Ephedrine Ephedra alkaloids

The six optically active alkaloids ephedrine, pseudoephedrine, norephedrine, norpseudoephedrine, and the N-methylated N-methylephedrine and N-methylpseudoephedrine are described in detail in Reti s review (2). Two new alkaloids of related structure have since been identified in Ephedra species, namely, (9-benzoylpseudoephedrine (271) and the oxazolidine derivative ephe-droxane (272). The 4-quinolone derivative ephedralone, recently isolated from Ephedra alata (273), may be of similar biogenetic origin as the ephedrines. Ephedra species also contain macrocyclic alkaloids of more complex structure (275). The two major Ephedra alkaloids (—)-ephedrine and (+)-pseudoephedrine are diastereomers. (—)-Ephedrine has the erythro and (+)-pseudoephedrine has the threo configuration. 

Ephedra, also known as Ma-Huang, is a central nervous system stimulant that is similar to amphetamine. Ephedra alkaloids (a material found in plants) with the active ingredient ephedrine have been used for medicinal purposes in China for... 

The Mormons were introduced to ephedra by Indians when they arrived in Utah. They used it as an alternate to tea and coffee, ironically, because their religious views prohibited use of those stimulants. Ephedra might be the oldest known human stimulant, because remains of the plant were discovered in a fifty thousand-year-old Neanderthal grave in Iraq. Modern medical use of ephedra began with the identification of the alkaloid ephedrine in 1923. 

Several alkaloids are present in Ephedra, with ephedrine being the most significant (Gruenwald et al. 1998). Ephedra sinica contains approxi-... 

Normal doses range from 15 to 30 mg of actual alkaloid (ephedrine), and the lethal dose is in the 1-2 g range. Side effects from ephedra use include headache, irritability, restlessness, anxiety, insomnia, tachycardia, urinary disorders, and vomiting. 

Pyruvic acid Ephedra alkaloids Phenyl C Cathine Cathinone Ephedrine Norephedrine... 

Once considered part of the Gnetaceac, Ephedra is now placed in a family of its own. A northern hemisphere genus with some representation in southern South America, Ephedra is the source of the ancient Chinese drug Ma-huang from which the alkaloid ephedrine and its relatives used in modern medicine are obtained. 

The oriental crude drug Ma Huang or Mao, prepared from certain species of the genus Ephedra, contains ephedrine, pseudoephedrine, and homologous compounds (2). Although alkaloids of the ephedrine type occur in several Ephedra species, only a few other plant sources are known (Table IV and V). 

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

Many cases of serious adverse effects and even fatalities have been reported that were linked with ephedra or ephedrine administration over the last 10 years. Haller and Benowitz published a review of 140 reports of adverse events related to the use of ephedra alkaloids that were submitted to the FDA between June 1997 and March 1999. Using standardized rating system for assessing causation, 31% of the cases were considered to be definitely or probably related to the use of ephedra alkaloid-containing supplements, and another 31% were deemed to be possibly related. Among these adverse events, 47% involved in cardiovascular symptoms and 18% involved the CNS. Hypertension was the most frequent adverse effect, followed by palpitations, tachycardia, or both stroke and seizures. Ten events led to death and 13 cases produced permanent disability. 

Additive stimulant effects of caffeine Caffeine is present in many products that contain ephedra alkaloids, and those who take these products might also be consuming considerable quantities of caffeine in coffee, tea, and soft drinks. Caffeine can enhance the undesirable effects of ephedrine on the heart, blood supply system, and brain function. 

All ephedra plants contain phenylalanine-derived alkaloids, including ephedrine, pseu-doephedrine, methylephedrine, and trace amounts of phenylpropanolamine. Previously marketed herbal supplements typically stated total ephedra alkaloid content, although actual levels of individual alkaloid varied depending on raw material and production runs. 

As with other sympathomimetic agents, theoretical drug interactions with ephedra alkaloids are possible. Despite this potential, only a handful of adverse drug interactions have been reported. This is especially pertinent when considering the extensive use of both ephedra-containing supplements and ephedrine- or pseudoephedrine-containing OTC products. The most notable interaction exists between nonselective monoamine oxidase inhibitors and ephedra- or ephedrine-containing products. 

European medical researchers have, for several years, used ephedrine to help promote weight loss, at least in the morbidly obese (11,12), and nutritional supplements containing naturally occurring ephedra alkaloids are sold in the United States for the same purpose. Clinical trials confirm that, taken... 

Ephedra was also sold in combination with many other herbs in obscure combinations. Labels frequently listed 10 or 15 different herbs, but, analysis usually disclosed only the ephedra alkaloids and caffeine as present in sufficient quantities to be physiologically active. After several well-publicized accidental deaths, products clearly intended for abuse, such as herbal ecstasy, and other look-alike drugs (products usually containing ephedrine or phenylpropanolamine designed to look like illicit methamphetamine, but in concentrations higher than recommended by industry or the FDA) were withdrawn from the market. Labels on these products were frequently misleading. For example, one might suppose that a product called Ephedrine 60 contained 60 mg of ephedrine when, in fact, the actual ephedrine content was 25 mg. 

Studies have shown that resultant effects are similar, regardless of whether pure synthetic ephedrine or naturally occurring ephedra is ingested (24,25). There are,however, significant enantioselective differences between the enantomers in both pharmacokinetic and pharmacodynamic effects. All of the ephedra alkaloids have important effects on the cardiovascular and respiratory systems, but not to the same degree. 

The ephedra alkaloids are all sympathomimetic amines, which means that a host of drug interactions are theoretically possible. In fact, only a handful of adverse drug interactions have been reported in the peer-reviewed literature. The most important of these involve the monoamine oxidase inhibitors (MAOI). Irreversible, nonselective MAOIs have been reported to adversely interact with indirectly acting sympathomimetic amines present in many cough and cold medicine. In controlled trials with individuals taking moclobemide, ephedrine s effects on pulse and blood pressure were potentiated, but only at higher doses than those currently provided in health supplements (137). Ephe-drine-MAOI interaction may, on occasion, be severe enough to mimic pheo-... 

Since there are two possible configurations for an asymmetrically substituted carbon atom, a structure containing n such centres will, in theory, possess 2 stereoisomers. The actual number of stereoisomers that exist may be less than this due to steric effects. Compounds that have the same stereochemistry at one chiral centre but different stereochemistry at the others are known as diastereoisomers (diastereomers) a good example is given by the alkaloids ephedrine and pseudoephedrine. Ephedrine (the (1R, 2S) diastereoisomer) is a natural product isolated from Ephedra (the Ma Huang plant) and known to Chinese medicine for over 3000 years. It was used in the last century for the treatment of asthma. Pseudoephedrine (the (IS, 2S) diastereoisomer) is a decongestant and a constituent of several over-the-counter cold and flu remedies (Figure 4.12). 

Guarana and tea are sources of caffeine that have inherent adrenergic properties as well as increasing the effects of stimulant substances such as ephedrine or ephedra alkaloids (see the earlier discussion of ephedrine). 

Nowadays the Ephedra species are mainly used for extraction of the active ingredient, the alkaloid (-) ephedrine. Not only the classical Chinese species E. sinica Stapf. is used, but mainly the species E.pferardiana. Wall ex. Stapf and E. major Host. =E. nebrodensis Finco), which both grow in India and Pakistan, and E. distachya L., which grows in Southern France. 

Herbal substitutes for dru [s of abuse A variety of herbal mixtures are offered for sale in magazines, on the internet and in so-called smart , eco or head shops. Many are marketed as herbal Ecstasy and the plants included in the formulations include Yohimbe bark, Kava-Kava (Piper methysticum),Y-3 e.emi, Hops, Jaborandi and Alisma. One product contains Kava-Kava, Guarana, Uva Ursi and Cascara bark. Many of the products sold as herbal Ecstasy contain either Ephedra sinica (Ma huang) or the Indian plant Sida cordifolia which both contain the alkaloid ephedrine (see R03c, Chapter VI). Other alkaloids may also occur, such as pseudoephedrine, norephedrine and norpseudoephedrine. The side-effects of ephedrine include tachycardia, anxiety, insomnia and arrythmias and a hypotensive crisis may develop if monamine oxidase inhibitors are also taken. Many adverse reactions and more than 20 deaths have been attributed to ephedrine and Ephedra consumption. Research conducted in the US shows that the daily intake of some Ephedra products would give ephedrine levels well above the recommended therapeutic doses. 

Additional catalysts have also been proposed for the reaction of Et2Zn with aromatic aldehydes, including (proline derivative 2.13 (R = CPh2OH) [110] and a four-membered analog [646], (1S,2R)-1.61 (R = S02Tol), 2.47, and pyridine-derived aminoalcohols [110, 644, 651, 1173]. Other catalysts include sulfur derivatives of ephedra alkaloids [645, 728], the Li diamide of piperazine 2.46, diamines 1.64 (R = 2-Py) and other related 2-aminopyridines [367, 648, 649, 1174], p-Hydroxysulfoximines have also been used as catalysts in these reactions [1175], as has an oxazaborolidine derived from ephedrine [1176],... 

Several amino alcohols have been isolated from Ephedra species ephedrine (3), norephedrine (1), pseudoephedrine (or t/ -ephedrine, 4), and norpseudoephedrine (2). The pseudocompounds are diastereomers of the corresponding alkaloids. 

In Italy several investigations have been carried out by La Floresta (137, 138), Carboni (139, 140, 141) Mulas and Safis (142), Alberti (143) and Simon (144), on local species of Sardinia and Sicily, to find suitable sources of ephedra alkaloids. It was found that E. nehrodensis contained high amounts of ephedrine and -ephedrine E. distachya (E. vulgaris Rich.) contained only /-ephedrine, while E. fragilis Desf., E. altissima Desf., and E. procera C. A. Mey E. nehrodensis Tineo ) were of low alkaloidal content. 

Ephedra alkaloids. Alkaloids from the shrubby joint fir [Ephedra, Ephedraceae) occurring in warm-temperate regions of the earth. The main alkaloid is ephedrine. Many of the constituents of Ephedra (Ma-Huang drug in Chinese traditional medicine) are hypotensive. 

From the ephedrae herba, ephedrine and related alkaloids were isolated as the main components.These alkaloids include (—)-ephedrine and (+)-pseudo-ephedrine, (-)-norephedrine and (+)-norpseudoephedrine. Among these alkaloids, the pseudo-type alkaloids are the diastereomers at the benzylic position of the other alkaloid, respectively. 

---