Oxytocic drugs

Oxytocic drugs

1. O X YT OC I C S DR BIBEK PAUDEL NEPALGUNJ MEDICAL COLLEGE KOHALPUR, NEPALGUNJ

2. O X YT OC I C S NGMC, DR BIBEK 3 T he drugs of varying c h e m i c a l n a t u r e t h a t h a v e t h e p o w e r t o stimulate the contraction of uterine muscles. A ka Uterotonics " one of the enduring achievements of modern science”.

3. Ergometrine & Methergin PGE 2 & PGF 2 ά NGMC, DR BIBEK 4

4. Oxytocic drugs U sed for : The contraction stress test to evaluate fetal well-being during the antepartum period Induction of labor Treatment of labor arrest Active management of labor Treatment of uterine atony and postpartum hemorrhage NGMC, DR BIBEK 5

5. 1.Oxytocin NGMC, DR BIBEK 6 i. Synthesis: pituitary hormone secreted by the posterior pituitary gland. secretion occurs by sensory stimulation from cervix ,vagina , and from suckling at breast.

6. NGMC, DR BIBEK 7

7. ii . S e c r e t i o N o f o x y t o c i n : NGMC, DR BIBEK 8

8. Mechanism of action NGMC, DR BIBEK 9 En dogenous or administered o x y t o c i n , m e m b r a n e r e c e p t o r P romotes the influx of ca ++ F rom extra cellular fluid from S.R In to the cell I ncrease in cytoplasmic ca , stimulates uterine contraction .

9. UTERUS a c t s t h r o u g h G p r o t e i n - c o u p l e d r e c e p t o r s A n d t h e phosphoinositide -calciu m second-messenger system to contract uterine smooth muscle. s t i m u l a t e s t h e r e l e a s e o f p r o s t a g l a n d i n s & leukotrienes that augment uterine contraction. s m a l l d o s e s i n c r e a s e s b o t h t h e f r e q u e n c y & the force of uterine contractions . At higher doses, it produces sustained contraction . NGMC, DR BIBEK 10

10. These contractions resemble the normal physiological contractions of uterus (contractions followed by relaxation) Immature uterus is resistant to oxytocin. Contract uterine smooth muscle only at term. Sensitivity increases to 8 fold in last 9 weeks and 30 times in early labor. NGMC, DR BIBEK 11

11. Compiled by: Prof. Anwar Baig 9 NGMC, DR BIBEK 12

12. OXYTOCIN first-line agent polypeptide structure produced in the paraventricular nucleus of the hypothalamus and released by the posterior pituitary gland roles of oxytocin in the obstetric population include induction and augmentation of labor, and prevention and treatment of postpartum uterine atony. NGMC, DR BIBEK 13

13. Structure/Activity short polypeptide consisting of 9 peptides C 46 H 66 N 12 O 12 S 2 structurally similar to vasopressin A disulfide bridge connects 2 cystines in the primary sequence (Cys1 and Cys 6), forming a ring. NGMC, DR BIBEK 14

14. stimulatory effect on myometrial contractility by increasing the intracellular concentration of calcium Oxytocin binds to a G-protein on the surface of the uterine myocyte, resulting in the generation of DAG and IP3 via phospholipase C on PIP2. rate-limiting step for the action of oxytocin is the concentration of oxytocin receptors on the myometrium Concentration of these receptors increase with Gestational age & is higher in the fundus than in Lower uterine segment. NGMC, DR BIBEK 15

15. Pharmacokinetics absorbed via IV, IM, buccal, or nasal mucosal routes IV has an immediate onset of action compared with IM, which takes ~ 3 to 7 minutes The half-life is 10 to 12 minutes linear increase in plasma concentration of oxytocin after a continuous infusion NGMC, DR BIBEK 16

16. Clinical Role Uterine atony DOC for prevention and treatment of uterine atony after vaginal and operative deliveries. It is also widely used to induce and augment the labor process. NGMC, DR BIBEK 17

17. Routes and Dosages Repeated exposure of the myometrial cells to oxytocin oxytocin receptor desensitization significant loss in the capacity to respond to additional oxytocin NGMC, DR BIBEK 18

18. Repeated doses ineffective 2 nd -line uterotonics (ergometrine, prostaglandins F2a and E1) The recommended dose, timing, and rate of administration for oxytocin during cesarean delivery remain ambiguous NGMC, DR BIBEK 19

19. Intravenous infusion 10-40 I/U of oxytocin in 500-1000 mL of 0.9 % NS R ate of infusion adjusted according to uterine tone, up to 500mL/hour. The rate is then decreased (1-2.5 I/U) as long as uterine tone is maintained and bleeding is not excessive. NGMC, DR BIBEK 20

20. Intramuscular administration IM 10 units is an acceptable alternatives to IV Infusion. Less effective than IV Onset is slower but the clinical effect lasts longer (probably >1hour vs 3-5 min with IV route) NGMC, DR BIBEK 21

21. Intravenous blous “Rule of Threes” algorithm to minimize the dose-related and rate-related side effects of oxytocin Initial 3 units of oxytocin given over 5 sec after delivery of the fetus, & uterine tone is assessed every 3 min thereafter An additional 3 units of oxytocin is given if inadequate tone is observed after each 3-minute interval. If a 3 rd bolus of oxytocin is given for inadequate tone and uterine atony continues, then a 2 nd -line uterotonic agent is recommended. NGMC, DR BIBEK 22

22. Side Effects and Contraindications S/E hemodynamic instability ( hypotension, tachycardia , MI & arrhythmias), nausea, vomiting, headache, and flushing NGMC, DR BIBEK 23

23. Side Effects and Contraindications Transient relaxation of vascular smooth muscle cells via Ca2- dependent stimulation of the nitric oxide pathway, which leads to peripheral vasodilation hypotension, a compensatory increase in heart rate stroke volume, cardiac output. NGMC, DR BIBEK 24

24. caution must be taken to patients with abnormal ventricular function, valvular stenosis, or hypovolemia NGMC, DR BIBEK 25

25. Due to its structural similarity to vasopressin, oxytocin administered in high dosages may lead to water intoxication, Hyponatremia seizures, and coma. NGMC, DR BIBEK 26

26. Methylergonovine NGMC, DR BIBEK 27

27. Introduction semisynthetic amide ergot derivative ACOG recommends a 2nd-line uterotonic for refractory uterine atony NGMC, DR BIBEK 28

28. Structure/Activity Methylergonovine should be administered only if it is clear and colorless. Storage = refrigerated. Stability is compromised when exposed to higher temperatures, light, or humidity Ergot alkaloids are serotonergic receptor agonist in the smooth muscles , weak antagonist of dopaminergic receptors and partial agonist of alpha-adrenergic receptors NGMC, DR BIBEK 29

29. Methylergonovine causes uterine contractions and relaxation at low doses, but causes sustained contractions and increased basal tone at high doses Uterine contraction = methylergonovine agonist effects on the 5-HT2 receptor found in uterine smooth muscle uterine contraction through direct stimulation of the a-adrenergic receptors in the uterus NGMC, DR BIBEK 30

30. Pharmacokinetics O/A of IV methylergonovine is 2- 5 min & after oral administration is 5-10 min The half-life of methylergonovine after IV is 2.3 hours and after oral administration is 2.7 hours Ergot alkaloids are mainly eliminated by hepatic metabolism. NGMC, DR BIBEK 31

31. Clinical Role Treatment for postpartum hemorrhage due to uterine atony or subinvolution At high doses, it creates sustained contractions in the uterus When compared with carboprost , methylergonovine has been associated with reduced risk of hemorrhage related morbidity in women with uterine atony refractory to oxytocin NGMC, DR BIBEK 32

32. Route and Dosage ACOG recommends methylergonovine at a dosage of 0.2 mg administered IM at a frequency of 2 to 4 hours as needed IM directly into the uterine corpus has been reported that inappropriate myometrial absorption was a suspected cause of MI , likely because the highly vascularized myometrial tissue increased the rate of systemic uptake Due to hypertensive or cerebrovascular events, intravenous injection is not recommended NGMC, DR BIBEK 33

33. Side Effects and Contraindications hypertension due to vasoconstriction associated with headaches or seizures Nausea and vomiting Rare s/e include bradycardia, tachycardia, dyspnea, thrombophlebitis, dizziness, and diarrhea coronary vasospasm, myocardial ischemia CAD or R/F for CAD are at increased risk of developing acute coronary syndrome or infarction R/F include smoking, obesity, diabetes, and high cholesterol NGMC, DR BIBEK 34

34. Methylergonovine goes through CYP3A4 metabolism Potent CYP3A4 inhibitors should be avoided. NGMC, DR BIBEK 35

35. CARBOPROST

36. CARBOPROST an analog of 15-methyl prostaglandin F2a. One cause of uterine atony may be a deficiency of prostaglandin F2a concentration increase during the third stage of labor. NGMC, DR BIBEK 37

37. Pharmacokinetics Carboprost is injected IM for the treatment of postpartum hemorrhage Plasma levels peak 20 minutes after injection, and decline by approximately half after 2 hours. Urinary excretion is the major route of elimination of carboprost Excretion of metabolites is almost complete 24 hours after subcutaneous administration in women. NGMC, DR BIBEK 38

38. Clinical Role 2 nd -line treatment for uterine atony For refractory uterine atony , both methylergonovine and carboprost are used in an effort to avoid surgical interventions such as ligation of the uterine or hypogastric arteries or peripartum hysterectomy. Carboprost is a treatment alternative for patients with hypertensive disorders, such as preeclampsia (a relative contraindication to methylergonovine), and for patients with atonic bleeding refractory to methylergonovine NGMC, DR BIBEK 39

39. Routes and Dosage Route : IM Dose : 250 mcg The dosage may be repeated every 15 to 30 minutes. Total dose should not exceed 2 mg (8 dosages). The need for repeated doses should be evaluated based on clinical effect. NGMC, DR BIBEK 40

40. Side Effects and Contraindications Nausea, vomiting, and diarrhea. Flushing, pyrexia, and myalgia The cause of these adverse effects is likely the stimulation of smooth muscle in the gastrointestinal tract. Moderate increases in blood pressure are often seen, caused by vascular smooth muscle contraction NGMC, DR BIBEK 41

41. Carboprost can precipitate bronchospasm, increased intrapulmonary shunt fraction abnormal ventilation-perfusion ratio, and hypoxemia. Patients with asthma are particularly susceptible to these complications Based on plasma clearance rates, the manufacturer recommends that breastfeeding be delayed for at least 6 hours after administration NGMC, DR BIBEK 42

42. MISOPROSTOL NGMC, DR BIBEK 43

43. MISOPROSTOL S ynthetic analog of prostaglandin E 1(PGE1) T he list of clinical applications include medically induced abortion medically assisted evacuation after miscarriage, Cervical ripening, induction of labor, and treatment of uterine atony NGMC, DR BIBEK 44

44. Structure/Activity PGE1 is rapidly metabolized, which hinders its utility via oral and parenteral routes, and it also produces more side effects while being less chemically stable. PGE1 has a carboxyl group at carbon 1 and a hydroxyl group at carbon 15. Misoprostol improves on the characteristics of PGE1 by having a methyl ester at carbon 1 (imparting greater duration of action), a carbon 16 methyl group, and hydroxyl group at carbon 16 rather than carbon 15. The modifications at carbon 16 increase oral activity, duration of action, and safety NGMC, DR BIBEK 45

45. Pharmacokinetics C linically useful routes include the following: oral, buccal, sublingual, vaginal, and rectal Sublingual administration yields the highest peak plasma concentrations of any route, and peak plasma concentrations are seen in approximately 30 minutes. NGMC, DR BIBEK 46

46. Vaginal administrations of misoprostol produce slower onset and a longer time to peak effect than routes involving the mouth. Buccal misoprostol exhibits a time to peak concentration and a gradual fall in concentration comparable to the kinetics of vaginal misoprostol Rectal misoprostol generates the slowest onset, with a long offset time comparable to that of vaginal misoprostol. NGMC, DR BIBEK 47

47. Misoprostol exhibits extensive renal clearance. R enal impairment may extend its half-life as well as increase bioavailability and maximum plasma concentrations. However, there is no recommended dose adjustment for patients in renal failure Misoprostol acid is found in breast milk for several hours after oral administration NGMC, DR BIBEK 48

48. Clinical Role 2 nd -line agent for treatment of uterine atony. W here the supply and storage of expensive, or light-sensitive or temperature sensitive medications is limited, misoprostol tablets offer an inexpensive and easy to-store uterotonic option In a meta-analysis of recent large randomized controlled trials involving misoprostol versus placebo, misoprostol effectively prevented postpartum hemorrhage and severe postpartum hemorrhage by 24% and 41%, respectively NGMC, DR BIBEK 49

49. Routes and Dosage As a 1 st -line treatment in situations in which active management of the third stage of labor is not possible FIGO & WHO recommends 600mcg orally when injectable uterotonics are not available. Repeat doses of misoprostol are not recommended for at least 2 hours, or 6 hours in patients exhibiting shivering and pyrexia . NGMC, DR BIBEK 50

50. Side Effects and Contraindications S/E are self-limited and may be more common with sublingual misoprostol administration due to its pharmacokinetics, notably the high peak serum concentrations that correspond to that route. FDA warning related to misoprostol applies to pregnant or potentially pregnant women due to its abortifacient and possible teratogenic effects NGMC, DR BIBEK 51

51. Tranexamic acid Antifibrinolytic drug that has been useful for both prevention & treatment of various clinical seeting Become standard care in the tx of patienrs with PPH 1 gm IV over 10 min For patient undergoing vaginal birth after cord clamping. For patient undergoing CS , before making skin incision S/E Thrombosis & thromboembolism (venous & arterial) NGMC, DR BIBEK 52

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55. Difference B/w Oxytocin and Prostaglandins Prostaglandins Oxytocin Character Contraction through out pregnancy Only at term Contraction soften the cervix Does not soften the cervix Cervix NGMC, DR BIBEK 56

56. Difference (cont’d) Prostaglandins Oxytocin Character Longer Shorter Duration of action Used for abortion in 2 nd trimester of pregnancy. Used as vaginal suppository for induction of labor Not used for abortion Used for induction and augmentation of labor and post partum hemorrhage uses NGMC, DR BIBEK 57

57. Difference b/w Oxytocin and Ergometrine Ergometrine Oxytocin Character Tetanic contraction ; doesn't resemble normal physiological contractions Resembles normal physiological contractions Contractions Only in P.partum hemorrhage *To induce &augment labor. *Post partum hemorrhage Uses Moderate onset Long duration of action Rapid onset Shorter duration of action Onset and Duration NGMC, DR BIBEK 58

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