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Natural Product: Ephedrine
Alexander McLeod Dewey
April 31, 2008
Ephedrine is an alkaloid derived from various plants in the genus Ephedra. This genus contains as many as 32 species. It belongs to the family Ephedraceae, and the order Ephedrales. Ephedra is a small gymnosperm shrub that grows in desert climates. The plant does not have leaves, rather long straw-like stalks. Ephedra has been used for over 5,000 years in herbal medicine. Known as Ma Huang by the Chinese, it was drunk in a tea form to treat bronchial asthma, the cold, flu, wheezing, and edema. Ephedra was also used by the ancient people of Northern India and Pakistan in order to alleviate bronchial asthma. The Indians of West Texas and Northern Mexico used another species of ephedra to cure renal disease. Another species was used in order to relieve urogenital disease. One of the most popular pieces of ephedra history is Mormon Tea. This was brewed by early settlers of the American Southwest using a variety of ephedra species. (Ephedra, 2008)
Figure 1. Ephedra
It wasn’t until recently that ephedrine was used commercially as a drug. Today, ephedrine is synthesized rather than extracted from ephedra due to complicated and low yield techniques. Ephedrine is made into either a odorless and colorless powdered or crystalline form. Ephedrine plays no well known role in the ephedra plant. It is possible that this plant synthesizes ephedrine for protection. Ephedrine when consumed in large doses may have significant undesirable effects. Therefore, its contents in the ephedra plant may keep it from being a food source for species sharing a habitat.
The IUPAC name for ephedrine is (1R,2S)-2-(methylamino)-1-phenylpropan-1-ol. This ten carbon compound contains a cyclohexane ring as well as two chiral centers. (Figure 2) This characteristic if chirality gives ephedrine a (1R,2R), (1S,2S) enantiomer and a (1R,2S), (1S,2R) form. These forms are pseudoephedrine and ephedrine respectively (Ephedrine Chemistry). This structure gives ephedrine unique abilities which make it very useful.
Figure 2. Ephedrine Structure
Ephedrine is classified as a central nervous stimulant. Its structure plays a key role in its activity in the body. Since it contains nitrogen, ephedrine acts on the adrenergic receptor system. This particular system involves a and b post-synaptic noradrenergic receptors that are targets of the catecholamines. In this case the catecholamines are epinephrine and norepinephrine neurotransmitters. However, the nervous system is incapable of distinguishing ephedrine from these catecholamines. Therefore, this binding activates the noradrenergic receptor causing a release of epinephrine (Adverse Events). Hence, ephedrine stimulates a sympathetic or a fight or flight response in which heart rate increases and vasoconstriction and bronchodilation occur. The species E. Sinica Ephedrine contains the most active form of ephedra. Ephedra also contains other less active forms of ephedrine such as pseudoephedrine, methylphedrine, norpseudophedrine, and norephedrine.
Little is understood completely about the biosynthesis of ephedrine by ephedra. 13C NMR shows that a labeled C 2 fragment is transferred from pyruvic acid into a methyl group on the adjacent carbon atom. It is also known that a C6-C1 unit related to benzoic acid or benzaldehyde is used to generate the carbon ring skeleton (Sorensen; Spenser). Ephedrine can be extracted from the ephedra plant a number of different ways. The ancient Chinese would harvest the plant in Autumn. They would then sun-dry and section the stalks. The dried stalks would then be boiled in a honey-water mixture until most of the water evaporated. This would concentrate the active ingredient to be used as treatment for a variety of different ailments (Ephedra). The early people of West Texas and Northern Mexico would prepare a medicine by roasting and grinding the seeds into flour. Ephedrine was also consumed in beverages similar to coffee and tea (Ephedra).
The solubility of ephedrine allows the powder extracts to be dissolved and consumed in water. However, the ephedra plant only contains a small amount of ephedrine. Chemical extraction procedures are very complicated and produce a low yield of ephedrine. Therefore, today’s ephedrine is made synthetically.
There are two common ways for synthetically producing ephedrine. The first involves a transformation of benzaldehyde using fermenting yeast. The result is L-phenylacetylcarbinol which can be reductively aminated to produce ephedrine. The other common synthetic technique is a reductive condensation reaction of L-1-phenyl-1-acetylcarbinol with methylamine. This reaction yields the L-ephedrine isomer which is identical to ephedrine (Pearson).
The structure of ephedrine and its chemical effect on the brain make it useful for several clinical, weight loss/athletic, and recreational applications. Ephedrine is included in topical nasal decongestants such as Vicks Vapor Rub or in nasal spays. Since ephedrine is a bronchodilator it is used to treat asthma patients. Ephedrine raises blood pressure and heart rate so it is used to treat hypotension. Ephedrine regiments have also been prescribed for allergies, narcolepsy, and even bedwetting. Up until a couple years ago, ephedrine was used in nutritional and diet supplementation as well as application to recreation. Ephedrine can act as an appetite suppressant. It was combined with caffeine and aspirin in order to increase metabolism. This effectively burns calories and promotes weight loss. Ephedrine was also used by body builders to improve energy and alertness as well as burn excess fat. Ephedrine makes the brain sharper, improves alertness and concentration better than caffeine and is used by many businessmen, athletes, and students. Ephedrine has a similar structure to amphetamines and can be converted so by the Birch reduction or red phosphorus method. Therefore ephedrine containing products are sought after by illegal drug manufacturers to produce methamphetamine.
Ephedrine has many uses that make it a key ingredient for clinical, recreational, and weight loss purposes. However, ephedrine has an even longer list of adverse effects. These negative side effects can cause much discomfort, serious complications, and possibly death. The more serious effects are found in users involved with prolonged habitual use or overdosing. Ephedrine can cause many cardiovascular complications such as tachycardia, cardiac arrhythmias, and angina pectoris (Adverse Events). Ephedrine also can cause vasoconstriction which leads to hypertension. Ephedrine can cause dermatological effects such as sweating, acne vulgaris, and flushing. Ephedrine can affect the gastrointestinal region by causing a loss of appetite or nausea. Ephedrine can increase urine output or make it difficult to urinate (Adverse Events).
The bulk of ephedrine’s mode of action takes place in the brain. This is where most serious of adverse conditions may result. Ephedrine can cause insomnia, delusions, hostility, panic, paranoia, confusion, agitation, restlessness, and even seizures. Hallucinations caused by ephedrine have been reported, however rare. The most serious effects are heatstroke, coma, or even death. There has been much controversy surrounding ephedrine products and their connection with the deaths of a number of athletes. Ephedrine also interferes with levels of dopamine and serotonin. Therefore it may cause both a physical and psychological dependence (Adverse Events).
These serious negative effects and ephedrine’s link with amphetamines make it subject to governmental regulations. On August 17 th 2006 the United States government outlawed the use of ephedrine in dietary supplements. Today it is only found in prescription and over the counter medications. Purchasing is limited and monitored depending on state regulations. Ephedrine containing medications are not found on shelves. They are sold from behind the counter and are kept in a locked safe. The government keeps a retrievable record for all purchases identifying name and address. This documentation is kept for two years (Pearson; Shaw). Proof of identity is also required for purchase. Accounts of any suspicious payments or inventory disappearances are reported to the Attorney General. The government has made the legal dose less than 8mg for both prescription and over the counter medications. Daily sales of ephedrine to one purchaser may not exceed 3.6 grams. Monthly sales may not exceed 9 grams (Pearson; Shaw). These drastic measures to regulate ephedrine are meant to minimize the amount of ephedrine illegally distributed for methamphetamine production.
Ephedrine has been utilized for thousands of years from many species of ephedra. It has been used for medical treatment as well as weight loss and recreation. Ephedrine’s structure and mode of action allow it to have both beneficial and adverse effects on the body. The use of ephedrine in illicit drug manufacturing makes it a regulated substance and is controlled both by the federal and state governments. As the study of ephedrine continues it will be interesting to see what new uses will be provides by this ancient natural product.
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Pearson, Durk, and Sandy Shaw. Ephedra. Food and Drug Administration. Rockville, 1995. 26 Feb. 2008 <www.emord.com/legal/ephedra.htm>.