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
CYP1, CYP2, CYP3

Uridine diphosphate glucuronyltransferase

UGT

Pregnancy affects these enzymes differently

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: timeaveraged value
Distribution of milk-to-plasma ratios

25 % >1 >2 1 or less

60 %

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