Amphetamine exerts its behavioral effects by altering the use of  monoamines  as neuronal signals in the brain, primarily in  catecholamine  neurons in the reward and executive function pathways of the brain. [ 39 ] [ 64 ]  The concentrations of the main neurotransmitters involved in reward circuitry and executive functioning, dopamine and norepinephrine, increase dramatically in a dose-dependent manner by amphetamine because of its effects on  monoamine transporters . [ 39 ] [ 64 ] [ 184 ]  The  reinforcing  and  motivational salience -promoting effects of amphetamine are due mostly to enhanced dopaminergic activity in the  mesolimbic pathway . [ 27 ]  The  euphoric  and locomotor-stimulating effects of amphetamine are dependent upon the magnitude and speed by which it increases synaptic dopamine and norepinephrine concentrations in the  striatum . [ 2 ]


Amphetamine has been identified as a potent  full agonist  of  trace amine-associated receptor 1  (TAAR1), a  G s -coupled  and  G q -coupled   G protein-coupled receptor  (GPCR) discovered in 2001, which is important for regulation of brain monoamines. [ 39 ] [ 190 ]  Activation of  TAAR1  increases  cAMP Tooltip cyclic adenosine monophosphate  production via  adenylyl cyclase  activation and inhibits  monoamine transporter  function. [ 39 ] [ 191 ]  Monoamine  autoreceptors  (e.g.,  D 2  short ,  presynaptic α 2 , and  presynaptic 5-HT 1A ) have the opposite effect of TAAR1, and together these receptors provide a regulatory system for monoamines. [ 39 ] [ 40 ]  Notably, amphetamine and  trace amines  possess high binding affinities for TAAR1, but not for monoamine autoreceptors. [ 39 ] [ 40 ]  Imaging studies indicate that monoamine reuptake inhibition by amphetamine and trace amines is site specific and depends upon the presence of TAAR1  co-localization  in the associated monoamine neurons. [ 39 ]


In addition to the neuronal monoamine  transporters , amphetamine also inhibits both  vesicular monoamine transporters ,  VMAT1  and  VMAT2 , as well as  SLC1A1 ,  SLC22A3 , and  SLC22A5 . [ sources 15 ]  SLC1A1 is  excitatory amino acid transporter 3  (EAAT3), a glutamate transporter located in neurons, SLC22A3 is an extraneuronal monoamine transporter that is present in  astrocytes , and SLC22A5 is a high-affinity  carnitine  transporter. [ sources 15 ]  Amphetamine is known to strongly induce  cocaine- and amphetamine-regulated transcript  (CART)  gene expression , [ 11 ] [ 197 ]  a  neuropeptide  involved in feeding behavior, stress, and reward, which induces observable increases in neuronal development and survival  in vitro . [ 11 ] [ 198 ] [ 199 ]  The CART receptor has yet to be identified, but there is significant evidence that CART binds to a unique  G i /G o -coupled   GPCR . [ 199 ] [ 200 ]  Amphetamine also inhibits  monoamine oxidases  at very high doses, resulting in less monoamine and trace amine metabolism and consequently higher concentrations of synaptic monoamines. [ 23 ] [ 201 ]  In humans, the only post-synaptic receptor at which amphetamine is known to bind is the  5-HT1A  receptor , where it acts as an agonist with low  micromolar  affinity. [ 202 ] [ 203 ]


The full profile of amphetamine's short-term drug effects in humans is mostly derived through increased cellular communication or  neurotransmission  of  dopamine , [ 39 ]   serotonin , [ 39 ]   norepinephrine , [ 39 ]   epinephrine , [ 184 ]   histamine , [ 184 ]   CART peptides , [ 11 ] [ 197 ]   endogenous opioids , [ 204 ] [ 205 ] [ 206 ]   adrenocorticotropic hormone , [ 207 ] [ 208 ]   corticosteroids , [ 207 ] [ 208 ]  and  glutamate , [ 188 ] [ 193 ]  which it affects through interactions with  CART ,  5-HT1A ,  EAAT3 ,  TAAR1 ,  VMAT1 ,  VMAT2 , and possibly other  biological targets . [ sources 16 ]  Amphetamine also activates seven human  carbonic anhydrase  enzymes, several of which are expressed in the human brain. [ 209 ]


Dextroamphetamine is a more potent agonist of  TAAR1  than levoamphetamine. [ 210 ]  Consequently, dextroamphetamine produces greater  CNS  stimulation than levoamphetamine, roughly three to four times more, but levoamphetamine has slightly stronger cardiovascular and peripheral effects. [ 41 ] [ 210 ]


In certain brain regions, amphetamine increases the concentration of dopamine in the  synaptic cleft . [ 39 ]  Amphetamine can enter the  presynaptic neuron  either through  DAT  or by diffusing across the neuronal membrane directly. [ 39 ]  As a consequence of DAT uptake, amphetamine produces competitive reuptake inhibition at the transporter. [ 39 ]  Upon entering the presynaptic neuron, amphetamine activates  TAAR1  which, through  protein kinase A  (PKA) and  protein kinase C  (PKC) signaling, causes DAT  phosphorylation . [ 39 ]  Phosphorylation by either protein kinase can result in DAT  internalization  ( non-competitive  reuptake inhibition), but  PKC-mediated  phosphorylation alone induces the  reversal of dopamine transport  through DAT (i.e., dopamine  efflux ). [ note 16 ] [ 39 ] [ 211 ]  Amphetamine is also known to increase intracellular calcium, an effect which is associated with DAT phosphorylation through an unidentified  Ca2+/calmodulin-dependent protein kinase  (CAMK)-dependent pathway, in turn producing dopamine efflux. [ 190 ] [ 188 ] [ 189 ]  Through direct activation of  G protein-coupled inwardly-rectifying potassium channels ,  TAAR1  reduces the  firing rate  of dopamine neurons, preventing a hyper-dopaminergic state. [ 186 ] [ 187 ] [ 212 ]


Amphetamine is also a substrate for the presynaptic  vesicular monoamine transporter ,  VMAT2 . [ 184 ] [ 185 ]  Following amphetamine uptake at VMAT2, amphetamine induces the collapse of the vesicular pH gradient, which results in the release of dopamine molecules from  synaptic vesicles  into the cytosol via dopamine efflux through VMAT2. [ 184 ] [ 185 ]  Subsequently, the cytosolic dopamine molecules are released from the presynaptic neuron into the synaptic cleft via reverse transport at  DAT . [ 39 ] [ 184 ] [ 185 ]


Similar to dopamine, amphetamine dose-dependently increases the level of synaptic norepinephrine, the direct precursor of  epinephrine . [ 49 ] [ 64 ]  Based upon neuronal  TAAR1   mRNA  expression, amphetamine is thought to affect norepinephrine analogously to dopamine. [ 39 ] [ 184 ] [ 211 ]  In other words, amphetamine induces TAAR1-mediated efflux and  non-competitive  reuptake inhibition at phosphorylated  NET , competitive NET reuptake inhibition, and norepinephrine release from  VMAT2 . [ 39 ] [ 184 ]


Amphetamine exerts analogous, yet less pronounced, effects on serotonin as on dopamine and norepinephrine. [ 39 ] [ 64 ]  Amphetamine affects serotonin via  VMAT2  and, like norepinephrine, is thought to phosphorylate  SERT  via  TAAR1 . [ 39 ] [ 184 ]  Like dopamine, amphetamine has low, micromolar affinity at the human  5-HT1A receptor . [ 202 ] [ 203 ]


Acute amphetamine administration in humans increases  endogenous opioid  release in several brain structures in the  reward system . [ 204 ] [ 205 ] [ 206 ]  Extracellular levels of  glutamate , the primary  excitatory neurotransmitter  in the brain, have been shown to increase in the striatum following exposure to amphetamine. [ 188 ]  This increase in extracellular glutamate presumably occurs via the amphetamine-induced internalization of  EAAT3 , a glutamate reuptake transporter, in dopamine neurons. [ 188 ] [ 193 ]  Amphetamine also induces the selective release of  histamine  from  mast cells  and efflux from  histaminergic neurons  through  VMAT2 . [ 184 ]  Acute amphetamine administration can also increase  adrenocorticotropic hormone  and  corticosteroid  levels in  blood plasma  by stimulating the  hypothalamic–pituitary–adrenal axis . [ 36 ] [ 207 ] [ 208 ]


In December 2017, the first study assessing the interaction between amphetamine and human  carbonic anhydrase  enzymes was published; [ 209 ]  of the eleven carbonic anhydrase enzymes it examined, it found that amphetamine potently activates seven, four of which are highly expressed in the  human brain , with low nanomolar through low micromolar activating effects. [ 209 ]  Based upon preclinical research, cerebral carbonic anhydrase activation has cognition-enhancing effects; [ 214 ]  but, based upon the clinical use of  carbonic anhydrase inhibitors , carbonic anhydrase activation in other tissues may be associated with adverse effects, such as  ocular  activation exacerbating  glaucoma . [ 214 ]


The oral  bioavailability  of amphetamine varies with gastrointestinal pH; [ 29 ]  it is well  absorbed  from the gut, and bioavailability is typically 90%. [ 10 ]  Amphetamine is a weak base with a  p K a  of 9.9; [ 3 ]  consequently, when the pH is basic, more of the drug is in its  lipid  soluble  free base  form, and more is absorbed through the lipid-rich  cell membranes  of the gut  epithelium . [ 3 ] [ 29 ]  Conversely, an acidic pH means the drug is predominantly in a water-soluble  cationic  (salt) form, and less is absorbed. [ 3 ]  Approximately  20%  of amphetamine circulating in the bloodstream is bound to  plasma proteins . [ 11 ]  Following absorption, amphetamine readily  distributes  into most tissues in the body, with high concentrations occurring in  cerebrospinal fluid  and  brain  tissue. [ 17 ]


The  half-lives  of amphetamine enantiomers differ and vary with urine pH. [ 3 ]  At normal urine pH, the half-lives of dextroamphetamine and levoamphetamine are  9–11  hours and  11–14  hours, respectively. [ 3 ]  Highly acidic urine will reduce the enantiomer half-lives to 7 hours; [ 17 ]  highly alkaline urine will increase the half-lives up to 34 hours. [ 17 ]  The immediate-release and extended release variants of salts of both isomers reach  peak plasma concentrations  at 3 hours and 7 hours post-dose respectively. [ 3 ]  Amphetamine is  eliminated  via the  kidneys , with  30–40%  of the drug being excreted unchanged at normal urinary pH. [ 3 ]  When the urinary pH is basic, amphetamine is in its free base form, so less is excreted. [ 3 ]  When urine pH is abnormal, the urinary recovery of amphetamine may range from a low of 1% to a high of 75%, depending mostly upon whether urine is too basic or acidic, respectively. [ 3 ]  Following oral administration, amphetamine appears in urine within 3 hours. [ 17 ]  Roughly 90% of ingested amphetamine is eliminated 3 days after the last oral dose. [ 17 ]


Lisdexamfetamine is a  prodrug  of dextroamphetamine. [ 215 ] [ 216 ]  It is not as sensitive to pH as amphetamine when being absorbed in the gastrointestinal tract. [ 216 ]  Following absorption into the blood stream, lisdexamfetamine is completely converted by  red blood cells  to dextroamphetamine and the  amino acid   L -lysine  by  hydrolysis  via undetermined  aminopeptidase   enzymes . [ 216 ] [ 215 ] [ 217 ]  This is the  rate-limiting step  in the  bioactivation  of lisdexamfetamine. [ 215 ]  The elimination half-life of lisdexamfetamine is generally less than 1 hour. [ 216 ] [ 215 ]  Due to the necessary conversion of lisdexamfetamine into dextroamphetamine, levels of dextroamphetamine with lisdexamfetamine peak about one hour later than with an equivalent dose of immediate-release dextroamphetamine. [ 215 ] [ 217 ]  Presumably due to its rate-limited activation by red blood cells,  intravenous administration  of lisdexamfetamine shows greatly delayed time to peak and reduced peak levels compared to intravenous administration of an equivalent dose of dextroamphetamine. [ 215 ]  The pharmacokinetics of lisdexamfetamine are similar regardless of whether it is administered orally,  intranasally , or intravenously. [ 215 ] [ 217 ]  Hence, in contrast to dextroamphetamine,  parenteral  use does not enhance the subjective effects of lisdexamfetamine. [ 215 ] [ 217 ]  Because of its behavior as a prodrug and its pharmacokinetic differences, lisdexamfetamine has a longer duration of therapeutic effect than immediate-release dextroamphetamine and shows reduced misuse potential. [ 215 ] [ 217 ]


CYP2D6 ,  dopamine β-hydroxylase  (DBH),  flavin-containing monooxygenase 3  (FMO3),  butyrate-CoA ligase  (XM-ligase), and  glycine  N -acyltransferase  (GLYAT) are the enzymes known to  metabolize  amphetamine or its metabolites in humans. [ sources 17 ]  Amphetamine has a variety of excreted metabolic products, including  4-hydroxyamphetamine ,  4-hydroxynorephedrine ,  4-hydroxyphenylacetone ,  benzoic acid ,  hippuric acid ,  norephedrine , and  phenylacetone . [ 3 ] [ 12 ]  Among these metabolites, the active  sympathomimetics  are  4-hydroxyamphetamine , [ 218 ]   4-hydroxynorephedrine , [ 219 ]  and norephedrine. [ 220 ]  The main metabolic pathways involve aromatic para-hydroxylation, aliphatic alpha- and beta-hydroxylation,  N -oxidation,  N -dealkylation, and deamination. [ 3 ] [ 221 ]  The known metabolic pathways, detectable metabolites, and metabolizing enzymes in humans include the following:


The  human metagenome  (i.e., the genetic composition of an individual and all microorganisms that reside on or within the individual's body) varies considerably between individuals. [ 227 ] [ 228 ]  Since the total number of microbial and viral cells in the human body (over 100 trillion) greatly outnumbers human cells (tens of trillions), [ note 18 ] [ 227 ] [ 229 ]  there is considerable potential for interactions between drugs and an individual's microbiome, including: drugs altering the composition of the  human microbiome ,  drug metabolism  by microbial enzymes modifying the drug's  pharmacokinetic  profile, and microbial drug metabolism affecting a drug's clinical efficacy and  toxicity  profile. [ 227 ] [ 228 ] [ 230 ]  The field that studies these interactions is known as  pharmacomicrobiomics . [ 227 ]


Similar to most  biomolecules  and other  orally administered   xenobiotics  (i.e., drugs), amphetamine is predicted to undergo promiscuous metabolism by  human gastrointestinal microbiota  (primarily bacteria) prior to absorption into the  blood stream . [ 230 ]  The first amphetamine-metabolizing microbial enzyme,  tyramine oxidase  from a strain of  E. coli  commonly found in the human gut, was identified in 2019. [ 230 ]  This enzyme was found to metabolize amphetamine,  tyramine , and phenethylamine with roughly the same binding affinity for all three compounds. [ 230 ]


Amphetamine has a very similar structure and function to the  endogenous  trace amines, which are naturally occurring  neuromodulator  molecules produced in the human body and brain. [ 39 ] [ 49 ] [ 231 ]  Among this group, the most closely related compounds are  phenethylamine , the parent compound of amphetamine, and  N -methylphenethylamine , a structural  isomer  of amphetamine (i.e., it has an identical molecular formula). [ 39 ] [ 49 ] [ 232 ]  In humans, phenethylamine is produced directly from  L-phenylalanine  by the  aromatic amino acid decarboxylase  (AADC) enzyme, which converts  L-DOPA  into dopamine as well. [ 49 ] [ 232 ]  In turn,  N -methylphenethylamine  is metabolized from phenethylamine by  phenylethanolamine  N -methyltransferase , the same enzyme that metabolizes norepinephrine into epinephrine. [ 49 ] [ 232 ]  Like amphetamine, both phenethylamine and  N -methylphenethylamine  regulate monoamine neurotransmission via  TAAR1 ; [ 39 ] [ 231 ] [ 232 ]  unlike amphetamine, both of these substances are broken down by  monoamine oxidase B , and therefore have a shorter half-life than amphetamine. [ 49 ] [ 232 ]


Amphetamine is a  methyl   homolog  of the mammalian neurotransmitter  phenethylamine  with the chemical formula  C 9 H 13 N . The carbon atom adjacent to the  primary amine  is a  stereogenic center , and amphetamine is composed of a racemic 1:1 mixture of two  enantiomers . [ 11 ]  This racemic mixture can be separated into its optical isomers: [ note 19 ]   levoamphetamine  and  dextroamphetamine . [ 11 ]  At room temperature, the pure free base of amphetamine is a mobile, colorless, and  volatile   liquid  with a characteristically strong  amine  odor, and acrid, burning taste. [ 22 ]  Frequently prepared solid salts of amphetamine include amphetamine adipate, [ 233 ]  aspartate, [ 29 ]  hydrochloride, [ 234 ]  phosphate, [ 235 ]  saccharate, [ 29 ]  sulfate, [ 29 ]  and tannate. [ 236 ]  Dextroamphetamine sulfate is the most common enantiopure salt. [ 50 ]  Amphetamine is also the parent compound of  its own structural class , which includes a number of psychoactive  derivatives . [ 4 ] [ 11 ]  In organic chemistry, amphetamine is an excellent  chiral ligand  for the  stereoselective synthesis  of  1,1'-bi-2-naphthol . [ 237 ]


The substituted derivatives of amphetamine, or "substituted amphetamines", are a broad range of chemicals that contain amphetamine as a "backbone"; [ 4 ] [ 51 ] [ 238 ]  specifically, this  chemical class  includes  derivative  compounds that are formed by replacing one or more hydrogen atoms in the amphetamine core structure with  substituents . [ 4 ] [ 51 ] [ 239 ]  The class includes amphetamine itself, stimulants like methamphetamine, serotonergic  empathogens  like  MDMA , and  decongestants  like  ephedrine , among other subgroups. [ 4 ] [ 51 ] [ 238 ]


Since the first preparation was reported in 1887, [ 240 ]  numerous synthetic routes to amphetamine have been developed. [ 241 ] [ 242 ]  The most common route of both legal and illicit amphetamine synthesis employs a non-metal reduction known as the  Leuckart reaction  (method 1). [ 50 ] [ 243 ]  In the first step, a reaction between phenylacetone and  formamide , either using additional  formic acid  or formamide itself as a reducing agent, yields  N -formylamphetamine . This intermediate is then hydrolyzed using hydrochloric acid, and subsequently basified, extracted with organic solvent, concentrated, and distilled to yield the free base. The free base is then dissolved in an organic solvent, sulfuric acid added, and amphetamine precipitates out as the sulfate salt. [ 243 ] [ 244 ]


A number of  chiral resolutions  have been developed to separate the two enantiomers of amphetamine. [ 241 ]  For example, racemic amphetamine can be treated with  d- tartaric acid  to form a  diastereoisomeric  salt which is  fractionally  crystallized to yield dextroamphetamine. [ 245 ]  Chiral resolution remains the most economical method for obtaining optically pure amphetamine on a large scale. [ 246 ]  In addition, several  enantioselective  syntheses of amphetamine have been developed. In one example,  optically pure   ( R )-1-phenyl-ethanamine  is condensed with phenylacetone to yield a chiral  Schiff base . In the key step, this intermediate is reduced by  catalytic hydrogenation  with a transfer of chirality to the carbon atom alpha to the amino group. Cleavage of the  benzylic  amine bond by hydrogenation yields optically pure dextroamphetamine. [ 246 ]


A large number of alternative synthetic routes to amphetamine have been developed based on classic organic reactions. [ 241 ] [ 242 ]  One example is the  Friedel–Crafts  alkylation of  benzene  by  allyl chloride  to yield beta chloropropylbenzene which is then reacted with ammonia to produce racemic amphetamine (method 2). [ 247 ]  Another example employs the  Ritter reaction  (method 3). In this route,  allylbenzene  is reacted  acetonitrile  in sulfuric acid to yield an  organosulfate  which in turn is treated with sodium hydroxide to give amphetamine via an  acetamide  intermediate. [ 248 ] [ 249 ]  A third route starts with  ethyl 3-oxobutanoate  which through a double alkylation with  methyl iodide  followed by  benzyl chloride  can be converted into  2-methyl-3-phenyl-propanoic  acid. This synthetic intermediate can be transformed into amphetamine using either a  Hofmann  or  Curtius rearrangement  (method 4). [ 250 ]


A significant number of amphetamine syntheses feature a  reduction  of a  nitro ,  imine ,  oxime , or other nitrogen-containing  functional groups . [ 242 ]  In one such example, a  Knoevenagel condensation  of  benzaldehyde  with  nitroethane  yields  phenyl-2-nitropropene . The double bond and nitro group of this intermediate is  reduced  using either catalytic  hydrogenation  or by treatment with  lithium aluminium hydride  (method 5). [ 243 ] [ 251 ]  Another method is the reaction of  phenylacetone  with  ammonia , producing an imine intermediate that is reduced to the primary amine using hydrogen over a palladium catalyst or lithium aluminum hydride (method 6). [ 243 ]


Amphetamine is frequently measured in urine or blood as part of a  drug test  for sports, employment, poisoning diagnostics, and forensics. [ sources 18 ]  Techniques such as  immunoassay , which is the most common form of amphetamine test, may cross-react with a number of sympathomimetic drugs. [ 255 ]  Chromatographic methods specific for amphetamine are employed to prevent false positive results. [ 256 ]  Chiral separation techniques may be employed to help distinguish the source of the drug, whether prescription amphetamine, prescription amphetamine prodrugs, (e.g.,  selegiline ),  over-the-counter drug  products that contain  levomethamphetamine , [ note 20 ]  or illicitly obtained substituted amphetamines. [ 256 ] [ 259 ] [ 260 ]  Several prescription drugs produce amphetamine as a  metabolite , including  benzphetamine ,  clobenzorex ,  famprofazone ,  fenproporex ,  lisdexamfetamine ,  mesocarb , methamphetamine,  prenylamine , and  selegiline , among others. [ 2 ] [ 261 ] [ 262 ]  These compounds may produce positive results for amphetamine on drug tests. [ 261 ] [ 262 ]  Amphetamine is generally only detectable by a standard drug test for approximately 24 hours, although a high dose may be detectable for  2–4  days. [ 255 ]


For the assays, a study noted that an  enzyme multiplied immunoassay technique  (EMIT) assay for amphetamine and methamphetamine may produce more false positives than  liquid chromatography–tandem mass spectrometry . [ 259 ]   Gas chromatography–mass spectrometry  (GC–MS) of amphetamine and methamphetamine with the derivatizing agent  ( S )-(−)-trifluoroacetylprolyl  chloride allows for the detection of methamphetamine in urine. [ 256 ]  GC–MS of amphetamine and methamphetamine with the chiral derivatizing agent  Mosher's acid chloride  allows for the detection of both dextroamphetamine and dextromethamphetamine in urine. [ 256 ]  Hence, the latter method may be used on samples that test positive using other methods to help distinguish between the various sources of the drug. [ 256 ]


Amphetamine was first synthesized in 1887 in Germany by Romanian chemist  Lazăr Edeleanu  who named it  phenylisopropylamine ; [ 240 ] [ 264 ] [ 265 ]  its stimulant effects remained unknown until 1927, when it was independently resynthesized by  Gordon Alles  and reported to have  sympathomimetic  properties. [ 265 ]  Amphetamine had no medical use until late 1933, when  Smith, Kline and French  began selling it as an  inhaler  under the brand name  Benzedrine  as a decongestant. [ 30 ]  Benzedrine sulfate was introduced 3 years later and was used to treat a wide variety of  medical conditions , including  narcolepsy ,  obesity ,  low blood pressure ,  low libido , and  chronic pain , among others. [ 52 ] [ 30 ]  During  World War II , amphetamine and  methamphetamine  were used extensively by both the  Allied  and  Axis  forces for their stimulant and performance-enhancing effects. [ 240 ] [ 266 ] [ 267 ]  As the addictive properties of the drug became known, governments began to place strict controls on the sale of amphetamine. [ 240 ]  For example, during the early 1970s in the United States, amphetamine became a  schedule II controlled substance  under the  Controlled Substances Act . [ 9 ]  In spite of strict government controls, amphetamine has been used legally or illicitly by people from a variety of backgrounds, including authors, [ 268 ]  musicians, [ 269 ]  mathematicians, [ 270 ]  and athletes. [ 28 ]


Amphetamine is illegally synthesized in  clandestine labs  and sold on the  black market , primarily in European countries. [ 271 ]  Among European Union (EU) member states in 2018, [update]  11.9 million adults of ages  15–64  have used amphetamine or methamphetamine at least once in their lives and 1.7 million have used either in the last year. [ 272 ]  During 2012, approximately 5.9  metric tons  of illicit amphetamine were seized within EU member states; [ 273 ]  the "street price" of illicit amphetamine within the EU ranged from  € 6–38  per gram during the same period. [ 273 ]  Outside Europe, the illicit market for amphetamine is much smaller than the market for methamphetamine and MDMA. [ 271 ]


As a result of the  United Nations  1971  Convention on Psychotropic Substances , amphetamine became a schedule II controlled substance, as defined in the treaty, in all 183 state parties. [ 31 ]  Consequently, it is heavily regulated in most countries. [ 274 ] [ 275 ]  Some countries, such as South Korea and Japan, have banned substituted amphetamines even for medical use. [ 276 ] [ 277 ]  In other nations, such as Brazil ( class A3 ), [ 278 ]  Canada ( schedule I drug ), [ 279 ]  the Netherlands ( List I drug ), [ 280 ]  the United States ( schedule II drug ), [ 9 ]  Australia ( schedule 8 ), [ 281 ]  Thailand ( category 1 narcotic ), [ 282 ]  and United Kingdom ( class B drug ), [ 283 ]  amphetamine is in a restrictive national drug schedule that allows for its use as a medical treatment. [ 271 ] [ 32 ]


Several currently marketed amphetamine formulations contain both enantiomers, including those marketed under the brand names Adderall, Adderall XR, Mydayis, [ note 1 ]  Adzenys ER,  Adzenys XR-ODT , Dyanavel XR, Evekeo, and Evekeo ODT. Of those, Evekeo (including Evekeo ODT) is the only product containing only racemic amphetamine (as amphetamine sulfate), and is therefore the only one whose  active moiety  can be accurately referred to simply as "amphetamine". [ 1 ] [ 36 ] [ 119 ]  Dextroamphetamine, marketed under the brand names Dexedrine and Zenzedi, is the only  enantiopure  amphetamine product currently available. A  prodrug  form of dextroamphetamine,  lisdexamfetamine , is also available and is marketed under the brand name Vyvanse. As it is a prodrug, lisdexamfetamine is structurally different from dextroamphetamine, and is inactive until it metabolizes into dextroamphetamine. [ 38 ] [ 216 ]  The free base of racemic amphetamine was previously available as Benzedrine, Psychedrine, and Sympatedrine. [ 2 ]  Levoamphetamine was previously available as Cydril. [ 2 ]  Many current amphetamine pharmaceuticals are  salts  due to the comparatively high volatility of the free base. [ 2 ] [ 38 ] [ 50 ]  However, oral suspension and  orally disintegrating tablet  (ODT)  dosage forms  composed of the free base were introduced in 2015 and 2016, respectively. [ 119 ] [ 284 ] [ 285 ]  Some of the current brands and their generic equivalents are listed below.


Asthmador  was a  nonprescription  treatment for the relief of bronchial  asthma  made by the R. Schiffmann Company.


It consisted of a mixture of  belladonna ,  stramonium  and  potassium perchlorate , [ 1 ]  and was a fine powder intended to be burned and the smoke inhaled. The primary  alkaloid  present in the mixture was  hyoscyamine , and when the powder was ingested rather than burned, could be used to induce hallucinations. In severe overdose it could hospitalize the patient or cause death.


Prior to the introduction of rescue inhalers in the mid-1950s this was an over-the-counter remedy for asthma attacks. Asthmador was sold in packets like cigarettes, in tins like pipe tobacco, or as an incense. The  paroxysms  would abate within a few minutes of inhaling the mixture. [ 1 ] [ 2 ]


This  hallucinogen -related article is a  stub . You can help Wikipedia by  expanding it .


AZD1305  is an experimental drug candidate that is under investigation for the management and reversal of  cardiac arrhythmias , specifically  atrial fibrillation  and  flutter .  In vitro  studies have shown that this combined-ion channel blocker inhibits rapidly the activating delayed-rectifier potassium current (IKr), L-type calcium current, and inward sodium current (INa). [ 1 ]


Atrial fibrillation (AF) is a form of cardiac arrhythmia that arises with disorganized and rapid action upotentials conducted through the atria, resulting in irregular atrial contraction. [ 2 ]   Causes of AF include hypertension, cardiomyopathies, alcohol consumption, viral infections, and sleep apnea, which can cause AF by increasing the occurrence of early after depolarizations (EADs). [ 3 ]  EAD is an abnormal depolarization and increase in action potential frequency that occurs in cardiac myocytes before normal repolarization is complete. [ 4 ] [ 5 ]


AZD1305 possesses class III anti-arrhythmic activity by blocking the  human ether-a-go-go-related gene  (hERG) potassium channel. [ 4 ]  hERG contributes to the formation of potassium ion channel proteins that are responsible for the conduction of the rapid delayed rectifying potassium current. [ 6 ]  Blocking this current prolongs action potential duration (APD), increases refractory period, and delays repolarization of cardiac myocytes in the ventricles and atria. [ 4 ]  Delayed repolarizations increase susceptibility to EAD.


AZD 1305 also acts on voltage gated sodium channels (Nav1.5) by attenuating the peak (INapeak) and late sodium current (INalate), though the latter current is more potently inhibited. [ 5 ]  Attenuation of INalate by AZD1305 is concentration-dependent and decreases the slope of depolarization and delays repolarization. INalate blockade by AZD1305 depressed the threshold of sodium channel excitation and prolongs APD. [ 7 ]  Blockade of IKr may lead to excessive prolongation of APD and repolarization instability, which may promote arrhythmic conditions in the heart, including EAD and Torsade de Pointes (TdP). [ 5 ]  Under IKr blockade a pronounced INalate can contribute to the development of arrhythmias by increasing repolarization variability. AZD1305 blockade of the INalate  modulates IKr-blockade induced APD instability, repolarization vulnerability, and variability in beat-to-beat APD. [ 4 ] [ 5 ]


In vivo ,  as well as in vitro studies discovered that inhibition of INa and IKr by AZD1305 is much greater in atrial versus ventricular myocytes. [ 1 ] [ 7 ]  This atrial-selective activity of AZD1305 prolongs effective refractory period (ERF) and induces post-repolarization refractoriness (PRR) in atrial myocytes, which aids in suppressing atrial fibrillation. [ 7 ]


AF and TdP may be induced with L-type calcium channel hyperactivity and increased calcium release from the sarcoplasmic reticulum. The L-type calcium current is also blocked by AZD 1305 which suppresses the intracellular rises in calcium levels and calcium oscillations that produce EADs. [ 1 ] [ 4 ]  The combined block of INa, IKr, and L-type calcium current is key to the anti-arrhythmic potential of AZD1305 compared IKr blockade alone. [ 1 ]


Available anti-arrhythmic agents (AAD) used for the maintenance of AF are often accompanied with the risk of developing ventricular pro-arrhythmias, as they are often limited to targeting a single ion channel (i.e., Dofeiltide) and have homogenous activity throughout the heart. [ 4 ]  AZD1305 offers the advantage of being an atrial-selective AAD and combined ion channel blocker that provides protection against EAD,  repolarization dispersion, and ventricular pro-arrhythmias. [ 1 ] [ 4 ] [ 7 ]  Simultaneously, AZD1305 suppresses AF in a safe and efficacious manner, which could potentially be an ideal first-line treatment option in the future. [ 1 ]


Cardiovascular agents  are drugs used to treat diseases associated with the heart or blood vessels. These medications are available for purchase only with a physician’s  prescription . They include, but are not limited to, drugs that target  hypertension  ( antihypertensives ),  hyperlipidemia  ( antihyperlipidemics ) and  blood clotting  (blood-thinners) to reduce the risk of  cardiovascular diseases .


Antihypertensive agents are classified according to their mechanism of actions. The most common classes prescribed are  diuretics ,  angiotensin-converting enzyme inhibitors  (ACEIs),  angiotensin II receptor blockers  (ARBs),  calcium channel blockers  (CCBs) and  beta-blockers .


Antihyperlipidemic agents most often prescribed are  statins ,  ezetimibe  and  fibrates . They either lower  low-density lipoprotein cholesterol  (LDL-C) or  triglyceride  (TG) levels in blood to manage  hypercholesterolaemia .


Blood-thinning agents, particularly  antiplatelets  and  anticoagulants , maintain smooth blood flow by preventing blood clot formation in blood vessels. Two main categories of antiplatelets are COX-1 inhibitors and  ADP receptor inhibitors , while anticoagulants include  vitamin K antagonists , direct oral anticoagulants (DOACs) and indirect thrombin inhibitors.


Since cardiovascular agents have narrow  therapeutic windows , a slight rise in dose may result in severe  toxicity . Hence, monitoring at baseline and during therapy is needed. For  drug overdose , stabilisation and  antidotes  help lower drug concentrations.


Cardiovascular agents are drugs that affect the rate and intensity of cardiac contraction, blood vessel diameters, blood volume, blood clotting and blood  cholesterol  levels. [ 1 ]  They are indicated to treat diseases related to the heart or the vascular system (blood vessels), such as  hypertension ,  hyperlipidemia ,  coagulation disorders ,  heart failure  and  coronary artery disease . [ 1 ]  These drugs are  prescription-only medicines , meaning that they should be administered strictly under a doctor’s instruction and can only be obtained by means of a doctor’s prescription.


Antihypertensive agents  comprise multiple classes of compounds that are intended to manage hypertension (high blood pressure).  Antihypertensive therapy aims to maintain a blood pressure goal of <140/90 mmHg in all patients, as well as to prevent the progression or recurrence of  cardiovascular diseases  (CVD) in hypertensive patients with established CVD. [ 2 ]  An optimal blood pressure control is essential to prevent target-organ damage associated with complications of hypertension such as  heart failure ,  ischemic heart diseases ,  stroke , and  renal failure , ultimately reducing the risk of premature mortality. [ 2 ]  Antihypertensives are classified by different mechanisms or sites of action. Some of the most commonly used drugs to treat hypertension include  diuretics ,  angiotensin-converting enzyme inhibitors  (ACEI),  angiotensin II receptor blockers  (ARBs),  calcium channel blockers  (CCBs), and  beta-blockers .


Diuretics  act primarily by reducing the reabsorption of sodium at different sites of the renal tubular system and consequently promoting the elimination of sodium and water with increased urine output. [ 3 ]


For loop diuretics, thiazide diuretics and thiazide-like diuretics, their common side effects include  hypokalemia ,  hyponatremia ,  metabolic alkalosis  and  hyperglycaemia . [ 4 ]  For potassium-sparing diuretics, its common side effects include  hyponatremia ,  hyperkalemia ,  metabolic acidosis  and sexual dysfunction specifically for spironolactone. [ 4 ] [ 5 ]


The use of diuretics should be avoided in patients with severe dehydration,  anuria  (absence of urine production). [ 4 ]  Diuretics are contraindicated in cases of severe electrolyte abnormalities and should not be administered until an electrolyte balance is restored. Special attention should be given to the use of thiazide and loop diuretics as they may exacerbate  diabetes  and  gout . [ 4 ]


Angiotensin-converting-enzyme inhibitors  (ACEI) block the conversion of angiotensin I to angiotensin II by inhibiting the action of angiotensin-converting-enzyme, causing the reduction of blood volume and peripheral vascular resistance. [ 6 ]


Some side effects of ACEI include hypotension,  renal insufficiency , and hyperkalemia. [ 7 ]  Dry cough is also a common side effect believed to be associated with decreased  bradykinin  breakdown.  Angioedema  is another possible but rare complication due to elevated levels of bradykinin. [ 6 ]


ACEI should not be used in combinations with angiotensin II receptor blockers (ARBs) or  direct renin inhibitors  and is contraindicated in people with a history of  angioedema  and pregnancy. [ 6 ] [ 8 ]  “Triple whammy”, the concurrent use of an ACEI with  diuretics  and  non-steroidal anti-inflammatory drugs  (NSAIDs), is also contraindicated as this combination has been correlated with an increased risk of  acute kidney injury . [ 8 ] [ 7 ]  ACEI should be used with caution in patients with renal impairment, and renal failure risk in severe bilateral  renal stenosis . [ 8 ]


Angiotensin II receptor blockers  (ARBs) work by inhibiting the action of angiotensin II on, specifically AT1 receptors to prevent the vasoconstrictor effects of this receptor and block the peripheral sympathetic activity. [ 9 ]


ARBs are generally well-tolerated, in which they are less likely to cause cough or angioedema compared to ACEI. Common side effects include hypotension,  renal insufficiency , and hyperkalemia. [ 7 ]


The contraindications of ARBs are similar to those of ACEI, including the contraindicated combinations with ACEI or direct renin inhibitors, "triple whammy" (the concurrent use of an ARB with diuretics and NSAIDs) and in patients with a history of  angioedema  and pregnancy. [ 6 ] [ 7 ] [ 8 ]  In addition, ARB should be used with caution in patients with renal impairment and renal failure risk in severe bilateral  renal stenosis [ 8 ]


Calcium channel blockers  (CCBs) preferentially block the  L-type voltage-gated calcium channels  to prevent the flow of calcium influx in the blood vessels and the heart, thereby reducing peripheral vascular resistance and cardiac output respectively. [ 10 ]


In general, the side effects of CCBs include  peripheral edema  and  gingival hyperplasia  when CCBs are used chronically. [ 11 ] [ 12 ]  To add on, DHP may cause  reflex tachycardia  and  peripheral edema , while non-DHP may cause  bradycardia  and worsening of cardiac function due to reduced cardiac contractility and cardiac conduction. [ 12 ] [ 13 ]


Non-dihydropyridines are contraindicated in patients with  heart failure with reduced ejection fraction  (HFrEF), and second- or third-degree  atrioventricular block . [ 13 ]  Special attention should be given to the coadministration of non-DHP with  beta-blockers  or  ivabradine  due to the increased risk of bradycardia. [ 13 ]  Since both DHP and non-DHP are metabolized through the  CYP3A4  system, grapefruit juice containing  furanocoumarins  (the potent inhibitors of the CYP3A4 enzyme) should be avoided. [ 13 ]


Beta-blockers  act as competitive antagonists that block the effects of  catecholamines  at  beta-adrenergic receptor  sites, resulting in reduced rate and force of contraction of the heart, as well as reduced peripheral vascular resistance. [ 14 ]


Some common side effects include increased airway resistance for non-selective beta-blockers, exacerbation of peripheral vascular diseases, and hypotension [ 15 ]


Beta-blockers are contraindicated in patients with second- or third-degree  atrioventricular block . In particular, beta-blockers with intrinsic sympathomimetic activity are contraindicated in patients with  myocardial infarction ,  heart failure  or severe  bradycardia . [ 15 ] [ 16 ]  Beta-blockers should be used with caution in patients with  asthma  or  chronic obstructive pulmonary disease  (COPD) due to bronchoconstriction, and in patients with  diabetes mellitus  (DM) due to masking of  hypoglycaemia . [ 16 ]


Antihyperlipidemic agents  are drugs used for the treatment of  dyslipidemia , a condition of abnormal lipid levels in the body. It is characterised by elevations of  low-density lipoprotein cholesterol  (LDL-C) and  triglycerides  (TGs) in the blood. [ 17 ]   Hypercholesterolaemia  induces the formation of plaques due to the buildup of excess cholesterol within the arterial wall. This increases the risk of, or aggravate,  atherosclerotic cardiovascular disease  (ASCVD). Therefore, antihyperlipidemic drugs are introduced for primary and secondary  coronary heart disease  prevention, as well as for reduction in mortality from acute coronary outcomes. [ 18 ]  These drugs include  statins ,  ezetimibe  and  fibrates .


Statins , also known as beta-hydroxy-beta-methylglutaryl-Coenzyme A (HMG-CoA) reductase inhibitors, are the  first-line  drugs for  hypercholesterolaemia . [ 19 ]  Examples of this drug class are  atorvastatin ,  rosuvastatin ,  fluvastatin ,  simvastatin ,  pravastatin  and  lovastatin .


Most efficacious in lowering LDL-C levels, statins block the action of  HMG-CoA reductase  through  competitive inhibition . [ 18 ]  HMG-CoA reductase, an enzyme found in  hepatocytes , is responsible for the conversion of  HMG-CoA  to  mevalonic acid  for cholesterol biosynthesis. Inhibition of this enzyme reduces the synthesis and thus, availability of endogenous cholesterol. This reduction in intracellular cholesterol, in turn, causes an increase in the number of  LDL receptors  on hepatic cells. The elevation of LDL receptor expression decreases the plasma LDL-C level by promoting hepatic uptake of LDL from circulation.


While statins are generally well-tolerated, severe adverse effects such as  hepatotoxicity  and myotoxicity may occur in rarity. Statin-induced hepatotoxicity can cause  autoimmune hepatitis  and an elevation in serum levels of hepatic enzymes such as  alanine aminotransferase , impairing liver function. [ 20 ]  Myotoxicity is commonly presented with statin-associated muscle symptoms (SAMS), which include  myalgia  and  myositis . [ 21 ]  In rare cases, they may progress into  rhabdomyolysis , a condition manifested by muscle  necrosis  and  myoglobinuria  due to heightened  creatine kinase  levels. [ 22 ] [ 23 ]  Another consequence of taking statins is the risk of developing new-onset diabetes, which is more prominent in individuals with high TG levels and  body mass index  (BMI). [ 19 ]  However, the risk is far outweighed by the benefits from statin therapy for the reduction in cardiovascular outcomes. [ 20 ]


Given the potential of statins to exacerbate liver and muscle abnormalities, contraindications of statins include  decompensated   liver cirrhosis ,  acute liver failure , unexplained and persistent elevations of serum transaminases, and myopathy. Moreover, statins are not recommended in pregnancy as they may cause foetal harm because of their mechanism of action. [ 19 ]


Metabolised by the  Cytochrome P450  (CYP450) enzyme, a major metabolic enzyme, simvastatin and lovastatin may accumulate in blood when administered with CYP450 inhibitors. [ 18 ] [ 24 ]  Some of these inhibitors are  azole antifungals ,  macrolides ,  CCBs ,  ticagrelor  (antiplatelet) and  grapefruit juice . Concomitant use of statins with CYP450 inhibitors, along with  gemfibrozil  (fibrate), increases the risk of  myopathy . [ 20 ] [ 23 ] [ 25 ]  This is especially significant in patients under  polypharmacy .


Ezetimibe  is a selective  cholesterol absorption inhibitor  that inhibits the intestinal absorption of cholesterol by binding to the  Niemann-Pick C1-Like 1  (NPC1L1) protein on the gastrointestinal epithelium. [ 23 ]  This reduces the delivery of cholesterol to the liver, which then induces the  upregulation  of LDL receptor expression, lowering hepatic cholesterol stores and enhancing  clearance  of circulating LDL. More often prescribed as  second-line therapy  for dyslipidemia, ezetimibe is used in individuals with statin  intolerance  or those who failed to achieve the target LDL-C level on statin  monotherapy . [ 26 ] [ 27 ]  In particular, ezetimibe and statin dual therapy have shown a 15% greater LDL-C decrease compared with same-dose statins alone, favouring recovery from  acute coronary syndrome . [ 23 ]


Whilst ezetimibe intolerance is uncommon, some reports have been made regarding gastrointestinal and musculoskeletal effects. [ 28 ]  Common adverse reactions of ezetimibe are nausea, abdominal pain, headache, fatigue,  arthralgia ,  myalgia  and  hypersensitivity reactions . [ 29 ]  On rare occasions, ezetimibe may cause  cholecystitis ,  pancreatitis , elevation of serum transaminase level and  rhabdomyolysis .


As  hepatic impairment  hinders the rate of ezetimibe metabolism by the liver, ezetimibe is not recommended in individuals with moderate or severe hepatic insufficiency due to prolonged systemic exposure to the drug. [ 19 ]  In addition, similar to combined statin and fibrate intake, individuals should avoid the concurrent use of ezetimibe with  gemfibrozil  as it would increase ezetimibe concentration in the body. [ 25 ]


Fibrates , known as derivatives of fibric acids, are  peroxisome proliferator-activated receptor alpha  (PPAR-α)  agonists  primarily used for lowering TG levels and management of  atherogenic  dyslipidemia. [ 30 ] [ 31 ] [ 32 ]  Typical drugs of the class include  fenofibrate ,  bezafibrate ,  ciprofibrate  and  gemfibrozil .


Through activation of PPAR-α receptors, fibrates decreases circulating TG via  upregulation  of  lipoprotein lipase  (LPL) expression and  downregulation  of  apolipoprotein C-III  (ApoC-III) gene expression. [ 23 ] [ 29 ]  LPL is a hepatic enzyme involved in  lipolysis , whereas ApoC-III is an inhibitor of LPL.


Comparable to statins and ezetimibe, fibrates are usually well-tolerated with mild adverse reactions, with the exception of gemfibrozil. Some of the more prevalent side effects are minor  gastrointestinal disturbances  such as abdominal pain and cholithiasis on account of the increased excretion of biliary cholesterol. [ 23 ]  Among atypical adverse effects,  myositis  can occur in patients under gemfibrozil therapy, especially in those with  renal insufficiency  or under co-treatment with statins. In contrast, the risk of myopathy is much lower if fenofibrate is used in replacement of gemfibrozil owing to its different  pharmacokinetic  pathway. Other rare effects are increased serum  transaminase  levels,  agranulocytosis  and  anaemia . [ 31 ]


As fenofibrate possess the same binding mechanism as  warfarin  in the blood, this combination should be addressed with caution as fenofibrate may potentiate the anticoagulant effect of warfarin. [ 33 ]  Furthermore, fibrates are contraindicated in patients with active liver disease, severe renal impairment or pre-existing  gallbladder disease , as well as in lactating mothers. [ 31 ]


Blood-thinning agents are divided into two groups,  antiplatelet drugs  and  anticoagulants . They are indicated to facilitate smooth blood flow within blood vessels by preventing the formation of  blood clots  and retarding their growth. [ 34 ]  Blood clots are formed to prevent an injured blood vessel from excessive bleeding by a mechanism called  hemostasis . The body has intrinsic mechanisms to dissolve the blood clot as the injury heals. However, it can be dangerous when clots do not dissolve naturally and develop within vessels, also known as  thrombosis . Hence, blood-thinning medications can be prescribed to reduce the risk of  cardiovascular diseases  led by blood clots, such as  myocardial infarction  (heart attack),  ischemic stroke , and  venous thromboembolism . [ 35 ]   Haemorrhage  (internal bleeding) is the most prominent side effect of blood-thinning therapy. [ 36 ]  Concomitant use of drugs that increase the risk of bleeding is not recommended. Meanwhile, patients should receive education about proper management of cuts, bruises and nosebleeds. The agents can be classified according to different mechanisms of action.


Antiplatelet drugs  inhibit blood cells called  platelets  from aggregating to form a clot.


Potent antiplatelet medications that irreversibly inhibit the activity of  cyclooxygenase  (COX), an  enzyme  involved in the synthesis of  thromboxane A 2  (TXA2) which is responsible for platelet activation and aggregation. The major member of this class is  aspirin . Some common adverse effects associated with this class of medications include  bronchospasm  and gastrointestinal disturbances such as  dyspepsia  and  nausea . Therefore, this class of drugs should be used with caution in patients with a history of  peptic ulcer disease . [ 34 ] [ 37 ]


Also known as P2Y12  receptor antagonists , they work by reversibly interacting with the P2Y12 receptor to inhibit the  adenosine diphosphate  (ADP) receptors on platelets, thus preventing the linkage of platelets by  fibrinogen . [ 34 ] [ 35 ]  ADP-induced platelet aggregation and activation are hence hindered. Examples include  clopidogrel ,  prasugrel  and  ticagrelor .  Clopidogrel  has a common drug interaction with  CYP2C19  inhibitors, particularly  omeprazole  and  esomeprazole  which are indicated for treatment of  peptic ulcer  and  gastro-oesophageal reflux disease (GERD) . As the activation of  clopidogrel  requires an enzyme called CYP2C19, its inhibitors should be avoided. [ 38 ]


Anticoagulants  are considered more aggressive than  antiplatelet drugs . [ 34 ]   Anticoagulants  work by interfering with various clotting factors to lengthen the time for  coagulation . This can be achieved by either reducing the formation of bioactive clotting factors or accelerating the inactivation of clotting factors.


Drugs that inhibit the formation of the vitamin K-dependent clotting factors and hence  thrombin , an endogenous protein involved in the  coagulation cascade . Vitamin K is an essential cofactor for the synthesis of clotting factors. By inhibiting  vitamin K epoxide reductase , an enzyme for activating the vitamin K available in the body, the formation of bioactive clotting factors can be reduced. Although  warfarin  is commonly prescribed, it exhibits a delayed onset of action, which takes approximately 5 to 7 days to reach its full therapeutic effect. [ 39 ]  Apart from  haemorrhage ,  jaundice  (yellowing of the skin and eyes) is also a common side effect caused by this class of drug. [ 34 ]


DOACs are agents that inhibit the formation of  thrombin  which is the central effector of coagulation derived from  factor Xa . They are categorised into  direct thrombin inhibitors  and  direct factor Xa inhibitors . Direct thrombin inhibitors bind to the active sites of free or clot-bound thrombin to inhibit its effects.  Dabigatran etexilate  is a common example which has a rapid onset of action. [ 40 ]  Whereas direct factor Xa inhibitors including  apixaban  and  rivaroxaban  directly bind to clotting factor Xa to block its activity, thus inhibiting thrombin formation. [ 34 ]  DOACs are advantageous over  warfarin  because of a wider  therapeutic window , which indicates safer and more effective use with minimal adverse effects. DOACs also have more stable and predictable anticoagulation effects. Therefore, routine coagulation monitoring is not required. [ 41 ]


Indirect thrombin inhibitors bind to  antithrombin  to enhance the rate of inactivation of clotting factors, indirectly inactivating thrombin through actions on antithrombin. [ 42 ]   Heparin  is a widely used anticoagulant. It is administered intravenously (into a vein) or subcutaneously (below the skin). Heparin can exert an immediate anti-clotting effect which is useful for the treatment of acute symptoms. [ 36 ]  Besides, heparin therapy is indicated for anticoagulation during pregnancy as it does not cross the  placenta  and is not associated with fetal malformations. [ 43 ] [ 44 ]


Cardiovascular agents generally have narrow  therapeutic indices , implying that small differences in dose or blood concentration may give rise to adverse drug reactions. [ 45 ]  Serious acute toxicity may result from accidental, intentional or  iatrogenic  overdose. [ 46 ]  Therefore, patients need to be aware of any unusual and serious side effects. Seek immediate medical attention if a  drug overdose  is suspected.


General management of acute poisoning requires stabilisation of the airway, breathing, and circulation. [ citation needed ]  Supportive treatment to reduce further absorption of the drug is achievable by the administration of  activated charcoal . [ 47 ]  Antidotes can be used to reverse effects of the overdosed medication if the exact poisoning agent is identified. However, only a few  antidotes  are available for cardiovascular medications.


Table 1: antidotes for cardiovascular agent overdose


For patients taking antihyperlipidemic agents,  liver function tests  have to be conducted before and during the therapy to monitor the elevation of liver enzymes which may result in  hepatotoxicity , especially for those undergoing  statin therapy . [ 52 ]  For patients taking blood-thinners, signs of severe bleeding should be monitored. The effect of  aspirin  can be life-threatening if taken over 150 mg/kg of body weight. [ 47 ]   The medication should be discontinued at the first sign of excessive bleeding.


Cathinone  ( / ˈ k æ θ ɪ n oʊ n / ; also known as  β-ketoamphetamine ) is a  monoamine   alkaloid  found in the  shrub   Catha edulis  ( khat ) and is chemically similar to  ephedrine ,  cathine ,  methcathinone  and other  amphetamines . It is probably the main contributor to the  stimulant  effect of  Catha edulis , also known as  khat . Cathinone differs from many other amphetamines in that it has a  ketone   functional group . Other phenethylamines that share this structure include the stimulants  methcathinone ,  MDPV ,  mephedrone  and the  antidepressant   bupropion .


Khat  has been cultivated in the  Horn of Africa  and  Arabian Peninsula  region of the world for thousands of years. It is most commonly chewed for the  euphoric  effect it produces. The active ingredient was first proposed in 1930, when  cathine  was identified as a predominant alkaloid in the plant. [ 4 ]  Cathine was thought to be the main active ingredient in khat until the 1960s, when it was found that the amount of cathine in the khat leaves is insufficient to produce the effects observed. In 1975, the United Nations Narcotic Laboratory analyzed khat leaves from  Yemen ,  Kenya  and  Madagascar  and found evidence of a different alkaloid, cathinone. [ 4 ]  Cathinone is molecularly similar to cathine, but is much more abundant in younger plants.  This finding caused scientists to speculate that cathinone was the true active ingredient in khat. [ 4 ]


A study was conducted in 1994 to test the effects of cathinone. Six volunteers who had never chewed khat were given an active khat sample and a cathinone-free  placebo  sample. [ 5 ]  The researchers analyzed the participants' moods, activity levels and blood pressure before and after consuming the khat or placebo. This analysis showed that cathinone produced amphetamine-like symptoms, leading the researchers to confirm that cathinone, not cathine, is the active ingredient in khat leaves. [ 5 ]


Over 20 million people in the  Arabian Peninsula  and  East Africa  chew khat leaves daily.  It is an important piece of the culture and economy in this region, especially in  Ethiopia  (where khat is said to have originated), Kenya,  Djibouti , Somalia and Yemen.  Men usually chew it during parties or other social gatherings while smoking cigarettes and drinking tea.  Farmers and other workers also use khat in the afternoon to reduce fatigue and hunger as the day goes on.  It functions like the  caffeine  in a strong cup of coffee as an anti-fatigue drug.  Students and drivers have been known to use it to stay alert for longer periods of time. [ 6 ]


In order to produce its desired effects, khat leaves should be chewed fresh.  The fresh leaves have a higher concentration of cathinone.  Waiting too long after cultivation to chew the leaf will allow the cathinone to break down into its less potent form, cathine.  Because of the need for quick chewing, it is a habit that has historically been prevalent only where the plant grows.  However, in the recent years with improvements in road and air transport, khat chewing has spread to all corners of the world.


The cultivation of khat in Yemen is a highly profitable industry for farmers.  Khat plants will grow differently depending on the climate they are grown in and each one will produce different amounts of cathinone. [ 7 ]   It generally grows best in coastal, hot climates.  In Yemen, the khat plant is named after the region in which it is grown.  The Nehmi khat plant has the highest known concentration of cathinone, 342.5 mg/100 g. [ 7 ]


Internationally, cathinone is a  Schedule I  drug under the  Convention on Psychotropic Substances . [ 8 ]  Circa 1993, the  DEA  added cathinone to the  Controlled Substances Act 's Schedule I.


The sale of khat is legal in some jurisdictions, but illegal in others (see  Khat (Regulation) ).  Substituted cathinones  were also often used as the key ingredient of recreational drug mixes commonly known as " bath salts " in the United States. [ 9 ] [ 10 ] [ 11 ] [ 12 ]


The table below shows the legality of khat and cathinone in various countries:


Cathinone has been found to stimulate the release of  dopamine  and inhibit the reuptake of  epinephrine ,  norepinephrine  and  serotonin  in the  central nervous system  (CNS). These  neurotransmitters  are all considered  monoamines  and share the general structure of an  aromatic ring  and an  amine  group attached by a two-carbon separator. [ 7 ]  Because cathinone is a  hydrophobic  molecule, it can easily cross cell membranes and other barriers, including the  blood–brain barrier . [ 32 ]  This property allows it to interact with the monoamine transporters in the  synaptic cleft  between  neurons . Cathinone induces the release of  dopamine  from brain striatal preparations that are prelabelled either with dopamine or its precursors. [ 33 ]  It is more specificllay a  norepinephrine–dopamine releasing agent  (NDRA) similarly to  amphetamine . [ 30 ] [ 31 ]


The metabolites of cathinone, cathine and norephedrine, also possess CNS stimulation, but create much weaker effects. [ 34 ]  The effects of cathinone on the body can be countered by a preceding administration of a  dopamine receptor antagonist . [ 34 ]  The antagonist prevents synaptic dopamine released by cathinone from  exerting its effect by binding to dopamine receptors.


Cathinone can also affect cholinergic concentrations in the gut and airways by blocking prejunctional  adrenergic receptors  (α 2  adrenergic) and activating  5-HT7  receptors, thereby inhibiting  smooth muscle  contraction. [ 32 ]  It can also induce dry mouth, blurred vision and increased blood pressure and heart rate. [ 7 ]


Cathinone is a weak agonist of the mouse, rat, and human  trace amine-associated receptor 1  (TAAR1). [ 35 ] [ 36 ]  In contrast to cathinone however, most other  cathinones  are not human TAAR1 agonists. [ 37 ] [ 36 ]  TAAR1 activation may auto-inhibit and constrain the  monoaminergic  effects of  monoamine releasing agents  possessing TAAR1 agonism. [ 37 ] [ 38 ]


Khat leaves are removed from the plant stalk and are kept in a ball in the cheek and chewed. Chewing releases juices from the leaves, which include the alkaloid cathinone. The absorption of cathinone has two phases: one in the  buccal mucosa  and one in the  stomach  and  small intestine . [ 5 ]  The stomach and small intestine are very important in the absorption of ingested alkaloids. [ 5 ]  At approximately 2.3 hours after chewing khat leaves, the maximum concentration of cathinone in blood plasma is reached. The mean residence time is 5.2 ± 3.4 hours. [ 5 ]  The elimination half-life of cathinone is 1.5 ± 0.8 hours. [ 5 ]  A two-compartment model for absorption and elimination best describes this data. However, at most, only 7% of the ingested cathinone is recovered in the urine. [ 5 ]  This indicates that the cathinone is being broken down in the body. Cathinone has been shown to selectively metabolize into R,S-(-)-norephedrine and cathine. The reduction of the  ketone  group in cathinone will produce cathine. This reduction is catalyzed by enzymes in the liver. The spontaneous breakdown of cathinone is the reason it must be chewed fresh after cultivation. [ 5 ]


The first documentation of the khat plant being used in medicine was in a book published by an Arabian physician in the 10th century. [ 7 ]  It was used as an  antidepressant  because it led to feelings of happiness and excitement. Chronic khat chewing can also create drug dependence, as shown by animal studies. [ 7 ]  In such studies, monkeys were trained to push a lever to receive the drug reward. As the monkeys' dependence increased, they pressed the lever at an increasing frequency. [ 7 ]


Khat chewing and the effects of cathinone on the body differ from person to person, but there is a general pattern of behavior that emerges after ingesting fresh cathinone: [ 7 ]


There are other effects not related to the CNS. The chewer can develop  constipation  and  heartburn  after a khat session. Long-term effects of cathinone can include  gum disease  or  oral cancer ,  cardiovascular disease  and  depression . [ 7 ]  The  withdrawal symptoms  of cathinone include  hot flashes ,  lethargy  and a great urge to use the drug for at least the first two days. [ 7 ]


The synthesis of cathinone in khat begins with L- phenylalanine  and the first step is carried out by L-phenylalanine ammonia lyase (PAL), which cleaves off an ammonia group and creates a carbon-carbon double bond, forming  cinnamic acid . [ 39 ]   After this, the molecule can either go through a beta-oxidative pathway or a non-beta-oxidative pathway.  The beta-oxidative pathway produces  benzoyl-CoA  while the non-beta-oxidative pathway produces  benzoic acid . [ 39 ]   Both of these molecules can be converted to 1-phenylpropane-1,2-dione by a  condensation reaction  catalyzed by a ThDP-dependent enzyme (Thiamine diphosphate-dependent enzyme) with  pyruvate  and producing CO 2 . [ 39 ]   1-phenylpropane-1,2-dione goes through a transaminase reaction to replace a ketone with an ammonia group to form (S)-cathinone.  (S)-Cathinone can then undergo a reduction reaction to produce the less potent but structurally similar cathine or norephedrine, which are also found in the plant. [ 39 ]


Aside from the beta- and non-beta-oxidative pathways, the biosynthesis of cathinone can proceed through a CoA-dependent pathway. The CoA-dependent pathway is actually a mix between the two main pathways as it starts like the beta-oxidative pathway and then when it loses CoA, it finishes the synthesis in the non-beta-oxidative pathway.  In this pathway, the trans-cinnamic acid produced from L-phenylalanine is ligated to a  Coenzyme A  (CoA), just like the beginning of the beta-oxidative pathway. [ 39 ]  It then undergoes  hydration  at the double bond.  This product then loses the CoA to produce  benzaldehyde , an intermediate of the non-beta-oxidative pathway.  Benzaldehyde is converted into benzoic acid and proceeds through the rest of the synthesis. [ 39 ]


Cathinone can be synthetically produced from propiophenone through a  Friedel-Crafts  acylation of propionic acid and benzene. [ 32 ]   The resulting  propiophenone  can be brominated, and the bromine can be substituted with ammonia to produce a racemic mixture of cathinone. A different synthetic strategy must be employed to produce enantiomerically pure (S)-cathinone.  This synthetic route starts out with the N-acetylation of the  optically active   amino acid , S-alanine. [ 32 ]   Then,  phosphorus pentachloride  (PCl 5 ) is used to chlorinate the  carboxylic acid  forming an acyl chloride. At the same time, a Friedel-Crafts acylation is preformed on benzene with  aluminum chloride  catalyst.  Finally, the  acetyl  protecting group is removed by heating with  hydrochloric acid  to form enantiomerically pure S-(-)-cathinone. [ 32 ]


Cathinone can be extracted from  Catha edulis , or synthesized from  α -bromopropiophenone (which is easily made from  propiophenone ). Because cathinone is both a  primary amine  and a  ketone , it is very likely to  dimerize , especially as a free base isolated from plant matter. [ 40 ]


The structure of cathinone is very similar to that of other molecules. By reducing the ketone, it becomes cathine if it retains its stereochemistry, or norephedrine if its stereochemistry is inverted. Cathine is a less potent version of cathinone and cathinone's spontaneous reduction is the reason that older khat plants are not as stimulating as younger ones.  Cathinone and amphetamine are closely related in that amphetamine is only lacking the ketone C=O group. [ 41 ]   Cathinone is structurally related to  methcathinone , in much the same way as  amphetamine  is related to  methamphetamine . Cathinone differs from amphetamine by possessing a  ketone   oxygen  atom (C=O) on the  β  (beta) position of the side chain. Advancements in synthesizing cyclic cathinones based on α-tetralone have employed chiral HPLC-CD techniques to determine the absolute configuration of enantiomers, an approach that may contribute to the development of pharmaceutical analogs with antidepressant potential. [ 42 ]  The corresponding substance  cathine , is a less powerful stimulant. The biophysiological conversion from cathinone to cathine is to blame for the depotentiation of  khat  leaves over time. Fresh leaves have a greater ratio of cathinone to cathine than dried ones, therefore having more psychoactive effects.


There are many cathinone derivatives that include the addition of an R group to the amino end of the molecule.  Some of these derivatives have medical uses as well.   Bupropion  is one of the most commonly prescribed antidepressants and its structure is Cathinone with a tertiary butyl group attached to the nitrogen and chlorine attached to the benzene ring  meta-  to the main carbon chain. [ 41 ]


Other cathinone derivatives are strong psychoactive drugs.  One such drug is  methylone , a drug structurally similar to  MDMA .


Cenderitide  (also known as  chimeric natriuretic peptide  or  CD-NP ) is a  natriuretic peptide  developed by the  Mayo Clinic  as a potential treatment for  heart failure . [ 1 ] [ 2 ] [ 3 ]  Cenderitide is created by the fusion of the 15 amino acid C-terminus of the snake venom  dendroaspis natriuretic peptide  (DNP) with the full  C-type natriuretic peptide  (CNP) structure. [ 2 ]  This peptide chimera is a dual activator of the natriuretic peptide receptors NPR-A and NPR-B and therefore exhibits the  natriuretic  and  diuretic  properties of DNP, as well as the antiproliferative and antifibrotic properties of CNP. [ 1 ] [ 3 ]


When faced with pressure overload, the heart attempts to compensate with a number of structural alterations including  hypertrophy  of cardiomyocytes and increase of extracellular matrix (ECM) proteins. [ 4 ] [ 5 ]  Rapid accumulation of ECM proteins causes excessive  fibrosis  resulting in decreased myocardial compliance and increased myocardial stiffness. [ 5 ] [ 6 ]  The exact mechanisms involved in excessive fibrosis are not fully understood but there is evidence that supports involvement from local growth factors  FGF-2 ,  TGF-beta  and platelet-derived growth factor. [ 7 ] [ 8 ] [ 9 ]  TGF-β1 plays an important role in cardiac remodelling through the stimulation of fibroblast proliferation, ECM deposition and myocyte hypertrophy. [ 10 ] [ 11 ] [ 12 ]  The increase in  TGF-beta 1  expression in a pressure-overloaded heart correlates with the degree of fibrosis, suggesting TGF-beta 1 involvement in the progression from a compensated hypertrophy to failure. [ 13 ] [ 14 ]  Through an autocrine mechanism, TGF-beta 1 acts on  fibroblasts  by binding TGF-beta 1 receptors 1 and 2. Upon receptor activation, the receptor-associated transcription factor  Smad  becomes  phosphorylated  and associates with Co-Smad. [ 15 ]  This newly formed Smad-Co-Smad complex enters the nucleus where it acts as a transcription factor modulating gene expression. [ 15 ]
Cardiac remodelling of the ECM is also regulated by the CNP/NPR-B pathway as demonstrated by the improved outcomes in  transgenic  mice with CNP over-expression subjected to myocardial infarction. [ 16 ] [ 17 ]  Binding of CNP to NPR-B catalyzes the synthesis of cGMP, which is responsible for mediating the anti-fibrotic effects of CNP. [ 18 ]
Fibrotic heart tissue is associated with an increase risk of ventricular dysfunction which can ultimately lead to  heart failure . [ 5 ] [ 19 ]  Thus, anti-fibrotic strategies are a promising approach in the prevention and treatment of  heart failure .


As cenderitide interacts with both NRP-A and NRP-B, this drug has antifibrotic potential. [ 1 ]  Binding of cenderitide to NRP-B elicits an antifibrotic response by catalyzing formation of  cGMP  similar to the response seen with endogenous CNP. Additionally,  in vitro  study of human fibroblasts demonstrates that cenderitide reduces  TGF-beta 1  induced  collagen  production. [ 1 ] [ 20 ]  These two proposed mechanisms illustrate therapeutic potential for the reduction of fibrotic remodelling in the  hypertensive  heart. Through combined effects of CNP and DNP, cenderitide treatment results in a reduction in stress on the heart (through natriuresis/diuresis) and inhibition of pro-fibrotic, remodeling pathways. [ 1 ]


A  cerebral vasodilator  is a  drug  which acts as a  vasodilator  in the  brain . [ 1 ] [ 2 ]  They are used to improve  blood flow  in people with  cerebrovascular insufficiency  and to treat  neurological disorders  secondary to this condition. [ 2 ]  A number of different cerebral vasodilators exist. [ 2 ] [ 1 ] [ 3 ]  An example is  ifenprodil , which has been marketed for use as a cerebral vasodilator in  France ,  Hong Kong , and  Japan . [ 4 ] [ 5 ] [ 6 ]  Other examples include  buphenine  (nylidrin),  isoxsuprine ,  oxyfedrine ,  suloctidil , and  tinofedrine . [ 7 ]


Similar drugs include  cerebral activators , or cerebral metabolism activators, like  bifemelane ,  indeloxazine , and  teniloxazine , which are also used to treat  cerebrovascular disease . [ 8 ] [ 9 ] [ 10 ] [ 11 ]


CXL 1020  is an  experimental drug  that is being investigated as a treatment for  acute decompensated heart failure . CXL 1020 functions as a  nitroxyl  donor; nitroxyl is the reduced,  protonated  version of  nitric oxide . [ 1 ]  Nitroxyl is capable of enhancing  left ventricular   contractility  without increasing  heart rate  by modifying normal Ca 2+  cycling through the  sarcoplasmic reticulum [ 2 ]  as well as increasing the sensitivity of cardiac  myofilaments  to Ca 2+ . [ 3 ]


Patients with acute decompensated heart failure have diminished left ventricular  systolic  and/or  diastolic  functioning. [ 4 ]  Impaired  ventricular function  can be a consequence of decreased sarcoplasmic reticulum Ca 2+  cycling and a corresponding decline in  cardiomyocyte  contraction. [ 2 ]   Reduced ventricular functioning limits the ability of the ventricles to fill with blood and pump blood to the rest of the body.


There are two mechanisms through which CXL 1020 is able to enhance the movement of Ca 2+  in and out of the sarcoplasmic reticulum. Sarcoplasmic reticulum CaATPase (SERCA) is an energy-dependent  ion pump  found the sarcoplasmic reticulum of cardiac myocytes that is responsible for transporting Ca 2+  within the  cytosol  back in to the  lumen  of the sarcoplasmic reticulum. [ 2 ]   The nitroxyl group that is donated by CXL 1020 initiates glutathiolation of SERCA at the cysteine 674 site, which in turn activates ATP-dependent Ca2+ transport. [ 5 ]  Therefore, stimulation of SERCA leads to accelerated uptake of Ca 2+  from the cytosol of the cardiac myocyte.


Secondly, the nitroxyl group from CXL 1020 interacts with  ryanodine receptors  (RyR), specifically  RyR2 , which is the predominant form found in cardiac tissue. [ 6 ]  Ryanodine receptors are located within the membrane of the sarcoplasmic reticulum and function to release Ca 2+  required for myofilament activation (Guyton, 2006).  Nitroxyl interacts with RyR2 to increase the probability of Ryanodine receptor opening, thereby enhancing Ca 2+  release from the sarcoplasmic reticulum. It is thought that nitroxyl modifies RyR2 function through its interaction with  thiol groups  present in the receptor, although the exact mechanism is unknown. [ 6 ]


Nitroxyl has also been shown to increase the sensitivity to cardiac myocytes to Ca 2+ , which in turn enhances the force of contraction. Its hypothesized that nitroxyl interacts with thiol groups present in myofilament proteins to increase the maximal Ca 2+  activated force of the myofilament, although the exact effect of nitroxyl on the myofilament is unknown. [ 3 ]


Daflon  is an oral micronized purified phlebotonic  flavonoid  fraction containing 90%  diosmin  and 10%  hesperidin . It is manufactured by  Laboratoires Servier  and often used to treat or manage disorders of the blood vessels. [ 1 ] [ 2 ]  Flavonoids are a type of  phytochemical  that have been associated with various effects on human health and are a component of many different  pharmaceutical ,  nutraceutical , and  cosmetic  preparations. [ 3 ]  Diosmin is a flavone  glycoside  that is derived from hesperidin. Hesperidin is a flavone that is extracted from citrus fruits. [ 4 ]


Daflon is not an FDA-approved medication, and therefore it cannot be advertised for treatment of diseases in the United States. Daflon is under preliminary research for its potential use in treating  vein  diseases, [ 5 ]  or  hemorrhoids . [ 6 ]  It is sold as a drug in  France , [ 7 ] [ 8 ]  Spain, [ 9 ]   Malaysia [ 10 ] [ 11 ]  and Belgium.


There is moderate certainty evidence for the effectiveness of daflon for slightly reducing oedema compared to placebo in the treatment of  chronic venous insufficiency . [ 12 ]   Little to no differences in quality of life after treatment with Daflon were found and there is low certainty evidence that this class of drugs do not influence ulcer healing. [ 12 ]   Diosmiplex, a micronized purified flavonoid fraction of daflon, with similar venous insufficiency indication, is sold as a prescription  medical food  in the US. [ 13 ]


Daflon plays a crucial role in the prevention of  perivascular   edema  formation and treatment of  venous stasis . This activity can be explained by its antagonist activity against  prostaglandin E2  (PgE2) and  thromboxane  (TxA2) biosynthesis leading to inhibition of inflammatory process. Moreover, it also has a contraction activity on the lymphatic vessels which cause the lymphatic flow maximal. [ 14 ]


For venous insufficiency, the dosage is 2 tablets of 500mg daily. For acute hemorrhoidal attack, the dosage is 6 tablets daily for 4 days, followed by 4 tablets daily over the next 3 days. [ 15 ]  For chronic venous disease, the dosage is 2 tablets a day for at least 2 months. [ 16 ]


Possible side effects include routine  gastric disorders  and neurovegetative disorders, however, toxicology studies indicate that diosmin is quite safe. [ 2 ]  Diosmin interacts in an inhibitory manner with some metabolic enzymes so  drug-interactions  are probable. [ 2 ]


Darapladib  is an inhibitor of  lipoprotein-associated phospholipase A2  (Lp-PLA 2 ) that is in  development  as a  drug  for treatment of  atherosclerosis . [ 1 ]


It was discovered by  Human Genome Sciences  in collaboration with  GlaxoSmithKline  (GSK). [ 2 ]


In November 2013, GSK announced that the drug had failed to meet Phase III endpoints in a trial of 16,000 patients with  acute coronary syndrome  (ACS). [ 3 ]  An additional trial of 13,000 patients (SOLID-TIMI 52) finished in May 2014. The study failed to reduce the risk of  coronary heart disease  death,  myocardial infarction , and urgent coronary  revascularization  compared with placebo in acute coronary syndrome patients treated with standard medical care. [ 4 ]


In 2022, Darapladib has been found to inhibit  intraerythrocytic  development of the malaria parasite  Plasmodium falciparum  by inhibition of the human host enzyme  peroxiredoxin 6 . [ 5 ]  The authors present data that the original target of Darapladib,  Lp-PLA 2 , is absent in the host  red blood cell .


Ephedrine  is a  central nervous system  (CNS)  stimulant  and  sympathomimetic agent  that is often used to prevent  low blood pressure  during  anesthesia . [ 11 ]  It has also been used for  asthma ,  narcolepsy , and  obesity  but is not the preferred treatment. [ 11 ]  It is of unclear benefit in  nasal congestion . [ 11 ]  It can be taken  by mouth  or by  injection into a muscle ,  vein , or  just under the skin . [ 11 ]  Onset with intravenous use is fast, while injection into a muscle can take 20   minutes, and by mouth can take an hour for effect. [ 11 ]  When given by injection, it lasts about an hour, and when taken by mouth, it can last up to four hours. [ 11 ]


Common  side effects  include  trouble sleeping ,  anxiety ,  headache ,  hallucinations ,  high blood pressure ,  fast heart rate ,  loss of appetite , and  urinary retention . [ 11 ]  Serious side effects include  stroke  and  heart attack . [ 11 ]  While probably safe in  pregnancy , its use in this population is poorly studied. [ 12 ] [ 13 ]  Use during  breastfeeding  is not recommended. [ 13 ]  Ephedrine works by  inducing the release of norepinephrine  and hence indirectly activating the  α-  and  β-adrenergic receptors . [ 11 ]  Chemically, ephedrine is a  substituted amphetamine  and is the (1 R ,2 S )- enantiomer  of  β-hydroxy- N -methylamphetamine . [ 14 ]


Ephedrine was first  isolated  in 1885 and came into commercial use in 1926. [ 15 ] [ 16 ]  It is on the  World Health Organization's List of Essential Medicines . [ 17 ]  It is available as a  generic medication . [ 11 ]  It can normally be found in plants of the  Ephedra  genus. [ 11 ] [ 18 ]   Over-the-counter   dietary supplements  containing ephedrine are illegal in the  United States , [ 11 ]  with the exception of those used in  traditional Chinese medicine , where its presence is noted by  má huáng . [ 11 ] [ 18 ]


Ephedrine is a non- catecholamine   sympathomimetic  with cardiovascular effects similar to those of  adrenaline /epinephrine: increased blood pressure, heart rate, and contractility. Like  pseudoephedrine  it is a  bronchodilator , with pseudoephedrine having considerably less effect. [ 19 ] [ 20 ]


Ephedrine may decrease  motion sickness , but it has mainly been used to decrease the sedating effects of other medications used for motion sickness. [ 21 ] [ 22 ]


Ephedrine is also found to have quick and long-lasting responsiveness in  congenital myasthenic syndrome  in early childhood and also even in adults with a novel  COLQ  mutation. [ 23 ]


Ephedrine is administered by intravenous boluses. Redosing usually requires increased doses to offset the development of  tachyphylaxis , which is attributed to the depletion of catecholamine stores. [ 19 ]


Ephedrine promotes modest short-term  weight loss , [ 24 ]  specifically fat loss, but its long-term effects are unknown. [ 25 ]  In mice, ephedrine is known to stimulate  thermogenesis  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 . Ephedrine also decreases  gastric emptying .  Methylxanthines  such as  caffeine  and  theophylline  have a synergistic effect with ephedrine for weight loss. This led to the creation and marketing of compound products. [ 26 ]  One of them, known as the  ECA stack , contains ephedrine with caffeine and aspirin. It is a popular supplement taken by  bodybuilders  seeking to cut body fat before a competition. [ 27 ]
A 2021 systematic review found that ephedrine led to a 2 kilograms (4.4 lb) weight loss greater than placebo, raised  heart rate , and reduced  LDL  and raised  HDL , with no statistically significant difference in  blood pressure . [ 28 ]


Ephedrine is available as a  prescription-only   pharmaceutical drug  in the form of an  intravenous   solution , under brand names including Akovaz, Corphedra, Emerphed, and Rezipres as well as in  generic forms , in the  United States . [ 29 ] [ 30 ]  It is also available  over-the-counter  in the form of 12.5 and 25   mg  oral   tablets  for use as a  bronchodilator  and as a 0.5% concentration  nasal spray  for use as a  decongestant . [ 30 ]  The drug is additionally available in  combination  with  guaifenesin  in the form of oral tablets and liquids. [ 30 ]  Ephedrine is provided as the  hydrochloride  or  sulfate   salt  in pharmaceutical formulations. [ 29 ] [ 30 ]


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 ,  acidosis ,  hypertension ,  hyperthyroidism ,  prostatic hypertrophy ,  diabetes mellitus ,  cardiovascular  disease, during delivery if maternal blood pressure is >130/80 mmHg, and during lactation. [ 31 ]


Contraindications  for the use of ephedrine include:  closed-angle glaucoma ,  phaeochromocytoma ,  asymmetric septal hypertrophy  (idiopathic hypertrophic subaortic stenosis), concomitant or recent (previous 14 days)  monoamine oxidase inhibitor  (MAOI) therapy, general  anaesthesia  with halogenated hydrocarbons (particularly halothane), tachyarrhythmias or ventricular fibrillation, or hypersensitivity to ephedrine or other stimulants. [ citation needed ]


Ephedrine should not be used at any time during pregnancy unless specifically indicated by a qualified physician and only when other options are unavailable. [ 31 ]


Ephedrine is a potentially dangerous natural compound; as of 2004 [update]  the US  Food and Drug Administration  had received over 18,000 reports of adverse effects in people using it. [ 32 ]


Adverse drug reactions  (ADRs) are more common with systemic administration (e.g. injection or oral administration) compared to topical administration (e.g. nasal instillations). ADRs associated with ephedrine therapy include  [ 33 ]


Overdose  of ephedrine may result in  sympathomimetic   symptoms  like  tachycardia  and  hypertension . [ citation needed ]


Ephedrine with  monoamine oxidase inhibitors  (MAOIs) like  phenelzine  and  tranylcypromine  can result in  hypertensive crisis . [ citation needed ]


Ephedrine, a  sympathomimetic amine , acts on part of the  sympathetic nervous system  (SNS). The principal mechanism of action relies on its indirect stimulation of the  adrenergic receptor  system by increasing activation of  α-  and  β-adrenergic receptors  via  induction of norepinephrine release . [ 40 ]  The presence of direct interactions with α-adrenergic receptors is unlikely but still controversial. [ 41 ] [ 20 ] [ 42 ] [ 43 ]   L -ephedrine, and particularly its stereoisomer  norpseudoephedrine  (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 , but less pronounced, as it releases norepinephrine and  dopamine  in the  brain . [ 44 ]


The  oral   bioavailability  of ephedrine is 88%. [ 6 ]  The  onset of action  of ephedrine orally is 15 to 60   minutes, via  intramuscular injection  is 10 to 20   minutes, and via  intravenous infusion  is within seconds. [ 11 ]


Its  plasma protein binding  is approximately 24 to 29%, with 5 to 10% bound to  albumin . [ 7 ] [ 8 ] [ 9 ]


Ephedrine is largely not  metabolized . [ 6 ]   Norephedrine  (phenylpropanolamine) is an  active metabolite  of ephedrine formed via  N - demethylation . [ 6 ] [ 10 ]  About 8 to 20% of an oral dose of ephedrine is demethylated into norephedrine, about 4 to 13% is  oxidatively   deaminated  into  benzoic acid , and a small fraction is converted into 1,2-dihydroxy-1-phenylpropane. [ 10 ]


Ephedrine is  eliminated  mainly in  urine , with 60% (range 53–79%)  excreted  unchanged. [ 6 ] [ 10 ]


The  elimination half-life  of ephedrine is 6   hours. [ 6 ]  Its  duration of action  orally is 2 to 4   hours and via intravenous or intramuscular injection is 60   minutes. [ citation needed ]


The elimination of ephedrine is dependent on urinary  pH . [ 10 ]


Ephedrine, or (−)-(1 R ,2 S )-ephedrine, also known as (1 R ,2 S )-β-hydroxy- N -methyl-α-methyl-β-phenethylamine or as (1 R ,2 S )-β-hydroxy- N -methylamphetamine, is a  substituted phenethylamine  and  amphetamine   derivative . It is similar in  chemical structure  to  phenylpropanolamine ,  methamphetamine , and  epinephrine  (adrenaline). It differs from methamphetamine only by the presence of a  hydroxyl  group (–OH). Chemically, ephedrine is an  alkaloid  with a  phenethylamine  skeleton found in various plants in the genus  Ephedra  (family  Ephedraceae ). It is most usually marketed as the  hydrochloride  or  sulfate   salt . [ 45 ]


It has an experimental  log P  of 1.13, while its predicted log P values range from 0.9 to 1.32. [ 14 ] [ 6 ] [ 46 ]  The  lipophilicity  of amphetamines is closely related to their  brain permeability . [ 47 ]  For comparison to ephedrine, the experimental log P of  methamphetamine  is 2.1, [ 48 ]  of  amphetamine  is 1.8, [ 49 ] [ 48 ]  of  pseudoephedrine  is 0.89, [ 50 ]  of  phenylpropanolamine  is 0.7, [ 51 ]  of  phenylephrine  is -0.3, [ 52 ]  and of  norepinephrine  is -1.2. [ 53 ]  Methamphetamine has high brain permeability, [ 48 ]  whereas phenylephrine and norepinephrine are  peripherally selective drugs . [ 54 ] [ 55 ]  The optimal log P for brain permeation and central activity is about 2.1 (range 1.5–2.7). [ 56 ]


Ephedrine hydrochloride has a melting point of 187−188   °C. [ 57 ]


The  racemic  form of ephedrine is  racephedrine  ((±)-ephedrine;  dl -ephedrine; (1 RS ,2 SR )-ephedrine). [ 58 ]  A  stereoisomer  of ephedrine is  pseudoephedrine . [ 58 ]   Derivatives  of ephedrine include  methylephedrine  ( N -methylephedrine),  etafedrine  ( N -ethylephedrine),  cinnamedrine  ( N -cinnamylephedrine), and  oxilofrine  (4-hydroxyephedrine). [ 58 ]   Analogues  of ephedrine include  phenylpropanolamine  (norephedrine) and  metaraminol  (3-hydroxynorephedrine). [ 58 ]


The presence of an  N - methyl group  decreases binding affinities at α-adrenergic receptors, compared with norephedrine. Ephedrine, though, binds better than  N -methylephedrine , which has an additional methyl group at the nitrogen atom. Also, the  steric  orientation of the hydroxyl group is important for receptor binding and functional activity. [ 42 ]


Ephedrine exhibits  optical isomerism  and has two  chiral  centres, giving rise to four  stereoisomers . By convention, the pair of  enantiomers  with the stereochemistry (1 R ,2 S ) and (1 S ,2 R ) is designated ephedrine, while the pair of enantiomers with the stereochemistry (1 R ,2 R ) and (1 S ,2 S ) is called pseudoephedrine.


The isomer which is marketed is (−)-(1 R ,2 S )-ephedrine. [ 59 ]


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  is drawn at the bottom). [ 59 ] [ 60 ]


Often, the  D / L  system (with  small caps ) and the d/l system (with  lower-case ) are confused. The result is that the levorotary l-ephedrine is wrongly named  L -ephedrine and the dextrorotary d-pseudoephedrine (the diastereomer) wrongly  D -pseudoephedrine.


The  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.


Ephedrine may be quantified in blood, plasma, or urine to monitor possible abuse by athletes, confirm a diagnosis of poisoning, or assist in a medicolegal death investigation. Many commercial  immunoassay  screening tests directed at the amphetamines cross-react appreciably with ephedrine, but chromatographic techniques can easily distinguish ephedrine from other phenethylamine derivatives. Blood or plasma ephedrine concentrations are typically in the 20–200   μg/L range in persons taking the drug therapeutically, 300–3000   μg/L in abusers or poisoned patients, and 3–20   mg/L in cases of acute fatal overdosage. The current  World Anti-Doping Agency  (WADA) limit for ephedrine in an athlete's urine is 10   μg/mL. [ 61 ] [ 62 ] [ 63 ] [ 64 ]


Ephedrine in its natural form, known as  máhuáng  (麻黄) in  traditional Chinese medicine , has been documented in China since the  Han dynasty  (206 BC – 220 AD) as an  antiasthmatic  and stimulant. [ 65 ]  In traditional Chinese medicine,  máhuáng  has been used as a treatment for asthma and bronchitis for centuries. [ 66 ]


In 1885, the chemical synthesis of ephedrine was first accomplished by Japanese  organic chemist   Nagai Nagayoshi  based on his research on  traditional Japanese  and  Chinese herbal medicines .


The industrial manufacture of ephedrine in China began in the 1920s, when  Merck  began marketing and selling the drug as ephetonin. Ephedrine exports from China to the West grew from 4 to 216 tonnes between 1926 and 1928. [ 67 ]


Ephedrine was first introduced for medical use in the  United States  in 1926. [ 32 ]


It was introduced in 1948 in  Vicks  Vatronol nose drops (now discontinued) which contained ephedrine sulfate as the active ingredient for rapid nasal decongestion.


Ephedrine  is the  generic name  of the drug and its  BAN Tooltip British Approved Name . [ 58 ] [ 45 ] [ 68 ]  Its  DCF Tooltip Dénomination Commune Française  is  ephédrine  while its  DCIT Tooltip Denominazione Comune Italiana  is  efedrina . [ 45 ] [ 68 ]  In the case of the  hydrochloride   salt , its generic name is  ephedrine hydrochloride  and this is its  USAN Tooltip United States Adopted Name ,  BANM Tooltip British Approved Name , and  JAN Tooltip Japanese Accepted Name . [ 58 ] [ 45 ] [ 68 ]  In the case of the  sulfate  salt, its generic name is  ephedrine sulfate  or  ephedrine sulphate  and the former is its  USAN Tooltip United States Adopted Name  while the latter is its  BANM Tooltip British Approved Name . [ 58 ] [ 45 ] [ 68 ]  A synonym of ephedrine sulfate is  isofedrol . [ 58 ]  These names all refer to the (1 R ,2 R )- enantiomer  of ephedrine. [ 58 ] [ 45 ]  The  racemic  form of ephedrine is known as  racephedrine  and this is its  INN Tooltip International Nonproprietary Name  and  BAN Tooltip British Approved Name , while the hydrochloride salt of the racemic form is  racephedrine hydrochloride  and this is its  USAN Tooltip United States Adopted Name . [ 69 ]


As a  phenethylamine , ephedrine has a similar chemical structure to  amphetamines  and is a  methamphetamine   analog  having the methamphetamine structure with a  hydroxyl  group at the  β position . Because of ephedrine's structural similarity to methamphetamine, it can be used to create methamphetamine using  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 , in that it uses  anhydrous ammonia  and  lithium  metal in the reaction. The second-most popular method uses red  phosphorus  and  iodine  in the reaction with ephedrine. Moreover, ephedrine can be synthesized into  methcathinone  via simple  oxidation . As such, ephedrine is listed as a table-I precursor under the  United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances . [ 70 ]


Ephedrine has been used as a  performance-enhancing drug  in  exercise  and  sports . [ 41 ] [ 71 ] [ 72 ] [ 73 ]  It can increase  heart rate ,  blood pressure , and  cardiac contractility  as well as act as a  psychostimulant . [ 41 ]  Ephedrine is often used in combination with  caffeine  for performance-enhancing purposes. [ 72 ] [ 73 ]


In  chemical synthesis , ephedrine is used in bulk quantities as a  chiral auxiliary  group. [ 74 ]


In  saquinavir  synthesis, the half-acid is resolved as its salt with l-ephedrine.


In January 2002,  Health Canada  issued a voluntary recall of all ephedrine products containing more than 8   mg per dose, all combinations of ephedrine with other stimulants such as caffeine, and all ephedrine products marketed for weight-loss or bodybuilding indications, citing a serious risk to health. [ 75 ]  Ephedrine is still sold as an oral nasal decongestant [ 76 ]  in 8   mg pills as a natural health product, with a limit of 0.4   g (400   mg) per package, the limit established by the Controlled Drugs and Substances Act as it is considered as Class A Precursor. [ 77 ]


In 1997, 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. [ 78 ]  This proposed rule was withdrawn, in part, in 2000 because of "concerns regarding the agency's basis for proposing a certain dietary ingredient level and a duration of use limit for these products." [ 79 ]  In 2004, the FDA created a ban on ephedrine alkaloids marketed for reasons other than asthma, colds, allergies, other disease, or traditional Asian use. [ 80 ]  On April 14, 2005, 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, [ 81 ]  but on August 17, 2006, the  U.S. Court of Appeals for the Tenth Circuit  in Denver upheld the FDA's final rule declaring all dietary supplements containing ephedrine alkaloids adulterated, and therefore illegal for marketing in the United States. [ 82 ]  Furthermore, ephedrine is banned by the NCAA, MLB, NFL, and PGA. [ 83 ]  Ephedrine is, however, still legal in many applications outside of dietary supplements. Purchasing is currently limited and monitored, with specifics varying from state to state.


The  House  passed the  Combat Methamphetamine Epidemic Act of 2005  as an amendment to the renewal of the  USA PATRIOT Act . Signed into law by President  George W. Bush  on March 6, 2006, the act amended the  US Code  (21 USC 830) concerning the sale of products containing ephedrine and the closely related drug  pseudoephedrine . Both substances are used as  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:


The law gives similar regulations to mail-order purchases, except the monthly sales limit is 7.5   g.


As a pure herb or tea,  má huáng , containing ephedrine, is still sold legally in the US. The law restricts/prohibits its being sold as a dietary supplement (pill) or as an ingredient/additive to other products, like diet pills.


Ephedrine and all  Ephedra  species that contain it are considered Schedule 4 substances under the  Poisons Standard . A Schedule 4 drug is considered a Prescription Only Medicine, or Prescription Animal Remedy – Substances, the use or supply of which should be by or on the order of persons permitted by State or Territory legislation to prescribe and should be available from a pharmacist on prescription under the  Poisons Standard .


In South Africa, ephedrine was moved to schedule 6 on 27 May 2008, [ 84 ]  which makes pure ephedrine tablets prescription only. Pills containing ephedrine up to 30 mg per tablet in combination with other medications are still available OTC, schedule 1 and 2, for sinus, head colds, and influenza.


Ephedrine was freely available in pharmacies in Germany until 2001. Afterward, access was restricted since it was mostly bought for unindicated uses. Similarly, ephedra can only be bought with a prescription. Since April 2006, all products, including plant parts, that contain ephedrine are only available with a prescription. [ 85 ]


Ephedrine is obtained from the plant  Ephedra sinica  and other members of the genus  Ephedra ,  from which the name of the substance is derived. Raw materials for the manufacture of ephedrine and traditional Chinese medicines are produced in China on a large scale. As of 2007, companies produced for export US$13 million worth of ephedrine from 30,000 tons of ephedra annually, or about ten times the amount used in traditional Chinese medicine. [ 86 ]


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. [ 87 ] [ unreliable source? ]


Ephedrine was long thought to come from modifying the amino acid  L -phenylalanine. [ 90 ]   L -Phenylalanine would be decarboxylated and subsequently attacked with ω-aminoacetophenone. Methylation of this product would then produce ephedrine. This pathway has since been disproven. [ 90 ]  A new pathway proposed suggests that phenylalanine first forms  cinnamoyl-CoA  via the enzymes  phenylalanine ammonia-lyase  and acyl CoA ligase. [ 88 ]  The cinnamoyl-CoA is then reacted with a hydratase to attach the alcohol functional group. The product is then reacted with a retro-aldolase, 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. [ 89 ]


Etafedrine  ( INN Tooltip International Nonproprietary Name ,  BAN Tooltip British Approved Name ), sold under the brand name  Nethaprin  among others and also known as  N -ethylephedrine , is a  sympathomimetic agent  used as a  bronchodilator  to treat  asthma . [ 2 ] [ 3 ] [ 4 ]  It was previously commercially available as both the  free base  and as the  hydrochloride   salt  from Sanofi-Aventis (now  Sanofi ) but is now no longer marketed. [ citation needed ]


Unlike  ephedrine  and  tyramine , etafedrine does not  induce the release  of  epinephrine  or  norepinephrine  and instead acts as a  selective   β 2 -adrenergic receptor agonist , thereby mediating its  bronchodilator  effects. [ 4 ] [ 5 ]


Fatty acid oxidation inhibitors  are a new potent class of drugs used in treatment of  stable  angina pectoris  and an addition in treatment of chronic  heart failure .


4-Fluoroephedrine  ( 4-FEP ) is a  "novel psychoactive substance"  and  substituted β-hydroxyamphetamine   derivative  related to  ephedrine . [ 1 ] [ 2 ] [ 3 ]