Drug distribution in pregnancy

Volume of distribution of drugs is increased by 5 litres at term. This affects predominantly water soluble (polar) molecules.

A fall in albumin concentration affects the binding of acidic drugs. Basic drugs predominantly bind to alpha-1-glycoprotein which falls to lesser extent and are therefore less affected. Most anaesthetic drugs are basic so are not affected, however fentanyl can bind to albumin so may have an exaggerated effect at term.

Plasma cholinesterase levels fall by 25% during pregnancy, though an increased volume of distribution balances this so the duration of action of drugs like suxamethonium is not really affected in vivo.

Drug distribution to the foetus

The placental membrane seperates foetal and maternal blood. This is phospholipid in nature, fused to form a single membrane. It is much less selective than the blood brain barrier, even molecules with only moderate lipid solubility can cross relatively easily.

Placental blood flow and free drug concentration in foetus affect the rate of transfer as governed by the Fick principle:

The rate of transfer of a gas through a sheet of tissue is proportional to the tissue area and the difference in gas partial pressures between the two sides, and inversely proportional to tissue thickness.

Vgas  alpha  frac{A}{T}  x  D  x  (P1-P2)

Where D is the diffusion constant (Graham’s law), stating that diffusion is proportional to solubility but inversely proportional to the square root of the molecular weight (or density).

D  alpha  frac{Solubility}{sqrt{MW}}

Ion trapping

The foetus has a lower pH than the mother due to increased pCO2 and immature kidneys not able to excrete organic acids as well as mature kidneys. These acids instead diffuse out via the placenta which is slower.

Basic drugs: [BH+] ⇐⇒[B] + [H+]

Foetal pH is lower, therefore more negative than the drugs pKa. Therefore more drug is ionised in the foetus and unable to diffuse back across the placenta.

e.g. Local anaesthetic toxicity, pethidine (metabolised to norpethidine by foetus which can be trapped).

Drugs at the time of birth

A newborn will commonly have anaesthetic drugs in it’s circulation.

Thiopentone crosses the placenta rapidly, peak umbilical artery levels occur within three minutes of maternal injection.

Non-depolarising muscle relaxants are large polar molecules that do not cross the placenta. However if the mother has suxamethonium apnoea, maternal levels will remain high and some transfer will occur – this is particularly a problem if the foetus has inherited the same enzyme deficiency.

Propofol is not licensed for use in late pregnancy, which is historically why thiopentone is used.

Foetal circulation

The foetal circulation is unique in the sense that less than 10% of cardiac output passes through the lungs. This is suited to life in utero because the foetus does not breathe, instead gets all it’s gas exchange via the placenta, however after birth this situation has to rapidly change to ensure survivial outside the womb.

Schematic

foetal circulation

Blood leaves the placenta via the umbilical vein with an oxygen saturation of around 80%. The ductus venosus shunts half of the blood across the liver directly into the inferior vena cava. The mixed venous blood oxygen saturation is around 65%. Two thirds of blood is shunted directly into the left atrium via the foramen ovale.

There is intense hypoxic pulmonary vasoconstriction, therefore the majority of the blood in the pulmonary artery flows through the ductus arteriosus into the aorta. Less than 10% of the cardiac output passes through the pulmonary circulation.

The umbilical arteries arise from the internal iliac arteries and pass to the placenta.

Birth

With the first breath a negative intrathoracic pressure of around -50cmH20 is generated, expanding the FRC and encouraging blood flow through the lungs. Ventilation of the alveoli reduces hypoxic pulmonary vasoconstriction and therefore reduces pulmonary vascular resistance. This reduces the amount of blood flowing across the ductus arteriosus and when the umbilical cord is clamped this raises the systemic vascular resistance and can reverse the flow of blood through the ductus.

Exposure to oxygenated blood and a drop in prostaglandin E2 causes closure of the ductus arteriosus in less than 24 hours.

Oxygen saturation at different points

Umbilical vein: 80%
IVC pre-ductus venosus: 25%
Mixed IVC: 65%
Aorta pre-ductus arteriosus: 60%
Descending aorta: 50%

Foetal haemoglobin

Contain two alpha and two gamma chains, the gamma chains do not bind to 2,3-diphosphoglycerate shifting the oxyhaemoglobin dissociation curve to the left. The P50 of foetal haemoglobin is 2.5kPa, compared to adult haemoglobin which is 3.5kPa. The Hb concentration is around 160g/l at birth.

A baby starts to synthesis haemoglobin A (adult haemoglobin: two alpha, two beta chains) a few weeks before birth and by the age of 2 years haemoglobin F is no longer present.