Ephedrine is a central nervous system (CNS) stimulant and sympathomimetic agent that is often used to prevent hypotension during anesthesia.[ It is of unclear benefit in nasal congestion.][ It can be taken by mouth or by intramuscular, intravenous, or just under the skin.][ Onset with intravenous use is fast, while injection into a muscle can take 20minutes, and by mouth can take an hour for effect.][ When given by injection, it lasts about an hour, and when taken by mouth, it can last up to four hours.][
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Common include insomnia, anxiety, headache, , hypertension, tachycardia, loss of appetite, and urinary retention.[ Serious side effects include stroke and heart attack.][ While probably safe in pregnancy, its use in this population is poorly studied.][ Ephedrine works by inducing the release of norepinephrine and hence indirectly activating the α- and β-adrenergic receptors.][ Chemically, ephedrine is a substituted amphetamine and is the (1 R,2 S)-enantiomer of β-hydroxy- N-methylamphetamine.]
Ephedrine was first chemical isolate in 1885 and came into commercial use in 1926.[ It can normally be found in plants of the Ephedra genus.]
Medical uses
Ephedrine is a non-catecholamine sympathomimetic with cardiovascular effects similar to those of adrenaline (epinephrine): increased blood pressure, heart rate, and contractility. Like pseudoephedrine, it is a bronchodilator, with pseudoephedrine having considerably less effect.
Ephedrine may decrease motion sickness, but it has mainly been used to decrease the sedating effects of other medications used for motion sickness.
Ephedrine is also found to have quick and long-lasting responsiveness in congenital myasthenic syndrome in early childhood and also even in adults with a novel COLQ mutation.
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.[
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Weight loss
Ephedrine promotes modest short-term weight loss,
Available forms
Ephedrine is available as a prescription-only pharmaceutical drug in the form of an intravenous solution, under brand names including Akovaz, Corphedra, Emerphed, and Rezipres as well as in generic drug, in the United States.
Contraindications
Ephedrine should not be used in conjunction with certain Antidepressant, namely norepinephrine–dopamine reuptake inhibitors (NDRIs), as this increases the risk of 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 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, hypoxia, hypercapnia, acidosis, hypertension, hyperthyroidism, prostatic hypertrophy, diabetes mellitus, cardiovascular disease, during delivery if maternal blood pressure is >130/80 mmHg, and during lactation.[Mayne Pharma. Ephedrine sulfate injection DBL (Approved Product Information). Melbourne: Mayne Pharma; 2004]
Contraindications for the use of ephedrine include: glaucoma, phaeochromocytoma, asymmetric septal hypertrophy (idiopathic hypertrophic subaortic stenosis), concomitant or recent (previous 14 days) monoamine oxidase inhibitor (MAOI) therapy, general anesthesia 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.
Side effects
Ephedrine is a potentially dangerous natural compound; the US Food and Drug Administration (FDA) had received over 18,000 reports of adverse effects in people using it.
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 [Joint Formulary Committee. British National Formulary, 47th edition. London: British Medical Association and Royal Pharmaceutical Society of Great Britain; 2004. ]
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Cardiovascular: tachycardia, cardiac Heart arrhythmia, angina pectoris, vasoconstriction with hypertension
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Dermatology: flushing, sweating, acne vulgaris
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Gastrointestinal: nausea
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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
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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
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Respiratory: dyspnea, pulmonary edema
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Miscellaneous: dizziness, headache, tremor, hyperglycemia reactions, dry mouth
Overdose
Overdose of ephedrine may result in sympathomimetic like tachycardia and hypertension.
Interactions
Ephedrine with monoamine oxidase inhibitors (MAOIs) like phenelzine and tranylcypromine can result in hypertensive crisis.
Pharmacology
Pharmacodynamics
+ Monoamine release by ephedrine and related agents (, nM) |
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| Notes: The smaller the value, the more strongly the substance releases the neurotransmitter. See also Monoamine releasing agent § Activity profiles for a larger table with more compounds. |
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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 activation of α- and β-adrenergic receptors via induction of norepinephrine release.
Pharmacokinetics
Absorption
The oral bioavailability of ephedrine is 88%.
Distribution
Its plasma protein binding is approximately 24 to 29%, with 5 to 10% bound to albumin.
Metabolism
Ephedrine is largely not drug metabolism.
Elimination
Ephedrine is eliminated mainly in urine, with 60% (range 53–79%) excretion unchanged.
The elimination half-life of ephedrine is 6hours.
The elimination of ephedrine is dependent on urinary pH.
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 amphetamine 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 (family Ephedraceae). It is most usually marketed as the hydrochloride or sulfate salt.
It has an experimental log P of 1.13, while its predicted log P values range from 0.9 to 1.32.
Ephedrine hydrochloride has a melting point of 187−188°C.
The racemic mixture form of ephedrine is racephedrine ((±)-ephedrine; dl-ephedrine; (1 RS,2 SR)-ephedrine).
The presence of an N-methyl group decreases binding affinities at α-adrenergic receptors, compared with norephedrine. Ephedrine, though, binds better than N-methylephedrine, which has an additional methyl group at the nitrogen atom. Also, the Stereochemistry orientation of the hydroxyl group is important for receptor binding and functional activity.
Nomenclature
Ephedrine exhibits and has two chiral centres, giving rise to four . By convention, the pair of 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.
In the outdated (+)-ephedrine is also referred to as D-ephedrine and (−)-ephedrine as L-ephedrine (in which case, in the Fischer projection, the Phenyl group is drawn at the bottom).
Often, the D/L 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 L-ephedrine and the dextrorotary d-pseudoephedrine (the diastereomer) wrongly D-pseudoephedrine.
The 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 20–200μg/L range in persons taking the drug therapeutically, 300–3000μg/L in abusers or poisoned patients, and 3–20mg/L in cases of acute fatal overdosage. The current World Anti-Doping Agency (WADA) limit for ephedrine in an athlete's urine is 10μg/mL.[WADA. The World Anti-Doping Code, World Anti-Doping Agency, Montreal, Canada, 2010. url ]
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 Asthma and stimulant.
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 from China to the West grew from 4 to 216 tonnes between 1926 and 1928.
Western medicine
Ephedrine was first introduced for medical use in the United States in 1926.
It was introduced in 1948 in Vicks Vatronol nose drops (now discontinued) which contained ephedrine sulfate as the active ingredient for rapid nasal decongestion.
Society and culture
Names
Ephedrine is the generic term of the drug and its .
Recreational use
As a phenethylamine, ephedrine has a similar chemical structure to amphetamines and is a methamphetamine analog 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 Redox 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 and iodine in the reaction with ephedrine. Moreover, ephedrine can be synthesized into methcathinone via simple oxidation. As such, ephedrine is listed as a table-I precursor under the United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances.[ Microsoft Word – RedListE2007.doc ]
Use in exercise and sports
Ephedrine has been used as a performance-enhancing drug in exercise and sports.
Other uses
In chemical synthesis, ephedrine is used in bulk quantities as a chiral auxiliary group.
In saquinavir synthesis, the half-acid is resolved as its salt with l-ephedrine.
Legal status
Canada
In January 2002, Health Canada issued a voluntary recall of all ephedrine products containing more than 8mg 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.
United States
In 1997, the FDA proposed a regulation on ephedra (the herb from which ephedrine is obtained), which limited an ephedra dose to 8mg (of active ephedrine) with no more than 24mg per day.[ Federal Register: June 4, 1997 (Volume 62, Number 107): Dietary Supplements Containing Ephedrine Alkaloids; Proposed Rule] 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."[ Federal Register: April 3, 2000 (Volume 65, Number 64): Dietary Supplements Containing Ephedrine Alkaloids; Withdrawal in Part] In 2004, the FDA created a ban on ephedrine alkaloids marketed for reasons other than asthma, colds, allergies, other disease, or traditional Asian use.[ 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] 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,
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 products containing ephedrine and the closely related drug pseudoephedrine. Both substances are used as Drug precursors in the illicit production of methamphetamine, and to discourage that use the federal statute included the following requirements for merchants who sell these products:
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A retrievable record of all purchases identifying the name and address of each party to be kept for two years
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Required verification of proof of identity of all purchasers
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Required protection and disclosure methods in the collection of personal information
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Reports to the Attorney General of any suspicious payments or disappearances of the regulated products
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Non-liquid dose form of regulated product may only be sold in unit-dose blister packs
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Regulated products are to be sold behind the counter or in a locked cabinet in such a way as to restrict access
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Daily sales of regulated products not to exceed 3.6g to a single purchaser, without regard to the number of transactions
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Monthly sales to a single purchaser not to exceed 9g of pseudoephedrine base in regulated products
The law gives similar regulations to mail-order purchases, except the monthly sales limit is 7.5g.
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 that 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,
Germany
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.[ Verordnung zur Neuordnung der Verschreibungspflicht von Arzneimitteln (AMVVNV). V. v. 21. Dezember 2005 BGBl. I S. 3632; Geltung ab 1. Januar 2006.]
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.
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.
Biosynthetic
Ephedrine was long thought to come from modifying the amino acid L-phenylalanine.
External links
