Drugs acting on the Uterus Flashcards
Oxytocics
The goal of labor induction is to stimulate uterine contractions before the spontaneous onset of labor, resulting in vaginal delivery. The benefits of labor induction must be weighed against the potential maternal and fetal risks associated with this procedure.
When the benefits of expeditious delivery are greater than the risks of continuing the pregnancy, inducing labor can be justified as a therapeutic intervention.
Cervical Ripening
The goal of cervical ripening is to facilitate the process of 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 unfavourable agents for cervical ripening may be used.
Pharmacological agents used for cervical ripening are the prostaglandins misoprostol (PGE1), and dinoprostone (PGE2).
Dinoprostone and Misoprostol
Prostaglandins
Dinoprostone (PGE2) and misoprostol (PGE1) act on the cervix to enable ripening by a number of mechanisms. Additionally they stimulate uterine contractions. Dinoprostone and misoprostol are typically 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 obviates the need for oxytocin in these patients.
Dinoprostone
Dinoprostone is a synthetic preparation of PGE2. Available as vaginal insert, and cervical gel.
Misoprostol
Misoprostol is a PGE1 analogue. It can be administered intravaginally, orally or sublingually.
NOTE: Misoprostol is not FDA-approved for obstetric indications. It is currently FDA- approved only for reducing the risk of NSAID–induced gastric ulcers in patients at high risk of complications from gastric ulcer.
Adverse Effects of Prostaglandins
Adverse effects of prostaglandins include tachysystole, fever, chills, vomiting and diarrhea.
Oxytocin
Labor Induction
Administration of oxytocin is probably the most common method of labor induction. Oxytocin is the preferred pharmacologic agent for inducing labor when the cervix is favorable or ripe. A ripening process should be used prior to administering oxytocin to women with unfavorable cervixes.
Oxytocin
Oxytocin is a peptide hormone produced in the hypothalamus and secreted by the posterior pituitary, that elicits milk ejection in lactating women. In pharmacologic doses oxytocin can be used to induce uterine contractions and maintain labor.
Oxytocin acts via specific G protein coupled receptors. Binding of oxytocin to its 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.
Additionally, activation of the oxytocin receptor leads to activation of the MAPK cascade and of cPLA2, resulting in increased prostaglandin synthesis, which further stimulates uterine contractions.
During the second half of pregnancy, uterine smooth muscle shows an increase in the expression of oxytocin receptors and becomes increasingly sensitive to the stimulant action of endogenous oxytocin. Pharmacologic concentrations of oxytocin powerfully stimulate uterine contraction.
Oxytocin is eliminated by the kidneys and liver, with a half-life of 5 minutes. For labor induction oxytocin is most commonly given as an IV infusion.
Adverse Effects
When oxytocin is used judiciously, serious toxicity is rare. The toxicity that does occur is due either 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.
Postpartum Hemorrhage
Management of Postpartum Hemorrhage
Uterine atony is the most common cause of postpartum hemorrhage and can be managed with uterine massage in conjunction with oxytocic drugs. Oxytocic agents used in the management of postpartum hemorrhage include oxytocin, ergot alkaloids and prostaglandins.
Oxytocin
Oxytocin is the first-line treatment for postpartum hemorrhage. Given IV or IM.
Methylergonovine
Ergot Alkaloids: Methylergonovine
Methylergonovine is a partial agonist at α-adrenergic receptors and some serotonin receptors. Methylergonovine acts on the smooth muscle of the uterus and increases the tone, rate, and amplitude of rhythmic contractions. The sensitivity of the uterus to the stimulant effects of ergot alkaloids increases dramatically during pregnancy, perhaps because of increasing dominance of α1 receptors as pregnancy progresses.
Adverse Effects
At the doses used for controlling postpartum bleeding, severe adverse effects are minimal.
Adverse reactions include hypertension, headache, and possible seizures. Nausea, vomiting, chest pains, difficulties in breathing, and leg cramps also have been reported.
Contraindications include angina pectoris, myocardial infarction, pregnancy,
and a history of a cerebrovascular accident, transient ischemic attack, or hypertension.
Methylergonovine can be found in breast milk, and therefore, it should not be administered longer than necessary, since prolonged use can lead to ergot poisoning (ergotism), including gangrene, in the nursing infant.
Prostaglandins in Postpartum Hemorrhage
Prostaglandins
Carboprost Tromethamine
Carboprost tromethamine is a synthetic analogue of PGF2α. Given IM.
Misoprostol
Misoprostol is a PGE1 analogue. Misoprostol is widely used in the treatment of postpartum hemorrhage. It can be administered vaginally or orally.
Tocolytics
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 for 48 hours 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.
All tocolytic agents are powerful drugs that must be used with extreme care, since pulmonary edema, myocardial infarction, respiratory arrest, cardiac arrest, and death can occur during tocolytic therapy.
**Absolute contraindications to tocolysis** include acute fetal distress (except during intrauterine resuscitation), chorioamnionitis, eclampsia or severe preeclampsia, fetal demise (of a singleton pregnancy), fetal maturity, and maternal hemodynamic instability.
The most common tocolytic agents used for the treatment of preterm labor are magnesium sulfate (MgSO4), indomethacin, and nifedipine.
No tocolytic is clearly the first-line choice. Clinical circumstances and physician preferences should dictate the choice.
Magnesium Sulfate
Magnesium Sulfate
Magnesium sulfate is widely used as the primary tocolytic agent because it has similar efficacy to terbutaline with far better tolerance.
Magnesium sulfate uncouples excitation–contraction in myometrial cells through inhibition of cellular action potentials.
Common maternal side effects include flushing, nausea, headache, drowsiness, and blurred vision.
The mother should be monitored for toxic effects, such as respiratory depression or even cardiac arrest, that can occur at supratherapeutic levels. In addition, magnesium sulfate readily crosses the placenta and may lead to respiratory and motor depression of the neonate.
Magnesium sulfate is given as continuous intravenous infusion.
Indomethacin
Indomethacin
Since certain prostaglandins are known to play a role in stimulating uterine contractions during normal labor, inhibitors of prostaglandin synthesis (NSAIDs), have been used to delay preterm labor.
Indomethacin has been the main NSAID for this use. Indomethacin is given orally or rectally.
NSAIDs have efficacy similar to that of terbutaline and are associated with infrequent maternal side effects. However, these agents readily cross 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. Since this effect is more common after 32 weeks’ gestation, indomethacin therapy is not usually recommended after 32 weeks.
Nifedipine
Nifedipine
The calcium channel blocking agent nifedipine acts by impairing the entry of Ca2+ into myometrial cells via voltage-dependent Ca2+ channels, and thereby inhibiting contractility.
Nifedipine has emerged as an effective and safe alternative tocolytic agent for the management of preterm labor. 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. Continuous monitoring of the fetal heart rate is recommended as long as the patient has contractions; the patient’s pulse and blood pressure should be carefully monitored.
Nifedipine is given orally.
Atosiban
Atosiban
Peptide analog of oxytocin. Competitive antagonist at oxytocin receptors. It decreases and stops uterine contractions. Not available in the US.
B2-Adrenoceptor Agonists
B2-Adrenoceptor Agonists
These drugs act by binding to β2-adrenoceptors. Activation of 2-adrenoceptors on myometrial cell membranes activates adenylyl cyclase. This causes a rise in cAMP which in turn activates protein kinase A. Protein kinase A 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-Adrenergic drugs have many adverse effects. These result both from their residual β1 activity and from their ability to stimulate β2-receptors elsewhere in the body. Adverse effects include palpitations, tremor, nausea, vomiting, nervousness, anxiety, chest pain, shortness of breath, hyperglycemia, hypokalemia, and hypotension. Serious complications include pulmonary edema, cardiac insufficiency, arrhythmias, myocardial ischemia, and maternal death.
Terbutaline is the only ß-sympathomimetic used as a tocolytic in the US. The preferred routes of administration are subcutaneous or intravenous infusion.
In February 2011, the FDA required the addition of a Black Box Warning and Contraindication to the terbutaline prescribing information to warn about the risk of use for preterm labor. The decision was based on reports of death and serious adverse reactions following administration of oral or injectable terbutaline to pregnant women. The new information states that the use of injectable terbutaline should be limited to a maximum of 72 hours to treat preterm labor, and that oral terbutaline shouldn’t be used at all to prevent or treat preterm labor.
