Ephedrine

Structural formula
General
Non-proprietary name	Ephedrine
other names	L - (-) - ephedrine (1 R , 2 S ) -2-methylamino-1-phenylpropan-1-ol
Molecular formula	C 10 H 15 NO
Brief description	white solid with a faint odor
External identifiers / databases
CAS number 299-42-3 50906-05-3 (hemihydrate) 50-98-6 ( hydrochloride ) 134-72-5 (sulfate) PubChem 9294 DrugBank DB01364 Wikidata Q219626
Drug information
ATC code	R01 AA03 R03 CA02 S01 FB02 A08 AA56
Drug class	Sympathomimetic
Mechanism of action	indirect sympathomimetic
properties
Molar mass	165.24 g mol −1 174.2 g mol −1 (hemihydrate) 201.7 g mol −1 (hydrochloride) 428.5 g mol −1 (sulfate)
Melting point	38-40 ° C 40 ° C (hemihydrate) 217–220 ° C (hydrochloride) 245 ° C (sulfate)
boiling point	225 ° C
pK s value	10.25
solubility	moderate in water (50 g l −1 at 20 ° C) soluble in ethanol and chloroform
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed GHS hazard labeling from  Regulation (EC) No. 1272/2008 (CLP) , expanded if necessary Caution H and P phrases H: 302 P: 280-301 + 312
Toxicological data	600 mg kg −1 ( LD 50 ,  rat ,  oral )
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Ephedrine is an alkaloid from the group of phenylethylamines . It has a stimulating effect and occurs naturally in plants of the genus seaweed . There it is the main alkaloid together with pseudoephedrine (its diastereomer ).

In isolated or synthetically produced form, ephedrine and pseudoephedrine are used for a variety of medical purposes due to their sympathomimetic effect. They used to be z. B. is often used against the symptoms of bronchial asthma , to decongest the nasal mucous membranes in the case of colds and in ophthalmology as a substitute for atropine . However, the risk / benefit ratio is considered to be unfavorable, which is why both substances are hardly needed anymore.

Ephedrine is still occasionally used today to treat hypotension and the sleeping sickness narcolepsy . Because it is chemically closely related to deoxyephedrine (methamphetamine), it can easily be used to make this illicit drug . Therefore, its levy is now strictly regulated in almost all countries.

history

Nagai Nagayoshi first isolated pure ephedrine from Ephedra vulgaris in 1885 . In the mid-1920s, ephedrine was rediscovered and characterized through studies by Carl Frederic Schmidt . The E. Merck company then launched it in synthetic form as a racemate under the brand name Ephetonin for the first time as an anti-asthmatic .

Occurrence

Chinese sea puff ( Ephedra sinica ) contains ephedrine in addition to other alkaloids.

Ephedrine in bottles

A well-known natural source of ephedrine is the seaweed variety Ephedra sinica . Its use as "Mahuang" ( 麻黃 ) in Chinese medicine can look back on a very long tradition. The circulatory strengthening effect was already quoted in " Pen-Tsao-Kang-Mu ".

Many other of the 45 or so known species of the Ephedraceae plant family also contain alkaloids that have an effect on the cardiovascular system. The two main alkaloids are ephedrine and pseudoephedrine . These make up 70–99% of the total alkaloid content. The ephedrine content is between 0% and 90% of the total alkaloid content, the pseudoephedrine content between 0.1 and 99%.

pharmacology

Ephedrine is an indirect sympathomimetic with a weaker but longer-lasting effect than the body's own stress hormone adrenaline . It works like this as a direct adrenoceptor - agonist blood pressure enhancing, heart stimulant, bronchi and widening appetite retardant. Because of this spectrum of activity, it is used in drugs against hypotension, chronic bronchitis , asthma attacks and to reduce the swelling of the mucous membranes in the case of colds and as a component of appetite suppressants.

Ephedrine releases norepinephrine and thus leads to an increase in adrenergic transmission . Since it has no hydroxyl groups on the phenyl ring , it can cross the blood-brain barrier (although not as efficiently as amphetamine or methamphetamine ). The usual dose is 25–50 mg; Doses over 50 mg can already lead to unpleasant side effects. The plasma half-life is approximately 3–6 hours.

Ephedrine reduces the rate of protein breakdown and presumably also increases protein synthesis . The increased body temperature results in a slightly increased need for resting energy in the body. A euphoric and aphrodisiac effect is also possible, but this is often associated with erectile dysfunction . An increase in physical performance could not be proven in studies for taking ephedrine alone, but some publications describe an increase in performance when combining ephedrine with caffeine.

In the event of an overdose, the side effects are manifold: restlessness, anxiety , nausea , insomnia , tremor , rapid pulse , sweating, difficulty breathing, confusion , hallucinations , delirium , headache and rarely cramps .

Legal position

Ephedrine and pseudoephedrine can be used as the base for the synthesis of the narcotic methamphetamine ( crystal meth ). Therefore, they are considered to be drug precursors requiring monitoring in the European Union . Dealing with them is therefore severely restricted in Germany by the Basic Substance Monitoring Act under threat of punishment. The product metamfetamine is recorded in Germany in Annex II to the Narcotics Act , so that trading with it and any possession is punishable.

Because of its appetite-suppressing and subjectively performance-enhancing effects, ephedrine ("Ephis") is often used as a doping agent, often in combination with caffeine and acetylsalicylic acid (also known as the ECA stack ). Ephedrine is one of the substances that are prohibited in connection with sports competitions.

In many countries, drugs containing ephedrine have been withdrawn from the market, for example to stimulate car drivers. The substance can be replaced by other active ingredients, whereby use for non-medical purposes can be prevented. In Germany, a combination preparation called Vencipon N was on the market, which contained 10 mg, a dose that was supposed to curb the appetite in order to support diets with medication. It was used as a stimulant in doses of around 50-70 mg. This preparation was therefore also withdrawn from the market. The cold remedy Wick MediNait contains a low concentration of ephedrine (20.7 mg per 100 ml) as a non-prescription drug.

Until 2001, ephedrine preparations were freely available in German pharmacies. Thereafter, free access was denied because these preparations were mainly purchased for non-medical use as appetite suppressants or intoxicants. Ephedra herb is also only available in German pharmacies with a prescription. Since a change in the Drug Law AMG from 1 April 2006 ephedrine-containing substances (incl. Parts of plants) require a prescription.

Driving a motor vehicle under the influence of ephedrine can constitute a criminal offense under Section 316 StGB, provided that it can be proven that the driver is unable to drive.

Manufacture and extraction

The precursor phenylacetylcarbinol is formed during the microbial acylation of benzaldehyde . The further steps are condensation of the phenylacetylcarbinol with methylamine and the subsequent catalytic reduction to ephedrine. In this way almost only the optically active L - (-) - form of the ephedrine arises .

However, the active ingredient can also be obtained from various types of ephedra , such as B. Ephedra distachya or Ephedra sinica . A production can be carried out similar to the production of caffeine from parts of plants by extraction .

Analytics

For the reliable qualitative and quantitative determination of ephedrine, the coupling of gas chromatography and HPLC with mass spectrometry is used after appropriate sample preparation . Derivatizations are often used for gas chromatographic evidence . The determination by means of HPLC can usually also be carried out without derivatization. This analysis is also suitable for the determination of ephedrine in food supplements.

Trade names

• Various generics, caniphedrine (CH, vet.)
• Helopyrin (A)

Web links

Commons : Ephedrine  - Collection of Images

Wiktionary: Ephedrine  - explanations of meanings, word origins, synonyms, translations

• Ephedrine . In: Erowid . (English)

Individual evidence

1. ↑ ^{a b c d} Entry on ephedrine in the GESTIS substance database of the IFA , accessed on February 1, 2016(JavaScript required) .
2. ↑ ^{a b c d} Entry on ephedrine. In: Römpp Online . Georg Thieme Verlag, accessed on March 5, 2011.
3. ^ ^{A b c d} Royal Pharmaceutical Society (Ed.): Clarke's Analysis of Drugs and Poisons FOURTH EDITION . Pharmaceutical Press, London / Chicago 2011, ISBN 978-0-85369-711-4 .
4. ↑ ^{a b} Entry on ephedrine in the ChemIDplus database of the United States National Library of Medicine (NLM) .
5. ↑ Entry on Ephedrine in the Classification and Labeling Inventory of the European Chemicals Agency (ECHA), accessed on February 1, 2016. Manufacturers or distributors can expand the harmonized classification and labeling .
6. ^ Albert Gossauer: Structure and reactivity of biomolecules , Verlag Helvetica Chimica Acta, Zurich, 2006, p. 248, ISBN 978-3-906390-29-1 .
7. ↑ Annual Report Physiology and Experimental Pharmacology. Springer, Volume 9, Issue 1, 1930, p. 831.
8. ↑ Ephedrine-Ephetonin (From the story of a forgotten and rediscovered remedy). ( Memento of the original from September 8, 2016 in the Internet Archive ) Info: The archive link was automatically inserted and not yet checked. Please check the original and archive link according to the instructions and then remove this notice. Short documentary, 1928/1929. 
9. ^ H. Kreitmair: Chemisches Zentralblatt, Volume 98, 1927, p. 1847.
10. ↑ H. Kreitmair: The effect of ephedrine Merck on the experimentally generated asthmatic attack. In: Klin Wochenschr . Volume 5, Number 51, 1926, pp. 2403-2404.
11. ↑ 中藥材 圖像 數據庫 - 麻黃 Mahuang. In: libproject.hkbu.edu.hk. Retrieved November 1, 2015 (Chinese). 
12. ↑ Bernd Schäfer: Natural substances in the chemical industry , spectrum Akademischer Verlag, 2007, pp. 376–377, ISBN 978-3-8274-1614-8 .
13. ↑ ^{a b} Federal Institute for Risk Assessment : Risk Assessment of Plants and Herbal Preparations, Ephedra spp. (Sea crow species). Pp. 223–239, Berlin 2012 (PDF; 1.8 MB).
14. ^ Wolf-Dieter Müller-Jahncke , Christoph Friedrich , Ulrich Meyer: Medicinal history . 2., revised. and exp. Ed. Wiss. Verl.-Ges, Stuttgart 2005, ISBN 978-3-8047-2113-5 , pp. 167 .
15. ^ Entry on Ephedrine in the DrugBank of the University of Alberta .
16. ↑ MD Vukovich, R. Schoorman, C. Heilman, P. Jacob, NL Benowitz: Caffeine-herbal ephedra combination increases resting energy expenditure, heart rate and blood pressure. In: Clinical and experimental pharmacology & physiology. Volume 32, number 1-2, 2005 Jan-Feb, pp. 47-53, doi : 10.1111 / j.1440-1681.2005.04152.x . PMID 15730434 .
17. ↑ Chee Chen, Ayu Muhamad, Foong Ooi: Herbs in exercise and sports. In: Journal of Physiological Anthropology. 31, 2012, p. 4, doi : 10.1186 / 1880-6805-31-4 , PMC 3375032 (free full text)
18. ^ Michael E. Powers: Ephedra and Its Application to Sport Performance: Another Concern for the Athletic Trainer? In: J Athl Train. 2001 Oct-Dec; 36 (4): pp. 420-424. PMC 155439 (free full text)
19. ↑ a substance listed in Annex I (Category 1) of Regulation (EC) No. 273/2004 of the European Parliament and of the Council of February 11, 2004 on drug precursors , for the purpose of Article 1
20. ↑ § 29 ff. Narcotics Act with Annex II to the BtMG, so not prescribable
21. ^ The World Anti-Doping Code: The 2009 Prohibited List, International Standard. ( Memento from July 19, 2014 in the Internet Archive ) (PDF; 177 kB) pp. 7–8.
22. ^ R. Hutterer: Fit in Inorganik: The exam training for physicians, chemists and biologists. Springer, 2012, ISBN 3-834-81901-8 limited preview in the Google book search
23. ↑ The Medical World. FK Schattauer-Verlag, 1956, pp. 130f.
24. ↑ T. Geschwinde: Drugs: Market forms and modes of action. 5th edition, Springer, 2007, ISBN 3-540-43542-5 , p. 445. Restricted preview in the Google book search
25. ↑ T. Herdegen: Short textbook pharmacology and toxicology. Georg Thieme Verlag, 2010, ISBN 3-13-152952-0 , p. 369. Restricted preview in the Google book search.
26. ↑ Ingredients of Wick Medinait juice. In: apotheken-umschau.de , accessed on November 6, 2017.
27. ^ Ordinance on the reorganization of the prescription requirement for medicinal products (AMVVNV). V. v. December 21, 2005 ( Federal Law Gazette I p. 3632 ); Valid from January 1, 2006.
28. ↑ Mohamed KM, Bakdash A: Comparison of 3 Derivatization Methods for the Analysis of Amphetamine-Related Drugs in Oral Fluid by Gas Chromatography-Mass Spectrometry. , Anal Chem Insights. 2017 Aug 24; 12: 1177390117727533. PMID 28890655
29. ↑ Gray N, Heaton J, Musenga A, Cowan DA, Plumb RS, Smith NW: Comparison of reversed-phase and hydrophilic interaction liquid chromatography for the quantification of ephedrines using medium-resolution accurate mass spectrometry. , J Chromatogr A. 2013 May 10; 1289: 37-46, PMID 23570855
30. ↑ Kojima A, Nishitani Y, Sato M, Kageyama S, Dohi M, Okano M: Comparison of urine analysis and dried blood spot analysis for the detection of ephedrine and methylephedrine in doping control. , Drug Test Anal. 2016 Feb; 8 (2): 189-98, PMID 25869885
31. ↑ Zhang J, Zhang Y, Wang Y: Validated quantification method for five ephedrines in dietary supplements using LC-MS / MS: Application to 503 cases. , J Chromatogr B Analyt Technol Biomed Life Sci. 2016 Dec 15; 1039: 1-7, PMID 27846433

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