Fetal & Neonatal Pharmacology Flashcards
Maternal therapeutics?
Exposure to maternal drugs may be a concern.
Overall use declining but remains a potential problem
Fetal therapeutics
- 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
Nearly all drugs cross
The placenta
Drug short- or long-term effects on?
Fetus are possible.
Trans-placental drug passage main characteristics?
- 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
Rationale for heparin use in pregnancy?
Mol. Wt < 600 traverse, Mol. Wt > 1000 don’t
Heparin = Mol. mass 12000–15000 g/mol
Energy dependent drug transporter proteins?
P-gp, MRP, & BCRP
Placenta capable of drug?
Metabolism: Aromatic oxidation, Hydroxylation, N-dealkylation, demethylation. May decrease fetal exposure & toxicity, but can increase exposure to carcinogens (Benzpyrene).
Percentage of placental blood enters fetal liver
before circulating to remainder of fetus?
40-60%: Hepatic metabolism affects toxicity profile.
The Thalidomide “Disaster”
Original use?
- 1950’s
- Originally envisaged as OTC sedative
- “Off label” use for morning sickness in pregnancy
The Thalidomide “Disaster”
Adverse Effects?
- Late 1950’s – early 1960’s
* First reports of teratogenic effects
The Thalidomide “Disaster”
Animal model?
• Animal tests in mice/rats showed no problem but
tests in rabbits did – which to believe?
The Thalidomide “Disaster”
Adverse Effects?
• Ultimately 10,000 people affected with phocomelia
• degenerative changes in aging population
• Negative animal tests delayed drug withdrawal
despite increasing evidence of human tragedy
Post-thalidomide
All new drugs tested for teratogenicity
Regulatory Standards Drugs?
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.
For a series of veterinary drugs rat
studies identified?
Teratogenicity in 61% of chemicals that were teratogens in any species,
A rat study and a rabbit study together identified teratogenicity in?
100% of these chemicals.
Relevance After decades of testing, thousands of
chemicals have been assessed for developmental toxicity?
Fewer than 10% of these have been determined to be human developmental toxicants.”
MECHANISM Teratogenicity:
Folate Antagonism Endocrine Disruption: Sex Hormones Neural Crest Cell Disruption Vascular Disruption Oxidative Stress Specific Receptor- or Enzyme-mediated
Folate Antagonism
FOLATE ANTAGONISM
DEPLETION OF VITAMIN B12; DHFR CO-FACTOR
FOLATE ANTIMETABOLITE
Endocrine Disruption: Sex Hormones
SEX HORMONE AGONISTS/ANTAGONISTS
ANDROGEN – ESTROGEN BALANCE
Neural Crest Cell Disruption
INTERFERENCE WITH NEURAL CREST MIGRATION
Pax3, CADHERINS
RETINOIC ACID (RA) & RETINOID X (RX) RECEPTORS
Vascular Disruption
RENAL BLOODFLOW + DEVELOPMENT
CYCLOOXYGENASE INHIBITORS
Oxidative Stress
ROS GENERATED BY FETAL METABOLISM (PG
SYNTHETASES + LIPOXYGENASES)
Specific Receptor- or Enzyme-mediated
CHOLESTEROL DEPLETION (MEMBRANES & SIGNALS) SEROTONIN RECEPTORS & TRANSPORTERS
Effect of Early SSRI Exposure
Pregnancy complications
Increase spontaneous abortion & risk of preeclampsia
Effect of Early SSRI Exposure
Pregnancy outcome
Increase preterm birth, decrease gestational length, decrease birth weight, & increase small for gestational age
Effect of Early SSRI Exposure
Monoamines (MOAs)
decrease serotonin, NE, & metabolites
Effect of Early SSRI Exposure
Congenital malformations
Increase Risk of anencephaly, craniosynostosis,
omphalocele, septal defects
Increase cardiac abnormalitites
Effect of Early SSRI Exposure
Persistent PAH
Increase Risk in infants
Effect of Early SSRI Exposure
Neurodevelopmental defects
Decrease Response to acute pain
Increase tremulousness; motor & psychomotor
developmental changes
Increase risk of autism
FDA pregnancy categories A: Define
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.
FDA pregnancy categories B: Define
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.
FDA pregnancy categories C: Define
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.
FDA pregnancy categories D: Define
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.
FDA pregnancy categories X: Define
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.
Pregnancy Exposure Registries Enroll women exposed to
Drug before pregnancy outcomes are known. Collect outcome data on maternal fetal and infant health.
Pregnancy Exposure Registries UNLESS registry is large?
Registries have limited ability to detect increased risk, especially for rare malformations.
Retrospective Cohort Studies can reveal?
Potential associations between maternal exposure and pregnancy outcome but cannot themselves establish a causal relationship.
Retrospective Cohort Studies Disadvantages:
- Recall bias – patient vs. medical record review
* Time elapsed between event and data collection
Case-Control Studies offers ability to?
Detect for a rare event. May be convincing enough evidence to establish causality.
Case-Control Studies Disadvantages:
– Recall bias – time bias
2007 FDA Amendments Act gave the FDA the authority to require?
Post-Marketing Requirement (PMR) that requires a pregnancy exposure registry, clinical lactation study, and/or pharmacokinetic studies in pregnant women.
DEVELOPMENTAL PHARMACOKINETICS
Eight areas of differences?
- SLOWER GI, BUT FASTER IM ABSORPTION
- MORE BODY H2O THAN LIPID IN EARLY LIFE
- LIMITED PROTEIN BINDING IN INFANTS
- LARGER LIVER/BODY WT. RATIO IN INFANTS
- IMMATURE ENZYMES IN NEONATES
- LARGER BRAIN/BODY WT. RATIO
- HIGHER BBB PERMEABILITY
- IMMATURE RENAL FUNCTION
Dose adjustment may be necessary in neonates due to?
An ongoing basis to account for the continual maturation of the various neonatal systems.
Pediatric Dosing Factors:
- Drugs may not be labeled for pediatric use
- Calculate based upon weight ratio to adult
- More accurately based upon surface area
The benefits of breastfeeding outweigh the?
Risk of exposure to most therapeutic agents via human milk.
Although most drugs and therapeutic agents do not pose a risk to the mother or nursing infant?
Careful consideration of the individual risk/benefit ratio is necessary for certain agents, particularly those that are concentrated in human milk.
Drugs in breast milk Factors:
- 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
Psychoactive drugs with infant serum concentrations exceeding 10% of maternal plasma concentrations?
Long-term effects of this exposure is unknown.
Pediatricians should be extra vigilant in?
Monitoring infant growth & neurologic development.
Paternal Teratogenicity can occur how?
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
Pregnancy outcomes data for environmental exposure to heavy metals, solvents, pesticides, anesthetic gases, or hydrocarbons supports the concept of?
Paternally mediated toxicity
