Drugs Acting on the Uterus

Question 1

What is the goal of labor induction?

Answer 1

To stimulate uterine contractions before the spontaneous onset of labor, resulting in vaginal delivery

Question 2

What is cervical ripening?

Answer 2

Cervical softening, thinning and dilating with resultant reduction in the rate of failed induction.
–if induction is indicated and the status of the cervix is unfavorable then agents for cervical ripening may be used

Question 3

The pharmacological agents used for cervical ripening are the prostaglandins —- misoprostol (PGE1) and dinorpstone (PGE2). How do the prostaglandins work?

Answer 3

Act on the cervix to enable ripening
Stimulate uterine contractions
–administered to promote cervical ripening as the first step in labor induction in women with unfavorable cervixes. (this alone initiates labor in many women and oxytocin is therefore not needed)

Question 4

Misoprostol is not FDA approved for obstetric indications. What is it approved for?

Answer 4

Reducing the risk of NSAID induced gastric ulcers in patients at high risk of complications from gastric ulcer

Question 5

What are the adverse effects of prostaglandins?

Answer 5

Tachysystole, chills, vomiting, and diarrhea

Question 6

Administration of oxytocin is the most common method for labor induction when the cervix is ripe. What are the other roles of oxytocin?

Answer 6

Elicits milk ejection in lactating women

Question 7

What is the MOA of oxytocin?

Answer 7

G protein coupled receptor

• -activates Gq and then PLC, which hydrolyses PIP2 to IP3 and DAG.
• -IP3 causes release of Ca2+ from the SR, while DAG activates PKC
• -Gq also causes activation of voltage regulated Ca2+ channels
• -Ca2+ activates MLCK, resulting in myometrial contraction

Question 8

During the second half of pregnancy, uterine smooth muscle shows an increase in the expression of oxytocin receptors and becomes what?

Answer 8

Increasingly sensitive to the stimulant action of endogenous oxytocin
–pharmacologic concentrations of oxytocin powerfully stimulate uterine contraction.

Question 9

What are the Adverse Effects of Oxytocin?

Answer 9

Serious Toxicity is Rare

• –toxicity occurs either due to excessive stimulation of uterine contractions or to inadvertent activation of vasopressin receptors
• -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 10

Moving on to postpartum hemorrhage, uterine atony is the most common cause of postpartum hemorrhage. How can this be managed?

Answer 10

Uterine massage in conjunction with oxytocic drugs

—drugs: oxytocin, ergot alkaloids, and prostaglandins

Question 11

What is the first line treatment for postpartum hemorrhage?

Answer 11

Oxytocin

Question 12

Methylergonovine is a partial agonist at alpha adrenergic receptors and some serotonin receptors. Therefore how is this drug used in postpartum hemorrhage?

Answer 12

Acts on smooth muscle of the uterus and increases the tone, rate and amplitude of rhythmic contractions
–sensitivity of the uterus to the stimulant effects of the drug increases dramatically during pregnancy, perhaps because of increasing dominance of alpha 1 receptors as pregnancy progresses

Question 13

What are the adverse effects of Methylergonovine?

Answer 13

Severe Adverse Effects are minimal
–can include HTN, headache and possible seizures
Contraindications (anything that vasoconstriction would make worse):
–angina pectoris, myocardial infarction, pregnancy, and a history of a CVA, TIA or HTN

Question 14

What are the effects of Methylergonovine on the fetus’?

Answer 14

Can be found in the breast milk

• -should not be given longer than needed
• –can cause ergot poisoning including gangrene in the nursing infant

Question 15

Next for postpartum hemorrhage are the prostaglandins, which drugs are used?

Answer 15

Carboprost Tromethamine (PGF2alpha): given IM
Misoprostol (PGE1): vaginally or orally

Question 16

Lastly are the uterine relaxant drugs (Tocolytics). When are these drugs used?

Answer 16

In labor that begins before 37 weeks gestation (aka preterm labor)
–patients need to be given bed rest, tocolytics and glucocorticoids (if gestational age is less than 34 weeks)

Question 17

What is the purpose of the Tocolytics?

Answer 17

Delay delivery for 48 hours to allow glucocorticoids given to the mother to achieve their maximum effect.
–again glucocorticoids are given to accelerate maturation of fetal lungs and decrease risk of neonatal resp distress syndrome

Question 18

What are the contraindications for the use of Tocolytic agents?

Answer 18

Acute fetal distress (except during intrauterine resuscitation)
Chorioamnionititis 
Eclampsia or severe preeclampsia 
Fetal Demise 
Fetal Maturity 
Maternal Hemodynamic Instability

Question 19

What are the common tocolytic agents used for the treatment of preterm labor?

Answer 19

Magnesium Sulfate (MgSO4), indomethacin and Nifedipine 
--no tocolytic is the first line choice

Question 20

First tocolytic agent is Magnesium Sulfate (MgSO4). What are some features of this drug?

Answer 20

Primary Tocolytic Agent
Uncouples excitation-contraction in myometrial cells through inhibition of cellular action potentials
AE: flushing, nausea, headache, drowsiness and blurred vision
Toxic Effects: respiratory depression or cardiac arrest. can cross the placenta and lead to respiratory and motor depression of neonate.

Question 21

Next tocolytic agent is Indomethacin (NSAID), what are some features?

Answer 21

Inhibitor of prostaglandin synthesis (NSAID) – delays preterm labor
Main NSAID used
Cross the placenta and can cause oligohydramnios due to a decrease in fetal renal blood flow if used for more than 48 hours
Can cause premature closure or construction of the ductus ateriosus, which is common after 32 weeks

Question 22

Next tocolytic agent is Nifedipine (Ca channel blocker), what are some features?

Answer 22

Impairing the entry of Ca2+ into myometrial cells via voltage dependent Ca2+ channels, and thereby inhibiting contractility
Associated with a more frequent successful prolongation of pregnancy
AE: maternal tachy, palpitations, flushing, headaches, dizziness, and nausea.

Question 23

Next Tocolytic drug is Atosiban, what are some features/

Answer 23

Competitive antagonist at oxytocin receptors

• -decreases and stops uterine contractions
• -not used in the US

Question 24

Last of the tocolytic drugs are beta 2 adrenoceptor agonist. What is their MOA?

Answer 24

Binding to Beta 2- adrenoceptors
–this activates adenylyl cyclase —- causes a rise in cAMP —activates Protein kinase A — phosphorylates smooth muscle myosin light chain kinase — results in a lower affinity of SmMLCK for the Ca2+ calmodulin complex. Therefore SmMLCK does not phosphorylate myosin, and the myometrial smooth muscle relaxes

Question 25

What are adverse effects of the beta 2 adrenoceptor agonist?

Answer 25

Results from their residual Beta 1 activity and their ability to stimulate B2 receptors elsewhere in the body
–palpitations, tremor, nausea, vomiting, nervousness, anxiety, chest pain, SOB, hyperglycemia, hypokalemia, and hypotension.

Question 26

What beta 2 agonist is used?

Answer 26

Terbutaline

–given SQ or IV

Question 27

In 2011 a black box warning and contraindications to terbutaline was placed why?

Answer 27

To warn about the risk of use for preterm labor

• -needs to be limited for a max use of 72 hours
• -oral should never be used