PHARM: Fetal-Neonatal Pharmacology

Question 1

What is the most commonly used drug class in pregnant women?

Answer 1

antibiotics

Question 2

What are the two most important factors in the transmission of a teratogen across the placenta?

Answer 2

duration (chronic use) and timing (early in pregnancy is worse for organ malformations)

Question 3

What is the absolute size restriction for drugs passing through the placenta?

Answer 3

molecular weight >1000

Question 4

True or False: The placenta has the capacity to conduct metabolic processes?

Answer 4

TRUE: (ex. aromatic oxidation—hydroxylation, N-dealkylation, demethylation) can convert drug materials passing from maternal to fetal tissue (may reduce OR increase toxicity).

Question 5

What is the major concern of energy dependent drug transporter proteins (can push drug against its concentration gradient) in the placenta?

Answer 5

polymorphisms that make them overactive

Question 6

True or False: the liver of the fetus is too immature to take part in maternal drug metabolism.

Answer 6

FALSE: fetus can also alter the toxicity profile!

Question 7

Why is drug binding important in pregnant women?

Answer 7

Limited plasma protein binding of drugs in the neonate is important clinically, because free drug can disperse better and is more quickly metabolized.
• Neonate has worse plasma protein binding (need to crank dose down)

Question 8

What drugs lead to folate antagonism?

Answer 8

Lamotrigene, cholestyramine, valproic acid

Question 9

How do Lamotrigene, cholestyramine, and valproic acid lead to teratogenicity?

Answer 9

Interference with folate causes interruption of RNA, DNA, and protein synthesis

Question 10

What drugs lead to neural crest disruption?

Answer 10

Bosentan

Isotretinoin

Question 11

How do Bosentan and Isotretinoin lead to teratogenicitiy?

Answer 11

Nuclear receptor target (Pax 3, RAR, RXR, cadherin) disruption can lead to down regulation of critical genes during neural crest embryologic development

Question 12

What drugs lead to fetal endocrine disruption?

Answer 12

DES, environmentals

Question 13

How do DES and environmentals casue teratogenicity?

Answer 13

If an organ is hormonally dependent, drugs that are hormonal agonists or antagonists can disrupt development

Question 14

What drugs lead to oxidative stress in fetuses?

Answer 14

Thalidomide (not in EVERY neonate exposed, only in the 14 day period when limbs form)

Question 15

How did thalidomide cause teratogenicity?

Answer 15

Prostaglandins and lipoxygenases are stimulated by teratogens and can lead to ROS that cause cellular dysfunction

Question 16

What drugs lead to vascular disruption in fetuses?

Answer 16

Misoprostol and ergotamine

Question 17

How do misoprostol and ergotamine cause teratogenicity?

Answer 17

interrupt adequate oxygenation of developing fetus though production of placental obstruction or spasm can lead to fetal hypoxia/damage

Question 18

What effects do ACEIs and ARBs have on the fetus?

Answer 18

Functional impairment of kidney

Question 19

What effects do SSRIs (ex. sumatriptan, fluoxetine) have on the fetus?

Answer 19

SSRIs act in unknown mechanism to cause congenital malformations, PAH, physical and developmental adversities (need to ask if depression is also playing a role in these).

Question 20

What effects do statins have on the fetus?

Answer 20

decrease availability of cholesterol for membrane structure and function in the fetus

Question 21

What effects do NSAIDs have on the fetus?

Answer 21

produce dysfunction by decreasing COX products in the cell (can lead to failure of DA closure if given in utero)

Question 22

What effects does warfarin have on the fetus?

Answer 22

Early, can cause fetal bleeding. Later it can cause other problems (scarring of organs).

Question 23

What may occur in newly delivered infants who have been acutely withdrawn from continued trans-placental drug transfer?

Answer 23

physical dependence manifests as withdrawal

Question 24

What are the most common symptoms of drug withdrawal in infants?

Answer 24

autonomic hyperactivity with irritability, excessive crying, poor feeding and abnormal reflexes

Question 25

What factors alter the onset of withdrawal symptoms in the infant?

Answer 25

drug type how much of the drug has accumulated in the CNS relative rate of release from tissue (rate of decline)

Question 26

How might you reduce the duration of adverse withdrawal symptoms?

Answer 26

re-exposing neonate to lower drug doses and tapering them down.

Question 27

What are the major receptor locations of opiates?

Answer 27

CNS depressant and GI (constipation

Question 28

What are CNS symptoms of opiate withdrawal?

Answer 28

``` CNS hyperactivity (ex. tremors, seizures, increased wakefulness, high-pitched cry, frequent yawning/sneezing, etc.) associated autonomic hyperactivity (ex. sweating, fever, nasal stuffiness) ```

Question 29

What are the GI symptoms of opiate withdrawal?

Answer 29

diarrhea, dehydration, vomiting, poor weight gain

Question 30

True or false: all drugs are tested for teratogenicity in at least 4 species.

Answer 30

FALSE: in two (rodent and non-rodent)

Question 31

What must a drug show to be classified as a teratogen?

Answer 31

1) must have characteristic set of malformations 2) must exert effects at a particular stage of fetal development 3) must show dose-dependent incidence

Question 32

Name the category of teratogenicity: Animal studies have shown adverse effects on fetus but there are no adequate studies in humans OR no adequate animal or human studies

Answer 32

C

Question 33

Name the category of teratogenicity: Studies in animals of humans demonstrate fetal abnormalities or adverse reaction—reports indicate evidence of fetal risk. Risk of use in pregnant woman clearly outweighs any possible benefit

Answer 33

X

Question 34

Name the category of teratogenicity: Animal studies have not demonstrated risk to fetus but no adequate studies in pregnant women OR animal studies show adverse effect but no risk to fetus during human studies

Answer 34

B

Question 35

Name the category of teratogenicity: | Studies have not demonstrated risk to fetus in first trimester; no evidence for later effects.

Answer 35

A

Question 36

Name the category of teratogenicity: Evidence of human fetal risk. Physician may encounter situations in which a drug of this category might be necessary during pregnancy if no alternative agent is available. Under these circumstances a careful analysis of the drugs known adverse effects, the patient's clinical condition, and significantly, the stage of pregnancy, should all be considered when making a decision as to whether or not a drug should be used.

Answer 36

D

Question 37

When does paternal teratogenicity occur?

Answer 37

Major toxicant exposure during spermatogenesis can lead to mutation in DNA or altered gene expression and toxic exposure of developing fetus to seminal fluid can also occur.

Question 38

Name the 3 "weird" drugs that lead to male teratogenicity.

Answer 38

enzalutamide leflunomide (DMARD) pregabalin (antiepileptic)

Question 39

What drugs are better dispersed in new-borns: lipophillic or hydrophillic agents?

Answer 39

little body fat for lipophilic drugs and a higher percentage of total body water and extracellular water for districution of hydrophilic agents

Question 40

Why do newborns have a significant increases in free drug fraction?

Answer 40

a reduced capacity for plasma protein binding by drugs in the neonate

Question 41

What is the problem with subcutaneous treatment of newborns?

Answer 41

good skin perfusion but immature regulation of vascular perfusion so subcutaneous administration may be absorbed in an erratic manner

Question 42

How do you best dose pediatric patients?

Answer 42

Pediatric dosing is most accurately based upon surface area, but you can calculate based upon (adult dose X (weight in kg/70).

Question 43

What drugs are best transmitted by breast milk? Why?

Answer 43

acidic with high fat content—so breast milk will concentrate basic drugs and lipid soluble drugs

Question 44

What drugs are not transmitted well by breast milk?

Answer 44

drugs that are highly protein bound

Question 45

What is preferred in pregnant patients: drugs with long or short half-lives? Why?

Answer 45

drugs with shorter half-lives are preferred so that you can dose the patient after they breast-feed their neonate so that the levels can decline before the next feeding

Question 46

What are the changes in the content of breast milk early v. later in the day? What implications does this have for maternal therapy?

Answer 46

higher fat in morning (so take water-soluble drugs in the morning), lower fat in afternoon

Question 47

What drug can RARELY can kill a baby by causing respiratory arrest if transported through the breastmilk ?

Answer 47

Codeine

Question 48

Are monoclonal antibodies a risk in infants?

Answer 48

contraversial, IgA is the major antibody absorbed from breast milk for the development of passive immunity as a means of early protection before developing a fully responsive immune system, but IgG antibodies can also be transported (FcRn)

Question 49

What adverse effects does chloral hydrate cause in the infant?

Answer 49

drowsiness if fed at peak concentrations

Question 50

What adverse effects does chloramphenicol cause in the infant?

Answer 50

too low for Grey baby syndrome; bone marrow suppression

Question 51

What adverse effects does diazepam cause in the infant?

Answer 51

sedation and accumulation in neonates

Question 52

What adverse effects does heroin cause in the infant?

Answer 52

narcotic dependence

Question 53

What adverse effects does iodine (labeled) cause in the infant?

Answer 53

thyroid suppression

Question 54

What adverse effects does methadone cause in the infant?

Answer 54

withdrawal if drug is interrupted

Question 55

What adverse effects does propylthiouracil cause in the infant?

Answer 55

thyroid suppression

Question 56

What drugs cause: 20% spontaneous aborption, 20% teratogenic craniofacial, cardiac and CNS defects?

Answer 56

Retin-A | Oral isotretinoin

Question 57

What drugs have CV abnormality 4X risk, CNS defects 3X risk in the 1st trimester?

Answer 57

ACEIs and ARBs (captopril)

Question 58

What effects do ACEIs and ARBs have int he 2nd/3rd trimesters?

Answer 58

oligohydramnios with fetal renal function due to low angiotensin in mother and baby that decreases placental blood flow and decreases vascularization of retina and kidney

Question 59

What drug causes yellow teeth in infants?

Answer 59

tetracycline

Question 60

What drug causes hypoplasia of the nose and extremities with mental retardation in infants?

Answer 60

coumadin (fetal warfarin syndrome)

Question 61

What drugs lead to facial, limb hypoplasia/mental retardation in infants?

Answer 61

Phenytoin; Valproate; Carbamazepine (anti-seizure medications)

Question 62

What drug leads to cardiac abnormalities (Ebstein anomaly—atrialized right ventricle) in infants?

Answer 62

Lithium

Question 63

What drug leads to phocomelia in infants?

Answer 63

Thalidomide

Question 64

What drug leads to cervical uterine abnormalities in babies; vaginal clear cell adenocarcinoma in infants?

Answer 64

DES

Question 65

What drug leads to abnormal fetal growth and fetal addiction; preterm birth; placental abruption in infants?

Answer 65

cocaine