Changes in drug response in the foetus

This chapter answers parts from Section D(iii) of the 2017 CICM Primary Syllabus, which expects the exam candidate to "describe alterations to drug response due to physiological change, with particular reference to ... the foetus". It also refers to the very similar Section B(vi), where the trainees' objective is to understand "the fate of drugs in the body, including ...  how it is affected by extremes of age, obesity, pregnancy (including foetal) and disease (particularly critical illness)".  Even though this matter comes up twice in the syllabus, the examiners have clearly viewed it as unreasonably esoteric, as it has never appeared in the exam (which begs the question, why include it in the syllabus).

In summary:

When googling "pharmacology of the foetus", one result bubbles to the surface. For some reason the 1972 article by Palmisano & Polhill is seen as the most useful result for this search. One cannot acquire the full-text version legally, which is perhaps for the best (because the article is not particularly good). In general, most of the papers we see on this topic tend to be from the 1970s, with academic silence thereafter - so much so that later authors (eg. Giacoia et al, 2009) complain that "societal and ethical constraints against human fetal research" have put it  "largely beyond the reach of investigation". This latter reference is probably the largest easily accessible source for information about the pharmacokinetics and pharmacodynamics of the human foetus. With the exception of various rare sources, this remained the main source for most of the information offered in this summary.

Transfer of drugs to the foetus

Where one would normally begin a pharmacokinetics answer with the subheading "absorption", that feels artificial and wrong when discussing the foetus, which is generally not expected to absorb xenobiotics orally. Drug transfer from the external environment to the foetus must therefore occur through the mother in some way. Let us count the ways:

• Through the placenta 
• By diffusion from the amniotic fluid
• By ingestion of amniotic fluid by the foetus
• By direct injection into the foetus (eg. of corticosteroids)

The placental route is by far the most important. The best reference for this is probably the free article by Griffiths & Campbell (2014). In short, there are several possible mechanisms for placental drug transfer:

• Diffusion (midazolam, paracetamol)
• Facilitated diffusion (antibiotics, steroids)
• Active transport (catecholamines)
• Pinocytosis 

Simple diffusion is one of the methods by which drugs can cross through the placenta from the maternal circulation into the foetal circulation, encountering some familiar Fickian determinants for their rate of transfer:

• Surface area (for the placenta, that's about 12m²)
• Thickness of the membrane (essentially the thickness of a capillary wall)
• Lipid solubility of the drugs (lipid-soluble drugs cross the placenta more easily)
• Size of the molecule (anything larger than 1000 Da tends to diffuse more slowly; anything smaller than 500 Da crosses effortlessly)
• Ionisation (poorly ionised drugs cross readily; well-ionised drugs such as neuromscular junction blockers tend to stay in the maternal circulation)

Several other factors unrelated to brutally simple diffusion are also acting here:

• Drug delivery obviously depends considerably on uterine blood flow
• Some drugs get actively transported into the placenta and metabolised there
• Some drugs may be extracted by the placenta from the foetal circulation
• Some drugs may be transported actively into the foetal circulation

What is the clinically relevant upshot of all this? Well. Without going into deep pharmacokinetic theory, pragmatic categories can be drawn to include drugs which are routinely used in ICU. This way, you can describe three main categories:

• Type 1 drugs: rapidly cross the placenta and equilibrate with foetal blood, eg.thiopentone, benzodiazepines, neostigmine, atropine, all opioids and volatile anaesthetics.
• Type 2 drugs: Active transport or ion trapping phenomena concentrate these in the foetal circulation, i.e. foetal blood levels often exceed those of the mother. Examples include ketamine and local anaesthetics
• Type 3 drugs: By a variety of mechanisms, these drugs are concentrated in the mother, and have trouble crossing into the foetal circulation (eg. suxamethonium, rocuronium)

If one were going to treat this topic seriously, one would probably also have to mention that the amniotic fluid interfaces with the foetus, and therefore intra-amniotic injection is a theoretically possible route of administration which could bypass maternal metabolism. Water-soluble drugs would take a while to act (the foetus would literally have to drink some amniotic fluid for this to be effective) but fat-soluble drugs would absorb relatively well, in a manner analogous to transdermal patch delivery. Stabbing pregnant women in the abdomen with long needles has obviously been an unappealing prospect to most non-sociopaths, and therefore this route of administration remains largely unexplored.

Foetal drug distribution

Some mechanisms act to increase the amount of free drug available to the foetal drug targets:

• Delivery of drugs to the foetal brain is increased because of the increased proportion of cardiac output diverted to the brain.
• Free drug concentration is increased by decreased protein binding.
• There is less proportionally less body fat to act as a "drug sink" (up until the final stages of pregnancy)

Some mechanisms act to decrease the amount of available free drug:

• Volume of body water is greater  (94% of total body weight at 16 weeks)
• Less skeletal muscle, thus less tissue binding
• The amniotic fluid acts as a functional extension of the body water compartment, as excreted amniotic fluid is reingested (producing recirculation)

Foetal blood proteins are for some reason particularly inefficient at binding drugs. Ehrnebo et al (1971) found that foetal free phenytoin, ampicillin and phenobarbital levels were all much higher in the foetus than in the adult (a 50% difference in some cases).   The reasons for this are numerous: for example, the total plasma protein concentration is reduced, and foetal albumin is sufficiently structurally different.

Metabolism of drugs by the foetus

Foetal circulation is characterised by some significantly weird features which make the metabolism of drugs in the foetus substantially different from the adult. In summary:

• Transplacental drug delivery occurs via the umbilical vein, which mainly perfuses the liver, but 20-40% of this blood flow ends up getting shunted directly into the systemic circulation via the inferior vena cava, i.e. there is some inherent bypass of first-pass metabolism
• Hypoxia increases this shunt; therefore, under hypoxic conditions more unmetabolised drug is delivered to the foetus

However, peculiarities of blood flow notwithstanding, the foetus should have some relatively normal metabolic capabilities. Glycine conjugation and sulfate conjugation reactions ("Phase II") are relatively well-developed from an early foetal age. Phase I reactions are also relatively adult-lloking, and most CYP enzymes are already present in the foetal liver from the first trimester onwards.  From the adult range of metabolic  enzymes, there are some notable absences during foetal life, which can affect drug metabolism:

• CYP2C is absent (it metabolises diazepam)
• CYP1A2 is absent (it metabolises caffeine and theophylline)
• Plasma esterases are decreased significantly (thus, longer duration of local anaesthetic effect)
• Glucuronyl transferases have less than 20% of adult activity (thus, longer duration of opiates, lorazepam, and some non-steroidal drugs)

Elimination of drugs by the foetus

Drugs or their metabolites can exit the foetus by two main methods:

• Through the umbilical vessels, and back to the mother
• Through the foetal kidneys, and into the amniotic fluid

The latter method produces some recirculation. The foetus continuosly drinks its own amniotic fluid and some of the excreted drugs/metabolites are re-ingested. They are also frequently either not absorbed or rapidly re-excreted, because the pH of amniotic fluid is around 7.1 and these drugs end up ion-trapped in it by their changed solubility. Moreover, even if they aren't ion-trapped, for many substances (especially water-soluble ones) the rate of diffusion out of the amniotic fluid (through the uterine wall into the mother, or back through the foetal skin) is going to be very slow. As a result, under certain circumstances the amniotic fluid concentration of a drug may exceed the foetal or maternal plasma concentration. Giacoia et al (2009) report that this behaviour is characteristic of water-soluble antibiotics such as ampicillin, penicillin, kanamycin, gentamicin, sulfonamides, methicillin, and some of the cephalosporins.

Pharmacodynamics in the foetus

The foetus is an inconvenient drug target and giving the mother drugs to treat the foetus is a fairly uncommon thing to do, apart from the steroids used to hasten lung maturation. As the result, we have basically no idea as to the differences in drug response in the foetus, nor are we particularly interested in this question. Situations where drugs end up affecting the foetus and where we actually care about it are therefore limited to the following circumstances:

• Steroids for lung maturation
• Abortificants
• Teratogenic drugs
• Drugs which cause non-teratogenic foetal toxicity 

This requires us (unfortunately) to unpack the term "teratogenic" and to review its definition.  Part One authors give an excellent definition of a teratogenic agent as "a drug which adversely affects foetal development causing a permanent abnormality", but unfortunately those guys do not constitute a peer-reviewed published literature source and from the colleges' viewpoint their unsanctioned definition is a rogue and apocryphal one, the use of which may compromise exam performance.  As usual, officially published literature has nothing better:

"Teratogens are agents that affect normal development and can give rise to congenital birth defects" (Basel, 2018)

"Teratogens are chemical, physical, or biologic agents that are able to induce developmental abnormalities"
(Fenderson, 2009)

"A teratogen is an agent that can disturb the development of the embryo or fetus, resulting in spontaneous abortion, congenital malformations, intrauterine growth retardation, mental retardation, carcinogenesis, or mutagenesis"
(Weissman, 2009)

"A teratogen has been defined ... as a chemical that increases the occurrance of structural or functional abnormalities in offspring if administered to either parent before conception, to the female during pregnancy, or directly to the developing organism"
(Loomis & Hayes, 1996)

None of these are particularly good. When all is lost, one resorts to using the pragmatic definitions offered by the Australian TGA to describe drugs which should not be used in pregnancy:

"Category X: Drugs which have such a high risk of causing permanent damage to the fetus that they should not be used in pregnancy or when there is a possibility of pregnancy."

Or:

"Category D: Drugs which have caused, are suspected to have caused or may be expected to cause, an increased incidence of human fetal malformations or irreversible damage."

The main reason to discuss this in the pharmacodynamics section is the argument that teratogenic effects are adverse effects of the drug on the foetus, which add an additional consideration to the selection of drugs and doses in pregnancy.