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FETAL CIRCULATION AND PLACENTAL TRANSFER OF DRUGS & ANAESTHETIC AGENTS Speaker : Dr Swati Bansal Moderator : Dr Priyanka Khurana University College of.

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Presentation on theme: "FETAL CIRCULATION AND PLACENTAL TRANSFER OF DRUGS & ANAESTHETIC AGENTS Speaker : Dr Swati Bansal Moderator : Dr Priyanka Khurana University College of."— Presentation transcript:

1 FETAL CIRCULATION AND PLACENTAL TRANSFER OF DRUGS & ANAESTHETIC AGENTS Speaker : Dr Swati Bansal Moderator : Dr Priyanka Khurana University College of Medical Sciences & GTB Hospital, Delhi

2 Contents Fetal circulation Transitional circulation Placental anatomy Mechanism and factors affecting transport Transfer of respiratory gases Drug transfer

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5 FETAL CIRCULATION Umbilical artery placenta Umbilical vein ( PaO2 – 32 mmHg) ( SaO %)

6 Liver Hepatic Circulation Inferior Vena Cava PO2 – mmHg SaO2 – 65-70% Ductus Venosus (40-60 %) Hepatic Vein (PaO2-27 mmHg SaO2-65%) Lower body (PaO mmHg) SaO2 35%

7 PREFERENTIAL FLOW STREAMING 66% 34% Highly oxygenated blood to brain Combined Ventricular output (PARALLEL CIRCULATION) SaO2 40% SaO % saO % SaO % - SaO %

8 FETAL OXYGEN TRANSPORT Hb concentration = 18 g/dl At term HbF approx 75%-84% of total Hb, between 6-12 months fetal Hb → adult Hb P 50 is 27mmHg for adult Hb, 19-21mmHg for fetal Hb  HbF – 2 α and 2 γ chains  2,3-DPG stabilizes deoxygenated Hb tetramer - ↓ O 2 affinity  γ chains donot readily bind to 2,3- DPG – Higher O 2 affinity of HbF  6-8% higher saturation on fetal side of membrane

9 OXYHEMOGLOBIN SATURATION CURVES Fetal Hb ODC is to the left of Adult Hb ODC

10 Fetal Circulation

11 UMBILICAL CORD CLAMPING EXPOSURE TO ROOM AIR TRANSITIONAL CIRCULATION ↓↓PVR ↑ SVR ↑ PULMONARY BLOOD FLOW ↑ OXYGENATION RESPONDS TO CHANGES IN PaO2, PaCO2, pH & CIRCULATING FACTORS SVR – systemic vascular resistance PVR – pulmonary vascular resistance ↑ SVR ↓PVR MECHANICAL INFLATION OF LUNGS (↑ alveolar O2 tension,↑PaO2,↓PaCO2) EDRF & PGs ↑ LT. ATRIAL FLOW ↓FORAMEN OVALE SHUNT F.O. CLOSURE DUCTUS ARTERIOSUS CONSTRICTION

12 Transitional & Neonatal Circulation  PVR & PAP continue to fall over the next 2-3 years  Decrease in PVR (80%) - first 24 hours & PAP falls below systemic pressure in normal infants  Babies delivered by C-section have a higher PVR than those born vaginally which reaches normal range 3 hours after birth

13 Transitional & Neonatal Circulation  The pulmonary vasculature of the newborn can respond to chemical mediators such as Histamine Acetylcholine Prostaglandins **All are vasodilators  Hypoxia, acidosis,hypercarbia and surgical stimulation can reverse this causing severe pulmonary constriction

14 Ductus Arteriosus  Functional closure hours after birth ( reversible in hypoxemia and hypovolemia)  Permanent closure 2-3 weeks  Remnant ligamentum arteriosum

15 Foramen Ovale  Increased pulmonary blood flow & left atrial distention cause closure  Functional closure- at birth, anatomical closure – by 1 year  maneuvers increase PVR increases RA & RV pressure  Right to left atrial shunt may occur in newborns & young infants

16 Placental transfer of drugs and Anaesthetic agents

17 Placental anatomy and circulation villous hemochorial type

18 Structure of chorionic villusCross section of villus

19 Fetal – Contained within vessels Umbilical Arteries → chorionic plate → branches to stem villi → capillaries in terminal villi → return via umbilical vein Maternal – Free-flowing lake uterine artery → spiral artery in basal plate Spiral arteries open into intervillous space bathing the villi (under arterial pressure) → towards chorionic plate (passing fetal villi) → veins in basal plate

20 MODES OF TRANSFER ACROSS PLACENTA 1. DIFFUSION WATER, LIPOPHILIC MOL GLUCOSE AMINOACIDS

21 2. ACTIVE TRANSPORT Primary active transport Secondary active transport Eg. Sodium potassium pump calcium pump Eg. Water soluble vitamins calcium, magnesium

22 3. BULK FLOW due to hydrostatic or osmotic gradient water movement depends upon sodium chloride pumping thus ATP dependant Hypoxia diminishes ATP 4. BREAKS Delicate villi break in intervillous space extruding contents in maternal circulation. eg alloimmunization and erythroblastosis fetalis

23 5. PINOCYTOSIS Eg : Ig G, iron

24 FICK PRINCIPLE : rate of drug transfer Q/t = K X A X ( Cm – Cf ) D Q/t – rate of diffusion K – diffusion coeff A – surface area of membrane Cm,Cf – maternal and fetal conc D – thickness of membrane

25 Factors Affecting Placental Transfer  Drug Factors 1.Protein binding – highly protein bound drugs are affected by the concentration of maternal and fetal plasma proteins which varies with gestational age and disease Albumin (lower binding affinity) increased transfer of drugs Alpha-1-acid glycoprotein (higher binding affinity) decreased transfer of drugs

26 2.Degree of ionization Henderson- Hasselbalch equation pH = pKa + log [ base ] [ acid ] In pregnancy -pH gradient between mother and fetus – fetal acidemia enhances the maternal to fetal transfer (ie “ ion-trapping” ) of basic drugs eg local anaesthetics and opioids

27 3. Lipid solubility 4. Charge of molecule (scoline highly ionized, thiopentone relatively nonionized ) 5. Size – molecular weight ( heparin 6000 Da, warfarin 330 Da) 6. Altered pharmacokinetics – altered volume of distribution of drugs due to increased TBW, progressive depression of hepatic microsomal enzymes increases the elimination t 1/2

28  Fetal factors 1. Fetal circulation Differential regional distribution of blood in fetus Maximum drug conc in liver Detoxification Redistribution of blood flow Hypoxia, intrauterine stress Higher drug conc to vital organs

29 2. Metabolic capacity metabolic enzymes in liver like glucouronyl transferase are immature leading to increased t ½ 3. Relatively deficient CNS myelination

30  Maternal factors 1.Drug concentration in maternal blood 2.Maternal blood flow ↓ perfusion - ↓ placental flow - less drug transfer (hypotension, or aortocaval compression) better placental function in LSCS - larger doses to reach fetus - minimal effective dose should be used Disease states alter placental transport (pre- eclampsia)

31  Placental factors 1.Placental binding 2.Placental metabolism 3.Diffusion capacity 4.Gestational age ( placenta is more permeable in early pregnancy ) 5.Area of placenta - ↓ in abruptio placentae, maternal hypertension, intrauterine infections, congenital defects however large placenta in erythroblastosis is hydropic does not ↑ transfer

32 UTERINE BLOOD FLOW UBF = uterine arterial pressure – uterine venous pressure uterine vascular resistance no autoregulation factors ↓ UBF 1. ↑ uterine venous pressure Uterine contractions Abruptio placentae Oxytocin overstimulation

33 2.↓ uterine arterial pressure Sympathetic block Hypovolemic shock Supine hypotensive syndrome 3.↑ uterine vascular resistance Essential hypertension Pre – eclampsia Sympathetic discharge Adrenal medullary activity Sympathomimetic drugs except ephedrine

34 UMBILICAL BLOOD FLOW At term 120ml/kg/min or 360 ml/min unaffected by moderate hypoxia but ↓ by severe hypoxia umbilical blood flow decreases with catecholamines and cord occlusion lateral or trendelenburg position can relieve cord compression

35 TRANSFER OF RESPIRATORY GASES OXYGEN TRANSPORT Placenta – 1/5 of the oxygen transfer efficiency of the adult lung 8ml O2/min per kg fetal body weight for growth and development. Oxygen transfer depends upon partial pressure gradient

36 Factors favoring transport 1.Difference in ODC – fetal ODC is to the left of maternal ODC enhancing O 2 uptake by fetal RBC 2.Double Bohr effect – fetal CO 2 transfer makes maternal blood acidic and fetal blood alkalotic causing right and left shift of respective ODC

37 CARBON DI OXIDE TRANSPORT Mainly HCO 3 (62%), dissolved CO2 (8%) Factors favoring fetal to maternal transfer 1. fetal pCO mmHg and maternal pCO mmHg 2. La Chatelier’s principle- fetal to maternal CO 2 movement causes shift in equilibrium of carbonic anhydrase reaction producing more CO 2 for diffusion 3. Haldane effect- deoxyHb in maternal blood has higher affinity for CO 2

38 DRUG TRANSFER Total drug dose to infant = Maternal concentration X F: M ratio of drug F:M Ratio = umbilical Vein Vs maternal venous concentration

39 INHALATIONAL AGENTS Rapid transfer low molecular weight lipid soluble + prolonged induction to delivery time Rapid transfer During GA-N2O, volatile agents ↑ in fetal circulation & prolonged delivery → neonatal depression

40 Induction to delivery interval – 8-10 mins → high inspired O 2 maintained & aorto – caval compression avoided U-D interval › 90 secs – fetal asphyxia, acidosis apparent partial placental separation premature fetal resp efforts impaired placental blood flow

41 INHALATIONAL AGENTS DRUGTRANSFERF:M HALOTHANEBRISK (<1 MIN)0.71 to 0.87 (›2 MAC ↓UBF ) ISOLFLURANERAPID0.7 DESFLURANE/ SEVOFLURANE ?RAPIDNO STUDIES NITROUS OXIDERAPID0.83(3 min exposure) NITROUS OXIDE:RAPIDLY CROSSES PLACENTA DIFFUSION HYPOXIA IN FETUS PRUDENT TO OXYGENATE NEONATES WITH INTRA UTERINE EXPOSURE

42 INTRAVENOUS AGENTS AGENTF:MCLINICAL IMPLICATIONS THIOPENTONE0.4 to 1.1Freely diffusible Marked decrease in placental BF Popular agent of choice PROPOFOL0.65 to 0.85(bolus 2 to 2.5 mg/kg) 0.50 to mg/kg/hr) FDA – category B drug Sedative effect on neonate Lower 1 and 5 min apgar scores (2.8 mg/kg) UBF no change KETAMINE ETOMIDATE 1.26( in 1.5 min)Rapidly crosses placenta Used in hypotension and asthma 0.5 Used in hemodynamic instability

43 BENZODIAZEPINES AGENTF:MREMARKS DIAZEPAM1Loss of baseline variability of FHR Dose dependent hypotonia (FLOPPY INFANT) Depression of temp. regulating system immature infants) MIDAZOLAM0.76(within 20 min levels fall quickly)

44 OPIOIDS DRUGSF:MREMARKS MORPHINE0.6Resp.depression & acidosis Max: hrs Loss of baseline variability of FHR Impaired acid-base balance Impaired neurobehavioral responses PETHIDINE<1 (Neonatal depression longer than pentazocine) PENTAZOCINE< pethidine FENTANYL0.37 to 0.57 SUFENTANIL0.81>maternal prot binding ALFENTANIL0.3↓ 1 min apgar score REMIFENTANIL0.88No adverse neonatal effects

45 LOCAL ANAESTHETICS Transfer across placenta depends upon pKa – degree of ionization at a particular pH fetal acidemia enhances the maternal to fetal transfer (ie “ ion-trapping” )

46 LOCAL ANESTHETICS AGENTF:MPROTEIN BINDING BUPIVACAINE0.3 90%(α1 acid glycoprotein) LIGNOCAINE0.55 (20% bound to maternal protein) ROPIVACAINE % protein bound

47 OTHER DRUGS MUSCLE RELAXANTS: Quaternary ammonium salts Do not readily cross placenta Succinylcholine – F:M=0 Vecuronium – Rocuronium – 0.06 Atracurium − 0.07 ANTICHOLINERGICS: Atropine (0.93) Glycopyrrolate (0.22) poorly crosses placenta

48 Other drugs…….. ANTICHOLINESTERASES: Quaternary ammonium compounds Limited placental transfer Neostigmine + Glycopyrrolate= fetal bradycardia Hence, neostigmine + atropine is preferred!!!!!!!

49 ANTI- HYPERTENSIVES Β- BLOCKERF:MREMARKS ATENOLOL0.9IUGR Neonatal bradycardia Hypoglycemia Resp.depression METOPROLOL1 LABETALOL0.3 PROPRANOLOL0.26 ( 3hrs prior) 1.0 ( long term ) LABETALOL - AGENT OF CHOICE IN PREGNANCY

50 ESMOLOL0.2 Fetal Bradycardia CLONIDINE 0.89 Significant ↓UBF, fetal hypoxia (300μg iv ) DEXMEDETOMIDINE 0.12 ▬ PHENOXYBENZAMINE (pheochromocytoma) 1.6 ▬ HYDRALAZINE 1.0 Fetal vasodilatation NITROGLYCERINE 0.18 Minimal changes in fetal UBF, PR, BP ACE –INHIBITORS ▬ Alter fetal renal function

51 VASOPRESSORS Ephedrine crosses placenta- F:M- 0.7 Ephedrine and phenylephrine – venoconstriction →improves VR → ↑ cardiac output restores uterine perfusion Phenylephrine (α agonist )- mesentric Vc → ↑ cardiac preload improves utero-placental circulation

52 Phenylephrine better ephedrine ( β-agonist mostly) ↓ readily crosses placenta ↓ fetal β adr stimulation ↑fetal catecholamine levels ↑ FHR & oxygen consumption ↓ fetal acidosis

53 Other drugs: ANTICOAGULANTS: Warfarin: No F:M ratio is measured Fetal loss & congenital anomalies Heparin: does not cross placenta (even at conc. Used in Ac. Thromboembolism) LMWH, Enoxaparin, Fondaparinux- no placental transfer ( in vitro studies ) ANTICOAGULANT OF CHOICE IN PREGNANCY

54 Newer drug delivery systems alter drug transfer and distribution eg liposome encapsulation of valproic acid Disease states affect transfer – glyburide lower F/M ratio 0.3

55 Drugs crossing placenta Anticholinergics Atropine Scopolamine Antihypertensive agents Beta-adrenergic receptor antagonists Nitroprusside Nitroglycerine Benzodiazepines Diazepam Midazolam Induction Agents Propofol Thiopentone

56 Inhalational anaesthetic Agents Halothane Isoflurane Nitrous oxide Local Anaesthetics Opioids Vasopressors Ephedrine

57 Drugs that Do Not Cross the Placenta Anticholinergic Glycopyrrolate Anticoagulants Heparin Muscle Relaxants Depolarizing – succinylcholine NDMRs

58 References Obstetric anesthesia- Principles & practice- 4 th edition. David H Chestnut Shnider and Levinson′s Anesthesia for Obstetrics Miller’s text book of anaesthesia, 7 th edition A practice of anaesthesia, wylie, 7 th edition. Clinical anesthesiology, Morgan, Mikhail, Murray, 4 th edition Textbook of Obstetrics- D.C Dutta Essential Pediatrics- O P Ghai- 6 th edition

59 Thank You


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