PHARM-neonatal

Question 1

Why might you prescribe corticosteroids to a pregnant mother?

Answer 1

to stimulate lung maturation of fetus

Question 2

why would you prescribe digoxin or flecanide to a pregnant mother?

Answer 2

treat a fetal arrhythmia

Question 3

why would you give NSAIDs to a pregnant mother?

Answer 3

to close the ductus arteriosus

Question 4

why would you give anti-HIV drugs to a pregnant mother?

Answer 4

to prevent the fetus from getting HIV from mom

Question 5

Do most drugs cross the placenta?

Answer 5

YES

Question 6

what are the 2 factors that determine the effects of drug therapy on the fetus?

Answer 6

timing and duration of exposure

Question 7

what is the most common drug class taken during pregnancy?

Answer 7

antibiotics

Question 8

about what percentage of pregnant women have depression?

Answer 8

20%

Question 9

what percentage of pregnant women with depression take an antidepressant during the pregnancy?

Answer 9

~10%

Question 10

what are the PK properties that determine whether a drug will cross the placental barrier?

Answer 10

• lipid solubility
• degree of ionization at physiologic pH
• MW <600 traverse
• duration and timing of exposure (most important)
• maternal plasma protein drug binding
• placental development and blood flow
• energy dependent drug transporter proteins (P-gp, MRP, BCRP)

Question 11

drugs that have a molecular weight greater than _____________ do not pass the placental barrier?

Answer 11

1000 (rationale for heparin use in pregnancy)

Question 12

what are the 2 most important factors regarding trans-placental drug passage?

Answer 12

duration and timing (short term unlikely to have AE vs. chronic)

Question 13

what are the energy dependent drug transporter proteins that may affect trans-placental drug passage?

Answer 13

P-gp
MRP
BCRP

Question 14

what kind of changes to the energy dependent drug transporter proteins could influence the extent of fetal drug exposure?

Answer 14

polymorphisms

Question 15

what role does the placenta play in placental drug metabolism?

Answer 15

has limited drug metabolic activity

• aromatic oxidation (hydryoxylation, N-dealkylation, demethylation)
• can decrease fetal exposure, decrease toxicity
• can increase exposure to carcinogens (benzpyrene)

Question 16

placental drug metabolism can increase the exposure to which notable carcinogen?

Answer 16

benzpyrene

Question 17

what is phocomelia?

Answer 17

seal-limbs

Question 18

why wasnt the thalidomide disaster quickly resolved?

Answer 18

negative animal tests delayed drug withdrawal despite increasing evidence of human tragedy

Question 19

what is the name of the protein that thalidomide binds to?

Answer 19

cerebion

Question 20

how does thalidomide cause phocomelia?

Answer 20

prevents expression of critical genes involved in limb development

Question 21

what are two modern uses of thalidomide therapy?

Answer 21

leprosy and multiple myeloma

Question 22

if a drug is going to cause an adverse effect on the developing fetus the pregnant mother must take it on a _____________basis

Answer 22

chronic

Question 23

what are the 3 things that show that a particular drug is teratogenic?

Answer 23

• characteristic set of malformations
• exert effects at a particular stage of development
• show dose-dependent incidence

Question 24

why do many pregnant mothers expose their baby to potentially dangerous drugs?

Answer 24

about 50% of pregnancies are unplanned so the mom may be not even realize she is pregnant until about 2 weeks

Question 25

what are the 2 types of species that are used to evaluate teratogenic potential?

Answer 25

rodent (rats) and non-rodent (rabbits)

Question 26

what are the 6 mechanisms of teratogenicity?

Answer 26

1. folate antagonism 2. neural crest disruption 3. endocrine disruption 4. oxidative stress 5. vascular disruption 6. specific receptor or enzyme-mediated effects

Question 27

which drug causes a folate antagonism?

Answer 27

lamotrigene

Question 28

which drug causes depletion of Vit. B12; DHFR co-factor

Answer 28

cholestyramine

Question 29

which 2 drugs are folate antimetabolites?

Answer 29

valproic acid and MTX

Question 30

which 2 drugs cause interference with neural crest migration?

Answer 30

bosentan (pax3, cadhereins) | isotretinoin (RA & RX receptors)

Question 31

which 2 drugs are teratogenic by having effects on sex hormone agonists/antagonists (androgen-estrogen) balance?

Answer 31

DES | environmentals

Question 32

which drug is teratogenic by having effects on ROS generated by fetal metabolism (PG synthetases & lipoxygenases)

Answer 32

thalidomide

Question 33

which 2 drugs cause problems with placental obstruction & spasm leading to fetal hypoxia?

Answer 33

misoprostol | ergotamine

Question 34

which 2 classes of drugs cause problems in renal bloodflow & development?

Answer 34

ACEis & ARBs

Question 35

which class of drugs is teratogenic by causing cholesterol depletion?

Answer 35

statins

Question 36

are the COX inhibitors teratogens?

Answer 36

yes

Question 37

which 2 drugs have teratogenic effects by acting on serotonin receptors & transporters?

Answer 37

sumatriptan | fluoxetine

Question 38

Explain the effect of early SSRI exposure on congenital malformations?

Answer 38

- increase risk of anencephaly, craniosynostosis, omphalocele, septal defects - increase risk of cardiac abnormalities

Question 39

explain the effect of early SSRI exposure on persistent PAH?

Answer 39

increased risk in infants

Question 40

can depression in a pregnant mother cause AE in the fetus?

Answer 40

YES

Question 41

what are some of the pregnancy complications of early SSRI exposure?

Answer 41

increased spontaneous abortion, increased risk of preeclampsia

Question 42

what are the effects of early SSRI exposure on pregnancy outcome?

Answer 42

``` increase preterm birth decrease gestational length decreased birth weight increase small for gestational age (smaller babies earlier) ```

Question 43

explain the effect of monoamines w/ early SSRI exposure?

Answer 43

decrease serotonin decrease NE decrease metabolites

Question 44

explain the neuro-developmental defects related to early SSRI exposure?

Answer 44

- decreased response to acute pain - increased tremulousness (motor & psychomotor develop. changes) - increased risk of autism

Question 45

what are pregnancy exposure registries?

Answer 45

- enroll women exposed to drug before pregn. outcomes are known - collect outcome data on maternal fetal & infant health - may focus on 1 or several drugs in same class - may be sponsored by drug maker or academic centers - size and duration limited by study objectives - UNLESS the registry is large, these have limited ability to detect risk, esp. for rare malformations

Question 46

how are retrospective cohort studies used in discovering drug teratogens?

Answer 46

they can reveal an association b/w maternal exposure & pregnancy outcome, but CANNOT establish a causal relationship

Question 47

how are case-control studies used in discovery drug teratogens?

Answer 47

offers ability to detect a rare event - may be convincing enough to establish causality - begins w/ outcome of interest

Question 48

what is the point of the 2007 FDA amendments act?

Answer 48

requires post-marketing studies when there is question of safety or possibility of teratogen, or when additional data are needed for safe use of an approved drug.

Question 49

what are some of the results of the use of isotretinoin during pregnancy?

Answer 49

``` CNS malformations hydrocephalus skull & head abnormalities IQ <85 thymus deficiency ```

Question 50

what do we make women do if they want to take isotretinoin?

Answer 50

sign full informed consent before prescription - 2 neg. pregn. tests + monthly tests - abstain from sex or use 2 methods of BC - register w/ nationwide survey - avoid blood donation-sharing meds

Question 51

describe the GI PK differences in neonates

Answer 51

slower GI, but faster IM absorption

Question 52

describe the body water PK differences in neonates:

Answer 52

more body water than lipid in early life

Question 53

describe the protein binding PK differences in neonates

Answer 53

limited protein binding in infants

Question 54

describe the liver PK differences in neonates:

Answer 54

larger Liver/body wt ratio in infants

Question 55

describe the enzymes PK differences in neonates:

Answer 55

immature enzymes in neonates

Question 56

describe the brain/body wt ratio in neonates:

Answer 56

larger brain/body-wt ratio

Question 57

describe the BBB PK differences in neonates:

Answer 57

higher BBB permeability

Question 58

describe the renal function in neonates:

Answer 58

immature renal function

Question 59

how does the half life of drugs typically change in babies?

Answer 59

drugs have much longer half lives (dose adjustment may be needed to account for continual maturation of various neonatal systems)

Question 60

what is a more accurate way than body wt to calculate pediatric dosing?

Answer 60

surface area

Question 61

what do you need to think carefully consider if you are going to use certain agents in a breastfeeding mom?

Answer 61

individual risk/benefit ratio

Question 62

caution is advised for drugs and agents with unproven benefits, long half-lives (which may lead to accumulation) and what 3rd category?

Answer 62

drugs having known toxicity to the mother or infant

Question 63

describe the pH and fat content of breast milk?

Answer 63

pH~7 and high fat content - will concentrate bases - will concentrate lipid soluble drugs

Question 64

if you are prescribing a drug to a breastfeeding mother do you want it to have a long or a short half life?

Answer 64

short half life

Question 65

when would you tell the breastfeeding mother to take her dose?

Answer 65

after breastfeeding

Question 66

when do you want to be most cautious with treating a mom who is breastfeeding?

Answer 66

be most cautious in early post-partum | -as breast milk buds mature they let in fewer drugs through the breast milk

Question 67

if a mom is breastfeeding and taking chloral hydrate what is the effect on the baby?

Answer 67

drowsiness if fed at peak concentrations

Question 68

if a mom is breastfeeding and taking chloramphenicol what is the effect on the baby?

Answer 68

too low for grey baby syndrome | -bone marrow suppression, blood dyscrasias

Question 69

if a mom is breastfeeding and taking diazepam what is the effect on the baby?

Answer 69

sedation; accumulation in neonates

Question 70

if a mom is breastfeeding and taking heroin what is the effect on the baby?

Answer 70

can produce narcotic dependence

Question 71

if a mom is breastfeeding and taking iodine (labeled) what is the effect on the baby?

Answer 71

thyroid suppression

Question 72

should a breastfeeding mom take lithium?

Answer 72

avoid unless levels quantitated

Question 73

what happens to the baby if a breastfeeding mom is taking methadone and then stops?

Answer 73

the baby will have withdrawal

Question 74

if a mom is breastfeeding and taking PTU what is the effect on the baby?

Answer 74

thyroid suppressed

Question 75

what are the 3 main categories of drugs that have effects on babies of breastfeeding moms?

Answer 75

1. drugs acting on CNS (sedation or dependence) 2. drugs that suppress thyroid function 3. chloramphenicol (BMS, blood dyscrasias)

Question 76

what class of drugs should make pediatricians extra vigilant in monitoring infant growth and neurologic development?

Answer 76

psychoactive drugs (w/ infant serum concentrations exceeding 10% of mom's)

Question 77

explain how a drug can cause paternal teratogenicity?

Answer 77

drug could lead to: - mutation in DNA or altered gene expression - direct contact w/ fetus via seminal fluid

Question 78

what are some of the results of paternal teratogenicity?

Answer 78

early pregnancy loss, stillbirth, preterm delivery, growth restriction

Question 79

what are the 4 major categories of drugs that cause paternal teratogenicity?

Answer 79

1. antivirals 2. anticancer 3. mAbs 4. retinoids Also: androgen receptor antagonist, DMARD, & antiepileptic agent