ICL 14.5: Pharmacology of Pregnancy

Question 1

what are some assumptions you make when giving medications to pregnant women?

Answer 1

1. treat pre-conception as pregnant
2. assume some placental crossing when giving a medication
3. birth defects happen regardless of medication or drug use (~4%)

it’s difficult to predict impact of exposure on developing fetus – although risk is always present, aim to limit/minimize risk when possible

4. uncontrolled disease states and/or a discontinued medication carry maternal and fetal risk as well

Question 2

what are pharmacokinetics?

Answer 2

describes the absorption, distribution, metabolism, and elimination of drugs in patients requiring drug therapy

Question 3

what is drug absorption/bioavailability?

Answer 3

the fraction of drug absorbed into the systemic circulation after extravascular administration is defined as its bioavailability

this is affected by the amount of drug that is absorbed across the intestinal epithelium as well as first pass metabolism as the drug crosses the intestine and liver on its way to the systemic circulation.

IV drugs are 100% bioavailable

Question 4

what is drug clearance?

Answer 4

the rate at which the body can remove a drug

it’s determined by blood flow to the organ that metbolized or eliminates the drug and the effieicny of the organ in extracting the drug from the bloodstream

Question 5

what is the extraction ratio of a drug?

Answer 5

the proportion of a drug taken up from the hepatic arterial circulation into hepatocytes, making it available for subsequent metabolism

Question 6

which drugs have high extraction ratios?

Answer 6

1. propranolol
2. verapamil
3. morphine
4. lidocaine

so the clearance of these drugs is equal to blood flow to the organ

Question 7

what does it mean if a drug has a low extraction ratio? which drugs have low ER?

Answer 7

clearance of the drug is equal to the product of the fraction unbound in the blood and the intrinsic ability of the organ to clear unbound drug from the blood

1. warfarin
2. theophylline
3. diazepam
4. phenobarbital

Question 8

what is volume of distribution of a drug?

Answer 8

Vd is a proportionality constant that relates the amount of drug in the body to the serum concentration

it’s used to indicate how extensively a systemic dose of medication is dispersed throughout the body

drugs that are highly bound to tissues, with a small proportion remaining in the intravascular space, will have a very high Vd

drugs that are highly bound to plasma proteins and/or have a large molecular weight will tend to concentrate intravascularly and will have a small Vd

Question 9

what is the half life of a drug?

Answer 9

the time required for serum concentrations to decrease by one-half after absorption and distribution are complete

it takes approximately three to five half-lives to reach steady-state concentrations during continuous dosing

it takes approximately 7 half-lives for a drug to be removed from the body

Question 10

what are the two phases by which the liver metabolizes drugs?

Answer 10

phase I reaction: oxidation, hydrolysis and reduction –> a. make the drug molecule more polar and water soluble so that it is prone to elimination by the kidney; predominantly carried out by the cytochrome P450 (CYP) family of enzymes

phase II reaction: conjugation –> forms glucuronides, acetates or sulfates and inactivates the pharmacologic activity of the drug and may make it more prone to elimination by the kidney

Question 11

what is absorption of a drug?

Answer 11

the movement of drug from the site of administration into the systemic circulation

Question 12

how is absorption of a drug effected during pregnancy?

Answer 12

absorption is the movement of drug from the site of administration into the systemic circulation

with pregnancy there is:
1. increased nausea/vomiting

2. decreased gastric acid production; increased gastric pH

nausea and vomiting in early pregnancy may decrease the amount of drug available for absorption following oral administration

no significant change in bioavailability during pregnancy have been identified

Question 13

how is the distribution of a drug effected during pregnancy?

Answer 13

distribution is the reversible transfer of a drug between different locations following its entry into the systemic circulation

during pregnancy:
1. increasing CO, SV, and HR

2. increased blood volume (40-45%)
3. increased maternal body fat
4. increased uterine perfusion

this leads to:
1. expanded extracellular volume and total body water will increase volume of distribution for hydrophilic drugs, leading to lower plasma concentrations

2. increased maternal body fat may increase the volume of distribution for lipophilic drugs
3. volume of distribution increases may impact initial drug concentrations after a loading dosed cause decreased peak plasma concentrations after multiple administrations
4. serum albumin and a1-acid glycoprotein concentrations decline during pregnancy due to increased blood volume which can impact highly protein bound drugs and non-oral administration of high extraction ratio drugs –> increased unbound medications
5. the fetus and the amniotic fluid can act as additional compartments, leading to increased drug accumulation and an apparent increase in volume of distribution of certain drugs

Question 14

how is drug metabolism impacted during pregnancy?

Answer 14

metabolism involves chemical modification of a drug through specialized enzymatic systems

during pregnancy there is:
1. increased hepatic arterial and portal venous blood flow

2. decreased serum albumin concentration, although total body albumin rises due to increased plasma volume

this leads to:
1. increased activity of CYP3A4, CYP2A6, CYP2D6, CYP2C9

2. CYP1A2 and CYP2C19 appear to undergo a gradual decrease in activity throughout gestation
3. phase II enzymes, i.e. uridine 5’-diphosphate glucuronosyltransferases (UGTs), is also altered during pregnancy, with a 200% increase in UGT1A4 activity during the first and second trimesters and a 300% increase during the third trimester

Question 15

how renal excretion effected during pregnancy?

Answer 15

renal excretion is based on GFR, tubular secretion and reabsorption

during pregnancy GFR and renal blood flow increase

despite a uniform increase in GFR during pregnancy, differences in renal tubular transport (secretion or reabsorption) can result in differing effects on renally cleared drugs

variations in drug clearances limit generalization about the effect of pregnancy on renally eliminated drugs

Question 16

how common are birth defects?

Answer 16

4%

1/28 and most are idiopathic

less than 1% caused by teratogen

Question 17

how do drugs cross into the placenta from the mother?

Answer 17

fetal vessels from the umbilical cord branching into villous trees are bathed by maternal blood entering the placenta via spiral arteries

trophoblast cells on the surface of the villous structures separate the maternal blood in the intervillous space from the fetal circulation

molecules are transported across the cell membrane via passive diffusion and active transport (uptake and efflux)

Question 18

which types of drugs cross the placenta easily?

Answer 18

1. small-molecular-weight and lipophilic drugs readily cross the placenta via passive diffusion
2. weak bases cross more easily (fetal pH is slightly more acidic than maternal pH)

facilitated diffusion (with a concentration gradient) and active transport (against a concentration gradient) allow for bidirectional transfer of larger compounds between the maternal and fetal circulations across the placenta

Question 19

which drug classes are known teratogens?

Answer 19

1. ACE inhibitors/ARBs
2. anticonvulsants
3. diethylstilbestrol
4. isotretinoin/high doses of vitamin A
5. lithium
6. methotrexate, aminoptrine
7. NSAIDs
8. thalidomide
9. warfarin

Question 20

what is the teratogenic effect and critical period associated with ACE inhibitors?

Answer 20

renal failure, anuria, oligohydramnios, pulmonary hypoplasia, intrauterine growth restriction, limbs contracture, skull hypoplasia

contraindicated after first trimester

Question 21

what is the teratogenic effect and critical period associated with anticonvulsants?

Answer 21

carbamazepine and valproic acid; oral cleft, skeletal, urogenital, craniofacial, digital, and cardiac malformations; microcephalia

valproic acid: abnormal neurologic development

critical period is during organogenesis for structural anomalies and valproic acid is contraindicated the whole pregnancy due to possible neurologic impairment

Question 22

what is the teratogenic effect and critical period associated with diethylstilbestrol?

Answer 22

girls: cervical or vaginal adenocarcinoma, incidence about 1/1000 exposures. Structural genital anomalies (eg, of cervix, vagina)
boys: genital anomalies, spermatogenesis anomalies

contraindicated in the 1st and 2nd trimesters

Question 23

what is the teratogenic effect and critical period associated with vitamin A?

Answer 23

spontaneous abortion, CNS, skull, eyes and ears malformations, micrognathia, oral cleft, cardiac malformations, thymus anomalies, mental retardation: estimated at 25%-30% (may be higher for neurologic development impairment)

they are all contraindicated throughout pregnancy

must discontinue isotretinoin 1 month before pregnancy and acitretin needs to be discontinued 3 years before pregnancy

Question 24

what is the teratogenic effect and critical period associated with lithium?

Answer 24

cardiac malformations: risk of 0.9%-6.8%

contraindicated during cardiac organogenesis (5-10 wk after LMP)

Question 25

what is the teratogenic effect and critical period associated with methotrexate?

Answer 25

spontaneous abortion, CNS and cranial malformations (large fontanelles, hydrocephalia, incomplete cranial ossification, craniosynostosis), oral cleft, ear, skeletal and limb malformations, mental retardation

contraindicated during organogenesis between 6 and 8 wk after LMP for structural
anomalies but some exceptions reported

stop 1-3 mo before pregnancy

Question 26

what is the teratogenic effect and critical period associated with NSAIDs?

Answer 26

in utero closure of ductus arteriosus (constriction is rare before 27 wk, 50%-70% at 32 wk (GA) and neonatal pulmonary hypertension

renal toxicity possible after prolonged use from second half of second trimester

contraindicated in 3rd trimester

Question 27

what is the teratogenic effect and critical period associated with thalidomide?

Answer 27

limb anomalies (amelia, phocomelia)

cardiac, urogenital, gastrointestinal, and ear malformations

contraindicated 34-50 d after LMP

Question 28

what is the teratogenic effect and critical period associated with warfarin?

Answer 28

if taken before 6 wk: no higher risk of anomaly

if taken between 6 and 12 wk: nasal hypoplasia, epiphysis dysplasia, vertebral malformations, rarely ophthalmic anomalies, scoliosis, hearing loss

between wk 6 and 12 after LMP

Question 29

the fraction of drug absorbed into the systemic circulation is called what?

Answer 29

bioavailability

Question 30

the proportion drug taken up from hepatic circulation to be metabolized is called what?

Answer 30

extraction ratio

Question 31

T/F: CYP enzymes may be impacted during pregnancy

Answer 31

true

Question 32

volume of distribution is used to ermine what?

Answer 32

loading dose

Question 33

1/2 life is used to determine what?

Answer 33

dosing interval

Question 34

which CYP enzyme activity is increased vs. decreased during pregnancy?

Answer 34

increased:
CYP3A4
CYP2D6
CYP2C9
UGT1A4
UGT1A1/9

decreased:
CYP2C19
CYP1A2
NAT2

Question 35

PT is a 29 y/o F with epilepsy currently controlled on Phenytoin 200mg po tid who would like to become pregnant. What preconception changes would you like to make before she becomes pregnant?

Additional Info:
Lamotrigine, levetiracetam, and phenytoin have 2-3% risk of major congenital malformation (MCM) – although lamotrigine and levetiracetam carry lowest risk

Phenytoin level – 19g/mL (therapeutic range 10-20g/mL)

Answer 35

she’s well controlled and she needs the medication so you can’t just stop it

since her phenytoin level is at the higher end of things then maybe just drop the dose so that it’s on the lower therapeutic range

also give folic acid supplementation

this AED drug not typically changed once she’s pregnant the exposure has already happened and when you switch medications you’re just increasing exposure to a new medication so just keep it the same

Question 36

patient stays on phenytoin due to past AED responses however you are able to get her dose down to 100 mg PO TID with a serum level of 11 micrograms/mL with no increased seizure activity and she’s taking folic acid. how might pregnancy effect the phenytoin levels?

Bioavailability: 85 - 95%

Time to peak: ER 4-12 hrs, IR 1.5-3 hrs

Vd: 0.6 - 0.7 L/kg

Protein Binding: 90 – 95%

Half-life: 7-42 hrs

Excretion: Urine (<5% as unchanged drug)

Substrateof CYP2C9 (major), CYP3A4 (minor)

Answer 36

1. CYP2C9 substrate and this enzyme has increased activity in pregnancy which will decreased phenytoin levels
2. medication is protein bound so decreased albumin will have higher unbound phenytoin and lead to higher activity!
3. N/V may impact ability to take orally and lead to decreased absorption and decreased effect

Question 37

CR is a 26 yo pregnant female (gestational age 12 weeks) currently taking Oxycontin 20mg po bid for chronic neck and back pain due to a past fall. She attempted to stop the medication when she found out she was pregnant but experienced withdrawal symptoms and pain that caused her to start taking it again. She scores a 30/40 on the NIDA Drug Screening Tool (High). She sees multiple providers to obtain her Oxycontin but denies illicit drug use. Her urine drug screen is negative except for opiates.

what are the fetal risks? how do you treat her?

Answer 37

opiate abuse problems but it’s good shes not using drugs so that’s good but the risks include:

1. preeclampsia
2. premature labor
3. placental insufficieny
4. low birthweight
5. neonatal abstinence syndrome (NAS)
6. potential future motor and cognitive impairments

treat her with CBT for chronic pain, close monitoring, pain contract, prescription monitoring, urine drug screens

pharmacologic treatment would be decrease the dose of current opiate, refer to opioid treatment program to switch to methadone* or buprenorphine

Question 38

what is pregnancy and lactation labeling rule?

Answer 38

PKKR

A,B,C letter categories for risk but this isn’t used any more; now we use labor and delivery pregnancy section

Question 39

what is the labor and delivery pregnancy section?

Answer 39

1. pregnancy exposure registry
2. risk summary
3. clinical considerations
4. data