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History and Epidemiology
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Ergot is the product of Claviceps purpurea, a fungus that contaminates rye and other grains. The spores of the fungus are both windborne and transported by insects to young rye, where they germinate into hyphal filaments. When a spore germinates, it destroys the grain and hardens into a curved body called the sclerotium, which remains the major commercial source of ergot alkaloids.71 The C. purpurea fungus produces diverse substances, including ergotamine, histamine, lysergic acid, tyramine, isomylamine, acetylcholine, and acetaldehyde.
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In 600 b.c. an Assyrian tablet mentioned grain contamination believed to be by C. purpurea. In the Middle Ages, epidemics causing gangrene of the extremities, with mummification of limbs, were depicted in the literature as blackened limbs resembling the charring from fire and caused a burning sensation expressed by its victims. The disease was called holy fire or St. Anthony’s fire, but the improvement that reportedly occurred when victims went to visit the shrine of St. Anthony was probably the result of a diet free of contaminated grain on the journey.37 Abortion and seizures were also reported to result from this poisoning. On the other hand, as early as 1582, midwives used ergot to assist in the childbirth process. In 1818, Desgranges was the first physician to use ergot for obstetric care, and in 1822 Hosack reported that ergot could be used for the control of postpartum hemorrhage.84 Since 1950, the clinical use of ergot derivatives is almost entirely limited to the treatment of vascular headaches. Ergonovine, another ergot derivative, is used in obstetric care for its stimulant effect on uterine smooth muscle and was formerly used in cardiac stress tests. Methylergonovine is used for postpartum uterine atony and hemorrhage. Cabergoline is used for hyperprolactinemia and in the treatment of Parkinson disease. Ergot derivatives were also used as “cognition enhancers,”87 to help manage orthostatic hypotension,78 and to prevent the secretion of prolactin.71
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Currently in the US, human poisoning epidemics from ergot grain infestations are prevented by government inspections of grain fields. If a grain field contains more than 0.3% affected grain, then it is rejected for commercial sale; in some years, as much as 36% of the grain was rejected.71 However, elsewhere in the world ergot toxicity remains a problem predominantly in animals.9,48
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Pharmacology and Pharmacokinetics
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All ergot alkaloids are derivatives of the tetracyclic compound 6-methylergoline. They can be divided into three groups: amino acid alkaloids (ergotamine, ergotoxine), dihydrogenated amino acid alkaloids, and amine alkaloids (Fig. 54–1).
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The pharmacokinetics of the ergot alkaloids are well defined by controlled human volunteer studies, whereas the toxicokinetics are essentially unknown (Table 54–2). Almost all of the ergots are poorly absorbed orally and there is considerable first-pass hepatic metabolism, resulting in highly variable bioavailability. Intramuscular absorption is unpredictable and actions are often delayed.63 Peak plasma concentrations with oral ergotamine occur within 45 to 60 minutes.63 The volume of distribution of ergotamine is approximately 2 L/kg and the half-life varies from 1.4 to 6.2 hours. Ergot alkaloids are metabolized in the liver, probably by CYP3A4, and the metabolites are excreted in the bile.7,71
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The pharmacologic effects of the ergot alkaloids can be subdivided into central and peripheral effects (Table 54–3). In the CNS, ergotamine stimulates serotonergic receptors, potentiates serotonergic effects, blocks neuronal serotonin reuptake, and has central sympatholytic actions.37,71 Ergotamine and dihydroergotamine interact with the 1A, 1B, 1D, 1F, 2A, 2C, 3, and 4 serotonin receptor subtypes, dopamine receptors and adrenergic receptors.8 The result is increased intrasynaptic serotonin activity in the median raphe neurons of the brainstem.68 Ergotamine and dihydroergotamine decrease the neuronal firing rate and stabilize the cerebrovascular smooth musculature, which make them useful drugs for both abortive and prophylactic treatment of migraine headaches.
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Peripherally, ergotamine and dihydroergotamine are α-adrenergic, 5-HT2A and 5-HT1B agonists and vasoconstrictors.76 The amino acid ergot alkaloids (ergotamine, ergotoxine) exhibit α-adrenergic agonism, and dehydrogenation (dihydroergotamine) of the lysergic acid nucleus increases the potency of this effect.71 Ergotamine is a more potent constrictor of peripheral arteries, whereas dihydroergotamine is a more potent vasoconstrictor.16Table 54–3 summarizes the pharmacologic actions of selected ergot alkaloids currently used in clinical medicine. The spectrum of effects depends on dose, host response, and physiologic conditions.
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The clinical effects following overdose are an extension of the therapeutic effects. At toxic doses, extreme vasoconstriction produces the characteristic ischemic changes that occur in ergotism.
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The cerebrovascular effects of ergot alkaloids are not as clearly understood. In migraine treatment, for example, therapeutic doses of ergotamine produce mild vasoconstriction via α-adrenergic agonism. This may be more pronounced in intracranial vessels that are already dilated during a migraine. In toxic doses, cephalic vasodilation may occur but the mechanism for this effect is unknown. One hypothesis is that toxic doses initially produce cerebral vasoconstriction and ischemia, just as occurs in the periphery, but since the cerebral vasculature cannot tolerate hypoxia and hypercapnia, rapid vasodilation then ensues to improve local perfusion. In addition, α-adrenergic receptors in the CNS function differently from those in the periphery, and it may be that CNS vascular tone cannot be maintained in the setting of local tissue hypoxia.
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Clinical Manifestations
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Ergotism, a toxicologic syndrome resulting from excessive use of ergot alkaloids, is characterized by intense burning of the extremities, hemorrhagic vesiculation, pruritus, formication, nausea, vomiting, and gangrene (Table 54–4). Headache, fixed miosis, hallucinations, delirium, cerebrovascular ischemia, and convulsions are also associated with this condition, which has been called “convulsive” ergotism.37 Chronic ergotism usually presents with peripheral ischemia of the lower extremities, although ischemia of cerebral, mesenteric, coronary, and renal vascular beds are well documented.3,27,28,69,70 Ergotism can also result from interactions of ergot derivatives with CYP3A4 inhibitors such as macrolide antibiotics and protease inhibitors, which increase bioavailability of ergots.6,7
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The vascular effects ascribed to ergot alkaloids are complex and sometimes conflicting (Table 54–3). Subintimal and medial fibrosis, vasospasm, and arteriolar and venous thrombi (stasis related) are all reported.56 Angiography can demonstrate distal, segmental vessel spasm with increased collateralization in patients with chronic ergotism. The coronary, renal, cerebral, ophthalmic, and mesenteric vasculature,70 as well as the vessels of the extremities, may also be affected.73 Neuropathic changes may be secondary to ischemia of the vasa nervorum.
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Bradycardia is a characteristic effect of the ergot alkaloids, and is believed to be a reflex baroreceptor-mediated phenomenon associated with vasoconstriction, but a reduction in sympathetic tone, direct myocardial depression, and increased vagal activity may also be factors.71
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Myocardial valvular abnormalities are reported with ergot alkaloids. Ergotamine, methysergide, pergolide, and cabergoline cause mitral and aortic valve leaflet thickening and immobility resulting in valvular regurgitation.29,69,90
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The treatment for a patient with ergot alkaloid toxicity depends on the nature of the clinical findings. Gastric emptying should rarely be used, if at all, because vomiting is a common early occurrence, and the ingestion may be complicated by seizures. After an acute oral overdose, 1 g/kg of activated charcoal should be administered orally. If emesis is present, antiemetics such as ondansetron or metoclopramide should be administered intravenously to facilitate the administration of activated charcoal. In mild cases, characterized by minimal pain of the extremities, nausea, or headache, supportive measures such as hydration and analgesia are all that are needed. Patients who develop mild symptoms of vasospasm, such as dysesthesias and minimal ischemic pain of the digits, should be treated with immediate release nifedipine 10 mg every 8 hours orally.15 With more serious cases, severe peripheral vasoconstriction may produce ischemic changes that include angina, myocardial infarction, cerebral ischemia, intermittent claudication, and internal organ/mesenteric ischemia. Intravenous sodium nitroprusside at a starting dose of 0.5 µg/kg/min is recommended and should be titrated until resolution of vasoconstriction.3,12,62 Phentolamine should be considered as well. Immediate release oral nifedipine at a dose of 10 mg every 8 hours can be administered as a second line therapy. Methylprednisolone at a dose of 1 mg/kg was reported to reverse ergotamine induced lower extremity arterial vasospasm that was not responsive to sodium nitroprusside and heparin.66
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Heparin or low molecular weight heparins should be administered to prevent sludging and subsequent clot formation. Benzodiazepines should be used to treat seizures or hallucinations.