Contraceptives/ drugs acting on the Uterus

Question 1

two types of oral contraceptives?

Answer 1

1. Combined Oral Contraceptives:
   • contain a combination of an estrogen and a
   progestin
2. Progestin-Only Oral Contraceptives

Question 2

• Two major approaches to prevent pregnancy?

Answer 2

1. Preventing ovulation

2. Impairing implantation

Question 3

Major mechanism by which we can prevent ovulation?

Answer 3

• by suppressing LH and FSH release
• by preventing fluctuations in estrogen levels
How?
• provide patient with stable estrogen levels!

Question 4

Estrogen component of oral contraceptives?

Answer 4

• Contain a combination of an estrogen and a progestin
• The estrogen is either ethinyl estradiol or mestranol
• Mestranol is a prodrug that is converted to ethinyl
estradiol

Question 5

• Progestins include:

Answer 5

Progestins include?
•Norethindrone 
•Norgestrel 
•Levonorgestrel 
•Desogestrel 
•Norgestimate 
•Drospirenone

Question 6

Progesterone androgenic activity variance?

Answer 6

• Almost all currently available progestins have some androgenic activity
• Progestins vary in their androgenic activity:
• Levonorgestrel and norgestrel: highest
• Norethindrone: lower

• Third-generation progestins, such as desogestrel and
norgestimate: even lower

• Drospirenone: antiandrogenic

Question 7

Combined oral contraceptives are available in?

Answer 7

• Combined oral contraceptives are available in monophasic, biphasic, and triphasic preparations
• Monophasic preparations contain fixed doses of estrogen and progestin in each active pill
• Biphasic and triphasic preparations contain varying
proportions of one or both hormones during the pill cycle

Question 8

Describe Biphasic and Triphasic preparation?

Answer 8

• Biphasic and triphasic preparations were introduced to reduce the amount and total monthly dose of progestins, and to mimic more closely the hormonal changes of the menstrual cycle
• There is no evidence that bi- or tri-phasic oral
contraceptives are superior to monophasic oral
contraceptives, or vice-verse, in the prevention of
pregnancy

Question 9

Overview of low dose oral contraceptives?

Answer 9

• The combined oral contraceptives most commonly used
today are called ‘low-dose’
• They contain 35 µg of ethinyl estradiol or less
• The low hormone content has decreased adverse effects and risks
• But they are more likely to result in contraceptive
failure if doses are missed

Question 10

Describe how most formulations are scheduled?

Answer 10

• Most of the formulations available have 21 hormonally active pills followed by 7 placebo pills to allow withdrawal
from bleeding
• This facilitates consistent daily pill intake

Question 11

Describe extended-cycle formulations and continuous combination regimens?

Answer 11

• Extended-cycle formulations increase the number of
hormone-containing pills to 84 days, followed by a 7-day
placebo phase
• This results in four menstrual cycles per year
• Continuous combination regimens provide hormone containing
pills for 21 days, then very-low-dose estrogen
and progestin for an additional 4-7 days

Question 12

MOA of combined oral contraceptives?

Answer 12

• Combination oral contraceptives work primarily before
fertilization to prevent conception
• They act by preventing ovulation
• They suppress LH and FSH release and ovulation does not occur
• Additionally, the progestin thickens cervical mucus thus preventing sperm penetration, and induces changes in the
endometrium that impair implantation

Question 13

Benefits of Combined Oral contraceptives?

Answer 13

• Reduction on the risk of endometrial cancer
• Reduction in the risk of ovarian cancer
• Improved regulation of menstruation
• Relief of benign breast disease
• Prevention of ovarian cysts
• Reduction in the risk of symptomatic pelvic inflammatory
disease
• Improvement in acne control

Question 14

Oral contraceptive adverse effects overview?

Answer 14

• The consensus is that contraceptives have more
beneficial than harmful effects
• Concerns about cardiovascular toxicity initially limited the long-term use of these drugs
• The decrease in estrogen and progestin content has led to a reduction in adverse effects
• Many adverse effects (eg nausea, bloating,
breakthrough bleeding) improve spontaneously by the third cycle
• Therefore, patient education and early reevaluation are
necessary to identify and manage adverse effects in an effort to improve compliance
• Many adverse effects can be avoided by adjusting the
estrogen and/or progestin content of the oral
contraceptive

Question 15

Adverse Effects First 3 slides of Oral Contraceptives?

Answer 15

Breakthrough Bleeding
• Most common adverse effect of oral contraceptives
• It is more of a problem with lower doses of estrogen
because estrogen stabilizes the endometrium

Headache
• Usually mild and transient
• However, migraine may be associated with
cerebrovascular accidents
• Women who develop migraines should stop taking the contraceptive

Insulin Resistance
• Progestins may cause insulin resistance by competing
with insulin for its receptor
• Current oral contraceptives have a low progestin content
and rarely cause hyperglycemia

Question 16

Adverse effects of oral contraceptives except cardiotoxicity and listed in first 3 slides?

Answer 16

Hirsutism
• Acne, oily skin and hirsutism are adverse effects of androgenic progestins
• The patient should be switched to a product with less androgenicity

Melasma
• Due to estrogen stimulation of melanocyte production

Amenorrhea
• Amenorrhea occurs in some patients

Dyslipidemia
• Most low-dose oral contraceptives have no impact on
HDL, LDL, triglycerides or total cholesterol

Carcinogenicity
• Oral contraceptives decrease incidence of endometrial
and ovarian cancer
• Their ability to induce other cancers is controversial

Depression
• Depression that requires cessation of therapy occurs in about 6% of patients treated with some preparations

Question 17

AE of oral contraceptives on cardiovascular system?

Answer 17

• Although rare, the most serious adverse effect of oral
contraceptives is cardiovascular disease
• This includes thromboembolism, thrombophlebitis,
hypertension, MI, cerebral and coronary thrombosis
• These adverse effects are most common among women who smoke and who are older than 35 years
• Estrogens increase production of factor VII, factor X and
fibrinogen, therefore increasing the risk of thromboembolic
events
• The risk is increase by obesity, smoking, hypertension and
diabetes

Question 18

Which antibacterial is implicated in metabolism of estrogen?

Answer 18

Liver Enzyme Induction
• Rifampin induces hepatic P450 enzymes and increases
metabolism of estrogen
• Use of a backup non hormonal contraceptive method during the course of rifampin therapy is recommended

Question 19

List other oral contraceptive inducers?

Answer 19

Liver Enzyme Induction
• Carbamazepine, oxcarbazepine, phenytoin,
phenobarbital, primidone, topiramate, vigabatrin and
St John’s Wort are P450 inducers
• They are known to increase metabolism of oral
contraceptives

Question 20

Describe drug interaction of antibacterials on estrogen?

Answer 20

• Ethinyl estradiol is conjugated in the liver, excreted in the bile, hydrolyzed by intestinal bacteria, and reabsorbed as
active drug
• Certain broad-spectrum antibiotics, by reducing the
population of intestinal bacteria, may interrupt the
enterohepatic circulation of estrogen
• This may decrease estrogen levels
• Various antibiotics have been reported to decrease
contraceptive efficacy
• However, the only antibiotic for which there is evidence
that it substantially lowers steroid levels is rifampin
• Women using combined oral contraceptives should be informed about the small risk of interactions with
antibiotics

Question 21

List the absolute contraindications of mixed oral contraceptive

Answer 21

• Pregnancy
• Thrombophlebitis or thromboembolic disorders
• Stroke or coronary artery disease
• Cancer of the breast
• Undiagnosed abnormal vaginal bleeding
• Estrogen-dependent cancer
• Benign or malignant tumor of the liver
• Uncontrolled hypertension
• Diabetes mellitus with vascular disease
• Age over 35 and smoking >15 cigarettes daily
• Thrombophilia
• Migraine with aura
• Active hepatitis
• Surgery or orthopedic injury with prolonged immobilization

Question 22

List the relative contraindications

Answer 22

• Migraine without aura
• Hypertension
• Heart of kidney disease
• Diabetes mellitus
• Gallbladder disease
• Cholestasis during pregnancy
• Sickle cell disease (S/S or S/C type)
• Lactation

Question 23

Contents of progestin only pills?

Answer 23

• Not widely used in the US

* Contain norethindrone or norgestrel

Question 24

Effects of progestin only pills?

Answer 24

• Slightly less effective than combined oral contraceptives
• No risk of thromboembolic events
• Other benefits: decreased dysmenorrhea, decreased
menstrual blood loss and decreased premenstrual
syndrome symptoms
• Unscheduled bleeding and spotting are common

Question 25

Progestin only pills MOA?

Answer 25

• Progestin-only pills are highly efficacious but block ovulation in only 60% to 80% of cycles • Their effectiveness is thought to be due largely to a thickening of cervical mucus, which decreases sperm penetration, and to endometrial alterations that impair implantation

Question 26

List 5 non oral progestin contraceptive methods?

Answer 26

* The Patch * The Ring * The Progestin Injection * The Progestin Implant * The Intrauterine Systems

Question 27

Describe the Contraceptive patch? Describe the Contraceptive Ring?

Answer 27

• Transdermal patch that contains both ethinyl estradiol and a progestin • Transvaginal delivery system that delivers ethinyl estradiol and a progestin

Question 28

Depo-provera overview and AE?

Answer 28

Depo-Provera® • Progestin-only injectable contraceptive • Contains depot medroxyprogesterone acetate (DMPA) • Given IM every 3 months • Extremely effective • Progestin diffuses out over time to provide a circulating level that prevents ovulation through negative feedback • High incidence of menstrual irregularities and weight gain • Causes significant loss of bone mineral density • A black-box warning cautions against the risk of potentially irreversible BMD loss associated with longterm use

Question 29

Describe Progestin Implants?

Answer 29

* Single 4 cm long implant, containing a progestin * Placed under the skin of the upper arm using a preloaded inserter * Effective for 3 years * Major adverse effect: irregular menstrual bleeding

Question 30

Describe Intrauterine system

Answer 30

* Levonorgestrel-releasing intrauterine system * It has a polyethylene body with a levonorgestrel reservoir * Effective for 5 years

Question 31

Other non-oral contraceptive methods?

Answer 31

* Barrier Contraceptives * Condoms * Diaphragms * Cervical Caps * Spermicides * Intrauterine Devices (IUD) * Fertility Awareness-Based Methods * Sterilization

Question 32

Describe Plan B and Next Choice?

Answer 32

* Both Plan B® and Next Choice® contain two tablets of levonorgestrel * The first tablet is taken within 72 hours of unprotected intercourse and the second 12 hours later * Adverse effects include nausea and vomiting * Available without a prescription for consumers ≥17

Question 33

Describe Plan B one step?

Answer 33

Plan B One-Step® • Plan B One-Step® contains one tablet of levonorgestrel to be taken within 72 hours after unprotected intercourse • Available without a prescription for consumers ≥17

Question 34

Describe Ella

Answer 34

Ella® • Ella® contains ulipristal acetate • Ulipristel acetate is a selective progesterone receptor modulator (SPRM) • It acts as a progesterone antagonist to inhibit or delay ovulation • A single tablet is taken within 5 days after intercourse • Adverse effects are similar to those of levonorgestrel • Available only by prescription

Question 35

Emergency postcoital contraception hormonal methods guidelines?

Answer 35

• Emergency postcoital contraception is used to prevent pregnancy after unprotected sexual intercourse • There are hormonal and non-hormonal methods of FDAapproved emergency contraception • Many norgestrel- or levonorgestrel-containing oral contraceptives can be used in high doses for emergency contraception • They are most effective when taken within 72 hours of unprotected intercourse

Question 36

Copper IUD timeframe?

Answer 36

• The copper IUD is also an approved method of emergency contraception • It has to be inserted within 5 days of intercourse

Question 37

Overview of cervical ripening?

Answer 37

• The goal of cervical ripening is to reduce the rate of failed induction • Pharmacologic agents for cervical ripening are used when induction is indicated and the status of the cervix is unfavorable • Drugs used for cervical ripening are the prostaglandins dinoprostone and misoprostol

Question 38

Diniprostine and Misoprostine overview, pk, and ae?

Answer 38

• Dinoprostone and misoprostol ripen the cervix by several mechanisms • Additionally, they stimulate uterine contractions • They are administered to promote cervical ripening in women with unfavorable cervixes • This alone initiates labor in many women, and obviates the need for oxytocin Dinoprostone • Synthetic preparation of PGE2 • Available as vaginal insert, and cervical gel Misoprostol • PGE1 analog • Can be administered intravaginally, orally or sublingually AE • Tachysystole • Fever • Chills • Vomiting • Diarrhea

Question 39

Oxytocin overveiw

Answer 39

Oxytocin is the preferred pharmacologic agent for inducing labor when the cervix is favorable or ripe • A ripening agent should be used before oxytocin in women with unfavorable cervixes • Peptide hormone, secreted by the posterior pituitary • Elicits milk ejection in lactating women • During the second half of pregnancy, uterine smooth muscle becomes increasingly sensitive to the stimulant action of endogenous oxytocin • In pharmacologic doses oxytocin can be used to induce uterine contractions and maintain labor

Question 40

Oxytocin MOA? Administration?

Answer 40

• Oxytocin acts via Gq protein coupled receptors • Activation of oxytocin receptors leads to activation of phospholipase C and release of calcium from the SR • Activation of oxytocin receptors also activates voltagegated Ca2+ channels • Ca2+ activates MLCK resulting in myometrial contraction • Oxytocin also increases prostaglandin synthesis, which further stimulates uterine contractions • For labor induction oxytocin is most commonly given as an IV infusion

Question 41

Oxytocin AE?

Answer 41

• Serious toxicity is rare • Excessive stimulation of uterine contractions before delivery can cause fetal distress, placental abruption, or uterine rupture • High concentrations of oxytocin can activate vasopressin receptors and thus cause excessive fluid retention, or water intoxication, leading to hyponatremia, heart failure, seizures, and death

Question 42

Management of Postpartum Hemorrhage?

Answer 42

• Uterine atony is the most common cause of postpartum hemorrhage • Managed with uterine massage and oxytocic drugs • Oxytocic agents used in the management of postpartum hemorrhage include: • Oxytocin (first-line, given IV or IM) • Ergot alkaloids • Prostaglandins

Question 43

Methylergonovine overview?

Answer 43

* Partial agonist at a-adrenergic receptors and some serotonin receptors * The sensitivity of the uterus to the stimulant effects of ergot alkaloids increases dramatically during pregnancy

Question 44

Methylergonovine AE?

Answer 44

* Severe adverse effects are minimal * Adverse reactions may include: * Hypertension * Headache * Nausea * Vomiting * Chest pains

Question 45

Methylergonovine contraindications?

Answer 45

* Contraindications: * Angina pectoris * Myocardial infarction * Pregnancy * Cerebrovascular accident * Ischemic attack * Hypertension

Question 46

Overview of two prostaglandins used for postpartum hemorrhage?

Answer 46

Carboprost Tromethamine • PGF2a analog • Given IM Misoprostol • PGE1 analog • Given vaginally or orally

Question 47

guidelines for tocolytic therapy?

Answer 47

• Labor that begins before 37 weeks of gestation is considered preterm • Preterm birth is the leading cause of neonatal mortality in the US • Management of preterm labor typically includes bed rest, tocolytics and glucocorticoids (if gestational age is <34 weeks) • The primary purpose of tocolytic therapy is to delay delivery to allow glucocorticoids given to the mother to achieve their maximum effect • Glucocorticoids accelerate maturation of fetal lungs and decrease risk of neonatal respiratory distress syndrome, intracranial bleeding, and mortality • The most common tocolytic agents used for the treatment of preterm labor are magnesium sulfate, indomethacin, and nifedipine • There is no tocolytic of first choice

Question 48

List uterine relaxants(tocolytics)

Answer 48

* Magnesium Sulfate * Indomethacin * Nifedipine * Atosiban * b2-adrenoceptor agonists

Question 49

Magnesium sulfate overview and adverse effects?

Answer 49

• Widely used as the primary tocolytic agent • It has similar efficacy to terbutaline with far better tolerance • Magnesium sulfate uncouples excitation-contraction in myometrial cells through inhibition of cellular action potentials • The mother should be monitored for toxic effects, such as respiratory depression or cardiac arrest • Magnesium sulfate crosses the placenta and may lead to respiratory and motor depression of the neonate

Question 50

Indomethacin Overview?

Answer 50

• Prostaglandins stimulate uterine contractions during normal labor • Therefore NSAIDs are used to delay preterm labor • Indomethacin is the main NSAID for this use • Infrequent maternal side effects • Indomethacin crosses the placenta and can cause oligohydraminos due to a decrease in fetal renal blood flow if used for more than 48 hours • Indomethacin can also cause premature closure or constriction of the ductus arteriosus • This effect is more common after 32 weeks’ gestation: indomethacin is therefore not recommended after 32 weeks

Question 51

Nifedipine Overview?

Answer 51

• Calcium channel blocker • Blocks entry of Ca2+ into myometrial cells, thereby inhibiting contractility • Effective and safe • Compared with other tocolytics nifedipine is associated with a more frequent successful prolongation of pregnancy • Adverse effects include maternal tachycardia, palpitations, flushing, headaches, dizziness, and nausea

Question 52

Atosiban moa?

Answer 52

* Competitive antagonist at oxytocin receptors | * Not available in the US

Question 53

B2 adrenoreceptor agonists MOA?

Answer 53

• Activation of b2-adrenoceptors on myometrium activates adenylyl cyclase. This causes a rise in cAMP which in turn activates PKA • PKA phosphorylates smooth-muscle myosin light chain kinase (SmMLCK) • Phosphorylation of SmMLCK results in a lower affinity of SmMLCK for the Ca2+-calmodulin complex • As a result, SmMLCK dose not phosphorylate myosin, and the myometrial smooth muscle relaxes

Question 54

B2 adrenoreceptor agonists AE?

Answer 54

• Palpitations, tremor, nausea, vomiting, nervousness, anxiety, chest pain, shortness of breath, hyperglycemia, hypokalemia, and hypotension • Serious complications: pulmonary edema, cardiac insufficiency, arrhythmias, myocardial ischemia, and maternal death • In February 2011, the FDA required the addition of a Black Box Warning and Contraindication to the terbutaline label to warn about the risk of use for preterm labor • The decision was based on reports of deaths and serious adverse reactions following administration of terbutaline to pregnant women • The use of injectable terbutaline should be limited to a maximum of 72 hours to treat preterm labor • Oral terbutaline should not be used to prevent or treat preterm labor

Question 55

List 3 abortificants?

Answer 55

* Mifepristone (antiprogestin) * Misoprostol (prostaglandin analog) * Methotrexate (folic acid antagonist)

Question 56

2 overviews of early abortion combinations?

Answer 56

• Mifepristone is given in combination with misoprostol to produce early abortion • Mifepristone is administered first followed by misoprostol 24-72h later • Major adverse effects: Cramping and diarrhea • Methotrexate is used off-label for early abortion • Patient is given an injection of methotrexate and pregnancy will abort within days-weeks of injection (similar to early miscarriage) • Major adverse effects: Nausea and cramping