Perinatal Pharmacology

Question 1

Function of the placenta

Answer 1

Creates a complex filter that has its own physiologic and metabolic properties, and places fetal and maternal circulations next to each other to allow transport, diffusion, etc without mixing the blood.

Question 2

Number of unbilical arteries and veins

Answer 2

Two arteries - O2 poor

One vein - O2 rich

Question 3

The six major factors that affect placental drug transfer and drug effects on the fetus

Answer 3

1. Chemical properties of the drug
2. The rate at which a drug crosses the placenta which yields the amount of the drug reaching the fetus
3. The duration of exposure to drug
4. Distribution characteristics in different fetal tissue
5. The stage of placental and fetal development at the time of exposure to the drug
6. The effects of drugs used in combination

Question 4

_____ drugs diffuse readily across the placenta and into the fetal circulation.

Answer 4

Lipophillic

Question 5

What kinds of drugs (pH wise) get stuck in fetal compartment and why

Answer 5

There is also an important difference in the pH of maternal blood versus fetal blood. Maternal blood has a pH of 7.4, and fetal blood has a pH of 7.3, thus basic drugs with a pKa above 7.4 will be more ionized in the fetal compartment, leading to ion trapping and hence to higher fetal levels. So, although ionized drugs have a more difficult time making it to the fetus, some of the ionized drugs that are able to make it to the fetus at low levels, may get trapped there and cause some damage.

Question 6

Main factor in protein binding

Answer 6

The degree of affinity with which the drug finds to the maternal proteins versus the fetal proteins

Question 7

What size drugs cross the placenta

Answer 7

Smaller molecules cross the placenta more readily. Drugs of molecular weight of 250 to 500 cross the placenta easily depending upon their lipids solubility and degree of ionization, those with molecular weight to 500 to 1,000 have more difficulty, and those greater than 1000 cross very poorly.

Question 8

Impact of drug transporters in placenta

Answer 8

These transporters can carry larger molecules to the fetus. This is a mechanism by which maternal antibodies can enter the fetal circulation, for example as in Rh incompatibility. Some drugs that successfully reach the fetus are also rapidly removed from the fetal circulation by the placental transporters and pumped back to the mother, notably viral protease inhibitors.

Question 9

Role of fetal circulation on drug diffusion

Answer 9

About 50% of umbilical venous blood flow enters the fetal liver, the remainder bypasses the liver and enters the general fetal circulation. So, about 50% of any drug that makes it through the placenta goes directly to fetal tissue beds without giving the fetal liver the opportunity to metabolize the drug.

In addition, blood returning from the fetus to the placenta via the umbilical artery can get shunted directly back to the fetus again by the placenta, creating a cyclic effect.

Question 10

Examples of treatment given to mother for fetus

Answer 10

The most common example is the use of systemic corticosteroids in pregnant women who are in preterm labor. The steroids are used to stimulate fetal lung maturation when labor happens earlier in pregnancy than full lung maturation.

Antiarrhythmic drugs have also been given to mothers to treat fetal cardiac arrhythmias.

And, of course, pregnant mothers with HIV are prescribed zidovudine to take systemically, which decreases by two thirds the risk of transmitting HIV to their fetus. In addition, the use of combination antiretroviral therapy can eliminate the risk of fetal infection almost entirely.

Question 11

Definition of toxic to fetus

Answer 11

• it creates symptoms in the baby after birth that must be managed and require additional intervention and care as the drug dependence lessens, BUT
• it does not (to current knowledge) permanently alter organ formation or function as a teratogen would.

Question 12

The baseline risk of a structural or functional neonatal abnormality in pregnancy without taking in any known teratogens is about ___

Answer 12

3%

Question 13

Most critical time for development when major structural anomalies can occur

Answer 13

3rd to 7th week

Question 14

MOA of vitamin A teratogen

Answer 14

Vitamin A analogues like isotretinoin or Retin-A are powerful teratogens that appear to alter the normal processes of differentiation and the fetus and in fetal tissue.

Question 15

MOA of antiseizure drug teratogenicity

Answer 15

Low levels of folic acid – neural tube defects

Give very high doses to avoid

Question 16

Features of fetal alcohol syndrome

Answer 16

Question 17

Category A drugs and examples

Answer 17

Adequate and well-controlled studies have failed to demonstrate a risk to the fetus in the first trimester of pregnancy (and there is no evidence of risk in later trimesters).

Example drugs or substances: levothyroxine, folic acid, liothyronine

Question 18

Category B drugs and examples

Answer 18

Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women.

Example drugs: metformin, hydrochlorothiazide, cyclobenzaprine, amoxicillin, pantoprazole

Question 19

Category C drugs and examples

Answer 19

Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

Example drugs: tramadol, gabapentin, amlodipine, trazodone

Question 20

Category D drugs and examples

Answer 20

There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

Example drugs: lisinopril, alprazolam, losartan, clonazepam, lorazepam

Question 21

Category X drugs and examples

Answer 21

Studies in animals or humans have demonstrated fetal abnormalities and/or there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience, and the risks involved in use of the drug in pregnant women clearly outweigh potential benefits.

Example drugs: atorvastatin, simvastatin, warfarin, methotrexate, finasteride