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Chapter: Basic & Clinical Pharmacology : Histamine, Serotonin, & the Ergot Alkaloids

Clinical Pharmacology of Ergot Alkaloids

In spite of their significant toxicities, ergot alkaloids are still widely used in patients with migraine headache or pituitary dysfunction, but only occasionally in the postpartum patient.


Clinical Uses

In spite of their significant toxicities, ergot alkaloids are still widely used in patients with migraine headache or pituitary dysfunction, but only occasionally in the postpartum patient.

A. Migraine

Ergot derivatives are highly specific for migraine pain; they are not analgesic for any other condition. Although the triptan drugs discussed above are preferred by most clinicians and patients, tra-ditional therapy with ergotamine can also be effective when given during the prodrome of an attack; it becomes progressively less effective if delayed. Ergotamine tartrate is available for oral, sub-lingual, rectal suppository, and inhaler use. It is often combined with caffeine (100 mg caffeine for each 1 mg ergotamine tartrate) to facilitate absorption of the ergot alkaloid.

The vasoconstriction induced by ergotamine is long-lasting and cumulative when the drug is taken repeatedly, as in a severe migraine attack. Therefore, patients must be carefully informed that no more than 6 mg of the oral preparation may be taken for each attack and no more than 10 mg per week. For very severe attacks, ergotamine tartrate, 0.25–0.5 mg, may be given intravenously or intramuscu-larly. Dihydroergotamine, 0.5–1 mg intravenously, is favored by some clinicians for treatment of intractable migraine. Intranasal dihydroergotamine may also be effective. Methysergide, which was used for migraine prophylaxis in the past, was withdrawn because of toxicity, .

B. Hyperprolactinemia

Increased serum levels of the anterior pituitary hormone prolactin are associated with secreting tumors of the gland and also with the use of centrally acting dopamine antagonists, especially the D2-blocking antipsychotic drugs. Because of negative feedback effects, hyperprolactinemia is associated with amenorrhea and infertility in women as well as galactorrhea in both sexes. Rarely, the prolac-tin surge that occurs around the end of term pregnancy may be associated with heart failure; cabergoline has been used to treat this cardiac condition successfully.

Bromocriptine is extremely effective in reducing the high levels of prolactin that result from pituitary tumors and has even been associated with regression of the tumor in some cases. The usual dosage of bromocriptine is 2.5 mg two or three times daily. Cabergoline is similar but more potent. Bromocriptine has also been used in the same dosage to suppress physiologic lactation. However, serious postpartum cardiovascular toxicity has been reported in association with the latter use of bromocriptine or pergolide, and this application is discouraged .

C. Postpartum Hemorrhage

The uterus at term is extremely sensitive to the stimulant action of ergot, and even moderate doses produce a prolonged and powerful spasm of the muscle quite unlike natural labor. Therefore, ergot derivatives should be used only for control of postpartum uterine bleeding and should never be given before delivery. Oxytocin is the preferred agent for control of postpartum hemorrhage, but if this peptide agent is ineffective, ergonovine maleate, 0.2 mg given intramuscularly, can be tried. It is usually effective within 1–5 minutes and is less toxic than other ergot derivatives for this application. It is given at the time of delivery of the placenta or immediately afterward if bleeding is significant.

D. Diagnosis of Variant Angina

Ergonovine given intravenously produces prompt vasoconstric-tion during coronary angiography to diagnose variant angina if reactive segments of the coronary arteries are present. In Europe, methylergometrine has been used for this purpose.

E. Senile Cerebral Insufficiency

Dihydroergotoxine, a mixture of dihydro-α-ergocryptine and three similar dihydrogenated peptide ergot alkaloids (ergoloid mesylates), has been promoted for many years for the relief of senility and more recently for the treatment of Alzheimer’s demen-tia. There is no useful evidence that this drug has significant benefit.

Toxicity & Contraindications

The most common toxic effects of the ergot derivatives are gastrointestinal disturbances, including diarrhea, nausea, and vomiting. Activation of the medullary vomiting center and of the gastrointestinal serotonin receptors is involved. Since migraine attacks are often associated with these symptoms before therapy is begun, these adverse effects are rarely contraindications to the use of ergot.

A more dangerous toxic effect—usually associated with over-dosage—of agents like ergotamine and ergonovine is prolonged vasospasm. This sign of vascular smooth muscle stimulation may result in gangrene and may require amputation. Bowel infarction has also been reported and may require resection. Peripheral vas-cular vasospasm caused by ergot is refractory to most vasodilators, but infusion of large doses of nitroprusside or nitroglycerin has been successful in some cases.

Chronic therapy with methysergide was associated with con-nective tissue proliferation in the retroperitoneal space, the pleural cavity, and the endocardial tissue of the heart. These changes occurred insidiously over months and presented as hydronephrosis (from obstruction of the ureters) or a cardiac murmur (from dis-tortion of the valves of the heart). In some cases, valve damage required surgical replacement. As a result, this drug was with-drawn from the US market. Similar fibrotic change has resulted from the chronic use of 5-HT agonists promoted in the past for weight loss (fenfluramine, dexfenfluramine).

Other toxic effects of the ergot alkaloids include drowsiness and, in the case of methysergide, occasional instances of central stimulation and hallucinations. In fact, methysergide was some-times used as a substitute for LSD by members of the so-called drug culture.

Contraindications to the use of ergot derivatives consist of the obstructive vascular diseases, especially symptomatic coronary artery disease, and collagen diseases.

There is no evidence that ordinary use of ergotamine for migraine is hazardous in pregnancy. However, most clinicians counsel restraint in the use of the ergot derivatives by pregnant patients. Use to deliberately cause abortion is contraindicated because the high doses required often cause dangerous vasocon-striction.

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