What medication is injected after the baby is delivered that prevents uterine atony?

19.2.2 Methergine (methylergonovine)

Methergine, a semi-synthetic ergot alkaloid, is a potent uterotonic that increases the force and frequency of uterine contractions at low doses. At higher doses, methergine can increase basal uterine tone and cause uterine tetany. In obstetrics, methergine is indicated for the treatment of postpartum hemorrhage secondary to uterine atony or subinvolution [17].

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 [18]. Although the uterine effects of ergots were discovered hundreds of years ago, the exact mechanism by which methergine causes myometrial contraction is not known. Ergot alkaloids are known to cause vasoconstriction, uterine contractions, and stimulation of central dopamine receptors [18]. Ergots have been shown to bind alpha adrenergic, serotonin (5-HT), and dopamine D1 receptors [19]. Based on several studies, it is likely that methergine specifically interacts with alpha adrenergic receptors on the myometrial cell (Figure 19.1). This interaction alters transmembrane calcium channel activity, causing an influx of calcium into the myometrial cell and activation of the contraction cascade [18, 20, 21].

After oral administration or intramuscular injection, methergine is rapidly absorbed and distributed throughout the plasma and extracellular fluid. Approximately 25% more medication is absorbed via the intramuscular route compared to oral [17]. Methergine is metabolized by the liver and excreted in the urine. The half-life of methergine is 3.4 hours (1.5–12.7 hours) when administered intramuscularly [17].

In the setting of postpartum hemorrhage, the preferred dose and route of methergine administration is 0.2 mg intramuscularly every 2–4 hours, 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 [22–24]. Alternatively, the medication can be administered orally at a dose of 0.2 mg every 6–8 hours for 2–3 days (maximum of 7 days).

Methergine should be avoided by those who are pregnant, those with uncontrolled hypertension, and those with a 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 [17].

4.11.2 Methylergometrine (methylergonovine)

Antiserotonin drugs

The antiserotonin medications include the ergots methysergide and methylergonovine (methylergometrine), as well as cyproheptadine and pizotifen. All of these medications block 5-HT2B and 5-HT2C excitatory receptors (Moskowitz, 1992b, c), implicated in migrainous vasodilation via a CGRP/nitric oxide mechanism. The ergots also have agonist effects at 5-HT1B and 5-HT1D receptors (Muller, 1992), which antagonize migraine via presynaptic inhibition of the release of neuroinflammatotory peptides, postsynaptic vasoconstriction, and inhibition of the transduction of peripheral nociceptive signals to the brainstem.

Methysergide (Sansert)

Methysergide is a semisynthetic ergot alkaloid that is structurally related to methylergonovine. The AHCPR technical report identified 17 controlled trials of methysergide for migraine prevention (Gray et al., 1999). Four placebo-controlled trials suggested that methysergide was significantly better than placebo at reducing headache frequency (Lance et al., 1963; Shekelle and Ostfeld, 1964; Pedersen and Moller, 1966; Ryan, 1968).

Table 27.7. Miscellaneous medications in the preventive treatment of migraine

Methysergide was associated with a higher incidence of adverse events than was placebo. Adverse events noted in trials and clinical practice included transient muscle aching, claudication, gastrointestinal complaints (nausea, vomiting, abdominal pain, and diarrhea), leg cramps, hair loss, weight gain, dizziness, giddiness, drowsiness, lassitude, paresthesia, and hallucinations. Frightening hallucinatory experiences after the first dose are not uncommon (Curran et al., 1967). Curran and Lance (1964) have treated leg claudication with vasodilators with some enhancement of methysergide's effectiveness, suggesting that its action on headache is not a result of vasoconstriction. The major complication of methysergide is the rare (1/5000) development of retroperitoneal, pulmonary, or endocardial fibrosis (Graham et al., 1966; Graham, 1967; Elkind et al., 1968; Bana et al., 1974).

Methysergide is indicated for the treatment of migraine and cluster headache. The dose ranges from 2 to 8 mg a day, with the higher doses being given two or three times a day. Some clinicians find they can use higher doses, up to 14 mg a day, without adverse events and with higher efficacy (Raskin, 1988a). Methysergide, in general, should not be taken continuously for long periods, since doing so may produce retroperitoneal fibrosis. Instead, the drug should be given for 6 months, stopped for 1 month, and then restarted. Some authorities use methysergide on a continuous basis with careful monitoring (Raskin, 1988a), which includes auscultation of the heart and annual echocardiography, chest X-ray, and abdominal MRI. The drug should be discontinued immediately if pulmonary or cardiac retroperitoneal fibrosis is suspected (Raskin, 1988a).

Contraindications to methysergide use include pregnancy, peripheral vascular disorders, severe arteriosclerosis, coronary artery disease, severe hypertension, thrombophlebitis or cellulitis of the legs, peptic ulcer disease, fibrotic disorders, lung diseases, collagen disease, liver or renal function impairment, valvular heart disease, debilitation, or serious infection. Patients who receive methysergide should remain under the supervision of the treating physician and be examined regularly for development of pulmonary, cardiac, or peritoneal fibrosis or vascular complications.

Methylergonovine

Pharmacokinetics

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Ergotamine undergoes extensive first-pass metabolism and has a very low oral bioavailability. In contrast, ergonovine and methylergonovine are rapidly absorbed and reach peak plasma levels in under 90 minutes, with plasma levels 10 times those of ergotamine.

The biologic activity (vasoconstriction) of ergotamine (24 hours or more) extends well beyond its elimination half-life of 2 hours. The elimination half-life of ergonovine is even shorter than that of ergotamine.

Ergotamine (oral, sublingual, rectal) and dihydroergotamine (injectable, nasal spray) are available in several dosage forms. The availability of nonoral dosage forms is important because patients with migraine also often have nausea and vomiting.

For postpartum hemorrhage, ergotamine should never be administered intravenously, because of concerns over excessive vasoconstriction leading to hypertension.

Ergotamine derivatives are metabolized via CYP3A4. Given the dangers associated with excessive ergotamine levels (see Side Effects), the concomitant use of strong CYP3A4 inhibitors should be avoided.

C. Uterine Hemorrhage

Uterine hemorrhage may be treated with a variety of techniques. Significant intraoperative blood loss should be treated in a timely fashion with blood products and/or autotransfusion by cell saver, if available.

1.

Administer oxytocin, 5 to 20 units IV, intramuscularly, or directly into the uterus for atony.

Administer methylergonovine (Methergine®), 0.2 mg intramuscularly, for atony.

Prostaglandin F2α (Hemabate) may be given intramuscularly or into the myometrium, in doses of 0.25 mg every 30 to 60 minutes to a maximum dose of 2 mg, for atony.

Administer misoprostol, 400 to 800 mg rectally. This is an off-label use of this drug.

A tourniquet may be applied to the lower uterine segment by tying a latex or rubber urinary-type catheter around it. This can provide time for uterine artery ligation or hysterectomy, or while help is being summoned.

Directly suture bleeding points.

Perform the B-Lynch suture procedure, which strangulates the arterial blood supply to the myometrium.37

Ligate the uterine artery by placing sutures in the lateral aspect of the uterus.

Ligate the uterine arteries medial to the ovaries.

Place interrupted, circular sutures parallel to the uterine incision anteriorly and completely through the wall of the uterus posteriorly.38

Proceed with hypogastric artery ligation.

Inflate a Foley catheter balloon (30 ml) in the lower uterine segment with the rest of the catheter protruding out the vagina and apply moderate traction.

Selective arterial embolization may be used but is often not timely or feasible.

Hysterectomy is often the procedure of last resort.

Cardiovascular

The cardiovascular effects of oxytocin are usually transient, but it should be used with caution. Oxytocin 10 IU (n = 20) or methylergometrine 0.2 mg (n = 20) were given to healthy women in a double-blind study after cesarean section under spinal anesthesia (37c). Ten non-pregnant healthy women were controls and received oxytocin 10 IU. Mean age was about 32 years. Transient hypotension, tachycardia, and ST segment/T wave depression occurred in those who received oxytocin, including the controls. Symptoms of flushing, chest pain, and dyspnea were related to the injection of oxytocin. Those who received methylergometrine had increased arterial pressure with no effect on heart rate.

Serotonin Antagonists

The antiserotonin migraine-preventive drugs are potent 5-HT2B and 5-HT2C receptor antagonists. Methysergide is a semisynthetic ergot alkaloid that is structurally related to methylergonovine. It is a 5-HT2 receptor antagonist and 5-HT1B/5-HTD agonist. It was probably the first drug developed for migraine prevention,159 but its usefulness is limited by reports of retroperitoneal and retropleural fibrosis associated with long-term, mostly uninterrupted, administration.160

Methysergide is effective.8,161 Adverse events include transient muscle aching, claudication, abdominal distress, nausea, weight gain, and hallucinations. The major complication is rare (1 per 2500) retroperitoneal, pulmonary, or endocardial fibrosis.161 To prevent this, a 4-week medication-free interval is recommended after 6 months of continuous treatment.2,161

Methysergide is indicated for the treatment of migraine and cluster headache. The dosage ranges from 2 to 8 mg/day, the higher doses being given two or three times a day. Clinicians find that some patients can take higher doses, up to 14 mg a day, without adverse events and with higher efficacy.162 To minimize early adverse events, patients can start with a dose of 1 mg/day and increase the dose gradually by 1 mg every 2 to 3 days. Methysergide, in general, should not be taken continuously for long periods, because this may produce retroperitoneal fibrosis.160,163,164 Instead, the drug should be given for 6 months, stopped for 1 month, and then restarted. To avoid an increase in headache when methysergide is stopped, the patient should be weaned off the drug over a 1-week period. Some authorities use methysergide on a continuous basis with careful monitoring,162 which includes auscultation of the heart and yearly echocardiography, chest radiography, and abdominal MRI. The drug should be discontinued immediately on suspicion of pulmonary or cardiac retroperitoneal fibrosis.162

Cyproheptadine, an antagonist at the 5-HT2, histamine H1, and muscarinic cholinergic receptors, is widely used in the prophylactic treatment of migraine in children.162,165,166 Cyproheptadine is available as 4-mg tablets. The total dosage ranges from 12 to 36 mg/day (given two to three times a day or at bedtime). Common adverse events are sedation and weight gain; dry mouth, nausea, lightheadedness, ankle edema, aching legs, and diarrhea are less common. Cyproheptadine may inhibit growth in children167 and reverse the effects of selective serotonin reuptake inhibitors.

Pizotifen, a benzocycloheptathiophene derivative, is a 5-HT2 receptor antagonist structurally similar to cyproheptadine.10 It is not available everywhere. According to the United States Headache Consortium guidelines,118 evidence was inconsistent for its efficacy. Analysis of the placebo-controlled trials suggested a large clinical effect that was statistically significant. Pizotifen was generally poorly tolerated.8 Substantial weight gain, tiredness, drowsiness, or a combination of these was frequently reported. Pizotifen was associated with a high rate of withdrawals from the study because of adverse events. Controlled and uncontrolled studies in Europe168 have shown this drug to be of benefit in 40% to 79% of patients. The dosage recommendation is 0.5 to 1 mg, one three times daily by titration. Adverse events include drowsiness, increased appetite, and weight gain.169