Pharmacokinetics of Pregnancy and Placental Transfer

Pharmacokinetic Changes in Pregnancy

changes in gastric motility, acidity, active transport Þ changes in maternal absorption of nutrients and drugs

increases in ECF, fat mass, plasma volume, addition of fetus Þ change volume of distribution (V_D)

changes in flow patterns (i.e Ý renal and placental flow) Þ changes in T_1/2 and clearance; potential fetal drug exposure

increased albumin and other binding proteins Þ change bioavailability, T_1/2, etc.

Þ conclusion: interpretation of lab results, drug prescriptions/dosing, etc are different for pregnant women

Placental Development

hemochorioendothelial placenta – fairly unique to humans; few models exist for study

fetal in origin (allows for genetic sampling without fetal damage)

chorionic villi develop with implantation and invade decidua; initially, villi are present on the entire surface which is surrounded by decidua. Within 4 weeks the embryo grows out into the uterine space surrounded by the decidua capsularis, chorion, and amnion.

on week 8 the chorionic villi on the decidua capsularis degenerate; only villi in the decidua basilis (decidua at site of implantation) remain.

on week 20 the decidua capsularis degenerates completely, leaving only 2 layers: the chorion lavae (smooth, avascular, outside layer) and the amnion (the inner layer of this balloon which has paracrine function)

as the fetus grows, the chorion lavae balloons out, pressing against the decidua parietalis (decidua lining the side of the uterus opposing site of implantation)

placental exchange is basically a lake of maternal blood bathing chorionic villi (simplified = cross-current exchanger)

villi continue to grow and branch during gestation such that exchange is 6-10x better in late gestation

Mechanisms of Transfer

barriers to passage – cellular layer of syncytiotrophoblast cells associated with basement membrane, villous stroma and associated basement membrane, capillary endothelium

mechanisms – same as that seen in other cells of the body

diffusion – depends on conc. gradient, persfusion, surface area, thickness of barrier, size, charge, protein binding of substrate; increases with lipid solubility, decreases with ionization and increasing size

most effective at MW < 500 D Þ O₂, CO₂, Ig, water, electolytes, anesthetics

facilitated diffusion – like diffusion but carrier mediated, so it is saturable and can be competitively inhibited

also may be unidirectional; sequestration allows a gradient to be built up

active transport – same as other tissues; allows for fetal sequestration even in maternal deficiency

pores for rapid water transfer and endocytosis for large proteins have been proposed, but are unproven

Þ consequences: fetal exposure to lipid soluble, low MW drugs is dependant mostly on timing, dose, and route of maternal administration; dosage must be adjusted to avoid fetal toxicity while maintaining maternal effectiveness

maternal perfusion considerations: during uterine contraction, venous blood is cut off and arterial bloodflow is reduced

fetal blood flow: 40% to placenta, 35% to fetus (5% to each of CNS, heart, GI; 2% to kidneys, liver, spleen; 4% to lung)

Membranes – the amnion/chorion/decidua barrier provides a three-layer membrane separating mother and fetus

substances from amnionic fluid can be transferred to the mother (may have role in initiation of labor) and vice-versa
provides a mechanical barrier to the fetus against infection and physical trauma
controls uterine/amnionic fluid volume homeostasis: 6-10x total volume is exchanged every day
may mediate maternal acceptance of the fetal allograft (protection from immune response)

Direct Placental Events – breaks can occur which lead to fetal-maternal blood exchange

13% of Rh^- mothers become sensitized to their Rh⁺fetuses
10% of mothers have fetal RBC’s in their circulation, and fetal karytypes have been isolated from mothers (possible fetus-safe method of genotyping?)
maternal cells have been found in fetuses

Transport Specifics

Oxygen: oxygen transfer to the fetus is improved by several factors

fetal side: fetal Hb is more concentrated and has higher oxygen affinity; Ý fetal pHÞ Ý offloading of maternal O₂ (Bohr effect)

maternal side: mother makes more 2,3-BPG Þ right shift in Hb affinity curve (less affinity)

Glucose: facilitated diffusion via GLUT 1 and 3; concentration gradient is main control; insulin independent (insulin doesn’t even cross the placenta); maternal insulin resistance allows her to maintain blood glucose levels; maternal hyperglycemia leads to fetal insulin synthesis and fat deposition

Other nutrients: simple diffusion (glycerol, FFA, amino acids); facilitated diffusion (glucose, lactate); active transport (Fe, Ca, P, I, heavy metals, essential amino acids, ascorbic acid); LDL via receptor mediated endocytosis

Other Stuff:

IgG is transferred via receptor-mediated pathway Þ passive immunity to fetus; IgM, IgA are from fetal production

anything in the amnion after 11 wks can be directly ingested: albumin, EGF, PTH-related peptide, drugs, etc.

unable to cross: heparin, most hormones (insulin, PTH, thyroxine, etc.), neutral fatty acids

infection first hits the placenta, then the fetus by direct invasion; malignancy can invade (i.e. melanoma)

heat is transferred down the gradient from fetus to mother (fetal temperature is always higher; Ý if blood flow ß )