The accidental ingestion of ergot alkaloids in contaminated grain can be traced back more than 2000 years from descriptions of epidemics of ergot poisoning (ergotism). The most dramatic effects of poisoning are dementia with florid hallucinations; prolonged vasospasm, which may result in gangrene; and stimulation of uterine smooth muscle, which in pregnancy may result in abortion. In medieval times, ergot poisoning was called St. Anthony’s fire after the saint whose help was sought in relieving the burning pain of vasospastic ischemia. Identifiable epidemics have occurred sporadically up to modern times (see Box: Ergot Poisoning: Not Just an Ancient Disease) and mandate continuous surveillance of all grains used for food. Poisoning of grazing animals is common in many areas because the fungus may grow on pasture grasses.
In addition to the effects noted above, the ergot alkaloids produce a variety of other central nervous system and peripheral effects. Detailed structure-activity analysis and appropriate semi-synthetic modifications have yielded a large number of agents of experimental and clinical interest.
Two major families of compounds that incorporate the tetracyclic ergoline nucleus may be identified; the amine alkaloids and the peptide alkaloids (Table 16–7). Drugs of therapeutic and toxicologic importance are found in both groups.
The ergot alkaloids are variably absorbed from the gastrointestinal tract. The oral dose of ergotamine is about 10 times larger than the intramuscular dose, but the speed of absorption and peak blood levels after oral administration can be improved by administration with caffeine (see below). The amine alkaloids are also absorbed from the rectum and the buccal cavity and after ergotism occurred in the small French village of Pont-Saint-Esprit in 1951. It was vividly described in the British Medical Journal in 1951 (Gabbai et al, 1951) and in a later book-length narrative account (Fuller, 1968). Several hundred individuals suffered symp-toms of hallucinations, convulsions, and ischemia—and several died—after eating bread made from contaminated flour. Similar events have occurred even more recently when poverty, famine, or incompetence resulted in the consumption of contaminated grain. Ergot toxicity caused by excessive self-medication with pharmaceutical ergot preparations is still occasionally reported. As noted in the text, epidemics of ergotism, or poisoning by ergot-contaminated grain, are known to have occurred sporadi-cally in ancient times and through the Middle Ages. It is easy to imagine the social chaos that might result if fiery pain, gangrene, hallucinations, convulsions, and abortions occurred simultane-ously throughout a community in which all or most of the people believed in witchcraft, demonic possession, and the visitation of supernatural punishments upon humans for their misdeeds. Fortunately, such beliefs are uncommon today. However, ergot-ism has not disappeared. A most convincing demonstration of
TABLE 16–7 Major ergoline derivatives (ergot alkaloids).
1Dihydroergotamine lacks the double bond between carbons 9 and 10.
administration by aerosol inhaler. Absorption after intramuscular injection is slow but usually reliable. Semisynthetic analogs such as bromocriptine and cabergoline are well absorbed from the gastrointestinal tract.
The ergot alkaloids are extensively metabolized in the body. The primary metabolites are hydroxylated in the A ring, and peptide alkaloids are also modified in the peptide moiety.
A. Mechanism of Action