Uterine Active Agents.docx

Uterine Active Agents & Drug Interactions with Pregnant Patients Uterus anatomy Uterine arteries (branches of internal iliac arteries) primary source of blood flow to gravid uterus. Uterine blood flow 500-900 ml/min. 20% of maternal CO in 3rd trimester. Perimetrium (outer) → myometrium (middle,...

Uterine Active Agents & Drug Interactions with Pregnant Patients Uterus anatomy Uterine arteries (branches of internal iliac arteries) primary source of blood flow to gravid uterus. Uterine blood flow 500-900 ml/min. 20% of maternal CO in 3rd trimester. Perimetrium (outer) → myometrium (middle, muscular) → endometrium (inner). Uterine atony Most common cause of postpartum hemorrhage. Complicates up to 10% of deliveries. Noncontracted uterus + bleeding = postpartum hemorrhage. Risk factors Low risk → singleton pregnancy, <4 previous deliveries, unscarred uterus, absence of hx of postpartum hemorrhage. Medium risk → prior cesarean or uterine sx, >4 previous deliveries, mx gestation, large uterine fibroids, chorioamnionitis, Mg sulfate use, prolonged oxytocin use. High risk → previa, accrete, increta, percreta; Hct <30%; bleeding at admission; known coagulation defect; hx of postpartum hemorrhage; abnormal VS. Uterine receptors Uterus is made up of smooth muscle with mx receptors: oxytocin receptors, prostaglandins, α1, β2. Oxytocin acts directly on oxytocin G-protein uterine receptors to stimulate Ca channels & ↑ prostaglandin production → smooth muscle contraction. α1 agonist: methylergonovine (methergine). Prostaglandins: misoprostol, hemabate. β2 agonist activation ↑ cAMP → ↓ Ca → smooth muscle relaxation. Mg competes with Ca receptors → uterine relaxation. Changes in Ca stimulated or blocked by receptors will either contract or relax uterine muscle. Tocolytics Meds used to slow/stop contractions. MOA: ↓ Ca or block prostaglandin synthesis. Indications: preterm labor (mostly), uterine tetany, retained placenta, fetal head entrapment. Goals of therapy: transfer mother to tertiary care facility, administer abx to prevent neonatal group-B strep infection, administer steroids to ↓ neonatal morbidity associated with immature lungs, tx any underlying cause of preterm labor. E.g.: CCB, β-mimetics, oxytocin antagonist, prostaglandin inhibitors. Magnesium IV bolus (4-6 g) over 20-30 mins followed by 1-2 g/hr infusion – CCB MOA: blocks Ca at binding sites on SR. Used for seizure prophylaxis with pre-eclampsia → ↑ seizure threshold. Fetal neuroprotection & ↓ incidence of cerebral palsy in infants born before 32 wks. Potentiates NMBs, risk of pulmonary edema, dependent on renal function for excretion. Will cross placenta → effects on fetus ↓ variability. Nifedipine – CCB MOA: antagonism of Ca channels at SR. Greater effect on uterus compared to other CCB. SE: maternal flushing, headache, hypotension, VAs + CCB → uterine atony. Uterine perfusion = (uterine arterial pressure – uterine venous pressure)/ uterine vascular resistance. Ritodrine & terbutaline – β-mimetics MOA: selective β2 agonist → ↑ cAMP → smooth muscle relaxation. Stimulation results in gluconeogenesis → ↑ BG & ↓ BG 2/2 reflex insulin secretion. Pulmonary implications on maternal side → pulmonary edema via ↑ pulmonary capillary permeability. Tx for preterm labor & uterine tetany. Terbutaline use for ECV to help prevent distress by ↓ uterine contraction after manipulation. Shown superior to Mg for tocolysis, inferior to CCB. Uterine hypertonicity → unopposed oxytocin induced tetany as Epi levels decrease after labor spinal or CSE. Uterine not perfused well → fetal distress. 25 mg IV/SQ. Indomethacin 50 mg oral/vaginal – prostaglandin synthetase inhibitors MOA: COX-1 & COX-2 inhibition → prevents prostaglandin synthesis. Prostaglandins are strong uterine stimulants. Prolongs pregnancy (by 2-7 days) in setting of preterm labor. Transient plt inhibition → no contraindication to neuraxial. SEs in fetus: premature closure of ductus arteriosus, oligohydramnios, necrotizing enterocolitis. Nitroglycerin 50 mg IV MOA: inhibits GC → ↑ cGMP → inhibits Ca influx → smooth muscle relaxation. Only used for RAPID uterine relaxation, such as head entrapment, extraction of twin baby, placental removal. SE: transient hypotension, headache, nausea. Uterotonics MOA: ↑ Ca → uterine contraction. Indication: postpartum hemorrhage (most common). Oxytocin (Pitocin) Hormone produced in hypothalamus, transported & stored in posterior pituitary prior to release. Rule of 3s: 3 units of Pit in 3 ml over 3 mins. Onset 1-2 mins, ½-life ~15 mins. Weak anti-diuretic activity. Recs to facilitate 3rd stage of labor & ↓ risk of postpartum hemorrhage. For laboring pt requiring c/s: slow 3IU bolus followed by 5-10 U infusion suggested. Labor induces changes in oxytocin receptor population. Early labor → oxytocin receptor population > term, non-laboring pts. Active labor (>7 cm dilated) → ↓ oxytocin receptors. Oxytocin induced labor vs. spontaneous labor: significant ↓ oxytocin binding sites in induced group. Continuous exposure of myometrium cells to oxytocin → significant loss in capacity to respond to oxytocin 2/2 receptor desensitization. Usually associated with ↑ CO because it ↓ SVR while causing an autotransfusion. Vasodilatory (peripherally) & vasoconstrictive effects (uterus) via same receptor V1aR. Methergine (methylergonovine) 0.2 mg IM MOA: α1 activation → uterine contraction. SE: peripheral vasoconstriction, NxV, retinal damage, pulmonary edema, cerebral hemorrhage. Caution in baseline hypertensive patients (gHTN, pre-E), pHTN. AVOID in parturient with chronic hypertensive, pre-eclampsia, PVD, & IHD. Prostaglandins Naturally occurring hormones & together with oxytocin are essential for uterine tone & adequate contractions. MOA: ↑ Ca → uterine contraction. 3rd line tx for uterine atony. If uterine atony persists, after oxytocin & methergine administration in women with reactive airway dz → administering this drug considered only with full appreciation of potential for precipitating severe & sometimes catastrophic bronchospasm. SE: NxV, diarrhea & fever. Misoprostol – PGE1 Uses including induction of labor & abortion, rectal or intravaginal for postpartum hemorrhage. Hemabate 250 mcg IM or intramyometrially – PGF2a 3rd line tx for postpartum hemorrhage. Caution in parturient with reactive airway disease. Contraindication: cardiac disease & pHTN. PGE2 ↑ SVR & PVR, bronchospasm possible, & ↑ intrapulmonary shunting → V/Q mismatch. Vasopressors Epinephrine 1:200,000 (15 mcg) – α1 & β1 agonist. Used in epidural “test dose” to r/o epidural catheter misplacement. Limited OB uses, prolongs action of LAs. Otherwise, used in emergent situations. Ephedrine – direct → α & β agonist, indirect → inhibits NE reuptake. Mainly used for hypotension following neuraxial placement. Crosses placenta & may ↑ fetal HR, associated with lower pH values in cord testing. Phenylephrine - α1 agonist Vasopressor of choice in maternal cocaine use. CO maintained even with drop in HR. Prophylactic dose before spinal/CSE → ↓ nausea & fetal distress. Antihypertensives Hydralazine 10-20 mg IV – direct arteriole dilator Mainly related to cHTN or pre-E. Minimal venous effects, treats pHTN with ↑ HR. Effect lasts 2-3 hrs. Labetalol 5-10 mg IV – (α:β potency 1:3 (PO), 1:7 (IV)) Maintains uterine blood flow. Used in tx of pre-E. Transexamic acid (TXA) 1 g over 30 mins, repeat 30 mins if bleeding continues Way to ↓ blood loss via reversible inhibition of plasminogen to plasmin, which promotes clot breakdown. No ↑ in thrombotic events.