Editing Ephedrine (section)

==Chemistry==
Ephedrine, or (−)-(1''R'',2''S'')-ephedrine, also known as (1''R'',2''S'')-β-hydroxy-''N''-methyl-α-methyl-β-phenethylamine or as (1''R'',2''S'')-β-hydroxy-''N''-methylamphetamine, is a [[substituted phenethylamine]] and [[substituted amphetamine|amphetamine]] [[chemical derivative|derivative]]. It is similar in [[chemical structure]] to [[phenylpropanolamine]], [[methamphetamine]], and [[epinephrine]] (adrenaline). It differs from methamphetamine only by the presence of a [[hydroxyl]] group (–OH). Chemically, ephedrine is an [[alkaloid]] with a [[phenethylamine]] skeleton found in various plants in the genus ''[[Ephedra (genus)|Ephedra]]'' (family [[Ephedraceae]]). It is most usually marketed as the [[hydrochloride]] or [[sulfate]] [[salt (chemistry)|salt]].<ref name="IndexNominum2004" />

It has an experimental [[partition coefficient|log P]] of 1.13, while its predicted log P values range from 0.9 to 1.32.<ref name="PubChem">{{cite web | title=Ephedrine | website=PubChem | url=https://pubchem.ncbi.nlm.nih.gov/compound/9294 | access-date=30 August 2024}}</ref><ref name="DrugBank" /><ref name="ChemSpider">{{cite web | title=L-(−)-Ephedrine | website=ChemSpider | date=30 August 2024 | url=https://www.chemspider.com/Chemical-Structure.8935.html | access-date=30 August 2024}}</ref> The [[lipophilicity]] of amphetamines is closely related to their [[blood–brain barrier|brain permeability]].<ref name="BharateMignaniWishwakarma2018">{{cite journal | vauthors = Bharate SS, Mignani S, Vishwakarma RA | title = Why Are the Majority of Active Compounds in the CNS Domain Natural Products? A Critical Analysis | journal = J Med Chem | volume = 61 | issue = 23 | pages = 10345–10374 | date = December 2018 | pmid = 29989814 | doi = 10.1021/acs.jmedchem.7b01922 | url = }}</ref> For comparison to ephedrine, the experimental log P of [[methamphetamine]] is 2.1,<ref name="SchepSlaughterBeasley2010">{{cite journal | vauthors = Schep LJ, Slaughter RJ, Beasley DM | title = The clinical toxicology of metamfetamine | journal = Clin Toxicol (Phila) | volume = 48 | issue = 7 | pages = 675–694 | date = August 2010 | pmid = 20849327 | doi = 10.3109/15563650.2010.516752 | url = | quote = Metamfetamine acts in a manner similar to amfetamine, but with the addition of the methyl group to the chemical structure. It is more lipophilic (Log p value 2.07, compared with 1.76 for amfetamine),<sup>4</sup> thereby enabling rapid and extensive transport across the blood–brain barrier.<sup>19</sup>}}</ref> of [[amphetamine]] is 1.8,<ref name="PubChem-Amphetamine">{{cite web | title=Amphetamine | website=PubChem | url=https://pubchem.ncbi.nlm.nih.gov/compound/3007 | access-date=26 July 2024}}</ref><ref name="SchepSlaughterBeasley2010" /> of [[pseudoephedrine]] is 0.89,<ref name="PubChem-Pseudoephedrine">{{cite web | title=Pseudoephedrine | website=PubChem | url=https://pubchem.ncbi.nlm.nih.gov/compound/7028 | access-date=25 July 2024}}</ref> of [[phenylpropanolamine]] is 0.7,<ref name="PubChem-Phenylpropanolamine">{{cite web | title=Norephedrine | website=PubChem | url=https://pubchem.ncbi.nlm.nih.gov/compound/26934 | access-date=26 July 2024}}</ref> of [[phenylephrine]] is -0.3,<ref name="PubChem-Phenylephrine">{{cite web | title=Phenylephrine | website=PubChem | url=https://pubchem.ncbi.nlm.nih.gov/compound/6041 | access-date=21 July 2024}}</ref> and of [[norepinephrine (medication)|norepinephrine]] is -1.2.<ref name="PubChem-Norepinephrine">{{cite web | title=Norepinephrine | website=PubChem | url=https://pubchem.ncbi.nlm.nih.gov/compound/439260 | access-date=26 July 2024}}</ref> Methamphetamine has high brain permeability,<ref name="SchepSlaughterBeasley2010" /> whereas phenylephrine and norepinephrine are [[peripherally selective drug]]s.<ref name="Eccles2007">{{cite journal | vauthors = Eccles R | title = Substitution of phenylephrine for pseudoephedrine as a nasal decongeststant. An illogical way to control methamphetamine abuse | journal = British Journal of Clinical Pharmacology | volume = 63 | issue = 1 | pages = 10–14 | date = January 2007 | pmid = 17116124 | pmc = 2000711 | doi = 10.1111/j.1365-2125.2006.02833.x }}</ref><ref name="FroeseDianGomez2020">{{cite journal | vauthors = Froese L, Dian J, Gomez A, Unger B, Zeiler FA | title = The cerebrovascular response to norepinephrine: A scoping systematic review of the animal and human literature | journal = Pharmacol Res Perspect | volume = 8 | issue = 5 | pages = e00655 | date = October 2020 | pmid = 32965778 | doi = 10.1002/prp2.655 | pmc = 7510331 | url = }}</ref> The optimal log P for brain permeation and central activity is about 2.1 (range 1.5–2.7).<ref name="PajouheshLenz2005">{{cite journal | vauthors = Pajouhesh H, Lenz GR | title = Medicinal chemical properties of successful central nervous system drugs | journal = NeuroRx | volume = 2 | issue = 4 | pages = 541–553 | date = October 2005 | pmid = 16489364 | pmc = 1201314 | doi = 10.1602/neurorx.2.4.541 | url = | quote = Lipophilicity was the first of the descriptors to be identified as important for CNS penetration. Hansch and Leo54 reasoned that highly lipophilic molecules will be partitioned into the lipid interior of membranes and will be retained there. However, ClogP correlates nicely with LogBBB with increasing lipophilicity and increasing brain penetration. For several classes of CNS active substances, Hansch and Leo54 found that blood-brain barrier penetration is optimal when the LogP values are in the range of 1.5-2.7, with a mean value of 2.1. An analysis of small drug-like molecules suggested that for better brain permeation46 and for good intestinal permeability55 the LogD values need to be greater than 0 and less than 3. In comparison, the mean value for ClogP for the marketed CNS drugs is 2.5, which is in good agreement with the range found by Hansch et al.22}}</ref>

Ephedrine hydrochloride has a melting point of 187−188{{nbsp}}°C.<ref name=Budavari>{{cite book | veditors = Budavari S | title = The Merck Index: An encyclopedia of chemicals, drugs, and biologicals | edition = 12th | location = Whitehouse Station | publisher = Merck }}</ref>

The [[racemic mixture|racemic]] form of ephedrine is [[racephedrine]] ((±)-ephedrine; ''dl''-ephedrine; (1''RS'',2''SR'')-ephedrine).<ref name="Elks2014" /> A [[stereoisomer]] of ephedrine is [[pseudoephedrine]].<ref name="Elks2014" /> [[Chemical derivative|Derivative]]s of ephedrine include [[methylephedrine]] (''N''-methylephedrine), [[etafedrine]] (''N''-ethylephedrine), [[cinnamedrine]] (''N''-cinnamylephedrine), and [[oxilofrine]] (4-hydroxyephedrine).<ref name="Elks2014" /> [[Structural analog|Analogue]]s of ephedrine include [[phenylpropanolamine]] (norephedrine) and [[metaraminol]] (3-hydroxynorephedrine).<ref name="Elks2014" />

The presence of an ''N''-[[methyl group]] decreases binding affinities at α-adrenergic receptors, compared with norephedrine. Ephedrine, though, binds better than [[N-Methylephedrine|''N''-methylephedrine]], which has an additional methyl group at the nitrogen atom. Also, the [[Stereochemistry|steric]] orientation of the hydroxyl group is important for receptor binding and functional activity.<ref name="Ma_2007" />

===Nomenclature===
[[File:Ephedrine and pseudoephedrine isomers.svg|class=skin-invert-image|thumb|400px|The four stereoisomers of ephedrine.]]

Ephedrine exhibits [[optical isomer]]ism and has two [[chirality (chemistry)|chiral]] centres, giving rise to four [[stereoisomer]]s. By convention, the pair of [[enantiomer]]s with the stereochemistry (1''R'',2''S'') and (1''S'',2''R'') is designated ephedrine, while the pair of enantiomers with the stereochemistry (1''R'',2''R'') and (1''S'',2''S'') is called pseudoephedrine.

The isomer which is marketed is (−)-(1''R'',2''S'')-ephedrine.<ref name=Reynolds>{{cite book | editor=Reynolds JEF | title=Martindale: The complete drug reference | edition=29th | year=1989 | publisher=Pharmaceutical Press | location=London | isbn= 978-0-85369-210-2 | vauthors = Reynolds J | title-link=Martindale: The complete drug reference }}</ref>

In the outdated [[Chirality (chemistry)#By configuration: D- and L-|<small>D</small>/<small>L</small> system]] (+)-ephedrine is also referred to as <small>D</small>-ephedrine and (−)-ephedrine as <small>L</small>-ephedrine (in which case, in the [[Fischer projection]], the [[Phenyl group|phenyl ring]] is drawn at the bottom).<ref name="Reynolds"/><ref>{{cite journal | vauthors = Patil PN, Tye A, Lapidus JB | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 148 | issue = 2 | pages = 158–68 | date = May 1965 | pmid = 14301006 | url = http://jpet.aspetjournals.org/content/148/2/158.full.pdf | title = A Pharmacological Study of the Ephedrine Isomers | doi = 10.1016/S0022-3565(25)27031-8 }}</ref>

Often, the <small>D</small>/<small>L</small> 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 <small>L</small>-ephedrine and the dextrorotary d-pseudoephedrine (the diastereomer) wrongly <small>D</small>-pseudoephedrine.

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

===Detection in body fluids===
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{{nbsp}}μg/L range in persons taking the drug therapeutically, 300–3000{{nbsp}}μg/L in abusers or poisoned patients, and 3–20{{nbsp}}mg/L in cases of acute fatal overdosage. The current [[World Anti-Doping Agency]] (WADA) limit for ephedrine in an athlete's urine is 10{{nbsp}}μg/mL.<ref>{{cite web |url= http://list.wada-ama.org/list/s6-stimulants |title=S6. Stimulants &#124; List of Prohibited Substances and Methods |access-date= 2015-10-19 |url-status=dead |archive-url= https://web.archive.org/web/20151023042222/http://list.wada-ama.org/list/s6-stimulants/ |archive-date=2015-10-23 }}</ref><ref>{{cite journal | vauthors = Schier JG, Traub SJ, Hoffman RS, Nelson LS | title = Ephedrine-induced cardiac ischemia: exposure confirmed with a serum level | journal = Journal of Toxicology. Clinical Toxicology | volume = 41 | issue = 6 | pages = 849–53 | year = 2003 | pmid = 14677795 | doi = 10.1081/clt-120025350 | s2cid = 23359388 }}</ref><ref>WADA. ''The World Anti-Doping Code'', World Anti-Doping Agency, Montreal, Canada, 2010. [http://www.wada-ama.org/Documents/World_Anti-Doping_Program/WADP-Prohibited-list/WADA_Prohibited_List_2010_EN.pdf url] {{webarchive|url=https://web.archive.org/web/20130911050811/http://www.wada-ama.org/Documents/World_Anti-Doping_Program/WADP-Prohibited-list/WADA_Prohibited_List_2010_EN.pdf |date=2013-09-11 }}</ref><ref>{{cite book | vauthors = Baselt R | title = Disposition of Toxic Drugs and Chemicals in Man | edition = 8th | publisher = Biomedical Publications | location = Foster City, CA | date = 2008 | pages = 542–544 }}</ref>