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Reproduction Pharmacology > Fetal & Neonatal Pharmacology > Flashcards

Fetal & Neonatal Pharmacology Flashcards

1
Q

Maternal therapeutics?

A

Exposure to maternal drugs may be a concern.

Overall use declining but remains a potential problem

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2
Q

Fetal therapeutics

A
  • 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
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3
Q

Nearly all drugs cross

A

The placenta

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4
Q

Drug short- or long-term effects on?

A

Fetus are possible.

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5
Q

Trans-placental drug passage main characteristics?

A
  • 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
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6
Q

Rationale for heparin use in pregnancy?

A

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

Heparin = Mol. mass 12000–15000 g/mol

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7
Q

Energy dependent drug transporter proteins?

A

P-gp, MRP, & BCRP

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8
Q

Placenta capable of drug?

A

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

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9
Q

Percentage of placental blood enters fetal liver

before circulating to remainder of fetus?

A

40-60%: Hepatic metabolism affects toxicity profile.

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10
Q

The Thalidomide “Disaster”

Original use?

A
  • 1950’s
  • Originally envisaged as OTC sedative
  • “Off label” use for morning sickness in pregnancy
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11
Q

The Thalidomide “Disaster”

Adverse Effects?

A
  • Late 1950’s – early 1960’s

* First reports of teratogenic effects

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12
Q

The Thalidomide “Disaster”

Animal model?

A

• Animal tests in mice/rats showed no problem but

tests in rabbits did – which to believe?

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13
Q

The Thalidomide “Disaster”

Adverse Effects?

A

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

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14
Q

Post-thalidomide

A

All new drugs tested for teratogenicity

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15
Q

Regulatory Standards Drugs?

A

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.

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16
Q

For a series of veterinary drugs rat

studies identified?

A

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

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17
Q

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

A

100% of these chemicals.

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18
Q

Relevance After decades of testing, thousands of

chemicals have been assessed for developmental toxicity?

A

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

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19
Q

MECHANISM Teratogenicity:

A 
Folate Antagonism
Endocrine Disruption: Sex Hormones
Neural Crest Cell Disruption
Vascular Disruption
Oxidative Stress
Specific Receptor- or Enzyme-mediated
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20
Q

Folate Antagonism

A

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

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21
Q

Endocrine Disruption: Sex Hormones

A

SEX HORMONE AGONISTS/ANTAGONISTS

ANDROGEN – ESTROGEN BALANCE

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22
Q

Neural Crest Cell Disruption

A

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

23
Q

Vascular Disruption

A

RENAL BLOODFLOW + DEVELOPMENT

CYCLOOXYGENASE INHIBITORS

24
Q

Oxidative Stress

A

ROS GENERATED BY FETAL METABOLISM (PG

SYNTHETASES + LIPOXYGENASES)

25
Q

Specific Receptor- or Enzyme-mediated

A 
CHOLESTEROL DEPLETION (MEMBRANES & SIGNALS)
SEROTONIN RECEPTORS & TRANSPORTERS
26
Q

Effect of Early SSRI Exposure

Pregnancy complications

A

Increase spontaneous abortion & risk of preeclampsia

27
Q

Effect of Early SSRI Exposure

Pregnancy outcome

A

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

28
Q

Effect of Early SSRI Exposure

Monoamines (MOAs)

A

decrease serotonin, NE, & metabolites

29
Q

Effect of Early SSRI Exposure

Congenital malformations

A

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

30
Q

Effect of Early SSRI Exposure

Persistent PAH

A

Increase Risk in infants

31
Q

Effect of Early SSRI Exposure

Neurodevelopmental defects

A

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

32
Q

FDA pregnancy categories A: Define

A

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.

33
Q

FDA pregnancy categories B: Define

A

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.

34
Q

FDA pregnancy categories C: Define

A

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.

35
Q

FDA pregnancy categories D: Define

A

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.

36
Q

FDA pregnancy categories X: Define

A

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.

37
Q

Pregnancy Exposure Registries Enroll women exposed to

A

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

38
Q

Pregnancy Exposure Registries UNLESS registry is large?

A

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

39
Q

Retrospective Cohort Studies can reveal?

A

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

40
Q

Retrospective Cohort Studies Disadvantages:

A
  • Recall bias – patient vs. medical record review

* Time elapsed between event and data collection

41
Q

Case-Control Studies offers ability to?

A

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

42
Q

Case-Control Studies Disadvantages:

A

– Recall bias – time bias

43
Q

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

A

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

44
Q

DEVELOPMENTAL PHARMACOKINETICS

Eight areas of differences?

A
  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
45
Q

Dose adjustment may be necessary in neonates due to?

A

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

46
Q

Pediatric Dosing Factors:

A
  • Drugs may not be labeled for pediatric use
  • Calculate based upon weight ratio to adult
  • More accurately based upon surface area
47
Q

The benefits of breastfeeding outweigh the?

A

Risk of exposure to most therapeutic agents via human milk.

48
Q

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

A

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

49
Q

Drugs in breast milk Factors:

A
  • 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
50
Q

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

A

Long-term effects of this exposure is unknown.

51
Q

Pediatricians should be extra vigilant in?

A

Monitoring infant growth & neurologic development.

52
Q

Paternal Teratogenicity can occur how?

A

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

53
Q

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

A

Paternally mediated toxicity

Reproduction Pharmacology (9 decks)

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