You are called to see a 24-year-old G3P3 woman who approximately 1 hour ago underwent a vaginal delivery of an 8 lb infant. The nurse is concerned that the patient is continuing to bleed more than would be expected, and that her uterine fundus does not feel firm. A brief history from the nurse reveals that the patient required IV oxytocin augmentation of her labor, but otherwise had an uncomplicated labor and delivery.
Her placenta delivered spontaneously and intact. She has no significant medical history. Examination of the patient reveals her to be comfortable and cooperative but she is mildly tachycardia Her uterine fundus is boggy and nontender on palpation. Vaginal examination shows no cervical or vaginal lacerations, but there is a steady flow of blood from the still-dilated cervix. You diagnose the patient as having a postpartum hemorrhage secondary to uterine atony and order an immediate intramuscular (DVI) injection of methylergonovine.
What is the mechanism of action of methylergonovine?
What are the common adverse effects of methylergonovine?
Answers to case: Ergot alkaloids
Summary: A 24-year-old woman has a postpartum hemorrhage secondary to uterine atony. She is given an IM injection of methylergonovine.
Mechanism of action of methylergonovine:
α-adrenoceptor agonist with activity on uterine smooth muscle, causing forceful and prolonged uterine contraction.
Side effects of methylergonovine:
hypertension, headaches, nausea, vomiting.
Clinical correlation
Methylergonovine is an amine ergot alkaloid with relatively selective activity at uterine smooth muscle. Ergot alkaloids are structurally similar to nor-epinephrine, dopamine, and serotonin. They can have agonist or antagonist effects on α-adrenoceptors, dopamine receptors, and serotonin receptors. Methylergonovine acts primarily via α-adrenoceptors and 5-HT2 receptors to cause tetanic uterine contraction.
This provides its therapeutic benefit in the treatment of postpartum hemorrhage because of uterine atony. This drug can have other effects mediated by α-adrenoceptors, including acute hypertensive reactions and vasospasm. It is contraindicated in patients with uncontrolled hypertension. Other common side effects include headaches, nausea, and vomiting.
Approach to pharmacology of the ergot alkaloids
Objectives
- Know the mechanism of action of the ergot alkaloids.
- Know the therapeutic uses and side effects of ergot alkaloids.
Definitions
Postpartum hemorrhage:
Vaginal bleeding exceeding 500 mL after a vaginal delivery or 1000 mL after a cesarean delivery. The most common etiology is uterine atony.
Migraine:
A familial disorder marked by periodic, usually unilateral, pulsatile headaches that begin in childhood or early adult life and tend to recur with diminishing frequency in later life. There are two closely related syndromes comprising what is known as migraine. They are classic migraine (migraine with aura) and common migraine (migraine without aura).
Class
The ergot alkaloids are produced by the fungi Claviceps purpurea. There are two major families of ergots: the peptide ergots and the amine ergots, all contain the tetracyclic ergoline nucleus. The peptide ergots include ergotamine, α-ergocryptine and bromocriptine; the amine ergots include lysergic acid, lysergic acid diethylamide, ergonovine, and methysergide. The ergots have agonist, partial agonist, and antagonist actions at α-adrenergic receptors and serotonin receptors, and agonist or partial agonist actions at central dopamine receptors.
Postpartum Hemorrhage
Ergonovine and its semisynthetic derivative, methylergonovine, cause powerful contractions of smooth muscle; the gravid uterus is especially sensitive to this drug. Postpartum hemorrhage is most often treated with oxytocin. In circumstances where oxytocin is not effective, methylergonovine causes forceful contractions of uterine smooth muscle that effectively stops the bleeding. This action appears to be mediated by agonist activity at α1-adrenergic receptors and agonist action at 5-HT2 receptors. Methylergonovine can be administered orally or IM; effects are seen in 3-5 minutes following IM administration. Acute administration of methylergonovine has few side effects.
Migraine Headache
Dihydroergotamine is useful in the management of migraines. It binds with high affinity to 5-HT1Dα and 5-HT1Dβ receptors. It also binds with high affinity to serotonin 5-HT1A, 5-HT2A, and 5-HT2C receptors, noradrenaline α2A, α2B, and a receptors, and dopamine D2L and D3 receptors. The therapeutic activity of dihydroergotamine in migraine is generally attributed to the agonist effect at 5-HT1D receptors. Two current theories have been proposed to explain the efficacy of 5-HT1D receptor agonists in migraine. One theory suggests that activation of 5-HT1D receptors located on carotid and intracranial blood vessels, including those on arteriovenous anastomoses, leads to vasoconstriction, which correlates with the relief of migraine headache.
The alternative hypothesis suggests that activation of 5-HT1D receptors on sensory nerve endings of the trigeminal system results in the inhibition of proinflammatory neuropeptide release. Adverse effects include GI disturbances including diarrhea, vomiting, and vasospasm. The triptans — sumatriptan, rizatriptan, almotriptan, and others — are selective 5-HT1D and 5-HT1B receptor agonists that are also useful for treating an acute migraine headache.
Methysergide is used for prophylaxis of migraine. It acts as a 5-HT2Ac antagonist to block 5-HT mediated vasoconstriction in vascular smooth muscle. It is effective in preventing or reducing the frequency of migraines in approximately 60 percent of patients. Chronic use of methysergide is associated with retroperitoneal fibroplasia and subendocardial fibrosis. For this reason drug-free periods are recommended if it is used chronically.
Endocrine Abnormalities
Bromocriptine is very effective in reducing the high levels of prolactin production that occur with certain pituitary tumors. It has also been used to suppress lactation. Bromocriptine is a potent dopamine receptor agonist, and its prolactin-suppressive actions are mediated via interaction with this receptor. Side effects are dose related and range from nausea to Parkinsonlike syndrome. Bromocriptine has been associated with postpartum cardiovascular toxicity.
Questions
[1] Methylergonovine is useful in treating postpartum hemorrhage because it does which of the following?
- Causes forceful contractions of the myometrium
- Causes rapid production of thrombin
- Is a potent vasoconstrictor
- Stimulates the activity of antithrombin III
[2] Which of the following would be the best drug to reduce prolactin levels in a patient with a pituitary tumor?
- Bromocriptine
- Ergonovine
- Ergotamine
- Methysergide
[3] A 35-year-old woman is noted to have dyspnea with exertion. Echocardiography identifies a restrictive cardiomyopathy with decreased flexibility of the heart. The cardiologist notes that one of his medications may be responsible. Which of the following agents is most likely the etiology?
- Bromocriptine
- Ergonovine
- Ergotamine
- Methysergide
Answers
[1] A. Although methylergonovine does cause vasoconstriction, its action in postpartum hemorrhage is mediated by forceful clamping of the myometrium, which restricts blood flow.
[2] A. Bromocriptine is a dopamine receptor agonist that is used to treat prolactin-secreting pituitary adenomas.
[3] D. Methysergide can induce a fibroelastosis of the heart, which leads to a restrictive cardiomyopathy.
Pharmacology pearls
Methysergide is useful for prophylaxis of migraine headaches but has no effect on an acute episode.
Bromocriptine is a dopamine receptor agonist and is used to treat prolactin-secreting pituitary adenomas.
Methylergonovine is used to treat postpartum hemorrhage caused by uterine atony and causes contraction of the uterine smooth muscle.
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