Lecture 27: Uterine drugs Flashcards
dinoprostone and misoprostol
- used for cervical ripening are the prostaglandins
- 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.
- Availableas vaginal insert, and cervical gel.
MISOPROSTOL
• PGE1 analogue.
• Can be administered intravaginally, orally or sublingually.
Adverse
- Tachysystole
- Fever
- Chills
- Vomiting
- Diarrhea
LABOR INDUCTION
- 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.
MOA
- Activation of oxytocin receptors leads to activation of phospholipase C and release of calcium from the SR.
- Activation of oxytocin receptors also activates voltage-gated Ca2+ channels.
- Ca2+ activates MLCK resulting in myometrial contraction.
- Oxytocin also increase sprostagl and in synthesis, which further stimulates uterine contractions.
Adverse
- 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 treatment for postpartum hemorrhage; Given IV or IM.
- Ergot alkaloids: esp. methylergonovine
- Prostaglandins
METHYLERGONOVINE
- ERGOT ALKALOIDS
- Partial agonist at α-adrenergic receptors and some serotonin receptors.
- The sensitivity of the uterus to the stimulant effects of ergot alkaloids increases dramatically during pregnancy.
Adverse
- Severe adverse effects are minimal.
- Hypertension
- Headache
- Nausea
- Vomiting
- Chest pains
Contraindications
- Angina pectoris
- Myocardial infarction
- Pregnancy
- Cerebrovascular accident
- Ischemic attack
- Hypertension
CARBOPROST TROMETHAMINE
PGF2α analogue.
Given IM.
MISOPROSTOL
- PGE1 analogue.
- Given vaginally or orally.
UTERINE RELAXANTS (TOCOLYTICS)
- 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.
UTERINE RELAXANTS (TOCOLYTICS)
- 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.
- MAGNESIUM SULFATE
- INDOMETHACIN
- NIFEDIPINE
- ATOSIBAN
- β2-ADRENOCEPTOR AGONISTS: many adverse
MAGNESIUM SULFATE
- 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.
Adverse
- 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
- 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 oligohydramnios 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
- 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
- Competitive antagonist at oxytocin receptors.
- Not available in the US
β2-ADRENOCEPTOR AGONISTS: MOA
- Activation of β2-adrenoceptorsonmyometrium 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 does not phosphorylate myosin, and the myometrial smooth muscle relaxes.
β2-ADRENOCEPTOR AGONISTS: ADVERSE EFFECTS
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.
