Pharmacotherapeutics in obstetrics

PHARMACOTHERAPEUTICS IN OBSTETRICS

DEEPTHY P. THOMASI YEAR MSC NURSING GOVT COLLEGE OF NURSING ALAPPUZHA

OXYCTOCICS IN OBSTETRICS

OXYTOCIN

ERGOT DERIVATIVES

PROSTAGLANDINS

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

OXYTOCIN

Preparations usedSynthetic oxytocinSyntometrineDesamino oxytocinOxytocin nasal solution

Effectiveness In later months of pregnancy and

during labour

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.

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 testPrinciples:

The test is based on the determination of respitratory function of the feto placental unit during induced contractions

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.

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.

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.

OXYTOCIN STIMULATION TESTMethods of administration:

Controlled intravenous infusionFor induction in labourUse in labour

Intramuscular5-10 units after the birth of the baby as an alternative to ergometrine

ADVERSE EFFECTSMATERNAL Uterine hyperstimulation Uterine rupture Water intoxication Hypotension Anti-diuresisFETAL Fetal distress, fetal hypoxia and fetal

death

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.

ERGOT DERIVATIVES Mode of action:Ergometrine acts directly on the myometrium EffectivenessIt 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.

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

ERGOT DERIVATIVES

Preparations Ampoules tabletErgometrine[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

Onset of actionRoutes Ergometrine MetherginIVIMOral

45-60sec6-7mt10 mt

5.min7 min10 min

ERGOT DERIVATIVESHazards: 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.

ERGOT DERIVATIVESCautions: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

ERGOT DERIVATIVESNurse’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.

PROSTAGLANDINSSourcearachidonic acidMechanism of actionPGF2α promotes myometrial

contractilityPGE2 helps cervical maturation

PROSTAGLANDINSUse 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.

PROSTAGLANDINSContraindications: Hypersensitivity to the compound. Uterine scar.Preparations Tablet. Vaginal suppository Vaginal pessry Prostin E2. Parentral

PROSTAGLANDINSAdvantages: 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.

PROSTAGLANDINSDrawbacks: 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.

ANTI-HYPERTENSIVE THERAPY

1. Sympathomimetics

1. adrenergicReceptor blocking agent

1. vasodilators

1. calciumchannel blockers

1. ACEI Inhibitors

Methyldopa Reserpine

Labetalol Propanalol

Hydralazine  Prazocin Sodium nitroprusside

Nifedipine nicardia

Captopril lisinopril

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 -CCFDose -orally 250mg bid may be increased to 1 gm tid

depending upon the response. -IV infusion 250-500mg

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

LABETALOLMechanism 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 effectSide effects Experience is less compared to methyl dopa.

efficacy and safety with short term use. Appear equal to methyl dopa.

PROPRANOLOLMechanism of action Beta adrenergic receptor blockerContraindication 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

PROPRANOLOL

Side effectsmaternal: 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

PRAZOCINMechanism 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/daySide effects -hypotension -nasal congestion -fluid retension

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

NIFEDIPINEMode 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.

SODIUM NITROPRUSSIDEMechanism of action: Direct vasodilator.Dose: Orally 6.25 bid.Side effects: Maternal

NauseaVomiting

FetalOligohydramniosIUGRFetal and neonatal renal failure.

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

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

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

FUROSEMIDEMaternal Weakness Fatigue muscle cramps hypokalemia hyponatremia hypokalemia hypochloremic

alkalosis postural

hypotension

fetal fetal compromise

due to decreased placental perfusion.

Thrombocytopenia Hyponatremia

HYDROCLOROTHIAZIDEMechanism 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.

TOCOLYTIC AGENTS

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

BETAMIMETICSCommonly used drugs: Terbutaline Ritodrine IsoxurpineMechanism of action: Activation of the intracellular enzymes

[adenylate cyclase, cAMP, protein kinase] reduces intracellular free calcium [Ca++] and inhibits the activation of MLCK

BETAMIMETICSDose: 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.

BETAMIMETICSSide effects:Maternal:HeadachePalpitationTachycardiaPulmonary edemaHypotensionCardiac failure

BETAMIMETICS Side effects Hyperglycemia ARDS Hyperinsulinemia Lactic academia Hypokalemia Even deathNeonatal: Hypoglycaemia Intraventricular haemorrhage

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.

CALCIUM CHANNEL BLOCKERS

  Nifedipine NicardipineMechanism of action: Nifedipine blocks the entry of calcium inside

the cell. Compared to β- mimetics, effects are less. It is equally effective to MgSO4.

Dose: Oral 10-20 mg every 6-8 hours.

CALCIUM CHANNEL BLOCKERS

Side effects: Maternal Hypotension Headache Flushing Nausea

MAGNESIUM SULPHATEMechanism of action: inhibition to calcium ion Contraindications: Myasthenia gravis Impaired renal functionDose: 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.

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

OXYTOCIN ANTAGONISTS: 

AtosibanMechanism of action: It blocks myometrial oxytocin receptors. Dose: I.V.infusion 300µg/min. initial bolus may be

needed.Side effects: Nausea Vomiting Chest pain

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.

MAGNESIUM SULPHATE

Side effects: MgSO4 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.

DIAZEPAMmode of action: central muscle relaxant and anticonvulsant.Dose: 20-40 mg IVSide effects: Maternal: Hypotension Fetal Respiratory depression Hypotonia Thermoregulatory problem

PHENYTOINMode of action: Centrally acting anticonvulsantDose: 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

ANTICOAGULANTS:HEPARINMechanism of action: It inhibits action of thrombinDose: 5000-10000 I.U. to be administered parenterally [SC or

IV]. Low molecular weight heparin is 2500 IUSide effects: Maternal: Haemorrhage Urticarial Thrombocytopenia Osteopenia. Fetal It does not cross the placenta

WARFARINMechanism 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.

ANALGESIA AND ANAESTHESIA IN OBSTETRICS

1. SEDATIVES AND ANALGESICS OPIOID ANALGESICS: PETHIDINEMechanism 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.

PETHIDINEContraindications:

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

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

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.

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

PENTACOZIN

dose of 30-40 mg Naloxone is an efficient and reliable

antagonist.Adverse effects Neonate respiratory depression secondary to

the medication crossing the placentaand affecting the fetus.

Unsteady ambulation of theclient. Inhibition of the mother’s ability to cope with

the pain of labor.

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

INHALATIONAL METHODS Nitrous oxide and air

Premixed nitrous oxide and oxygen

Trichloroethylene

Methoxyflurane, isoflurane, enflurane

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.

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.

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.

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.

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 canresult in serious toxicity.

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% NO2 , 50% oxygen and a trace of halothane. Relaxation is maintained with non-depolarizing muscle relaxant [ vecuronium 4 mg or atracurium 25 mg].

FETAL HAZARDS ON MATERNAL MEDICATION DURING PREGNANCY

Mechanism of teratogenicityFolic acid deficiency.Epoxides or arena oxides Environmental and genes

abnormalities.Maternal disease and drugsHomebox genes

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.

PLACENTAL TRANSFER OF DRUGSThe 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.

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.

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

drug Teratogenic effect

Cytotoxic drugs-Diethyl stilbestrol 

-androgenic steroids

-lithium 

-anticonvulsantsPhenytoin

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.

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

drugs Teratogenic effect

-metronidazole

 -ACE inhibitors

-vitamin K[large dose]

-all live viral vaccines

-narcotics

-anaesthetic agents

-anticogulants[warfarin]-antidepressants[imipramine]-benzodiazapines

o No evidence of fetal or neonatal toxicity, high doses regimens should not be used.

o IUGR, fetal and neonatal renal failure.

o Hyperbilirubinemia and kernicterus. 

o Potentially dangerous to the fetus. 

o Depression of CNS-apnoea, bradycardia and hypothermia.

o Convulsion, bradycardia, acidosis, hypoxia, and hypertonia.

o Fetal bleeding and anomalies. o cardiovascular abnormalities.

 o Growth restriction, CNS dysfunction.

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.

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.

THANK YOU……..