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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 Stimulants (also often referred to as psychostimulants or colloquially as uppers) is an overarching term that covers many drugs including those that increase activity of the central nervous system and the body, drugs that are pleasurable and inv ...
that is often used to prevent low blood pressure 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, co ...
,
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,
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 oxygenated ...
, 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 Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms. Long-term high bl ...
,
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 (s ...
, loss of appetite, and inability to urinate. Serious side effects include
stroke A stroke is a disease, medical condition in which poor cerebral circulation, blood flow to the brain causes cell death. There are two main types of stroke: brain ischemia, ischemic, due to lack of blood flow, and intracranial hemorrhage, hemorr ...
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 ma ...
. 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 bre ...
is not recommended. Ephedrine works by increasing the activity of the α and β
adrenergic receptor 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 bet ...
s. 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. 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 ...
. It can normally be found in plants of the '' Ephedra'' 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 acti ...
, 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 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 hea ...
with cardiovascular effects similar to those of epinephrine: increased blood pressure, heart rate and contractility. Like
pseudoephedrine Pseudoephedrine (PSE) is a sympathomimetic drug of the phenethylamine and amphetamine chemical classes. It may be used as a nasal/sinus decongestant, as a stimulant, or as a wakefulness-promoting agent in higher doses. It was first charact ...
it is a bronchodilator, 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 in early childhood and also even in the adults with a novel
COLQ Acetylcholinesterase collagenic tail peptide also known as AChE Q subunit, acetylcholinesterase-associated collagen, or ColQ is the collagen-tail subunit of acetylcholinesterase found in the neuromuscular junction. In humans it is encoded by the '' ...
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, 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 m ...
. Ephedrine also decreases
gastric emptying Gastrointestinal physiology is the branch of human physiology that addresses the physical function of the gastrointestinal (GI) tract. The function of the GI tract is to process ingested food by mechanical and chemical means, extract nutrients and ...
. Methylxanthines such as
caffeine Caffeine is a central nervous system (CNS) stimulant of the methylxanthine chemical classification, class. It is mainly recreational drug use, used recreationally as a Nootropic, cognitive enhancer, increasing alertness and attentional perfor ...
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. Diet ...
, 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 o ...
seeking to cut body fat before a competition.


Recreational use

As a
phenethylamine Phenethylamine (PEA) is an organic compound, natural monoamine alkaloid, and trace amine, which acts as a central nervous system stimulant in humans. In the brain, phenethylamine regulates monoamine neurotransmission by binding to trace am ...
, 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 Methamphetamine (contracted from ) is a potent central nervous system (CNS) stimulant that is mainly used as a recreational drug and less commonly as a second-line treatment for attention deficit hyperactivity disorder and obesity. Methamp ...
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 hydrox ...
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 Methamphetamine (contracted from ) is a potent central nervous system (CNS) stimulant that is mainly used as a recreational drug and less commonly as a second-line treatment for attention deficit hyperactivity disorder and obesity. Methamp ...
. 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 wast ...
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 soli ...
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 Ea ...
and
iodine Iodine is a chemical element with the Symbol (chemistry), 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 , ...
in the reaction with ephedrine. Moreover, ephedrine can be synthesized into methcathinone 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 ...
. As such, ephedrine is listed as a table-I precursor under the ''
United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances The United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances of 1988 is one of three major drug control treaties currently in force. It provides additional legal mechanisms for enforcing the 1961 Single Co ...
''.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 immunoa ...
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.


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 Bupropion, sold under the brand names Wellbutrin and Zyban among others, is an atypical antidepressant primarily used to treat major depressive disorder and to support smoking cessation. It is also popular as an add-on medication in the cas ...
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 Fluoxetine, sold under the brand names Prozac and Sarafem, among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is used for the treatment of major depressive disorder, obsessive–compulsive diso ...
in that its primary mode of therapeutic action involves norepinephrine and to a lesser degree dopamine, but it also releases some
serotonin Serotonin () or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Its biological function is complex and multifaceted, modulating mood, cognition, reward, learning, memory, and numerous physiological processes such as vomiting and va ...
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 p ...
,
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'' describe ...
,
hypertension Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms. Long-term high b ...
,
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,
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 ...
,
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 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 fluid within the eye rema ...
, phaeochromocytoma, asymmetric septal hypertrophy (idiopathic hypertrophic subaortic stenosis), concomitant or recent (previous 14 days)
monoamine oxidase inhibitor Monoamine oxidase inhibitors (MAOIs) are a class of drugs that inhibit the activity of one or both monoamine oxidase enzymes: monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B). They are best known as effective antidepressants, esp ...
(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 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 ...
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 medici ...
, 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
arrhythmia Arrhythmias, also known as cardiac arrhythmias, heart arrhythmias, or dysrhythmias, are irregularities in the heartbeat, including when it is too fast or too slow. A resting heart rate that is too fast – above 100 beats per minute in adult ...
s, angina pectoris,
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 Hypertension (HTN or HT), also known as high blood pressure (HBP), is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. High blood pressure usually does not cause symptoms. Long-term high b ...
* Dermatological: flushing, sweating,
acne vulgaris Acne, also known as ''acne vulgaris'', is a long-term skin condition that occurs when dead skin cells and oil from the skin clog hair follicles. Typical features of the condition include blackheads or whiteheads, pimples, oily skin, and po ...
*
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: 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 ...
: restlessness, 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 Mania, also known as manic syndrome, is a mental and behavioral disorder defined as a state of abnormally elevated arousal, affect, and energy level, or "a state of heightened overall activation with enhanced affective expression together wi ...
/
hallucinations 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 ...
(rare except in previously existing psychiatric conditions),
delusions A delusion is a false fixed belief that is not amenable to change in light of conflicting evidence. As a pathology, it is distinct from a belief based on false or incomplete information, confabulation, dogma, illusion, hallucination, or som ...
,
formication Formication is the sensation resembling that of small insects crawling on (or under) the skin when nothing is actually there. It is one specific form of a set of sensations known as paresthesias, which also include the more common prickling, t ...
(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 c ...
, hostility,
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 reac ...
, agitation * Respiratory:
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 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 mod ...
, 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.


Chemistry and nomenclature

Ephedrine is a
sympathomimetic 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 hea ...
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 atoms have been replaced by a substituent ...
and
substituted amphetamine 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 s ...
. 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 cont ...
,
methamphetamine Methamphetamine (contracted from ) is a potent central nervous system (CNS) stimulant that is mainly used as a recreational drug and less commonly as a second-line treatment for attention deficit hyperactivity disorder and obesity. Methamp ...
, and
epinephrine Adrenaline, also known as epinephrine, is a hormone and medication which is involved in regulating visceral functions (e.g., respiration). It appears as a white microcrystalline granule. Adrenaline is normally produced by the adrenal glands and ...
(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 simila ...
with a
phenethylamine Phenethylamine (PEA) is an organic compound, natural monoamine alkaloid, and trace amine, which acts as a central nervous system stimulant in humans. In the brain, phenethylamine regulates monoamine neurotransmission by binding to trace am ...
skeleton found in various plants in the genus '' Ephedra'' (family Ephedraceae). 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 bet ...
. It is most usually marketed as the hydrochloride or sulfate salt. Ephedrine exhibits optical isomerism and has two chiral 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 anti ...
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 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 s ...
and a structural
methamphetamine Methamphetamine (contracted from ) is a potent central nervous system (CNS) stimulant that is mainly used as a recreational drug and less commonly as a second-line treatment for attention deficit hyperactivity disorder and obesity. Methamp ...
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 hydrox ...
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, 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 hydroge ...
is drawn at the bottom). Often, the D/L system (with
small caps In typography, small caps (short for "small capitals") are characters typeset with glyphs that resemble uppercase letters (capitals) but reduced in height and weight close to the surrounding lowercase letters or text figures. This is technic ...
) 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 IUPAC names 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 ''Ephedra sinica'' (also known as Chinese ephedra or Ma Huang) is a species of '' Ephedra'' native to Mongolia, Russia (Buryatiya, Chita, Primorye), and northeastern China ( Gansu, Hebei, Heilongjiang, Jilin, Liaoning, Nei Mongo ...
'' 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. 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, acts on part of the
sympathetic nervous system The sympathetic nervous system (SNS) is one of the three divisions of the autonomic nervous system, the others being the parasympathetic nervous system and the enteric nervous system. The enteric nervous system is sometimes considered part of t ...
(SNS). The principal mechanism of action relies on its indirect stimulation of the
adrenergic receptor 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 bet ...
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 (which is also present in ''
Catha edulis Khat or qat ( ''ch’at''; Oromo: ''Jimaa'', so, qaad, khaad, khat or chat, ar, القات ''al-qāt'') is a flowering plant native to eastern and southern Africa. Khat contains the alkaloid cathinone, a stimulant, which is said to cause ...
'') has indirect
sympathomimetic 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 hea ...
effects and due to its ability to cross the
blood–brain barrier The blood–brain barrier (BBB) is a highly selective semipermeable border of endothelial cells that prevents solutes in the circulating blood from ''non-selectively'' crossing into the extracellular fluid of the central nervous system where ne ...
, it is a CNS
stimulant Stimulants (also often referred to as psychostimulants or colloquially as uppers) is an overarching term that covers many drugs including those that increase activity of the central nervous system and the body, drugs that are pleasurable and inv ...
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 and
dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. Dopamine constitutes about 80% o ...
in the
substantia nigra The substantia nigra (SN) is a basal ganglia structure located in the midbrain that plays an important role in reward and movement. ''Substantia nigra'' is Latin for "black substance", reflecting the fact that parts of the substantia nigra ap ...
. 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 Steric effects arise from the spatial arrangement of atoms. When atoms come close together there is a rise in the energy of the molecule. Steric effects are nonbonding interactions that influence the shape ( conformation) and reactivity of ions ...
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 acti ...
, has been documented in China since the
Han dynasty The Han dynasty (, ; ) was an Dynasties in Chinese history, imperial dynasty of China (202 BC – 9 AD, 25–220 AD), established by Emperor Gaozu of Han, Liu Bang (Emperor Gao) and ruled by the House of Liu. The dynasty was preceded by th ...
(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
Nagai Nagayoshi was a Japanese pharmacist, best known for his study of ephedrine. Early life Nagai was born in Myōdō District, Awa Province in what is now Tokushima Prefecture, as the son of a doctor and started studying ''rangaku'' medicine at the Dutch M ...
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

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 Health Canada (HC; french: Santé Canada, SC)Health Canada is the applied title under the Federal Identity Program; the legal title is Department of Health (). is the department of the Government of Canada responsible for national health poli ...
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 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 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 * Distr ...
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 A house is a single-unit residential building. It may range in complexity from a rudimentary hut to a complex structure of wood, masonry, concrete or other material, outfitted with plumbing, electrical, and heating, ventilation, and air cond ...
passed the Combat Methamphetamine Epidemic Act of 2005 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 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 Pseudoephedrine (PSE) is a sympathomimetic drug of the phenethylamine and amphetamine chemical classes. It may be used as a nasal/sinus decongestant, as a stimulant, or as a wakefulness-promoting agent in higher doses. It was first charact ...
. Both substances are used as
precursors Precursor or Precursors may refer to: *Precursor (religion), a forerunner, predecessor ** The Precursor, John the Baptist Science and technology * Precursor (bird), a hypothesized genus of fossil birds that was composed of fossilized parts of unr ...
in the illicit production of
methamphetamine Methamphetamine (contracted from ) is a potent central nervous system (CNS) stimulant that is mainly used as a recreational drug and less commonly as a second-line treatment for attention deficit hyperactivity disorder and obesity. Methamp ...
, 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 In most common law jurisdictions, the attorney general or attorney-general (sometimes abbreviated AG or Atty.-Gen) is the main legal advisor to the government. The plural is attorneys general. In some jurisdictions, attorneys general also have exec ...
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 Amphetamine (contracted from alpha- methylphenethylamine) is a strong central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, and obesity. It is also commonly used ...
*
Methamphetamine Methamphetamine (contracted from ) is a potent central nervous system (CNS) stimulant that is mainly used as a recreational drug and less commonly as a second-line treatment for attention deficit hyperactivity disorder and obesity. Methamp ...
* Phenylephrine * Propylhexedrine *
Pyrovalerone (Centroton, 4-Methyl-β-keto-prolintane, Thymergix, O-2371) is a psychoactive drug with stimulant effects via acting as a norepinephrine-dopamine reuptake inhibitor (NDRI), and is used for the clinical treatment of chronic fatigue or letharg ...
* Norephedrine * Halostachine * Metaraminol * Oxyfedrine *
Pseudoephedrine Pseudoephedrine (PSE) is a sympathomimetic drug of the phenethylamine and amphetamine chemical classes. It may be used as a nasal/sinus decongestant, as a stimulant, or as a wakefulness-promoting agent in higher doses. It was first charact ...
* Synephrine


References


External links

* * * {{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