Contraceptives/ drugs acting on the Uterus Flashcards
two types of oral contraceptives?
- Combined Oral Contraceptives:
• contain a combination of an estrogen and a
progestin - Progestin-Only Oral Contraceptives
• Two major approaches to prevent pregnancy?
- Preventing ovulation
2. Impairing implantation
Major mechanism by which we can prevent ovulation?
• by suppressing LH and FSH release
• by preventing fluctuations in estrogen levels
How?
• provide patient with stable estrogen levels!
Estrogen component of oral contraceptives?
• 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
• Progestins include:
Progestins include? •Norethindrone •Norgestrel •Levonorgestrel •Desogestrel •Norgestimate •Drospirenone
Progesterone androgenic activity variance?
- 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
Combined oral contraceptives are available in?
• 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
Describe Biphasic and Triphasic preparation?
• 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
Overview of low dose oral contraceptives?
• 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
Describe how most formulations are scheduled?
• 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
Describe extended-cycle formulations and continuous combination regimens?
• 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
MOA of combined oral contraceptives?
• 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
Benefits of Combined Oral contraceptives?
• 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
Oral contraceptive adverse effects overview?
• 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
Adverse Effects First 3 slides of Oral Contraceptives?
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
Adverse effects of oral contraceptives except cardiotoxicity and listed in first 3 slides?
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
AE of oral contraceptives on cardiovascular system?
• 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
Which antibacterial is implicated in metabolism of estrogen?
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
List other oral contraceptive inducers?
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
Describe drug interaction of antibacterials on estrogen?
• 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
List the absolute contraindications of mixed oral contraceptive
- 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
List the relative contraindications
- 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
Contents of progestin only pills?
- Not widely used in the US
* Contain norethindrone or norgestrel
Effects of progestin only pills?
• 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
Progestin only pills MOA?
• 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
List 5 non oral progestin contraceptive methods?
- The Patch
- The Ring
- The Progestin Injection
- The Progestin Implant
- The Intrauterine Systems
Describe the Contraceptive patch?
Describe the Contraceptive Ring?
• Transdermal patch that contains both ethinyl estradiol and a progestin
• Transvaginal delivery system that delivers ethinyl
estradiol and a progestin
Depo-provera overview and AE?
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
Describe Progestin Implants?
- 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
Describe Intrauterine system
- Levonorgestrel-releasing intrauterine system
- It has a polyethylene body with a levonorgestrel reservoir
- Effective for 5 years
Other non-oral contraceptive methods?
- Barrier Contraceptives
- Condoms
- Diaphragms
- Cervical Caps
- Spermicides
- Intrauterine Devices (IUD)
- Fertility Awareness-Based Methods
- Sterilization
Describe Plan B and Next Choice?
- 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
Describe Plan B one step?
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
Describe Ella
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
Emergency postcoital contraception hormonal methods guidelines?
• 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
Copper IUD timeframe?
• The copper IUD is also an approved method of
emergency contraception
• It has to be inserted within 5 days of intercourse
Overview of cervical ripening?
• 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
Diniprostine and Misoprostine overview, pk, and ae?
• 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
Oxytocin overveiw
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
Oxytocin MOA? Administration?
• 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
Oxytocin AE?
• 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
Management of Postpartum Hemorrhage?
• 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
Methylergonovine overview?
- 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
Methylergonovine AE?
- Severe adverse effects are minimal
- Adverse reactions may include:
- Hypertension
- Headache
- Nausea
- Vomiting
- Chest pains
Methylergonovine contraindications?
- Contraindications:
- Angina pectoris
- Myocardial infarction
- Pregnancy
- Cerebrovascular accident
- Ischemic attack
- Hypertension
Overview of two prostaglandins used for postpartum hemorrhage?
Carboprost Tromethamine
• PGF2a analog
• Given IM
Misoprostol
• PGE1 analog
• Given vaginally or orally
guidelines for tocolytic therapy?
• 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
List uterine relaxants(tocolytics)
- Magnesium Sulfate
- Indomethacin
- Nifedipine
- Atosiban
- b2-adrenoceptor agonists
Magnesium sulfate overview and adverse effects?
• 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
Indomethacin Overview?
• 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
Nifedipine Overview?
• 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
Atosiban moa?
- Competitive antagonist at oxytocin receptors
* Not available in the US
B2 adrenoreceptor agonists MOA?
• 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
B2 adrenoreceptor agonists AE?
• 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
List 3 abortificants?
- Mifepristone (antiprogestin)
- Misoprostol (prostaglandin analog)
- Methotrexate (folic acid antagonist)
2 overviews of early abortion combinations?
• 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
