonged induction delivery interval with better safety profile with fewer episodes of hyperstimulation.The increased induction to delivery interval may increase the chances for fetal infection and chorioamionitis .

10. carbetocin Heat-stable analogue of oxytocin, does not require refrigeration Half-life  85–100 minutes. Elimination half life is 40 min Longer action Disadvantage – Cost Rs-450 vs 18 for Pitocin use only postpartum Dose : 100 ug  im or iv injection . Contractile effects start within two minutes and lasts for about one hour Adverse effects: nausea, vomiting, abdominal pain, itching skin, increased body temperature, trembling and weakness. chest pain, dizziness,  anemia , chills and sweating, metallic taste,  tachycardia  and respiratory distress

11. Contraindications Cardiovascular disease Hypertension

12. ERGOT DERIVATIVES Ergometrine - alkaloid isolated from a fungus Claviceps purpurea Methergine - semisynthetic product derived from lysergic acid. Effective in hemostasis – to stop bleeding from the uterine sinuses, either following delivery or abortion. Produces tetanic uterine contractions – no polarity Acts through 5HT2 and alpha adrenergic receptors Dose 0.2 mg IM repeated after 15 min , then 4 th hourly , max 5 doses slow IV and oral

13. Uses Active management of third stage of labor - Prevent atonic uterine bleeding following delivery, abortion or expulsion of hydatidiform mole Adverse effects nausea and vomiting,diarrhoea , muscle cramps vasoconstrictive action - may precipitate HTN, myocardial infarction, stroke and bronchospasm, gangrene of the toes may interfere with lactation by lowering prolactin level Contraindications - Heart disease or severe hypertensive disorders, Asthma, Seizures

14. PROSTAGLANDINS 20-carbon carboxylic acids with a cyclopentane ring derived from prostanoic acid , synthesized from the essential fatty acid, arachidonic acid Paracrine/autocrine hormones Play a prominent role in myometrial contractility, relaxation, and inflammation. Prostaglandins interact with a family of eight different G-Protein–Coupled Receptors) which are expressed in myometrium and cervix Through prostaglandin isomerases, prostaglandin H2 is converted to active prostaglandins. These include prostaglandins E2 (PGE2 ), F2 α ( PGF2 α ), and I2 (PGI2 ). Late in pregnancy, amnionic prostaglandin biosynthesis is increased

15. PROSTAGLANDINS PGE1,PGE2 and PGF2 α used clinically Their half-life in the peripheral circulation is about 1–2 minutes Decidua is the main source of PGF2α, fetal membranes (amnion) produce PGE2 and the myometrium mainly produce PGI 2 PGs promote myometrial contraction irrespective of the duration of gestation, whereas oxytocin acts predominantly on the uterus at term or in labor

16. Prostaglandin E2 for cervical ripening /induction Relatively expensive and require refrigeration Vaginal tablet 3 mg dinoprostone ( Prostin E2 ). In the posterior fornix followed by 3 mg after 6–8 hours maximum 6 mg. Vaginal pessary (with retrieval device) releasing dinoprostone 10 mg over 24 hours. It is removed when cervical ripening is adequate. CERVIPRIME ( Dinoprostone ) gel—500 µg into the cervical canal, below the level of internal os or 1–2 mg in the posterior fornix Parenteral: PGE2 (IV)— Prostin E2 containing 1 mg/mL,

17. PGF2 α Prostodin / Carboprost A smooth muscle stimulant and is a recognized second-line agent for use in the management of postpartum uterine atony unresponsive to oxytocin and ergometrine. Used in treatment of PPH 250 µg/mL IM repeat at 15-90min max 8 doses Administered by deep intramuscular injection or direct intramyometrial injection Peripheral intramuscular injection yields peak plasma concentrations at 15 minutes in contrast to less than 5 minutes for the intramyometrial route Side effects of PG F2-alpha include nausea, vomiting, diarrhea, bronchospasm and systemic hypertension. Pulmonary edema and cardiovascular collapse also reported C/I – Asthma, Hypertension

18. Methyl ester of PGE1 (Misoprostol) Rapidly absorbed and is effective for induction of labor and cervical ripening. Initially used for peptic ulcer disease. Transvaginal vs Oral misoprostol 25–50 µg every 3–6 hours by oral or vaginal route for IOL Buccal or sublingual misoprostol is also used for induction of labor and vaginal delivery. Oxytocin when needed may be added after 4 hours

19. USES Induction of abortion Termination of molar pregnancy Cervical ripening, Induction of labor , Augmentation of labor Management of atonic postpartum hemorrhage

20. Advantages Cheap, stable at room temperature, long self life, Easily administered (oral, vaginal or rectal) Less side effects. Induction delivery interval is short. Need of oxytocin augmentation is less. Failure of induction is less

21. CONTRAINDICATIONS: Hypersensitivity to the compound ,Uterine scar PGE2 - Active cardiac, pulmonary, renal or hepatic disease; hypotension. Caution in  asthma, glaucoma or raised intraocular pressure, or renal or hepatic dysfunction and in those with ruptured membranes PGF2 α -Bronchial asthma , Pul HTN

22. TOCOLYTICS Beta-adrenergic agonists Magnesium sulfate Calcium-channel blockers - Nifidipine NSAIDs - Indomethacin Oxytocin antagonist - Atosiban

23. β- Adrenergic Receptor Agonists Isoxsuprine , ritodrine and terbutaline β-Agonist agents cause retention of sodium and water, and with time—usually 24 to 48 hours— these can cause volume overload - Pulmonary edema Increased capillary permeability, cardiac rhythm disturbances, and myocardial ischemia. Betamimetics are known to cause serious maternal side effects including nausea, tachycardia, tremor, headache, chest pain and pulmonary oedema, pulmonary edema, hypotension, cardiac failure, hyperglycemia , ARDS, hyperinsulinemia, lactic acidemia , hypokalemia and even death Fetal : Tachycardia, heart failure, IUFD. Neonatal: Hypoglycemia and intraventricular hemorrhage

24. Isoxsuprine ( Duvadilan ) 40mg in 500ml NS titrated drip foll by 10mg orally/IM Q8H Watch out for tachycardia, hypotension,tremors , pul edema , MI, hypoglycemia , hyperkalemia Duvadilan retard 40mg bd C/I - cardiac , thyroid disorders, anemia Ritodrine is given by IV infusion, 50 µg/min and is increased by 50 µg every 10 min until contractions cease Terbutaline -Subcutaneous dosages of 0.25 mg(250 mcg) – Tachysystole, ECV

25. Magnesium Sulfate Acts as calcium antagonist , blocks glutaminergic receptors and inhibits presynaptic glutamate release Intravenous magnesium sulfate, given as a 4-6 g loading dose and followed by a continuous infusion of 2 g/ hr upto 12hr Therapeutic range 4-7meq/ml Bone thinning and fractures in fetuses exposed for more than 5 to 7 days. This was attributed to low calcium levels in the fetus MgSO4 is relatively safe. Common maternal side effects are flushing, perspiration, headache and muscle weakness, rarely pulmonary edema. Neonatal side effects are lethargy, hypotonia, rarely respiratory depression. Contraindication: Myasthenia gravis and impaired renal function, Myocardial ischemia Uses : Tocolysis, anticonvulsant, fetal neuroprotection

26. MgSO4 in eclampsia Zuspans regime 4g iv loading dose foll by 1-2g/hr iv Pritchard regime 4g IV bolus, 10 g IM bolus( 5 g in each buttock), foll by 5g IM Q4H in alternate buttock Monitor - RR 16/min Urine output 25ml/hr Deep tendon reflexes Antidote 10ml 10% calcium gluconate IV over 10 min

27. Monitoring Mg SO4

28. Prostaglandin Inhibitors Indomethacin, a nonselective cyclooxygenase inhibitor Indomethacin is administered orally or rectally. Loading dose 50-100 mg PO or PR followed by 25 -50 mg every 6 hrs for 48 hrs. Maternal: Heartburn, asthma GI bleeding, thrombocytopenia, renal injury, platelet dysfunctions. Fetal and Neonatal side effects: Constriction of the ductus arteriosus (due to inhibition of synthesis of PGI2 and PGE2 ) if given >72 hours and beyond 32 weeks Oligohydramnios if given beyond 32 weeks, Neonatal pulmonary hypertension IUGR , necrotizing enterocolitis and intraventricular hemorrhage, acute renal failure Oligohydramnios is reversible with drug discontinuation. Contraindications: Hepatic &renal disease, active peptic ulcer, coagulation disorders,asthma

29. Nitric Oxide Donors Potent smooth-muscle relaxants nitroglycerin administered orally, transdermally , or intravenously 10mg/24 hour GTN transdermal patch maternal hypotension is a common side effect

30. Calcium channel blockers Nifedipine, Nicadipine , Verapamil Nifedipine 10–20 mg every 3–6 hrs or 40mg in first hour followed by 20mg 8 hourly Side effects:(Maternal) Hypotension, headache, flushing and nausea Combined therapy with β mimetics or MgSO4 should be avoided as nifedipine enhances the neuromuscular blocking effects of magnesium, which can interfere with pulmonary and cardiac function

31. Atosiban Nonapeptide, desamino oxytocin analogue acts an oxytocin-receptor antagonis t Fewer maternal adverse effects Nausea, vomiting, chest pain   S ingle initial intravenous bolus of 6.75 mg , followed by an  intravenous infusion  of 300 µg/min for the first 3 hours and then 100 µg/min for up to 18 hours. U se of atosiban , even at very early pregnancy, to decrease the frequency of uterine contractions to enhance success of pregnancy eg IVF preg Expensive

32. HORMONES and related drugs

33. ESTROGEN PROGESTERONE GONADOTROPINS ANTI GONADOTROPINS ANTIESTROGENS including AROMATASE INHIBITORS ANTIPROGESTERONES ANDROGENS ANTIANDROGENS SERMS SPRMS GnRH ANALOGUES & ANTAGONISTS ANTI DOPAMINERGIC ( PROLACTIN LOWERING)

34. Estrogens Estrogen is derived from Greek " oestros "(a periodic state of sexual activity in female mammals), and genos (generating) The first estrogen to be discovered was estrone(1929, Adolf Butenandt and Edward Adelbert Doisy ) C18 steroid compounds containing a phenolic ring  synthesized from androgens, specifically testosterone and androstenedione, by the enzyme aromatase.

35. Natural oestrogens -estradiol, estrone, estriol, conjugated equine estrogens (CEE). Synthetic C18 estrogen is ethinyl estradiol Synthetic nonsteroidal estrogens include diethylstilbestrol (DES) and selective estrogen-receptor modulators

36. The four major naturally occurring estrogens in women are estrone (E1),  estradiol  (E2), estriol (E3), and  estetrol  (E4). The predominant estrogen during - reproductive years - Estradiol (E2) - menopause - Estrone - pregnancy - Estriol  Estetrol  (E4) is produced only during pregnancy

37. ESTROGENS Natural : water soluble conjugated estrogen as Premarin (Equine conjugated estrogen). It is obtained from the urine of pregnant mares . It is available as tablets 0.3 mg , 0.625 mg and 1.25 mg and as injection of 20 mg ampoules for IM or IV injection. Synthetic: Oral Injectable Cream/Gel Pessary Implant Patch

38. Synthetic estrogens Oral : Ethinyl estradiol ( Lynoral ) 0.01 mg and 0.05 mg Estradiol valerate 1–2 mg. Mestranol — 0.05 mg. Estriol succinate ( Evalon ) — 1–2 mg. Injectable: Estradiol valerate as progynon depot (Schering) – 10 mg ampoule. Estradiol benzoate or dipropionate – 1 mg and 5 mg ampoule. Cream: Vaginal cream– dienestrol (0.1 mg/gm), Estriol (1 mg/gm). Percutaneous cream—delivers 3 mg of estradiol in each daily 5 gm application Premarin cream, Evalon cream Gel: Estradiol gel 1 mg Pessary: Dienestrol or diethyl stilbestrol pessary. Implants: Subcutaneous implants of 50 mg and 100 mg of 17 β estradiol (effect lasts for 6 months) Transdermal patch: It contains 3.2 mg of 17 β estradiol releasing about 50 µg of estradiol in 24 hours. It should be applied below the waist line and changed twice a week

39. USES Replacement therapy , Oral contraception, Menopausal symptoms , Hypo-ovarian function, Senile or atrophic vaginitis, Vulvovaginitis in childhood, DUB- acute bleeding can be stopped by oral conjugated estrogen in a dose of 10 mg a day. The bleeding usually stops within 24 hours. Alternatively, 25 mg may be given intravenously every 4 hours for 3 doses Delayed puberty C ervical mucus hostility: To improve the quality of the cervical mucus in infertility, low dose of estrogen (ethinyl estradiol 0.01 mg) may be given cyclically, from day 1–14 . As an adjunct to clomiphene therapy Stress incontinence (GSI) in postmenopausal women to improve the tone of collagen tissue Intersex state: In Turner’s syndrome (45, XO) or gonadal dysgenesis (46, XY), androgen insensitivity syndrome (46, XY),

40. Contraindications of Estrogen History of venous thromboembolism , active liver disease, severe hypertension, organic heart disease , estrogen dependent tumors like breast Ca Adverse effects – Increased incidence of endometrial and breast carcinoma, thromboembolism , cerebral thrombosis and hemorrhage . • Nausea, vomiting • Breast tenderness • Breakthrough bleeding • Weight gain

41. Tibolone ( Livial ) synthetic steroid with weak estrogenic, progestogenic, and androgenic activity . The estrogenic effects of tibolone may show tissue selectivity in their distribution used in menopausal hormone therapy and in the treatment of postmenopausal osteoporosis and endometriosis 2.5mg daily Wt gain, hirsuitism , ca endometrium, breast, ovary VTE

42. Anti estrogens Selective estrogen receptor modulators (SERMs) like tamoxifen,  clomifene , and raloxifene, The ER silent antagonist and selective estrogen receptor degrader (SERD)  fulvestrant , Aromatase inhibitors like anastrozole, Letrozole Antigonadotropins including androgens/anabolic steroids,  Progestogens, GnRH analogues.

43. Anti estrogens - USES ntiestrogens are used for: Estrogen deprivation therapy  in the treatment of ER-positive  breast cancer , endometriosis, fibroid Ovulation induction  in  infertility  due to  anovulation Male hypogonadism Gynecomastia  ( breast development  in men) A component of  hormone replacement therapy  for  transgender men

44. Induction of ovulation Endometriosis Fibroid Precocious puberty DUB Premenstrual syndrome Advanced breast carcinoma Contraception Endometrial resection/ablation

45. Side effects hot flashes osteoporosis breast atrophy vaginal dryness vaginal atrophy depression   reduced  libido

46. side effects hot flushes, vaginal dryness, dyspareunia, headache and depression (menopause-like symptoms), Acne, muscle pain, back pain, dry skin are also noted. There is decrease in both, the trabecular (lumbar spine) and cortical (femoral neck) bone mineral density (osteoporosis) when used for more than 6 monthss . Add-back therapy consists of low dose combined estrogen (conjugated estrogen 0.625 mg) and progestin ( medroxy progesterone 2.5 mg) therapy regimens daily. Add-back therapy prevents bone loss and other side effects.

47. Progesterones progestogens include natural progesterone and synthetic progestogens, which are called progestins. Progestins can be classified as derivatives of either 19-norprogesterone or 19-nortestosterone 19-norprogesterones, the most commonly used are medroxyprogesterone acetate and megestrol acetate.

48. Progesterone Pregnanes : medroxyprogesterone acetate, nomegestrol acetate Estranes : Norethindrone, norethindrone acetate, ethynodiol diacetate, norethynodrel Gonanes: levonorgestrel, desogestrel , norgestimate , gestodene

49. First generation : 1) Estranes derived from testosterone : norethindrone , norethynodrel, norethindrone acetate , ethynodiol diacetate 2) Pregnanes derived from 17-OH progesterone : medroxyprogesterone acetate , chlormadinone acetate Second generation : Gonanes derived from testosterone- levonorgestrel , norgestrel Third generation : Gonane (Levonorgestrel) derivatives desogestrel , gestodene , norgestimate / norelgestromine , etonorgestrel Fourth generation 1) Non ethylated estranes : dienogest , drospirenone 2) Pregnanes (19-norprogesterones) nestorone , nomegestrol acetate, trimegestone

50. When administered with ethinyl estradiol, the newer generation progestins have an increased risk of venous thrombo embolism compared to their older counterparts.

51. Progesterone is also available as natural and micronized natural progesterone Derived from Mexican yams, soybeans or animal sources. The value of micronization of natural progesterone is that increases its absorption and bioavailability. The micronized progesterone has fewer metabolic and vascular side effects than the synthetic progestins. It has not been used yet in hormonal contraceptives

52. Dydrogesterone , a synthetic retroprogesterone , 10mg tablet Orally active No androgenic or estrogenic properties Weak mineralocorticoid activity Does not inhibit ovulation Immuno modulating action Association with congenital heart disease

53. Side effects •Nausea • leg cramps • mastalgia •Weight gain due to salt and water retention •Acne • scanty periods due to androgenic progestins • loss of libido • Virilism •Headaches• Depression and mood changes—may be due to low level of pyridoxin as progestins alter the tryptophan metabolism. •Lipid profile—increase in LDL and decrease in HDL level

54. USES Endometriosis Dysmenorrhea Luteal phase defect (LPD) endometrial hyperplasia and endometrial carcinoma Premenstrual syndrome Luteal support Postponement of menstruation Hormone replacement therapy (HRT): Estrogen and/or progestins are used for contraception and for treating abnormal uterine bleeding, endometriosis, leiomyomas, PCOS, and menopausal symptoms

55. Combined Preparations (Estrogen and Progestogen) Contraception — The commonest and widely use of combined preparations is in the field of fertility control Dysfunctional uterine bleeding ,Endometriosis , Dysmenorrhoea , Postponement of period, Premenstrual syndrome, Idiopathic hirsutism—cyclic therapy of combined preparations containing 50 µg of ethinyl estradiol together with new progestin is more effective, Hormone replacement therapy (HRT)

56. DRUGS in Obstetrics & Gynecology ……………….continued

57. THE GONADOTROPINS FOLLICLE STIMULATING HORMONE LUTEINIZING HORMONE HUMAN CHORIONIC GONADOTROPIN Heterodimers that share an identical α chain and a distinct β chain that confers receptor specificity. The β chains of hCG and LH are nearly identical, and these two hormones are used interchangeably. All the gonadotropin preparations are administered by subcutaneous or intramuscular injection, usually on a daily basis. Half-lives vary by preparation and route of injection from 10 to 40 hours.

58. Menotropins or human menopausal gonadotropins ( hMG ) - extracted from the urine of postmenopausal women and contained FSH and LH at a 1:1 ratio - Pergonal - 75 IU FSH and 75 IU LH. Urofollitropin , also known as uFSH , is a purified preparation of human FSH extracted from the urine of postmenopausal women. Metrodin - purified urinary FSH Metrodin HP – highly purified urinary FSH Used to induce ovulation in females. In males, increases testosterone production for treatment of low sperm count and delayed puberty. 75 -450 IU S/C or I/M daily from day 2 -6 with follicle monitoring Side effect : OHSS

59. Follicle-Stimulating Hormone Two recombinant forms of FSH ( rFSH ) are also available: follitropin alfa and follitropin beta High purity and biological potency Completely LH free, but more expensive Gonal -f - follitropin alfa Recogon -follitropin beta

60. Luteinizing Hormone Lutropin alfa, the recombinant form of human LH use in combination with follitropin alfa for stimulation of follicular development in infertile women with profound LH deficiency

61. Human Chorionic Gonadotropin ( Profasi , Pregnyl ) It is a glycoprotein consisting of a 92-amino-acid α chain identical to that of FSH, LH, and TSH , and a β chain of 145 amino acids that resembles that of LH except for the presence of a carboxyl terminal sequence of 30 amino acids not present in LH. Choriogonadotropin alfa ( rhCG ) is a recombinant form of hCG The preparation of hCG that is purified from human urine is administered by intramuscular injection, whereas rhCG is administered by subcutaneous injection. Trigger ovulation as LH surrogate Human Chorionic Gonadotropin (HCG): 5000 to 10,000 units IM once 1 day following the last dose of menotropins Recombinant Chorionic Gonadotropin (r-HCG): 250 mcg subcutaneously once 1 day following last dose of follicle-stimulating agent Used for luteal support

62. ANTI-GONADOTROPINS Danazol , Gestrinone Endometriosis ,Precocious puberty , DUB, PMS, fibroid, benign fibrocystic disease of the breasts (breast pain) ,Prior to hysteroscopic endometrial ablation, to make the endometrium thin The side effects are mostly related to hypoestrogenic and androgenic activity . Dose :100 -800 mg in divided dose

63. Side effects of Danazol

64. Antiestrogens ( Clomiphene, Aromatase inhibitors,Tamoxifen ) All are SERMs ( estrogenic on ovulation, anti estrogenic on endometrium and cervical mucus) Clomiphene citrate a mixture of two isomers, enclomiphene —a potent anti-estrogen and zuclomiphene , a weak antiestrogen (62:38) Used for Induction of ovulation , Male infertility with defective spermatogenesis due to hypogonadotropic-hypogonadism Side effects: These include visual disturbances, headache, hot flushes, breast tenderness, abdominal discomfort, loss of hair, rashes and ovarian enlargement and multiple pregnancy. Hyperstimulation syndrome Dose : 50mg oral from day 2-5 x 5days , Incremental by 50 mg in next cycle, max 250mg/d Clomiphene resistance- no ovulation in 6 months, failure – no pregnancy in 6 months despite ovulation

65. Aromatase Inhibitors Letrozole 2.5 mg given from D3 to D7 or single dose 30mg on D3 Anastrozole 1mg daily x 5days Reduces Estrogen levels , thereby increasing FSH secretion Monofollicular development, no anti estrogenic effect on endometrium, better pregnancy rate Also used in adjuvant treatment of breast cancer

66. Tamoxifen Similar to clomiphene both structurally and functionally. It has got both estrogen antagonist(breast) and agonist effects(endometrium) Induction of ovulation, treatment of benign breast diseases. postmenopausal breast carcinoma, recurrent endometrial carcinoma Started at 20 mg daily x 5 years

67. Anti-Progesterone Mifepristone (RU 486) It is a competitive antagonist of progesterone and glucocorticoid receptors. It is a derivative of 19-nortestosterone. It binds competitively to progesterone receptors and nullifies the effect of endogenous progesterone Uses: Therapeutic abortion, Uterine fibroids (Emergency contraception , Induction of labor , Ectopic pregnancy,endometriosis , Cushing’s syndrome) Mifepristone is contraindicated in the presence of adrenal failure, long-term oral corticosteroid therapy (although inhaled and topical steroids are fine), hemorrhagic disorders, inherited porphyria, and hemophilia or anticoagulant use Dose : 200 -600mg for medical abortion, 10-25 mg for fibroid,100mg/day for endometriosis

68. Androgens It may be used in cases of frigidity and premenstrual syndrome either orally or as an implant. In postmenopausal or perimenopausal woman, androgens are combined with estrogen to improve libido. It is used in male infertility DHEA improves ovarian reserve- used in infertility

69. Anti-Androgens Cyproterone acetate, Spironolactone , Flutamide, Finasteride Cyproterone acetate: Anti-androgenic progestogen . It inhibits gonadotropin secretion and also acts as a competitive androgen receptor antagonist. It decreases 5 α- reductase activity and reduces LH secretion . It also acts as a potent progestogen Use: It is used in the idiopathic hirsutism or hyperandrogenic state Dose: Cyproterone acetate 2 mg is most frequently used in combination with ethinyl estradiol. Side effects are—weight gain, loss of libido, mastalgia

70. SERM a SERM may act as an estrogen agonist in a low-estrogen state, such as menopause, but as a competitive antagonist in a patient with high circulating estradiol levels The SERM ospemifene ( Osphena ) may have favorable characteristics for long-term relief of genitourinary syndrome of menopause . The SERM bazedoxifene is combined with CEE and marketed as Duavee . This coupled approach yields a drug group categorized as tissue-selective estrogen complexes (FSECs). The goal of TSECs is to provide estrogen agonist/ antagonist profiles that optimize clinical efficacy and safety.

71. SPRM Antiprogestins universally prompt antagonist effects upon binding to the progesterone receptor. SPRMs exert antiprogestational effects in some tissues but progestational effects in others. Selective progesterone-receptor modulators are used in emergency contraception and for treatment of abnormal uterine bleeding, leiomyomas, and endometriosis Ullipristal acetate has been linked to possible severe liver damages Dose : 30mg within 120 hours of unprotected intercourse 5-10 mg daily upto 6 months for fibroid

72. Ulipristal acetate (UPA) SPRM used as emergency contraceptive( Ella) For myoma treatment ( Esmya , Fibristal ) prescribed in 5-mg oral daily doses for up to 12 weeks. UPA acts as a potent antiprogestin in myomas and shrinks their volume. UPA performs comparably with leuprolide acetate to shrink myoma volume and controlled heavy menstrual bleeding .But unlike GnRH receptor agonists, it avoids the gonadotropin flare and hypoestrogenic side effects. Estradiol levels lie in the midfollicular range The effect of UPA on the endometrium is not that of a pure antagonist. Progesterone-receptor modulator-associated endometrial changes (PAECs) reflect dyssynchronous growth between glands and stroma. PAECs are not linked to short-term higher rates of endometrial hyperplasia or cancer . PAECs revert within 3 to 6 months following drug cessation

73. GnRH Gonadotropin releasing hormone is a decapeptide that is produced in the hypothalamus stimulating the release of LH and FSH GnRH is typically produced in a pulsatile manner With continued non-pulsatile stimulation, LH and FSH synthesis are inhibited

74. The GnRH agonists, which have greater potency and a longer half-life than native GnRH, produce an initial stimulation of pituitary gonadotrophs that results in secretion of follicle-stimulating hormone and luteinizing hormone and the expected gonadal response. This response is followed by downregulation and inhibition of the pituitary-gonadal axis. Synthetic analogs of GnRH include goserelin , histrelin , leuprolide, nafarelin , and triptorelin

75. Continuous administration of gonadorelin or its longer-acting analogs produces a biphasic response. During the first 7–10 days, an agonist effect results in increased concentrations of gonadal hormones in males and females; this initial phase is referred to as a flare . After this period, the continued presence of GnRH results in an inhibitory action that manifests as a drop in the concentration of gonadotropins and gonadal steroids.

76. Short-acting injection (once per day): buserelin , histrelin , leuprorelin, triptorelin Long-acting depot injection or injected pellet (once every one to six months): leuprorelin, triptorelin Injected implant (once every one to three months): buserelin , goserelin , leuprorelin Surgically implanted pellet (once per year): histrelin , leuprorelin Nasal spray (two to three times per day): buserelin , nafarelin

77. GnRH agonists

78. Leuprolide acetate IVF cycles – for controlled ovarian hyperstimulation Hypothalamic hypogonadotropic hypogonadism in male infertility Fibroid Endometriosis

79. GNRH RECEPTOR ANTAGONISTS The GnRH antagonists promptly suppress pituitary gonadotropin by GnRH-receptor competition, thereby avoiding the initial stimulatory phase of the agonists. Ganirelix, cetrorelix , and degarelix (peptides) Elagolix , Relugolix (non peptide small molecules) Ganirelix s/c 0.25 mg daily maintains GnRH antagonism. Alternatively, a single 3.0-mg dose of cetrorelix suppresses LH secretion for 96 hours. Degarelix therapy is initiated with 240 mg administered as two subcutaneous injections. Maintenance dosing is with an 80-mg subcutaneous injection every 28 days. Elagolix 150 mg once a day and 200 mg twice a day, orally Relugolix 10-14mg daily, orally

80. GnRH antagonist:

81. Bromocriptine ( Parlodel ) Ergot derivative partial agonist of the dopamine D2 receptor. used in the treatment of pituitary tumors, Parkinson's disease, hyperprolactinaemia , neuroleptic malignant syndrome, and, as an adjunct, type 2 diabetes. side effects are nausea, orthostatic hypotension, headaches, and vomiting through stimulation of the brainstem vomiting centre Vasospasms Hyperprolactinemia -1.25 to 2.5 milligrams (mg) once a day taken at bedtime , increase dose by 1.25 or 2.5 mg every 3 to 7 days upto 10mg/day Use to suppress milk production after childbirth oral bromocriptine 2.5 mg once daily for 3 days for suppression of lactation

82. Cabergoline ( Dostinex ) Ergot derivative and a potent dopamine D2 receptor agonist Long half life ( 63 -109 hrs ) - twice a week dosing Caution in uncontrolled hypertension, heart valve disorder, pleural, pericardial, and retroperitoneal fibrosis 0.25 mg orally twice a week -Increase dose in increments of 0.25 mg twice a week every 4 weeks For inhibition of lactation cabergoline should be administered during the first day post-partum. The recommended therapeutic dose is 1 mg (two 0.5 mg tablets) given as a single dose. For suppression of established lactation the recommended therapeutic dosage regimen is 0.25 mg (one-half 0.5 mg tablet) every 12 hours for two days (1 mg total dose) OHSS – 0.5mg OD x 8days

83. MISCELLANEOUS Antihypertensives Methotrexate Tranexamic acid Metformin Insulin Anticoagulants Iron Calcium Folic acid Anti D Corticosteroids

84. Antihypertensives Labetolol Alphadopa Nifedipine Hydrallazine

85. Labetolol First line drug in GestHTN /preeclampsia Alpha1 and beta1&2 blocker – reduces peripheral vascular resistance without altering HR , stroke volume or cardiac output Rapd onset 1-2 min Orally alpha : beta blockade is 1:3. IV it is 1:7 Started at 100mg twice daily and increased to max 1200mg/day In hypertensive emergency- IV 20mg slowly stepped up by 20-40-80 -80mg every 30 min or 1-2 mg/min infusion to max 300mg Watch out for sudden hypotension and cerebral haemorrhage, fetal bradycardia FGR C/I – Reactive airway, bradycardia, heart block, pul edema

86. Alpha Methyl dopa Used to be first line in pregnancy. Suitable in chronic hypertension Centrally acting alpha agonist – reduces systemic vascular resistance Onset of action in 48 hours 250mg twice or thrice daily, increased to 500mg qid max

87. Nifedipine Calcium channel blocker Oral tablets 10-20mg Q4H-Q8H to max 120mg/day Rapid onset 5-10min SR formulation is available Oral capsule 5-10 mg to bring down BP quickly S/L not used for fear of drastic BP fall Head ache is a common side effect. Also hypotension, tachycardia C/I cardiac failure, decreased ejection fraction

88. Nifedipine Uses Antihypertensive 2 nd line Tocolytic 30mg stat and 20 mg q8h upto 72 hr

89. Hydrallazine Beta blocker and diuretic – arteriolar dilator Oral & IV Hypertensive emergencies – 10-20mg slow infusion repeated every 4-6 hours

90. Methotrexate Folate antagonist Medical management of Ectopic pregnancy -single dose regimen 1.0 mg/kg or 50 mg/m2 i.m without folinic acid Trophoblastic disease - Five-day low-dose methotrexate IV or IM; maximum of 25mg/m2 daily for five days, repeated every 14 days OR eight-day regimen 1 mg/kg Im on days one, three, five and seven with folinic acid rescue (days two, four six and eight), repeated every 14 to 16 days Oral or IM/IV Routine monitoring of the complete blood count, liver function tests, and creatinine A dverse effects include: hepatotoxicity, ulcerative stomatitis, leukopenia and predisposition to infection

91. Tranexamic acid Antifibrinolytic, clot stabilising Inhibits conversion of plasminogen to plasmin PPH- 1gm IV max 2g /24 hr (WHO trial) HMB 1.5-3g/day in 3 divided doses oral Surgical bleeding 1-1.5g 2-4 times in 24 hrs WOMAN trial, CRASH 2 trial

92. Metformin Biguanide OHA Safe in pregnancy Decrease hepatic gluconeogenesis, increase insulin sensitivity and reduce appetite Uses: GDM/ diabetes in pregnancy, PCOD Side effects- hypoglycemia , lactic acidosis, diarrhoea, flatulence, nausea Dose : 500mg /850mg/1000mg/extended release Bid to tid max 2550 mg/24hrs

93. Insulins Peptide hormone from beta cells of pancreas with multiple metabolic functions Synthetic insulin made by recombinant DNA technology Subcutaneous/inhaled Basal /Prandial insulin Insulin analogues safe in pregnancy – Lispro, Aspart and Detemir Side effects : hypoglycemia , weight gain

94. Heparin(unfractionated) A glycosaminoglycan acts by inactivating thrombin& factor Xa Given IV/SC Safe for use during pregnancy and breastfeeding Protamine sulfate ina dose of 1 mg per 100 units of heparin that had been given over the past 6 hours acts as antidote side-effects of heparin - heparin-induced thrombocytopenia - platelet count should be monitored every 2–3 days - osteoporosis, - hyperkalemia Half-life of about one to two hours after infusion APTT, anti Xa and platelet counts to be monitored

95. LMWH LMWHs are the agents of choice for antenatal and postnatal thromboprophylaxis. Half-life of four to five hours - Once or twice daily subcutaneous dosing Average molecular weight: heparin is about 15 kDa and LMWH is about 4.5 kDa Monitoring of anti- Xa levels or APTT is not required. The risk of bleeding, heparin-induced thrombocytopenia and osteoporosis substantially lower with LMWH Safe in pregnancy and breastfeeding LMWH is contraindicated in patients with kidney disease in whom unfractionated heparin can be used safely.

96. Dose is weight dependant

97. Warfarin Use in pregnancy is restricted to the few situations e.g. some women with mechanical heart valves. Warfarin crosses the placenta leading to an increased risk of congenital abnormalities . C/I in first TM Warfarin embryopathy (hypoplasia of nasal bridge, congenital heart defects, ventriculomegaly, agenesis of the corpus callosum, stippled epiphyses) Increase in the risk of spontaneous miscarriage, stillbirth,neurological problems in the baby and fetal and maternal haemorrhage . Safe in breastfeeding- postpartum

98. Newer anticoagulants ORAL - Dabigatran, Rivaroxaban, Apixaban – not recommended in pregnancy and lactation PARENTERAL - Fondaparinux, Danaparoid - may be used with caution

99. Iron Requirement 0.8mg/d in 1 st TM 4mg/d in 2 nd TM 6mg/d in 3 rd TM Oral preparations FeSO4,Ferrous fumarate, gluconate, ascorbate, bisglycinate Ferric polymaltose, ferric citrate, liposomal iron Ferrous salts are better absorbed Min 60mg elemental iron. On empty stomach or 1 hour after food pref with Vit C. Increase in Hb 1g/dl in 2wks Side effects – GI intolerance, constipation

100. Parenteral iron Iron sucrose 200mg/d in 100ml NS or diluted with blood in 20 min Ferric carboxy maltose 20mg/kg infused over 15 min Iron dextran Indications : Intolerance to oral iron, Malabsorption

101. Folic acid vitamin B9, water-soluble RDA 400mcg/d In high risk women on anticonvulsants or h/o NTD - 4mg/d National Iron+ Initiative - 100 mg elemental iron and 500 mcg of folic acid 1 tablet daily for 100 days, starting after the first trimester, at 14–16 weeks of gestation. To be repeated for 100 days post-partum Weekly iron –folic acid supplementation (WIFS) NNAPP National Nutritional anemia prophylaxis programme Anemia mukt Bharat

102. Calcium RDA 1200mg/d Carbonate, Citrate, Lactate, Gluconate Prevention of preeclampsia Continue throughout lactation Vitamin D

103. Antenatal corticosteroids Betamethasone 12mg IM Q24H x 2doses Dexamethasone 6mg IM Q12H x 4 doses Improves fetal lung maturity Decreases incidence of RDS, IVH NEC, sepsis, mortality within 4 hours of life Most effective 2-7 days after inj Corticosteroids should be offered to women between 24+0 and 34+6weeks’ gestation in whom imminent preterm birth is anticipated One rescue dose if last dose was > 7 days ago ASTECS 2 trial, ALPS trial

104. Anti D To prevent Rh isoimmunisation Rhogam inj - Rho(D) Immune Globulin (Human) manufactured from human plasma containing anti-D- 300 μg or 1500 IU MICRhoGAM - 50 μ g or 250 IU Half life 24 days 300 μ g neutralises 30ml blood/15ml RBC within 72 hours of delivery, but ASAP Anti-D Ig should be given to all non- sensitised RhD -negative women who have a spontaneous ,threatened, complete or incomplete miscarriage after 12+0 weeks of gestation in a dose of 250 iu Also ectopic gestation RAADP- Routine antenatal anti-D prophylaxis - single-dose and two-dose regimen – Two doses of 500 iu anti-D Ig at 28 and 34 weeks of gestation, or a single dose of 1500 iu at 28 weeks of gestation.

105. HPV vaccine