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  Nutrients  Metabolites  Electrolytes  Maternal  Steroid

O2,CO2, Glucose, Amino acids,FFA Urea, Bilirubin, Creatinine Na, K, Cl, Ca Albumin,Thyroxine,Insulin Cortisol,estrogen IgG Carbon monoxide CMV,toxoplasma,HIV etc. Cocaine,alcohol,phenytoin,ana estthetics,sedatives,analgesic s Anti-Rh antibodies

proteins

Hormones
HARMFUL

 Immunoglobulins

 Poisonous  Infectious  Drugs

gases agents

 Immunoglobulins

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 effects. Pethidine Norpethidi side

life(hrs) Mother Foetus

4 19

ne

21 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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