Pharmacokinetics
and dynamics in
pregnancy –
Placental barrier
Dr. Inunil Piyadigama
Consultat Obstetrician and Gynaecologist
Acting director
BH Kahawatta

Introduction
• Maternal physiology have evolved to favour the development and growth of the placenta and
the fetus
• Variations in physiology may alter the pharmacokinetics or pharmacodynamics that
determines drug dosing and effect
• Detailed pharmacologic information is required to adjust therapeutic treatment strategies
during pregnancy
• Understanding both pregnancy physiology and the gestation-specific pharmacology of
different agents is necessary to achieve effective treatment and limit maternal and fetal risk

Problems
• Most drug studies have excluded pregnant
women based on often-mistaken concerns
regarding fetal risk
• Over two-thirds of women receive
prescription drugs while pregnant
• Treatment and dosing strategies based on
data from healthy male volunteers with
little adjustment for the complex
physiology of pregnancy and its unique
disease states

Concepts of pharmacology
• Fundamental concept in pharmacology
• A drug must reach the target tissues at sufficient concentration to exert its
therapeutic effects
• This should not cause significant adverse events
• Pharmacokinetics (PK) describes the time course of drug concentration in the body
• This involves the evaluation of drug absorption, distribution, metabolism, elimination,
and transport

Drug absorption
• The movement of drug from the site of administration into the systemic circulation

Bioavailability
• Bioavailability, the fraction or percentage of active drug medication that reaches the
systemic circulation intact by any route
• IV drugs are 100% bioavailable
• Intramuscular and subcutaneous administration may lead to a delay in time to reach
maximal concentration but has less effect on bioavailability
• Increased local blood flow and vasodilation are thought to facilitate drug absorption
following intramuscular or subcutaneous drug delivery

Oral route
• The greatest variability in drug absorption is seen when a medication is
administered orally
• For orally administered medications, the bioavailability is affected by
• The amount absorbed across the intestinal epithelium
• First-pass metabolism as the drug crosses the intestine and the liver on
its way to the systemic circulation
• Stomach pH, food, gut transit time, gut metabolism, uptake, and efflux
transport processes may impact oral drug bioavailability

Pregnancy
changes
affecting drug
absorption
• Nausea and vomiting in early pregnancy
• Gastric acid production is decreased
• Mucus secretion is increased
• Overall leads to increase in gastric pH
• Reduce intestinal transit time
• Increased cardiac output and intestinal
blood flow may allow for increased drug
absorption overall

Pregnancy
effects on
drug
absorption

Drug distribution
• Reversible transfer of a drug between different locations following its entry into the systemic
circulation
• Drug distribution is influenced by various factors including
• Tissue perfusion
• Tissue binding
• Lipid solubility
• Plasma protein binding

Volume of
distribution
(Vd)
• Indicates how extensively a systemic dose of
medication is ultimately dispersed throughout
the body
• A theoretical volume that an administered drug
would occupy if it was uniformly distributed at a
concentration observed in plasma
• Vd is important to determine the loading dose of
a drug needed to achieve a certain therapeutic
concentration
• Variations in Vd mainly affect the plasma
concentration of the drug
• This can directly impact a drug’s therapeutic and
adverse effects

• Drugs that are highly bound to
plasma proteins and/or have a
large molecular weight will tend to
concentrate intravascularly and
will have a small Vd
• Drugs that predominantly remain
within the vascular system will
have a Vd estimate close to plasma
volume
• Drugs that are not bound to any
proteins in the body will have a Vd
estimate close to total body water
• Drugs that are highly bound to
tissues, with a small proportion
remaining in the intravascular
space, will have a very high Vd

Pregnancy and Vd
• Increase in cardiac output starting in early pregnancy, plateauing by 16 weeks of
gestation 7 L/min and remaining elevated until delivery
• Stroke volume starting at 20 weeks of gestation and a gradual increase occurs
with maternal heart rate reaching 90 beats per min at rest in the third trimester
• 42% increase in plasma volume, reaching over 3.5 L at 38 weeks of gestation
• increases in total body water and in all body fluid compartments
• Expanded extracellular volume and total body water will increase volume of
distribution for hydrophilic drugs, leading to lower plasma concentrations

• Maternal body fat expands by approximately 4 kg, increasing the volume of distribution for
lipophilic drugs
• Plasma protein binding of drugs decreases during pregnancy due to reduced concentrations of
both albumin and alpha 1-acid glycoprotein
• Albumin concentrations decrease on average by 1% at 8 weeks, 10% at 20 weeks, and 13% at 32
weeks
• Decreased protein binding leads to higher concentrations of free drug
• This favours more distribution to tissues
• Ex - Phenytoin and Tacrolimus, efficacy and toxicity are expected to be related to unbound drug
concentration in plasma

• Blood flow to the uterus increases 10-fold from 50 to 500 mL/min at term
• Small-molecular-weight and lipophilic drugs readily cross the placenta
• Fetus and the amniotic fluid can act as additional compartments, leading to
increased drug accumulation and an apparent increase in volume of
distribution of certain drugs

Drug metabolism
• Chemical modification of a drug through specialized enzymatic systems
• Inactive pro-drugs, metabolism is necessary to convert the drug into an
active compound
• For most drugs, metabolism leads to loss of drug activity
• Liver accounts for the metabolism of a vast majority of drugs
• Intestine and the placenta can also contribute to the clearance of certain
drugs

Clearance
• Clearance is the volume of blood/plasma that is completely cleared off
the drug in a unit of time
• Determines drug exposure as measured by the area under the plasma
concentration vs time curve and a body’s overall ability to eliminate a
drug

• The clearance of a drug in the liver is determined by hepatic blood flow and the
extraction ratio of the drug in the liver
• The extraction ratio (ER) refers to the proportion of a drug taken up from the hepatic
arterial circulation into hepatocytes, making it available for subsequent metabolism.
• For high ER drugs (e.g., morphine and propranolol), overall hepatic elimination is limited
only by hepatic perfusion (blood flow).
• In contrast, hepatic clearance of low ER drugs (e.g., diazepam, fluoxetine, or caffeine) is
limited by intrinsic metabolic capacity of hepatic cells and the unbound fraction of the
drug in plasma, and it would be changed little by changes in hepatic perfusion

Hepatic drug metabolism
• Phase I (oxidation, reduction, or hydrolysis) reactions that introduce
more polar or reactive moieties into drug molecules
• Carried out by the cytochrome P450 (CYP) family of enzymes
• CYP3A4 (50–100%), CYP2A6 (54%), CYP2D6 (50%), and CYP2C9
(20%) are all increased during pregnancy
• Leads to lower levels of Nifedipine, Indinavir, Glyburide
• CYP1A2 and CYP2C19 appear to undergo a gradual decrease in
activity with advancing gestation
• Phase II (conjugation) reactions to glucuronic acid, sulfate, or other
moieties that favour excretion into urine or bile
• Uridine 5’-diphosphate glucuronosyltransferases (UGTs), is also
altered during pregnancy, with a 200% increase in UGT1A4 activity
during the first and second trimesters and a 300% increase during
the third trimester
• Lamotrigine levels are significantly reduced

Variations in metabolism
• Metabolic enzyme activity is highly variable, affected by
• Ethnicity
• Gender
• Age
• enzyme polymorphisms
• Certain enzymes are involved in the metabolism of numerous drugs and create a potential for co-administered
medications to impact drug clearance
• PK of nifedipine, used for tocolysis, noted differences in drug clearance due to genetic variability in a specific allele of the
CYP3A5 coding gene
• 17-hydroxyprogesterone caproate (17-OHPC) (a drug used to prevent preterm delivery) modestly increased the activity of
CYP2C19.
• It follows that dosage of CYP2C19 substrates, for example, tricyclic antidepressants, proton pump inhibitors, and
propranolol, may have to be increased

Summary of
metabolism
For drugs with a narrow therapeutic
window, an increased clearance
during pregnancy can lead to sub-
therapeutic concentrations and
worsening disease control
Conversely, to avoid increased
toxicity, drug doses may need to be
adjusted in the postpartum period,
when pregnancy-related metabolic
enzyme activity changes resolve

Drug elimination
• Renal drug excretion depends on GFR, tubular secretion, and reabsorption
• GFR is 50% higher by the first trimester and continues to increase until the last week of pregnancy
• If a drug is solely excreted by glomerular filtration, its renal clearance is expected to parallel changes in GFR during pregnancy.
• For example, cefazolin and clindamycin exhibit increased renal elimination during pregnancy
• Differences in renal tubular transport (secretion or reabsorption) can result in differing effects on renally cleared drugs
• clearance of lithium is doubled during the third trimester compared to preconception
• digoxin, which is 80% renally-cleared, is merely 20–30% higher during the third trimester compared to postpartum
• clearance of atenolol is only 12% higher across pregnancy

Drug transport
• Transporters in hepatic sinusoids determine drug uptake into hepatocytes where they
may undergo biotransformation
• Transporters in biliary canaliculi govern secretion into bile
• Transporters on both the apical and the basolateral surfaces of renal epithelial cells
govern tubular secretion and reabsorption
• Drug transporter distribution, substrate specificity, and activities are important
determinants governing
• Drug absorption
• Drug excretion
• The extent of drug entry into target organs

Placenta
• Fetal development is dependent
upon the transport of nutrients by
the placenta toward the fetal side
and that of products of fetal
metabolism for elimination by the
mother
• Placenta produces and secretes
hormones that affect the maternal
physiology and endocrine state
• Transfers immunoglobulins
providing immunity to the fetus

• late 1950s and early 1960s, the devastating series of thalidomide-induced birth defects
raised awareness of the imperfect state of the placenta as a barrier to drug transfer
• There has also been increasing interest in the deliberate use of maternally administered
drugs designed to cross the placenta and provide therapeutic effects on the fetus.

Placental structure
At term, the placenta weighs almost 500 g
Has a diameter of 15–20 cm
A thickness of 2–3 cm
A surface area of almost 15 m2
The basic structural unit of the placenta is the chorionic villus

Chorionic villus
• Transport role is mediated by the
syncytiotrophoblasts, the
functional cell of the placenta
• These cells have a polarized
plasma membrane consisting of a
brush border at the maternal side
and a border membrane on the
fetal side
• At term, only a single layer of
syncytiotropho- blast separates
maternal blood and fetal capillary
endothelium
• Most xenobiotics cross the
placental barrier by simple
diffusion

Placental blood flow
• The pressure is about 80 – 100 mm Hg in the uterine arteries, 70 mm Hg in the spiral arteries and
only 10 mm Hg within the intervillous space
• The umbilical arteries divide into chorionic arteries and end as capillaries within the villi
• Substances in the maternal blood pass from the intervillous space through the
syncytiotrophoblast, fetal connective tissue, and the endothelium of the fetal capillaries into the
fetal blood
• Maternal uterine blood flow at term is 600 ml min21, 80% of which passes to the placenta
• There is no autoregulation in the uteroplacental circulation
• Flow is directly related to the mean uterine perfusion pressure and inversely related to uterine
vascular resistance

Placental
drug
transfer
• Almost all drugs will eventually cross the placenta
to reach the fetus
• The effects of drugs on the fetus may be either
direct or may be mediated via the alteration of
uteroplacental blood flow.
• Three types of transfers occur

Placental
drug transfer
types
I. Complete transfer (type1drugs): for example,
thiopental Drugs
Rapidly cross the placenta with pharmacologically
significant concentrations equilibrating in maternal
and fetal blood
II. Exceeding transfer (type 2 drugs): for example,
ketamine
These drugs cross the placenta to reach greater
concentrations in fetal compared with maternal
blood.
III. Incomplete transfer (type 3 drugs): for example,
succinylcholine
These drugs are unable to cross the placenta
completely, resulting in higher concentrations in
maternal compared with fetal blood.

Factors
determining
placental
transfer
• Physical
Placental surface area
Placental thickness
pH of maternal and fetal blood Placental
metabolism
Uteroplacental blood flow
Presence of placental drug transporters
• Pharmacological
Molecular weight of drug
Lipid solubility
pKa
Protein binding
Concentration gradient across placenta

Mechanisms of drug
transfer across the placenta
• A – Simple diffusion
• B – Facilitated diffusion using a carrier
• C – Active transport using ATP
• D - Pinocytocis

Simple diffusion – Midazolam, paracetamol
• Transfer is either transcellularly through the syncytiotrophoblast layer or paracellularly
through water channels incorporated into the membrane
• Dependent on a concentration gradient
• In the normal placenta, the villous surface area and blood flow to the placenta increase
with gestation
• The placental membranes also thin out and the cytotrophoblast layer almost completely
disappears
• Dependent on the diffusion constant of the drug

Determinants of diffusion constant
• Molecular weight
• Most of the drugs used are < 500 Da
• Lipid solubility
• Degree of ionization
• Neuromuscular blocking agents are highly ionized and do not cross
• pH of maternal blood reduces in labour
• Protein binding
• Free fraction is able to transfer

Facilitated diffusion - cephalosporins and glucocorticoids
• Drugs structurally related to endogenous compounds are often trans- ported by
facilitated diffusion
• Energy input is not required since drug transfer occurs down a con- centration gradient
• Facilitated diffusion will be inhibited if the carrier molecules become saturated by both
drug and endogenous substrates

Active transport - norepinephrine and dopamine
• Active transport utilizes energy
• Transport substances against a concentration or electrochemical gradient
• Transport is carrier-mediated and saturable and there is competition between related
molecules

Placental
drug
transporters
• A number of placental drug transporters have been
identified
• The family of multi-drug resistance protein (MRPs)
• Phosphoglycoprotein (P-gp)
• Breast cancer resistance protein (BCRP)
• These are the most studied so far
• P-gp is expressed on the apical microvillous surface
• BCRP is mostly identified on the basolateral membrane
and fetal blood vessels
• P-gp include endogenous compounds such as cortisol,
aldosterone, and bilirubin as well as various drugs such as
antibiotics, antiretrovirals, and steroids
• Substrates of BCRP include antibiotics, antiretrovirals,
calcium channel blockers, estrogen, and porphyrins

Factors
affecting
placental
transporters
• Both oestrogen and progesterone appear to
increase expression of P-gp and BCRP in
trophoblast cell lines
• Hypoxia reduces expression
• Prolonged exposure to dexamethasone reduces
expression
• Inflammatory cytokines
• SSRI - Maternal SSRI use in the first and the third
trimesters has been linked to congenital
anomalies and neonatal complications,
respectively
• P-gp and BCRP expression was lower in placentas
from women with preeclampsia compared to
term placentas from uncomplicated pregnancies

Thank you

Which drugs can easily pass the placental barrier
a) Drugs having molecular weight less than 1000 Dalton
b) Moderate to high lipid solubility
c) Drugs having a molecular weight less than 1000 Dalton and
moderate to high lipid solubility, analgesics and antibiotics
d) Analgesics, antibiotics etc

All of the following drugs cross the placenta except
a) Phenytoin
b) Diazepam
c) Morphine
d) Heparin

Which of the normal physilogical changes in pregnancy is associated
with slower drug metabolism?
a) Delayed gastric emptying
b) Increased body fat volume
c) Increased cardiac output
d) Increased GFR
e) Increased third space volume

A 27 year old woman is treated for severe bronchiolitis at 38 weeks. Her
baby born at 41 weeks of gestation has neonatal haemolysis
Which drug taken by the mother for bronchitis is the cause of the baby’s
neonatal haemolysis?
a) Chloramphenicol
b) Co-trimoxazole
c) Doxycycline
d) Erythromycin
e) Streptomycin