Fetal & Neonatal Pharmacology

Question 1

When is the fetus at the greatest risk for AEs related to teratogenic exposure?

Answer 1

3-8 weeks after fertilization

Question 2

What might be an effect of taking NSAIDs during pregnancy?

Answer 2

NSAIDs, by inhibiting the production of PGs, will permit premature closure of the ductus arteriosus

Question 3

T or F. Nearly all drugs have the capacity to pass across the placenta.

Answer 3

T. Effects in the fetus are dependent upon the timing and duration of drug exposure, and the effects that the drug has in the developing fetal tissues and organs.

Question 4

T or F. The placenta can conduct some metabolic processes and therefore convert materials passing from maternal to fetal tissues.

Answer 4

T.

Question 5

What CYPs are downregulated in pregnancy?

Answer 5

CYP2C19, 1A2, NAT2 (all others increase in activity)

Question 6

What are some factors that influence trans-placental drug passage ability?

Answer 6

• lipid solubility and degree of ionization
• Molecular weigh (less than 600 traverse and over 1000 dont ever)- this is the rationale for using heparin in pregnancy

Question 7

Remember that although most drugs cross the placenta done concentration gradients, some utilize pumps such as P-gp, OCTN, and OAT and that polymoprhisms in these pumps can affect drug exchange

Question 8

Remember that the placenta is capable of its own form of metabolism and that, for the majority of cases, it will tend to reduce the toxicity of drugs passing through it, but on occasion (as is the case with benzpyrene) can increase the toxicity

From the placenta, some, but not all of the blood also passes through the maturing liver where further limited metabolism may occur.

Question 9

Thalidomide use for morning sickness during pregnancy can result in what abnormalities?

Answer 9

phocomelia, or seal limbs

Question 10

Exposure to a drug that is teratogenic during the formation of an organ is most likely to lead to major malformation, whereas exposure during later times, will tend to produce more subtle developmental changes, rather than obvious disfigurement.

Answer 10

Teratogens rarely produce adverse effects with a single exposure. For a drug to produce adverse effects, the expectant mother must take it on a more chronic basis, although not necessarily for the entire pregnancy.

Question 11

Question 12

What must occur for a drug to be designated as a teratogen?

Answer 12

it must show characteristic malformations, these must occur at a particular stage of fetal development, and the effects must exhibit dose dependency.

NOTE: Given that there is an underlying incidence of birth defects of unknown etiology, it is sometimes difficult to establish a causal relationship for a drug that only produces a very low incidence of adverse outcomes.

Question 13

How do current drug developmental regulations attempt to prevent teratogenic effects?

Answer 13

Current drug developmental regulations require all new candidate drugs to be tested in 2 species, with the vast majority being tested in rats and rabbits

Question 14

What are the main mechanisms through which drugs are known to contribute to teratogenicity?

Answer 14

Folate antagonism;

Neural crest disruption;

Endocrine disruption;

Oxidative stress;

Vascular disruption; and

Specific receptor- or enzyme-mediated events.

Question 15

What are some drugs that have been shown to be teratogenic via folate antagonism (and thus DNA and RNA synthesis dysfunction)?

Answer 15

methotrexate, trimehtoprim, and lamotrigene

vaproic acid is also a folate antimetabolite

Question 16

What are some nuclear receptor targets whose functional disruption can lead to up or down regulation of critical genes during neural crest embryologic development?

Answer 16

Pax 3, cadherin, RAR and RXR

Question 17

What drugs interfere with the functioning of Pax3, Cadherins and RA and RX receptors?

Answer 17

bosentan and isotretinoin

Question 18

How does thalidomide cause birth defects such as phecomalia?

Answer 18

prostaglandins and lipoxygenases are important in cellular function and their stimulation by teratogens such as thalidomide generates ROS can lead to cellular dysfunction.

Question 19

What are some drugs that can interrupt the adequate oxygenation of the developing fetus through placental obstruction or spasm and thus can lead to fetal hypoxia and consequent damage?

Answer 19

Misoprostol and ergotamine

Question 20

ACEIs and ARBS are teratogenic to which organs?

Answer 20

renal bloodflow and development

Question 21

Are statins teratogenic?

Answer 21

Yes, they disrupt availability of vital cholesterol for membrane structure and function. Thus, the statin drugs can produce widespread fetal dysfunction.

Question 22

FDA pregnancy categories are based on a scale of ABCDX. What does A mean? B?

Answer 22

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

B: 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 23

FDA pregnancy categories are based on a scale of ABCDX. What does C mean? D?

Answer 23

C: 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.

D: 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 24

What does category X mean?

Answer 24

X: 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 25

Question 26

Recent changes to the legislation governing the FDA permits this authority to require post marketing studies whenever the drug approval committee retains questions about drug safety that can only be clarified when the drug is out in the “real world”.

Answer 26

Question 27

What are some ways in which the potential for a clinical agent to produce birth defects is monitored?

Answer 27

The use of pregnancy exposure registries in which women taking the drug of interest will be identified before the outcome of pregnancy is known and information on both mother and infant collected.

These registries can be open for many years and the total number of enrollees depends upon how significant the use of the specific drug is in relation to the treated disease. As indicated for very rare adverse outcomes, only registries with a large enrollment are capable of statistically defining a causally-related event.

Question 28

Notes baout Isotretinoin

Answer 28

This drug is used in the treatment of acne. Female patients taking this drug are counseled about its teratogenicity and must sign a consent form before using, they must have negative pregnancy tests and use adequate methods of birth control. They are also expected to register their use of this drug with a national database

Question 29

T or F. Pts must avoid donating blood while taking isotretinoin

Answer 29

T.

Question 30

What fetal malformations are associated with Isotretinoin use?

Answer 30

CNS malformations, hydrocephalus, skull and head abnormalities, thymus deficiency, low IQ

Question 31

T or F. Newborn have relatively poor metabolic capacity that matures over the 1st year or so

Answer 31

T.

Question 32

How are pharmacokinetics different in neonates?

Answer 32

At birth there is very little body fat for lipophilic drugs to distribute into, but on the other hand a higher percentage of total body water and extracellular water for distribution of hydrophilic agents.

there is also reduced capacity for plasma protein binding by drugs in the neonate compared to the older child or adult. For drugs that are normally highly protein bound, this can result in a significant increase in the free drug fraction, especially if there is the acute administration of another high affinity drug that results in protein binding displacement, and potential increased distribution and exaggerated end organ effects.

Question 33

What are some other physiologic differences in neonates compared to older children and adults?

Answer 33

• variability in both gastric acidity and bile acid secretion and in the capacity for metabolism within the GI. tract.
• relatively immature renal function that requires several years to reach maturity. This can compromise the elimination of drugs by this route.
• skin of the newborn is thin compared to an older infant but that perfusion is good. However, the newborn has immature regulation of vascular perfusion, such that a subQ administered drug may be absorbed in an erratic manner compared to that in an older child.

Question 34

Summarize the differences of pharmacokinetics of neonates

Answer 34

• Slower GI, but faster IM absorption
• more body water than lipids early in life
• limited protein binding
• larger liver:BW ratio in infants
• larger brain:BW ratio in infants
• immature renal function
• higher BBB permeability

Question 35

Half-life trends in neonates

Answer 35

Half lives are longer in the neonate than in the older child or the adult.

2nd, as you will observe with the anti-epileptic drug phenytoin, the pharmacokinetics continue to change as the neonate ages (ie. half-life decreases rapidly); these changes can occur over a period of days rather than weeks or months. From a practical standpoint then, it should not be surprising that drug doses may be adjusted to reflect this increasing maturation of organ function.

Question 36

Generally dose adjustment in neonates is made on a ___ basis, although adjustment would be more accurately considered on the basis of body surface area

Answer 36

weight percentage

Question 37

Where are Opiate receptors primarily located?

Answer 37

predominantly in the brain and in the enteric nervous system of the GI tract.

Question 38

What effect would an opiate have in the CNS? In the GI?

Answer 38

In the CNS, an opiate would be sedating. In the GI tract, opiates are notorious for producing constipation as an adverse effect. Remove the opiate and the GI tract exhibits the opposite characteristics.

Question 39

So what symptoms/signs in a neonate might suggest neonatal narcotic abstinence (withdrawal) syndrome?

Question 40

What autonomic symptoms/signs might suggest neonatal narcotic abstinence (withdrawal) syndrome?

Answer 40

increased sweating, nasal stuffiness (mottling), fever (temp instability)

Question 41

What are some signs indicating maternal narcotic abuse during pregnancy?

Answer 41

–Current behavior (absent, late, or inadequate prenatal care); previous history (admitted drug abuse, unexplained late fetal demise; precipitous labor, severe mood swings)

Question 42

What other things need to be on the DDx if you suspect withdrawal symptoms in a neonate?

Answer 42

–Withdrawal signs in the newborn may mimic other conditions, such as infection, hypoglycemia, hypocalcemia, hyperthyroidism, intracranial hemorrhage, hypoxic-ischemic encephalopathy, and hyperviscosity

–No clinical signs should be attributed solely to drug withdrawal on the basis of a positive maternal history without carefully excluding other causes.

Question 43

Like many medical situations, treatment of opiate withdrawal depends upon the severity of the symptoms. It can range from simple environmental and support measures to the use of tapering doses of opiate agonists like morphine or methadone

Answer 43

Question 44

How is the composition of breat milk different than that of blood?

Answer 44

Milk is more acidic than blood and has a higher fat content, both of which can lead to increased concentration of maternal drugs (especially basic and lipid soluble drugs) in breast milk

Question 45

How should a mother who is taking potentially teratogenic drugs and breatfeeding be advised?

Answer 45

You should advise to coordinate the maternal dosing after feeding to lower risk of transmission, and prefer drugs with short half-lives

Question 46

What are some drugs that have shown to be contraindicated for use by a mother during breast-feeding?

Answer 46

-Chloramiphenicol

Diazepam

Heroin

Iodine

Lithium

Methadone

PTU

Question 47

What are the effects of chloramphenicol on a neonate via breast-feeding?

Answer 47

chloramphenicol, an antimicrobial agent that produces a well-defined grey baby syndrome if administered directly to a neonate, but is also capable of producing blood dyscrasias and bone marrow suppression through exposure by breastmilk.

Question 48

What are the effects of diazepam on a neonate via breast-feeding?

Answer 48

sedation and accumulation in neonates

Question 49

What are the effects of heroin on a neonate via breast-feeding?

Answer 49

narcotic dependence

Question 50

Question 51

What drugs are absolutely conrtaindicated for a MAN to take if he is currently trying to get pregnant?

Answer 51

Boceprevir and Telaprevir