Although much of the vasoconstriction elicited by ergot alkaloids can be ascribed to partial agonist effects at α adrenoceptors, some may be the result of effects at 5-HT receptors. Ergotamine, ergonovine, and methysergide all have partial agonist effects at 5-HT2 vascular receptors. The remarkably selective antimigraine action of the ergot derivatives was originally thought to be related to their actions on vascular serotonin receptors. Current hypotheses, however, emphasize their action on prejunctional neuronal 5-HT receptors.
After overdosage with ergotamine and similar agents, vasospasm is severe and prolonged (see Toxicity, below). This vasospasm is not easily reversed by α antagonists, serotonin antagonists, or combinations of both.
Ergotamine is typical of the ergot alkaloids that have a strong vasoconstrictor action. The hydrogenation of ergot alkaloids at the 9 and 10 positions (Table 16–6) yields dihydro derivatives that have reduced serotonin partial agonist and vasoconstrictor effects and increased selective α-receptor-blocking actions.
3. Uterine smooth muscle—The stimulant action of ergot alkaloids on the uterus, as on vascular smooth muscle, appears to combine α agonist, serotonin agonist, and other effects. Furthermore, the sensitivity of the uterus to the stimulant effects of ergot increases dramatically during pregnancy, perhaps because of increasing dominance of α1 receptors of the uterus as pregnancy progresses. As a result, the uterus at term is more sensitive to ergot than earlier in pregnancy and far more sensitive than the nonpregnant organ.
In very small doses, ergot preparations can evoke rhythmic contraction and relaxation of the uterus. At higher concentrations, these drugs induce powerful and prolonged contracture. Ergonovine is more selective than other ergot alkaloids in affecting
FIGURE 16–4 Effects of ergot derivatives on contraction of isolated segments of human basilar artery strips removed at surgery. All of the ergot derivatives are partial agonists; and all are more potent than the full agonists, norepinephrine and serotonin. DHE, dihydroergotamine; ERG, ergotamine; 5-HT, serotonin; MS, methysergide; MT, methylergometrine; NE, norepinephrine. (Reproduced, with permission, from Müller-Schweinitzer E. In: 5-Hydroxytryptamine Mechanisms in Primary Headaches. Olesen J, Saxena PR [editors]. Raven Press, 1992.) the uterus and is an agent of choice in obstetric applications of the ergot drugs although oxytocin, the peptide hormone, is preferred in most cases.
4. Other smooth muscle organs—In most patients, the ergot alkaloids have little or no effect on bronchiolar or urinary smooth muscle. The gastrointestinal tract, on the other hand, is quite sensitive. In some patients, nausea, vomiting, and diarrhea may be induced even by low doses. The effect is consistent with action on the central nervous system emetic center and on gastrointestinal serotonin receptors.
Despite their significant toxicities, ergot alkaloids are still widely used in patients with migraine headache or pituitary dysfunction. They are used only occasionally in the postpartum patient.
A. Migraine