Chapter: Modern Pharmacology with Clinical Applications: Uterine Stimulants and Relaxants

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Uterine Stimulants

Oxytocin (Pitocin, Syntocinon) is a cyclic 8–amino acid peptide that is synthesized in the paraventricular nu-cleus of the hypothalamus and transported within hy-pothalamic neurons (in association with neurophysin) to the posterior pituitary for storage.

UTERINE STIMULANTS

 

Oxytocin

 

Oxytocin (Pitocin, Syntocinon) is a cyclic 8–amino acid peptide that is synthesized in the paraventricular nu-cleus of the hypothalamus and transported within hy-pothalamic neurons (in association with neurophysin) to the posterior pituitary for storage. Its mechanism of action involves the direct stimulation of oxytocin recep-tors found on the myometrial cells. Oxytocin circulates unbound in the plasma, where it has a half-life of ap-proximately 15 minutes. It is primarily inactivated in the kidneys and liver.

 

Oxytocin is generally considered to be the drug of choice for inducing labor at term. In combination with amniotomy, oxytocin is highly successful in inducing and augmenting labor. When given oxytocin, approxi-mately 80% of patients with documented labor disor-ders progress into labor and deliver vaginally. It has also been used following incomplete abortion after 20 weeks of gestation (although use of prostaglandins may be preferred in this instance), and it may be used after full-term delivery to prevent or control uterine hemorrhage. Oxytocin in high doses is used to induce abortion. An oxytocin challenge test (an assessment of the fetal heart rate in response to oxytocin-induced contractions) can be performed in certain high-risk (e.g., those with hy-pertension, diabetes, preeclampsia) obstetrical patients as a measure of fetal well-being.

 

Inappropriate use of oxytocin can lead to uterine rupture, anaphylactoid and other allergic reactions, and possibly maternal death. Prolonged stimulation of uter-ine contractions can result in the following fetal adverse reactions: persistent uteroplacental insufficiency, sinus bradycardia, premature ventricular contractions, other arrhythmias, and fetal death. Prolonged use of oxytocin can lead to water intoxication secondary to the antidi-uretic hormone–like effects of oxytocin. Maternal and fetal cardiovascular parameters should be monitored during oxytocin administration.

 

Oxytocin may be given by intravenous infusion (e.g., labor induction), intramuscular injection (e.g., control of postpartum bleeding), or as a nasal spray (e.g., to pro-mote milk ejection).

 

Ergonovine Maleate and Methylergonovine Maleate

 

Ergonovine (Ergotrate) and methylergonovine (Meth-ergine) are compounds obtained either directly or semi-synthetically from ergot, a fungus that grows on rye and other grains. These compounds stimulate uterine smooth muscle directly, thereby increasing muscular tone and enhancing the rate and force of rhythmical contractions. Ergonovine also stimulates cervical con-tractions. These drugs are capable of inducing a sus-tained tetanic contraction, which can shorten the final stage of labor and aid in the reduction of postpartum blood loss. Both are commonly used for the routine ex-pulsion of the placenta after delivery and in postpartum and postabortal atony and hemorrhage.

 

Both drugs are partial agonists at α-adrenergic re-ceptors and at some serotonin and dopamine receptors; they also can inhibit the release of endothelial-derived relaxation factor. They may induce arterial vasocon-striction and have minor actions on the central nervous system. Their α-adrenergic blocking activity is relatively weak compared with those of other ergot alkaloids.

 

Absorption is rapid and largely complete after oral administration, and onset of action occurs in 5 to 15 minutes and lasts about 3 hours. Both ergonovine and methylergonovine can be given intramuscularly or in-travenously, although intravenous administration can be associated with transient but severe hypertension. These compounds undergo hepatic metabolism, with elimination primarily by renal excretion of metabolites. They also can be found in breast milk, and therefore, neither drug should be administered longer than neces-sary, since prolonged use can lead to ergot poisoning (ergotism), including gangrene, in the nursing infant.

 

Adverse reactions associated with their administra-tion include hypertension, headache, and possible seizures. Nausea, vomiting, chest pains, difficulties in breathing, and leg cramps also have been reported. These alkaloids should not be used in cases of threat-ened spontaneous abortion or in patients with known allergies to the drugs. Contraindications generally in-clude angina pectoris, myocardial infarction, pregnancy, and a history of a cerebrovascular accident, transient ischemic attack, or hypertension.

 

Dinoprostone, Carboprost Tromethamine, and Misoprostol

 

Dinoprostone (Prostin E2) is a naturally occurring prostaglandin E2 found in mammalian tissues, human seminal plasma, and menstrual fluid . Carboprost tromethamine (Hemabate, Prostin/15M) is a synthetic analogue of the naturally occurring prostaglandin PGF2 . Both drugs stimulate uterine smooth muscle contractions and can be used to induce abortion during gestation weeks 12 to 20. Abortion was successful in 96% of the cases in which these agents were used, with complete passage of fetal products oc-curring more than 75% of the time without surgical in-tervention. The mean time to abortion after drug ad-ministration was 16 hours. The prostaglandins are more effective stimulants of uterine contraction through the second trimester of pregnancy than is oxytocin. Inhibi-tion of endogenous prostaglandin synthesis with a non-steroidal antiinflammatory agent, such as aspirin or ibuprofen, can increase the length of gestation, prolong spontaneous labor, or interrupt premature labor.

 

Dinoprostone is slowly absorbed from the amniotic fluid into the systemic circulation. It and its metabolites readily cross the placenta and can concentrate in the fe-tal liver. Dinoprostone is primarily metabolized in the maternal lungs and liver and has a half-life in plasma and amniotic fluid of less than 1 minute and 3 to 6 hours, respectively. Carboprost also is metabolized in maternal lung and liver but somewhat more slowly than dinopro-stone. It is primarily eliminated by renal excretion of its metabolites, with small amounts appearing in the feces.

 

Because dinoprostone produces cervical ripening along with stimulation of the uterus, it has been used as an alternative to oxytocin for the induction of labor. Preparations of dinoprostone can be placed in either the cervix or the posterior fornix. Prepidil is a formula-tion and delivery system of dinoprostone that delivers a dose of 0.5 mg into the cervix, while Cervidil consists of the drug embedded in a plastic matrix. The matrix is de-signed to deliver a dose of 0.3 mg per hour for 12 hours.

Carboprost has been used successfully to control postpartum bleeding that was secondary to loss of uter-ine tone and where the myometrium was unresponsive to oxytocin, ergonovine, or methylergonovine. Given in-tramuscularly, carboprost causes an almost immediate and sustained uterine contraction. Clinical experience has shown that the use of this agent has saved many women from operative interventions (including hys-terectomy) to control postpartum hemorrhage.

 

Misoprostol (Cytotec) is a prostaglandin E1 analogue that is being evaluated as a cervical ripening agent. It also is used in the treatment and prevention of peptic ulcer disease . Clinical trials show that misoprostol is an effective agent for both cervical ripen-ing and labor induction. It appears to be as effective as dinoprostone and is much less expensive.

 

While adverse reactions are common following the use of abortion-inducing doses of the prostaglandins, most are not serious. Gastrointestinal disturbances in-clude nausea, vomiting, and diarrhea. Transient fever, retained placental fragments, excessive bleeding, de-creased diastolic blood pressure, and headache also have been noted. These drugs should be used with cau-tion in patients with asthma, cervicitis, vaginitis, hyper-tension or hypotension, anemia, jaundice, diabetes, or epilepsy. They should not be used in patients with acute pelvic inflammatory disease, drug hypersensitivity, or an active renal, hepatic, or cardiovascular disorder. Since prostaglandins are potentially carcinogenic, if preg-nancy is not effectively terminated following their use, another method should be used. The prostaglandins are not generally used concomitantly with oxytocin because of the possibility of uterine rupture.

 

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