Placental

transfer of drugs

Dr. Manish Singhal

11 Feb 2008
 Structure

Matern
al

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
Placenta
 Transfer of products between the
maternal and fetal blood
 Transfer of immunity by transfer of
immunoglobulins from the mother
 Endocrine function

 Detoxification of drugs and

substances transferred from the
mother.
 Mechanisms of Placental
Transport
 Simple diffusion----oxygen, carbon dioxide,
fatty acids
 Facilitated diffusion--glucose
 Secondary active transport----Amino
acids
 Active transport---Iron, Calcium,Iodine
 Pinocytosis----IgG
 Bulk transport– Electrolytes and water
Although the placenta acts as a barrier
between the maternal and foetal
tissues it is not a perfect barrier as it
was believed to be earlier.
 Substances that cross the
placenta
Substances Examples
BENEFICIAL
Gases O2,CO2,
Nutrients Glucose, Amino acids,FFA
Metabolites Urea, Bilirubin, Creatinine
Electrolytes Na, K, Cl, Ca
Maternal proteins Albumin,Thyroxine,Insulin
Steroid Hormones Cortisol,estrogen
Immunoglobulins IgG
HARMFUL
Poisonous gases Carbon monoxide
Infectious agents CMV,toxoplasma,HIV etc.
Drugs Cocaine,alcohol,phenytoin,ana
estthetics,sedatives,analgesic
Immunoglobulins s
Anti-Rh antibodies
Rate of transfer across a membrane
is governed by the Fick Principle:
Q/t = K * A ( Cm – Cf) / D

Q/t is the rate of diffusion

K is the diffusion coefficient
A is the area of the membrane
Cm-Cf is the concentration gradient
D is the thickness of the membrane
 Factors affecting drug
transfer
 Lipid solubility
 Degree of Ionisation
 pH of maternal blood
 Protein binding
 F/M concentration gradient
 Placental blood flow.
 Molecular weight of the drug
 Lipid Solubility : Lipophilic molecules
readily diffuse.
 Degree of Ionisation: Only non-ionised
fraction can diffuse
 pH of maternal blood: Acts by affecting
the degree of ionisation.This effect depends on
the pKa of the drug
 Protein binding: Unbound drug diffuses.
Acidosis reduces the bound fraction
 Molecular weight: Drugs with molecular
weights <600 Da readily diffuse.

Foeto-Maternal concentration ratios (F/M) of

 OPIOIDS
ALL OPIOIDS CROSS THE PLACENTA IN SIGNIFICANT AMOUNTS

Pethidine : It is 50% protein bound and has an

almost unrestricted placental transfer. Maximum
uptake foetal uptake occurs 2-3 hours after a
maternal i/m dose.
Longer half lives of pethidine and it’s metabolite in
the foetus hence there is a risk of cumulative
Half
side effects. Pethidine Norpethidi
life(hrs)
Mother 4 ne 21
Foetus 19 62
 Morphine: Poorly lipid soluble but
weakly protein bound and readily
crosses placenta
 Fentanyl : Highly lipid soluble and
rapidly crosses the placenta, but is
largely protein bound(85%)
Anaesthesiology 2007;106;843-63 :
Practice guidelines for obstetric
anaesthesia, a report by ASA taskforce on
obstetric anaesthesia : Demonstarted
superiority of neuraxial anaesthesia with
opioids vs parenteral opioids.
 Anaesthesiology Vol 104,Issue 1
(Jan’06)Ngan Kee et.al: Remifentanil at
a 1mcg/kg bolus causes neonatal
depression with a F/M of 0.73, neonatal
resus facilities recommended.
 A’logy Vol 106,Issue 5 ( May ’07):
Opioids administered via neuraxial route
 Local Anaesthetics
 Cross the placenta by simple diffusion
 Commonly used LA have low mol. wt.,
high lipid solubility and low
ionisation.
 “Ion trapping” : Local anaesthetic
accumulation in the foetus due to foetal
acidosis.
 Transfer to the foetus is also affected by:
Dose
Site of administration—paracervical vs
epidural
Use of adjuvants like epinephrine.
 Highly protein bound drugs like
 Inhalational agents
 High lipid solubility and low mol. wt.
facilitate rapid transfer.
 Halothane F/M 0.87
 Diffusion hypoxia may occur in
neonates exposed to nitrous oxide
immediately prior to delivery (F/M
0.83)
 Induction agents
 Thiopentone : F/M 0.4-1.1 , Highly
lipophilic and 75% protein bound.
Rapidly crosses placenta
 Propofol : F/M 0.65-0.85. Exact
pharmacokinetic data not available.
 Muscle Relaxants
 Highly ionised and poorly lipid
soluble, hence DO NOT cross
placenta
 Anti-cholinergics
 The placental transfer correlate
directly with their ability to cross the
BBB. Atropine rapidly crosses,
Glycopyrollate is poorly transferred.
 Benzodiazepines
 Diazepam readily crosses. It is
highly non-ionised and very
lipophilic. F/M 1 within minutes of
injection and reaches 2 within 1 hour.
 Midazolam: F/M 0.76, but has a
short half-life.
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