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Drugs in pregnancy:pharmacokinetics and

pharmacodynamics in motherand foetus

Britt-Ingjerd Nesheim 2009

Drugs for the breastfeeding woman

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Clinical pharmacology in pregnancy

Placental passage

Pharmacokinetics Mother

Foetus

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Clinical pharmacology in pregnancy

Placental passage

Pharmacokinetics Mother

Foetus

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Placental passage

Passive diffusion

Facilitated diffusion

Active transport against a concentration

gradient

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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 ofbasic drugs

Time

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Clinical pharmacology in pregnancy

Placental passage

Pharmacokinetics Mother

Foetus

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Pharmacokinetics in pregnancy

Absorption Increased pH in the gastric ventricle

Decreased motility

Sparse data

Nothing to suggest changed absorption

in pregnancy

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Pharmacokinetics in pregnancy

Distribution

Increased plasma volume

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Pharmacokinetics in pregnancy

Distribution Increased plasma volume

Increased volume of interstitial fluid

Increased volume of distribution?

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Pharmacokinetics in pregnancy

Plasma protein binding Decreased concentration of plasma

proteins At term 70 80 % of nonpregnant values

Of importance for monitoring drugs wheretotal plasma concentration is measured

(phenytoin, valproate)

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Pharmacokinetics in pregnancy

Metabolism Cytochrome P450

CYP1, CYP2, CYP3 Uridine diphosphate

glucuronyltransferase

UGT

N-acetyltransferase

NAT

Pregnancy affects

these enzymes -differently

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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 specificeffects on tubular mechanisms

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Metabolism in the foetus

Hepatic metabolism underdeveloped

Beneficial, because a water solublemetabolite would have a slow / no diffusion

back to the mother

Epoxides

Placental diffusion back

Newborns also have a slow drugmetabolism

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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

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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)

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Milk-to-plasma drug concentration

ratio Varies over time

Therefore: time-averaged value

Distribution of milk-to-plasmaratios

25 %

15 %60 %

> 1

> 2

1 or less

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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

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

Relation between the Level of Exposure of an Infant to a Drug Excreted in Breast Milk and theRate 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

Reprinted from Ito and Koren, NEJM

2000, 343(2):118-126

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Drugs requiring careful assessment

of risks - cardiovascular Acebulol

Amiodarone Atenolol

Nadolol Sotalol

May accumulate in neonate because ofhigh milk-to-plasma ratio and slow

excretion

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Drugs considered to be safe

Propranolol

Labetolol