Page 309 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 16 Histamine, Serotonin, & the Ergot Alkaloids 295

the uterus and is an agent of choice in obstetric applications of the even been associated with regression of the tumor in some
ergot drugs although oxytocin, the peptide hormone, is preferred cases. The usual dosage of bromocriptine is 2.5 mg two or
in most cases. three times daily. Cabergoline is similar but more potent.
Bromocriptine has also been used in the same dosage to sup-
4. Other smooth muscle organs—In most patients, the ergot press physiologic lactation. However, serious postpartum car-
alkaloids have little or no effect on bronchiolar or urinary smooth diovascular toxicity has been reported in association with the
muscle. The gastrointestinal tract, on the other hand, is quite latter use of bromocriptine or pergolide, and this application
sensitive. In some patients, nausea, vomiting, and diarrhea may be is discouraged (see Chapter 37).
induced even by low doses. The effect is consistent with action on
the central nervous system emetic center and on gastrointestinal C. Postpartum Hemorrhage
serotonin receptors. 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
CLINICAL PHARMACOLOGY OF derivatives should be used only for control of postpartum uterine
ERGOT ALKALOIDS bleeding and should never be given before delivery. Oxytocin is
the preferred agent for control of postpartum hemorrhage, but
Clinical Uses if this peptide agent is ineffective, ergonovine maleate, 0.2 mg
given intramuscularly, can be tried. It is usually effective within
Despite their significant toxicities, ergot alkaloids are still widely 1–5 minutes and is less toxic than other ergot derivatives for this
used in patients with migraine headache or pituitary dysfunction. application. It is given at the time of delivery of the placenta or
They are used only occasionally in the postpartum patient.
immediately afterward if bleeding is significant.
A. Migraine D. Diagnosis of Variant Angina
Ergot derivatives are highly specific for migraine pain; they are Ergonovine given intravenously has been used to produce
not analgesic for any other condition. Although the triptan drugs prompt vasoconstriction during coronary angiography to diag-
discussed above are preferred by most clinicians and patients, tra- nose variant angina if reactive segments of the coronary arteries
ditional therapy with ergotamine can also be effective when given are present. In Europe, methylergometrine has been used for
during the prodrome of an attack; it becomes progressively less this purpose.
effective if delayed. Ergotamine tartrate is available for oral, sub-
lingual, rectal suppository, and inhaler use. It is often combined E. Senile Cerebral Insufficiency
with caffeine (100 mg caffeine for each 1 mg ergotamine tartrate)
to facilitate absorption of the ergot alkaloid. Dihydroergotoxine, a mixture of dihydro-α-ergocryptine and
The vasoconstriction induced by ergotamine is long-lasting three similar dihydrogenated peptide ergot alkaloids (ergoloid
and cumulative when the drug is taken repeatedly, as in a severe mesylates), has been promoted for many years for the relief
migraine attack. Therefore, patients must be carefully informed of signs of senility and, more recently, for the treatment of
that no more than 6 mg of the oral preparation may be taken for Alzheimer’s dementia. There is no useful evidence that this drug
each attack and no more than 10 mg per week. For very severe has significant benefit.
attacks, ergotamine tartrate, 0.25–0.5 mg, may be given intrave-
nously or intramuscularly. Dihydroergotamine, 0.5–1 mg intrave- Toxicity & Contraindications
nously, is favored by some clinicians for treatment of intractable The most common toxic effects of the ergot derivatives are
migraine. Intranasal dihydroergotamine may also be effective. gastrointestinal disturbances, including diarrhea, nausea, and
Methysergide, which was used for migraine prophylaxis in the vomiting. Activation of the medullary vomiting center and of the
past, was withdrawn because of toxicity, see below. gastrointestinal serotonin receptors is involved. Since migraine
attacks are often associated with these symptoms before therapy
B. Hyperprolactinemia is begun, these adverse effects are rarely contraindications to the
Increased serum levels of the anterior pituitary hormone prolactin use of ergot.
are associated with secreting tumors of the gland and also with A more dangerous toxic effect—usually associated with
the use of centrally acting dopamine antagonists, especially the overdosage—of agents like ergotamine and ergonovine is
D -blocking antipsychotic drugs. Because of negative feedback prolonged vasospasm. This sign of vascular smooth muscle
2
effects, hyperprolactinemia is associated with amenorrhea and stimulation may result in gangrene and may require amputation.
infertility in women as well as galactorrhea in both sexes. Rarely, Bowel infarction has also been reported and may require resection.
the prolactin surge that occurs around the end-of-term pregnancy Vasospasm caused by ergot is refractory to most vasodilators, but
may be associated with heart failure; cabergoline has been used to infusion of large doses of nitroprusside or nitroglycerin has been
treat this cardiac condition successfully. successful in some cases.
Bromocriptine is extremely effective in reducing the high Chronic therapy with methysergide was associated with con-
levels of prolactin that result from pituitary tumors and has nective tissue proliferation in the retroperitoneal space, the pleural