Uterotonic


A uterotonic, also known as ecbolic, are pharmacological agents used to induce contraction or greater tonicity of the uterus. Uterotonics are used both to induce labor, and to reduce postpartum hemorrhage.
Labor induction in a patient's third trimester of pregnancy may be required due to medical necessity or may be desired for social reasons. Generally, labor induction is indicated when the risk of carrying the pregnancy outweighs the risk of delivering. These reason include, but are not limited to pregnancies that are prolonged, prelabor rupture of the fetal membranes, and concerns about the health and safety of the mother and/or child. There are multiple techniques available to stimulate uterine contractions including mechanical, pharmacological, and alternative medicine methods to initiate contractions prior to spontaneous onset of labor.
Postpartum hemorrhage, also known as PPH, is defined as a loss of 500 mL or greater of blood within 24 hours after giving birth. It is one of the leading causes of maternal mortality in women and adolescent girls worldwide, with mothers from low-resource countries being at a larger risk when compared to mothers of higher-resource countries. Occurring in 5% of all women giving birth, these emergent situations require adequate responses in a timely fashion and the proper resources in order to prevent the death of the mother.
Labor and delivery is a sequential process that results in the birth of a fetus and placenta. It is dependent on maternal and fetal chemical signals to stimulate muscles in the uterus to contract and relax. Of such signals include prostaglandins and oxytocin. Uterotonics can be utilized in these chemical pathways in order to medically stimulate contractions in labor induction or to treat postpartum hemorrhage.

Types of Uterotonics

Oxytocin

Oxytocin is a peptide hormone produced in the hypothalamus that plays an important role in many physiological functions. These functions include, enhancing mood social relationships, promotion of maternal behaviors and stimulations of uterine contractions among others roles. Uterine muscle contractions are induced via a G-protein pathway stemming from the oxytocin receptor, the binding and activation site of oxytocin.. When oxytocin binds to its associated receptors in the uterus, a cascade is initiated that results in an increase in calcium and subsequently an increase in muscle contractions. The release of oxytocin helps to facilitate stronger contractions during labor to aid in delivery of the fetus. Additionally, during pregnancy, the uterine muscles have an increased concentration of oxytocin receptors, leading to an increased response to oxytocin as well.
Oxytocin's Role in Labor Induction
Oxytocin is the most commonly used agent for labor induction. It is given intravenously since it is easily degraded by the body if given orally. While a patient is on oxytocin, it is important to monitor the mother and the fetus, specifically the mother's uterine activity and the fetal heart rate. The more common side effects of oxytocin include tachysystole, hyponatremia, and hypotension. Tachysystole is an increased rate of uterine contractions. If this occurs, it can be managed by lowering the dosage of oxytocin. Hyponatremia is a decreased concentration of sodium in the body as a result of increased fluids. This occurs due to oxytocin's similar structure to vasopressin. Hypotension, or low blood pressure, is also a common side effect due to oxytocin's ability to relax smooth muscle of vessels. In comparison to women in spontaneous labor, women in induced labor on oxytocin experience a longer latent phase, however the duration of labor after reaching active labor, the duration of labor is considered equal.
Oxytocin's Role in Postpartum Hemorrhage
The most common cause of postpartum hemorrhage is a loss of muscle tone in the uterus. Normally, the uterus will contract to constrict blood vessels and decrease the flow of blood to prevent bleeding out. However, if there is a loss of muscle tone, see uterine atony, there is an increased risk of bleeding. Oxytocin is the first-line pharmacological step to help prevent PPH and treat PPH.

Analogs of Oxytocin

Oxytocin plays an integral role in regulation of many of the body's biological processes- especially labor regulation. Since its structure was revealed in 1953, it has been the subject of intensive research. Some of the analogs produced from extensive modification of its chemical structure residues have produced drugs and therapies that are utilized as uterotonics. Similar to oxytocin, analogues bind to oxytocin receptors found along the muscles of the uterus and act as an agonist. During pregnancy, the number of oxytocin receptors increase until reaching their peak near completion of the pregnancy. An important note is that not all analogs of oxytocin work as an receptor agonist or as a uterotonic. Some may have oppose uterine contractility such as atosiban.
Some uterotonics act as analogues of oxytocin. An oxytocinergic or oxytocic chemical pathway is one responding to oxytocin or its analogues, and an oxytocinergic or oxytocic agent is any of these agents, oxytocin or its analogues, with similar physiologic effect, chemical interaction, or both.

Indirect Oxytocinergics

are derived from the cell membrane phospholipids through a series of enzymatic reactions. Phospholipase A2 cleaves arachidonic acid from membrane phospholipids and is eventually converted to prostaglandins by cyclooxygenase-1 and cyclooxygenase-2. Due to this mechanism, prostaglandins have a presence in many areas of the body and allow for diverse physiological and pathological functions. Primarily known for its role in mediating inflammation: pain, swelling, redness, and warmth, prostaglandin synthesis is a target for many drugs. Inhibition of COX-1 and COX-2 by aspirin and non-steroidal anti-inflammatory drugs prevents the inflammatory response and can also prevent homeostatic functions of the stomach and GI system that may lead to ulcers and bleeding.
Prostaglandins have been attributed to partaking in the mechanisms of uterine activity during labor. The presence of prostaglandins and PG receptors increases throughout the pregnancy and increase expression of oxytocin receptors as well. Two PG subtypes, E and F, play fundamental roles in labor, PG E receptors, activated by PGE1 and PGE2 are more uteroselective and will stimulate contraction or relaxation depending on the subtype. PG F receptors will stimulate myometrial contraction, although the stimulus from PG F receptors are inferior to oxytocin. For this reason, injectable PGs are not used as first line treatment. Adverse effects of injectable PGs include hypotension and pulmonary edema.
Ergot Alkaloids refer to a set of medications derived from the rye ergot fungus with mixed receptor activity that work to increase uterine muscle tone. Unlike oxytocinergic uterotonics, ergot alkaloids work primarily through agonistic activity of serotonin receptors along the smooth muscles of the uterine wall.