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-Ephedrine_molecule_from_xtal_ball.png) (−)-(1R,2S)-ephedrine chemical structure (top) and ball-and-stick model (bottom) | |
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| Pronunciation | /ɪˈfɛdrɪn/ ⓘ or/ˈɛfɪdriːn/ |
| Trade names | Akovaz, Corphedra, Emerphed, others |
| Other names | (−)-Ephedrine; (1R,2S)-Ephedrine; (1R,2S)-β-Hydroxy-N-methylamphetamine; (1R,2S)-β-Hydroxy-N-methyl-α-methyl-β-phenethylamine |
| AHFS/Drugs.com | Ephedrine:Monograph HCl:Monograph Sulfate:Monograph |
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| Routes of administration | By mouth,intravenous (IV),intramuscular (IM),subcutaneous (SC) |
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| Bioavailability | 88%[6] |
| Protein binding | ~24–29% (5–10% toalbumin)[7][8][9] |
| Metabolism | Largely unmetabolized[6][10] |
| Metabolites | •Norephedrine[6][10] |
| Onset of action | Oral: 15–60 minutes[11] IMTooltip Intramuscular injection: 10–20 minutes[11] IVTooltip Intravenous administration: Rapid[11] |
| Eliminationhalf-life | 6 hours[6] |
| Duration of action | Oral: 2–4 hours IV/IM: 60 minutes |
| Excretion | Mainlyurine (60% unchanged)[6] |
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| ECHA InfoCard | 100.005.528 |
| Chemical and physical data | |
| Formula | C10H15NO |
| Molar mass | 165.236 g·mol−1 |
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Ephedrine is acentral nervous system (CNS)stimulant andsympathomimetic agent that is often used to preventlow blood pressure duringanesthesia.[11] It has also been used forasthma,narcolepsy, andobesity but is not the preferred treatment.[11] It is of unclear benefit innasal congestion.[11] It can be takenby mouth or byinjection into a muscle,vein, orjust under the skin.[11] Onset with intravenous use is fast, while injection into a muscle can take 20 minutes, and by mouth can take an hour for effect.[11] When given by injection, it lasts about an hour, and when taken by mouth, it can last up to four hours.[11]
Commonside effects includetrouble sleeping,anxiety,headache,hallucinations,high blood pressure,fast heart rate,loss of appetite, andurinary retention.[11] Serious side effects includestroke andheart attack.[11] While probably safe inpregnancy, its use in this population is poorly studied.[12][13] Use duringbreastfeeding is not recommended.[13] Ephedrine works byinducing the release of norepinephrine and hence indirectly activating theα- andβ-adrenergic receptors.[11] Chemically, ephedrine is asubstituted amphetamine and is the (1R,2S)-enantiomer ofβ-hydroxy-N-methylamphetamine.[14]
Ephedrine was firstisolated in 1885 and came into commercial use in 1926.[15][16] It is on theWorld Health Organization's List of Essential Medicines.[17] It is available as ageneric medication.[11] It can normally be found in plants of theEphedra genus.[11][18]Over-the-counterdietary supplements containing ephedrine are illegal in the United States,[11] with the exception of those used intraditional Chinese medicine, where its presence is noted bymá huáng.[11][18]
Ephedrine is a non-catecholaminesympathomimetic with cardiovascular effects similar to those ofadrenaline (epinephrine): increased blood pressure, heart rate, and contractility. Likepseudoephedrine, it is abronchodilator, with pseudoephedrine having considerably less effect.[19][20]
Ephedrine may decreasemotion sickness, but it has mainly been used to decrease the sedating effects of other medications used for motion sickness.[21][22]
Ephedrine is also found to have quick and long-lasting responsiveness incongenital myasthenic syndrome in early childhood and also even in adults with a novelCOLQ mutation.[23]
Ephedrine is administered by intravenous boluses. Redosing usually requires increased doses to offset the development oftachyphylaxis, which is attributed to the depletion of catecholamine stores.[19]
Ephedrine promotes modest short-termweight loss,[24] specifically fat loss, but its long-term effects are unknown.[25] In mice, ephedrine is known to stimulatethermogenesis in thebrown adipose tissue, but because adult humans have only small amounts of brown fat, thermogenesis is assumed to take place mostly in theskeletal muscle. Ephedrine also decreasesgastric emptying.Methylxanthines such ascaffeine andtheophylline have a synergistic effect with ephedrine for weight loss. This led to the creation and marketing of compound products.[26] One of them, known as theECA stack, contains ephedrine with caffeine and aspirin. It is a popular supplement taken bybodybuilders seeking to cut body fat before a competition.[27]A 2021 systematic review found that ephedrine led to a 2 kilograms (4.4 lb) weight loss greater than placebo, raisedheart rate, and reducedLDL and raisedHDL, with no statistically significant difference inblood pressure.[28]
Ephedrine is available as aprescription-onlypharmaceutical drug in the form of anintravenoussolution, under brand names including Akovaz, Corphedra, Emerphed, and Rezipres as well as ingeneric forms, in the United States.[29][30] It is also availableover-the-counter in the form of 12.5 and 25 mgoraltablets for use as abronchodilator and as a 0.5% concentrationnasal spray for use as adecongestant.[30] The drug is additionally available incombination withguaifenesin in the form of oral tablets and liquids.[30] Ephedrine is provided as thehydrochloride orsulfatesalt in pharmaceutical formulations.[29][30]
Ephedrine should not be used in conjunction with certainantidepressants, namelynorepinephrine–dopamine reuptake inhibitors (NDRIs), as this increases the risk of symptoms due to excessive serum levels of norepinephrine.[citation needed]
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 tofluoxetine in that its primary mode of therapeutic action involves norepinephrine and to a lesser degree dopamine, but it also releases someserotonin from presynaptic clefts. It should not be used with ephedrine, as it may increase the likelihood of side effects.[citation needed]
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 during lactation.[31]
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, generalanesthesia with halogenated hydrocarbons (particularlyhalothane), tachyarrhythmias or ventricular fibrillation, or hypersensitivity to ephedrine or other stimulants.[citation needed]
Ephedrine should not be used at any time during pregnancy unless specifically indicated by a qualified physician and only when other options are unavailable.[31]
Ephedrine is a potentially dangerous natural compound; as of 2004[update] the USFood and Drug Administration (FDA) had received over 18,000 reports of adverse effects in people using it.[32]
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[33]
Overdose of ephedrine may result insympathomimeticsymptoms liketachycardia andhypertension.[citation needed]
Ephedrine withmonoamine oxidase inhibitors (MAOIs) likephenelzine andtranylcypromine can result inhypertensive crisis.[citation needed]
| Compound | NETooltip Norepinephrine | DATooltip Dopamine | 5-HTTooltip Serotonin | Ref | ||
|---|---|---|---|---|---|---|
| Dextroamphetamine (S(+)-amphetamine) | 6.6–7.2 | 5.8–24.8 | 698–1765 | [36][37] | ||
| S(–)-Cathinone | 12.4 | 18.5 | 2366 | [38] | ||
| Ephedrine ((–)-ephedrine) | 43.1–72.4 | 236–1350 | >10000 | [36] | ||
| (+)-Ephedrine | 218 | 2104 | >10000 | [36][38] | ||
| Dextromethamphetamine (S(+)-methamphetamine) | 12.3–13.8 | 8.5–24.5 | 736–1291.7 | [36][39] | ||
| Levomethamphetamine (R(–)-methamphetamine) | 28.5 | 416 | 4640 | [36] | ||
| (+)-Phenylpropanolamine ((+)-norephedrine) | 42.1 | 302 | >10000 | [38] | ||
| (–)-Phenylpropanolamine ((–)-norephedrine) | 137 | 1371 | >10000 | [38] | ||
| Cathine ((+)-norpseudoephedrine) | 15.0 | 68.3 | >10000 | [38] | ||
| (–)-Norpseudoephedrine | 30.1 | 294 | >10000 | [38] | ||
| (–)-Pseudoephedrine | 4092 | 9125 | >10000 | [38] | ||
| Pseudoephedrine ((+)-pseudoephedrine) | 224 | 1988 | >10000 | [38] | ||
| Notes: The smaller the value, the more strongly the substance releases the neurotransmitter. See alsoMonoamine releasing agent § Activity profiles for a larger table with more compounds. | ||||||
Ephedrine, asympathomimetic amine, acts on part of thesympathetic nervous system (SNS). The principal mechanism of action relies on its indirect stimulation of theadrenergic receptor system by increasing activation ofα- andβ-adrenergic receptors viainduction of norepinephrine release.[40] The presence of direct interactions with α-adrenergic receptors is unlikely but still controversial.[41][20][42][43]L-ephedrine, and particularly its stereoisomernorpseudoephedrine (which is also present inCatha edulis) has indirectsympathomimetic effects and due to its ability to cross theblood–brain barrier, it is aCNSstimulant similar toamphetamines, but less pronounced, as it releases norepinephrine anddopamine in thebrain.[44]
Theoralbioavailability of ephedrine is 88%.[6] Theonset of action of ephedrine orally is 15 to 60 minutes, viaintramuscular injection is 10 to 20 minutes, and viaintravenous infusion is within seconds.[11]
Itsplasma protein binding is approximately 24 to 29%, with 5 to 10% bound toalbumin.[7][8][9]
Ephedrine is largely notmetabolized.[6]Norephedrine (phenylpropanolamine) is anactive metabolite of ephedrine formed viaN-demethylation.[6][10] About 8 to 20% of an oral dose of ephedrine is demethylated into norephedrine, about 4 to 13% isoxidativelydeaminated intobenzoic acid, and a small fraction is converted into 1,2-dihydroxy-1-phenylpropane.[10]
Ephedrine iseliminated mainly inurine, with 60% (range 53–79%)excreted unchanged.[6][10]
Theelimination half-life of ephedrine is 6 hours.[6] Itsduration of action orally is 2 to 4 hours and via intravenous or intramuscular injection is 60 minutes.[citation needed]
The elimination of ephedrine is dependent on urinarypH.[10]
Ephedrine, or (−)-(1R,2S)-ephedrine, also known as (1R,2S)-β-hydroxy-N-methyl-α-methyl-β-phenethylamine or as (1R,2S)-β-hydroxy-N-methylamphetamine, is asubstituted phenethylamine andamphetaminederivative. It is similar inchemical structure tophenylpropanolamine,methamphetamine, andepinephrine (adrenaline). It differs from methamphetamine only by the presence of ahydroxyl group (–OH). Chemically, ephedrine is analkaloid with aphenethylamine skeleton found in various plants in the genusEphedra (familyEphedraceae). It is most usually marketed as thehydrochloride orsulfatesalt.[45]
It has an experimentallog P of 1.13, while its predicted log P values range from 0.9 to 1.32.[14][6][46] Thelipophilicity of amphetamines is closely related to theirbrain permeability.[47] For comparison to ephedrine, the experimental log P ofmethamphetamine is 2.1,[48] ofamphetamine is 1.8,[49][48] ofpseudoephedrine is 0.89,[50] ofphenylpropanolamine is 0.7,[51] ofphenylephrine is -0.3,[52] and ofnorepinephrine is -1.2.[53] Methamphetamine has high brain permeability,[48] whereas phenylephrine and norepinephrine areperipherally selective drugs.[54][55] The optimal log P for brain permeation and central activity is about 2.1 (range 1.5–2.7).[56]
Ephedrine hydrochloride has a melting point of 187−188 °C.[57]
Theracemic form of ephedrine isracephedrine ((±)-ephedrine;dl-ephedrine; (1RS,2SR)-ephedrine).[58] Astereoisomer of ephedrine ispseudoephedrine.[58]Derivatives of ephedrine includemethylephedrine (N-methylephedrine),etafedrine (N-ethylephedrine),cinnamedrine (N-cinnamylephedrine), andoxilofrine (4-hydroxyephedrine).[58]Analogues of ephedrine includephenylpropanolamine (norephedrine) andmetaraminol (3-hydroxynorephedrine).[58]
The presence of anN-methyl group decreases binding affinities at α-adrenergic receptors, compared with norephedrine. Ephedrine, though, binds better thanN-methylephedrine, which has an additional methyl group at the nitrogen atom. Also, thesteric orientation of the hydroxyl group is important for receptor binding and functional activity.[42]
Ephedrine exhibitsoptical isomerism and has twochiral centres, giving rise to fourstereoisomers. By convention, the pair ofenantiomers 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.
The isomer which is marketed is (−)-(1R,2S)-ephedrine.[59]
In the outdatedD/L system (+)-ephedrine is also referred to asD-ephedrine and (−)-ephedrine asL-ephedrine (in which case, in theFisher projection, thephenyl ring is drawn at the bottom).[59][60]
Often, theD/L system (withsmall caps) and the d/l system (withlower-case) are confused. The result is that the levorotary l-ephedrine is wrongly namedL-ephedrine and the dextrorotary d-pseudoephedrine (the diastereomer) wronglyD-pseudoephedrine.
TheIUPAC names of the two enantiomers are (1R,2S)- respectively (1S,2R)-2-methylamino-1-phenylpropan-1-ol. A synonym iserythro-ephedrine.
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 commercialimmunoassay 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 currentWorld Anti-Doping Agency (WADA) limit for ephedrine in an athlete's urine is 10 μg/mL.[61][62][63][64]
Ephedrine in its natural form, known asmáhuáng (麻黄) intraditional Chinese medicine, has been documented in China since theHan dynasty (206 BC – 220 AD) as anantiasthmatic and stimulant.[65] In traditional Chinese medicine,máhuáng has been used as a treatment for asthma and bronchitis for centuries.[66]
In 1885, the chemical synthesis of ephedrine was first accomplished by Japaneseorganic chemistNagai Nagayoshi based on his research ontraditional Japanese andChinese herbal medicines.
The industrial manufacture of ephedrine in China began in the 1920s, whenMerck 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.[67]
Ephedrine was first introduced for medical use in theUnited States in 1926.[32]
It was introduced in 1948 inVicks Vatronol nose drops (now discontinued) which contained ephedrine sulfate as the active ingredient for rapid nasal decongestion.
Ephedrine is thegeneric name of the drug and itsBANTooltip British Approved Name.[58][45][68] ItsDCFTooltip Dénomination Commune Française isephédrine while itsDCITTooltip Denominazione Comune Italiana isefedrina.[45][68] In the case of thehydrochloridesalt, its generic name isephedrine hydrochloride and this is itsUSANTooltip United States Adopted Name,BANMTooltip British Approved Name, andJANTooltip Japanese Accepted Name.[58][45][68] In the case of thesulfate salt, its generic name isephedrine sulfate orephedrine sulphate and the former is itsUSANTooltip United States Adopted Name while the latter is itsBANMTooltip British Approved Name.[58][45][68] A synonym of ephedrine sulfate isisofedrol.[58] These names all refer to the (1R,2R)-enantiomer of ephedrine.[58][45] Theracemic form of ephedrine is known asracephedrine and this is itsINNTooltip International Nonproprietary Name andBANTooltip British Approved Name, while the hydrochloride salt of the racemic form isracephedrine hydrochloride and this is itsUSANTooltip United States Adopted Name.[69]
As aphenethylamine, ephedrine has a similar chemical structure toamphetamines and is amethamphetamineanalog having the methamphetamine structure with ahydroxyl group at theβ position. Because of ephedrine's structural similarity to methamphetamine, it can be used to create methamphetamine usingchemical reduction in which ephedrine's hydroxyl group is removed; this has made ephedrine a highly sought-after chemical precursor in theillicit manufacture ofmethamphetamine.
The most popular method for reducing ephedrine to methamphetamine is similar to theBirch reduction, in that it usesanhydrous ammonia andlithium metal in the reaction. The second-most popular method uses redphosphorus andiodine in the reaction with ephedrine. Moreover, ephedrine can be synthesized intomethcathinone via simpleoxidation. As such, ephedrine is listed as a table-I precursor under theUnited Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances.[70]
Ephedrine has been used as aperformance-enhancing drug inexercise andsports.[41][71][72][73] It can increaseheart rate,blood pressure, andcardiac contractility as well as act as apsychostimulant.[41] Ephedrine is often used in combination withcaffeine for performance-enhancing purposes.[72][73]
Inchemical synthesis, ephedrine is used in bulk quantities as achiral auxiliary group.[74]
Insaquinavir synthesis, the half-acid is resolved as its salt with l-ephedrine.
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.[75] Ephedrine is still sold as an oral nasal decongestant[76] 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.[77]
In 1997, theFDA 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.[78] 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."[79] In 2004, the FDA created a ban on ephedrine alkaloids marketed for reasons other than asthma, colds, allergies, other disease, or traditional Asian use.[80] On April 14, 2005, theU.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,[81] but on August 17, 2006, theU.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.[82] Furthermore, ephedrine is banned by the NCAA, MLB, NFL, and PGA.[83] 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.
TheHouse passed theCombat Methamphetamine Epidemic Act of 2005 as an amendment to the renewal of theUSA PATRIOT Act. Signed into law by PresidentGeorge W. Bush on March 6, 2006, the act amended theUS Code (21 USC 830) concerning the sale of products containing ephedrine and the closely related drugpseudoephedrine. Both substances are used asprecursors in theillicit production ofmethamphetamine, and to discourage that use the federal statute included the following requirements for merchants who sell these 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.
Ephedrine and allEphedra species that contain it are considered Schedule 4 substances under thePoisons 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 thePoisons Standard.
In South Africa, ephedrine was moved to schedule 6 on 27 May 2008,[84] which makes pure ephedrine tablets prescription only. Pills containing ephedrine up to 30 mg per tablet in combination with other medications are still available OTC, schedule 1 and 2, for sinus, head colds, and influenza.
Ephedrine was freely available in pharmacies in Germany until 2001. Afterward, 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.[85]
Ephedrine is obtained from the plantEphedra sinica and other members of the genusEphedra, 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.[86]
Most of the l-ephedrine produced today for official medical use is made synthetically as the extraction and isolation process fromE. sinica is tedious and no longer cost-effective.[87][unreliable source?]
Ephedrine was long thought to come from modifying the amino acidL-phenylalanine.[90]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.[90] A new pathway proposed suggests that phenylalanine first formscinnamoyl-CoA via the enzymesphenylalanine ammonia-lyase and acyl CoA ligase.[88] The cinnamoyl-CoA is then reacted with a hydratase to attach the alcohol functional group. The product is then reacted with a retro-aldolase, formingbenzaldehyde. Benzaldehyde reacts withpyruvic acid to attach a 2-carbon unit. This product then undergoes transamination and methylation to form ephedrine and its stereoisomer, pseudoephedrine.[89]
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),4 thereby enabling rapid and extensive transport across the blood–brain barrier.19
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
Defendants-appellants, 459 F.3d 1033 (10th Cir. 2006)
