lecture 10: tocolytics, oxytocics, and antenatal drugs

estrogen

___ increases oxytocin receptor expression

prostaglandins E2 and F2a

these increase collagenase activity in the cervix → softening & thinning (cervical ripening) followed by cervical dilation to allow the baby to move through the birth canal

coupled to Gq

•↑PLC, ↑IP3, ↑Ca2+

2nd messengers of oxytocin

•Regular uterine contractions with cervical dilation or effacement changes between 20 0/7 and 36 6/7 weeks gestation

•Initial presentation of regular uterine contractions and cervical dilation of at least 2 cm

define pre-term labor

17-hydroxyprogesterone acetate IM weekly or vaginal progesterone suppositories starting between 16-24 weeks and continued through 36 wks

management of pregnant pts with history of pre-term labor

diminish cervical ripening

MOA of progesterone to stop pre term labor

•Bed rest

•Hydration

•Cervical cerclage

non pharm treatments to prevent PTL

antenatal steroids

non-tocolytic therapy of PTL

•β-agonists

•Calcium channel blockers

•Magnesium sulfate

•NSAIDs

name the classes of tocolytic therapies (contraction suppressants)

betamethasone (2 dose IM given 24 hrs apart)

dexamethasone (4 doses given 12 hrs apart)

preferred antenatal steroids

•to speed up lung development in preterm fetuses and reduce the risk of respiratory distress syndrome.

primary indication of antenatal steroids

accelerate developmennt of type 1 and type 2 pneumocytes

MOA of antenatal steroids

•Recommended between 24-34 weeks gestation where delivery is anticipated within 7 days; may repeat if previous course given >14 days prior

-benefits begin within 24 hours of initiation

recommendation time for antenatal steroids

Hypoglycemia

fetal adverse effects of steroids

•Steroid side effects (AMS, hypertension, hyperglycemia)

maternal adverse effects of steroids

•Used for 48-72 hours to:

1.Postpone delivery to allow for antenatal corticosteroid administration and maximum effect (24 hrs)

2.Allow time for transportation of mother to equipped facility for high-risk pregnancies

3.Prolong pregnancy when underlying self-limited conditions exist that can cause labor

timing of tocolytic use

•<34 weeks gestation

•Regular uterine contractions with cervical changes

•Generally, avoid use pre-viability

criteria for administration of toclytics

Terbutaline

preferrerd beta adrenergic agonist tocolytic

terbutaline

MOA: •β2-adrenergic receptor agonist

•Myometrium relaxation via increased levels of cAMP and decreased MLCK

Terbutaline

indications: Asthma/Bronchospasm; off-label: Premature labor (a first-line agent

•IV or SQ: Avoid prolonged parenteral use (>48-72h)

administration of terbutaline

-maternal: hypokalemia, tachyarrhhythmia, hyperglycemia, HTN, or paradoxical hypotension

-fetal: tachycardia

adverse effects of terbutaline

don't administer oral formulation

BBW of terbutaline

nifedipine

preferred calcium channel blocker tocolytic

nifedipine

MOA: •Dihydropyridine voltage gated calcium channel blocker

•↓ intracellular calcium concentrations leading to smooth muscle relaxation

dizziness, flushing, hypotension

-avoid in CV disease, hypotension

maternal AE of nifedipine

magnesium sulfate

MOA: tocolytic that •Inhibits calcium channels, decreasing intracellular calcium concentrations and relaxing uterine smooth muscle

magnesium sulfate

Indications:

•Eclampsia/pre-eclampsia, hypomagnesemia, constipation

•Off-label: Tocolytic

magnesium sulfate

adverse effects: flushing, diaphoresis

CI: myasthenia gravis

magnesium sulfate

•If birth anticipated < 32 weeks, can be used for neuroprotection

•Reduces severity and risk of cerebral palsy in neonate

avoid using >5-7 days (longer use associated with low calcium and osteopenia and fractures in neonate)

max time period of use of magnesium sulfate

indomethacin

preferred NSAID tocolytic

indomethacin

MOA: •Inhibits cyclooxygenase, decreasing prostaglandin synthesis (PGF2a)

•Prevents activation of uterine EP1 and FP receptors, leading to myometrial relaxation

indomethacin

first line tocolytic and may be used for closure of patent ductus arteriosus in neonates

•Premature constriction of ductus arteriosus, platelet inhibition, necrotizing enterocolitis, intracranial hemorrhage and renal dysfunction

fetal adverse effects of inndomethacin

32 weeks (ductus arteriosus)

do not use indomethacin at >____ weeks gestation

indomethacin and magnesium sulfate (avoids hypotension that can be seen when Mg combined with nifedipine or terbutaline)

tocolytics that can be used in combination

•Maintenance therapy (i.e. after initial 48-72 hours) with tocolytics is ineffective for preventing preterm birth and improving neonatal outcomes and is not recommended for this purpose

is maintenance therapy of tocolytic effective?

preterm premature rupture of membranes before 34 weeks gestation

indication for prophylactic antibiotics in PTL

•7-day course of broad-spectrum antibiotics

--> Ampicillin + erythromycin IV x 48 h then PO amoxicillin or erythromycin base

prophylactic abx used in PPROM

•postdatism, hypertension, growth restriction, PROM without active labor onset, social factors

indications of labor induction

•placenta previa, low lying or transverse placenta, pelvic structural abnormality, prolapsed umbilical cord, active herpes flare

contraindications to labor induction

prostaglandins

indicated to promote cervical ripening if bishop score is less than 6

oxytocics

drug class to increase uterine contractions

antibiotics, oxytocics, anesthetics and analgesics

medications used to induce labor

•Oxytocin

•Prostaglandins

•Ergot alkaloid

list the oxytocics

•GBS bacteriuria

•Previous birth to infant with invasive GBS

•Screening between 35-37 weeks pregnancy (updated 36-38 weeks this year): Positive vaginal/rectal GBS culture

•treat patients with fever >100.4 F, membrane rupture >18 hours, or <37 weeks gestation if no prental care

indications for group B strep prophylaxis

-no penicillin allergy: penicillin G or ampicillin IV every 4 hours until delivery

-with allergy: cefazolin , clindamycin (if risk of anaphylaxis)

abx of choice for group B strep

•Oxytocin receptor agonist

•May also stimulate local prostaglandin and leukotriene release

•Contracts uterine smooth muscle

-contracts myoepithelial cells surrounding mammary aveloli

MOA of oxytocin

5 min

half life of oxytocin

-bolus can cause hypotension, fetal distress, placental abruption, fluid retention

adverse effects of oxytocin

•Fetal distress, placenta previa, prolapsed umbilical cord, pelvic structure abnormalities and active herpes

CI to oxytocin

prostaglandin analog

inducing labor if bishop score is less than 6

use oxytocin for induction or spontaneous labor

inducing labor if bishop score is greater than 8

dinopristone, misoprostol, carboprost

prostaglandin analogs used for cervical ripening, PPH

•Dinoprostone (endocervically and vaginally)

•Misoprostol (PO and vaginally)

PG analogs for cervical ripening and their administration

•Misoprostol

Carboprost

PG analogs for postpartum hemorrhage a

•asthma; avoid in hypertension, active hepatic, cardiac, or pulmonary disease

CI to carboprost

•Fetal monitor for duration of use + 15 mins following removal

fetal monitoring recommendation with PG analog use

methylergonovine

ergot alkaloid used in prevention of postpartum hemorrhage

methylergonovine

•Acts non-selectively as a partial 5-HT2A agonist and α1-adrenergic agonist

•↑PLC, ↑IP3, ↑Ca2+

•Directly contracts uterine and vascular smooth muscle

•(IM, IV and PO)

administration of methylergonovine

•Nausea, vomiting diarrhea, increased blood pressure, flushing and chills

adverse effects of methylergonovine

•Consider uterine artery embolization, intrauterine balloon catheters, surgery if uterotonic therapy fails

tx of PPH if uterotonic therapy fails

tranexamic acid

MOA: •Antifibrinolytic agent; forms a reversible complex which competitively inhibits plasminogen, resulting in inhibition of fibrinolysis

thromboembolic events

adverse effects of TXA

-Misoprostol only

-Mifepristone + misoprostol

-Methotrexate + misoprostol

-Oxytocin

pharm interventions for pregnancy termination (use up to 10 weeks gestation in some states)

misoprostol

synthetic prostaglandin E1 analog, used to terminate

•Higher incidence of AE

•Monotherapy = lower efficacy

mifepristone

-synthetic steroid

-competitively binds and inhibits progesterone receptor activation causing uterine contractions--> used in pregnancy termination

•Patient takes mifepristone orally on day 1 & misoprostol 24-48h later either orally, buccally, or vaginally

how do you take mifepristone + misoprostol

methotrexate

•folate antimetabolite that competitively inhibits folate-dependent steps in nucleic acid synthesis

•Inhibits critical step in growth for the rapidly dividing ectopic trophoblast

•Monotherapy for ectopic pregnancy; combined with misoprostol as an abortifacient

indications for methotrexate in pregnancy