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.

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