Pregnancy PK + Developmental Toxicology

Changes in the Cardiovascular System + Blood in PREGNANCY

Do the following increase or decrease?

• plasma volume

• cardiac output

• stroke volume

• heart rate

ALL INCREASE

**you are now pumping blood for TWO people so you need more of it and to push more of it out

what happens to the serum albumin concentration and serum colloid osmotic pressure during pregnancy?

DECREASE

Do coagulation factors and fibrinogen increase or decrease in pregnancy?

INCREASE

what happens to the inferior vena cava (brings deoxygenated blood into the heart) in pregnant individuals?

vena cava is compressed by the uterus

what happens to renal blood flow and glomerular filtration rate in pregnancy?

both INCREASE

During pregnancy, changes are made to which enzymes in the liver? Are they increased or decreased?

oxidative liver enzymes such as CYP450

some increased some decreased

what increases in the lungs due in pregnant women?

minute ventilation (total inhaled and exhaled in one minute)

tidal volume (inhaled and exhaled in normal breath)

Physiological Changes in Stomach and Intestines:

• nausea and vomiting

• _______ gastric emptying

• prolonged _________ _________ _________ _________

• gastrointestinal _________

• delayed gastric emptying

• small bowel transit time (longer time in the small intestine)

• reflux

do pregnant women have more or less hemoglobin?

less hemoglobin

which CYP450/ liver enzymes increase in activity during pregnancy?

CYP 2A6 and 2D6

CYP 2C9 and 3A4

UGT 1A4

6s got their own thing goin

2C9 isnt with 2C19 this time but w/ 3A4

and UGT 1A4 is loner

would you see higher or lower of the following substrates in pregnant individuals and why?

CYP1A2- caffeine, clozapine theophylline, olanzapine, (CCOT)— all end with eine

CYP2C19- proguanil

INCREASED levels of substrates because

CYP1A2 and 2C19 are DECREASED so the substrates wont be metabloized

which substrates would you see an increase in pregnant woman and why ?

• caffeine, clozapine, olanzapine, theophylline (decreased CYP1A2)

• proguanil (decreased CYP2C19)

would you expect higher or lower levels of the following substrates in pregnant women?

CYP2A6 - nicotine

CYP2D6 - fluoxetine, citalopram, metoprolol, dextromethorphan (md fc—6 is too young to be a doctor)

CYP2C9- phenytoin and glyburide (interesting name like 2C19)

CYP3A4- midazolam, indinavir, nifenidine (min- usually max)

UGT1A2 - lamotrigine

decreased substrates because the CYP activity of the following are increased in pregnant woman

further along in gestation levels of CYP1A2 increase/decrease

causing an increase/decrease in caffeine, clozapine, olanzapine, theophylline

CYP1A2 activity decrease

substrates increase

would there be a higher or lower AUC (concentration/time graph) for midazolam in post partum women or in pregnant women?

greater midazolam AUC in postpartum women bc/ it is metabolized by CYP3A4 which is enhanced during pregnancy

Increased digoxin clearance in pregnant women is due to which two enhanced transporters?

pregnancy clearance: 73± 22 (51-95mL/min) greater than 51

postpartum clearance: 37 ± 14 (23-51)

OATP (takes from blood into proximal tubule cell)

P-gp (takes from proximal tubule cell into filtrate)

Increased Amoxicillin clearance in pregnant women is due to which an increase in the ______ trasnporter and decrease in _______ and _______ transporters

2nd Trimester: 280± 105 (175- 385)

3rd Trimester: 259 ± 54 (205-313)

Postpartum: 167± 47 (120-214)

increased OAT (bring amoxicillin into the proximal tubule)

decreased hPEPT1 and hPEPT2 (allow for reabsorption of amoxicillin)

Increased Metformin clearance in pregnant women is due to an incrrease in which two transporters?

T2: 480 ± 190 (290-670)

T3: 419 ± 78 (341-497)

Post Partum: 313± 98 (215-411)

OCT2 and MATE1

Will there always be more drugs in the mother’s blood than in the milk?

NO there CAN be more drug in the milk than mothers blood

the milk:blood ratio can be greater than 1 for some drugs

which drugs should be avoided due to increased exposure to prenatal and postnatal babies through milk? (you will find more of these drugs in the milk than mothers blood)

1. aspirin

2. opioids (morphine, codeine, oxycodone)

3. amphetamines

4. lithium

5. marijuana

6. anticancer drugs

what is early milk from the first few days referred to as?

colostrum

what gives colostrum (early milk) its yellow color?

immunoglobins that are paracellularly transferred between cells into the milk to build babies immunity

Which types of drugs will make it into the milk?

• high/low concentrations in maternal plasma

• low molecular weight less than _______

• high/low protein binding

• pass easily into the _______ (due to high _________)

• Drugs with high/low pka will get trapped in the milk due to the milk’s high/low pH

• high

• 800

• low (able to leave blood into milk)

• brain lipophilicity

• high pka stuck in low pH milk

is the milk basic or acidic?

which type of drugs would get entrapped in the milk due to their pka?

milk is acidic (low pH)

basic drugs (high pka) would get trapped in milk bc/ they are charged in acidic environments

which cells separate maternal blood with milk?

lactocytes (epithelia) in alveoli

which efflux transporter is used to take drugs out of lactocytes and into the milk ?

BCRP

is the pH of the mothers blood or milk lower?

pH or milk is lower (7) than mothers plasma (7.4)

_____ _______ is secreted from the lactocytes into the milk

drugs that are ______ can be secreted within them

milk fat

lipophilic

does BCRP on the apical side of mammary tissue increase neonatal exposure to drugs?

YES because it allows drugs to efflux out of lactocytes and into the milk

breast milk atenolol peak concentrations are _____ and _____ that maternal plasma peak

Does atenolol reach toxic concentration levels in infants?

higher later

NO due to the babies own ADME processes not all of the drug in the breastmilk is transported to its target of action

BELOW 10 ng/mL

is mammary clearance of atenolol INTO breastmilk greater 2-4 weeks postpartum or 3+ months postpartum?

greater mammary clearance = greater amount in milk 2-4 weeks postpartum compared to 3 months

the longer that atenolol is in the body after pregnancy, the less that makes it into the milk

how long is human gestation (period in womb)?

after how many weeks is a baby considered to be full term?

40 weeks

38 weeks

are babies more or less likely to be susceptible to teratogens during the first 2 weeks of gestation?

LESS likely (they have just merely been implanted, blood supply is not connected yet to be able to transfer drugs from mom to baby)

what happens during the first two weeks of pregnancy?

• dividing zygote

• implantation

• bilaminar embryo

which weeks are considered to be the embryonic phase?

which organs are developed at this stage of pregnancy?

3-8 weeks = embryonic phase

CNS and heart

eyes

arms and legs

teeth

palate

external genetalia

if a child is born with a morphologic abnormality, it is most likely that it had happened during which stage of gestation?

embryonic (3-8 weeks)

if a child is born with a physiological or minor morphological defect, it most likely occurred during which stage of gestation?

9-38 weeks

When would you experience physiological defects (loss or gain of function) vs morphological defects (physical defect) in gestation?

morphological - 3-8 weeks

physiological - 9-38 weeks

toxicity that disrupts specific developmental programming (organogenesis)

teratogens

what can be considered a teratogen

drugs, chemicals, AND hormones that cause toxicity impacting development

TRUE/FALSE: effects of all teratogens are evidently visible

FALSE

not all teratogens are visible

lithium (mood stabilizer) is a teratogen

what effect does it have on the fetus?

cardiac defects

which teratogen leads to

• hypoplastic nasal bridge AND chrondodysplasia (1st trimester)

• CNS malformations (2nd trimester)

• risk of bleeding (3rd trimester)

warfarin

which teratogen leads to

• craniofacial

• limb

• growth deficiencies

phenytoin

which teratogen leads to

• neural tube defects

• cardiac and limb malformations

valproic acid/ valproate

which teratogen leads to

• neuraltube defects

• fingernail hypoplasia

carbamazepine

which teratogen leads to

• cardiac defects

• masculinization

sex hormones

which teratogen leads to

• high risk of craniofacial

• cardiac

• CNS anomalies

retinoic acids (Accutane)

which teratogen leads to

• phocomelia

thalidomide

which teratogen leads to

• renal damage

ACE inhibitors (prils)

what are the two teratogenic effects you may see if taking warfarin during your first trimester?

1. hypoplastic nasal bridge

2. chondrodysplasia - stippling in the sacral and tarsal bones

______ _______ is a neural tube defect that is observed in pregnant woman taking _________ drugs such as ________ and ________ _______

what causes the defect?

spina bifida

antiepileptic

carbamazepine + valproic acid

caused by disruption to folate homeostasis

what defect results if folate homeostasis is disrupted?

spina bifida (neural tube defect)

which drug was used to prevent miscarriages in pregnant women from 1947-1971 (ineffective)?

did this drug increase progesterone or estrogen?

diethylstilbesterol

increased estrogen, even though now progesterone is known to prevent pre-term labor and the onset of parturition

was diethylstilbesterol pharmacologically appropriate?

NO the drug was made of estrogen and was meant to prevent pre-term labor but PROEGESTERONE is the pharmacologically appropriate drug to use to prevent miscarriage

what did the increased levels of estrogen from taking diethylstilbesterol during pregnancy lead to?

what age did you start seeing these effects in the children ?

clear cell adenocarcinoma of the vagina (40x more likely to develop than the average woman) and

increased risk of testicular cancer and infertility in males

SEEN IN 20s

were the effects of diethyltstilbessterol transgenerational?

YES

after 4 months of gestation __________ enters the fetal circulation and chelates the __________ leading to

• discoloration of infant teeth (yellow-gray brown)

• enamel hypoplasia

tetracycline

calcium

streptomycin: risk of __________ in the fetus by affecting 8th ______ nerve (rare toxicity)

ototoxicity (ear)

cranial

which two antibiotics are teratogenic? what do they lead to?

tetracycline- discoloration of teeth/ enamel hypoplasia

streptomycin - ototoxicity

THALIDOMIDE

Drugs can act as teratogens at specific stages of development:

• was thalidomide a prescription or OTC drug?

• what was thalidomide used for?

• was it approved by the US?

• OTC

• morning sickness

• NO it was approved in Germany and throughout Europe

THALIDOMIDE:

• disrupts LIMB formation in the “_____ ________” stage of pregnancy

  • 10,000 cases of ________ (only 50% survived)

• ______ _______ development occurs between the ___th and ____th week of embryonic life

• other toxicities such as deformed _______, _____ , _______ ______, ________, and ______ defects

• Which FDA individual was responsible for preventing the approval of thalidomide in the US?

• vulnerable widow phocomelia (extremely short limbs)

• limb bud 4th and 7th

• eyes, heart, urinary tract, vision, and hearing

• Frances Oldham Kelsey

what is the pH of the stomach of babies

• in utero (in womb) and newborn

• 1-2 days old

• 1 week - 2 years (toddler)

• 2+ years

• 7

• 1-3

• 7

• 1-2 (final pH into adulthood)

what is achlorhydria which is seen in infants and toddlers (up to 2 years)?

decreased HCl production in the stomach

stomach is at pH 7 at these stages compared to 1-2 for adults

do infants and toddlers absorb weakly basic drugs or weakly acidic drugs better?

weakly basic because the pH of their stomach is basic (7) which keeps basic drugs unionized and able to make it to the blood and acidic drugs ionized unable to leave the stomach and go into the blood stream

would infants/toddlers absorb more penicillin or phenobarbital into their blood stream?

penicillin bc/ it is weakly basic and will remain unionized and able to cross to blood in pH 7 in stomach

phenobarbital which is weakly acidic will be charged in basic stomach pH and remain trapped in stomach

do weakly basic (acid-labile) drugs such as penicillin have an increased or decreased nonionized/ionized ratio in infants and toddlers?

what about weakly acidic drugs?

weakly basic = increased nonionized/ionized

weakly acidic = decreased nonionized/ionized

which enzymes are only present prenatally (before birth) and dramatically decrease (virtually 0 activity) in adulthood?

CYP 3A7 (turns into 3A4 in adults)

FMO1

SULT1A3

which enzymes are active postnatally (not present before birth)?

CYP 2C9, 2C19, 2D6, 2E1, 3A4

FMO3

most UGT

which enzymes are present and active both before birth and after (constant expression) ?

CYP 3A5

SULT 1A1

TPMT

• CYP3A7, FMO1, SULT 1A3

• CYP 3A5, SULT 1A1, TPMT

• CYP 2C9, 2C19, 2D6, 2E1, 3A4, FMO3, most UGTs

Which lines represent each?

• grey (only prenatal)

• dashed (constant)

• black solid (only postnatal)

which CYP enzymes are present in the fetus (but low activity) ?

CYP 3A4, 1A1, 3A5

which CYP enzymes appear after birth?

• _______(weeks to 3 months)

• _________ and __________ (days)

• _________/______

• ______________

• CYP3A4

• CYP2D6 and 2C9

• CYP2C18/ 19

• CYP2E1

which enzyme(s) appear after 3-6 months?

CYP1A2

the human FETAL LIVER is a ________ tissue meaning it can create blood cells

hematopoietic

_______, __________, and ________ exceed adult capacity by 6-12 months of life

1A2, 2C99, and 3A4

_______ switches to ______ postnatally

________ metabolizes endogenous substrates in eutero

CYP3A7 to 3A4

3A7

______is relatively constant throughout gestation and postnatally

CYP3A5

the metabolism of _______ DECREASES as you age because of the decrease in which enzyme?

the metabolism of ______ INCREASES as you age because of the gradual increase in which enzyme?

metabolism of testosterone by 3A7 decreases as you age

metabolism of dehydroepiandrosterone by 3A4 increases as you age

how would levels of testosterone and dehydroepiandrosterone fluctuate as one ages?

higher testosterone as you age (less metabolism by 3A7)

lower dehydroepiandrosterone as you age (higher metabolism by 3A4)

Explain how a 3 week baby would metabolize DM?

DM —> DX (using 2D6) —> Glucoronidation (UGT)

How would a 6 month baby metabolize DM?

DM —> DX (using CYP 2D6) —> 3HM (using CYP 3A4) —> glucoronidation (UGT)

OR DM —> DMM (using CYP 3A4) —> 3HM ( using 2D6)

* since baby is older than 2 months they can use 3A4 for metabolism

What are two ways to get 3HM from Dethromethorphan?

Will you see 3HM in a 1 month old?

DM—> DX (2D6) —> 3HM (3A4)

DM —> DMM (3A4) —> 3HM (2D6)

NO to get to 3HM you need both 3A4 and 2D6 only get 3A4 when you are 2 months

CYP 1A2 converts __________ (bronchodilator for neonates) into __________ after 35-40 weeks

Theophyline to 1-3 dimethyluric acid

A 23 week baby (post conceptual — counting weeks since mothers last period)is on theophylline to treat their apnea, upon taking a urine sample will we see more theophyline or 1-3 dimethyluric acid?

Theophyline. Only at 35 weeks can the baby begin to metabolize theophyline to dimethyluric acid using CYP 1A2

What are the main modes of metabolism of chloramphenicol?

Glucoronidation (90%) and renal excretion (<10%)

What is cholarmphenicol used for?

Which organelle can it be toxic to?

Build up of chloramphenicol can lead to which syndrome?

Inhibits bacterial protein synthesis ( bacteriostatic)

Mitochondria

Grey baby syndrome

What causes grey baby syndrome?

Symptoms include:

Build up of chloramphenicol due to lack of Glucoronidation (deficient UGT) and renal excretion