vagina in girls in their late teens whose mothers had been
givendiethylstilbestrolduring the pregnancy. Exposure
tostilbestrolin utero has also been associated with a
T-shaped uterus and other structural abnormalities of the
genital tract, and increased rates of ectopic pregnancy and
premature labour.ABSORPTIONGastric emptying and small intestinal motility are reduced. This
is of little consequence unless rapid drug action is required.
Vomiting associated with pregnancy may make oral drug
administration impractical.DISTRIBUTIONDuring pregnancy, the blood volume increases by one-third,
with expansion in plasma volume (from 2.5 to 4 L at term) being
disproportionate to expansion in red cell mass, so that haemat-
ocrit falls. There is also an increase in body water due to a larger
extravascular volume and changes in the uterus and breasts.
Oedema, which at least one-third of women experience
during pregnancy, may add up to 8 L to the volume of extra-
cellular water. For water-soluble drugs (which usually have a
relatively small volume of distribution), this increases the
apparent volume of distribution and, although clearance is
unaltered, their half-life is prolonged. During pregnancy, the
plasma protein concentration falls and there is increased com-
petition for binding sites due to competition by endogenous
ligands, such as increased hormone levels. These factors alter
the total amount of bound drug and the apparent volume of
distribution. However, the concentration of free drug usually
remains unaltered, because a greater volume of distribution of
free drug is accompanied by increased clearance of free drug.
Thus, in practice, these changes are rarely of pharmacological
significance. They may cause confusion in monitoring of
plasma drug levels, since this usually measures total (rather
than free) drug concentrations.METABOLISMMetabolism of drugs by the pregnant liver is increased, largely
due to enzyme induction, perhaps by raised hormone levels.
Liver blood flow does not change. This may lead to an increased
rate of elimination of those drugs (e.g. theophylline), for
which enzyme activity rather than liver blood flow is the main
determinant of elimination rate.RENAL EXCRETIONExcretion of drugs via the kidney increases because renal plasma
flow almost doubles and the glomerular filtration rate increases
by two-thirds during pregnancy. This has been documented for
digoxin,lithium,ampicillin,cefalexinandgentamicin.PHARMACOKINETICS INPREGNANCY 47Key points- The background incidence of serious congenital
abnormality recognized at birth is 2–3%. - Environmental and genetic factors can influence a
drug’s effect. - Maternal disease can affect the fetus.
- Studies of large doses in pregnant animals are of
doubtful relevance. - Effects may be delayed (e.g. diethylstilbestrol).
- Meticulous data collection is required for drugs
administered during pregnancy and outcome, including
long-term follow up. At present the Medicines and
Healthcare products Regulatory Agency (MHRA) requests
records of all drugs administered to a mother who
bears an abnormal fetus. More complete (but with
inherent practical difficulties) data collection by the
MHRA, the National Teratology Information Services,
the pharmaceutical industry and drug information
agencies on all prescriptions during pregnancy with
long-term follow up of offspring is required.
PHARMACOKINETICS IN PREGNANCY
Known differences in drug effects in pregnancy are usually
explained by altered pharmacokinetics (Figure 9.2).
DrugAbsorption↓Metabolism↑↑Renal Excretion↑
blood flowCYP450
inductionPlasma drug
concentration
↑ ↔ or↓↑Volume of distribution
↓Plasma albumin↑Vomiting
↓Gastric emptying
↓Small intestinal motilityFigure 9.2:Pharmacokinetic changes in pregnancy.
Key points
Known differences in drug effects can usually be explained
by altered pharmacokinetics. Increased volume of
distribution, hepatic metabolism and renal excretion all
tend to reduce drug concentration. Decreased plasma
albumin levels increase the ratio of free drug in plasma.