ANESTHETIC PHARMACOLOGY DURING PERINATAL PERIOD

1. PERINATAL
PHARMACOLOGY
PRESENTER : DR. RAJESH MUNIGIAL
MODERATOR : DR. MAMATHA H .K
HOD : DR. ARUN KUMAR A
SSIMS & RC , DAVANAGERE

2.  Perinatal period comprises of period between 28th
week of gestational to less than seven days of life .

3. Fetal circulation

4.  Access of drugs to the fetus
 Pharmacodynamic aspects of drug action in fetus
Aspects of drug therapy during
pregnancy

5.  Distribution of drug from maternal circulation to placenta
 Placental sequestration by intracellular binding to placental
component by placental metabolism
 Transfer of placental to fetal and maternal circulation
Transplacental transfer of drugs
comprises 3 process

6. Mechanism of drug transfer

7.  Most drugs cross the placenta by simple diffusion
 It occurs down the concentration gradient which is
influenced by
 Rate of drug administration
 Volume of drug administration
 Rate of drug clearance
 The Ph of the fetal plasma also influences the rate of
drug transfer across the placenta
 Ex: paracetamol, midazolam
Simple diffusion

8.  Lipid solubility
 Molecular size
 Protein binding
 Placental and fetal metabolism
Drug factors affecting transfer

9.  Lipid soluble drugs readily cross the placenta whereas
ionized drugs do not
 Eg: thiopentone can readily cross the placenta and cause
sedation & apnea in newborn
 Volume of distribution for water soluble drugs is increased
Lipid solubilty

10.  Placenta excludes drugs of high molecular weight
 Mw : 250-500 are readily permeable
 Mw: 500-1000 , greater difficulty in crossing the placenta
 Mw: >1000 excluded or diffuse very poorly
Molecular weight

11.  Plasma protein binding of a drug will inhibit placental
transfer .
 Highly lipid soluble may anyway transfer despite avid
protein binding
 Plasma protein affinity may be different in fetal
circulation vs maternal
 Thus free fetal plasma concentration may be higher
than free maternal plasma concentration of the drug at
equilibrium.
Protein binding

12.  Protein binding plays a very important role in determining the
amount of free drug that is available to cross the placenta
,because it is the free fraction that crosses placenta.
 Fetal albumin concentrations progressively increase during
fetal development to the point being higher than maternal
values b term gestation.

13.  Only the non ionized fraction of a partly ionised drug crosses
the placental membrane.
 The degree to which a drug is ionised depends on its pka and
the ph of maternal blood
 Most drugs used in the anaesthesia practice are poorly ionised
and readily get transferred across the placenta , except
neuromuscular blocking agents which are highly ionised.
DEGREE OF IONISATION

14.  It is a form of passive transport that is
dependent on transmembrane proteins.
 These proteins assist transport of polar
molecules and charged ions that are unable to
passively cross the biological membrane.
 Ex; glucocorticoids and cephalosporins
Facilitated diffusion

15.  It has characteristics similar to facilitated
diffusion in that it is carrier mediated.
 It requires cellular energy and the transport of
substances occurs across an electrochemical
or concentration gradient.
 Ex: dopamine , norepinephrine
Active transport

16. Pinocytosis and phagocytosis involves solutes being
invaginated into the cell membrane and then
transferred across the membrane to the opposite side
.
These process are too slow to have any significant
impact on foetal drug concentration.
Pinocytosis

17. Q/t = KA(Cm − Cf) D
 q/t : quantity transferred in unit time
 K : drug diffusion constant
 A: placental area for transfer
 D : diffusion distance across membrane
 Cm and Cf are the maternal and fetal concentration
of drugs
Ficks law of diffusion :

18.  Uterine blood flow varies from 100ml/min in non
pregnant state to 700ml/min in pregnant state .
 Vasculature is dilated
 Uterine ands placental blood flow is mainly depended
on maternal cardiac output.
Uteroplacental physiology

19.  GAS EXCHANGE :
Placenta is wholly responsible for the transfer of oxygen
and carbon dioxide ,to and from the developing fetus
Functions of placenta

20.  Oxygen is a small molecule which readily crosses the
placenta by passive diffusion .
 Oxygen transfer to foetus is enhanced by BOHR effect. At
the materno fetal interface , maternal blood takes up more
co2 and becomes acidotic . This causes a rightward shift of
the maternal ODC curve which favours oxygen release to
fetus .
 At the same time , fetal blood releases co2 and becomes
more alkalotic , it leads to leftward shift of fetal odc curve
favouring fetal take up of o2.
 This is called DOUBLE BOHR EFFECT.
OXYGEN

22.  Co2 transfer from foetus to mother is facilitated by HALDANE
effect(the increased capacity of deoxygenated blood to carry
co2 compared to oxygenated blood).
 As maternal blood releases oxygen(producing deoxyhb)it is
able o carry more co2as bicarbonate and carbaminHB.
 At the same time as fetal blood takes up oxygen to form
oxyHB , it has reduced affinity for CO2 and therefore releases
co2 to mother .
 The combination of these two events is called as DOUBLE
HALDANE EFFECT.
Carbon dioxide

23.  O2 and 2,3 DPG compete with HBF for binding, the reduced
affinity of HBF for 2,3 DPG causes the HBF to bind to o2
tighter .
 P50 is 27mmhg for adults whereas it is only 20mmhg for
fetus. This causes a left shift in odc curve
OXYGEN HEMOGLOBIN DISSOCIATION CURVE

24. ABOSORPTION AND UPTAKE :
 Oral absorption and bioavailability not affected
Intestinal motility decreased and delayed gastric emptying
 Cardiac output is increased to 30-50%during pregnancy and
increase blood flow to skin and mucous membrane enhances
absorption from these sites.
 Reduced FRC and increased MV lead to increased uptake of
inhalational anaesthetic agents.
MATERNAL PHARMACOKINETICS

25.  Increased cardiac output during pregnancy causes
increased distribution of drugs to tissues.
 Drugs acting peripherally will be delivered to their site
quickly.
 A delay in arterial and brain anaesthetic
concentrations will result from increased peripheral
perfusion.
DISTRIBUTION

26.  Plasma albumin concentration is reduced to about 70% of normal ,
whereas apha 1 glycopotein is largely unchanged.
 The total (free+bound) concentration of drug will decrease , and it
may necessary to reset the therapeutic range lower to
compensate.

27.  Some cytochrome p450 isoenzymes (CYP3A4,CYP2D6 AND
CYP2C9) and UGT isoenzymes are increased activity and
increases metabolism of dug like phenytoin midazolam and
morphine.
 CYP1A2 an CYP2C19 have decreased activity ,caffeine and
theophylline metabolism reduced
Metabolism

28.  RBF is increased by 60-80% and GFR is increase by
50%, renal excretion of unchanged drugs is
increased.
 Increased minute ventilation enhances elimination
of inhalational anesthetic agents.
Elimination

29.  The F/M ratio provides a quantitative measurement that
helps delineate the degree o fetal exposure of drugs
administered to mother.
 But this ratio does not provide information on rate of
drug transfer or amount of drug that has already been
transferred
Placental transfer and metabolism

30.  Fetal ph is lower than materal ph , so weak bases become
more ionised in the fetus , thus limiting their transfer back
across placenta .
 Normally difference in ph is only 0.1 and this ION TRAPPING is
irrelevant , but fetal acidosis can significantly increase the
fetal concentration of drugs like local anesthetics.

32.  They metabolize , but at a reduced rate .
 RBF is minimal till near near term and excreted
products would just pass into amniotic fluid to be
swallowed
 Elimination is mainly depended on placental transfer
 Large MV promotes neonatal elimination of
inhalational agents
Fetal and neonatal elimination

33.  Depend on enzyme maturity and hepatic blood flow
 Phase 1 reactions (oxidation , reduction , hydrolysis ) :
mature to adult value by 6months of age
 Phase 2 reaction : sulfation is mature at birth
 Glucoronidation , acetylation and glycination mature by
1 year of age
Hepatic metabolism of drug

34. PHARMACODYNAMICS

35.  Requirement of iv anesthetic agents is reduced by 8-18%.
THIOPENTONE :
 Rapid transfer due to its high lipid solubility
 For hypnosis reduced by 17%
 For anesthesia reduced by 18%
 For induction reduced by 35%
 T half increases by 26hrs compared to 11 hrs in non pregnant
state.
 Induction dose : 4mg/kg
 F/M : 0.87-0.96
 Highly bound to albumin
 It is extensively uptake by fetal liver with decreased plasma
levels reaching fetal brain
IV ANESTHESTIC AGENTS

36.  F/M 0.6-0.7
 Produces severe hypotension
 Awareness is more with propofol
 Increasing uterine blood flow results in increased maternal
venous concentrations .
 Decreased extraction of propofol from the maternal
circulation is due to shortened contact time with placental
tissue.
 Propofol @2.5mg/kg does not affect neonatal APGAR
SCORES
 But at high doses like 9mg/kg causes neonatal depression
PROPOFOL

37. KETAMINE :
F/M 1.26
Lipid soluble
1mg/kg – no neonatal depression
At high doses lower apgar scores and neonatal muscular
hypertonicity
ETOMIDATE
 F/M : 0.04-0.5
 Its affets on fetus are similar to thiopentone (similaities in apgar
scores is observed)
 Quick acting and rapid hydrolysis, hence short duration of action
 Very minimal effects on maternal hemodyanmics (0.3mg/kg)

38. DIAZEPAM :
 F/M 0.9 -1
 T half :10-14hrs
 A dosage of o.3mg/kg is acceptable
 If >30mg in maternal circulation in conditions like in
ecclampsia , metabolic passage in fetus occurs and can
cause floppy infant syndrome (apnea , hypotonia ,
hypothermia )
MIDAZOLAM :
 F/M o.6 is preferred
 Use of midazolam has not ben associated with new born
sedation
BENZODIAZEPINES

39.  Volatile agents are highly lipid soluble and can cross placenta freely
 Blood gas coefficient is low in neonates .
 Cross placenta and can depress frequency , amplitude , duration of uterine
contraction
 Complete inhibition at MAC2
 Mac requirement reduces by 25-40%
 Inhalational induction is faster because increased minute ventilation and
reduced FRC .
 Reduced uterine tone and hypotension are potential side effects
INHALATIONAL AGENTS

40. Halothane
 with induction to delivery time averaging 10.8 minutes , an F/M
ratio of 0.71 is reported after exposure to 0.5% halothane .
 There is correlation of duration of exposure to halothane and
measured F/M ratio.
 It is quickly eliminated since the blood gas partition coefficient is
less in newborns
 As soon as respiration is stabilized it is eliminated
 It is the best uterine relaxant
Isoflurane
 0.8% rapidly crosses the placenta resulting in F/M ratio of 0.71 ,
being less soluble it eliminates faster.

41.  F/M o.18 at 19min of exposure and decreases at 36min of
exposure
 Diffusion hypoxia can occur during rapid elimination of
nitrous from fetus and can be prevented by administering
supplemental o2 to fetus exposed to n2o immediately
before delivery.
 Prolonged exposure may inhibit DNA synthesis so avoid in
first trimester
NITROUS OXIDE

42.  They do not readily cross placenta
SUCCINYLCHOLINE
 has not been detected in umbilical cord
 1-1.5mg/kg iv has rapid onset
 >10mg/kg required for detection
 Reduced cholinesterase levels are seen in pregnancy ,
possibly prolonged action may be seen
Muscle relaxants

43.  F/M 0.06 to 0.11 for vecuronium , it was seen that degree of
placnetal transfer decreases as the time interval from
maternal injection to delivery of newborn increases.
 O.o7 for atracurium, no adverse affects are seen with
maternally administered atracurium.
 0.16 for rocuroonium
NON DEPOLARISING MUSCLE
RELAXANTS

44.  Increased lipid solubility causes increased trans placental
transfer
 Increased maternal sensitivity , fetal withdrawal , IUGR with
tonic use
PETHIDINE :
F/M 0.6 immediately
1 after 2 hours
Neonatal CNS and respiratory depression
Within 90 seconds found in umbilical cord
Maternal level falls more rapidly than fetal levels
OPIODS

45.  Highly protein bound compared to morphine
 Predisposed to trapping in fetus in presence of fetal
compromise
 Baby should be delivered within 1 hour of pethidine
administration
 T half : 13-23 hrs
 Nor pethidine : t half 62hrs

46.  F/M 0.6 following 10-15mg IM maternally
 It is seen that morphine exposed fetuses had absent or
decreased fetal breathing movements and non reactive non
stress tests
 Intrathecal administration : F/M 0.9
 The impact of 1000mcg intrathecal related in very low
umbilical levels of morphine
MORPHINE :

47. Fentanyl :
 Maternal epidural : F/M 0.37-0.57
 In 1 min it appears in fetal blood
 It is a basic drug , more ionised in fetus than in the mother ,
hence predisposed to ion trapping leading to fetal hypoxia.
REMIFENTANYL
It crosses the placenta but is rapidly metabolized by the fetus
and its use for labor analgesia has not been associated with
adverse neonatal effects.
ALFENTANYL :
Following an iv dose of 30mc/kg , F/M ratio of 0.31 is seen and it
decreases to 0.28 in patient receiving epidural analgesia with
loading dose of 30mcg/kg and infusuion of 30mcg/kg/hr

49. LIGNOCAINE :
 The f/m ratio for lidocaine has been reported to be 0.9 in a
perfused human cotyledon after 2 hour
 There can be accumulation of lidocine in fetus and can
cause acidosis
 Despite accumulation it wont alter fetal heart rate , blood
pressure , arterial ph , blood gas responses to asphyxia
 There is a very little back transfer of lidocaine from fetal
circulation back to maternal circulation.
LOCAL ANAESTHETICS

50.  The f/m ratio is reported to be 0.56 after 2 hours
 Mode of placental transfer of bupivacaine is primarily by
passive diffusion.
 Fetal bupivacaine rises with increasing maternal doses
 The f/m ratio is highly influenced by transplacental AAG
gradient given that bupivacaine is highly protein bound.
 Increased risk of toxicity is seen
 Low intrathecal doses to be used
BUPIVACAINE

51. Neostigmine
It is a quaternary ammonium compound but is a small molecule
which is able to cross the placenta more rapidly than glycop
 In few cases profound fetal bradycardia has been reported
 Atropine can be used to prevent fetal bradycardia caused by
neostigmine
Edrohonium:
It is ionised quaternary compound with minimal placental
transfer , but it causes preterm labour
ANTICHOLINESTERASE AGENTS

52.  Atropine : it rapidly causes placenta , F/M ratio of 1.0.
Has no effects on fetal arterial pressure , heart rate or
beat to beat variability
 Glycopyrollate : F/M 0.13 , doesn’t cross the placenta.
ANTICHOLINERGIC AGENTS

53.  Ephedrine and phenylephrine are commonly used o treat
hypotension
 Ephedrine increases maternal arterial pressure by increasing
cardiac output via beta 1 receptors , with smaller contribution
via alpha 1 vasoconstriction
 F/M ratio 0.71
 It has minimal effects on uteroplacental blood flow
 It increases fetal heart rate and beat to beat variabiity
 It decreases umbilical artery ph , probably through stimulating
increase in fetal metabolic rate
Vasoactive drugs

54.  Phenylephrine increases maternal arterial pressure by
vasoconstriction through its direct effect on alpha 1
receptors
 F/M ratio is 0.17
 It prevents maternal hypotension without causing fetal
acidosis, when combined with rapid crystalloid infusion
immediately after spinal anesthesia

55.  Warfarin : it readily crosses placenta and causes
chondrodysplasia .
Heparin :
 Large molecular weight 20000-40000 , doesn’t cross the
placenta .
 Tinzaparin : it is a LMWH , can cause aplasia cutis
 Enoxaparin : no placental transfer
ANTICOAGULANTS :

56.  INSULIN : doesn’t cross placenta
But glucose can cross and produce foetal hypeinsulinemia and
neonatal hypoglycemia
GLYBURIDE : F/M < 0.3
High protein binding , rapid clearance.
ANTI HYPERGLYCEMIC AGENTS

57.  ONDANSETRON : F/M 0.41 , no major neonatal
malformations .
 METOCLOPROMIDE : if used in first trimester can cause
malformations , spontaneous abortion or decreased birth
weight. Chronic use causes tardive dyskinesia
 DEXAMETHASONE ; 3 to 4 fold increase in cleft lip and palate
If used in first trimester.
ANTIEMETICS :

58.  Alpha methyl dopa (F/M 1.17)has the least effects on
uteroplacental hemodynamics , hence ideal option for
treatment of hypertension in parturient population.
 Beta blockers can cross placenta and increase levels of
insulin and decrease in glucagon causing hypoglycemia in
newborn .
 Labetolol : mixed alpha/beta antagonist , F/M ratio of 0.38.
produces mild neonatal bradycardia , clinically insignificant.
Antihypertensives

59.  Dexmedetomidine : F/M 0.88 , no adverse effects are
seen .
 Nitroglycerin : F/M ratio 0.18 , decrease in foetal pao2
when compared to control group have been seen .

60.  Albutrol is the preferred short acting b2 agonist
 Salmetrol is preferred long acting b2 agonist
 Budesonide is the recommended inhaled corticosteroid
 5lipoxygenase inhibitors and leukotriene antagonists have
no adverse events and can be used
RESPIRATORY DRUGS

61. CATEGORY A DRUGS :
They hold no risk
No anesthetics come under this category
CATEGORY B DRUGS :
no evidence of risk in humans
Induction agents : propfol , methohexital
Inhalational agents : sevoflurane , desflurane ,enflurane
Opiods : pethidine
NMB : rocuromnium , cis atracurium
LOCAL ANESTHETICS : ropivacaine , lignocaine
U.S FDA drug classification system

62. CATEGORY C DRUGS :
Risk cannot be ruled out
Thiopentone , etomidate , ketamine
Halothane , isoflurane
Morphine , fentanyl , alfentanyl , sufentanyl
Succinycholine , vecuronium , atracurium
Bupivacaine , tetracaine

63. CATEGORY D DRUGS :
Evidence of risk is present
Diazepam and midazolam
CATEGORY X DRUGS :
No anesthetic drugs
Alcohol , warfarin , cocaine , phenytoin , thalidomide

64.  Stoeltings pharacology and physiology in anesthtesia
practice , 5th edition
 Shnider and Levinson's Anesthesia for Obstetrics (5th, 2012)
 Chestnut's Obstetric Anesthesia Principles and Practice, 5th
Ed. 2014
 Miller,s anaesthesia
REFERENCES

65. THANK YOU !!!