Placental Placental transfer of drugstransfer of drugs

Dr. Manish SinghalDr. Manish Singhal11 Feb 200811 Feb 2008

StructureStructure

Maternal

Foetal

Placenta is a fetomaternal organ. The foetal portion is known as the villous chorion, the maternal portion as the decidua basalis.

Functions of the Functions of the PlacentaPlacenta

Transfer of products between the Transfer of products between the maternal and fetal bloodmaternal and fetal blood

Transfer of immunity by transfer of Transfer of immunity by transfer of immunoglobulins from the motherimmunoglobulins from the mother

Endocrine functionEndocrine function Detoxification of drugs and Detoxification of drugs and

substances transferred from the substances transferred from the mother.mother.

Mechanisms of Placental Mechanisms of Placental TransportTransport

Simple diffusion----Simple diffusion----oxygen, carbon dioxide, oxygen, carbon dioxide, fatty acidsfatty acids

Facilitated diffusion--Facilitated diffusion--glucoseglucose

Secondary active transport----Secondary active transport----Amino Amino acidsacids

Active transport---Active transport---Iron, Calcium,IodineIron, Calcium,Iodine

Pinocytosis----Pinocytosis----IgGIgG

Bulk transport– Bulk transport– Electrolytes and waterElectrolytes and water

Although the placenta acts as a barrier Although the placenta acts as a barrier between the maternal and foetal tissues between the maternal and foetal tissues it is not a perfect barrier as it was it is not a perfect barrier as it was believed to be earlier.believed to be earlier.

Substances that cross the Substances that cross the placentaplacenta

SubstancesSubstances ExamplesExamplesBENEFICIALBENEFICIAL

GasesGases O2,CO2,O2,CO2,NutrientsNutrients Glucose, Amino acids,FFAGlucose, Amino acids,FFAMetabolitesMetabolites Urea, Bilirubin, CreatinineUrea, Bilirubin, CreatinineElectrolytesElectrolytes Na, K, Cl, CaNa, K, Cl, CaMaternal proteinsMaternal proteins Albumin,Thyroxine,InsulinAlbumin,Thyroxine,InsulinSteroid HormonesSteroid Hormones Cortisol,estrogenCortisol,estrogenImmunoglobulinsImmunoglobulins IgGIgG

HARMFULHARMFULPoisonous gasesPoisonous gases Carbon monoxideCarbon monoxideInfectious agentsInfectious agents CMV,toxoplasma,HIV etc.CMV,toxoplasma,HIV etc.DrugsDrugs Cocaine,alcohol,phenytoin,anCocaine,alcohol,phenytoin,an

aestthetics,sedatives,analgesiaestthetics,sedatives,analgesicscs

ImmunoglobulinsImmunoglobulins Anti-Rh antibodiesAnti-Rh antibodies

Rate of transfer across a membrane Rate of transfer across a membrane is governed by the Fick Principle:is governed by the Fick Principle:

Q/t = K * A ( Cm – Cf) / DQ/t = K * A ( Cm – Cf) / D

Q/tQ/t is the rate of diffusion is the rate of diffusion

KK is the diffusion coefficient is the diffusion coefficient

AA is the area of the membrane is the area of the membrane

Cm-CfCm-Cf is the concentration gradient is the concentration gradient

DD is the thickness of the membrane is the thickness of the membrane

Factors affecting drug Factors affecting drug transfertransfer

Lipid solubilityLipid solubility Degree of IonisationDegree of Ionisation pH of maternal bloodpH of maternal blood Protein bindingProtein binding F/M concentration gradientF/M concentration gradient Placental blood flow.Placental blood flow. Molecular weight of the drugMolecular weight of the drug

Lipid SolubilityLipid Solubility : : Lipophilic molecules readily Lipophilic molecules readily diffuse.diffuse.

Degree of IonisationDegree of Ionisation: : Only non-ionised Only non-ionised fraction can diffusefraction can diffuse

pH of maternal bloodpH of maternal blood: : Acts by affecting the Acts by affecting the degree of ionisation.This effect depends on the pKa of degree of ionisation.This effect depends on the pKa of the drugthe drug

Protein bindingProtein binding: : Unbound drug diffuses. Unbound drug diffuses. Acidosis reduces the bound fractionAcidosis reduces the bound fraction

Molecular weightMolecular weight: : Drugs with molecular Drugs with molecular weights <600 Da readily diffuse.weights <600 Da readily diffuse.

Foeto-Maternal concentration ratios (F/M)Foeto-Maternal concentration ratios (F/M) of drugs of drugs are frequently used as an index of placental transfer of are frequently used as an index of placental transfer of drugs.drugs.

OPIOIDSOPIOIDSALL OPIOIDS CROSS THE PLACENTA IN SIGNIFICANT AMOUNTSALL OPIOIDS CROSS THE PLACENTA IN SIGNIFICANT AMOUNTS

PethidinePethidine : : It is 50% protein bound and has an It is 50% protein bound and has an almost unrestricted placental transfer. almost unrestricted placental transfer. Maximum uptake foetal uptake occurs 2-3 hours Maximum uptake foetal uptake occurs 2-3 hours after a maternal i/m dose.after a maternal i/m dose.

Longer half lives of pethidine and it’s metabolite in Longer half lives of pethidine and it’s metabolite in the foetus hence there is a risk of cumulative the foetus hence there is a risk of cumulative side effects.side effects.Half Half

life(hrs)life(hrs)PethidinePethidine NorpethidiNorpethidi

nene

MotherMother 44 2121

FoetusFoetus 1919 6262

MorphineMorphine: Poorly lipid soluble but : Poorly lipid soluble but weakly protein bound and readily weakly protein bound and readily crosses placentacrosses placenta

FentanylFentanyl : Highly lipid soluble and : Highly lipid soluble and rapidly crosses the placenta, but is rapidly crosses the placenta, but is largely protein bound(85%)largely protein bound(85%)

Anaesthesiology 2007;106;843-63Anaesthesiology 2007;106;843-63 : Practice : Practice guidelines for obstetric anaesthesia, a report by guidelines for obstetric anaesthesia, a report by ASA taskforce on obstetric anaesthesia : ASA taskforce on obstetric anaesthesia : Demonstarted superiority of neuraxial anaesthesia Demonstarted superiority of neuraxial anaesthesia with opioids vs parenteral opioidswith opioids vs parenteral opioids..

Anaesthesiology Vol 104,Issue 1 (Jan’06)Ngan Anaesthesiology Vol 104,Issue 1 (Jan’06)Ngan KeeKee et.alet.al: : Remifentanil at a 1mcg/kg bolus causes Remifentanil at a 1mcg/kg bolus causes neonatal depression with a F/M of 0.73, neonatal neonatal depression with a F/M of 0.73, neonatal resus facilities recommended.resus facilities recommended.

A’logy Vol 106,Issue 5 ( May ’07):A’logy Vol 106,Issue 5 ( May ’07): Opioids Opioids administered via neuraxial route have better foetal administered via neuraxial route have better foetal outcome as compared to via parentral outcome as compared to via parentral administrationadministration. .

Local AnaestheticsLocal Anaesthetics Cross the placenta by simple diffusionCross the placenta by simple diffusion Commonly used LA have Commonly used LA have low mol. wt., high low mol. wt., high

lipid solubility and low ionisation.lipid solubility and low ionisation. ““Ion trappingIon trapping” : Local anaesthetic ” : Local anaesthetic

accumulation in the foetus due to foetal acidosis.accumulation in the foetus due to foetal acidosis. Transfer to the foetus is also affected by: Transfer to the foetus is also affected by:

DoseDoseSite of administration—paracervical vs epiduralSite of administration—paracervical vs epiduralUse of adjuvants like epinephrineUse of adjuvants like epinephrine..

Highly protein bound drugs like Bupivacaine will Highly protein bound drugs like Bupivacaine will have lesser placental transfer and lower F/M have lesser placental transfer and lower F/M ratios.ratios.

Inhalational agentsInhalational agents

High lipid solubility and low mol. wt. High lipid solubility and low mol. wt. facilitate rapid transfer.facilitate rapid transfer.

Halothane F/M 0.87Halothane F/M 0.87 Diffusion hypoxia may occur in Diffusion hypoxia may occur in

neonates exposed to nitrous oxide neonates exposed to nitrous oxide immediately prior to delivery (F/M immediately prior to delivery (F/M 0.83)0.83)

Induction agentsInduction agents

ThiopentoneThiopentone : F/M 0.4-1.1 , Highly : F/M 0.4-1.1 , Highly lipophilic and 75% protein bound. lipophilic and 75% protein bound. Rapidly crosses placentaRapidly crosses placenta

PropofolPropofol : F/M 0.65-0.85. Exact : F/M 0.65-0.85. Exact pharmacokinetic data not available.pharmacokinetic data not available.

Muscle RelaxantsMuscle Relaxants

Highly ionised and poorly lipid Highly ionised and poorly lipid soluble, hence soluble, hence DO NOTDO NOT cross cross placentaplacenta

Anti-cholinergicsAnti-cholinergics

The placental transfer correlate The placental transfer correlate directly with their ability to cross the directly with their ability to cross the BBB. BBB. AtropineAtropine rapidly crosses, rapidly crosses, GlycopyrollateGlycopyrollate is poorly transferred. is poorly transferred.

BenzodiazepinesBenzodiazepines

DiazepamDiazepam readily crosses. It is readily crosses. It is highly non-ionised and very highly non-ionised and very lipophilic. F/M 1 within minutes of lipophilic. F/M 1 within minutes of injection and reaches 2 within 1 injection and reaches 2 within 1 hour.hour.

MidazolamMidazolam: F/M 0.76, but has a : F/M 0.76, but has a short half-life.short half-life.

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