Pharmacology of Obstetrics Flashcards
Utertonic Agents Function
- Promotes contractions of uterine smooth muscle
Tocolytic Agents Function
- Suppresses contractions of uterine smooth muscle
Clinical reasons to soften cervix and enhance uterine contraction
- Induction of labor (before spontaneous contractions)
*limit an extended pregnancy
*membrane rupture w/o labor
*gestational hypertension or diabetes
*prevent early rupture of membrane
*aid in placental insufficiency
- Augmentation of labor
- Therapeutic abortion (or post-spontaneous abortion)
- Post-partum hemorrhage (PPH) control- the leading cause of maternal mortality worldwide
Clinical reasons to suppress uterine contractions
- Prevent/delay premature labor to buy time to:
*give antenatal corticosteroids time to work to get fetal lungs producing surfactant
*get mo to a facility w/ proper lvl NICU
Major Categories of Uterotonic Agents
- Some classes of prostaglandins
*PGE (1 and 2)
*PGF2alpha
*used for cervical ripening and induction
- Oxytocin
*used for induction/augmentation; OT for PPH
- Progesterone receptor antagonist
*same use as oxytocin
- Ergots
*used for PPH
Major Categories of Tocolytic Agents
- Progesterone (preventative)
- MgSO4
- Ca2+ channel blockers
- Oxytocin antagonists
- Beta-adrenergic agonists
- Prostaglandin synthesis (cyclooxygenase) inhibitors
- Nitric oxide donors
Ca2+ effect on Uterine contraction
- Increasing Ca2+ promotes contraction
- Decreasing Ca2+ prevents contraction
General mechanism in myometrial cell leading to contraction
- Action potential depolarize myometrial cell membrane
- Opening of voltage-gated Ca2+ channels; entry of Ca2+
- Ca2+ binds calmodulin
- Activates myosin light-chain kinase (MLCK)
- Enables interaction of myosin w/ actin needed for contraction
- MLCP activation—>relaxation
Uterotonic Agents Maternal Contraindications
- Unfavorable prior uterine incision type
- Contracted or distorted pelvic anatomy
- Abnormally implanted placentas
- Active infection or cervical cancer
Uterotonic Agents Fetal Contraindications
- Substantial macrosomia
- Severe hydrocephalus
- Malpresentation
Adverse effects from prolonged stimulation of uterine contraction
- Persistent uteroplacental insufficiency
- Sinus bradycardia
- Arrhythmias
- Fetal death
Prostaglandins
- Cyclic fatty acid compounds derived from arachidonic acid
- Endogenous PGs are produced by placenta and fetus
- Decreased by progesterone
- Increased by estrogen
- Inhibitory prostaglandins (prostacyclins) also expressed throughout pregnancy which may play a role in quiescence
Clinical use of prostaglandins in pregnancy
- Increase uterine smooth muscle contractility
- Aid in cervical ripening
*increases efficacy of induction
*safest in women w/ unscarred uterus
- More effective than oxytocin in stimulating uterine contraction thru second trimester
- Abortifacient weeks 12-20
Prostaglandins MOA for cervical ripening
In cervix, PG causes:
- Dissolution of collagen bundles
- Increases the submucosal water content
Prostaglandin MOA for uterine contraction
- Inc. IP3-mediated Ca2+ release from SR
- Inc. freq. of APs, thus inc. Ca2+ entry thru VGCCs
- Activate non-specific cation channels (inc. Ca2+)
- PGEs activate MLCK and inactivate MLCP by blocking adenylyl cyclase (cAMP, PKA)
5, PGF2alpha may also inc. Ca2+ sensitivity of apparatus
Dinoprostone
- Naturally occuring PGE2
- Approved for single-dose cervical ripening
- Clinical trials show it may be less effetive than other PGs
- Available forms: gel, time-release vaginal insert, and 10mg suppository
Misoprostrol
- PGE1 analogue
- Cheaper than dinoprostone and has shorter half-life (so easier to manage)
- Can be vaginal or oral
- Higher rates of uterine contraction abnormality, but otherwise similar safety profile to dinoprostone
- Effective for ripening and induction, though off-label use
Carboprost tromethamine
- “Hemabate”
- Synthetic analogue of PGF2alpha
- Upregulates oxytocin receptors and gap junctions in myometrium to promote contractions
- Used for:
*2nd trimester abortion
*PPH caused by uterine atony if oxytocin doesn’t work
Prostaglandins Adverse Reactions
- Uterine tachysystole (>5 contractions in a 10min period); check for fetal heart rate abnormalities
- GI disturbance- N/V, diarrhea
- Transient fever
- Retained placental fragments
- Excessive bleeding
- Decrease diastolic BP
- Headache
Prostaglandin cautiously used in patients with
- Asthma
- Cervicitis
- Vaginitis
- Inc. or dec. BP
- Anemia
- Jaundice
- Diabetes
- Epilepsy
Prostaglandins Contraindicated in patients with
- Acute PID
- Drug hypersensitivity
- Active renal, hepatic or CV disorders
Oxytocin
- Most common induction agent
*so common that “oxytocis” is often used synonymously w/ uterotonics
*Pitocin, Sytocinon
- Hormone made in hypothalamus (paraventricular n.)
- Stored in and released by posterior pituitary
- Short plasma t1/2; 3-6min.
- Cannot be given orally; degraded by GI enzymes
- By end of pregnancy, OT receptors increase 300 fold
Oxytocin uses in pregnancy/labor
- Labor induction, but variable responses
*not always successful, but still the best thing we have for labor induction (works best following PGE)
*maximal effective dose is diff. pt to pt
- Labor augmentation
- Following incomplete abortion after 20wks gestation
- After delivery to prevent/control uterine hemorrhage
- In high doses to induce abortion
- Inappropriate use can lead to uterine rupture, anaphylaxis, or maternal death
Oxytocin MOA
- Inc. IP3 mediated Ca2+ release from SR
- Inc. freq. of APs, thus inc. Ca2+ entry thru VGCCs
- Inhibits Ca2+ efflux
- May directly inhibit MLCP
- Stimulates release of PGE2 and F2alpha
Oxytocin Risks and Adverse Effects
- Uterine hyperstimulation- risk may be increased w/ PGE+OT
*tachysystole (>5 contractions in 10min. over a 30min. window)
*hypertonus (contraction lasting >2min.)
- Uterine rupture
- Amniotic fluid embolism
- Fetal distress
- Hypernatremia/H2O intoxication w/ prolonged use (secondary to ADH-like effects of oxytocin); rare, but can lead to convulsions, coma, death
Mifepristone (RU-486)
- Competitive progestin antagonist in the presence of progesterone
- Induces uterine contractions by causing progesterone withdrawal
- Sensitizes uterus to contractile prostaglandins
- +prostaglandin (misoprostol) = abortifacient in early pregnancies
Ergots
- Produced by a fungus that causes disease in plants
- Aides in the reduction of postpartum blood loss
- Postpartum and postabortal atony and hemorrhage
- Generally not first-line treatment
- Not for long-term use (2-3days, 7 max)
Methylergonovine
- Ergot like derivative
- Directly stimulates uterine smooth muscle
*inc. muscle tone
*enhances rate and force of rhythmical contraction
- Induce arterial vasoconstriction
Methylergonovine MOA
- Partial agonist of alpha-adrenergic receptors
- Some 5-HT (serotonin), dopamine receptor activity
- Inhibits the release of EDRF (endothelial-derived relaxation factor)
Methylergonovine Adverse Reactions
- Hypertension (b/c of alpha-adrenergic actions)
- Headache
- Seizures?
- N/V
- Chest pain
- Difficulty breathing
- Can affect lactation due to effects on prolactin
- Leg cramps
- Prolonged use leads to ergot poisoning including gangren in the nursing infant
*signs include severe uterine cramping, CV changes, cyanosis, muscle pain, tingling and other signs of impaired peripheral circulation
Methylergonovine Contraindications
- Angina pectoris
- MI
- History of CV accident, transient ischemic attack or hypertension (b/c potential for seizures arrhythmias, CVA or MI)
Tocolytics Effects and Limitations
- Once labor starts, none of these drugs can hold off labor for more than 7 days; most only 48hrs max
- Provides enough time to:
*give antenatal corticosteroids to get fetal lungs producing surfactant
*get mom to a facility w/ proper lvl NICU
- ~20% of cases, hydration and bed rest may suffice to stop contractions
Tocolytic Agents Contraindications
- Intrauterine fetal demise
- Lethal fetal anomaly
- Nonreassuring fetal status
- Preeclampsia w/ severe features or eclampsia
- Maternal hemorrhage w/ hemodynamic instability
- Intraamniotic infection
Progesterone
- Tocolytic
- Preventative only- must be given early in pregnancy
- Will not help once preterm labor begins
- Maintains uterine quiescence
- Silences myometrial contractility
- Promotes cervical competency
- Hyperpolarizes uterine smooth muscle membranes
- Progesterone withdrawal—> parturition triggering
17alpha-hydroxalase
- Enzymes that placenta lacks
- Converts progesterone to estrogen
*b/c placenta lacks this, progesterone is kept at consistent lvls
*placenta makes estrogens from fetal androgens (E3 is main pregnancy estrogen)
Progesterone MOA
- Dec. Ca2+ entry and release from SR
- Can act thru nuclear and membrane PRs to alter gene expression, dec. contractibility of myometrial cells (preventing gap junctions)
- Membrane PRs couple to Ca2+ signaling pathways
- Inhibits PG synthesis
- May inhibit OT binding to receptor
Progesterone as preventative therapy for premature labor
- 17 alpha-hydroxyprogesterone caproate (17-OHPC)
- Weekly IM injection starting week 16-20 until 36
- Helps to maintain progesterone lvls needed for uterine quiescence
- Approved by FDA to “reduce the risk of preterm delivery before 37wks…in women w/ a history of at least 1 spontaneous preterm birth”
- NOT effective in women pregnant w/ multiples
Progesterone Side Effects
- Blood clots
- Depression
- GI issues (nausea, diarrhea)
- Local reactions to shots
Progesterone Contraindications
- Blood clots/clotting problems
- Breast cancer or history
- Liver problems
- Uncontrolled high BP
MgSO4
- Often the first-line tocolytic in USA, though treating premature labor is an off-label use
- Approved to prevent seizures in preeclampsia
- Thought to be relatively safe for mom and fetus if used no longer than 5-7 days
- May provide neuroprotection to preemie (dec. risk of cerebral palsy
- IV admin.
MgSO4 MOA
- Not completely clear, but likely:
- Antagonizes/competes w/ Ca2+
- Dec. extracellular Ca2+ entry and release of Ca2+ from SR
- Inc. Ca2+-dependent ATPase (promotes Ca2+ uptake by SR)
- Activates adylate cyclase
- Inc. Nitric oxide synthase
- Overall effect is relaxation of smooth muscle
MgSO4 Adverse Effects
- May see signs of Mg2+ toxicity after 5.5mEq/L
- Life threatening Mg2+ toxicity can be counterd w/ calcium gluconate
- Fetal signs = low apgar scores or hypotonia
- Bone abnormalities in fetuses w/ >5 days MgSO4 exposure
Calcium Gluconate
- Counters life threatening Mg2+ toxicity
MgSO4 Contraindications
- Myasthenia gravis
- Myocardial compromise
- Cardiac conduction defects
- Impaired renal function can increase likelihood of Mg2+ toxicity
Nifedipine
- Ca2+ channel blocker most commonly used for tocolysis
- One of the longest-acting tocolytics (can delay labor for ~7days)
- Optimal dosing is not establish
*t1/2 = 2-3hrs
*duration of action (PO) = 6hrs
- Almost completely metabolized by liver; excreted by kidney
Nifedipine Adverse Effects
- Peripheral vasodilator
*nausea, flushing, headache, dizziness, palpatations
*some reports of hypotension, but not as much CV impact as other drugs (beta-agonists)
- Respiratory depression may occur in women also taking MgSO4
Nifedipine Contraindications
- Hypersensitivity to Ca2+ channel blockers
- Hypotension
- Preload
- Use with care in women with:
*left ventricular dysfunction
*CHF
Anti-oxytocins
- Competitive antagonists at OTRs
*blocks pathway that causes release of intracellular Ca2+
Atosiban
- Anti-oxytocin
- Competitive inhibitors of OTRs and vasopressin V1a receptors
- Questionable efficacy
- Not approved for use in USA, but used in Europe
- IV admin.
Beta-adrenergic agonists
- B2-AR agonists
- Activates adenylyl cyclase—> inc. cAMP—>activtes PKA
- Inactivates MLCK
- Decreases Ca2+
Terbutaline
- Off-label
- Beta-adrenergic agonist
- Can only hold off preterm labor for 48-72hrs, which is fine b/c…
- NOT FOR PROLONGED USE in pregnant women (beyond 48-72hrs); can be fatal
- Risk of post-partum hemorrhage b/c B2-AR agonists occupy receptor for a long-time (thus oxytocin will be ineffective)
Indomethacin
- Prostaglandin synthesis (COX) inhibitor
- NSAID (like motrin)
- Most commonly used COX inhibiting tocolytic
- Cannot be used for more than 2-3 days, but not effective for longer than that anyway
Indomethacin MOA
- Decreases PG production in myometrium
- Many PGs in uterus are uterotonics, so these drugs decrease contractions
- May inhibit both isoforms of COX (1 and 2)
Indomethacin Maternal Adverse Effects
Side effects of nonspecific COX inhibitors
- Nausea
- Esophageal reflux
- Gastritis
- Emesis
- Platelet dysfunction
Side effects of COX2 inhibitors
- Reduced severity of GI adverse effects
- Boxed warning for CV outcomes such as stroke
Indomethacin Fetal Adverse Effects
COX inhibitors in fetus:
- Premature closure of ductus arteriosus
- Can lead to primary pulmonary hypertension
- Dependent on:
*duration of exposure (ex, indomethacin exposure >48hrs)
*gestational age
+most common after 31-32wks
+Indomethacin NOT recommended for use after 32wks
- Oligohydramnios
- Occurred in 70% of pts treated w/ indomethacin for >72hrs
*COX inhib—> dec. fetal urine—> dec. amniotic fluid
Contraindications of COX inhibitors
- Platelet dysfunction
- Bleeding diabetes
- Hepatic dysfunction
- GI ulcers
- Renal dysfunction
- Asthma w/ hypersensitivity to aspirin
Galactogogues
- Lactation stimulators
- Used to induce, maintain, and increase milk production
- Often needed after preterm labor
Herbal supplements thought to be galactogogues
- Fenugreek
- Fennel
- Goat’s rue
- Asparagus
- Anise
- Milk thistle
Drugs to stimulate lactation
- Stimulates synthesis and release of prolactin by antagonizing dopamine D2 receptors
- Many are antipsychotics
- Most common pharmaceutical galactogogues are:
*Metoclopramide
*Domperidone (banned in USA, used in Canada)
*Chlorpromazine
Metoclopramide
- Stimulates lactation
- t1/2 = 156.7min
Metoclopramide adverse effects in mothers
- Anxiety
- GI disorders
- Insomnia
- Severe depression
- Seizures
Metoclopramide adverse effects in infants
- Intestinal discomfort
Domperidone
- Stimulates lactation
- not approved by FDA b/c was assoc. w/ cardiac arrhythmia and sudden death in moms
- Additonal ADRs in moms: dry mouth, GI disorders
- No ADRs in babies
- Newer studies have found diff. results (no serious ADRs in moms)
- t1/2 = 7.5hrs
-Chlorpromazine
- Stimulates lactation
- t1/2 = 16-30hrs
Chlorpromazine adverse effects in mothers
- Weight gain
- Movement disorder (Tardive dyskinesia, pseudo-parkinsonism)
Chlorpromazine adverse effects in babies
- Lethargy
- Reduced behavioral performance
Cabergoline
- Drug to suppress lactation
- Specific D2 receptor agonist
- Used primarily for prolactinomas
- >600ug dose within 24hrs of delivery very effective in stopping lactation
- Side effects may be a concern
*simlar to bromocriptine, which causes hypertension, stroke, seizures and psychosis when used to stop lactation
*cabergoline thought to be safer, but not enough data
Lactation Proccess Chart
