Drugs in pregnancy:

pharmacokinetics and
pharmacodynamics in mother
and foetus
Drugs for the breastfeeding woman

Britt-Ingjerd Nesheim 2009

Clinical pharmacology in pregnancy
Placental passage
Pharmacokinetics
Mother
Foetus
Clinical pharmacology in pregnancy
Placental passage
Pharmacokinetics
Mother
Foetus
 Placental passage
Passive diffusion
Facilitated diffusion
Active transport against a concentration
gradient
What regulates placental passage?
Lipid solubility
Water soluble molecules pass if low molecular weight
Molecular size
Example: Heparin / Fragmin (dalteparin)
Protein binding
Degree of ionization
Foetal plasma slightly more acidic ion trapping of
basic drugs
Time
Clinical pharmacology in pregnancy
Placental passage
Pharmacokinetics
Mother
Foetus
 Pharmacokinetics in pregnancy
Absorption
Increased pH in the gastric ventricle
Decreased motility

Sparse data
Nothing to suggest changed absorption
in pregnancy
 Pharmacokinetics in pregnancy
Distribution

Increased plasma volume

 Pharmacokinetics in pregnancy
Distribution
Increased plasma volume
Increased volume of interstitial fluid

Increased volume of distribution?

 Pharmacokinetics in pregnancy
Plasma protein binding
Decreased concentration of plasma
proteins
At term 70 80 % of nonpregnant values
Of importance for monitoring drugs where
total plasma concentration is measured
(phenytoin, valproate)
 Pharmacokinetics in pregnancy
Metabolism
Cytochrome P450 Pregnancy affects
CYP1, CYP2, CYP3 these enzymes -
Uridine diphosphate differently
glucuronyltransferase
UGT
N-acetyltransferase
NAT
 Pharmacokinetics in pregnancy
Excretion
Glomerular filtration rate increased 50 % in
1. trimester, 80 % in 2. trimester
Changes in tubular excretion or
reabsorption? Unknown
-lactam antibiotics: increased clearance
Varying effects probably drug specific
effects on tubular mechanisms
 Metabolism in the foetus
Hepatic metabolism underdeveloped
Beneficial, because a water soluble
metabolite would have a slow / no diffusion
back to the mother
Epoxides
Placental diffusion back
Newborns also have a slow drug
metabolism
 Pharmacodynamics in the foetus
The same as in the adult body
Cell membrane receptors in 1. trimester
Mother sedated foetus sedated
Hepatic enzyme induction
Abstinence
Excretion of drugs in breast milk
Depending on
Plasma protein binding
Ionization
Lipophilicity
Molecular weight
Kinetics in the mother
Passive diffusion
Carrier-mediated transport (e.g.
Cimetidine)
 Milk-to-plasma drug concentration
ratio
Varies over time
Therefore: time- Distribution of milk-to-plasma
averaged value ratios

25 %
>1
>2
60 % 1 or less
15 %
 Determinants of level of exposure
Depending on
Amount of milk taken by infant
Milk-to-plasma ratio
Clearance by infant

Most important
 Relation between the Level of Exposure of an Infant to a Drug Excreted in Breast Milk and the
Rate of Clearance of the Drug by the Infant, According to the Ratio of the Drug Concentration in
the Milk to the Drug Concentration in Maternal Plasma

Ito S. N Engl J Med 2000;343:118-126

Reprinted from Ito and Koren, NEJM

2000, 343(2):118-126
Drugs requiring careful assessment
of risks - cardiovascular
Acebulol
Amiodarone
Atenolol
Nadolol
Sotalol

May accumulate in neonate because of

high milk-to-plasma ratio and slow
excretion
 Drugs considered to be safe
Propranolol
Labetolol