2 ObjectivesAt the end of the lectures, students should be able to know and understand the:1.Drugs used to induce & augment labor.2.Drugs used to control post partum hemorrhage.3.Drugs used to induce pathological abortion.4.Drugs used to arrest premature labor.5.The mechanism of action and adverse effects ofeach drug.
3 Drugs affecting uterine contractility Oxytocic drug :Drugs stimulate uterine smooth muscles during pregnancy , produce contraction that promotes rapid laborTocolytics:Drugs relax uterine smooth muscles
9 Pharmacokinetics of oxytocin Destroyed in GITNot effective orallyGiven IV or nasal spray ( in cases of impaired milk ejection)Not bound to plasma proteinsEliminated by liver & kidneysHalf life = 5 minutes
10 Pharmacodynamics of oxytocin Mechanism of actionActs through GPCR activation of phospholipase C production of IP3 mobilization of calcium from its stores (SR)Also, activates voltage sensitive calcium channels causing an increase in cytoplasmic calcium level that stimulates uterine contraction .
11 Pharmacological actions of oxytocin UterusSmall doses stimulates both the frequency and force of uterine contractility particularly of the fundus segment of the uterus.These contractions resemble the normal physiological contractions of uterus (contractions followed by relaxation)
13 Large doses causes sustained contractions Immature uterus is resistant to oxytocin.Contract uterine smooth muscle only at termSensitivity increases to 8 fold in last 9 weeks and 30 times in early labor.Clinically oxytocin is given only when uterine cervix is soft and dilated.
14 Cont.Mammary glandsStimulate myoepithelial cells surrounding mammary alveoli produce milk productionWithout oxytocin induced contraction lactation can not occur.
15 Therapeutic Uses of Oxytocin Facilitation of labor at term IV-infusion (Reinforcement of labor)2- Induction of labor for conditions requiring early vaginal delivery ( I.V infusion ) e.g.Placental insufficiency ( mild preeclampsia, maternal diabetes)Post maturityPremature rupture membranesUterine inertia
16 Therapeutic Uses of Oxytocin (continue) 3- Post partum uterine hemorrhage after vaginal or cesarean delivery(I.M)(ergometrine is often used)4- Impaired milk ejectionOne puff in each nostril 2-3 min before nursing5- Incomplete abortion
17 Adverse effects Fetal Distress, death Maternal Uterine rupture Fluid retention, water intoxicationHyponatremia, heart failureSeizuresDeathBolus injection can produce hypotension, so used as infusion at a controlled rate
18 Contraindications a) Hypersensitivity b) Prematurity c) Abnormal fetal positiond) Evidence of fetal distresse) Cephalopelvic disproportionPrecautionsa) Multiple pregnancyb) Previous c- sectionc) Hypertension
20 Effects on the UterusAlkaloid derivatives induce TETANIC CONTRACTION of uterus without relaxation in between(not like normal physiological contractions)It causes contractions of uterus as a whole i.e. fundus and cervix(tend to compress rather than to expel the fetus)Difference between oxytocin & ergots??
22 Ergot alkaloids( pharmacokinetics) Absorbed orally from GIT (tablets)Usually given I.MExtensively metabolized in liver.90% of metabolites are excreted in bile
23 Preparations Clinical uses Syntometrine(ergometrine 0.5 mg Post partum hemorrhageHastens involution of the uterusPreparationsSyntometrine(ergometrine 0.5 mg+ oxytocin 5.0 I.U), I.M.
24 Side effects Nausea, vomiting, diarrhea Hypertension Vasoconstriction of peripheral blood vessels ( toes & fingers)Gangrene
25 Contraindications: Induction of labor 1st and 2nd stage of labor vascular diseaseSevere hepatic and renal impairmentSevere hypertension
26 Prostaglandins Dinoprostone ( synthetic PGE2) Given intravaginally as a gel or tabletGiven extra-amniotically as a solution1st metabolism in lung ( 95%)Metabolized in local tissuesMetabolites excreted in urineSome absorption directly through cervix & lymphatics into maternal circulationHalf-life min
27 Effects of dinoprostone Stimulation of G protein coupled PGE2 receptors contraction of myometriumRipening of cervix due to direct effect on cervicalcollagenase resulting in softeningHas natriuretic effectSuperior to oxytocin for women with pre-eclampsia , as no fluid retention
28 Therapeutic uses of dinoprostone Facilitation of labor at termInduction of laborMedical AbortifacientUsed as vaginal suppositories alone or with oral misoprostol
30 Carboprost: 15 methyl PGF2α Analog Therapeutic usesInduction of laborTo control PPH IMIFor 2nd trimester abortion , single intra-amniotic injection
31 Adverse effects Vomiting, diarrhea Transient rise of temperature BronchoconstrictionFetal toxicity uncommon
32 Misoprostol ( synthetic PGE1) Given intravaginally as a gel or tablets
33 Contraindications of prostaglandins: a) Mechanical obstruction of deliveryb) Fetal distressc) Predisposition to uterine rupturePrecautions:a) Asthmab) Multiple pregnancyc) Glaucomad) Uterine rupture
34 Difference B/w Oxytocin and Prostaglandins CharacterContraction through out pregnancyOnly at termContractionsoften the cervixDoes not soften the cervixCervix
35 Difference (cont’d) Prostaglandins Oxytocin Character Longer Shorter Duration of actionInduce abortion in 2nd trimester of pregnancy.Used as vaginal suppository for induction of laborInduce and augment labor and post partum hemorrhageuses
36 Difference b/w Oxytocin and Ergometrine CharacterTetanic contraction ; doesn't resemble normal physiological contractionsResembles normal physiological contractionsContractionsOnly in postpartum hemorrhageTo induce &augment labor.*Post partum hemorrhageUsesModerate onsetLong duration of actionRapid onsetShorter duration of actionOnset and Duration