Exam 4 - OB/GYN Flashcards
PREGNANCY AND LACTATION
..
Thalidomide
Thalidomide
- Used as anxiolytic for pregnant patients.
- Teratogen.
- Causes birth defects of limbs.
Kefauver-Harris Drug amendment to food, drug, and cosmetic act
-Need to prove efficacy and safety now
1st trimester
- Most risk for teratogenic effects on fetus
- Vision organogenesis
What drugs used most commonly during pregnancy?
90% of women take at least one medication during pregnancy
OTC medications
- Acetaminophen – 65% of pregnant women used; benign
- Ibuprofen – 18%
- Pseudoephedrine – 15%
Antidepressants
Teratogenesis
Any significant postnatal change in function or form in an offspring after prenatal treatment.
Congenital Anomalies
Includes congenital malformations and those defects related to change in function.
Congenital Malformations
Structural abnormalities of prenatal origin that are present at birth and seriously interfere with viability or physical well being of fetus.
Examples of Known Teratogens (non-inclusive)
ACE Inhibitors Androgenic hormones Cigarette smoking Cocaine Warfarin (Coumadin®) Isotretinoin (Accutane®) Lithium Phenytoin Thalidomide Valproic acid
Isotretinoin (Accutane®)
REMS
Determinants of Teratogenicity
Epidemiological Studies
- Case reports, Case control, Cohort studies
- Voluntary reporting systems
- No randomized controlled trials
Animal studies
-Beneficial in determining the relative toxicity of an agent usually; can NOT be extrapolated directly to humans.
Pharmaceutical Industry Disclaimer:
-The safe use of this drug in pregnancy has not been established and it should only be used if the anticipated BENEFITS outweigh the potential risks…
Stages of Fetal Development
Pre-implantation and presomite stages:
0-14 days post-conception
Organogenesis
~14-56 days post-conception
Most critical period; organs start to develop (1st trimester)
Fetal period
~57 days to 40 weeks
Histogenesis and functional maturation
How do drugs effect developing fetus?
Factors
- Stage of pregnancy during exposure, i.e. NSAIDs (B>D)
- Route of administration (IV vs. something not systemically absorbed)
- Dose, duration, etc.
Effects
- Destruction of fetus
- Structural anomalies
- Growth retardation
- CNS abnormalities
NSAIDs
- Category D in 3rd trimester
- Safe early on in pregnancy, but in third trimester, might close ductus arteriosus too soon
How do you know if a drug will be transferred from mom to the fetus?
- The more lipid soluble a drug is, the more likely it will pass through placenta.
- Charged and more polar drugs are water soluble and less likely to pass through the placenta.
- Ion trapping – fetal pH lower than mother. Something with no charge and lipophillic can cross placenta, but becomes negatively charged so it can’t diffuse back out.
Molecular weight (daltons) mw = 250 – 500 – very easily crosses mw = 500 – 1000 – easily crosses mw = >1000 – very poor Low the MW, the more likely it is to cross the placenta.
Protein Binding - More drug bound by serum proteins, the less that’s available to go cross placenta.
If a protein binds and kicks the drug off, then there’s more free drug to go to placenta.
How do you protect fetus from exposure to drugs?
2 main mechanisms protect fetus from drugs in maternal circulation:
Placental function:
- Semipermeable barrier, prevents things from crossing.
- Limited drug metabolism by placenta.
Drugs enter the fetus through the umbilical vein:
- 40-60% of the umbilical blood flow enter into the fetal liver
- Liver has enzymes to metabolize drugs.
Category A
A : Controlled studies in women fail to demonstrate risk in fetus during first trimester; fetal harm remote.
SAFE to use in pregnancy.
- Tylenol
- Folic acid
- Vitamins
Category B
Animal studies do not indicate risk to fetus and there have been no controlled studies in human women.
Animal studies have indicated risk, but human studies failed to demonstrate risk.
- NSAIDs in early pregnancy
- Zofran
Category C
C : Animal studies indicate risk and no adequate controlled human studies; risk vs. benefit
Not enough studies to say if the drug is okay or not
-Opioids?
Category D
D : Positive evidence of fetal risk but there may be certain situations in which benefits outweigh risk.
Patient might die if they don’t take the drug.
-Warfarin
Category X
X : There is definite fetal risk and the risk outweighs any benefit in pregnant women: CONTRAINDICATED.
-Acutane
How is drug transferred in breast milk?
General principles
Similar characteristics apply to transfer in breast milk as a placental transfer.
- Lipid solubility: high lipid solubility has easier transfer.
- Hind milk higher lipid content. ~produced towards beginning of lactation; concentrated, high fat milk.
- Charge - Ion trapping based on pH of milk vs. mom.
- Molecular size
- Protein binding
What additional factors influence how much drug can be transferred into breast milk?
-Time since delivery, i.e. initial post birth period there’s large gaps in mammary alveolar cells, which allow larger drugs to go through (close within 2 weeks postpartum, less transfer).
- Major determinant is maternal serum concentration
- i.e. Higher drug conc. in blood stream = more can transmit to milk.
- May be able to strategically schedule feedings for mom to have exposure without exposing the baby.
-pH of breast milk – 6.35 – 7.67: acidic is more likely to have ion trapping.
Pregnancy Label Changes
- Old nomenclature was not useful to assess risk, i.e. Cat C.
- Updates include reproductive risks – contraception, pregnancy testing, etc.
NEW LABELING:
- Pregnancy (L&D)
- Lactation
- Females and Males of Reproductive Potential (i.e. acutane)
Warfarin
- Category D
- Woman with mechanical heart valves might need it.
- Otherwise, considered X.
Odansetron
- Category B
- No risk to fetus, but unsure if it is excreted into the breast milk.
How do you treat a pregnant patient with nausea and vomiting?
Caused by dietary changes. Try to minimize triggers.
- Pyridoxine (B6) (A), given in combination with Doxylamine (A)
Diclegis – combination product, extended release $$$ - 5-HT3 Antagonists
-Ondansetron (MC) (B)
-Granisetron (B)
-Dolasetron (B)
More expensive agents $$
MW ~400; most likely passes into breastmilk, but not expected to harm infant. - Metoclopramide (Reglan) and promethazine (Phenergan)
- Dopamine blockade and antimuscarinic
- More likely to cause sedation and risk for extrapyramidal effects with larger doses (Parkinsonian effects)
What cardiac effects could you see with Ondansetron?
QTc prolongation
How do you treat a pregnant patient with heartburn?
Eating more frequent, small meals per day.
- Sucralfate (Carafate) - useful
- H2 receptor antagonists can be used if above does not resolve symptoms (ranitidine, famotidine, etc.)
- PPI are likely safe, but have less evidence for use – use if H2 blockers fail (omeprazole)
AVOID:
- Antacids in moderation, use LOW Na containing products (avoids HTN).
- Avoid sodium bicarbonate and magnesium trisilicate.
How do you treat a pregnant patient with constipation?
- Increase fiber and water intake
- Moderate exercise
- Bulk forming laxatives are DOC because they are not absorbed
»Methylcellulose, psyllium husk (Metamucil) - Surfactants (stool softeners)
»Docusate sodium (C) - Osmotic laxatives may be used for short-term intermittent use:
»Polyethylene glycol (Miralax)* MC,
lactulose, sorbitol, magnesium salts - Stimulants may be used occaisionally.
Avoid prolonged/repeated use of mineral oil – possible decreased fat soluble vitamins absorption.
»Senna, Bisacodyl
How do you treat a pregnant patient with hemorrhoids?
Try to avoid constipation!!
External topical products preferred (lower absorption) due to high rate of systemic absorption from internal products.
- Preparation H (hydrocortisone or phenylephrine)
- Tucks (witch hazel) – ok
- Sitz baths
How do you treat a pregnant patient with diarrhea?
Diarrhea
-Stool bulking agents are DOC
»Methylcellulose, psyllium husk (Metamucil)
-Loperamide (B)
»Works peripherally on GI opioid receptors to slow down tract.
How do you treat a pregnant patient with HTN during pregnancy?
Nondrug management
- Activity restriction (VTE)
- Stress reduction
- Exercise
Calcium 1-2 g daily decreases relative risk of HTN and preeclampsia (can cause constipation).
Magnesium sulfate
- Decreases risk of progression from preeclampsia to eclampsia
- Used to treat eclamptic seizures
- Smooth muscle relaxer to draw BP down.
- Benzodiazepines and phenytoin should be AVOIDED
How do you do chronic management for a pregnant patient with HTN during pregnancy?
Labetalol – 3rd gen. beta adrenergic blocker. Also has some alpha blocking effects.
- Being used as first line therapy in many places
- PO for chronic management, IV for acute tx.
Methyldopa – previous DOC
-Stimulates alpha 2 receptors (acts as false neurotransmitter after metabolism).
Other agents
- Calcium channel blockers (DHP) - nifedipine
- Nitroprusside or nitroglycerin for rapid IV treatment
How do you treat gestational diabetes mellitus?
Dietary modification is key.
Insulin is DOC during pregnancy and lactation (B)
-Does not cross the placenta! :)
Glyburide (sulfonylurea)
- Minimally crosses placenta
- Stimulates pancreas to release insulin
- Can cause fetal depletion of insulin
Metformin
- Insulin sensitizer at liver and skeletal muscle
- Appears to lack teratogenicity, but insulin is really preferred tx.
How do you treat a pregnant patient for an acute thromboembolism?
LMWH (enoxaparin)
-Recommended over UFH (heparin) and Warfarin (known teratogen)
Continue treatment throughout pregnancy and 6 weeks after delivery (minimum total of 3 months of therapy if they have a clot).
How do you treat a pregnant patient for a UTI?
UTI – always treat, even if asymptomatic.
Nitrofurantoin (macrocrystal) (B)
- Does not cover proteus species
- Inhibits bacterial carbohydrate metabolism and disrupts bacterial cell wall formation
Amoxicillin (B)
-Increasing risk of resistant E. coli
Cephalosporin (B)
ALL ARE COMPATIBLE WITH BREAST FEEDING :)
How do you treat PAIN in pregnancy?
Acetaminophen is DOC (B)
NSAIDS
(B) during 1st and 2nd trimester
(D) in 3rd trimester – premature closure of ductus arteriosus
Morphine
(B) during 1st and 2nd trimester for short periods of time
(D) if prolonged use or high doses at term
What closes ductus arteriosus after delivery?
- Indomethicin
- IV ibuprofen
How do you treat postpartum depression?
Selective Serotonin Reuptake Inhibitors (SSRIs)
-Effective agents
-Very few reports of adverse effects in infants exposed to SSRIs.
»Possibility for withdrawal effects (mild)
-Long-term developmental effects after exposure through breast milk are unknown.
Example agents:
- Citalopram (Celexa®)
- Escitalopram (Lexapro®)
- Paroxetine (Paxil®) 1.2-2 fold increased risk of cardiac malformations in 1st trimester.
- Fluoxetine (Prozac®) - long half life.
TCAs - 2nd line agent
- All excreted into breastmilk in low concentrations
- No adverse effects have been reported
Example agents:
- Amitriptyline (Elavil®)
- Nortriptyline (Pamelor®)
- Desipramine (Norpramin®)
What SSRI can cause cardiac malformations when given in the first trimester?
Paroxetine (Paxil®)
1.2-2 fold increased risk of cardiac malformations in 1st trimester
How can SSRI affect the fetus?
- Low fetal birth weight
- Less surfactant produced
Folic Acid
All women capable of becoming pregnant should consume 400 µg of folic acid daily to prevent neural tube defects (NTDs).
Women who have given birth to an infant with an NTD, should consume 4 mg folic acid beginning at least 1 month prior to conception.
Tocolytic therapy
- Purpose – postpone delivery
- Used when there are regular uterine contractions with cervical changes
4 classes:
- Beta agonists
Terbutaline (Brethine) – beta 2 selective agent; relaxes uterine muscle. Similar effects to albuterol, but given IV or PO. - Calcium channel blockers
Nifedipine – fewer ADE than other agents, appear to be more efficacious than other agents!!!! Treats HTN. - Magnesium – limited data for usefulness.
- NSAIDs – indomethacin, may be preferred if hypotension is a concern.
Progesterone
Tocolytic?
- 17-a-hydroxyprogesterone given IM weekly at week 16-36
- Given to high risk women with history of preterm birth; prevents maturation of cervix.
- Used to be compounded, now hydroxyprogesterone (Makena) is available $$$
How do you facilitate cervical ripening to induce labor?
Oxytocin (Pitocin)
- Most commonly used agent! Oxytocin receptors upregulated at time of pregnancy
- ADR: arrhythmia including PVCs, bleeding due to afibrinogenemia
Dinoprostone (Cervidil)
- Given vaginally
- Prostaglandin E2 analog
- Removed when labor begins or after 12 hours
- Must monitor fetal heart rate: risk of low HR.
Misoprostol (Cytotek)
- Prostaglandin E1 analog
- Also used in NSAID induced ulcer treatment, termination of pregnancy
Labor Pain Mgmt:
- Most often administered as an epidural infusion.
- Fentanyl/bupivacaine most common combination.
ADE
- Hypotension, pruritus, inability to void (need catheter).
- Prolongation of first and second stages of labor (ex: wife 16hr labor).
- Spinal headache due to puncture of the subarachnoid space.
Why are epidurals preferred?
- They go in epidural space; fetus is not exposed.
- Can control level of anesthesia you provide to mother.
ESTROGENS/PROGESTINS
…
What estrogens are produced in women?
Major estrogens produced in women
- Estradiol – major secretory product of the ovary
- Estrone and estriol - converted in the liver or periphery
What are the equine estrogens (used as supplements)?
Equilenin and equilin
- Captured in the urine and purified
- Premarin® - Pregnant Mare Urine
Synthetic estrogens:
Used in estrogen replacement therapy and oral contraceptive products.
- Ethinyl estradiol
- Micronized estradiol
- Estradiol cypionate
- Estradiol valerate
- Estropipate
-Conjugated estrogens
»Mixtures of estrogenic compounds
Whats an important PK trait of synthetic estrogens?
- Highly protein bound
- Bind to alpha2 globulin (sex hormone-binding globulin) and albumin
Estradiol => estrone and estriol
- Conjugated metabolites excreted in bile
- Hydrolyzed in intestine to active form, become re-absorbable compounds.
- Enterohepatic recirculation
High ratio of hepatic to peripheral effects
- Adverse effects
- Avoided liver effects by giving other routes (vaginal, transdermal, injection)
How does estrogen work when it gets to the cells?
- Bound estrogens disassociate from SHBG (sex hormone binding globulin).
- Cross cell membrane
- Enter nucleus and bind estrogen receptors
When estrogen gets into the cells, what happens?
-Hormone complex forms dimers (mixtures of ERα and ERβ)
- Bind to estrogen response elements (EREs)
- Regulates various genes and transcription
- Effects of binding can be tissue specific due to interaction with coregulators, tissue types, etc.
Clinical effects of estrogen: female growth and sexual maturation
- Stimulates development of vagina, uterus, secondary sex characteristics
- Growth phase and epiphyseal closing of long bones at puberty; stronger bones.
- Hair growth and body fat distribution
Clinical effects of estrogen: endometrial effects
- Develops endometrial lining
- Interaction with progesterone encourages regular bleeding and shedding of endometrial lining.
- Continuous exposure to estrogens leads to hyperplasia and abnormal bleeding.
- Progesterone effect is important to slough lining and reduce risk of cancer.
Clinical effects of estrogen: Metabolic effects.
- Normal structure and function of skin and blood vessels
- Decrease bone resorption (stimulates apoptosis of osteoclasts and antagonizes parathyroid hormone)
- Stimulates adipose tissue development
- Higher serum protein levels (due to liver effects)
- Increase in HDL, reduction of total plasma cholesterol, increased TG
How does estrogen impact the liver?
Coagulation effects
- Enhance coagulability: make more clotting factors.
- Increased factors II, VII, IX, X
- Decreased antithrombin III
Other effects
- Affects mood and libido
- Produces edema and fluid retention
Primary Hypogonadism
- Can replace deficiency in patients affected by developmental failure of ovaries, premature menopause, castration, or menopause.
- Can begin at 11-13 years to stimulate secondary sex characteristics and menses, prevent osteoporosis, etc.
Tx: Estrogen
When is estrogen given in relation to the cycle?
What do you add after first uterine bleeding?
- Given on days 1-21 of each month to simulate normal estrogen levels.
- Progestin added on after first uterine bleeding
Postmenopausal hormonal therapy (HRT)
- Loss of menstrual periods, vasomotor symptoms, sleep disturbances, genital atrophy
- Acceleration of bone loss (vertebral, hip, wrist fractures)
- Changes in lipids leading to atherosclerotic changes: LDL increases, LDL receptors decrease (not cleared as well).
Tx: Estrogen
Estrogen - cardioprotective?
Estrogens thought to be cardioprotective
- Women’s Health Initiative showed no benefit
- Possible increased cardiovascular and breast cancer risk
When starting postmenopausal hormonal therapy, what should be considered?
Optimal therapy must consider CV status, osteoporosis, breast cancer, endometrial cancer risk factors
- Transdermal or vaginal estrogens associated with lower risk
- Lowest dose should be used for symptom management (hot flashes, etc.)
Atrophic vaginitis
Topical preparations may be used for atropic vaginitis alone
Hysterectomy patients -
What hormone replacement therapy can they be on?
- Patients with hysterectomy can receive estrogens alone
- Progestins not required to reduce endometrial hyperplasia and cancer risk
Don’t have endometrial lining to worry about hyperplasia/CA
Osteoporosis prevention and treatment:
-Take calcium, vitamin D, and exercise status
High risk:
-Thin, Caucasian smokers who are inactive and have low calcium intake
Other uses of estrogens:
- Ovulation suppression in intractable dysmenorrhea
- Pt comes into ER for intractable bleeding. Can give big dose of estrogen to cut off.
-Suppression of ovarian function in treatment amenorrhea and hirsutism due to excessive androgen secretion
