Module 21

Question 1

How does the placenta compare with the blood brain barrier with respect to acting as a barrier to the passage of drugs?

Answer 1

• Many drugs do not reach therapeutic concentrations in the brain because of the blood brain barrier, which is composed of tight junctions that prevent drugs from passing between cells rather than going through cell membranes, and many transporters that pump drugs out of the brain.
  
  • In contrast, there are no tight junctions in the placenta, and although there are transporters, they are very different from those in the BBB and do not keep most drugs from reaching the fetus. To a first approximation you have to assume that, with the exception of very highly charged drugs such as heparin, the fetus is exposed to anything that is in the mother’s blood

Question 2

Can biological drugs such as infliximab cross the placenta?

Answer 2

• Yes, It is important to protect the newborn from infections, and one protection that has evolved is a transporter that transports antibodies from the mother to the fetus. This transporter also transports drugs that are antibodies such as infliximab.

Question 3

How would protein binding and volume of distribution of a drug in the mother affect exposure of the fetus?

Answer 3

• In general it has little effect. Although it would not apply to drugs with a very short half-life, when the mother takes a drug that reaches steady state in her blood, the free drug will also reach steady state in the fetus.
  In general the drug will also be protein bound and have a large volume of distribution in the fetus. Protein binding and large volume of distribution may slow down the process, but essentially there is 9 months to reach steady state in the fetus

Question 4

In general, how does the concentration of a drug in a nursing baby compare with the concentration of the same drug in the mother? Are protein binding and volume of distribution important factors?

Answer 4

• Unlike exposure of the fetus to drugs that the mother takes in which there is basically an equilibrium between the mother and fetus, there is no such equilibrium between a nursing baby and the mothers blood – it is a one way street.
  
  • In this case protein binding and a high volume of distribution do significantly decrease drug exposure of the nursing baby. Even if there is low protein binding and a low volume of distribution, and assuming that the concentration of the drug is the same in the mother’s milk as in her blood, the concentration in a nursing baby will be approximately 10% that in the mother.
  • However, there are factors that can change this ratio. For example, milk is slightly acidic relative to blood; therefore, basic drugs will have somewhat higher concentrations in milk than blood because of ion trapping.
    ○ And even if the concentration of drug in the milk is the same as that in the mother, if the drug is not cleared as rapidly in the baby it can accumulate. There is one case in which a baby died because the mother was taking codeine. She happened to be an ultra rapid metabolizer, and so most of the codeine was converted to morphine. Glucuronidation is impaired in the newborn, and so after several days the morphine accumulated to a lethal concentration in the baby.

Question 5

What issues should be considered when a pregnant or nursing mother is being treated with a psychotropic drug (especially antidepressant, antipsychotic)?

Answer 5

The long-term effects of CNS drugs on the fetus are unknown. The exposure of a nursing baby is less, and therefore the risk is lower, although most CNS drugs are basic amines and are subject to ion trapping.
However, decisions should be made on a risk vs benefit evaluation

Question 6

What issues should be considered when a pregnant or nursing mother is diabetic? Does insulin cross the placenta?

Answer 6

• There are two types of patients: a woman who has type I diabetes before pregnancy, and the other is a woman who develops gestational diabetes.
  
  • Treating a pregnant woman who has type I diabetes is a delicate balance. Uncontrolled hyperglycemia is not good for the mother or the fetus. Early in the pregnancy the fetus cannot synthesize glucose and is very susceptible to hypoglycemia. However, insulin does not significantly cross the placenta; therefore, direct effects of insulin on the fetus is not an issue. Obviously insulin requirements change during pregnancy, which further complicates the situation.
  • The other scenario is gestational diabetes, i.e. when a woman develops diabetes during pregnancy, which is basically type II diabetes. The oral drugs for type II diabetes cross the placenta, and therefore there is a reluctance to treat pregnant women with the usual drugs used to treat type II diabetes, and insulin is recommended. However, insulin can cause hypoglycemia, which can cause severe damage to the fetus, and metformin does not cause hypoglycemia. There are studies that suggest that women who are treated with metformin on average have a better outcome than those treated with insulin. Insulin is definitely a challenge if the woman is not reliable.

Question 7

What metabolic enzymes are deficient in the newborn, and give examples of substrates that are affected?

Answer 7

• Glucuronidation and amino acid (glycine) conjugation metabolic activity are very low in the newborn.
  ○ Glucuronidation is obvious because glucuronidation is the mode of clearance of bilirubin, and newborns, especially premature babies are often jaundiced.
  
  • Another classic example is chloramphenicol, which in newborns causes “grey baby syndrome”, a toxic reaction to the drug caused by impaired clearance.
    I gave the example in PHM144 of amino acid conjugation deficiency resulting in metabolic acidosis when sterile water containing benzyl alcohol was used to administer medications to premature babies. The benzyl alcohol was oxidized to benzoic acid, but the babies could not clear the benzoic acid, which in adults is conjugated with glycine to form hippuric acid. Acetaminophen should also be avoided because glucuronidation is a major mode of clearance.