Ephedrine

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Ephedrine
(-)-Ephedrin.svg
Ephedrine-3d-CPK.png
Systematic (IUPAC) name
(R*,S*)-2-(methylamino)-1-phenylpropan-1-ol
Clinical data
AHFS/Drugs.com monograph
Pregnancy cat. A (AU) C (US)
Legal status Prescription Only (S4) (AU) Schedule VI (CA) P (UK) Behind the Counter (BTC) (US)
Routes oral, IV, IM, SC
Pharmacokinetic data
Bioavailability 85%
Metabolism minimal hepatic
Half-life 3–6 hours
Excretion 22-99% renal
Identifiers
CAS number 299-42-3 YesY
ATC code C01CA26 R01AA03, R01AB05 (combinations), R03CA02, S01FB02, QG04BX90
PubChem CID 5032
IUPHAR ligand 556
DrugBank DB01364
ChemSpider 8935 YesY
UNII GN83C131XS YesY
KEGG D00124 YesY
ChEBI CHEBI:15407 YesY
ChEMBL CHEMBL211456 YesY
Chemical data
Formula C10H15NO 
Mol. mass 165.23
 YesY (what is this?)  (verify)

Ephedrine (/ɨˈfɛdrɪn/ or /ˈɛfɨdrn/; not to be confused with ephedrone) is a sympathomimetic amine commonly used as a stimulant, concentration aid, decongestant, appetite suppressant, and to treat hypotension associated with anaesthesia.

Ephedrine is similar in molecular structure to the well-known drugs phenylpropanolamine and methamphetamine, as well as to the important neurotransmitter epinephrine (adrenaline). Chemically, it is an alkaloid with a phenethylamine skeleton found in various plants in the genus Ephedra (family Ephedraceae). It works mainly by increasing the activity of norepinephrine (noradrenaline) on adrenergic receptors.[1] It is most usually marketed as the hydrochloride or sulfate salt.

The herb Ephedra sinica, used in traditional Chinese medicine, contains ephedrine and pseudoephedrine as its principal active constituents. The same may be true of other herbal products containing extracts from other Ephedra species.

History[edit]

Ephedrine in its natural form, known as má huáng (麻黄) in traditional Chinese medicine, has been documented in China since the Han dynasty (206 BC – 220 AD) as an antiasthmatic and stimulant.[2] In 1885, the chemical synthesis of ephedrine was first accomplished by Japanese organic chemist Nagai Nagayoshi based on his research on Japanese and Chinese traditional herbal medicines. The industrial manufacture of ephedrine in China began in the 1920s, when Merck began marketing and selling the drug as ephetonin. Ephedrine exports between China and the West grew from 4 to 216 tonnes between 1926 and 1928.[3]

Chemistry and nomenclature[edit]

The four stereoisomers of ephedrine

Ephedrine exhibits optical isomerism and has two chiral centres, giving rise to four stereoisomers. By convention, the pair of enantiomers with the stereochemistry (1R,2S and 1S,2R) is designated ephedrine, while the pair of enantiomers with the stereochemistry (1R,2R and 1S,2S) is called pseudoephedrine. Ephedrine is a substituted amphetamine and a structural methamphetamine analogue. It differs from methamphetamine only by the presence of a hydroxyl (OH).

The isomer which is marketed is (–)-(1R,2S)-ephedrine.[4]

Ephedrine hydrochloride has a melting point of 187−188°C.[5]

In the outdated d/l system (+)-ephedrine is also referred to as l-ephedrine and (—)-ephedrine as d-ephedrine (in the Fisher projection, then the phenyl ring is drawn at bottom).[4][6]

Often, the d/l system (with small caps) and the d/l system (with lower-case) are confused. The result is that the levorotary l-ephedrine is wrongly named l-ephedrine and the dextrorotary d-pseudoephedrine (the diastereomer) wrongly d-pseudoephedrine.

The IUPAC names of the two enantiomers are (1R,2S)- respectively (1S,2R)-2-methylamino-1-phenylpropan-1-ol. A synonym is erythro-ephedrine.

Agricultural sources[edit]

Ephedrine is obtained from the plant Ephedra sinica and other members of the Ephedra genus. Raw materials for the manufacture of ephedrine and traditional Chinese medicines are produced in China on a large scale. As of 2007, companies produced for export US$13 million worth of ephedrine from 30,000 tons of ephedra annually, 10 times the amount used in traditional Chinese medicine.[7]

Synthetic sources[edit]

Most of the l-ephedrine produced today for official medical use is made synthetically as the extraction and isolation process from E. sinica is tedious and no longer cost effective.[8]

Mechanism of action[edit]

Ephedrine, a sympathomimetic amine, acts on part of the sympathetic nervous system (SNS). The principal mechanism of action relies on its indirect stimulation of the adrenergic receptor system by increasing the activity of noradrenaline at the postsynaptic α- and β-receptors.[1] The presence of direct interactions with α-receptors is unlikely, but still controversial.[9][10][11] L-Ephedrine, and particularly its stereoisomer norpseudoephedrine (which is also present in Catha edulis) has indirect sympathomimetic effects and due to its ability to cross the blood-brain barrier, it is a CNS stimulant similar to amphetamines, but less pronounced, as it releases noradrenaline and dopamine in the substantia nigra.[12]

The presence of an N-methyl group decreases binding affinities at α-receptors, compared with norephedrine. Ephedrine, though, binds better than N-methylephedrine, which has an additional methyl group at the N-atom. Also the steric orientation of the hydroxyl group is important for receptor binding and functional activity.[9]

Medical use[edit]

Ephedrine Sulphate (1932), Ephedrine Compound (1932), and Swan-Myers Ephedrine Inhalant No. 66 (circa 1940)

Ephedrine is a potentially dangerous substance; as of 2004 the US Food and Drug Administration had received over 18,000 reports of adverse effects in people using it.[13]

Indications[edit]

In traditional Chinese medicine, má huáng has been used as an attempted treatment for asthma and bronchitis for centuries.[14]

Both ephedrine and pseudoephedrine increase blood pressure and act as bronchodilators, with pseudoephedrine having considerably less effect. [11]

Ephedrine promotes modest short-term weight loss,[15] specifically fat loss, but it is not recommended for this, and is ineffective in the long term.[16] In mice, as well as weight loss, ephedrine is known to stimulate thermogenesis in the brown adipose tissue, but because adult humans have only small amounts of brown fat, thermogenesis is assumed to take place mostly in the skeletal muscle. Ephedrine also decreases gastric emptying. Methylxanthines such as caffeine and theophylline have a synergistic effect with ephedrine with respect to weight loss, and so does aspirin.[citation needed] This led to creation and marketing of compound products.[17] One of them, known as the ECA stack, contains caffeine and aspirin besides ephedrine, and is a popular supplement taken by body builders to cut down body fat before a competition. It increases performance in athletes, and has a synergistic effect with caffeine.[18]

Adverse effects[edit]

Adverse drug reactions (ADRs) are more common with systemic administration (e.g. injection or oral administration) compared to topical administration (e.g. nasal instillations). ADRs associated with ephedrine therapy include:[19]

The neurotoxicity of l-ephedrine is disputed. [20]

Contraindications[edit]

Ephedrine should not be used in conjunction with certain antidepressants, namely serotonin-norepinephrine reuptake inhibitor]]s (NRDIs), as this increases the risk of the above symptoms due to excessive serum levels of norepinephrine.

Bupropion is an example of an antidepressant with an amphetamine-like structure similar to ephedrine, and it is known as NDRI. Its action bears more resemblance to amphetamine than to fluoxetine in that its primary mode of therapeutic action involves norepinephrine and to a lesser degree dopamine, but it also releases some serotonin from presynaptic clefts. It should not be used with ephedrine, as it may increase the likelihood of the above side effects.

Ephedrine should be used with caution in patients with inadequate fluid replacement, impaired adrenal function, hypoxia, hypercapnia, acidosis, hypertension, hyperthyroidism, prostatic hypertrophy, diabetes mellitus, cardiovascular disease, during delivery if maternal blood pressure is >130/80 mmHg, and lactation.[21]

Contraindications for the use of ephedrine include: closed-angle glaucoma, phaeochromocytoma, asymmetric septal hypertrophy (idiopathic hypertrophic subaortic stenosis), concomitant or recent (previous 14 days) monoamine oxidase inhibitor (MAOI) therapy, general anaesthesia with halogenated hydrocarbons (particularly halothane), tachyarrhythmias or ventricular fibrillation, or hypersensitivity to ephedrine or other stimulants.

Ephedrine should not be used at any time during pregnancy unless specifically indicated by a qualified physician and only when other options are unavailable.[21]

Recreational and illicit use[edit]

Ephedrine tablets

Anecdotal reports have suggested ephedrine helps studying, thinking, or concentrating to a greater extent than caffeine. Some students and some white-collar workers have used ephedrine (or Ephedra-containing herbal supplements) for this purpose, as well as some professional athletes and weightlifters. It is common for many athletes to use stimulants while exercising. Such use of ephedrine has been associated with stimulant dependence, as well as deaths from heatstroke in athletes and circulatory problems such as aortic aneurysm in weightlifters, though these side effects are rare.

As a phenylethylamine, ephedrine has a similar chemical structure to amphetamines and is a methamphetamine analogue having the methamphetamine structure with a hydroxyl group at the β position. Because of ephedrine's structural similarity to methamphetamine, it can be used to create methamphetamine using chemical reduction in which ephedrine's hydroxyl group is removed; this has made ephedrine a highly sought-after chemical precursor in the illicit manufacture of methamphetamine. The most popular method for reducing ephedrine to methamphetamine is similar to the Birch reduction, in that it uses anhydrous ammonia and lithium metal in the reaction. The second-most popular method uses red phosphorus, iodine, and ephedrine in the reaction.

In E for Ecstasy[22] (a book examining the uses of the drug MDMA in the UK) the writer, activist, and Ecstasy advocate Nicholas Saunders highlighted test results showing that certain consignments of the drug also contained ephedrine. Consignments of Ecstasy known as "Strawberry" contained what Saunders described as a "potentially dangerous combination of ketamine, ephedrine and selegiline," as did a consignment of "Sitting Duck" Ecstasy tablets.[23]

Through oxidation, ephedrine can be easily synthesized into methcathinone. Ephedrine is listed as a table-I precursor under the United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances.[24]

Detection of use[edit]

Ephedrine may be quantified in blood, plasma, or urine to monitor possible abuse by athletes, confirm a diagnosis of poisoning, or assist in a medicolegal death investigation. Many commercial immunoassay screening tests directed at the amphetamines cross-react appreciably with ephedrine, but chromatographic techniques can easily distinguish ephedrine from other phenethylamine derivatives. Blood or plasma ephedrine concentrations are typically in the 20-200 µg/l range in persons taking the drug therapeutically, 300-3000 µg/l in abusers or poisoned patients and 3–20 mg/l in cases of acute fatal overdosage. The current WADA limit for ephedrine in an athlete's urine is 10 µg/l.[25][26][27]

Other uses[edit]

In chemical synthesis, ephedrine is used in bulk quantities as a chiral auxiliary group. [28]

Ephedrine as chiral auxiliary

Legality[edit]

Canada[edit]

In January 2002, Health Canada issued a voluntary recall of all ephedrine products containing more than 8 mg per dose, all combinations of ephedrine with other stimulants such as caffeine, and all ephedrine products marketed for weight-loss or bodybuilding indications, citing a serious risk to health.[29] Ephedrine is still sold as an oral nasal decongestant in 8 mg pills, OTC.

USA[edit]

In 1997, the FDA proposed a regulation on ephedra (the herb from which ephedrine is obtained), which limited an ephedra dose to 8 mg (of active ephedrine) with no more than 24 mg per day.[30] This proposed rule was withdrawn, in part, in 2000 because of "concerns regarding the agency's basis for proposing a certain dietary ingredient level and a duration of use limit for these products."[31] In 2004, the FDA created a ban on ephedrine alkaloids marketed for reasons other than asthma, colds, allergies, other disease, or traditional Asian use.[32] On April 14, 2005, the U.S. District Court for the District of Utah ruled the FDA did not have proper evidence that low dosages of ephedrine alkaloids are actually unsafe,[33] but on August 17, 2006, the U.S. Court of Appeals for the Tenth Circuit in Denver upheld the FDA's final rule declaring all dietary supplements containing ephedrine alkaloids adulterated, and therefore illegal for marketing in the United States.[34] Furthermore, ephedrine is banned by the NCAA, MLB, NFL, and PGA.[35] Ephedrine is, however, still legal in many applications outside of dietary supplements. Purchasing is currently limited and monitored, with specifics varying from state to state.

The House passed the Combat Methamphetamine Epidemic Act of 2005 as an amendment to the renewal of the USA PATRIOT Act. Signed into law by President George W. Bush on March 6, 2006, the act amended the US Code (21 USC 830) concerning the sale of ephedrine-containing products. The federal statute included these requirements for merchants who sell these products:

  • A retrievable record of all purchases identifying the name and address of each party to be kept for two years
  • Required verification of proof of identity of all purchasers
  • Required protection and disclosure methods in the collection of personal information
  • Reports to the Attorney General of any suspicious payments or disappearances of the regulated products
  • Non-liquid dose form of regulated product may only be sold in unit-dose blister packs
  • Regulated products are to be sold behind the counter or in a locked cabinet in such a way as to restrict access
  • Daily sales of regulated products not to exceed 3.6 g without regard to the number of transactions
  • Monthly sales not to exceed 9 g of pseudoephedrine base in regulated products

The law gives similar regulations to mail-order purchases, except the monthly sales limit is only 7.5 g.

As a pure herb or tea, má huáng, containing ephedrine, is still sold legally in the USA. The law restricts/prohibits its being sold as a dietary supplement (pill) or as an ingredient/additive to other products, like diet pills.

South Africa[edit]

In South Africa, ephedrine was moved to schedule 6 on 27 May 2008,[36] which makes the substance legal to possess but available by prescription only.

Germany[edit]

Ephedrine was freely available in pharmacies in Germany until 2001. Afterwards, access was restricted since it was mostly bought for unindicated uses. Similarly, ephedra can only be bought with a prescription. Since April 2006, all products, including plant parts, that contain ephedrine are only available with a prescription.[37]

Synthesis[edit]

Ephedrine can be synthesized from benzaldehyde in a few different ways. According to the first, benzaldehyde is condensed with nitroethane, giving 2-methyl-2-nitro-1-phenylethanol, which is reduced to 2-methyl-2-amino-1-phenylethanol.[38][39] The necessary L-isomer is isolated from the mixture of isomers by crystallization. Methylation of this gives ephedrine.

Ephedrine synthesis 1.png

The second method consists of the fermentation of glucose by yeast carboligase in the presence of benzaldehyde, which during the process turns into phenylacetylcarbinol. This is reduced by hydrogen in the presence of methylamine to give the desired ephedrine.[40][41]

Ephedrine synthesis 2.png

See also[edit]

References[edit]

  1. ^ a b Merck Manuals > EPHEDrine Last full review/revision January 2010
  2. ^ Woodburne O. Levy; Kavita Kalidas (26 February 2010). Norman S. Miller, ed. Principles of Addictions and the Law: Applications in Forensic, Mental Health, and Medical Practice. Academic Press. pp. 307–308. ISBN 978-0-12-496736-6. 
  3. ^ Frank Dikotter; Lars Peter Laamann (16 April 2004). Narcotic Culture: A History of Drugs in China. University of Chicago Press. p. 199. ISBN 978-0-226-14905-9. 
  4. ^ a b Martindale (1989). Edited by Reynolds JEF, ed. Martindale: The complete drug reference (29th ed.). London: Pharmaceutical Press. ISBN 0-85369-210-6. 
  5. ^ Budavari S, editor. The Merck Index: An encyclopedia of chemicals, drugs, and biologicals, 12th edition. Whitehouse Station: Merck
  6. ^ Popat N. Patil, A. Tye and J.B. LaPidus A pharmacological study of the ephedrine isomers JPET May 1965 vol. 148, no. 2, pp. 158-168. Full PDF
  7. ^ Long, Professor. http://www.chinadialogue.net/article/show/single/en/692-Chinese-medicine-s-great-waste-of-resources
  8. ^ Chemically Synthesized Ephedrine Put Into Mass Production in China
  9. ^ a b Guoyi Ma, et al. Pharmacological Effects of Ephedrine Alkaloids on Human {alpha}1- and {alpha}2-Adrenergic Receptor Subtypes J. Pharmacol. Exp. Ther.; nr. 322 pp. 214-221 (july 2007) PDF
  10. ^ Shigeaki Kobayashi, et al. The Sympathomimetic Actions of l-Ephedrine and d-Pseudoephedrine: Direct Receptor Activation or Norepinephrine Release? Anesth Analg 2003; 97, pp.1239-1245.
  11. ^ a b Drew, et al. Comparison of the effects of D-(-)-ephedrine and L-(+)-pseudoephedrine on the cardiovascular and respiratory systems in man. Br J Clin Pharmacol. 1978; 6, pp 221-225. PDF
  12. ^ Munhall AC, Johnson SW. (2006). "Dopamine-mediated actions of ephedrine in the rat substantia nigra." Brain Res. 1069 (1 ): 96-103. PMID 16386715
  13. ^ Palamar J (January 2011). "How ephedrine escaped regulation in the United States: a historical review of misuse and associated policy". Health Policy (Review) 99 (1): 1–9. doi:10.1016/j.healthpol.2010.07.007. PMID 20685002. 
  14. ^ Ford MD, Delaney KA, Ling LJ, Erickson T, editors. Clinical Toxicology. Philadelphia: WB Saunders; 2001. ISBN 0-7216-5485-1 Research Laboratories; 1996. ISBN 0-911910-12-3
  15. ^ Shekelle, P. G.; Hardy, M. L.; Morton, S. C.; Maglione, M.; Mojica, W. A.; Suttorp, M. J.; Rhodes, S. L.; Jungvig, L.; Gagné, J. (2003). "Efficacy and Safety of Ephedra and Ephedrine for Weight Loss and Athletic Performance: A Meta-analysis". JAMA: the Journal of the American Medical Association 289 (12): 1537–1545. doi:10.1001/jama.289.12.1537. PMID 12672771.  edit
  16. ^ Dwyer, J. T.; Allison, D. B.; Coates, P. M. (2005). "Dietary Supplements in Weight Reduction". Journal of the American Dietetic Association 105 (5): S80–S86. doi:10.1016/j.jada.2005.02.028. PMID 15867902.  edit
  17. ^ George A. Bray; Claude Bouchard (2004). Handbook of obesity. CRC Press. pp. 494–496. ISBN 978-0-8247-4773-2. 
  18. ^ Magkos, F.; Kavouras, S. A. (2004). "Caffeine and ephedrine: Physiological, metabolic and performance-enhancing effects". Sports medicine (Auckland, N.Z.) 34 (13): 871–889. doi:10.2165/00007256-200434130-00002. PMID 15487903.  edit
  19. ^ Joint Formulary Committee. British National Formulary, 47th edition. London: British Medical Association and Royal Pharmaceutical Society of Great Britain; 2004. ISBN 0-85369-587-3
  20. ^ Txsci.oxfordjournals (2000).
  21. ^ a b Mayne Pharma. Ephedrine sulfate injection DBL (Approved Product Information). Melbourne: Mayne Pharma; 2004
  22. ^ Saunders, N., & Heron, L., (1993) E for Ecstasy (Paperback), N. Saunders, London. (ISBN 0950162884)
  23. ^ See: [1] for details online.
  24. ^ Microsoft Word - RedListE2007.doc
  25. ^ Schier JG, Traub SJ, Hoffman RS, Nelson LS. Ephedrine-induced cardiac ischemia: exposure confirmed with a serum level. Clin. Toxicol. 41: 849-853, 2003.
  26. ^ WADA. The World Anti-Doping Code, World Anti-Doping Agency, Montreal, Canada, 2010. url
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  28. ^ Chiral Polycyclic Ketones via Desymmetrization of Dihaloolefins Giuseppe Borsato, Anthony Linden, Ottorino De Lucchi, Vittorio Lucchini, David Wolstenholme, and Alfonso Zambon J. Org. Chem.; 2007; 72(11) pp 4272 - 4275; (Note) doi:10.1021/jo070222g
  29. ^ "Health Canada requests recall of certain products containing Ephedra/ephedrine". Health Canada. January 9, 2002. Archived from the original on February 6, 2007. Retrieved July 7, 2009. 
  30. ^ Federal Register: June 4, 1997 (Volume 62, Number 107): Dietary Supplements Containing Ephedrine Alkaloids; Proposed Rule
  31. ^ Federal Register: April 3, 2000 (Volume 65, Number 64): Dietary Supplements Containing Ephedrine Alkaloids; Withdrawal in Part
  32. ^ Federal Register: February 11, 2004 (Volume 69, Number 28): Final Rule Declaring Dietary Supplements Containing Ephedrine Alkaloids Adulterated Because They Present an Unreasonable Risk; Final Rule
  33. ^ [2]
  34. ^ [3]
  35. ^ http://www.drugfreesport.com/drug-resources/faq.asp
  36. ^ http://www.doh.gov.za/docs/pr/2008/pr0527.html
  37. ^ Verordnung zur Neuordnung der Verschreibungspflicht von Arzneimitteln (AMVVNV). V. v. 21. Dezember 2005 BGBl. I S. 3632; Geltung ab 1. Januar 2006.
  38. ^ Spath, K. Gohring, Monatsh. Chem., 41, 319 (1920)
  39. ^ Manske, R. H. F.; Johnson, T. B. (1929). Journal of the American Chemical Society 51 (2): 580. doi:10.1021/ja01377a032.  edit
  40. ^ W. Klawehn, G. Hilderbrandt, U.S. Patent 1,956,950 (1934)
  41. ^ Merck Chem. Fab. E, DE 469782  (1926)