Pharmacotherapeutics in obstetrics

1. PHARMACOTHERAPEUTICS IN OBSTETRICS DEEPTHY P. THOMAS I YEAR MSC NURSING GOVT COLLEGE OF NURSING ALAPPUZHA

2. OXYCTOCICS IN OBSTETRICS OXYTOCIN ERGOT DERIVATIVES PROSTAGLANDINS

3. OXYTOCIN It is synthesised in the supra-optic and para ventricular nuclei of the hypothalamus . a half life of 3-4 minutes and duration of action of approximately 20 minutes Mode of action receptor and voltage mediated calcium channels amniotic and prostaglandin decidual production

4. OXYTOCIN Preparations used Synthetic oxytocin Syntometrine Desamino oxytocin Oxytocin nasal solution Effectiveness In later months of pregnancy and during labour

5. Indications THERAPEUTIC: Pregnancy: Early: to accelerate abortion. To stop bleeding following evacuation of the uterus. Used as an adjunct of abortion along with other abortifacient agents. Late: To induce labour. To facilitate cervical ripening for effective induction. Augmentation of labour. Uterine intertia .

6. Indications Labour: In active management of third stage of labour. Following expulsion of placenta. Pueperium : To minimize the blood loss and to control the PPH.   DIAGNOSTIC: Contraction stress test Principles: The test is based on the determination of respitratory function of the feto placental unit during induced contractions

7. cst Candidates for CST: Intra uterine growth restriction. Postmaturity . Hypretensive disorders of pregnancy. Diabetes Contraindications: Compromised fetus . Previous history of caesarean section. Complications likely to produce preterm labour. APH.

8. Interpretation : cst Positive: persistent late deceleration of FHR following 50 % or more uterine contrations . Negative: no late deceleration or significant variable deceleration. Suspicious: inconsistent but definite decelerations do not persist with more uterine contractions. Unsatisfactory: poor quality of recording or adequate uterine contraction is not achieved. Hyperstimultaion : Deceleration of FHR with uterine contraction lasting > 90 seconds or occurring more frequently than every 2 minutes.

9. Oxytocin stimulation test Procedure Inference Contraindications of oxytocin: Pregnancy: Grand multipara. Contracted pelvis. History of caesarean or hysterotomy . Malpresentation . Labour: All the contraindications in pregnancy. Obstructed labour. Inco-ordinate uterine action. Fetal distress. Any time: Hypovolemic state. Cardiac disease.

10. Oxytocin stimulation test Methods of administration: Controlled intravenous infusion For induction in labour Use in labour Intramuscular 5-10 units after the birth of the baby as an alternative to ergometrine

11. Adverse effects MATERNAL Uterine hyperstimulation Uterine rupture Water intoxication Hypotension Anti-diuresis FETAL Fetal distress, fetal hypoxia and fetal death

12. Nurse’s responsibilities Assess Intake output ratio. Uterine contractions and FHR. Blood pressure, pulse and respiration. Administer By IV infusion. Monitor drop rate. Make crash cart available. Evaluate Length and duration of contractions. Notify physician of contractions lasting over 1 minute or absence of contrcations . Teach To report increased blood loss, abdominal cramps or increased temperature.

13. ERGOT DERIVATIVES Mode of action: Ergometrine acts directly on the myometrium Effectiveness It is highly effective in hemostasis Indications: Therapeutic: To stop the atonic uterine bleeding following delivery, abortion or expulsion of hydatidiform mole. Prophylactic: Against excessive haemorrhage following delivery.

14. ERGOT DERIVATIVES CONTRAINDICATIONS: Prophylactic : Suspected plural pregnancy. Organic cardiac diseases. Severe pre- eclampsia and eclampsia Rh- negative mother. Therapeutic: Heart disease or severe hypertensive disorders

15. ERGOT DERIVATIVES Preparations Ampoules tablet Ergometrine [ ergonovine ]   Methergin [methyl- ergonovine ] Syntometrine [Sandoz] 0.25 mg or 0.5 mg   0.2 mg   0.5 mg ergometrine + 5 units of syntometrine 0.5 mg   0.5-1 mg

16. Onset of action Routes Ergometrine Methergin IV IM Oral 45-60sec 6-7mt 10 mt min 7 min 10 min

17. ERGOT DERIVATIVES Hazards: Common side effects are nausea and vomiting. Precipitate rise of blood pressure, myocardial infarction, stroke and bronchospasm because of vasoconstrictive effect. Prolonged use may result in gangrene formation of the toes. Prolonged use in puerperium may interfere with lactation.

18. ERGOT DERIVATIVES Cautions: Ergometrine should not be used during pregnancy, first stage of labour, second stage of labour, second stage prior to crowning of the head and in breech delivery prior to crowning

19. ERGOT DERIVATIVES Nurse’s responsibilities: Assess Blood pressure, pulse and respiration. Watch for signs of haemorrhage. Administer Orally or IM in deep muscle mass. Have emergency cart readily available. Evaluate Therapeutic effect: decreased blood loss. Teach To report increased blood loss, abdominal cramps, headache, sweating, nausea, vomiting or dyspnoea.

20. PROSTAGLANDINS Source arachidonic acid Mechanism of action PGF 2α promotes myometrial contractility PGE 2 helps cervical maturation

21. PROSTAGLANDINS Use in obstetrics Induction of abortion. Termination of molar pregnancy. Induction of labour. Cervical ripening prior to the induction of abortion or labour. Acceleration of labour. Management of atonic PPH. Medical management of tubal ectopic pregnancy.

22. PROSTAGLANDINS Contraindications: Hypersensitivity to the compound. Uterine scar. Preparations Tablet . Vaginal suppository Vaginal pessry Prostin E 2 . Parentral

23. PROSTAGLANDINS Advantages: It has got a powerful oxytocic effect, irrespective of period of pregnancy. As such it can be used independently specially in the induction of abortion with success. In later months it can be used for acceleration of labour. It has got no anti diuretic effect.

24. PROSTAGLANDINS Drawbacks: It is costly. Unpleasant side effects on systemic use are nausea, vomiting, diarrhoea, pyrexia or bronchospasm. When used as abortifacient , extensive lacerations may occur. Tachysystole .

25. ANTI-HYPERTENSIVE THERAPY Sympathomimetics adrenergic Receptor blocking agent vasodilators calcium channel blockers ACEI Inhibitors Methyldopa   Reserpine Labetalol   Propanalol Hydralazine   Prazocin   Sodium nitroprusside Nifedipine   nicardia Captopril   lisinopril

26. METHYLDOPA Mechanism of action -Drugs of first choice -Central and peripheral anti-adrenergic action -Effective and safe for both mother and fetus . Contraindications -hepatic disorders -psychic patients -CCF Dose -orally 250mg bid may be increased to 1 gm tid depending upon the response. -IV infusion 250-500mg

27. METHYLDOPA Side effects - maternal : postural hypotension haemolytic anemia sodium retension excessive sedation coomb’s test may be positive. - fetal : intestinal ileus

28. LABETALOL Mechanism of action Combined alpha and beta adrenergic blocking agents. Contraindication hepatic disorders. Dose orally: 100mg tid . May be increased upto 800 mg daily. -IV infusion [hypertensive crisis] 1-2 mg/ mt until desired effect Side effects Experience is less compared to methyl dopa . efficacy and safety with short term use. Appear equal to methyl dopa .

29. PROPRANOLOL Mechanism of action Beta adrenergic receptor blocker Contraindication bronchial asthma. renal insufficiency. diabetes. Cardiac failure The drug is better avoided for long term therapy during pregnancy. Dose orally: 80-120 mg in divided doses

30. PROPRANOLOL Side effects maternal : severe hypotension sodium retension Bradycardia Bronchospasm CCF hypoglycaemia . fetal : bradycardia and impaired fetal responses to hypoxia, IUGR when began in I and II trimester. - neonatal : hypoglycaemia

31. PRAZOCIN Mechanism of action -selective post synaptic blocker. Decrease plasma renin activity. -reduces cardiac preload and after load. Contraindication Low first dose, to avid hypotension and syncope. Dose Orally 1 mg bd may be increased upto 20 mg/day Side effects -hypotension -nasal congestion -fluid retension

32. HYDRALAZINE Mechanism of action Arteriolar vasodilator. Contraindication Because of the variable sodium retention, diuretics should be used. Dose orally: 100mg/day in 4 divided doses. -IV : 5mg bolus followed by 25g in 200 ml NS at a rate of 2.5 mg/ hr to be doubled every 30 mts. Side effects - maternal : hypotension,tachycardia , arrhythmia, palpitation, lupus like syndrome. - fetal : reasonably safe. - neonatal : thrombocytopenia

33. NIFEDIPINE Mode of action: Direct arteriolar vasodilation. Dose: Orally 5-10 mg TID. Contraindications: Simultaneous use of magnesium sulphate could be hazardous due to synergic effect. Side effects: Flushing Hypotension Head ache Tachycardia Inhibition of labour.

34. SODIUM NITROPRUSSIDE Mechanism of action: Direct vasodilator. Dose: Orally 6.25 bid. Side effects: Maternal Nausea Vomiting Fetal Oligohydramnios IUGR Fetal and neonatal renal failure.

35. NITROGLYCERINE Mechanism of action Release mainly venous but also arteriolar smooth muscles. Dose: Given as IV infusion 5µg/min. to be increased at every 3-5 min. upto 100µg/min. Side effects: Tachycardia Headache Methaemoglobinaemia

36. DIURETICS Diuretics are used in the following conditions during pregnancy . Pregnancy induced hypertension with massive edema . Eclampsia with pulmonary edema . Severe anemia in pregnancy with heart failure. Prior to blood transfusions in severe anemia . As as adjunct to certain antihypertensive drugs, such as hydralazine or dioxide

37. FUROSEMIDE Mechanism of action Acts o loop of the Henle by increasing excretion of sodium and chloride. Dose 40 mg tab, daily following breakfast for 5 days a week. In acute conditions, parentrally 40-120 mg daily. Contraindications: Hypersensitivity

38. FUROSEMIDE Maternal Weakness Fatigue muscle cramps hypokalemia hyponatremia hypokalemia hypochloremic alkalosis postural hypotension fetal fetal compromise due to decreased placental perfusion. Thrombocytopenia Hyponatremia

39. HYDROCLOROTHIAZIDE Mechanism of action: Acts on distal tubule by increasing excretion of water, sodium, chloride and potassium. It is used in edema and hypertension. Dose: PO 25-100 mg/day. Side effects: Polyuria, glycosuria, frequency. Nausea, vomiting, anorexia. Rash, urticarial, fever. Increased creatinine , decreased electrolytes.

40. TOCOLYTIC AGENTS Betamimetics prostaglandin synthetase inhibitors magnesium sulphate calcium channel blockers oxytocin receptor antagonists nitric oxide donors antibiotics .

41. BETAMIMETICS Commonly used drugs: Terbutaline Ritodrine Isoxurpine Mechanism of action: Activation of the intracellular enzymes [ adenylate cyclase , cAMP , protein kinase] reduces intracellular free calcium [ Ca ++ ] and inhibits the activation of MLCK

42. BETAMIMETICS Dose: Ritodrine is given by IV infusion, 50µg/min. and increased by 50µg every 10 min. until contractions cease. Maximum dose of 350µg/ min. may be given. Infusion is continued for about 12 hours after contraction cease. Terbutaline has longer half life and has fewer side effects. Subcutaneous injection of 0.25 mg every 3-4 hours is given. Isoxurpine is given as IV drip 100 mg in 5D. Rate 0.2 µg/minute. To continue for at least 2 hours after contraction ceases. Maintenance is by IM 10mg six hourly for 24 hours, tab 10 mg 6-8 hourly.

43. BETAMIMETICS Side effects : Maternal: Headache Palpitation Tachycardia Pulmonary edema Hypotension Cardiac failure

44. BETAMIMETICS Side effects Hyperglycemia ARDS Hyperinsulinemia Lactic academia Hypokalemia Even death Neonatal: Hypoglycaemia Intraventricular haemorrhage

45. INDOMETHACIN Mechanism of action: Reduces synthesis of PGs thereby reduces intracellular free Ca ++ , activation of MLCK and uterine contractions. Dose: Loading dose , 50 mg P.O. or .P.R. followed by 25mg every 6 hrs for 48 hours. Side effects: Maternal Heart burn G.I. bleeding Asthma Thrombocytopenia Renal injury.

46. CALCIUM CHANNEL BLOCKERS   Nifedipine Nicardipine Mechanism of action: Nifedipine blocks the entry of calcium inside the cell. Compared to β- mimetics , effects are less. It is equally effective to MgSO 4 . Dose: Oral 10-20 mg every 6-8 hours.

47. CALCIUM CHANNEL BLOCKERS Side effects: Maternal Hypotension Headache Flushing Nausea

48. MAGNESIUM SULPHATE Mechanism of action: inhibition to calcium ion Contraindications : Myasthenia gravis Impaired renal function Dose: Loading dose: 4-6 gm I.V. over 20-30 min. followed by an infusion of 1-2 gm / hr to continue tocolysis for 12 hours after contarctions have stopped.

49. MAGNESIUM SULPHATE Side effects: Maternal Flushing Perspiration Headache Muscle weakness Pulmonary edema rarely Neonatal Lethargy Hypotonia Respiratory depression rarely.

50. OXYTOCIN ANTAGONISTS :   Atosiban Mechanism of action: It blocks myometrial oxytocin receptors. Dose : I.V.infusion 300µg/min. initial bolus may be needed. Side effects: Nausea Vomiting Chest pain

51. ANTICONVULSANTS 1. MAGNESIUM SULPHATE: Mode of action: It decreases the acetylcholine release from the nerve endings. Dose: IM – loading dose: 4 gm IV [20% solution] over 3-5 min. to follow 10 gm deep IM, 5gm in each buttocks. Maintenance dose : 5gm deep IM on alternate buttocks every 4 hrs. IV- loading dose: 4-6 gm IV over 15-20 min. maintenance dose: 1-2 gm /hr. IV infusion.

52. MAGNESIUM SULPHATE Side effects: MgSO 4 is relatively safe and is the drug of choice. Muscular paresis[ diminished knee jerks], respiratory failure. Renal function to be monitored. Antidote: Injection of calcium gluconate 10% 10 ml IV.

53. DIAZEPAM mode of action: central muscle relaxant and anticonvulsant. Dose: 20-40 mg IV Side effects: Maternal : Hypotension Fetal Respiratory depression Hypotonia Thermoregulatory problem

54. PHENYTOIN Mode of action: Centrally acting anticonvulsant Dose: 10 mg/ kg IV at the rate not more than 50 mg/ min followed 2 hrs later by 5 mg/kg. In epilepsy 300-400 mg daily orally in divided doses. Side effects: Maternal Hypotension Cardiac arrhythmias Phlebitis at injection site. Fetal Fetal hydantoin syndrome

55. ANTICOAGULANTS: HEPARIN Mechanism of action: It inhibits action of thrombin Dose : 5000-10000 I.U. to be administered parenterally [SC or IV]. Low molecular weight heparin is 2500 IU Side effects: Maternal : Haemorrhage Urticarial Thrombocytopenia Osteopenia. Fetal It does not cross the placenta

56. WARFARIN Mechanism of action: Interferes with synthesis of vit K dependent factors . Dose: 10 mg orally Side effects: Maternal Haemorrhage Fetal Contradi’s syndrome [skeletal and facial anomalies] Optic atropy Microcephaly Chondrodisplasia punctate.

57. ANALGESIA AND ANAESTHESIA IN OBSTETRICS 1. SEDATIVES AND ANALGESICS OPIOID ANALGESICS: PETHIDINE Mechanism of action: Inhibits ascending pain pathways in CNS , increase pain threshold and alters pain perception. Indications: Moderate to severe pain in labour, postoperative pain, abruption placentae, pulmonary edema . Dose: Injectable preparations contains 50mg/ml can be administered SC, IM,IV. Its dose is 50-100 mg IM combined with promethazine.

58. PETHIDINE Contraindications: Should not be used IV within 2 hrs and IM within 3 hrs of expected time of delivery of the baby, for fear of birth asphyxia. It should not be used in cases of preterm labour and when respiratory reserve of the mother is reduced

59. Side effects: Maternal Drowsiness Dizziness Confusion Headache Sedation Nausea Vomiting Fetal Respiratory depression Asphyxia

60. FENTANYL Mechanism of action: Inhbits ascending pathways in CNS, increases pain threshold and alters pain perception. Indications: Moderate to severe pain in labour, post operative apin an dadjunct to general anaesthetic. Dose: 0.05 to 0.1 mg IM q1-2 hrs prn . Available in injectable form, 0.05 mg/ml.

61. Side effects: Dizziness Delirium Euphoria Nausea Vomiting Muscle rigidity Blurred vision

62. PENTACOZIN dose of 30-40 mg Naloxone is an efficient and reliable antagonist . Adverse effects Neonate respiratory depression secondary to the medication crossing the placenta and affecting the fetus . Unsteady ambulation of the client. Inhibition of the mother’s ability to cope with the pain of labor .

63. TRANQUILIZERS DIAZEPAM:Usual dose is 5-10 mg. MIDAZOLAM: Dose of 0.05 mg/kg is given intravenously COMBINATION OF NARCOTICS AND TRANQUILIZERS BUTORPHANOL and NALBUPHINE

64. INHALATIONAL METHODS Nitrous oxide and air Premixed nitrous oxide and oxygen Trichloroethylene Methoxyflurane , isoflurane , enflurane

65. EPIDURAL AND SPINAL REGIONAL ANALGESIA Adverse effects nausea and vomiting. Inhibition of bowel and bladder elimination sensations. Bradycardia or tachycardia. Hypotension. Respiratory depression. Allergic reaction and pruritus.

66. PUDENDAL BLOCK It consists of a local anesthetic such as lidocaine ( Xylocaine ) or bupivacaine (Marcaine) being administered transvaginally into the space in front of the pudendal nerve .

67. EPIDURAL ANAESTHESIA Epidural block consists of a local anesthetic bupivacaine (Marcaine) along with an analgesic morphine ( Duramorph ) or fentanyl ( Sublimaze ) injected into the epidural space at the level of the fourth of fifth vertebrae. Adverse effects Maternal hypotension. Fetal bradycardia . Inability to feel the urge to void. Loss of the bearing down reflex.

68. SPINAL BLOCK Spinal block consists of a local anaesthetic injected into the subarachnoid space into the spinal fluid at the third, fourth, or fifth lumbar interspace, alone or in combination with an analgesic such as fentanyl . Adverse effects Maternal hypotension. Fetal bradycardia . Loss of the bearing down reflex.

69. PARACERVICAL BLOCK It consists of lidocaine ( Xylocaine ) being injected into the cervical mucosa early in labor during the first stage to block the pain of uterine contractions. Adverse effects include fetal bradycardia . Improper technique can result in serious toxicity.

70. GENERAL ANAESTHESIA 100% oxygen is administered by tight mask fit for more than 3 minutes. Induction of anaesthesia is done with the injection of thiopentone sodium 200-250 mg as a 2.5 % solution IV.,followed by refrigerated suxamethonium 100 mg. the patient is intubated with cuffed ET tube. Anaesthesia is maintained with 50% NO 2 , 50% oxygen and a trace of halothane. Relaxation is maintained with non-depolarizing muscle relaxant [ vecuronium 4 mg or atracurium 25 mg].

71. FETAL HAZARDS ON MATERNAL MEDICATION DURING PREGNANCY Mechanism of teratogenicity Folic acid deficiency . Epoxides or arena oxides Environmental and genes abnormalities. Maternal disease and drugs Homebox genes

72. Maternal- fetal drug transfer and the hazards: before D 31: Teratogen produces an all or none effect. D31-d71: It is the critical period for organ formation. After D 71: The development of other organs continues .

73. Placental transfer of drugs The factors responsible for transfer are: Molecular weight [molecular wght more than 1000 Da do not cross the placenta]. Concentration of free drug. Lipid solubility. Utero-placental blood flow. Placental solubility.

74. guidelines If the benefit outweighs the potential risks, only then can the particular drugs be used with prior counselling. Only, well tested and reputed drugs are to be prescribed and that too using the minimum therapeutic dosage for the shortest possible duration.

75. CATEGORY DESCRIPTION EXAMPLE A Adequate studies in pregnant woman have failed to show a risk to the fetus in the first trimester of pregnancy; there is no evidence of risk in last trimester. Thyroid hormone B Animal studies have shown an adverse effect on the fetus . But, there are no adequate studies on humans. Pregnancy risk is unknown. Insulin C Animal studies have shown an adverse effect on the fetus , but there are no adequate studies on humans, or there are no adequate studies in animals or humans. Pregnancy risk is unknown. Docusate-sodium   D There is evidence of risk to the human fetus , but potential benefits of use in pregnant woman may be acceptable despite potential risks. Lithium acetate X Studies in animals or humans show fetal abnormalities, or adverse reaction reports indicate evidence of fetal risk. The risks involved clearly outweigh potential benefits isotretinoin

76. drug Teratogenic effect Cytotoxic drugs -Diethyl stilbestrol   -androgenic steroids -lithium   -anticonvulsants Phenytoin Valproate     -aspirin - paracetamol multiple fetal malformations and abortion. vaginal adenosis , cervical hoods, uterine hypoplasia of the female offspring. masculinization of the female offspring. cardiovascular anomalies, neonatal goitre, hypotonia and cyanosis.   benefits of treatment outweigh the risks to the fetus . Polytherapy should be avoided. Increase risk of neural tube defects, neonatal bleeding.   high doses in the last few weeks cause premature closure of ductus arteriosus . Persistent pulmonary hypertension and kernicterus in newborn . amount too small to be harmful.

77. drug Tertogenic effect antimalarials   -corticosteroids -aminoglycosides -chloramphenicol -tetracycline   -quinolones -long acting sulphonamides - nitrofurantoin chloroquine , quinine- no evidence of fetal toxicity in therapeutic doses; benefits outweighs the risk. high doses[ >10 mg prednisolone daily] may produce fetal and neonatal adrenal suppression. Auditory or vestibular damage. Gray baby syndrome [peripheral vascular collapse]. Dental discolouration [yellowish] and deformity. Inhibition of bony growth- should be avoided. Arthropathy in animal studies Neonatal hemolysis , jaundice and kernicterus.   Hemolysis in newborn with G6 PD deficiency, if used at term

78. drugs Teratogenic effect -metronidazole   -ACE inhibitors -vitamin K[large dose] -all live viral vaccines - narcotics -anaesthetic agents - anticogulants [warfarin] -antidepressants [imipramine] - benzodiazapines No evidence of fetal or neonatal toxicity, high doses regimens should not be used . IUGR, fetal and neonatal renal failure . Hyperbilirubinemia and kernicterus.   Potentially dangerous to the fetus .   Depression of CNS-apnoea, bradycardia and hypothermia. Convulsion, bradycardia , acidosis, hypoxia, and hypertonia. Fetal bleeding and anomalies.   cardiovascular abnormalities.   Growth restriction, CNS dysfunction.

79. MATERNAL DRUG INTAKE AND BREASTFEEDING Transfer of drugs through breast milk depends on following factors: Chemical properties Molecular weight Degree of protein binding Ionic dissociation Lipid solubility Tissue pH. Drug concentration. Exposure time.

80. Drugs identified as having effect on lactation and the neonate Bromide: Rash. Drowsiness, and poor feeding. Iodides: Neonatal hypothyroidism Chloramohenicol : Bone marrow toxicity Oral pill: Suppression of lactation. Bromocriptine : Suppression of lactation. Ergot: Suppression of lactation. Metronidazole: Anorexia, blood dyscrasias , irritability, weakness, neurotoxic disorders. Anticoagulants: Haemorrhagic tendency. Isoniazid: Anti-DNA activity and hepatotoxicity. Anti-thyroid drugs and radioactive iodine: Hypothyroidism and goitre, agranulocytosis . Diazepam, opiates, phenobarbitone : Sedation effect with poor sucking reflex.

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