Uterotonics and tocolytics


Introduction

The uterus has two major components: the cervix and the corpus. The uterine cervix comprises the external os, the internal os, and the cervical canal that connects them. The corpus comprises the uterine fundus and the main uterine body. Anatomically, there are four layers of the uterus. The outermost layer, the perimetrium, is serosal in nature and is analogous to the peritoneum. Beneath the serosal layer lies the parametrium, a layer of connective tissue connecting the uterus to the other tissues of the pelvis. The myometrium lies beneath these outer layers and is primarily composed of smooth muscle tissue. The innermost layer is the endometrium composed of glandular epithelial tissue.

While each layer serves an important function in pregnancy and parturition, it is the myometrium that is of primary concern during parturition. The uterine myocytes are capable of significant enlargement during pregnancy to accommodate the growing fetus. Although there are multiple factors that trigger the beginning of labor (some of which remain unknown), one factor is activation of stretch receptors within the myometrium that trigger regular uterine contractions. During normal labor contractions, the fundus serves as the pacemaker for the contractions and sends electrical impulses throughout the myometrium causing coordinated contraction of the myocytes.

Obstetric providers often need to alter uterine contraction activity in the care of pregnant women. Medications that induce or augment uterine contraction are known as uterotonics, while medications that reduce or arrest uterine contractions are known as tocolytics. Uterotonic medications are also used to ripen or prepare the cervix for dilation and to effect uterine contractions to control uterine bleeding. It should be noted that the use of most of these uterine medications is not FDA approved and is considered off-label usage. There is, however, considerable evidence to support their clinical use.

Uterotonics

Uterotonics are by far the most common drugs administered on any labor and delivery suite. Clinically, they are used primarily for induction or augmentation of labor and to prevent and/or control postpartum hemorrhage. All agents in this category cause uterine contraction, but each does so through a different pathway. It is important to have a working knowledge of each medication, as each can cause as much harm as good ( Table 18.1 ).

Table 18.1
Uterotonics.
Medication Clinical indication Route Dose Frequency Considerations
Oxytocin (Pitocin®) Induction/augmentation of labor Intravenous Low-dose regimen: Start at 0.5–2 milliunits/min Increase by 1–2 milliunits/min every 15–40 min, maximum dose 20–40 milliunits/min Titrate to maternal response and fetal tolerance. Goal is 2–5 contractions in 10 min
High-dose regimen: Start at 6 milliunits/min Increase by 3–6 mU/min every 15–40 min, maximum dose 40 mU/min Titrate to maternal response and fetal tolerance. Goal is 2–5 contractions in 10 min
Postpartum hemorrhage Intravenous Prophylactic:
10–20 units in 1 L isotonic solution; run 500 mL over 30 min, then 125 mL/h for 3.5 h
Treatment:
40 units in 1 L isotonic solution; infuse rapidly until bleeding is controlled, then titrate to maintain uterine tone
Continuous Observe for signs of water intoxication with rapid infusion of large amount of oxytocin
Intramuscular 10 units (thigh, gluteal, or myometrial) Once
Methylergonovine (Methergine®) Postpartum hemorrhage Intramuscular 0.2 mg Can repeat dose every 2–4 h, maximum 5 doses Avoid in women with uncontrolled HTN. Use in women with preeclampsia or HTN should only be considered if benefits outweigh risk
Oral 0.2 mg Can repeat dose every 6–8 h for 2–3 days (maximum 7 days)
Carboprost – PGF2α (Hemabate®) Postpartum hemorrhage Intramuscular 250 mcg Can repeat dose every 15–90 min (maximum 8 doses or 2 mg) Avoid in patients with asthma or pulmonary disease, can cause bronchoconstriction
Administer antidiarrheal medication
Misoprostol – PGE1 (Cytotec®) a Cervical ripening/labor induction Oral or vaginal 25 mcg Can repeat dose of 25–50 mcg every 3–6 h Hold dose if more than 2 contractions in 10 min
Oxytocin can be started 4 h after last dose
Postpartum hemorrhage Rectal 800–1000 mcg Single dose
Dinoprostone – PGE2 (Cervidil®) Cervical ripening/labor induction Vaginal insert 1 insert contains 10 mg Continual release for 12 h If cervical ripening not achieved after 12 h, may repeat
Oxytocin can be started 30–60 min following removal
Caution in patients with asthma or glaucoma
Dinoprostone – PGE2 (Prepidil®) Cervical ripening/labor induction Vaginal (cervical canal) 0.5 mg Single dose If cervical ripening not achieved after 6 h, may repeat
Oxytocin can be started 6 h after last dose
Caution in patients with asthma or glaucoma
Dinoprostone – PGE2 (Prostin®) Postpartum hemorrhage Rectal or vaginal 20 mg Single dose Caution in patients with asthma or glaucoma

a Misoprostol for cervical ripening/labor induction and for postpartum hemorrhage is an off-label use.

Oxytocin

Oxytocin is a polypeptide composed of nine amino acids. Endogenous oxytocin is primarily produced by the hypothalamus and is stored and released from the posterior pituitary gland (neurohypophysis). Oxytocin has multiple functions, mostly related to sexuality (orgasm), reproduction (uterine contractions), and lactation (milk ejection). It also has a role in social bonding and mood regulation.

Synthetic exogenous oxytocin is bioidentical to its natural endogenous analog. As a uterotonic medication, it is currently approved for medically indicated labor induction (i.e., premature rupture of membranes, diabetes, hypertension, preeclampsia, etc.), labor augmentation, and as an adjunctive therapy in the management of an incomplete or inevitable abortion. Additionally, oxytocin is a first-line agent for the treatment of postpartum hemorrhage secondary to uterine atony or subinvolution.

Oxytocin stimulates uterine contractions by increasing intracellular calcium. In the uterus, oxytocin binds to the oxytocin receptors located on the myometrial cell membrane and stimulates phospholipase C ( Fig. 18.1 ).

Figure 18.1, Contractant and relaxant pathways of a myometrial cell. CaCAM , calcium–calmodulin complex; CAM , calmodulin; IP3 , inositol triphosphate; MLCK , myosin light-chain kinase; Oxy , oxytocin; Pg , prostaglandin; PIP2 , phosphatidylinositol 4,5-biphosphate; PLC , phospholipase C; Ptase , phosphate kinase; SPR , sarcoplasmic reticulum.

This leads to increased production of inositol triphosphate which acts to mobilize intracellular calcium by promoting release from the sarcoplasmic reticulum. Binding to the oxytocin receptor also induces an influx of extracellular calcium through nonselective, cation channels on the myometrial cell membrane. Intracellular calcium then binds with calmodulin to form the calcium–calmodulin complex. This complex activates myosin light-chain kinase (MLCK), the key regulator of smooth muscle contractility. MLCK phosphorylates myosin which in turn binds actin, initiating myometrial smooth muscle contraction [ ].

Because of the potential for significant harm to pregnant women and their fetuses, oxytocin is listed as a “high-alert” medication by the Institute for Safe Medication Practices [ ]. Mismanagement of oxytocin often results in litigation against physicians, nurses, and midwives. In is incumbent upon providers, therefore, to have an understanding of the pharmacokinetics of oxytocin and published clinical practice guidelines. Despite extensive information on the pharmacokinetics of oxytocin, there is considerable disagreement about optimal dosing regiments of oxytocin for induction and augmentation of labor [ ]. Oxytocin has an onset of action within 3–5 min and a half-life of 10–12 min. Steady state (the point where the plasma concentration is stable such that the full effect of that concentration of the medication will be observed) is not achieved until 30–60 min, which corresponds to 3–5 half-lives [ ]. Response to exogenous oxytocin administration is highly variable [ ]. A rare but serious maternal side effect is water intoxication secondary to the antidiuretic properties of oxytocin. This condition has been reported in women who received oxytocin in D5 water and/or high-dose protocols (>20 milliunits/min) for prolonged periods of time. To avoid this, it is recommended that oxytocin be administered with an isotonic solution, and strict intake and output should be monitored.

The primary risk to the fetus is interruption in oxygen delivery from the placenta. For this reason, patients receiving oxytocin for induction or augmentation of labor should be placed on continuous electronic fetal and uterine monitoring by a competent registered nurse and obstetric provider. Unless there are other contraindications, patients may be monitoring continuously with reliable telemetry-based fetal and uterine monitoring.

Dosing regimens are categorized as either high dose or low dose. High-dose regimens usually begin with a dose of 6 milliunits/min, with incremental increases of 1–6 milliunits/min every 15–40 min, and a maximum dose of 40 milliunits/min [ ]. Low-dose regimens usually begin with a dose of 0.5–1 milliunits/min, with incremental increases of 1–2 milliunits/min every 15–40 min, and a maximum dose 20–40 milliunits/min [ ]. A Cochrane systematic review concluded that high-dose regimens do not increase the rate of vaginal delivery within 24 h, do not decrease total time in labor, do not increase cesarean section rates, but they do result in increased rates of uterine tachysystole [ ]. Additionally, a large retrospective study concluded that there were no significant differences in neonatal outcomes or cesarean section rates between patients that received high-dose versus low-dose regimens, but the study did not make conclusions about the rate of uterine tachysystole [ ]. In conclusion, there are not any significant advantages for high-dose regimens. General knowledge about medication dosing is to use the lowest effective dose for the shortest duration possible to achieve the desired outcomes. For these reasons, the author recommends using low-dose dosing regimens.

Prolonged exposure to exogenous oxytocin results in desensitization of oxytocin receptors [ ]. The receptors are downregulated, and by 4 h, around half of the receptors are no longer exerting an effect when bound to oxytocin. This downregulation of oxytocin receptors may result in dysfunctional labor patterns and paradoxically prolong labor as well as increase risk for postpartum hemorrhage [ , ].

Oxytocin is also used as an adjunctive therapy for incomplete, inevitable, and elective abortions in the first and second trimester but is less effective than other methods using mifepristone and/or misoprostol [ ].

Oxytocin is a first-line medication for preventing and controlling postpartum hemorrhage. Usual dosing for postpartum hemorrhage prophylaxis is 10–20 units in 1000 mL of isotonic solution. An initial bolus of 500 mL is given over 30 min, then reduced to 125 mL/h for the next 3.5 h. Alternatively, 10 units may be administered IM [ , ]. For the treatment of postpartum hemorrhage, 40 units of oxytocin mixed in 1000 mL of isotonic solution should be infused rapidly until bleeding is controlled, then titrated to maintain uterine tone [ ].

Methylergonovine

Methylergonovine, a semisynthetic ergot alkaloid, is a potent uterotonic that increases the force and frequency of uterine contractions at low doses. At higher doses, methylergonovine can increase basal uterine tone and cause uterine tetany. In obstetrics, methylergonovine is indicated for the treatment of postpartum hemorrhage secondary to uterine atony or subinvolution [ ].

The uterotonic properties of ergot alkaloids have been known for centuries. Their use as a labor stimulant was first described by Adam Louicer in 1582 [ ]. Although the uterine effects of ergots were discovered hundreds of years ago, the exact mechanism by which methylergonovine causes myometrial contraction is not known. Ergot alkaloids are known to cause vasoconstriction, uterine contractions, and stimulation of central dopamine receptors.

Ergots have been shown to bind alpha adrenergic, serotonin, and dopamine D1 receptors. It is likely that methylergonovine specifically interacts with alpha adrenergic receptors on the myometrial cell ( Fig. 18.1 ). This interaction alters transmembrane calcium channel activity, causing an influx of calcium into the myometrial cell and activation of the contraction cascade [ ].

After oral administration or intramuscular injection, methylergonovine is rapidly absorbed and distributed throughout the plasma and extracellular fluid. Approximately 25% more medication is absorbed via the intramuscular route compared to oral [ ]. Methylergonovine is metabolized by the liver and excreted in the urine. The half-life of methylergonovine is 3.4 h (1.5–12.7 h) when administered intramuscularly [ ].

In the case of postpartum hemorrhage, the preferred dose and route of methylergonovine administration is 0.2 mg intramuscularly every 2–4 h, for a maximum of five doses. It can also be directly injected into the uterus; however, one should be careful to avoid intravascular administration as this has been reported to result in acute coronary vasospasm and/or myocardial infarction [ ]. Alternatively, the medication can be administered orally at a dose of 0.2 mg every 6–8 h for 2–3 days (maximum of 7 days).

Methylergonovine should be avoided by those who are pregnant, those with uncontrolled hypertension, and those with sensitivity to the drug. Methergine use in postpartum women with preeclampsia should only be considered if the benefits outweigh the risks. Common side effects include nausea, vomiting, hyper- or hypotension, and headache. Patients should be monitored closely for any adverse side effects after administration of the drug.

Prostaglandins

Prostaglandins are potent uterotonics with utility in several circumstances in obstetrics including facilitation of second trimester abortion, cervical ripening, labor induction, and the treatment of postpartum hemorrhage. The prostaglandins used in obstetrics include prostaglandin E2 (PGE2) (dinoprostone), prostaglandin E1 (PGE1) (misoprostol), and prostaglandin F2α (PGF2α) (carboprost).

The prostaglandins used in obstetric practice are synthetic analogs of endogenous prostaglandins which are cyclic, unsaturated fatty acids. Prostaglandins are grouped into subtypes (A,B,C,D,E,F,G,H,I,J,K) according to the chemical substitution on the pentane ring. All prostaglandins are excreted by the kidneys, so their use in the presence of renal insufficiency warrants caution. All of the prostaglandin preparations have common side effects: abdominal pain, diarrhea, nausea, vomiting, headache, paresthesias, fever, and shivering. They all may have the potential to increase or decrease systolic blood pressure. Therefore, patients should be closely monitored when administering any prostaglandin.

Prostaglandins are most commonly used to ripen and prepare the uterine cervix for labor. Prostaglandins promote the softening and distensibility of the cervix which often leads to early cervical effacement and dilatation. Prostaglandins cause uterine contractions by altering membrane permeability and increasing intracellular calcium. They promote the formation of gap junctions, facilitating transmission of signals throughout the myometrium. Additionally, they upregulate the expression of oxytocin receptors in the uterus which in turn promotes contractility.

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