Ephedrine
Clinical data | |
---|---|
Pronunciation | /ɪˈfɛdrɪn/ ⓘ or /ˈɛfɪdriːn/ |
Trade names | Akovaz, Corphedra, Emerphed, others |
AHFS/Drugs.com | Ephedrine: Monograph HCl: Monograph Sulfate: Monograph |
Pregnancy category |
|
subcutaneous (SC) | |
ATC code | |
Legal status | |
Legal status | |
Pharmacokinetic data | |
Bioavailability | 85% |
Metabolism | Minimal liver |
Onset of action | IV (seconds), IM (10 min to 20 min), by mouth (15 min to 60 min)[6] |
Elimination half-life | 3 h to 6 h |
Duration of action | IV/IM (60 min), by mouth (2 h to 4 h) |
Excretion | 22% to 99% (urine) |
Identifiers | |
| |
JSmol) | |
| |
| |
(what is this?) (verify) |
Ephedrine is a
Common side effects include trouble sleeping, anxiety, headache, hallucinations, high blood pressure, fast heart rate, loss of appetite, and urinary retention.[6] Serious side effects include stroke and heart attack.[6] While likely safe in pregnancy, its use in this population is poorly studied.[7][8] Use during breastfeeding is not recommended.[8] Ephedrine works by increasing the activity of the α and β adrenergic receptors.[6]
Ephedrine was first isolated in 1885 and came into commercial use in 1926.
Medical use
Ephedrine is a non-
Ephedrine may decrease motion sickness, but it has mainly been used to decrease the sedating effects of other medications used for motion sickness.[14][15]
Ephedrine is also found to have quick and long-lasting responsiveness in congenital myasthenic syndrome in early childhood and also even in the adults with a novel COLQ mutation.[16]
Ephedrine is administered by intravenous boluses. Redosing usually requires increased doses to offset the development of tachyphylaxis, which is attributed to the depletion of catecholamine stores.[12]
Weight loss
Ephedrine promotes modest short-term
Recreational use
As a
The most popular method for reducing ephedrine to methamphetamine is similar to the
Detection of use
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 World Anti-Doping Agency (WADA) limit for ephedrine in an athlete's urine is 10 µg/mL.[23][24][25][26]
Contraindications
Ephedrine should not be used in conjunction with certain antidepressants, namely
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 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 side effects.
Ephedrine should be used with caution in patients with inadequate fluid replacement, impaired adrenal function,
Ephedrine should not be used at any time during pregnancy unless specifically indicated by a qualified physician and only when other options are unavailable.[27]
Adverse effects
Ephedrine is a potentially dangerous natural compound; as of 2004[update] the US Food and Drug Administration had received over 18,000 reports of adverse effects in people using it.[28]
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:[29]
- Cardiovascular: angina pectoris, vasoconstriction with hypertension
- 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
- delusions, formication (may be possible, but lacks documented evidence) paranoia, hostility, panic, agitation
- dyspnea, pulmonary edema
- Miscellaneous: dizziness, headache, tremor, hyperglycemic reactions, dry mouth
Other uses
In chemical synthesis, ephedrine is used in bulk quantities as a chiral auxiliary group.[30]
In saquinavir synthesis, the half-acid is resolved as its salt with l-ephedrine.
Chemistry and nomenclature
Ephedrine is a
It is most usually marketed as the hydrochloride or sulfate salt.Ephedrine exhibits
The isomer which is marketed is (−)-(1R,2S)-ephedrine.[33]
Ephedrine hydrochloride has a melting point of 187−188 °C.[34]
In the outdated
Often, the D/L system (with
The
Sources
Agricultural
Ephedrine is obtained from the plant Ephedra sinica and other members of the genus Ephedra, from which the name of the substance is derived. 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, or about ten times the amount used in traditional Chinese medicine.[38]
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.[39][unreliable source?]
Biosynthetic
Ephedrine was long thought to come from modifying the amino acid L-phenylalanine.[40] 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.[40] A new pathway proposed suggests that phenylalanine first forms cinnamoyl-CoA via the enzymes phenylalanine ammonia-lyase and acyl CoA ligase.[36] 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.[37]
Mechanism of action
Ephedrine, a
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 nitrogen atom. Also the steric orientation of the hydroxyl group is important for receptor binding and functional activity.[41]
- Compounds with decreasing α-receptor affinity
-
Norephedrine
-
Ephedrine
-
N-Methylephedrine
History
Asia
Ephedrine in its natural form, known as máhuáng (麻黄) in traditional Chinese medicine, has been documented in China since the Han dynasty (206 BC – 220 AD) as an antiasthmatic and stimulant.[44] In traditional Chinese medicine, máhuáng has been used as a treatment for asthma and bronchitis for centuries.[45]
In 1885, the chemical synthesis of ephedrine was first accomplished by Japanese
The industrial manufacture of ephedrine in China began in the 1920s, when Merck began marketing and selling the drug as ephetonin. Ephedrine exports from China to the West grew from 4 to 216 tonnes between 1926 and 1928.[46]
Western medicine
Introduced in 1948 Vicks Vatronol nose drops (now discontinued) contained ephedrine sulfate as the active ingredient for rapid nasal decongestion.
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.[47] Ephedrine is still sold as an oral nasal decongestant[48] in 8 mg pills as a natural health product, with a limit of 0.4 g (400 mg) per package, the limit established by the Controlled Drugs and Substances Act as it is considered as Class A Precursor.[49]
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.[50] 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."[51] In 2004, the FDA created a ban on ephedrine alkaloids marketed for reasons other than asthma, colds, allergies, other disease, or traditional Asian use.[52] 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,[53] 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.[54] Furthermore, ephedrine is banned by the NCAA, MLB, NFL, and PGA.[55] 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
- 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 to a single purchaser, without regard to the number of transactions
- Monthly sales to a single purchaser 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 7.5 g.
As a pure herb or tea, má huáng, containing ephedrine, is still sold legally in the US. The law restricts/prohibits its being sold as a dietary supplement (pill) or as an ingredient/additive to other products, like diet pills.
Australia
Ephedrine and all Ephedra species which contain it are considered Schedule 4 substances under the Poisons Standard. A Schedule 4 drug is considered a Prescription Only Medicine, or Prescription Animal Remedy – Substances, the use or supply of which should be by or on the order of persons permitted by State or Territory legislation to prescribe and should be available from a pharmacist on prescription under the Poisons Standard.
South Africa
In South Africa, ephedrine was moved to schedule 6 on 27 May 2008,[56] which makes pure ephedrine tablets prescription only. Pills containing ephedrine up to 30mg per tablet in combination with other medications are still available OTC, schedule 1 and 2, for sinus, head colds and influenza.
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.[57]
References
- ^ Anvisa (2023-03-31). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 2023-04-04). Archived from the original on 2023-08-03. Retrieved 2023-08-15.
- ^ "Ephedrine Hydrochloride 15mg Tablets Summary of Product Characteristics (SmPC)". emc. Retrieved 8 October 2020.
- ^ "Ephedrine Nasal Drops 1.0% Summary of Product Characteristics (SmPC)". emc. 11 March 2015. Archived from the original on 24 October 2020. Retrieved 8 October 2020.
- ^ "Akovaz- ephedrine sulfate injection". DailyMed. 16 April 2020. Retrieved 8 October 2020.
- ^ "Title 21: Food And Drugs Part 341—Cold, Cough, Allergy, Bronchodilator, And Antiasthmatic Drug Products For Over-The-Counter Human Use". Electronic Code of Federal Regulations. Retrieved 8 October 2020.
- ^ a b c d e f g h i j k l m n "Ephedrine". The American Society of Health-System Pharmacists. Archived from the original on 2017-09-09. Retrieved 8 September 2017.
- ISBN 9781608317080. Archivedfrom the original on 2017-09-08.
- ^ a b "Ephedrine Pregnancy and Breastfeeding Warnings". Archived from the original on 5 August 2017. Retrieved 8 October 2017.
- ISBN 9781439854266. Archivedfrom the original on 2017-09-08.
- ISBN 9783527607495.
- hdl:10665/345533. WHO/MHP/HPS/EML/2021.02.
- ^ ISBN 978-1-260-47379-7.
- ^ PMID 687500.
- ISBN 978-0-1997-4790-0.
- ISBN 978-1437710694.
- S2CID 266124150.
- PMID 12672771.
- PMID 15867902.
- ISBN 978-0-8247-4773-2. Archivedfrom the original on 2014-06-26.
- S2CID 1966020.
- PMID 34832979.
- ^ Microsoft Word – RedListE2007.doc Archived February 27, 2008, at the Wayback Machine
- ^ "S6. Stimulants | List of Prohibited Substances and Methods". Archived from the original on 2015-10-23. Retrieved 2015-10-19.
- S2CID 23359388.
- ^ WADA. The World Anti-Doping Code, World Anti-Doping Agency, Montreal, Canada, 2010. url Archived 2013-09-11 at the Wayback Machine
- ^ Baselt R (2008). Disposition of Toxic Drugs and Chemicals in Man (8th ed.). Foster City, CA: Biomedical Publications. pp. 542–544.
- ^ a b Mayne Pharma. Ephedrine sulfate injection DBL (Approved Product Information). Melbourne: Mayne Pharma; 2004
- PMID 20685002.
- ISBN 0-85369-587-3
- PMID 17474779.
- ^ a b "EPHEDrine". Merck Manuals. January 2010. Archived from the original on 24 March 2011.
- S2CID 41083359.
- ^ ISBN 978-0-85369-210-2.
- ^ Budavari S (ed.). The Merck Index: An encyclopedia of chemicals, drugs, and biologicals (12th ed.). Whitehouse Station: Merck.
- PMID 14301006.
- ^ S2CID 28159196.
- ^ ISSN 0002-7863.
- ^ Long C (15 January 2007). "Chinese medicine's great waste of resources". Archived from the original on 30 May 2016. Retrieved 9 May 2016.
- ^ "Chemically Synthesized Ephedrine Put into Mass Production in China". November 5, 2001. Archived from the original on June 29, 2011.
- ^ .
- ^ S2CID 86429875.
- PMID 14570629.
- S2CID 40626692.
- ISBN 978-0-12-496736-6.
- ISBN 0-7216-5485-1.
- ISBN 978-0-226-14905-9.
- ^ "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.
- PMID 25532441.
- ^ Legislative Services Branch (2021-03-18). "Consolidated federal laws of canada, Controlled Drugs and Substances Act". laws-lois.justice.gc.ca. Archived from the original on 2021-07-30. Retrieved 2021-07-30.
- ^ Federal Register: June 4, 1997 (Volume 62, Number 107): Dietary Supplements Containing Ephedrine Alkaloids; Proposed Rule
- ^ Federal Register: April 3, 2000 (Volume 65, Number 64): Dietary Supplements Containing Ephedrine Alkaloids; Withdrawal in Part
- ^ 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
- ^ "Nutraceutical Corporation; Solaray, Inc., Plaintiffs-appellees, v. Andrew Von Eschenbach, Acting Commissioner, U.S. Food and Drug Administration; United States Food and Drug Administration; Michael O. Leavitt, Secretary of the Department of Health and Human Services; Department of Health and Human Services; United States of America" (PDF). Archived from the original (PDF) on 2011-07-10. Retrieved 2010-07-01.
Defendants-appellants, 459 F.3d 1033 (10th Cir. 2006)
- ^ Nutraceutical Corporation; Solaray, Inc. Plaintiffs-Appellees vs. Andrew Von Eschenbach, Acting Commissioner, US.. Food and Drug Administration; United States Food and Drug Administration; Michael O. Leavitt, Secretary of the Department of Health and Human Services; Department of Health and Human Services; United States of America, We find that the FDA correctly followed the congressional directive to analyze the risks and benefits of EDS in determining that there is no dosage level of EDS acceptable for the market. (United States Court of Appeals Tenth Circuit August 17, 2006).[dead link]
- ^ "Sport Drug Testing – Drug Programs & Policy – Athletics". Archived from the original on 2011-02-10. Retrieved 2011-03-21.
- ^ "Rescheduling of Medicines that Contain Ephedrine". Archived from the original on 2009-06-28. Retrieved 2009-04-18.
- ^ Verordnung zur Neuordnung der Verschreibungspflicht von Arzneimitteln (AMVVNV). Archived 2014-05-17 at the Wayback Machine V. v. 21. Dezember 2005 BGBl. I S. 3632; Geltung ab 1. Januar 2006.