This presentation discusses pharmacological agents used in obstetrics and their placental transfer. It begins by reviewing the basic mechanisms of placental drug transfer and factors that affect maternal to fetal drug transfer. It then reviews various anesthetic agents and other drugs used in obstetrics, including their placental transfer properties and anesthetic implications. The presentation concludes by reviewing oxytocics that stimulate uterine contraction.

1. Pharmacological Agents In
Obstetrics And Placental Transfer of
Drugs
Presenter:
Dr Krishna Dhakal
Moderator :
Assist Prof Dr Tara Gurung
Dr Jay Prakash Thakur
2/7/2019 Department Of Anesthesiology , PMWH 1

2. Objectives
• To review basic mechanism of placental drug transfer
• To review the factors affecting maternal to fetal drug transfer
• To review various anesthetic agents and other drugs used in
obstetrics and their anesthetic implications
• To review Food and drug administration(FDA) category of
drugs used in pregnancy
2/7/2019 Department Of Anesthesiology , PMWH 2

3. Placental drug transfer
• Period of greatest concern begins
at 15-18 days when
organogenesis begins
• Reaches a peak at 30 days
postconception
• Susceptibility decreases until days
55-60 becomes minimal through
day 90
2/7/2019 Department Of Anesthesiology , PMWH 3

4. Placental drug transfer
• Pregnant women show different pharmacodynamics and
pharmacokinetic effects
• Maternal and fetal concentrations of a drug - influenced by
drug metabolism in the mother, the placenta, the fetus, and
also by changes during delivery
• Maternal drug administration affect the fetus in two ways:
• Direct fetal effect-via transplacental passage into the fetal
circulation,
• Indirect effect- by affecting uteroplacental blood flow
2/7/2019 Department Of Anesthesiology , PMWH 4

5. Mechanisms of drug transfer
Drugs which transfer
from the maternal to
the fetal blood –
• carried into the
intervillous space
• pass through the
syncytiotrophoblast,
• Fetal connective
tissue,
• The endothelium of
fetal capillaries.
2/7/2019 Department Of Anesthesiology , PMWH 5

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7. Three types of transfer across the placenta
1. Complete transfer (Type 1 drugs): E.g Thiopental
Drugs -rapidly cross the placenta with pharmacologically
significant concentrations equilibrating in maternal and fetal
blood.
2. Exceeding transfer (Type 2 drugs): E.g Ketamine
Drugs cross the placenta to reach greater concentrations in
fetal compared with maternal blood.
3. Incomplete transfer (Type 3 drugs): E.g Succinylcholine
Drugs - unable to cross the placenta completely, result -
higher concentrations in maternal compared with fetal blood.
2/7/2019 Department Of Anesthesiology , PMWH 7

8. Mechanism of Placental Transfer
A. Passive diffusion
B. Facilitated diffusion
C. Active transport
D. Pinocytosis(endocytosis)
E. Bulk transfer
2/7/2019 Department Of Anesthesiology , PMWH 8

9. Passive diffusion:
• Transfer -either transcellularly
through the syncytiotrophoblast
layer or paracellularly through
water channels incorporated into
the membrane.
• Dependent on a concentration
gradient across the placenta with
drug passively moving from areas
of high to low concentration.
• e.g. midazolam and paracetamol
2/7/2019 Department Of Anesthesiology , PMWH 9

10. Fick’s law of diffusion
This states that the rate of
diffusion per unit time is directly
proportional to the surface area
of the membrane (placenta) and
the concentration gradient
across it, and inversely
proportional to the thickness of
the membrane.
2/7/2019 Department Of Anesthesiology , PMWH 10

11. Facilitated diffusion:
• Drugs structurally related to
endogenous compounds - often
transported by facilitated diffusion.
• It needs a carrier substance within
the placenta to facilitate transfer
across it.
• e.g. Cephalosporins and
Glucocorticoids
2/7/2019 Department Of Anesthesiology , PMWH 11

12. Active transport
• Active transport utilizes energy, usually
in the form of ATP, to transport
substances against a concentration or
electrochemical gradient.
• Carrier-mediated and saturable
• e.g. Norepinephrine and Dopamine
2/7/2019 Department Of Anesthesiology , PMWH 12

13. Pinocytosis
• Drugs - completely enveloped into
invaginations of the membrane and -
released on the other side of the cell.
• Very little - known about this method
of transfer and about the drugs which
cross the placenta by this mechanism
2/7/2019 Department Of Anesthesiology , PMWH 13

14. Bulk Transfer
• Major mechanism of passage of
drugs across most capillary
endothelial membrane, except those
in CNS.
• Movement occurs from high pressure
to low pressure
• Faster than diffusion
• Chemical nature of drug make no
difference
2/7/2019 Department Of Anesthesiology , PMWH 14

15. • Transfer of a drug across the placenta
• The ratio of its fetal umbilical vein to maternal venous
concentrations (UV/MV),
• Uptake by fetal tissues
• Ratio of its fetal umbilical artery to umbilical vein
concentrations (UA/UV).
2/7/2019 Department Of Anesthesiology , PMWH 15

16. Factors affecting maternal to fetal Drug Transfer
Increased transfer Decreased Transfer
1.Size –molecular weight <1000 Dalton >1000 dalton
2.Charge of Molecule Uncharged Charged
3.Ph Vs Drug PKa Higher proportion of
unionized drug in maternal
plasma
Higher proportion of
ionized drug in maternal
plasma
4.Placental efflux
transporter protein(p-
glycoprotein)
Absent Present
5.Binding protein type Albumin(lower binding
affinity)
Alpha 1 acid glycoprotein
6.Free( Unbound) Drug High Low
2/7/2019 Department Of Anesthesiology , PMWH 16

17. Factors affecting maternal to fetal Drug Transfer contd..
• Timing of administration both relative to delivery as well as
contractions
• Lipophilicity
Highly lipophilic substances can accumulate in the placenta
• Location
paracervical > epidural (caudal > lumbar) > IM > subarachnoid
2/7/2019 Department Of Anesthesiology , PMWH 17

18. Local Anesthesia
• Local anaesthetics - weak bases and have relatively low
degrees of ionization at physiological pH.
• Bound to Alpha 1 acid -glycoprotein
• Placental transfer depends on three factors:
• pKa
• Maternal and fetal pH
• Degree of protein binding
2/7/2019 Department Of Anesthesiology , PMWH 18

19. Local anesthetics
• Bupivacaine and ropivacaine -highly lipid soluble but have a
high degree of protein binding.
• Lidocaine - less lipid soluble than bupivacaine but has a
lower degree of protein binding - will also cross the
placenta.
• Chloroprocaine -least placental transfer because rapidly
broken down by plasma cholinesterase.
2/7/2019 Department Of Anesthesiology , PMWH 19

20. Local anesthetics
Ion trapping
• If the fetus is compromised it may become acidotic- more
of the fetal local anesthetic will be ionised and unable to
return to the maternal circulation.
• Can result in fetal toxicity.
2/7/2019 Department Of Anesthesiology , PMWH 20

21. Local anesthetic in SAB
Local anesthetic dose requirement for is reduced.
1. Decrease in CSF protein -greater proportion of free and active drug
2. Elevated CSF pH increases the unionized fraction of local anesthetics
3. Distension of epidural veins result in a decrease in CSF volume
4. ↓ vol of csf in vertebral column, ↓ epidural space Labor induced ↑
in csf pressue
5. ↑ neurosensitivity to local anesthetics
2/7/2019 Department Of Anesthesiology , PMWH 21

22. LA in epidural
• Pregnancy-increased epidural blood volume, decreasing the
capacity of the epidural space and decreasing the volume of
lumbar cerebrospinal fluid- increased spread of local anesthetic.
• Bupivacaine,
• 0.25%) are used for continuous epidural analgesia, the
second stage of labor may be prolonged by approximately
15–30 min
• 0.125% or less shows no evidence of prolonging labor
2/7/2019 Department Of Anesthesiology , PMWH 22

23. Inhalational Agents
• Volatile anaesthetic agents readily cross the placenta - are highly
lipid soluble and have low molecular weights.
• MAC value decreased- increased level of progesterone and
increase in B-endorphine levels
• Inhalational agent produces less fetal depression when MAC<1
and delivery occurs within 10 min
• Volatile inhalational anesthetics decrease blood pressure and
utero-placental blood flow.
• Causes uterine relaxation
2/7/2019 Department Of Anesthesiology , PMWH 23

24. Inhalational Agents
• Depression of contractility of uterus caused by enflurane,
halothane, and isoflurane- dose dependent
• Low doses (<0.75 MAC) of these agents- do not interfere with the
effect of oxytocin on the uterus
• Higher dose –uterine atony and increase blood loss at delivery
• Desflurane and sevoflurane do not increase postpartum blood
loss.
2/7/2019 Department Of Anesthesiology , PMWH 24

25. • Nitrous oxide
• Crosses the placenta rapidly.
• Nitrous oxide combined with isoflurane or halothane provide
good analgesia and does not increase blood loss.
• Diffusion hypoxia - occur in neonates exposed to nitrous
oxide immediately before delivery -supplemental oxygen
required
• Both in early and term pregnancy, the median concentration
of nitrous oxide - reduced by 25% to 27% on the neonate.
2/7/2019 Department Of Anesthesiology , PMWH 25
Inhalational Agents

26. Intravenous agents
Propofol
• Very lipid soluble and able to cross the placenta easily.
• Are associated with small reduction in uterine blood flow
due to decrease in maternal blood pressure
• It has been associated with transient depression of Apgar
scores and neurobehavioural effects in the neonate
2/7/2019 Department Of Anesthesiology , PMWH 26

27. Intravenous agents
Ketamine
• Rapidly crosses the placenta.
• Does not cause neonatal depression
• Higher doses -cause respiratory depression and muscular
hypertonicity
• Ketamine - used in hypovolemic and asthmatic patients
• Causes uterine hypertonicity and uterine artery
vasoconstriction at doses>2mg/kg
2/7/2019 Department Of Anesthesiology , PMWH 27

28. Intravenous agents
STP
• Highly lipid soluble
• Weakly acidic,
• 75% protein bound,
• 50 % ionized at physiological PH
• Crosses placenta easily
• Dose less than 4mg/ kg – doesn’t produce neonatal depression
2/7/2019 Department Of Anesthesiology , PMWH 28

29. Benzodiazepines
• Cross placenta
• In large doses - used for induction but causes cause
significant neonatal side effects “floppy infant syndrome”
2/7/2019 Department Of Anesthesiology , PMWH 29

30. Opioids
• Increased sensitivity to opioids
• Used as labor analgesia and for postoperative pain control
after cesarean delivery
• Also used in spinal or epidural analgesia
• All the opioids readily cross the placenta
• Minimally decrease the progression of labour
• Commonly used opioids : pethidine, morphine, butorphanol,
and nalbuphine, fentanyl, sufentanil
2/7/2019 Department Of Anesthesiology , PMWH 30

31. Opioids
• Pethidine –longer half life due to active metabolite nor-
meperidine, respiratory depression in neonate
• Morphine poor lipid solubility , crosses placenta because of
poor protein binding
• Newborns -more sensitive to respiratory depressant effect
of morphine when compared with other opioids
2/7/2019 Department Of Anesthesiology , PMWH 31

32. Opioids
Fentanyl-
• Highly lipid soluble and albumin bound,
• Crosses placenta easily less respiratory depressant
• Fentanyl have minimal neoanatal effects unless large
intravenous doses >1 mcg/kg given immediately before
delivery.
• Epidural or intrathecal fentanyl, sufentanil, and, to a lesser
extent, morphine, generally produce minimal neonatal
effects
2/7/2019 Department Of Anesthesiology , PMWH 32

33. Muscle relaxant
• All the muscle relaxants do not cross the placenta except
gallamine
• Decrease in plasma cholinesterase levels by 25% from early
pregnancy
• Prolonged neuromuscular blockade with suxamethonium is
uncommon -increased volume of distribution.
• The common side effects of succinylcholine such as
fasciculations and myalgias,are significantly decreased in
pregnant
2/7/2019 Department Of Anesthesiology , PMWH 33

34. Muscle relaxant
• Non-depolarising muscle relaxants have a prolonged
duration of action
• Neuromuscular monitoring with a nerve stimulator is
recommended.
2/7/2019 Department Of Anesthesiology , PMWH 34

35. Anticholinergics
• Transfer of anticholinergic drugs across the placenta mimics
the transfer of these drugs across the blood–brain barrier.
• Glycopyrrolate - quaternary (polar) ammonium compound
which is fully ionized - poorly transferred across the placenta.
• Atropine - lipid-soluble tertiary amine (nonpolar)which
demonstrates complete placental transfer
2/7/2019 Department Of Anesthesiology , PMWH 35

36. Neostigmine
A quaternary ammonium compound but is a small molecule
which is able to cross the placenta more rapidly than
glycopyrrolate.
• Cases reported- where neostigmine has been used with
glycopyrrolate to reverse NMB in pregnancy-profound fetal
bradycardia
• For GA in pregnancy where the baby is to remain in utero-
advisable to use neostigmine with atropine than with
glycopyrrolate
2/7/2019 Department Of Anesthesiology , PMWH 36

37. Vasopressors
• Uterine vasculature has both alpha and beta adrenergic
receptors
• Alpha-1 receptor- uterine contraction, Beta-2 receptor- uterine
relaxation
• Phenylephrine - a drug of choice for treating maternal
hypotension associated with less fetal acidosis than ephedrine
• Small doses of phenylephrine (40 mcg)- increase uterine blood
flow in normal parturients by raising arterial blood pressure
2/7/2019 Department Of Anesthesiology , PMWH 37

38. Anticoagulants
• Anticoagulation therapy during pregnancy - often necessary
despite its association with maternal and fetal morbidity.
• Maternal administration of warfarin -results in a higher rate of
fetal loss and congenital anomalies
• Heparin does not appear to cross the placenta
• Low-molecular-weight heparin (LMWH) - limited placental
transfer
• Enoxaparin - no alteration in fetal anti-IIa or anti-Xa activity.
2/7/2019 Department Of Anesthesiology , PMWH 38

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40. Oxytocics
Agents that stimulate uterine contraction
• Indication
• To induce or augument labor
• To control postpartum uterine atony and bleeding
• To induce therapeutic abortion
• Drugs
• Synthetic posterior pituitary hormone : oxytocin
• Ergot alkaloids: ergonovine and methylergonovine
(methergine)
• Prostaglandins: prostaglandin 15-methyl F2α
(carboprost), prostaglandin E1 (misoprostol)
2/7/2019 Department Of Anesthesiology , PMWH 40

41. Oxytocin
• MOA: act on uterine smooth muscle to stimulate frequency
and force of contraction.
• Half life 3-5min
• Side effects
• CVS: vasodilation, hypotension, reflex tachycardia and
arrhythmias
• Fetal distress-hyperstimulation
• Uterine tetany
• In high doses it may have an antidiuretic effect , produce
water intoxication, cerebral edema and subsequent
convulsion
2/7/2019 Department Of Anesthesiology , PMWH 41

42. Ergot alkaloids
• Methergine - intense and prolonged uterine contractions
• Given- after delivery to treat uterine atony
• Severe hypertension –
• Avoided in patients with peripheral vascular disease,
preeclampsia, hypertension or coronary disease
• Dose: 0.2mg IM or iv in dilute form over 10 min
• IV injection - associated with severe hypertension, convulsion,
stoke, retinal detachment, coronary vasospasm, MI
2/7/2019 Department Of Anesthesiology , PMWH 42

43. Carboprost
• Synthetic analogue of prostaglandin F2
• Stimulate uterine contraction
• Often used to treat refractory PPH
• Dose : 250mcg IM or Intramyometrially, can repeat in
every 15-90min to a maximum of 2 g.
• Side effects: nausea , vomiting, fever, diarrhea
• CI: Asthmatic patient
2/7/2019 Department Of Anesthesiology , PMWH 43

44. Tocolytic agents
• Used to delay or stop premature labor in patients with viable
fetuses less than or equal to 34 weeks gestation
• Drugs used :
• Beta2 adrenergic agonist - Terbutaline, Ritodrine
• Magnesium sulphate
• Cyclooxygenase inhibitor - indomethacin
• Calcium channel blocker - nifedipine
2/7/2019 Department Of Anesthesiology , PMWH 44

45. • Indications:
• To stop preterm labor
• To slow or arrest labor while initiating other therapeutic
measures.
• To allow transfer from community hospital to a tertiary
centre .
• Contraindications:
• Chorioamnionitis
• Fetal distress
• IUFD
• Severe hemorrhage
2/7/2019 Department Of Anesthesiology , PMWH 45
Tocolytic agents

46. Magnesium sulphate
• MOA: antagonized intracellular calcium and inhibits
myometrial contraction
• It is a CNS depressant and anticonvulsant
• Uses
• Prevention of eclamptic seizure
• Stop premature labor
• Hypomangnesemia
• Polymorphic ventricular tachycardia(torsade de
pointes)
2/7/2019 Department Of Anesthesiology , PMWH 46

47. Magnesium sulphate
• Dose: 4 gm IV loading dose over 20 min followed by a
2g/h infusion
• It crosses the placenta easily - cause neonatal hypotonia,
hyporeflexia and respiratory depression
• Interaction with neuromuscular blocking agents
• Side effects:
• Hypotension
• Hyporeflexia
• Muscle weakness
• Sedation
• Decrease urine output
2/7/2019 Department Of Anesthesiology , PMWH 47

48. Serum Magnesium level
2/7/2019 Department Of Anesthesiology , PMWH 48
• Normal serum plasma level: 1.5- 2.5 meq/L
• Therapeutic serum level : 4-6 meq/L
• Loss of deep tendon reflex:>7-10 meq/L
• Respiratory depression :10-13meq/L
• Altered Atrioventricular conduction and
complete heart block :15.0-25.0 mEq/L
• Cardiac arrest: >25.0 mEq/L
Lu JF,Nightingale CH. Magnesium sulfate in eclampsia and pre-eclampsia. Clin
Pharmacokinet. 2000; 38:305–314

49. In 1979, FDA introduced a classification of fetal risks
due to Drugs
• Category A : No risk in controlled human studies
• Category B : No risk in animal studies . No studies in pregnant
women.
• Category C: Animal studies have shown an adverse effect on
the fetus and there are no adequate and well-controlled
studies in humans, but potential benefits may warrant use of
the drug in pregnant women despite potential risks.
• Category D : Positive evidence of risk
• Category X: Contraindication in pregnancy
2/7/2019 Department Of Anesthesiology , PMWH 49

50. FDA category ratings of Specific Anesthetic agents
2/7/2019 Department Of Anesthesiology , PMWH 50

51. Systems Category A Category B
Central nervous
system
Magnesium sulfate Propofol, clozapine
Cardiovascular drugs Tranexamic acid, Torsemide,
Dobutamine, hydrochlorothiazide,
LMWH,
Endocrine Thyroxine Metformin, glucagon, insulin
Sitagliptin, acarbose
Gastointestinal
system
Doxylamine Ranitidine, ondansetron,
Rabeprazole, cimetidine,
glycopyrrolate, pantoprazole,
omeprazole,
Pain Management EMLA, lidocaine , ropivacaine,
oxycodone , acetaaminophen,
2/7/2019 Department Of Anesthesiology , PMWH 51

52. • Any Queries ?
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53. Let’s have some brain storm..
2/7/2019 Department Of Anesthesiology , PMWH 53

54. • Passive diffusion of substance
across the placenta is enhanced
by all of the following except
1. Low molecular weight of the
substance
2. High water solubility of the
substance
3. Low degree of ionization of
the substance
4. Large concentration gradient
of the drugs
2/7/2019 Department Of Anesthesiology , PMWH 54
Answer- 2. High water
solubility of the
substance
Factors promoting
diffusion across placental
membrane:
Low maternal protein
binding, low molecular
weight, a low degree of
ionization and a large
degree of concentration
gradient

55. • Regional anesthesia technique that can be used for forceps
deliveries include all of the following except
1. Bilateral pudendal nerve block
2. Paracervical block
3. Subarachnoid block
4. Caudal block
2/7/2019 Department Of Anesthesiology , PMWH 55
Answer 2: Paracervical block
Factors affecting maternal to
fetal transfer
Location
paracervical > epidural (caudal
> lumbar) > IM > subarachnoid

56. • Among the following drugs the least to transfer to fetus
from mother is
1. Ketamine
2. Atropine
3. Succinylcholine
4. Midazolam
2/7/2019 Department Of Anesthesiology , PMWH 56
Answer. 3: Succinylcholine
Neuromuscular blocking agents are large, poorly
lipid soluble, and highly ionized molecules. They
cross the placenta very slowly and pose no
significant clinical problems to the neonate
Midazolam-Benzodiazepines are highly lipid
soluble and unionized and therefore exhibit rapid
and complete diffusion across the placenta.
Atropine - Atropine is a lipid-soluble tertiaryamine
which demonstrates complete placental transfer
Ketamine- Rapidly crosses the placenta.

57. Which local Anesthesia would you prefer for epidural for a
parturient patient who has presented with a decompensating
fetus(hypoxia) and why ??
1. Bupivacaine
2. Chloroprocaine
3. Ropivacaine
4. Levo bupivacaine
2/7/2019 Department Of Anesthesiology , PMWH 57
Answer 2 : chloroprocaine (pKa 8.7)
is the drug of choice for epidural
analgesia and a decompensating fetus,
because it does not participate in ion
trapping
Bupivacaine , levo bupivacaine,
Ropivacaine-pka 8.1

58. Summary
• Variations in maternal physiology may alter the
pharmacokinetics and pharmacodynamics that determines
drug dosing and effect
• There are basically five main mechanisms of drug transfer
across the placenta namely- passive diffusion, facilated
diffusion, active transport, pinocytosis and bulk transfer.
• Physical factors affecting drug transfer across the placenta
includes -placental surface area, Placental thickness, pH of
maternal and fetal blood , concentration gradient across
placenta ,Uteroplacental blood flow, presence of placental
drug transporters
2/7/2019 Department Of Anesthesiology , PMWH 58

59. Summary
• In addition, pharmacological factors affects maternal-fetal
exchange ie. molecular weight of drug, Lipid solubility, pKa of
drugs, protein binding
• Understanding both pregnancy physiology and the gestation-
specific pharmacology of different anesthetic agents is
necessary to achieve effective treatment and limit maternal
and fetal risk.
2/7/2019 Department Of Anesthesiology , PMWH 59

60. References
• Morgan & Mikhail’s Clinical Anesthesiology 5th Edition
• Chestnut’s Obstetrics Anesthesia Principles And Practice-5th
Edition
• Williams Obstetrics -24th edition
• Continuing Education in Anaesthesia, Critical Care & Pain |
Volume 15 Number 2 2015
• Internet : www.openanesthesia.org , www.frca.co.uk
• Questions and answers –Anesthesia comprehensive review –
Hall 5th edition
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