Ephedrine is a
central nervous system
The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...
(CNS)
stimulant that is often used to prevent
low blood pressure
Hypotension is low blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood. Blood pressure is indicated by two numbers, the systolic blood pressure (the top number) and the di ...
during
anesthesia
Anesthesia is a state of controlled, temporary loss of sensation or awareness that is induced for medical or veterinary purposes. It may include some or all of analgesia (relief from or prevention of pain), paralysis (muscle relaxation), ...
.
It has also been used for
asthma
Asthma is a long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wheezing, cou ...
,
narcolepsy
Narcolepsy is a long-term neurological disorder that involves a decreased ability to regulate sleep–wake cycles. Symptoms often include periods of excessive daytime sleepiness and brief involuntary sleep episodes. About 70% of those affect ...
, and
obesity
Obesity is a medical condition, sometimes considered a disease, in which excess body fat has accumulated to such an extent that it may negatively affect health. People are classified as obese when their body mass index (BMI)—a person's ...
but is not the preferred treatment.
[ It is of unclear benefit in ]nasal congestion
Nasal congestion is the blockage of nasal breathing usually due to membranes lining the nose becoming swollen from inflamed blood vessels.
Background
In about 85% of cases, nasal congestion leads to mouth breathing rather than nasal breathin ...
.[ It can be taken by mouth or by ]injection into a muscle
Intramuscular injection, often abbreviated IM, is the injection of a substance into a muscle. In medicine, it is one of several methods for parenteral administration of medications. Intramuscular injection may be preferred because muscles ha ...
, vein
Veins are blood vessels in humans and most other animals that carry blood towards the heart. Most veins carry deoxygenated blood from the tissues back to the heart; exceptions are the pulmonary and umbilical veins, both of which carry oxygenat ...
, or just under the skin.[ Onset with intravenous use is fast, while injection into a muscle can take 20 minutes, 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.][
Common side effects include trouble sleeping, anxiety, headache, ]hallucination
A hallucination is a perception in the absence of an external stimulus that has the qualities of a real perception. Hallucinations are vivid, substantial, and are perceived to be located in external objective space. Hallucination is a combinati ...
s, high blood pressure, fast heart rate
Tachycardia, also called tachyarrhythmia, is a heart rate that exceeds the normal resting rate. In general, a resting heart rate over 100 beats per minute is accepted as tachycardia in adults. Heart rates above the resting rate may be normal (su ...
, loss of appetite, and inability to urinate.[ Serious side effects include stroke and ]heart attack
A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which may tr ...
.[ While likely safe in pregnancy, its use in this population is poorly studied.] Use during breastfeeding
Breastfeeding, or nursing, is the process by which human breast milk is fed to a child. Breast milk may be from the breast, or may be expressed by hand or pumped and fed to the infant. The World Health Organization (WHO) recommends that br ...
is not recommended.[ Ephedrine works by increasing the activity of the α and β adrenergic receptors.][
Ephedrine was first isolated in 1885 and came into commercial use in 1926.] It is on the World Health Organization's List of Essential Medicines
The WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health s ...
. It is available as a generic medication
A generic drug is a pharmaceutical drug that contains the same chemical substance as a drug that was originally protected by chemical patents. Generic drugs are allowed for sale after the patents on the original drugs expire. Because the active ch ...
.[ It can normally be found in plants of the '']Ephedra Ephedra may refer to:
* Ephedra (medicine), a medicinal preparation from the plant ''Ephedra sinica''
* ''Ephedra'' (plant), genus of gymnosperm shrubs
See also
* Ephedrine
Ephedrine is a central nervous system (CNS) stimulant that is of ...
'' genus. Dietary supplements containing ephedrine are illegal in the United States, with the exception of those used in traditional Chinese medicine
Traditional Chinese medicine (TCM) is an alternative medical practice drawn from traditional medicine in China. It has been described as "fraught with pseudoscience", with the majority of its treatments having no logical mechanism of action ...
, where its presence is noted by ''má huáng''.[
]
Medical use
Ephedrine is a non-catecholamine
A catecholamine (; abbreviated CA) is a monoamine neurotransmitter, an organic compound that has a catechol (benzene with two hydroxyl side groups next to each other) and a side-chain amine.
Catechol can be either a free molecule or a su ...
sympathomimetic with cardiovascular effects similar to those of epinephrine: increased blood pressure, heart rate and contractility. Like pseudoephedrine it is a bronchodilator
A bronchodilator or broncholytic (although the latter occasionally includes secretory inhibition as well) is a substance that dilates the bronchi and bronchioles, decreasing resistance in the respiratory airway and increasing airflow to the lung ...
, with pseudoephedrine having considerably less effect.
Ephedrine may decrease motion sickness
Motion sickness occurs due to a difference between actual and expected motion. Symptoms commonly include nausea, vomiting, cold sweat, headache, dizziness, tiredness, loss of appetite, and increased salivation. Complications may rarely include de ...
, 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
Congenital myasthenic syndrome (CMS) is an inherited neuromuscular disorder caused by defects of several types at the neuromuscular junction. The effects of the disease are similar to Lambert-Eaton Syndrome and myasthenia gravis, the difference ...
in early childhood and also even in the adults with a novel COLQ mutation.
Ephedrine is administered by intravenous bolues. Redosing usually requires increased doses to offset the development of tachyphylaxis, which is attributed to the depletion of cathecolamine stores.[
]
Weight loss
Ephedrine promotes modest short-term weight loss
Weight loss, in the context of medicine, health, or physical fitness, refers to a reduction of the total body mass, by a mean loss of fluid, body fat ( adipose tissue), or lean mass (namely bone mineral deposits, muscle, tendon, and other co ...
, specifically fat loss, but its long-term effects are unknown. In mice, ephedrine is known to stimulate thermogenesis
Thermogenesis is the process of heat production in organisms. It occurs in all warm-blooded animals, and also in a few species of thermogenic plants such as the Eastern skunk cabbage, the Voodoo lily ('' Sauromatum venosum''), and the giant w ...
in the brown adipose tissue
Brown adipose tissue (BAT) or brown fat makes up the adipose organ together with white adipose tissue (or white fat). Brown adipose tissue is found in almost all mammals.
Classification of brown fat refers to two distinct cell populations with si ...
, but because adult humans have only small amounts of brown fat, thermogenesis is assumed to take place mostly in the skeletal muscle
Skeletal muscles (commonly referred to as muscles) are organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other types of muscl ...
. Ephedrine also decreases gastric emptying. Methylxanthine
Xanthine ( or ; archaically xanthic acid; systematic name 3,7-dihydropurine-2,6-dione) is a purine base found in most human body tissues and fluids, as well as in other organisms. Several stimulants are derived from xanthine, including caffeine, ...
s such as caffeine
Caffeine is a central nervous system (CNS) stimulant of the methylxanthine class. It is mainly used recreationally as a cognitive enhancer, increasing alertness and attentional performance. Caffeine acts by blocking binding of adenosine to ...
and theophylline
Theophylline, also known as 1,3-dimethylxanthine, is a phosphodiesterase inhibiting drug used in therapy for respiratory diseases such as chronic obstructive pulmonary disease (COPD) and asthma under a variety of brand names. As a member of the ...
have a synergistic effect with ephedrine with respect to weight loss. This led to creation and marketing of compound products. One of them, known as the ECA stack
The ECA stack is a drug combination used in weight loss and as a stimulant. ECA is an initialism for ephedrine, caffeine, and aspirin, with variants of it including the EC stack, which removes the aspirin for those who can not tolerate it. Dietar ...
, contains ephedrine with caffeine and aspirin. It is a popular supplement taken by bodybuilders
Bodybuilding is the use of progressive resistance exercise to control and develop one's muscles (muscle building) by muscle hypertrophy for aesthetic purposes. It is distinct from similar activities such as powerlifting because it focuses ...
seeking to cut body fat before a competition.
Recreational use
As a phenethylamine, ephedrine has a similar chemical structure to amphetamines
Substituted amphetamines are a class of compounds based upon the amphetamine structure; it includes all derivative compounds which are formed by replacing, or substituting, one or more hydrogen atoms in the amphetamine core structure with sub ...
and is a methamphetamine analogue having the methamphetamine structure with a hydroxyl
In chemistry, a hydroxy or hydroxyl group is a functional group with the chemical formula and composed of one oxygen atom covalently bonded to one hydrogen atom. In organic chemistry, alcohols and carboxylic acids contain one or more hydroxy ...
group at the β position. Because of ephedrine's structural similarity to methamphetamine, it can be used to create methamphetamine using chemical reduction 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
The Birch reduction is an organic reaction that is used to convert arenes to cyclohexadienes. The reaction is named after the Australian chemist Arthur Birch and involves the organic reduction of aromatic rings in an amine solvent (traditionally ...
, in that it uses anhydrous ammonia
Ammonia is an inorganic compound of nitrogen and hydrogen with the formula . A stable binary hydride, and the simplest pnictogen hydride, ammonia is a colourless gas with a distinct pungent smell. Biologically, it is a common nitrogenous was ...
and lithium
Lithium (from el, λίθος, lithos, lit=stone) is a chemical element with the symbol Li and atomic number 3. It is a soft, silvery-white alkali metal. Under standard conditions, it is the least dense metal and the least dense solid ...
metal in the reaction. The second-most popular method uses red phosphorus
Phosphorus is a chemical element with the symbol P and atomic number 15. Elemental phosphorus exists in two major forms, white phosphorus and red phosphorus, but because it is highly reactive, phosphorus is never found as a free element on Ear ...
and iodine
Iodine is a chemical element with the symbol I and atomic number 53. The heaviest of the stable halogens, it exists as a semi-lustrous, non-metallic solid at standard conditions that melts to form a deep violet liquid at , and boils to a vi ...
in the reaction with ephedrine. Moreover, ephedrine can be synthesized into methcathinone
Methcathinone (α-methylamino- propiophenone or ephedrone) (sometimes called "cat" or "jeff" or "catnip" or "M-Kat" or "kat" or "intash" ) is a monoamine alkaloid and psychoactive stimulant, a substituted cathinone. It is used as a recreationa ...
via simple oxidation
Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is the gain of electrons or a ...
. As such, ephedrine is listed as a table-I precursor under the ''''.[Microsoft Word – RedListE2007.doc]
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
An immunoassay (IA) is a biochemical test that measures the presence or concentration of a macromolecule or a small molecule in a solution through the use of an antibody (usually) or an antigen (sometimes). The molecule detected by the immunoass ...
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
The World Anti-Doping Agency (WADA; french: Agence mondiale antidopage, AMA) is a foundation initiated by the International Olympic Committee based in Canada to promote, coordinate, and monitor the fight against drugs in sports. The agency's key ...
(WADA) limit for ephedrine in an athlete's urine is 10 µg/mL.
Contraindications
Ephedrine should not be used in conjunction with certain antidepressants, 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
Hypercapnia (from the Greek ''hyper'' = "above" or "too much" and ''kapnos'' = "smoke"), also known as hypercarbia and CO2 retention, is a condition of abnormally elevated carbon dioxide (CO2) levels in the blood. Carbon dioxide is a gaseous pro ...
, acidosis
Acidosis is a process causing increased acidity in the blood and other body tissues (i.e., an increase in hydrogen ion concentration). If not further qualified, it usually refers to acidity of the blood plasma.
The term ''acidemia'' describes ...
, hypertension, hyperthyroidism
Hyperthyroidism is the condition that occurs due to excessive production of thyroid hormones by the thyroid gland. Thyrotoxicosis is the condition that occurs due to excessive thyroid hormone of any cause and therefore includes hyperthyroidis ...
, prostatic hypertrophy
Benign prostatic hyperplasia (BPH), also called prostate enlargement, is a noncancerous increase in size of the prostate gland. Symptoms may include frequent urination, trouble starting to urinate, weak stream, inability to urinate, or loss o ...
, diabetes mellitus
Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ap ...
, cardiovascular
The blood circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the entire body of a human or other vertebrate. It includes the cardiovascular system, or vascular system, tha ...
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
In medicine, a contraindication is a condition that serves as a reason not to take a certain medical treatment due to the harm that it would cause the patient. Contraindication is the opposite of indication, which is a reason to use a certain tre ...
for the use of ephedrine include: closed-angle glaucoma
Glaucoma is a group of eye diseases that result in damage to the optic nerve (or retina) and cause vision loss. The most common type is open-angle (wide angle, chronic simple) glaucoma, in which the drainage angle for aqueous humor, fluid withi ...
, phaeochromocytoma
Pheochromocytoma (PHEO or PCC) is a rare tumor of the adrenal medulla composed of chromaffin cells, also known as pheochromocytes. When a tumor composed of the same cells as a pheochromocytoma develops outside the adrenal gland, it is referred t ...
, asymmetric septal hypertrophy (idiopathic hypertrophic subaortic stenosis), concomitant or recent (previous 14 days) monoamine oxidase inhibitor (MAOI) therapy, general anaesthesia
Anesthesia is a state of controlled, temporary loss of sensation or awareness that is induced for medical or veterinary purposes. It may include some or all of analgesia (relief from or prevention of pain), paralysis (muscle relaxation), a ...
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.
Adverse effects
Ephedrine is a potentially dangerous natural compound; the US Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
had received over 18,000 reports of adverse effects in people using it.
Adverse drug reaction
An adverse drug reaction (ADR) is a harmful, unintended result caused by taking medication. ADRs may occur following a single dose or prolonged administration of a drug or result from the combination of two or more drugs. The meaning of this term ...
s (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
The ''British National Formulary'' (BNF) is a United Kingdom (UK) pharmaceutical reference book that contains a wide spectrum of information and advice on prescribing and pharmacology, along with specific facts and details about many medicine ...
, 47th edition. London: British Medical Association and Royal Pharmaceutical Society of Great Britain; 2004.
*Cardiovascular: tachycardia
Tachycardia, also called tachyarrhythmia, is a heart rate that exceeds the normal resting rate. In general, a resting heart rate over 100 beats per minute is accepted as tachycardia in adults. Heart rates above the resting rate may be normal ( ...
, cardiac arrhythmias, angina pectoris
Angina, also known as angina pectoris, is chest pain or pressure, usually caused by insufficient blood flow to the heart muscle (myocardium). It is most commonly a symptom of coronary artery disease.
Angina is typically the result of obstru ...
, vasoconstriction
Vasoconstriction is the narrowing of the blood vessels resulting from contraction of the muscular wall of the vessels, in particular the large arteries and small arterioles. The process is the opposite of vasodilation, the widening of blood vess ...
with hypertension
*Dermatological
Dermatology is the branch of medicine dealing with the skin.''Random House Webster's Unabridged Dictionary.'' Random House, Inc. 2001. Page 537. . It is a speciality with both medical and surgical aspects. A dermatologist is a specialist medical ...
: flushing, sweating, acne vulgaris
*Gastrointestinal
The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans and ...
: nausea
*Genitourinary
The genitourinary system, or urogenital system, are the organs of the reproductive system and the urinary system. These are grouped together because of their proximity to each other, their common embryological origin and the use of common pathw ...
: 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
*Nervous system
In biology, the nervous system is the highly complex part of an animal that coordinates its actions and sensory information by transmitting signals to and from different parts of its body. The nervous system detects environmental changes th ...
: restlessness, confusion
In medicine, confusion is the quality or state of being bewildered or unclear. The term "acute mental confusion" , insomnia
Insomnia, also known as sleeplessness, is a sleep disorder in which people have trouble sleeping. They may have difficulty falling asleep, or staying asleep as long as desired. Insomnia is typically followed by daytime sleepiness, low energy, ...
, mild euphoria, mania/ hallucinations (rare except in previously existing psychiatric conditions), delusions, formication (may be possible, but lacks documented evidence) paranoia
Paranoia is an instinct or thought process that is believed to be heavily influenced by anxiety or fear, often to the point of delusion and irrationality. Paranoid thinking typically includes persecutory beliefs, or beliefs of conspiracy co ...
, hostility
Hostility is seen as form of emotionally charged aggressive behavior. In everyday speech it is more commonly used as a synonym for anger and aggression.
It appears in several psychological theories. For instance it is a facet of neuroticism in ...
, panic
Panic is a sudden sensation of fear, which is so strong as to dominate or prevent reason and logical thinking, replacing it with overwhelming feelings of anxiety and frantic agitation consistent with an animalistic fight-or-flight reactio ...
, agitation
*Respiratory
The respiratory system (also respiratory apparatus, ventilatory system) is a biological system consisting of specific organs and structures used for gas exchange in animals and plants. The anatomy and physiology that make this happen varies gre ...
: dyspnea
Shortness of breath (SOB), also medically known as dyspnea (in AmE) or dyspnoea (in BrE), is an uncomfortable feeling of not being able to breathe well enough. The American Thoracic Society defines it as "a subjective experience of breathing di ...
, pulmonary edema
*Miscellaneous: dizziness, headache, tremor, hyperglycemic
Hyperglycemia is a condition in which an excessive amount of glucose circulates in the blood plasma. This is generally a blood sugar level higher than 11.1 mmol/L (200 mg/dL), but symptoms may not start to become noticeable until even ...
reactions, dry mouth
The neurotoxicity of l-ephedrine is disputed.
Other uses
In chemical synthesis
As a topic of chemistry, chemical synthesis (or combination) is the artificial execution of chemical reactions to obtain one or several products. This occurs by physical and chemical manipulations usually involving one or more reactions. In moder ...
, ephedrine is used in bulk quantities as a chiral auxiliary
In stereochemistry, a chiral auxiliary is a stereogenic group or unit that is temporarily incorporated into an organic compound in order to control the stereochemical outcome of the synthesis. The chirality present in the auxiliary can bias the ...
group.
:
In saquinavir
Saquinavir (SQV), sold under the brand names Invirase and Fortovase, is an antiretroviral drug used together with other medications to treat or prevent HIV/AIDS. Typically it is used with ritonavir or lopinavir/ritonavir to increase its effect ...
synthesis, the half-acid is resolved as its salt with l-ephedrine.
Chemistry and nomenclature
Ephedrine is a sympathomimetic amine
In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen
Hydrogen is the chemical element wi ...
and substituted amphetamine. It is similar in molecular structure to phenylpropanolamine
Phenylpropanolamine (PPA) is a sympathomimetic agent which is used as a decongestant and appetite suppressant. It was commonly used in prescription and over-the-counter cough and cold preparations. In veterinary medicine, it is used to contr ...
, methamphetamine, and epinephrine (adrenaline). Chemically, it is an alkaloid
Alkaloids are a class of basic, naturally occurring organic compounds that contain at least one nitrogen atom. This group also includes some related compounds with neutral and even weakly acidic properties. Some synthetic compounds of similar ...
with a phenethylamine skeleton found in various plants in the genus ''Ephedra Ephedra may refer to:
* Ephedra (medicine), a medicinal preparation from the plant ''Ephedra sinica''
* ''Ephedra'' (plant), genus of gymnosperm shrubs
See also
* Ephedrine
Ephedrine is a central nervous system (CNS) stimulant that is of ...
'' (family Ephedraceae
Ephedraceae is a family of gymnosperms belonging to Gnetophyta, it contains only a single extant genus, '' Ephedra'', as well as a number of extinct genera from the Early Cretaceous.
Taxonomy
File:Eamesia chinensis.png, '' Eamesia''
File:Chengi ...
). It works mainly by increasing the activity of norepinephrine
Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" (from Latin '' ad' ...
(noradrenaline) on adrenergic receptors
The adrenergic receptors or adrenoceptors are a class of G protein-coupled receptors that are targets of many catecholamines like norepinephrine (noradrenaline) and epinephrine (adrenaline) produced by the body, but also many medications like beta ...
.[ It is most usually marketed as the hydrochloride or sulfate salt.
Ephedrine exhibits ]optical isomer
In chemistry, a molecule or ion is called chiral () if it cannot be superposed on its mirror image by any combination of rotations, translations, and some conformational changes. This geometric property is called chirality (). The terms are d ...
ism and has two chiral
Chirality is a property of asymmetry important in several branches of science. The word ''chirality'' is derived from the Greek (''kheir''), "hand", a familiar chiral object.
An object or a system is ''chiral'' if it is distinguishable from i ...
centres, giving rise to four stereoisomer
In stereochemistry, stereoisomerism, or spatial isomerism, is a form of isomerism in which molecules have the same molecular formula and sequence of bonded atoms (constitution), but differ in the three-dimensional orientations of their atoms in ...
s. By convention, the pair of enantiomer
In chemistry, an enantiomer ( /ɪˈnænti.əmər, ɛ-, -oʊ-/ ''ih-NAN-tee-ə-mər''; from Ancient Greek ἐνάντιος ''(enántios)'' 'opposite', and μέρος ''(méros)'' 'part') – also called optical isomer, antipode, or optical ant ...
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.
Ephedrine is a substituted amphetamine and a structural methamphetamine analogue. It differs from methamphetamine only by the presence of a hydroxyl
In chemistry, a hydroxy or hydroxyl group is a functional group with the chemical formula and composed of one oxygen atom covalently bonded to one hydrogen atom. In organic chemistry, alcohols and carboxylic acids contain one or more hydroxy ...
group (—OH).
The isomer which is marketed is (−)-(1''R'',2''S'')-ephedrine.
Ephedrine hydrochloride has a melting point of 187−188 °C.[Budavari S, editor. The Merck Index: An encyclopedia of chemicals, drugs, and biologicals, 12th edition. Whitehouse Station: Merck]
In the outdated D/L system (+)-ephedrine is also referred to as D-ephedrine and (−)-ephedrine as L-ephedrine (in which case, in the Fisher projection
In chemistry, the Fischer projection, devised by Emil Fischer in 1891, is a two-dimensional representation of a three-dimensional organic molecule by projection. Fischer projections were originally proposed for the depiction of carbohydrates a ...
, the phenyl ring
In organic chemistry, the phenyl group, or phenyl ring, is a cyclic group of atoms with the formula C6 H5, and is often represented by the symbol Ph. Phenyl group is closely related to benzene and can be viewed as a benzene ring, minus a hydrogen ...
is drawn at the bottom).
Often, the D/L system (with small caps) and the d/l system (with lower-case
Letter case is the distinction between the letters that are in larger uppercase or capitals (or more formally ''majuscule'') and smaller lowercase (or more formally ''minuscule'') in the written representation of certain languages. The writing ...
) 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 IUPAC name
In chemical nomenclature, a preferred IUPAC name (PIN) is a unique name, assigned to a chemical substance and preferred among the possible names generated by IUPAC nomenclature. The "preferred IUPAC nomenclature" provides a set of rules for choo ...
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.
Sources
Agricultural
Ephedrine is obtained from the plant '' Ephedra sinica'' and other members of the genus ''Ephedra Ephedra may refer to:
* Ephedra (medicine), a medicinal preparation from the plant ''Ephedra sinica''
* ''Ephedra'' (plant), genus of gymnosperm shrubs
See also
* Ephedrine
Ephedrine is a central nervous system (CNS) stimulant that is of ...
,'' 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. 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. A new pathway proposed suggests that phenylalanine first forms cinnamoyl-CoA via the enzymes phenylalanine ammonia-lyase and acyl CoA ligase. 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.
Mechanism of action
Ephedrine, a sympathomimetic amine
Sympathomimetic drugs (also known as adrenergic drugs and adrenergic amines) are stimulant compounds which mimic the effects of endogenous agonists of the sympathetic nervous system. Examples of sympathomimetic effects include increases in heart ...
, 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 the activity of norepinephrine
Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" (from Latin '' ad' ...
at the postsynaptic α and β receptors.[Merck Manuals > EPHEDrine]
Last full review/revision January 2010 The presence of direct interactions with α receptors is unlikely, but still controversial.[Guoyi Ma, et al]
''Pharmacological Effects of Ephedrine Alkaloids on Human 1- and 2-Adrenergic Receptor Subtypes''
''J. Pharmacol. Exp. Ther.'' 322: pp. 214–221 (July 2007
PDF
/ref> L-ephedrine, and particularly its stereoisomer norpseudoephedrine Norpseudoephedrine may refer to:
* Cathine (or D-norpseudoephedrine), the (+)-enantiomer and most widely known form of the compound
* L-Norpseudoephedrine, the (-)-enantiomer of the compound
An article for the racemic mixture of the compoun ...
(which is also present in '' Catha edulis'') has indirect sympathomimetic effects and due to its ability to cross the blood–brain barrier, it is a CNS stimulant similar to amphetamines
Substituted amphetamines are a class of compounds based upon the amphetamine structure; it includes all derivative compounds which are formed by replacing, or substituting, one or more hydrogen atoms in the amphetamine core structure with sub ...
, but less pronounced, as it releases noradrenaline
Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" (from Latin '' ad'', ...
and dopamine in the substantia nigra.
The presence of an ''N''-methyl group
In organic chemistry, a methyl group is an alkyl derived from methane, containing one carbon atom bonded to three hydrogen atoms, having chemical formula . In formulas, the group is often abbreviated as Me. This hydrocarbon group occurs in ma ...
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.
;Compounds with decreasing α-receptor affinity
RS-Norephedrine.svg,
RS-Ephedrine.svg,
RS-N-Methylephedrine.svg,
History
Asia
Ephedrine in its natural form, known as ''máhuáng'' (麻黄) in traditional Chinese medicine
Traditional Chinese medicine (TCM) is an alternative medical practice drawn from traditional medicine in China. It has been described as "fraught with pseudoscience", with the majority of its treatments having no logical mechanism of action ...
, has been documented in China since the Han dynasty
The Han dynasty (, ; ) was an imperial dynasty of China (202 BC – 9 AD, 25–220 AD), established by Liu Bang (Emperor Gao) and ruled by the House of Liu. The dynasty was preceded by the short-lived Qin dynasty (221–207 BC) and a warr ...
(206 BC – 220 AD) as an antiasthmatic and stimulant. In traditional Chinese medicine, ''máhuáng'' has been used as a treatment for asthma and bronchitis for centuries.
In 1885, the chemical synthesis of ephedrine was first accomplished by Japanese organic chemist
Organic chemistry is a subdiscipline within chemistry involving the scientific study of the structure, properties, and reactions of organic compounds and organic materials, i.e., matter in its various forms that contain carbon atoms.Clayden, J. ...
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
Merck refers primarily to the German Merck family and three companies founded by the family, including:
* the Merck Group, a German chemical, pharmaceutical and life sciences company founded in 1668
** Merck Serono (known as EMD Serono in the Unite ...
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
Introduced in 1948 Vicks
Vicks is an American brand of over-the-counter medications owned by the American companies Procter & Gamble and Helen of Troy Limited. Vicks manufactures NyQuil and its sister medication, DayQuil as well as other medications in the “Quil” l ...
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. Ephedrine is still sold as an oral nasal decongestant in 8 mg pills as a natural health product, with a limit of 0.4g per package, the limit established by the Controlled Drugs and Substances Act as it is considered as Class A Precursor.
United States
In 1997, the FDA
The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...
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. 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." In 2004, the FDA created a ban on ephedrine alkaloids marketed for reasons other than asthma, colds, allergies, other disease, or traditional Asian use. On April 14, 2005, the U.S. District Court for the District of Utah
The United States District Court for the District of Utah (in case citations, D. Utah) is the federal district court whose jurisdiction is the state of Utah. The court is based in Salt Lake City with another courtroom leased in thstate courtho ...
ruled the FDA did not have proper evidence that low dosages of ephedrine alkaloids are actually unsafe, but on August 17, 2006, the U.S. Court of Appeals for the Tenth Circuit
The United States Court of Appeals for the Tenth Circuit (in case citations, 10th Cir.) is a federal court with appellate jurisdiction over the district courts in the following districts:
* District of Colorado
* District of Kansas
* Distri ...
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. Furthermore, ephedrine is banned by the NCAA, MLB, NFL, and PGA. 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 House passed the Combat Methamphetamine Epidemic Act of 2005
The Combat Methamphetamine Epidemic Act of 2005 (CMEA) is federal legislation enacted in the United States on March 9, 2006, to regulate, among other things, retail over-the-counter sales of following products because of their use in the manufactu ...
as an amendment to the renewal of the USA PATRIOT Act
The USA PATRIOT Act (commonly known as the Patriot Act) was a landmark Act of the United States Congress, signed into law by President George W. Bush. The formal name of the statute is the Uniting and Strengthening America by Providing Appro ...
. Signed into law by President George W. Bush
George Walker Bush (born July 6, 1946) is an American politician who served as the 43rd president of the United States from 2001 to 2009. A member of the Republican Party, Bush family, and son of the 41st president George H. W. Bush, he ...
on March 6, 2006, the act amended the US Code
In the law of the United States, the Code of Laws of the United States of America (variously abbreviated to Code of Laws of the United States, United States Code, U.S. Code, U.S.C., or USC) is the official compilation and codification of the ...
(21 USC 830) concerning the sale of products containing ephedrine and the closely related drug pseudoephedrine. Both substances are used as 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:
* 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 (October 2015).[Poisons Standard October 2015 ] 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 (October 2015).
South Africa
In South Africa, ephedrine was moved to schedule 6 on 27 May 2008, 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.''Verordnung zur Neuordnung der Verschreibungspflicht von Arzneimitteln (AMVVNV).''
V. v. 21. Dezember 2005 BGBl. I S. 3632; Geltung ab 1. Januar 2006.
See also
* Amphetamine
* Methamphetamine
* Phenylephrine
Phenylephrine is a medication primarily used as a decongestant, to dilate the pupil, to increase blood pressure, and to relieve hemorrhoids. In the United States, it was previously used orally as an over-the-counter decongestant to relieve nas ...
* Propylhexedrine
Propylhexedrine, sold under the brand name Benzedrex, is a nasal decongestant, appetite suppressant, and psychostimulant medication. It is used medicinally for relief of congestion due to colds, allergies and allergic rhinitis.
Propylhexedrin ...
* Pyrovalerone
* Norephedrine
Phenylpropanolamine (PPA) is a sympathomimetic agent which is used as a decongestant and appetite suppressant. It was commonly used in prescription and over-the-counter cough and cold preparations. In veterinary medicine, it is used to contro ...
* Halostachine
* Metaraminol
Metaraminol, previously sold under the brand name Aramine among others and also known as metaradrine, is a stereoisomer of ''meta''-hydroxynorephedrine (3,β-dihydroxyamphetamine), is a potent sympathomimetic amine used in the prevention and tr ...
* Oxyfedrine
* Pseudoephedrine
* Synephrine
Synephrine, or, more specifically, ''p''-synephrine, is an alkaloid, occurring naturally in some plants and animals, and also in approved drugs products as its ''m''-substituted analog known as neo-synephrine. ''p''-Synephrine (or formerly Sympat ...
References
External links
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{{Authority control
Amphetamine alkaloids
Chinese inventions
Decongestants
Ergogenic aids
Han dynasty
Norepinephrine releasing agents
Wikipedia medicine articles ready to translate
Traditional Chinese medicine
World Health Organization essential medicines
Phenylethanolamines