Use Of Pharmaceuticals In Pregnancy

Question 1

General Pharmacologic Considerations in Pregnancy (Pregnant patient vs. Fetus)

Answer 1

Pregnancy patients must be considered as TWO patients

Pregnancy patient:

1. Treatment of chronic diseases generally continues during pregnancy
2. New conditions may emerge that require pharmacotherapy
3. Physiologic changes can influence drug pharmacokinetics

Fetus:

1. The placental barrier is SEMIPERMEABLE
2. Fetal therapeutics
3. Teratogenic concerns

• In general, lowest effective doses and monotherapies (if effective) are most desirable. If non-pharmacologic management is applicable, use it!

Question 2

Conditions that should be treated throughout pregnancy include: (7)

Answer 2

1. Allergic Rhinitis and Asthma
2. Diabetes
3. Epilepsy
4. HIV infection
5. Hypertension
6. Mental Health Conditions (i.e., psychosis)
7. Thyroid Disorders

Question 3

Pregnancy may influence development of existing or new chronic conditions (5)

Answer 3

1. GI conditions: Constipation, hemorrhoids, GERD, etc.
2. Gestational diabetes mellitus
3. HTN disorders of pregnancy: HDPs complicate ~10% of pregnancies (preeclampsia-eclampsia, chronic HTN, chronic HTN with superimposed preeclampsia, gestational HTN)
4. Thyroid abnormalities
5. Thromboembolism (DVT)

Question 4

Common acute conditions during pregnancy (3)

Answer 4

1. Headache (tension and migraine)
   - Primary headaches treated with NSAIDs or non-pharmacologic methods
   - Secondary headaches may be indicative of underlying pathology (DVT, eclampsia, stroke, etc.)
2. Urinary Tract Infections
   - Treatment is essential for prevention of pyelonephritis
3. Sexually transmitted infections (preexisting or newly acquired)
   - Treatment is essential to prevent transmission to fetus
   - E.g., congenital syphilis (treat with penicillin!)

Question 5

Physiologic changes during pregnancy can influence pharmacotherapy (2)

Answer 5

Physiologic changes begin in the 1st trimester and peak during the 2nd trimester.

1. Factors that increase by 30-50%:
   - Maternal plasma volume (will dilute drug concentration)
   - Cardiac output
   - Glomerular Filtration (drug is eliminated faster if renallly excreted)
2. Physiologic changes during pregnancy may necessitate the use of other therapies:
   - Increased cardiac workload/heart failure may require cardiac glycosides and diuretics
   - Pregnancy-induced diabetes may require insulin

Question 6

Absorptive changes in pregnancy (2)

Answer 6

1. Decreased absorption of drugs: Nausea/vomiting, delayed gastric emptying
2. Increased gastric pH may affect absorption of weak acids/bases (stomach pH less acidic!)

Question 7

Distributive changes in pregnancy (2)

Answer 7

1. Body fat increases: fat-soluble drugs may have greater volume of distribution (Vd) —> lower plasma concentrations
2. Protein binding decreases: decreases serum albumin results in increased free drug concentration, HOWEVER, the free drug is more readily metabolized and/or filtered, so there is NO DISCERNIBLE EFFECT on plasma drug concentrations

Question 8

Metabolic changes in pregnancy (1)

Answer 8

1. Elevated hormone levels may influence liver enzyme activity
   - Estrogen, progesterone rise
   - Elimination of some drugs increased
   - Elimination of some drugs decreased

Question 9

The placenta is a semipermeable barrier, BUT…

Answer 9

Transplacental drug transfer can still occur!

Question 10

The placental barrier creates a new pharmacokinetic compartment (3)

Answer 10

1. Drugs can move from the maternal circulation to the fetal circulation by DIFFUSION
2. Drug factors AFFECTING transplacental diffusion:
   - Lipid solubility
   - Molecular weight
   - Electrical charge
   - Degree of protein binding
3. Stage of the placenta may determine permeability

Question 11

Factors AFFECTING transplacental drug transfer: (5)

Answer 11

1. Lipid solubility: Fat-soluble opioids and antibiotics easily diffuse
2. Molecular weight: MW < 500 Da readily cross, MW = 600-1000 cross slowly, MW > 1000 rarely accumulate (Heparin, insulin do not cross in detectable amounts!)
3. Electrical charge: Fetal pH is slightly lower (more acidic) than maternal pH. Weak bases diffuse across placenta, ionize, and become trapped/accumulate.
4. Degree of protein binding: Maternal plasma albumin progressively DECREASES, while fetal plasma albumin progressively INCREASES —> some protein-bound drugs can accumulate in fetal plasma.
5. Protein transporters: P-glycoprotein (P-gp) transporters pump drugs back into the maternal circulation

Question 12

Placental and fetal drug metabolism (2)

Answer 12

1. Placental metabolism vs. biotransformation: Biotransformation of ethanol may increase or augment toxicity
2. Drugs enter the fetal circulation via the umbilical vein: ~40–60% of umbilical venous blood flow enters fetal liver. Remainder enters general fetal circulation. Active metabolites of some drugs may affect the fetus adversely.

Question 13

Fetal therapeutics (3)

Answer 13

1. Emerging area in perinatal pharmacology to target the fetus
2. Case studies only, controlled studies not conducted yet: corticosteroids to stimulate fetal lung maturation when preterm birth is expected; antiarrhythmic drugs given to mothers can treat of fetal cardiac arrhythmias
3. Maternal use of HIV drugs (zidovudine) decreases transmission of HIV from the mother to the fetus, but *combinations of three antiretroviral agents can eliminate fetal infection almost entirely!

Question 14

Teratogens definition (2)

Answer 14

1. Teratogenic effects can include:
   - Major malformations
   - Intrauterine growth restriction (cigarette smoke)
   - Stillbirth (cigarette smoke)
   - Miscarriage (alcohol)
   - Neurocognitive delay (alcohol, valproic acid)
2. To be considered teratogenic, a substance or process must:
   - Result in a characteristic SET of MALFORMATIONS
   - Exert its effects at a particular STAGE of fetal development
   - Show a DOSE-DEPENDENT incidence

Question 15

Example Teratogen: Alcohol and Fetal Alcohol Syndrome (3)

Answer 15

1. Chronic exposure to ethanol may result in fetal alcohol spectrum disorders
2. Predictable set of abnormalities that occurs in a time- and dose-dependent manner
3. Severity of fetal alcohol syndrome depends on degree and duration of ethanol exposure, particularly during the first and second trimesters

Question 16

Teratogenic mechanisms (5)

Answer 16

1. Direct effect on maternal tissues: Secondary or indirect effects on fetal tissues
2. Interference with passage of oxygen or nutrients through the placenta (cigarette smoke)
3. Direct actions on the processes of differentiation in developing tissues: Many Vitamin A analogs (isotretinoin, etretinate) may alter the normal processes of differentiation
4. Deficiency of a critical substance: e.g., antiepileptic medications may cause folic acid deficiency and neural tube defects
5. Mechanisms are likely multifactorial

Question 17

Developmental time and duration of exposure can influence type and severity of effects (2)

Answer 17

1. Continued exposure to a teratogen may produce CUMULATIVE effects
   - Several organs going through varying stages of development may be affected by chronic exposure
2. A SINGLE intrauterine exposure to a drug can affect the fetal structures undergoing rapid development at the time of exposure
   - THALIDOMIDE-induced PHOCOMELIA (malformation of limbs): Only requires a brief exposure during the 4TH - 7TH weeks of gestation
   - Thalidomide was used as an ANTIEMETIC to reduce symptoms of morning sickness

Question 18

Assessing drug safety during pregnancy is based upon the quality of the evidence (3)

Answer 18

1. Types of Evidence:
   - Randomized, controlled trials (most desirable but uncommon)
   - Animal studies
   - Case reports
   - Case-control studies
   - Prospective cohort studies
   - Historical cohort studies
   - Voluntary reporting systems
2. The FDA developed risk categories to guide clinicians regarding medication risk during pregnancy
   - A = considered safe during pregnancy
   - X = considered teratogenic (causes KNOWN birth defects!)
   - To rank Category A, a controlled trial is required to establish safety
3. New labeling requirements include pregnancy and lactation subsections

Question 19

Preconception planning (2)

Answer 19

1. Many pregnancies are unplanned: some behaviors and exposures impart risk before pregnancy is detected
2. Preconception care can reduce risk of birth defects: modification of behavioral, biomedical, and social risks during entire reproductive age

Question 21

Drugs use during lactations (4)

Answer 21

1. Most drugs administered to lactating women are detectable in breast milk: Low concentration of drugs in breast milk result in a total amount SUBSTANTIALLY LOWER than a therapeutic dose
2. Patients taking required and safe medications can breastfeed: Advise to take medication 30–60 minutes after nursing and 3–4 hours before next feeding
3. Many patients avoid breast-feeding due to misperception of risk: Formula feeding is associated with higher infant morbidity and mortality in all socioeconomic groups
4. EXCEPTIONS:
   - TETRACYCLINE (abx) concentrations in breast milk reach ~70% of maternal serum concentrations: Risk of permanent tooth staining and bone growth problems in the infant
   - ISONIAZID (Tx for TB) rapidly reaches equilibrium between breast milk and maternal blood: pyridoxine supplements should be administered to mother to avoid deficiency in infant