Lecture 18: Pregnancy Pharmacokinetics & Developmental Toxicology

decrease

effect of pregnancy on CYP1A2

increase

effect of pregnancy on CYP2A6

increase

effect of pregnancy on CYP2D6

increase

effect of pregnancy on CYP2C9

decrease

effect of pregnancy on CYP2C19

increase

effect of pregnancy on CYP3A4

increase

effect of pregnancy on UGT1A4

40 weeks

length of gestation

increase P-gp

transporter for digoxin

increased OAT, decreased PEPTs

transporters for amoxicillin

increased OCT2, increased MATE1

transporters for metformin

preferential accumulation in breast milk

milk-to-plasma (M:P) exceeds 1

colostrum

early milk (1st few days)

drug features that may favor transfer

• high concentrations in maternal plasma

• low molecular weight (<800)

• low protein binding

• high lipophilicity

• drugs with high pKa can be ionized / trapped in milk

• BRCP substrate

drugs with CYP1A2

caffeine, theophylline, olanzapine, clozapine

drugs with CYP2A6

nicotine

drugs with CYP2D6

fluoxetine, citalopram, metoprolol, dextromethorphan

drugs with CYP2C9

phenytoin, glyburide

drugs with CYP2C19

proguanil

drugs with CYP3A4

midazolam, indinavir

drugs with UGT1A4

lamotrigine

paracellular transfer

What type of transport do the gaps between cells in colostrum allow?

drugs of concern in lactation

aspirin, diuretics, opioids, nicotine, amphetamines, lithium, cannabis, anticancer

embryonic period

weeks 1-8

fetal period

weeks 9-38

teratogenicity

disrupts normal developmental programming (during organogenesis)

order of risk of spina bifida from seizure drugs

valproic acid > carbamazepine > phenytoin

limb and cardiac malformation from seizure drugs

phenytoin

fingernail hypoplasia from seizure drugs

carbamazepine

mechanism of seizure drugs during pregnancy

disrupts folate metabolism and HDAC inhibition → impair normal neural tube closure

mechanism of isotretinoin during pregnancy

alters neural crest cell migration

Tetralogy of Fallot

What cardiac malformation can isotretinoin cause?

phocomelia

What disease characterized by abnormal limbs can thalidomide cause?

weeks 3-4

sensitive window for seizure drugs

weeks 3-5

sensitive window for isotretinoin

weeks 4-6

sensitive window for thalidomide

mechanism of thalidomide in pregnancy

blocks angiogenesis needed for limb formation

toxicity of diethylstilbesterol in females

clear cell adenocarcinoma of vagina in female offspring

toxicity of diethylstilbesterol in males

increased risk of testicular cancer, infertility

weeks 6-12

sensitive window of diethylstilbesterol

mechanism of diethylstilbesterol in pregnancy

potent agonism of estrogen receptors altering expression of HOX genes for vaginal wall development

toxicity of warfarin in early pregnancy

crosses placenta and causes fetal warfarin syndrome

toxicity of warfarin in late pregnancy

CNS abnormalities due to impaired fetal coagulation

mechanism of warfarin in pregnancy

inhibition of vitamin K

Potter Syndrome

What condition characterized by pulmonary hypoplasia do ACE inhibitors cause?

2nd and 3rd trimesters

sensitive window of ACE inhibitors

mechanism of ACE inhibitors

ACE inhibitors prevent angiotensin II from kidney development and renal blood flow

tetracycline

enters fetal circulation and chelated the calcium after 4th month of gestation

streptomycin/gentamicin

risk of ototoxicity in fetus by affecting 8th cranial nerve

bioavailability of weakly basic drugs

infants > adults

bioavailability of weakly acidic drugs

adults > infants

enzymes that decrease after birth

CYP3A7, FMO1, SULT1A3, acetylation

enzymes that stay constant

CYP3A5, TPMT, SULT1A1, GSTs

enzymes that increase after birth

CYP1A2, 2C9, 2C19, 2D6, 2E1, 3A4, FMO3, most UGTs, amino acid conjugation

0.5 months

When is CYP2D6 active?

2 months

When is CYP3A4 active?

1-3 months

When is CYP1A2 expressed?

kernicterus

What does low UGT put infants at risk from due to bilirubin build up?

mechanism of chloramphenicol

inhibits bacterial protein synthesis

chloramphenicol excretion

extensive glucuronidation (90%), renal excretion (<10%)

symptoms of Grey Baby Syndrome days 3-6

jaundice, nause/vomiting/anorexia

symptoms of Grey Baby Syndrome day 4

cyanosis and green stools

symptoms of Grey Baby Syndrome days 5-6

pallor, death

syndrome characterized by build up of benzoic acid, phase II glycine conjugation immature in newborns

Gasping Baby Syndrome

9 weeks

When do nephrons begin to form?

36 weeks

When are nephrons completely formed but functionally immature?

5%

receive only __ of cardiac output as kids compared to 20% of adults

50%

filtration is at __ of adult rate at birth

20%

secretion is at __ of adult rate at birth

halothane, isoniazid, acetaminophen

rare in children due to immature CYP2E1

gentamicin

reduced active uptake into tubules in neonates

Reye’s Syndrome

What is the syndrome characterized by acute swelling of liver and brain in children and adolescents?

etiology of Reye’s syndrome

mitochondrial dysfunction → impaired fatty acid beta-oxidation → microvesicular steatosis, hyperammonemia, encephalopathy

effect of stimulants in adults

stimulate CNS

effects of stimulants in children

control ADHD

effects of antihistamines in adults

sedating

effects of antihistamines in infants/toddlers

activating