Drugs and Pregnancy_Toxicology (Rowe 1)

Question 1

What are reproductive toxicity concerns (4)?

Answer 1

Fertility, Developmental Toxicity, Parturition (med taken in preg), Lactation

Question 2

What are the concerns with Developmental Toxicity (4)?

Answer 2

Growth alteration, structural anomalies, functional neurobehavioral disorders, death

Question 3

What is the chance of pregnancy anomaly regardless of med exposure?

Answer 3

3-5%

Question 4

What are the causes of structural anomalies (4)?

Answer 4

Genetic, Chromosomal, Multifactorial, Unknown

Question 5

What are the preventable causes of structural anomalies?

Answer 5

Drug induced or drug deficient

Question 6

What are the essential criteria to consider when thinking about drug toxicity (4)?

Answer 6

1) Exposure during critical period (if they miss the critical period it won’t effect development of that structure)
2) Specific defect or syndrome
3) Consistent finding in 2 or more epidemiolocal studies
Rare exposure associated with rare anomaly

Question 7

What is drug dose relationship?

Answer 7

At which dose does the drug cause harm in the critical period or in pregnancy

Question 8

Why is it hard to determine drug dose relationship (3) ?

Answer 8

Threshold (AKA NOEL - No Observed Effect Level) : often unknown

Rarely quantified in terms of weight, body surface area, concentration

Unable to determine incremental exposure vs. death (ex, as dose increases will severity of anomaly increase till death?)

Question 9

What should we consider with assessment of medication in pregnancy (4)?

Answer 9

1. Is there human pregnancy data available?
2. What about information for medications in the same class?
   – NSAIDs, ACEIs, SSRIs, Fluoroquinolones
3. Does the drug cross the placenta and reach the embryo or fetus?
4. What toxicity does it cause in animals? (this one is least relevant)

Question 10

What should you consider about whether a drug can cross the placenta (7)?

Answer 10

• Plasma concentration (systemic bioavailability)
• Molecular weight (< 600 Daltons)
• Plasma elimination half-life (↑ with time at maternal-fetal interface)
• Lipid solubility (cross membrane easier)
• Ionization at physiologic pH
• Plasma protein binding
• Placental metabolizing enzymes

Question 11

What should you consider with plasma [] w crossing the placenta?

Answer 11

If low systemic circulation unlikely that the drug will cross into the placenta

Question 12

What should you consider with molecular weight of drugs w crossing the placenta?

Answer 12

Less than 600 Daltons have trouble crossing the placenta (if they can cross the BBB they can usually cross placenta

Question 13

What should you consider with drug half life and crossing the placenta?

Answer 13

As the drug is in pregnant person’s plasma it creates a new EQ with placenta, therefore short half life less likely to cross placenta

Single dose or recurring dose

Question 14

What should you consider with drug lipid solubility and crossing placenta?

Answer 14

Increased lipid solubility increases chance of crossing placenta

Question 15

What should you consider with pKA/Ionization and crossing placenta?

Answer 15

pKA greater than 7.3-8 get a charge put on them when put in a slightly more acidic environment (ie. Milk compartments and placenta slightly more acidic)

So basic drugs can get charged and trapped in placenta/milk

Question 16

What should you consider with protein binding and crossing placenta?

Answer 16

More protein bound harder to get into placenta (bigger)

Question 17

What should you consider with metabolism and crossing placenta?

Answer 17

Some drugs are metabolized by enzymes in placenta, figuring out which ones

Question 18

What clinical factors should we consider w pregnancy and meds?

Answer 18

What would happen if medication was stopped or not prescribed?
* e.g. Sepsis, seizure, exacerbation of disease or complication of pregnancy

Timing in pregnancy?
Does medication affect Labour process or Neonate at birth

Question 19

Recognize 3 concerns with the use of FDA risk categories

Answer 19

1) Not an actual progression from A-X but uses that way
2) Did not consider timing, dose route, duration frequency
Does not consider incidence, severity, reversibility

Question 20

Drugs of concern in pregnancy?

Answer 20

○ ACE Inhibitors
■ Used for: hypertension, renal disease, diabetes
○ Antineoplastic agents
■ Used for: chemotherapy
○ Alcohol
■ Used for: pleasure
○ Substances (eg. cocaine)
■ Used for: pleasure
○ Thalidomide
■ Used for: cancer treatment
○ Antiepileptic Medications (eg. valproic acid, phenytoin, carbamazepine)
■ Used for: epilepsy
○ Antibiotics (eg. sulfamethoxazole/trimethoprim, tetracyclines, fluoroquinolones)
■ Used for: treating infections
○ Lithium
■ Used for: bipolar disorder
○ Misoprostol
■ Used for: preventing ulcers, inducing miscarriage
○ Fluconazole (dose dependent)
■ Used for: fungal/yeast infections
○ Statins
■ Used for: stroke, heart attack, diabetes
○ Warfarin
■ Used for: stroke, heart attack, deep vein thrombosis
○ NSAIDs
■ Used for: pain management