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
ADR Estrogen: Uterine bleeding
How do you avoid?
- Major cause of postmenopausal uterine bleeding
- Could also be due to endometrial carcinoma.
- Use smallest dose of estrogen possible.
- Give estrogens cyclically so that bleeding occurs during withdrawal period.
-Endometrial hyperplasia prevented by co-administration of a progestin. IMPORTANT.
ADR Estrogen: Cancer
Increased breast cancer with prolonged use
-Use of SERMs (tamoxifen) for high risk patients
Endometrial carcinoma
-Give progestin to prevent risk
Adenocarcinoma in young women
- Linked to maternal use of diethylstilbestrol
- Teratogen; increases cancer risk
ADR Estrogen: Non-specific.
Nausea/vomiting Breast tenderness Hyperpigmentation Migraines Cholestasis Hypertension (holding onto water and salt)
Use lowest dose possible
Estrogen CI
- Estrogen dependent neoplasm
- Undiagnosed genital bleeding - R/O cancer
- Liver disease, will worsen effects PO
- Thromboembolic disorders
- Smokers
Progestins
- Act at androgen receptors and mineralocorticoid receptors (AR, MR)
- SE from AR: hirsutism, lower voice, irregular cycles
-Norgestrel (high AR activity)
-Levonorgestrel (high AR activity)
Most commonly used.
- Norethindrone (more PR, less AR activity)
- Norgestimate (low AR, little ER activity)
- Desogestrel (less AR, no ER; better HDL)
- Drospirenone (anti-MR, anti-AR)
Mineralcorticoid effects can worsen edema. Antagonists can lead to weight losss from fluid loss.
Drospirenone (anti-MR, anti-AR)
Yaz
- Anti-mineralcorticoid effects!!
- May see weight loss from loss of fluid
- Anti-androgen receptor activity
Androgen receptor activity:
Increased androgen receptor activity will worsen lipid profile.
Progestins MOA/PK
MOA
- Works similarly to other steroids discussed
- Binds to progesterone response element; go to nucleus to activate receptors and change gene transcription.
PK
- Rapidly absorbed
- High first-pass effect
- Excreted into the urine
Physiological effects of progestins:
- Little effects on lipids, unless high AR activity
- Increased basal insulin levels and insulin response to glucose
- Competes with aldosterone in kidney, leading to increased release of aldosterone activity (worsens edema).
- Maturation and secretory changes in endometrium??
What’s a benefit to using synthetic progestins?
- Have minimal androgenic, anabolic activity
- Reduce side effects
Uses of progestins:
- Hormone replacement therapy
- Long term ovarian suppression
- Used in dysmenorrhea, endometriosis, and bleeding disorders when estrogens are contraindicated.
Progestins in long term ovarian suppression:
Can be used along in large parenteral doses:
- Medroxyprogesterone acetate (Depo-Provera)
- Given IM every 90 days
- Prolonged anovulation and amenorrhea
- Takes longer to return to normal ovulation
- Not good for near-future pregnancies
ADR: Progestins
- May increase blood pressure
- Androgenic progestins can lower HDL
HORMONE REPLACEMENT THERAPY
……post menopausal, primary deficiencies, those with pituitary tumors.
HRT indications:
FDA Approved Indications
-Treatment of moderate to severe vasomotor symptoms associated with menopause
- Treatment of vulvar and vaginal atrophy
- Dryness, dyspareunia, atrophic vaginitis topical products
-Prevention of postmenopausal osteoporosis
Estrogen-Progestin Therapy
Estrogen-Progestin Therapy
- Used in patient who have not had a hysterectomy (i.e. intact uterus)
- Estrogen + progestin every day or Estrogen day 1-25, Progestin last 10-14 days, drug free on days 26-30.
- Like prior to menopause.
Estrogen therapy
Estrogen therapy
- Used in patients with hysterectomy
- Don’t need progestin since they’re not at risk for endometrial cancer
- Continuous or cyclic estrogen
Low dose oral contraceptives
-Higher dose of estrogen than typical hormone replacement (4-6 times as much).
What has higher estrogen levels? HRT or OCP
What has higher estrogen levels?
- HRT - trying to mimic what patient would make on own
- OCP - trying to shut cycle down; need higher doses
HRT Dosage forms
- Oral – undergo first-pass metabolism, stimulate hepatic proteins, stimulates production of clotting factors and cholestasis
- Transdermal – preferred in women with history of HTN, increased TG, risk for VTE, cholelithiasis
- Intravaginal – preferred for vaginal symptoms only
- Can still see substantial systemic absorption of estrogens – good for systemic effects
- Minimal vaginal absorption: vaginal tablets and ring (Estring) - provide high dose therapy at site of action; limits systemic absorption.
Estrogen only products are best for what types of patients?
Those who have had a full hysterectomy; don’t have intact uterus.
Transdermal Estrogen Products
17-beta estradiol (MC):
PATCH: -Alora -Climara - 1x/week -Estradiol -Estraderm -Menostar - 1x/week -Minivelle -Oesclim -Vivelle dot >Rest are 2x/week >Bad memory - once per day >Caregiver - once per week
GEL
- Divigel
- Estrogel
- Elestrin
SPRAY
-Evarnist
Patient needs HRT, PMHx: VTE
Transdermal product needed
Vaginal Estrogen Products
17-beta estradiol:
-Estrace vaginal cream
Conjugated estrogens:
-Premarin vaginal cream
Estrone:
-Estragyn vaginal cream
Vulvovaginal atrophy, tx:
17-beta estradiol:
-Estrace vaginal cream
Atrophic vaginitis
Kraurosis vulvae
Dyspareunia
Tx:
Conjugated estrogens:
-Premarin vaginal cream
Senile vaginitis
Prurit vulvae
Kraurosis vulvae
Tx:
Estrone:
-Estragyn vaginal cream
Rings
Estring: 17 beta estradiol
Fremring: estradiol acetate
Give once every 90 days, then replaced.
Tablet
Estradiol: Vagiferm
Combination estrogen-progesterone products
Important for those with an intact uterus!!!!
ORAL: Conjugated estrogen, plus medroxyprogesterone acetate: -Premphase - CYCLIC -Prempro -Premplus
Ethinyl estradiol, plus norethindrone acetate:
- Femhrt
- Activella
- Activelle LE
- Angeliq
17B estradiol
-Prefest
Conjugated estrogen and medorxyprogesterone acetate
-Premplus cycle
TRANSDERMAL
17B estradiol and norethindrone acetate:
Combipatch
Estalis
17B estradiol and levonorgestrel
-Climara pro
PROGESTROGENS
Medroxyprogesterone acetate
-Provera, Provera Pak
Micronized progesterone
-Prometrium
Other drugs to prevent vasomotor symptoms of menopause:
Antidepressants
- SSRIs
- Venlafaxine (SNRI)
- Desvenlafaxine (SNRI)
- Anticonvulsants -Gabapentin
- Antihypertensives -Clonidine
Clonidine decrease catelcholamines to prevent manifestations like hot flashes.
SNRI
cause symptoms similar to hot flash
- SE of drugs, not actual hot flash
- Venlafaxine
- Desvenlafaxine
64y/o female, hysterectomy. Mother had breast cancer.
What product should be used for her atrophic vaginitis?
-Need a breast cancer work up before administering any estrogen-based products.
ORAL CONTRACEPTIVES
….
What’s used for hormonal contraception?
Estrogens and progestins
- Have intact uterus
- Stunt growth of endometrium
Monophasic
Monophasic – constant dosage of both during menstrual cycle
*least like a normal cycle
Biphasic
Biphasic – dosage of one or both components changed ONCE during the cycle
Triphasic
Triphasic – dosage of one or both components changed TWICE during the cycle
Last 7 days of birth control pack:
Placebo pills; keep patient compliance
Hormone contraception MOA
Selective inhibition of pituitary function that results in inhibition of ovulation; body won’t release FSH and LH (since there’s estrogen giving negative feedback loop).
Combination agents
- Change in cervical mucus
- Uterine endometrium
- Motility and secretion in uterine tubes
- Decreased likelihood of conception and implantation
What type of hormonal birth control doesn’t always inhibit ovulation?
Progestins alone don’t always inhibit ovulation
Risk for failure is higher
What effects are seen on the ovaries for patients on hormonal contraception?
-Depressed ovarian function – smaller during therapy
- Most patients return to normal menstrual patterns once discontinued
- 75% ovulate in first cycle, 97% by third, some remain amenorrheic for several years
What effects are seen on the uterus for patients on hormonal contraception?
- Hypertrophy and polyp formation
- Thicker, less copious mucus
What effects are seen on the breasts for patients on hormonal contraception?
- Enlargement
- Suppresses lactation
What effects are seen hematologically for patients on hormonal contraception?
- Birth control increases production in clotting factors VII, VIII, IX, X
- Decrease in antithrombin III
- Thromboembolic concerns
What drug uses anti-thrombin 3 to work better?
Heparin and fondaparinux
-Use antithrombin 3 to catalyze and speed up reaction.
Warfarin
Prevents production of factors II, VII, IX, X
What physiologic effects happen on skin of those taking OCP?
- Hyperpigmentation
- Dark complexions, esp in exposure to UV light
Androgen effects can cause or worsen acne.
What drugs increase metabolism of OCP?
Preggo risk can be increased by drugs that increase metabolism of drug (phenytoin), antibiotics that inhibit enterohepatic recycling
Phenytoin - enzyme inducer
Antiepileptics
Antibiotics
Patient education: What do you tell a patient on an OCP if you’re prescribing them antibiotics?
Use a back up.
Why is hormonal contraception used for endometriosis?
- Estrogen alone may be sufficient to alleviate pain :)
- Need progestin on board to minimize hypertrophy
- To limit adverse effects, use smallest dose of estrogen possible
What are the MILD adverse effects of hormonal contraception?
- Nausea, mastalgia
- Breakthrough bleeding, edema
- Headache – mild and transient, can make migraine worse
- Possible increase risk of cerebrovascular accidents
- D/C therapy if migraine coincides with therapy
Withdrawal bleeding may fail to occur
>Confusion about pregnancy
>Can try other agents if problematic
How can you limit breakthrough bleeding?
- Caused by too much estrogen.
- Limiting the dose of estrogen or using a progesterone with more androgenic effects.
How can you limit edema?
Progesterone causes MC effects (water/Na retention).
Mineralcorticoid antagonist has neutral effects on weight.
What are the MODERATE adverse effects of hormonal contraception?
- BTB
- Weight gain
- Increased pigmentation
- Acne
- Hirsutism
- Urethral dilation
- Vagination infections are MC and more difficult to treat
- Amenorrhea
When is BTB most common?
How do you treat?
- MC in progestin only products
- Occurs in low dose preparations as well (prefer low dose prodts., but if you go too low, can have BTB).
Tx:
-Biphasic and triphasic products decrase BTB without increase in total hormone content (estrogen)
When does weight gain occur?
How do you treat?
-Occur in androgen-like progestins due to MC effects of water retention/lipid panel
Tx:
-Shift to product with less progestin effect or dieting
When does increased pigmentation occur?
- Increases in time.
- 40% experience after 8yrs.
- Reversible but slow to occur
- Exacerbated by vitamin D deficiency
Why does acne occur? How can you avoid it?
-Androgen-like effects
Tx:
-Large dose estrogens can improve acne.
How can you avoid hirsutism?
- Aggravated by androgenic progestins
- Switch to less androgenic agent
How can you avoid ureteral dilation?
-Prone to UTI
How can you avoid amenorrhea?
- Occur in patient with prior irregularities
- May have undx: prolactinomas
What are the SEVERE adverse effects of hormonal contraception?
- VTE
- MI
- CVD
- GI
- Depression - require discontinuation
- Cancer
Oral contraceptives and risk of VTE:
- Risk is three fold higher while on low-dose OC
- Increased during first month of use and remains constant
- Returns to normal within a month of discontinuing
- Hypercoagulable states at higher risk
-Risk related to estrogen only
Oral contraceptives and risk of MI:
- Increased risk in obese, HTN, diabetes
- Higher in smokers
- Increased atherogenesis, coronary arterial spasm
- Androgenic progestins can lower HDL
Oral contraceptives and risk of CVA
Risk of stroke
Highest in women above 35 years
Oral contraceptives and GI issues
- Cholestatic jaundice
- Seen in first three cycles normally
- Jaundice and pruritus resolve 1-8 weeks after discontinuation.
- Happens with PO products
- Switch to IV (parenteral prodts).
OCPs and cancer…
- Reduced risk of endometrial and ovarian cancer
- Lifetime risk of breast cancer appears unaffected…
-Cervical cancer risk increased in women with HPV (unless they got gardasil).
Progestins - 1st gen.
Norethindrone
Ethynodiol diacetate - +
Norgestrel - +++
Norethindrone acetate
Most of androgenic effects you’ll have.. Also, estrogenic.
Progestins - 2nd gen.
Levonorgestrel - ++++
Has a large androgenic affect - worsens acne, hirsutism.
Worst one on chart!
Progestins - 3rd gen.
Norgestimate
Desogestrel
Lose that androgenic effect
Progestins - 4th gen.
Drospirenone
Best one to start a patient on
Yaz
Has androgen receptor antagonist effects and anti-MC effects (lose a lot of side effects with this product).
When ya don’t wanna give OCPs, dude?
8 important things.
- Thrombophlebitis, cardio vascular, cerebrovascular disorders
- Unknown cause of vaginal bleed, could be cancerous!!!
- Estrogen dependent tumors
- Heart failure - worsened by water retention and edema.
- Adolescents who haven’t undergone epiphyseal closure; don’t want premature closure. Could cause growth stunting.
- Hepatic enzyme inducers (rifampin, phenytoin, etc.) - drive levels of contraceptives down; leads to accidental pregnancy.
- Antibiotics
- Pregnancy
Progestin only contraception
- Better for patients who you don’t want to start estrogen in!
- As effective as other combination products
- Higher abnormal bleeding, but decreases over time.
- Amenorrhea common in patients.
- Delayed return to ovulation.
MC: Progesterone only mini pills or Depo Provera (medroxyprogesterone) oil IM, lasts 90 days.
If a patient wants to get pregnant during a certain timeline, what do you have to be careful about?
“Married for a year and trying to get pregnant”
- Delayed return to ovulation
- Progestin only prodt. may not be the best product for them.
Post coital contraceptives
“Morning after pills”
-Can be estrogen, progestin only or combination. Progestin ONLY are recommended.
- 99% effective when given within 72 hours of sex. The earlier to take the better.
- Administer with antiemetics (40% N/V)
If patient throws up within one hour after taking morning after pill:
Readminister the dose
If patient throws up more than one hour after taking morning after pill:
Dose has already been absorbed at that point; dont have to take another.
Morning after pills, names:
L-Norgesterel (Plan B, One Step)
MC - take one dose or two doses 12 hrs apart (easier on the stomach).
- Ethinyl estradiol
- Diethylstillbestrol
- Mifepristone (day 1) with misoprostol (day 3)
- Norgestrel with ethinyl estradiol
How can you use oral contraceptive pack as “Plan B”?
Can use multiple pills to get same effect.
- Not as recommended.
- OK if cost is an issue.
- 100mcg estrogen
- 0.5mg progestin
- Needed 12 hours apart, 2 doses.
Beneficial effects of morning after pill:
Reduced risk of
- Ovarian cysts
- Ovarian and endometrial cancer
- Ectopic pregnancy
- Iron deficiency - less bleeding and holding onto more iron.
- Rheumatoid arthritis
- Endometriosis
- Acne improved.
- Hirsutism improved.
- with less androgenic progestins.
How do you start OCP tx?
- Start with a combination pill
- Use lowest effective estrogen content (30-50 mcg)
- Acceptable level of side effects
- Give 3 month supply to see how they like it.
What day should you start your oral contraceptive?
1st Sunday after the onset of menses
-Avoids withdrawal bleeding on the weekends.
Post-pregnancy: 3-4 weeks post delivery, but supresses lactation
Post abortion - 1st Sunday after abortion.
When should you use alternative methods (“back up methods”) of birth control?
- Initial cycle (controversial)
- Missed pills, especially with low estrogen doses
- Severe diarrhea (clearing too quickly and not absorbing the drug enough, risk for failure)
- Antibiotics - alter enterohepatic recycling.
What do you do if you miss a single pill?
Take as soon as remembered
What do you do if you miss two pills?
Take 2 pills a day for 2 days
What do you do if you miss three pills?
- Risk for failure too high
- Back up contraceptives
- D/C for rest of pills and restart on a new Sunday
What do you do if your patient on OCP has missed periods (or failure of withdrawal bleeding)?
No missed pills = pregnancy test after 1st missed period
How do you reschedule the menstrual cycle?
Honeymooning - can reschedule a woman’s period to make sure she’s not on her period during an event (honeymoon, spring break, etc).
Skip placebo and take active pills until event is over
Stopping pills?
- Don’t need a rest period.
- If you have a desire to become pregnant, allow for 3 regular cycles prior to conception.
- Success higher at that point bc ovulation is normal
Progestin pills - delayed ovulation; may need to wait longer than 3 months
Breakthrough bleeding:
- If during first 3 months, resolves over time.
- If present after 3 months, manipulate doses.
- Bleeding on days 1-14 indicates estrogen deficiency.
- Bleeding on days 15-21 indicates a progestin deficiency.
Medroxyprogesterone acetate (Depo-Provera)
- LA formulation
- 150 mg injected every 3 months; good for non-compliant patients.
- Duration of effect 4-6 weeks longer than usual 3 month interval (need to keep “topped off”).
- Very irregular menstrual bleeding patterns (amenorrhea is very common)
Levonorgestrel (Mirena)
- Progestin prodt.
- Lasts 5yrs.
Ethinyl estradiol/etonogestrel (Nuva Ring)
- Implant 3 weeks in, 1 week out
- Simulates a normal period
- Keep in refridgerator
What do you do if Nuva Ring falls out during sex?
Put it back in and you’re good to go..
Etonogestrel (Implanon)
- 10% irregular bleeding
- Changed every 3 years
- Systemic effects
Intrauterine copper contraceptic (Paragard)
- Slow release of copper impairs implantation and sperm transport/fertilization
- Changed in 10 years
INHIBITORS AND ANTAGONISTS
…
Selective Estrogen Receptor Modulator
First agent was tamoxifen (Nolvadex)
- Competitive, partial agonist, inhibitor of estradiol.
- Agonist in bone and endometrium, antagonist in breast tissue.
-MOA: Recruitment of various co-regulators. Different action at different heterodimers.
Used for:
- Palliative care of breast cancer in postmenopausal women
- Breast cancer prevention in high-risk women
- Given orally (will antagonize metastases as well)
- ADR: hot flashes and vomiting
Tamoxifen (Nolvadex)
-Prevention of loss of lumbar spine bone density
- Improvements in lipid changes
- Lower atherosclerosis risk
- Related to partial agonist activity
- Increased endometrial cancer risk, vaginal bleeding (partial agonist in endometrium - hyperplasia and bleeding).
- Thromboembolism
Raloxifene (Evista)
- Partial estrogen agonist-antagonist
- Estrogenic effects on lipids and bone
- Doesn’t stimulate endometrium or breast
Approved uses:
- Prevention of postmenopausal osteoporosis
- Prevention of breast cancer in high-risk women
Clomiphene (Clomid)
- Older partial agonist, binds up hypothalamic estrogen receptors to inhibit negative feedback loop (increase release of LH and FSH).
- Ovulation inducing agent.
Danazol (Danocrine)
-Weak progestational, androgenic, and glucocorticoid effects
- Suppresses ovarian function
- Inhibits midcycle surge of LH and FSH
- Used to treat endometriosis
- Used in hematologic or allergic disorders
- Hemophilia, Christmas disease, ITP, angioneurotic edema
-ADR: weight gain, edema, decreased breast size, acne/oily skin, hair growth, deepening of the voice
Aromatase inhibitors
Anastrozole (Arimedex)
- Inhibits aromatase (conversion of testosterone to estradiol)
- Effective in women resistant to tamoxifen
Letrozole (Femara)
Exemestane (Aromasin)
-Irreversible aromatase inhibitor
-ADR: Fewer pro-estrogen issues than tamoxifen. Most risk for fractures.
