Fetal & Neonatal Pharmacology

Question 1

Maternal therapeutics?

Answer 1

Exposure to maternal drugs may be a concern.

Overall use declining but remains a potential problem

Question 2

Fetal therapeutics

Answer 2

• Stimulation of lung maturation-corticosteroids
• Treatment of fetal arrhythmias-digoxin, flecainide
• Ductus arteriosus patency - NSAIDs promote closure
• Anti-HIV drugs used to prevent infection from mother

Question 3

Nearly all drugs cross

Answer 3

The placenta

Question 4

Drug short- or long-term effects on?

Answer 4

Fetus are possible.

Question 5

Trans-placental drug passage main characteristics?

Answer 5

• Lipid solubility
• Degree of ionization at physiologic pH
• Mol. Wt < 600 traverse, Mol. Wt > 1000 don’t
• Duration & timing of exposure-most important
• Maternal plasma protein drug binding
• Placental development and blood flow
• Energy dependent drug transporter proteins

Question 6

Rationale for heparin use in pregnancy?

Answer 6

Mol. Wt < 600 traverse, Mol. Wt > 1000 don’t

Heparin = Mol. mass 12000–15000 g/mol

Question 7

Energy dependent drug transporter proteins?

Answer 7

P-gp, MRP, & BCRP

Question 8

Placenta capable of drug?

Answer 8

Metabolism: Aromatic oxidation, Hydroxylation, N-dealkylation, demethylation. May decrease fetal exposure & toxicity, but can increase exposure to carcinogens (Benzpyrene).

Question 9

Percentage of placental blood enters fetal liver

before circulating to remainder of fetus?

Answer 9

40-60%: Hepatic metabolism affects toxicity profile.

Question 10

The Thalidomide “Disaster”

Original use?

Answer 10

• 1950’s
• Originally envisaged as OTC sedative
• “Off label” use for morning sickness in pregnancy

Question 11

The Thalidomide “Disaster”

Adverse Effects?

Answer 11

• Late 1950’s – early 1960’s

* First reports of teratogenic effects

Question 12

The Thalidomide “Disaster”

Animal model?

Answer 12

• Animal tests in mice/rats showed no problem but

tests in rabbits did – which to believe?

Question 13

The Thalidomide “Disaster”

Adverse Effects?

Answer 13

• Ultimately 10,000 people affected with phocomelia
• degenerative changes in aging population
• Negative animal tests delayed drug withdrawal
despite increasing evidence of human tragedy

Question 14

Post-thalidomide

Answer 14

All new drugs tested for teratogenicity

Question 15

Regulatory Standards Drugs?

Answer 15

Drugs and pesticides are evaluated in 2 species, one rodent and one non-rodent.
The vast majority of studies are conducted in rats and rabbits.

Question 16

For a series of veterinary drugs rat

studies identified?

Answer 16

Teratogenicity in 61% of chemicals that were teratogens in any species,

Question 17

A rat study and a rabbit study together identified teratogenicity in?

Answer 17

100% of these chemicals.

Question 18

Relevance After decades of testing, thousands of

chemicals have been assessed for developmental toxicity?

Answer 18

Fewer than 10% of these have been determined to be human developmental toxicants.”

Question 19

MECHANISM Teratogenicity:

Answer 19

Folate Antagonism
Endocrine Disruption: Sex Hormones
Neural Crest Cell Disruption
Vascular Disruption
Oxidative Stress
Specific Receptor- or Enzyme-mediated

Question 20

Folate Antagonism

Answer 20

FOLATE ANTAGONISM
DEPLETION OF VITAMIN B12; DHFR CO-FACTOR
FOLATE ANTIMETABOLITE

Question 21

Endocrine Disruption: Sex Hormones

Answer 21

SEX HORMONE AGONISTS/ANTAGONISTS

ANDROGEN – ESTROGEN BALANCE

Question 22

Neural Crest Cell Disruption

Answer 22

INTERFERENCE WITH NEURAL CREST MIGRATION
Pax3, CADHERINS
RETINOIC ACID (RA) & RETINOID X (RX) RECEPTORS

Question 23

Vascular Disruption

Answer 23

RENAL BLOODFLOW + DEVELOPMENT

CYCLOOXYGENASE INHIBITORS

Question 24

Oxidative Stress

Answer 24

ROS GENERATED BY FETAL METABOLISM (PG

SYNTHETASES + LIPOXYGENASES)

Question 25

Specific Receptor- or Enzyme-mediated

Answer 25

``` CHOLESTEROL DEPLETION (MEMBRANES & SIGNALS) SEROTONIN RECEPTORS & TRANSPORTERS ```

Question 26

Effect of Early SSRI Exposure | Pregnancy complications

Answer 26

Increase spontaneous abortion & risk of preeclampsia

Question 27

Effect of Early SSRI Exposure | Pregnancy outcome

Answer 27

Increase preterm birth, decrease gestational length, decrease birth weight, & increase small for gestational age

Question 28

Effect of Early SSRI Exposure | Monoamines (MOAs)

Answer 28

decrease serotonin, NE, & metabolites

Question 29

Effect of Early SSRI Exposure | Congenital malformations

Answer 29

Increase Risk of anencephaly, craniosynostosis, omphalocele, septal defects Increase cardiac abnormalitites

Question 30

Effect of Early SSRI Exposure | Persistent PAH

Answer 30

Increase Risk in infants

Question 31

Effect of Early SSRI Exposure | Neurodevelopmental defects

Answer 31

Decrease Response to acute pain Increase tremulousness; motor & psychomotor developmental changes Increase risk of autism

Question 32

FDA pregnancy categories A: Define

Answer 32

Adequate studies in pregnant women have not demonstrated a risk to the fetus during the 1st trimester of pregnancy and there is no evidence of risk in 2nd or 3rd.

Question 33

FDA pregnancy categories B: Define

Answer 33

Animal studies have not demonstrated a risk to the fetus but there are no adequate studies in pregnant women; or, animal studies have shown an adverse effect but adequate studies in pregnant women have not demonstrated a risk to the fetus during the 1st trimester of pregnancy, and there is no evidence of risk in 2nd or 3rd.

Question 34

FDA pregnancy categories C: Define

Answer 34

Animal studies have shown an adverse effect on the fetus, but there are no adequate studies in humans; or there are no animal reproduction studies and no adequate studies in humans.

Question 35

FDA pregnancy categories D: Define

Answer 35

There is evidence of human fetal risk, but the potential benefits from the use of the drug in pregnant women may be acceptable despite its potential risks.

Question 36

FDA pregnancy categories X: Define

Answer 36

Studies in animals or humans demonstrate fetal abnormalities or adverse reaction; reports indicate evidence of fetal risk. Risk of use in a pregnant woman clearly outweighs any possible benefit.

Question 37

Pregnancy Exposure Registries Enroll women exposed to

Answer 37

Drug before pregnancy outcomes are known. Collect outcome data on maternal fetal and infant health.

Question 38

Pregnancy Exposure Registries UNLESS registry is large?

Answer 38

Registries have limited ability to detect increased risk, especially for rare malformations.

Question 39

Retrospective Cohort Studies can reveal?

Answer 39

Potential associations between maternal exposure and pregnancy outcome but cannot themselves establish a causal relationship.

Question 40

Retrospective Cohort Studies Disadvantages:

Answer 40

* Recall bias – patient vs. medical record review | * Time elapsed between event and data collection

Question 41

Case-Control Studies offers ability to?

Answer 41

Detect for a rare event. May be convincing enough evidence to establish causality.

Question 42

Case-Control Studies Disadvantages:

Answer 42

– Recall bias – time bias

Question 43

2007 FDA Amendments Act gave the FDA the authority to require?

Answer 43

Post-Marketing Requirement (PMR) that requires a pregnancy exposure registry, clinical lactation study, and/or pharmacokinetic studies in pregnant women.

Question 44

DEVELOPMENTAL PHARMACOKINETICS | Eight areas of differences?

Answer 44

1. SLOWER GI, BUT FASTER IM ABSORPTION 2. MORE BODY H2O THAN LIPID IN EARLY LIFE 3. LIMITED PROTEIN BINDING IN INFANTS 4. LARGER LIVER/BODY WT. RATIO IN INFANTS 5. IMMATURE ENZYMES IN NEONATES 6. LARGER BRAIN/BODY WT. RATIO 7. HIGHER BBB PERMEABILITY 8. IMMATURE RENAL FUNCTION

Question 45

Dose adjustment may be necessary in neonates due to?

Answer 45

An ongoing basis to account for the continual maturation of the various neonatal systems.

Question 46

Pediatric Dosing Factors:

Answer 46

* Drugs may not be labeled for pediatric use * Calculate based upon weight ratio to adult * More accurately based upon surface area

Question 47

The benefits of breastfeeding outweigh the?

Answer 47

Risk of exposure to most therapeutic agents via human milk.

Question 48

Although most drugs and therapeutic agents do not pose a risk to the mother or nursing infant?

Answer 48

Careful consideration of the individual risk/benefit ratio is necessary for certain agents, particularly those that are concentrated in human milk.

Question 49

Drugs in breast milk Factors:

Answer 49

* Neonate consumes 1L milk per day * Milk: acidic ~pH 7 vs. blood (7.4), + high fat content will concentrate bases & lipid soluble drugs * Lower transfer of highly protein bound drugs * Drugs with short half-life preferred * Dose after feeding - allows for levels to decline * Most cautious in early post-partum

Question 50

Psychoactive drugs with infant serum concentrations exceeding 10% of maternal plasma concentrations?

Answer 50

Long-term effects of this exposure is unknown.

Question 51

Pediatricians should be extra vigilant in?

Answer 51

Monitoring infant growth & neurologic development.

Question 52

Paternal Teratogenicity can occur how?

Answer 52

Germ cells become functional spermatogonia in 64 days. Drug or toxicant exposure could lead to: – Mutation in the DNA or altered gene expression – Direct contact with fetus via seminal fluid

Question 53

Pregnancy outcomes data for environmental exposure to heavy metals, solvents, pesticides, anesthetic gases, or hydrocarbons supports the concept of?

Answer 53

Paternally mediated toxicity