Ephedrine
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Ephedrine is a sympathomimetic amine and substituted amphetamine 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.<ref name=merck/> 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.
Medical use
Ephedrine is a potentially dangerous natural compound; Template:Asof the US Food and Drug Administration had received over 18,000 reports of adverse effects in people using it.<ref name=Palamar2010>Template:Cite journal</ref>
Both ephedrine and pseudoephedrine increase blood pressure and act as bronchodilators, with pseudoephedrine having considerably less effect. <ref name='drew'>Template:Cite journal</ref>
Ephedrine promotes modest short-term weight loss,<ref>Template:Cite journal</ref> specifically fat loss, but its long-term effects are unknown.<ref>Template:Cite journal</ref> In mice 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. This led to creation and marketing of compound products.<ref name="BrayBouchard2004">Template:Cite book</ref> 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.<ref>Template:Cite journal</ref>
Recreational use
As a phenethylamine, 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.
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.<ref name=UN>Microsoft Word - RedListE2007.doc</ref>
Detection of use
Ephedrine may be quantified in blood, plasma, or urine to monitor possible ***** 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 the*****utically, 300-3000 µg/l in *****rs 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/ml.<ref>https://list.wada-ama.org/list/s6-stimulants/</ref><ref>Template:Cite journal</ref><ref>WADA. The World Anti-Doping Code, World Anti-Doping Agency, Montreal, Canada, 2010. url</ref><ref>R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 542-544.</ref>
Contraindications
Ephedrine should not be used in conjunction with certain antidepressants, namely norepinephrine-dopamine reuptake inhibitors (NDRIs), 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 an NDRI. Its action bears more resemblance to amphetamine than to fluoxetine in that its primary mode of the*****utic 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.<ref name =Mayne>Mayne Pharma. Ephedrine sulfate injection DBL (Approved Product Information). Melbourne: Mayne Pharma; 2004</ref>
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.<ref name =Mayne />
Adverse effects
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:<ref name=JFC>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</ref>
- Cardiovascular: tachycardia, cardiac arrhythmias, angina pectoris, vasoconstriction with hypertension
- Dermatological: flushing, sweating, acne vulgaris
- Gastrointestinal: nausea
- Genitourinary: decreased urination due to vasoconstriction of renal arteries, difficulty urinating is not uncommon, as alpha-agonists such as ephedrine constrict the internal urethral sphincter, mimicking the effects of sympathetic nervous system stimulation
- Nervous system: restlessness, confusion, insomnia, mild euphoria, mania/hallucinations (rare except in previously existing psychiatric conditions), delusions, formication (may be possible, but lacks documented evidence) paranoia, hostility, panic, agitation
- Respiratory: dyspnea, pulmonary edema
- Miscellaneous: dizziness, headache, tremor, hyperglycemic reactions, dry mouth
The neurotoxicity of l-ephedrine is disputed. <ref>Txsci.oxfordjournals (2000).</ref>
Other uses
In chemical synthesis, ephedrine is used in bulk quantities as a chiral auxiliary group. <ref>Template:Cite journal</ref>
In saquinavir synthesis, the half-acid is resolved as its salt with l-ephedrine.
Chemistry and nomenclature
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 group (OH).
The isomer which is marketed is (–)-(1R,2S)-ephedrine.<ref name=Reynolds>Template:Cite book</ref>
Ephedrine hydrochloride has a melting point of 187−188 °C.<ref name=Budavari>Budavari S, editor. The Merck Index: An encyclopedia of chemicals, drugs, and biologicals, 12th edition. Whitehouse Station: Merck</ref>
In the outdated [[Chirality (chemistry)#By configuration: D- and L-|Template:Smallcaps system]] (+)-ephedrine is also referred to as Template:Smallcapsephedrine and (−)-ephedrine as Template:Smallcapsephedrine (in the Fisher projection, then the phenyl ring is drawn at bottom).<ref name="Reynolds"/><ref>Template:Cite journal</ref>
Often, the Template:Smallcaps 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 Template:Smallcapsephedrine and the dextrorotary d-pseudoephedrine (the diastereomer) wrongly Template:Smallcapspseudoephedrine.
The IUPAC names of the two enantiomers are (1R,2S)- respectively (1S,2R)-2-methylamino-1-phenylpropan-1-ol. A synonym is erythro-ephedrine.
Sources
Agricultural
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.<ref name=Chen>Long, Professor. https://www.chinadialogue.net/article/show/single/en/692-Chinese-medicine-s-great-waste-of-resources</ref>
Synthetic
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.<ref>Chemically Synthesized Ephedrine Put Into Mass Production in China</ref>
Biosynthetic
Ephedrine was long thought to come from modifying the amino acid L-Phenylalanine.<ref name="sciencedirect.com">Template:Cite web</ref> L-Phenylalanine would be decarboxylated and subsequently attacked with ω-aminoacetophenone. Methylation of this product would then produce ephedrine. This pathway has since been disproven.<ref name="sciencedirect.com"/> A new pathway proposed suggests that phenylalanine first forms cinnamoyl-CoA via the enzymes phenylalanine ammonia-lyase and acyl CoA ligase.<ref name="Hertweck"/> The cinnamoyl-CoA is then reacted with a hydratase to attach the alcohol functional group. The product is then reacted with a retro-aldolase, forming benzaldehyde. Benzaldehyde reacts with pyruvic acid to attach a 2 carbon unit. This product then undergoes transamination and methylation to form ephedrine and its stereoisomer, pseudoephedrine.<ref name="Grue-Sorensen 3714–3715"/>
Mechanism of action
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.<ref name=merck>Merck Manuals > EPHEDrine Last full review/revision January 2010</ref> The presence of direct interactions with α-receptors is unlikely, but still controversial.<ref name='Ma'>Guoyi Ma, et al. Pharmacological Effects of Ephedrine Alkaloids on Human {alpha}1- and {alpha}2-Adrenergic Receptor Subtypes J. Pharmacol. Exp. Ther. 322: pp. 214-221 (july 2007) PDF</ref><ref>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.</ref><ref name='drew'/> 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.<ref>Template:Cite journal</ref>
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.<ref name='Ma'/>
- Compounds with decreasing α-receptor affinity
History
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.<ref name="principles">Template:Cite book</ref> In 1885, the chemical synthesis of ephedrine was first accomplished by Japanese organic chemist Nagai Nagayoshi based on his research on traditional Japanese and Chinese 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.<ref name="Dikotter">Template:Cite book</ref>
In traditional Chinese medicine, má huáng has been used as a treatment for asthma and bronchitis for centuries.<ref name=Ford>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</ref>
Legality
Canada
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.<ref name="health-canada">Template:Cite web</ref> Ephedrine is still sold as an oral nasal decongestant in 8 mg pills, OTC.
United States
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.<ref>Federal Register: June 4, 1997 (Volume 62, Number 107): Dietary Supplements Containing Ephedrine Alkaloids; Proposed Rule</ref> 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."<ref>Federal Register: April 3, 2000 (Volume 65, Number 64): Dietary Supplements Containing Ephedrine Alkaloids; Withdrawal in Part</ref> In 2004, the FDA created a ban on ephedrine alkaloids marketed for reasons other than asthma, colds, allergies, other disease, or traditional Asian use.<ref>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</ref> 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,<ref>[1]</ref> 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.<ref>[2]</ref> Furthermore, ephedrine is banned by the NCAA, MLB, NFL, and PGA.<ref>https://www.drugfreesport.com/drug-resources/faq.asp</ref> 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
In South Africa, ephedrine was moved to schedule 6 on 27 May 2008,<ref>https://www.doh.gov.za/docs/pr/2008/pr0527.html</ref> which makes the substance legal to possess but available by prescription only.
Germany
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.<ref>Verordnung zur Neuordnung der Verschreibungspflicht von Arzneimitteln (AMVVNV). V. v. 21. Dezember 2005 BGBl. I S. 3632; Geltung ab 1. Januar 2006.</ref>
See also
References
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