Ephedra action

Commercial samples containing approximately 400 mg of ephedra per capsule yield roughly 5 mg of ephedrine, 1 mg of pseudoephedrine, and less than 1 mg of methylephedrine (White et al. 1997). For a dose of four capsules, yielding approximately 20 mg of ephedrine, the elimination half-life is 5.2 hours. The time to reach maxium concentration is 3.9 hours. Compared to pure ephedrine tablets, the elimination kinetics of ephedra are comparable. However, ephedra showed somewhat different absorption kinetics (e.g., lag time, area under the concentration-time curve, and maximum plasma concentration). So, ephedra tablets may vary from pure ephedrine in the onset of action, but the durations of action are grossly equivalent. 

By early 2003, however, the FDA had received 16,000 reports of "adverse events" apparently related to use of the product. Among these events were two deaths, four heart attacks, nine strokes, one seizure, and five psychiatric events for which no explanation other than use of the product could be found. Although ephedra accounts for less than 1 percent of all sales of dietary supplements, it accounts for 64 percent of all adverse events reported to the FDA. The agency s decision to take action against ephedra may have been influenced by the death of 23-year-old Baltimore Orioles pitcher Steve Bechler on February 19, 2003, a tragedy attributed to the baseball player s use of ephedra. 

Ephedrine is an alkaloid that is present in various forms of the ephedrine family, and which is still extracted from Ephedra sinica and Ephedra equisetina. Because of the presence of two asymmetric atoms, there are four isomeric forms. Pseudoepinephrine (d-isoephrine) is a stereoisomer with pharmacological action that differs slightly from ephedrine. The pharmacological action of ephedrine is typical of noncatecholamine sympathomimetics of mixed action. It stimulates both a- and 8-adrenoreceptors, and simultaneously causes a release of norepinephrine from synaptic neurons. Its vasoconstrictive ability is approximately 100 times weaker than that of epinephrine however, the duration of action is approximately 10 times longer. It is much less toxic than epinephrine, which allows it to be used widely in medicine. 

DSHEA severely limited when the FDA could take action to protect the public and what actions could be taken. The burden of proof to show harm is now placed on the FDA. Moreover, dietary supplement manufacturers are not required to report adverse dietary supplement events. In fact, between 1994 and 1999 fewer than 10 of the 2500 adverse events associated with dietary supplements and reported to the FDA were reported by the manufacturer (53). The Office of Inspector General concluded the spontaneous adverse event reporting system has difficulty generating signals of possible public health concern due to limited medical information, product information, manufacturer information, consumer information, and ability to analyze trends (57). One weight loss supplement manufacturer is reported to have withheld from the FDA 14,684 complaints of adverse events regarding ephedra, which included heart attacks, strokes, seizures, and deaths (53). 

Ephedra distachya L. China 1-ephedrine, 1-methylephedrine, 1-norephedrine, methylephedrine, d-pseudoephedrinem, d-N-methy lpseudoephedrine. 30-3133 This herb is toxic. Treat asthma, sympathomimetic action, relieve headache, body ache, and coughing, lower fever by increasing perspiration. 

Various species of Ephedra grow in different parts of the world. It is believed that the Chinese species contain the official levorotatory ephedrine, whereas the same species and other varieties from Europe yield only dextrorotatory pseudoephedrine. East Indian species range from rich to none. Ephedrine exists in the seed of another, totally unrelated Indian plant, Sida cordifolia, which was also used in folk medicine. Ma huang also contains another alkaloid, ephedine, which lowers blood pressure and has other complex actions. 

This alkaloid was first isolated from Ephedra equisetina, a plant (ma huang) that has been used as medicine by the Chinese since antiquity. Most of the present supply is probably synthetic. Its chemical structure is closely related to epinephrine and tyramine, and differs from epinephrine chiefly by the absence of the two phenolic hydroxyls. Its effects on the circulation, intestines, bronchi, iris, etc., are superficially similar to those of epinephrine. It requires that larger doses be given but they are more lasting, due probably to ephedrine s much greater stability and resistance to oxidation. The effects can be produced by oral administration. Unlike epinephrine, it is not sensitized by cocaine or by denervation. From this, it has been argued that its point of attack is not sympathomimetic but muscular. It also stimulates the CNS. A number of isomers with similar actions are known. Ephedrine is used therapeutically in hay fever and asthma, in which it is less... 

The FDA has been receiving reports of adverse effects related to ephedra use since the early 1990s. Many of the initial concerns were linked to one ephedra product—Formula One. However, when state and federal agencies investigated the product, they could not prove that it contained ephedra, and after the manufacturer of Formula One reformulated the product, reports of adverse events linked with the product ceased. But there have been many reports of adverse events associated with ephedra since 1994. The severity of those events spurred the FDA to action, which sought an independent review in an attempt to determine if ephedra had been the cause. Another purpose of the independent review was to determine the risks of consuming ephedra. 

Ephedra consists of a mixture of different members of the Ephedraceae family E. sinica, E. equisetina, and E. ger-ardiand). Its actions are due to the presence of ephedrine and pseudoephedrine. 

Unlike the situation with ephedra, in many cases we simply have no idea what the components do. The constituents of some herbal drugs seem to work synergistically and cannot be separated without loss of activity of the preparation. Herbal preparations are most often used as crude mixtures and are not standardized or analyzed for the content of the active principlc(s). Hence, the chemistry of medicinal herbs cannot be treated in the same way as that of. say. a pure antibiotic or a calcium channel blocker. The medicinal chemistry of the actions, interactions, and side effects of herbal products is complex and difficult to assess clinically and chemically. Frequently, some of the compounds present... 

Table 2 Federal and State regulatory actions against ephedra and ephedrine-containing alkaloids ...

In the United States, (+)-norpseudoephedrine, in its pure form, is considered a Schedule IV controlled substance. However, because of the small amounts of this alkaloid in ephedra plants or extracts, the Drug Enforcement Administration (DEA) had never stated or proposed that ephedra products were subject to the scheduling requirements of the Controlled Substances Act. Quite the contrary, DEA published a proposed rule in 1998 that stated DEA s intent to exempt legitimate ephedra products in finished form from regulation even as chemical mixtures. Other regulatory sanctions and actions on ephedra rendered action on this regulation moot. 

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