Review of common obstetric drugs: Yutopar, Piton-S and Methergine

1. Review of common obstetric drugs: Yutopar, Piton-S and Methergine R1 顏廷珊

2. Yutopar • Ritodrine • a direct-acting sympathomimetic with predominantly beta-adrenergic activity and a selective action on beta(2) receptors • Tocolytic agent: decreases uterine contractility arrest premature labor • 50mg/5ml/amp

3. A recommended initial rate of infusion is 0.05mg/minute increased at intervals of 10 minutes by 0.05 mg increments until there is evidence of patient response, which is usually at a rate of 0.15 to 0.35 mg/min

4. Cautions • Contraindicated for use before the 20th week of pregnancy • Pre-existing maternal medical conditions that would be seriously affected by the known pharmacologic properties of a beta-mimetic drug such as hypovolemia, cardiac arrhythmias associated with tachycardia or digitalis intoxication, uncontrolled hypertension, pheochromocytoma, and bronchial asthma already treated by beta-mimetics and/or steroids • Contraindications of tocolytic therapy

5. Use cautiously in combination with corticosteroids and observe for pulmonary edema. Persistent maternal tachycardia greater than 140 beats per minute may be a sign of impending pulmonary edema

6. Adverse reactions • Blood: neutropenia, leukocytosis, agranulocytosis • Cardiovascular: - an increase in systolic blood pressure and a decrease in diastolic blood pressure- arrhythmia (rarely associated with abnormalities of EKG), chest pain, or tightness have been reported in 1% to 3% of patients receiving intravenous ritodrine - tachycardia: occurs in 80% to 100% of the patients receiving intravenous ritodrine , a mean maximum increase of 41 beats/min - Bradycardia has been noted following ritodrine withdrawal

7. Respiratory:-pulmonary edema: The frequency of ritodrine-induced pulmonary edema in pregnant women is 0.25% or less - may be delayed, sometimes occurring after delivery or up to 24 hours after discontinuation of the drug- non-cardiac in origin - The pathogenesis of ritodrine-induced pulmonary edema has not been clearly established

8. Proposed mechanisms: 1. Pre-existing peripheral edema, undiagnosed cardiac or lung disease, and steroid administration, twin-gestations 2. Fluid overload: to counteract hypotension due to increased intravascular capacity ; the antidiuretic effect of ritodrine within 24 to 48 h of the therapy, resulting in retention of sodium and water.

9. 3. Heart failure due to myocardial fatigue or ischemia caused by a ritodrine-induced increase in heart rate; depression of the beta-adrenergic receptors, resulting in a poor response of myocardial contractility to exogenous inotropic support 4. Ritodrine-induced damage to pulmonary capillaries (through the activation of the complement system) resulting in increased permeability

10. Ritodrine administration in diabetic and some nondiabetic patients increases insulin requirements. If glucose levels are not monitored, KETOACIDOSIS can occur. • Ritodrine frequently causes HYPOKALEMIA because of a marked increase in plasma insulin, which results in stimulation of cellular uptake of potassium. However, perioperative rebound HYPERKALEMIA (peak potassium levels 6.8 to 7.9 mmol/L) has been reported 90 to 150 minutes after cessation of intravenous ritodrine (total dose 1 to 10 grams).

11. Anesthetic considerations • Tachycardia, arrhythmia, bradycardia, carefully titrate ephedrine • Watch out for fluid overload, the risk for pulmonary edema • Glucose level, electrolyte imbalance( K )

12. Piton-S • Oxytocin • 10 IU/1ml/amp, in 500ml N/S, 20 mU/ml • Uterine stimulant, by increasing intracellular concentrations of calcium in uterine myometrial tissue • OXYTOCIN also has pressor and antidiuretic activity which may be exhibited with high doses • Antidiuresis appears to be initiated by the direct action of oxytocin on the kidney. The action of the drug stimulates renal tubular absorption of free water.

13. Induction or stimulation of labor: normally infused at an initial rate of 0.5 to 2 mU/min, > 9-10 mu/min are rarely required • Postpartum bleeding: a total of 10 U may be infused at a rate of 20 to 40 mU/min iv; 3 to 10 u may be given im • Treatment of abortion

14. Cautions • Monitor closely in patients being treated with pressor agents for hypotension • Restricted fluid intake may be indicated since OXYTOCIN may produce antidiuretic effects

15. Adverse reactions • Cardiovascular:- The cardiovascular effects of oxytocin used postpartum consist of HYPOTENSION followed by a period of HYPERTENSION - arrhythmias: maternal VPC- peripheral arteriospasm- myocardial infarction: coronary artery spasm(?) maybe related to supine hypotension, epidural anesthesia, ephedrine, cigarette smoking, intravenous oxytocin

16. Central nervous system: seizure-like episodes, headache, memory dysfunction and subarachnoid hemorrhage • Fluid- electrolyte effect: - antidiuretic effect: at an infusion rate of 15 mU/min and is reported to be maximal at 45 mU/min- water intoxication and hyponatremia: Continuous intravenous infusion of oxytocin in electrolyte-free solutions has resulted in water intoxication- Ocular bleeding and blurred vision, pulmonary edema

17. Others: Nausea and vomiting, uterine hypertonia or rupture, flushing

18. Intravenous Oxytocin in Patients Undergoing Elective Cesarean SectionAnesth Analg 1997;84:753-6 • randomized, double-blind, dose-response study • 40 healthy term parturients presenting for elective cesarean section • All subjects underwent a neuraxial anesthetic with epidural anesthesia (n = 8) or spinal anesthesia (n = 32) • Women with placenta previa, multiple gestation, preeclampsia, macrosomia, polyhydromnios, oligohydramnios, uterine fibroids, and more than two previous cesarean sections were excluded from the study, as were women with evidence of a bleeding diathesis

19. Method • Subjects were assigned by random number tables to one of four groups to receive oxytocin 5, 10, 15, or 20 IU, respectively. IV oxytocin was administered at a rate of 1.0 IU/min via an infusion pump immediately after clamping of the umbilical cord.

20. The attending surgeon assessed uterine tone based on a linear analog scale (LAS) ranging from 0(atony) to 10 (completely contracted) • Blood loss during the operation was estimated semiquantitatively by a single blinded observer (MCS) • The time intervals between uterine incision to delivery of the fetus (I-D) and that between delivery to closure of the uterus (D-C) were recorded • Hematocrit was recorded prior to surgery and again between postoperative Days 1 and 2.

21. Results • 17 patients underwent a primary cesarean section while 18 patients had a second and 5 patients a third cesarean section. • No difference could be demonstrated between the number of previous cesarean sections and LAS at 5, 10, 15, and 20 min (5 min, P = 0.93; 10 min, P = 0.52; 15 min, P = 0.90; 20 min, P = 0.93). • Similarly there was no difference in the EBL (P = 0.86) or the change in hematocrit (P = 0.46) and the number of previous cesarean sections. • No patient received ephedrine to treat hypotension after delivery of the fetus, or supplemental oxytocin in the recovery room.

23. Uterine tone, as assessed by the LAS, was equal in the four groups at each of the four recorded intervals

24. The quantity of EBL and the difference between the pre- and postoperative hematocrit were also the same in each of the four groups. • The I-D and the D-C intervals were similar in all groups

25. Discussion • The most important finding of this study is that 5 IU of oxytocin is as effective as 20 IU in healthy parturients undergoing elective cesarean section. • Due to the effects of estrogen, the uterine oxytocin receptor population increases progressively during pregnancy to reach a peak at term. Therefore, at this stage of gestation, the uterus is extremely sensitive to the effects of oxytocin. Perhaps 5-20 IU of oxytocin is too large a dose, being on the plateau of the dose-response curve

26. Oxytocin has a weak antidiuretic effect which may lead to fluid retention; use in conjunction with dextrose-based IV fluids has been associated with pulmonary edema • 20-30 mL/kg body weight to be administered; when added to the 40% to 50% increase in the plasma volume resulting from the physiological changes of pregnancy, may stress the cardiovascular system • Oxytocin may exacerbate this situation

27. Since oxytocin has dose-dependent side effects, it appears prudent to use the minimal effective dose • The results of our study have demonstrated that there is no benefit on uterine tone and blood loss of administering more than 5 IU oxytocin during elective cesarean section

28. Methergine • Methylergonovine • 0.2mg/1ml/amp • Methylergonovine is an ergot derivative with direct uterine and vascular smooth muscle contractile properties

29. 0.2 milligram after delivery of the anterior shoulder, after delivery of the placenta, or during the puerperium, which may be repeated every 2 to 4 hours as needed • This drug should not be routinely administered intravenously because of the possibility of inducing sudden hypertensive and cerebrovascular accidents. If intravenous administration is considered essential as a life-saving measure, Methergine should be given slowly over a period of no less than 60 seconds, with careful monitoring of blood pressure

30. Cautions • Caution in patients with sepsis, obliterative vascular disease, or hepatic or renal impairment • Slow administration of INTRAVENOUS methylergonovine over at least 1 minute, with careful monitoring of blood pressure • Strict avoidance of intra-arterial or periarterial injection

31. Adverse reactions • Cardiovascular: - Hypertension - vasoconstriction- postpartum myocardial infarction: coronary artery spasm (?) • Central nervous system: -headache, tinnitus, hallucination • Others: nausea and vomiting, foul taste, abdominal pain, diarrhea, uterine hypertonus

32. Effects of methylergometrine and oxytocin on thoracic epidural pressure during cesatrean section -J.Obstet.Gynaecol. Res Vol29, No3:180-185, Jun 2003 Introduction : • It is well known that enlargement of the uterus during pregnancy can lead to distension of the epidural veins as a result of impeded venous return through inferior vena cava. • Labor and uterine contractions increase intrathoracic and intra-abdominal pressure, which have the potential to increase the epidural pressure, this normalized immediately after delivery. • We examine the effects of intravenous oxytocics administered after delivery on changes in thoracic epidural pressure in parturtients undergoing CS under spinal anesthesia.

33. Materials and methods • 60 parturient, ASA class I or II • Elective CS under combined spinal and epidural anesthesia • Hydration with Solita-T, 10ml/kg/h, until 5 min after fetal delivery • Epidural : T11-T12, threaded 5cm cephalad, filling with 0.3ml N/S connected to pressure transducer • Spinal: 11-12 mg isobaric buvivacaine at L3-4 • Spine hypotension syndrome was routinely treated by manual left uterine displacement

34. After double ligation of the umbilical cord, 0.2 mg of methylergometrine as a bolus IV, or 10 U of oxytocin diluted in 10 ml of N/S as IV over 30s. • Epidural pressure, noninvasive BP, HR 5 min after intrathecal bupivacain; immediately before skin incision; immediately after delivery of the placenta; 5min after delivery of the fetus

35. Results • There was no difference in patient demographics, the amount of local anesthetics use, the level of sensory block between the two groups

36. Epidural pressure • O: ergometrine • Increased significantly in both groups after delivery • Placenta-del: oxy> ergo • CS5m: ergo> oxy

37. Mean blood pressure • In ergo group: BP increased after fetal delivery than pre-incision • In oxy group: decreased • At placenta-del, and CS5m: ergo> oxy

38. Heart rates • HR were significantly lower at pre-incision compared with SB5m in both groups. • HR increased after oxytocin treatment.

39. Discussion • During pregnancy, the enlarged uterus compresses the IVC  vertebral venous plexus, epidural venous plexus, and azygous vein  cephalad displacement of CSF relative reduction in the size of the subarachnoid space • Changes in epidural pressure generally correlate with changes in CSF pressure • Changes in epidural venous flow have a greater influence on epidural pressure than do changes in CSF pressure

40. Uterine contraction  increases blood flow through IVC and epidural venous plexus increase in lumbar epidural pressure • “auto-transfusion”: increase in 300-500 ml of central venous blood , 10-25% of cardiac output • Central venous pressure and epidural pressure increase simultaneously with an increase in intrauterine pressure

41. In previous study, epidural pressure normalized immediately after delivery. • In our study, oxytocics used to facilitate uterine contraction during CS increased epidural pressure

43. Changes in epidural pressure induced by oxytocics were associated with uterine contraction • Epidural pressure measurement may be useful in monitoring “autotransfusion ” induced by uterine contraction

44. My question is… • Some parturient complained of chest tightness/ discomfort after delivery of placenta and the beginning of piton-s IV infusion • No obviously EKG ST-T changes • Vital signs: relatively stable • O2 supply; off piton-s; mild sedation • May last for 1-2 hr postpartum and resolved spontaneously

45. Intense uterine contraction and involution suddenly relieve IVC obstruction  increased cardiac output as much as 80%  transient heart strain • Autotransfusion was intensified by oxytocics, such as oxytocin and methergine • Pre-op ritodrine use? • The coronary artery spasm caused by oxytocics?

46. Reference • Clinical anesthesiology • Micromedex drug information online • Case report of myocardial infarction in labor, Nicole E, Am J Obstet Gynecol 1991;165:1383-4 • Severe peripheral arteriospasm following oxytocin administration, Shmuel Evron el, AmJ Obstet Gynecol, 1986;155:657-8 • Postpartum myocardial infarction induced by methergine, Keith S el, Am J Emerg Med 1998;16:502-4 • Intravenous Oxytocin in Patients Undergoing Elective Cesarean Section, Anesth Analg 1997;84:753-6 • Effects of methylergometrine and oxytocin on thoracic epidural pressure during cesatrean section -J.Obstet.Gynaecol. Res Vol29, No3:180-185, Jun 2003