Induction And Analgesia During Labor Flashcards
Pharmacology of Parturition (Labor) - 4
- Pharmacologically relevant targets in parturition regulate smooth muscle contraction
- Tocolytics PREVENT/DELAY labor onset by REDUCING smooth muscle contraction
- Oxytocics (a.k.a. uterotonics) INDUCE labor by PROMOTING smooth muscle contraction
- Pathways converge on myosin light-chain kinase (MLCK)
Myosin light-chain kinase (MLCK) and Uterine Muscle (3)
- ACTIVE MLCK is essential in smooth muscle CONTRACTION
- MLCK is ACTIVATED by Ca2+/calmodulin complex
- Myometrial cell CONTRACTION is mediated by increased Ca2+ levels - MLCK is DEACTIVATED by phosphorylation
- Myometrial cell RELAXATION is promoted by phosphorylation of MLCK
Pharmacological targets of MLCK activity (2)
- Agonism of CRH, PGE2, and ß2-adrenergic receptors promotes RELAXATION
- Agonism of Gs coupled-receptors INCREASES cAMP-mediated PHOSPHORYLATION - Agonism of thrombin, oxytocin, and prostaglandin F receptors promotes CONTRACTION
- Agonism of Gq coupled-receptors INCREASES intracellular Ca2+ levels
General Principles of Tocolytic Pharmacology (3)
- Preterm delivery = delivery occurring before 37 weeks of gestation
- > 10% of pregnancies in the U.S. are preterm
- Associated with neonatal respiratory distress syndrome, pulmonary hypertension, and intracranial hemorrhage - Tocolytic agents are effective in delaying preterm delivery in ~80% of women
- Indicated when delaying delivery up to 48 hours is beneficial to fetus and cervical dilation is not advanced
- Generally not used past 34 weeks gestation - These agents do not decrease overall occurrence of preterm labor or alleviate complications!
Tocolytics postpone delivery long enough to: (3)
- Administration of corticosteroids to the fetus to promote fetal lung development
- Transportation to a facility equipped to deal with high-risk deliveries
- Prolongation of pregnancy in the presence of underlying, self-limited conditions that can cause labor
- E.g., pyelonephritis, abdominal surgery, or other conditions unlikely to cause recurrent preterm labor
Pregnancy can be prolonged by 48 hours to 1 week
Contraindications of tocolytic therapy (8)
- Previability
- Intrauterine fetal demise
- Lethal fetal anomaly
- Intrauterine infection
- Fetal distress
- Severe preeclampsia
- Vaginal bleeding
- Maternal hemodynamic instability
General MOA of Tocolytic Agents and their Classes (2 MOA, 6 Classes)
- Decreased Ca2+/calmodulin availability (decreases uterine contractility)
- Increased phosphorylation (increases uterine relaxation)
Most effective classes:
- COX inhibitors
- Ca2+ channel blockers
- B2-adrenergic receptor agonists
Less effective classes:
- Oxytocin receptor antagonists
- MgSO4 (magnesium sulfate)
- Nitric oxide (NO) donors
COX inhibitors: indomethacin (General, MOA, PK, ADRs, contraindications)
General: First-line agent for tocolysis between 24-32 weeks of gestation
MOA: Non-specific COX inhibitor (reduced PGF synthesis). Reduce stimulation of uterine contractions by decreasing available intracellular Ca2+.
PK: Administered orally or rectally
Maternal ADRs:
- COX-2 inhibitors carry BLACK BOX WARNING: CV toxicity (myocardial infarction, stroke)
- Risk of inhibited platelet function
- N/V, GERD, gastritis, and emesis
Fetal ADRs:
- May induce closure in utero of ductus arteriosus causing impaired circulation
- May reduce amniotic fluid and cause oligohydramnios
Contraindicated beyond 32 weeks of gestation
Ca2+ channel blockers: Nifedipine (General, MOA, PK, ADRs)
General: First-line agent for tocolysis between 32-34 weeks of gestation or for contraindication to indomethacin (24-32 weeks)
MOA: Blocks voltage-gated Ca2+ channels. Reduces stimulation of uterine contractions.
PK: Administered parenterally or orally
Maternal ADRs:
- Peripheral vasodilator: headache, flushing, and dizziness, palpitations, severe hypotension possible
- No direct effect on pacemaking or AV node conduction
- Safer than ß2-adrenergic agonists
No discernible impact on fetus.
Selective B2-adrenergic receptor agonists: terbutaline and ritodrine (General, MOA, PK, ADRs)
General: Terbutaline is FDA-approved for asthma with off-label tocolytic use. Used as second-line agents for 32-34 weeks of gestation.
MOA: B2-adrenergic receptor agonists RELAX myometrium by stimulating cAMP and MLCK phosphorylation.
PK: Administered PO, IV, or subcutaneously
Maternal ADRs:
- Tachycardia, hypotension, pulmonary edema, metabolic effects
- BLACK BOX WARNING: maternal cardiotoxicity and death with prolonged use
Fetal ADRs:
- Drug crosses the placenta
- Similar ADR profile as maternal side
*Ritodrine was FDA-approved for tocolysis, but has been withdrawn from market due to unfavorable ADRs
Oxytocin receptor antagonists: Atosiban (MOA, PK, ADRs)
MOA: Decreases intracellular Ca2+ concentration and decreases uterine contractions. Mimics effectiveness of B2-adrenergic receptor agonists.
PK: Administered IV for 2-48 hours
ADRs:
- Hypersensitivity
*Not FDA approved
MgSO4 and NO (MOA, PK, ADRs, and Contraindications)
MgSO4
MOA: Competes with Ca2+ at voltage-gated and ligand-gated Ca2+ channels. Decreases intracellular Ca2+ and decreases uterine contractions. Also used to treat preeclampsia.
PK: Administered parenterally. Renally excreted.
Maternal ADRs:
- Diaphoresis, flushing, Mg2+ toxicity
Fetal ADRs:
- Bone abnormalities with long-term exposure
Contraindicated in myasthenia gravis, cardiac compromise.
NO
MOA: Activates phosphokinase G via cGMP signaling to phosphorylate MLCK and promote uterine relaxation.
Contraindicated in hypotensive patients.
Indications for Agents Used to Induce Labor - Oxytocics (Uterotonics) - Maternal Factors (9) and Fetal Factors (9)
Maternal factors:
- Preeclampsia
- Eclampsia
- HELLP (hemolysis, elevated liver enzymes, low platelet count)
- Diabetes (pregestational or gestational)
- Chronic hypertension
- Heart disease
- Intrauterine infection
- Augmentation of protracted labor
- Postpartum hemorrhage (uterine atony)
Fetal factors:
- Late-term or postterm pregnancy
- Fetal abnormality
- Chorioamnionitis
- Premature rupture of membranes
- Placental insufficiency
- Oligohydramnios
- Suspected intrauterine growth restriction
- Fetal demise
- Multiple gestation
Prostaglandins, Oxytocin, and Parturition (4)
- PGE2 and oxytocin are required for the onset of parturition
- PGE2 or PGF2a produces DOSE-DEPENDENT increases in:
- Uterine tone
- Frequency of contractions
- Intensity of contractions - Effects of prostaglandins increase as pregnancy progresses
- Prostaglandins and oxytocin used in sequence to promote cervical ripening and induction, respectively
Prostaglandin Agents (Dinoprostone and Misoprostol) MOA and PK
Indications: Cervical ripening prior to labor induction
- Dinoprostone (PGE2) (FDA-approved)
- Available as a gel
- Administered intracervically or as a vaginal insert (next to cervix) - 12 hours for cervical ripening, remove 30 minutes prior to induction, induce with oxytocin - Misoprostol (PGE1) (off-label use)
- Available in tablets that can be administered orally, vaginally, or rectally
- Allow at least 4 hours before induction with oxytocin
Prostaglandin Agents (Dinoprostone and Misoprostol) ADRs - 8 and Contraindications - 7
ADRs:
- Fetal heart rate deceleration
- Fetal distress
- Emergency cesarean section
- Uterine hypertonicity
- Nausea
- Vomiting
- Fever
- Peripartum infection
Prostaglandin contraindications:
- History of asthma (smooth muscle contraction effect can worsen asthma)
- Glaucoma
- Myocardial infarction
- Unexplained vaginal bleeding
- Chorioamnionitis
- Ruptured membranes
- Previous cesarean section
Induction of Labor with Oxytocin (2)
- Regimen and quantity of oxytocin must be individualized
- Use lowest effective dose for each patient
- Precise IV administration via continuous-infusion pump
- Begin with low dose infusion (ex: 0.5-2 mU/mL)
- Increase every 30-60 minutes as needed to maintain labor (maxiumum 20 mU/min)
- Constant observation is required - Discontinue if tachysystole (> 5 contractions per 10 min) or fetal distress occurs
Oxytocin ADRs and Contraindications
ADRs:
- Excessive uterine contractions
- Placental blood flow to fetus is transiently reduced
- Deceleration of fetal heart rate/fetal hypoxia may require immediate C-section
- Off-target activation of vasopressin receptors (fluid retention/water intoxication) causing hyponatremia, heart failure, seizures, death; hypotension
Contraindications:
- Fetal distress or malpresentation
- Placental abruption or other risk of uterine rupture (previous surgery)
Contraindications to Labor Induction (8)
Any problem that could be made worse by intensifying contractions is always a contraindication or cause for concern!
- Contracted pelvis
- Placenta previa
- Vasa previa
- Previous classical cesarean section
- Myomectomy entering the endometrial cavity
- Breech presentation (relative)
- Previous C-section with low transverse uterine scar (relative)
- Complications: oligohydramnios; multiple gestation; grand multiparity; prematurity; suspected fetal macrosomia (all relative)
Labor Induction (Complications)
Maternal considerations:
- Induction of labor may be more distressing than judicious delay or c-section
- Failure of induction
- Prolonged labor (uterine inertia)
- Tetanic contractions of the uterus (tumultuous labor)
- Premature placental separation, uterine rupture, cervix laceration
- Intrauterine infection
- Postpartum hemorrhage
Fetal considerations:
- Induction of labor increases risk of prematurity
- Calculation of date of conception may be inaccurate
- Cord prolapse (amniotomy)
- Fetal heart rate abnormalities (oxytocin) or poor Apgar score
Non-pharmacologic methods of obstetric pain management (2)
- Continuous support during labor provides best outcomes
- Nurses, midwives, coaches, doulas, childbirth educators
- Fewer operative vaginal or cesarean deliveries
- Fewer requests for pain medication - Warm baths and acupuncture temporarily reduce pain
General principles of obstetric analgesia and anesthesia (7)
- Psychologically prepared patients require less medication
- Do not promise painless labor
- Anticipate and address anxieties before and during early labor - Treatment must be individualized to each patient
- Variations in response, preference, and adverse reactions - Know the limitations, dangers, contraindications and advantages of each drug administered
- Analgesia is the loss or modulation of pain perception
- Anesthesia is the total loss of sensory perception
- Transplacental drug transfer occurs with systemic analgesics and CNS depressant effects may affect fetus or newborn
Analgesics & Anesthetics used during labor (6)
- Tranquilizers: Benzodiazepines - Used for anxiety; midazolam’s SHORT HALF LIFE reduces risk of fetal kernicterus, hypotonia, hyperthermia, heart rate abnormalities compared to longer acting (diazepam).
- Narcotic Agents: Codeine (IM), Merperidine (IM/IV), Fentanyl (epidural) - Most common choice; Parenteral opioids (compared with epidural analgesia). Lower rate of oxytocin augmentation; shorter stages of labor; fewer instrumental deliveries and cesarean sections for fetal distress.
- Inhalation anesthetics: NO, sevoflurane, desflurance, isoflurane - Significant fetal concentrations achieved. Pregnant patients are more sensitive than nonpregnant patients, increased risk of obutndation and aspiration. SHOULD BE INTUBATED.
- Propofol: Ideal for induction of general anesthesia in pregnant patients.
- Etomidate: Minimal cardiorespiratory effects makes it useful for hemodynamically unstable patients.
- Ketamine: Widely used as adjunctive agent; maternal cardiovascular status and uterine blood flow are well-maintained, blood pressure and cardiac output are stimulated; useful in major blood loss setting when rapid induction of anesthesia is required; narrow margin of safety and hallucinogenic.
Non-systemic analgesia and major sites of placement (5)
- Indication: maternal request (~60% of patients choose epidural analgesia)
- Epidural analgesia
- Catheter introduced into epidural space
- Opioid and/or anesthetic administered - Spinal-epidural (intrathecal) analgesia
- Injection of single opioid bolus into subarachnoid space followed by epidural catheter (immediate and sustainable pain relief) - Major benefit: the patient-controls analgesia
- Lower total dose over the course of labor compared with continuous IV infusion - Risks of epidural analgesia:
- Prolongation of the first and second stages of labor
- Higher numbers of instrumental deliveries and cesarean sections (for fetal distress)
- Maternal fever
