Huang and the Ephedra Alkaloids

Chinese medical practitioners in the 15th century recommended ephedra as an antipyretic and antitussive agent. Modem physicians use intravenous ephedrine for the prophylaxis and treatment of hypotension caused by spinal anesthesia, particularly during cesarean section (see Chapter 29). 

Marshmallow has demulcent, expectorant, emollient, diuretic, antilithic, and vulnerary properties. Traditionally, it has been used internally for the treatment of respiratory catarrh and cough, peptic ulceration, inflammation of the mouth and pharynx, enteritis, cystitis, urethritis and urinary calculus, and topically for abscesses, boils, and varicose and thrombotic ulcers. 

Mate is believed to possess CNS-stimulant, thymoleptic, diuretic, antirheumatic, and mild analgesic properties. Traditionally, it has been used for psychogenic headache and fatigue, nervous depression, rheumatic pains, and specifically for headache associated with fatigue. 

Meadowsweet is reputed to have stomachic, mild urinary antiseptic, antirheumatic, astringent, and antacid properties. Traditionally, it has been used for atonic dyspepsia with heartburn and hyperacidity, acute catarrhal cystitis, rheumatic muscle and joint pains, diarrhea in children, and specifically for the prophylaxis and treatment of peptic ulcers. 

Mistletoe has hypotensive, cardiac-depressant, and sedative properties. Traditionally, it is used for high blood pressure, arteriosclerosis, nervous tachycardia, hypertensive headache, chorea, and hysteria. 

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Ephedra (ma huang) is a popular botanical incorporated into a variety of formulations for weight loss, energy or performance enhancement, and symptomatic control of asthma. A pharmacodynamic interaction leading to a fatality has been reported with concurrent use of caffeine and ephedra (62), possibly as a result of additive adrenergic agonist effect of the ephedrine alkaloids and caffeine on the cardiovascular system and the CNS (63). Ephedra was recently withdrawn from the market (64). 

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. 

In the United States, ephedrine alkaloids are derived from the Ephedra sinica, or ma huang plant. Most ephedra supplements contain a standard extract of 6-8% ephedrine alkaloids. Other herbs and ingredients, including caffeine, may also be added to ephedra supplements. 

Of course, this restriction has caused some consternation among herbalists or Chinese practitioners who still believe that within the context of traditional use, Ma Huang has its merits. In Canada, the ephedrine alkaloid is limited to levels well below the excesses seen in U.S. products, a policy that allows the continued sale of traditional Chinese Ephedra products. Canada also allows Ephedra to be included in products used for nasal congestion in the following small doses 8 mg/dose or 32 mg/day of ephedrine and 400 mg/ dose or 1600 mg/day. However, Health Canada has issued several warnings regarding the illegal sale of Ephedra and the potential risks that are involved, particularly when it is combined with caffeine or other stimulants. 

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. 

Several bases, other than ephedrine and i -ephedrine, have been identified in Ma Huang. Smith found 1-iV-methylephedrine (146) and nor-d-i -ephedrine (147) in the sirupy alkaloidal residue obtained in the manufacture of ephedrine. Nagai and Kanao (149), working up thoroughly a Ma Huang extract, confirmed Smith s observations and separated another new alkaloid, d-A-methyl- f -ephedrine. Kanao (150) succeeded in isolating a sixth ephedra base, 1-norephedrine. 

From Ma Huang there have also been isolated a volatile basic compound, benzylmethylamine, by Chen, Stuart and Chen (151) and ephedine, and an alkaloid of undetermined structure, by Chou and Chu (152). Wolfes (153) showed that the European ephedras contain the same alkaloids as the Chinese species. 

This alkaloid was found by Smith (146) in Ma Huang and by Wolfes in European Ephedra and isolated from the residue of the ephedrine manufacture with aid of the picrate, m.p. 144 . It was synthesized and... 

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. 

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 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). 

The Chinese drug ma huang (Ephedra sinica Stapf) has been used in China for more than SOOOyears. The alkaloid that is responsible for the CNS stimulant effects is ephedrine. The levorotatory erythro isomer ( l)is the most active of the four possible stereoisomers with that structural formula. Khat (kat, or qat) or Abyssinian tea Catha edulis Forskal) is the product from a small tree or shrub indigenous to tropical East Afiica. Khat leaves are chewed habitually by peoples in East Africa and certain other Arabian countries, and produce a mild CNS stimulant effect (2). The principal... 

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). 

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