L20: Drugs in Pregnancy

Question 1

Period of organogenesis

Answer 1

First trimester

Question 2

2 main concerns when giving a drug in pregnancy

Answer 2

Whether the drug is teratogenic

Whether the drug can affect the fetus near term

Question 3

Example of a drug that can cause hemolytic anemia if given to a fetus near term

Answer 3

UTI drugs

Question 4

Teratogen:

Answer 4

agents that cause birth defects, congenital malformation, abnormal development in an exposed embryo or fetus:

Dose-dependent; selective for target organs
May exert effects at specific time in development
Caution in women of childbearing age
Contraception recommended or required→ not everyone realizes right away when pregnant

Question 5

Thalidomide is super teratogenic, but most toxic during _____

Answer 5

Weeks 3-7

Question 6

Example of a category A drug

Answer 6

Folic acid

Question 7

Category A

Answer 7

Controlled studies show no risks

Adequate, well-controlled studies in pregnant women demonstrate no risk in any trimester of pregnancy

Question 8

Category B

Answer 8

No evidence of risk in humans

ONE of the following:
Adequate, well-controlled studies in pregnant women have not shown and increased risk of fetal abnormalities despite adverse findings in animals,
In the absence of adequate human studies, animal studies indicate no fetal risk.

Question 9

Category C

Answer 9

Risk cannot be ruled out

No adequate, well-controlled human studies; adverse effects shown in animal studies, or are lacking, possibility of fetal harm

Question 10

Category D

Answer 10

Positive evidence of human fetal risk

Studies in humans have demonstrated fetal risk. “WARNING” statement about such drugs appeared on the package insert.

Question 11

Category X

Answer 11

Contraindicated in pregnancy

Known teratogens
Use requires contraception
“Contraindication” section of the package insert.

Question 12

8.1

Answer 12

Pregnancy

Question 13

8.2

Answer 13

Lactation

Question 14

8.3

Answer 14

Females and males of reproductive Potential

Question 15

Drug absorption in pregnancy

Answer 15

Drug absorption: high circulating levels of progesterone slow gastric emptying and gut motility, resulting in slower drug absorption

Question 16

Drug metabolism in pregnancy

Answer 16

Drug metabolism: hepatic drug metabolizing enzymes are induced during pregnancy – may lead to rapid metabolic degradation of drugs, particularly lipid soluble drugs.

Question 17

Drug excretion in pregnancy

Answer 17

Drug excretion: renal plasma flow increased by 100% and glomerular filtration rate by 70%, drugs that are eliminated by the kidney are eliminated more rapidly than non-pregnant women.

Question 18

Increases in total blood volume in pregnancy

Answer 18

Increase in total blood volume: change in cardiac output, blood pressure and glomerular filtration rate – leads to changes in volume of distribution of drug and metabolism, absorption, excretion, protein binding, placenta passage.

Question 19

Always assume that ______

Answer 19

any drug taken during pregnancy will reach the fetus

Question 20

Placenta:

Answer 20

semipermeable
barrier and site of metabolism
(oxidation reactions)

Question 21

Placental and fetal metabolism

Answer 21

The placenta metabolizes some drugs but may also produce toxic metabolites (e.g., ethanol). Drugs that enter the fetal circulation may be metabolized by the fetal liver, and metabolites may be more toxic than the parent drugs.

Question 22

Examples of conditions that SHOULD be treated in pregnant mothers

Answer 22

Thyroid disorders, the baby also needs T3 for development

Hypertension

Hyperglycemia

Question 23

Drugs that may have beneficial effects in fetus

Answer 23

Avoiding preterm labor

Corticosteroids to mature lung

Antivirals to prevent transmission of herpes or HIV

Drugs for fetal heart problems

Folic acid (cat A) to prevent neural tube defects→ 400 ug/day → prevent development of neural tube defects

Question 24

Mechanisms for drugs not used in pregnancy

Answer 24

Damage or inhibit synthesis of DNA and/or RNA (i.e. Actinomycin D)

Antimetabolites and other cancer treatments: rapidly proliferating cells affected most

Radiation: therapeutic or accidental, free radicals can damage enzymes

Thalidomide: folic acid antagonist

Isotretinoin: affects cell differentiation/proliferation

Hormones may alter development

Question 25

Drugs that are ______ soluble cross the membrane, drugs that are _______ don't

Answer 25

Cross: highly lipid soluble Don't cross: highly ionized

Question 26

Salicylate crosses the placenta by ____-

Answer 26

Salicylate is highly ionized BUT it has a small non-ionized highly lipid soluble fraction that crosses readily

Question 27

Why can heparin be used in pregnancy?

Answer 27

>1000 molecular weight, can't cross the placenta

Question 28

Why can warfarin cross the placenta?

Answer 28

Molecular weight <500

Question 29

What's the exception to the molecular weight rule?

Answer 29

Large antibodies are transferred across the membrane

Question 30

How does the placenta keep out drugs?

Answer 30

Drug transporters: The P-glycoprotein transporter (MDR) pumps many drugs and toxic compounds back into the maternal circulation, keeping them from crossing the placenta

Question 31

Which drugs are pumped out of the placenta by P-glycoprotein transporter?

Answer 31

Vincristine Doxorubicin Protease inhibitors for HIV.

Question 32

Protein binding in the fetus

Answer 32

The binding affinity of fetal proteins is lower, so drugs that may be highly bound in the maternal blood may be less so in the fetus. Highly lipid soluble drugs like anesthetics are more influenced by rate of blood flow.

Question 33

Placental and fetal metabolism

Answer 33

the placenta metabolizes some drugs but may also produce toxic metabolites (e.g., ethanol). Drugs that enter the fetal circulation may be metabolized by the fetal liver, and metabolites may be more toxic than the parent drugs.

Question 34

What's the big lesson from DES use?

Answer 34

Teratogenic effects are not always seen immediately

Question 35

Diethylstilbestrol

Answer 35

1940-1971 treatment of threatened abortion | Dosage was equivalent to estrogenic effect of 55,666 birth control pills

Question 36

Diethylstilbestrol | abnormalities

Answer 36

1st trimester→ Multiple abnormalities of the vagina, cervix, and uterus consisting of vaginal and/or cervical ridges Adenocarcinoma of the vagina or cervix has developed in some of these daughters as they entered their 20s

Question 37

Warfarin is a _____

Answer 37

Oral vitamin K antagonist that causes embryofetopathy

Question 38

Warfarin syndrome abnormalities

Answer 38

``` Saddle nose, Depressed nasal bridge Epiphyseal stippling Vertebral calcifications Intellectual disability Short neck Fetal death ```

Question 39

Thalidomide was used to _______

Answer 39

Sedative, combat nausea in pregnant women

Question 40

Thalidomide causes _______

Answer 40

Damage DNA through oxidative stress→ limb deformities

Question 41

Thalidomide has ______ and is subject to strict controls

Answer 41

Orphan drug status

Question 42

Isotretinoin use and MOA

Answer 42

Systemic tx of severe acne: activate retinoic acid receptors that bind to specific DNA sequences and affect cellular differentiation and proliferation, or induce apoptosis.

Question 43

Isotretinoin abnormalities

Answer 43

Extremely teratogenic: even 1 exposure in first 3 weeks Birth defects : hydrocephaly; microcephaly; intellectual disability; ear and eye abnormalities; cleft lip and palate and heart defects, Increased the risk of miscarriage, premature delivery, infant deaths.

Question 44

iPLEDGE program for use in women:

Answer 44

For isotrentinoin (-) pregnancy test 2 forms of birth control→ on surgical or hormonal→ start 1 month before + continue 1 month after therapy

Question 45

Ribavirin is used to treat

Answer 45

HCV | RSV

Question 46

Ribavirin causes

Answer 46

malformations of skull, palate, eye, jaw, limbs, skeleton, and GI tract Intrauterine fetal death Male and female-mediated teratogenicity Aerosolized exposure problematic

Question 47

Avoiding ribavirin teratogenicity

Answer 47

hCG: before use, q month while using and 6 months after Both men and women of childbearing potential must use 2 forms of effective contraception during treatment and for 6 months after discontinuation

Question 48

Anticonvulsants

Answer 48

Very common teratogen in women of childbearing age Safety concerns: mother, developing fetus, neonate/infant Seizure control correlates with plasma drug concentrations: Metabolism concerns: steady state plasma concentrations of antiepileptic drugs tend to fall unless the drug doses are increased – increased maternal glomerular filtration and renal clearance (gabapentin); increased biotransformation (induction of p450s) increase elimination; dilutional effect from increased maternal fluid.

Question 49

Anticonvulsants treat

Answer 49

Epilepsy psychiatric disorders pain management

Question 50

Lowest risk anticonvulsants

Answer 50

*** levetiracetam lamotrigine *** gabapentin clonazepam

Question 51

Never give this anticonvulsant

Answer 51

Valproate

Question 52

Medium risk anticonvulsants, avoid

Answer 52

Phenytoin Phenobarbitone Carbamazepine Topiramate

Question 53

Feta hydantoin syndrome

Answer 53

cleft lip, cleft palate, congenital heart disease, slowed growth, mental deficiency: phenytoin, phenobarbitone

Question 54

Carbamazepine | Topiramate abnormalities

Answer 54

Craniofacial abnormalities, developmental delay, mental retardation

Question 55

Valproate abnormalities

Answer 55

1st trimester→ major and minor malformations: Neural tube defects→ spina bifida, cleft lip/palate Cardiovascular abnormalities, endocrine disorders, genitourinary defect, limb defects, facial abnormalities Developmental delay, autism/autism spectrum disorder