ICL 14.5: Pharmacology of Pregnancy Flashcards
what are some assumptions you make when giving medications to pregnant women?
- treat pre-conception as pregnant
- assume some placental crossing when giving a medication
- 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
- uncontrolled disease states and/or a discontinued medication carry maternal and fetal risk as well
what are pharmacokinetics?
describes the absorption, distribution, metabolism, and elimination of drugs in patients requiring drug therapy
what is drug absorption/bioavailability?
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
what is drug clearance?
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
what is the extraction ratio of a drug?
the proportion of a drug taken up from the hepatic arterial circulation into hepatocytes, making it available for subsequent metabolism
which drugs have high extraction ratios?
- propranolol
- verapamil
- morphine
- lidocaine
so the clearance of these drugs is equal to blood flow to the organ
what does it mean if a drug has a low extraction ratio? which drugs have low ER?
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
- warfarin
- theophylline
- diazepam
- phenobarbital
what is volume of distribution of a drug?
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
what is the half life of a drug?
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
what are the two phases by which the liver metabolizes drugs?
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
what is absorption of a drug?
the movement of drug from the site of administration into the systemic circulation
how is absorption of a drug effected during pregnancy?
absorption is the movement of drug from the site of administration into the systemic circulation
with pregnancy there is:
1. increased nausea/vomiting
- 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
how is the distribution of a drug effected during pregnancy?
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
- increased blood volume (40-45%)
- increased maternal body fat
- 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
- increased maternal body fat may increase the volume of distribution for lipophilic drugs
- volume of distribution increases may impact initial drug concentrations after a loading dosed cause decreased peak plasma concentrations after multiple administrations
- 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
- 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
how is drug metabolism impacted during pregnancy?
metabolism involves chemical modification of a drug through specialized enzymatic systems
during pregnancy there is:
1. increased hepatic arterial and portal venous blood flow
- 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
- CYP1A2 and CYP2C19 appear to undergo a gradual decrease in activity throughout gestation
- 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
how renal excretion effected during pregnancy?
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
how common are birth defects?
4%
1/28 and most are idiopathic
less than 1% caused by teratogen
how do drugs cross into the placenta from the mother?
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)
which types of drugs cross the placenta easily?
- small-molecular-weight and lipophilic drugs readily cross the placenta via passive diffusion
- 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
which drug classes are known teratogens?
- ACE inhibitors/ARBs
- anticonvulsants
- diethylstilbestrol
- isotretinoin/high doses of vitamin A
- lithium
- methotrexate, aminoptrine
- NSAIDs
- thalidomide
- warfarin
what is the teratogenic effect and critical period associated with ACE inhibitors?
renal failure, anuria, oligohydramnios, pulmonary hypoplasia, intrauterine growth restriction, limbs contracture, skull hypoplasia
contraindicated after first trimester
what is the teratogenic effect and critical period associated with anticonvulsants?
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
what is the teratogenic effect and critical period associated with diethylstilbestrol?
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
what is the teratogenic effect and critical period associated with vitamin A?
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
what is the teratogenic effect and critical period associated with lithium?
cardiac malformations: risk of 0.9%-6.8%
contraindicated during cardiac organogenesis (5-10 wk after LMP)
what is the teratogenic effect and critical period associated with methotrexate?
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
what is the teratogenic effect and critical period associated with NSAIDs?
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
what is the teratogenic effect and critical period associated with thalidomide?
limb anomalies (amelia, phocomelia)
cardiac, urogenital, gastrointestinal, and ear malformations
contraindicated 34-50 d after LMP
what is the teratogenic effect and critical period associated with warfarin?
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
the fraction of drug absorbed into the systemic circulation is called what?
bioavailability
the proportion drug taken up from hepatic circulation to be metabolized is called what?
extraction ratio
T/F: CYP enzymes may be impacted during pregnancy
true
volume of distribution is used to ermine what?
loading dose
1/2 life is used to determine what?
dosing interval
which CYP enzyme activity is increased vs. decreased during pregnancy?
increased: CYP3A4 CYP2D6 CYP2C9 UGT1A4 UGT1A1/9
decreased:
CYP2C19
CYP1A2
NAT2
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 – 19g/mL (therapeutic range 10-20g/mL)
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
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)
- CYP2C9 substrate and this enzyme has increased activity in pregnancy which will decreased phenytoin levels
- medication is protein bound so decreased albumin will have higher unbound phenytoin and lead to higher activity!
- N/V may impact ability to take orally and lead to decreased absorption and decreased effect
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?
opiate abuse problems but it’s good shes not using drugs so that’s good but the risks include:
- preeclampsia
- premature labor
- placental insufficieny
- low birthweight
- neonatal abstinence syndrome (NAS)
- 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
what is pregnancy and lactation labeling rule?
PKKR
A,B,C letter categories for risk but this isn’t used any more; now we use labor and delivery pregnancy section
what is the labor and delivery pregnancy section?
- pregnancy exposure registry
- risk summary
- clinical considerations
- data
