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Dextroamphetamine

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Dextroamphetamine
Clinical data
Trade namesDexedrine, Dextrostat, Dexamphetamine
AHFS/Drugs.comMonograph
MedlinePlusa605027
License data
Pregnancy
category
  • AU: B3
Dependence
liability		Moderate to High
Routes of
administration		Oral (only medically-utilized route)
ATC code
Legal status
Legal status
Pharmacokinetic data
BioavailabilityOral 75–100%[2]
MetabolismHepatic: CYP2D6,[6] DBH,[7] and FMO[8]
Elimination half-life10-12 hours[3][4]
ExcretionRenal (45%);[5] urinary pH-dependent
Identifiers
  • (2S)-1-phenylpropan-2-amine
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.000.103 Edit this at Wikidata
Chemical and physical data
FormulaC9H13N
Molar mass135.20622 g·mol−1
3D model (JSmol)
Density0.913 g/cm3
Boiling point201.5 °C (394.7 °F)
Solubility in water20 mg/mL (20 °C)
  • C[C@@H](N)CC1=CC=CC=C1
  • InChI=1S/C9H13N/c1-8(10)7-9-5-3-2-4-6-9/h2-6,8H,7,10H2,1H3/t8-/m0/s1 checkY
  • Key:KWTSXDURSIMDCE-QMMMGPOBSA-N checkY
  (verify)

Dextroamphetamine (USAN), Dexamphetamine (AAN)[9][10] and Dexamfetamine (INN and BAN) is a potent psychostimulant and amphetamine stereoisomer prescribed for the treatment of attention deficit-hyperactivity disorder (ADHD) in children and adults as well as for a sleep disorder known as narcolepsy. Dextroamphetamine is also widely used by military air forces as a 'go-pill' during fatigue-inducing mission profiles such as night-time bombing missions.

The amphetamine molecule has two stereoisomers: levoamphetamine and dextroamphetamine. Dextroamphetamine is the dextrorotatory, or "right-handed", enantiomer of the amphetamine molecule. Dextroamphetamine is available as a generic drug or under several brand names, including Dexedrine and Dextrostat, Dexamphetamine. Dextroamphetamine is also an active metabolite of the prodrug Vyvanse.

Uses

Further information: Amphetamine § Uses

Medical

Dexedrine Spansule 5, 10 and 15 mg capsules

Dextroamphetamine is used for the treatment of ADHD and narcolepsy.[11] Dextroamphetamine may be used under circumstances other than (indicated) for off-label use in the following conditions:

Investigational uses

Though such use remains out of the mainstream, dextroamphetamine has been successfully applied in the treatment of certain categories of depression as well as other psychiatric syndromes.[12] Such alternate uses include reduction of fatigue in cancer patients,[13] antidepressant treatment for HIV patients with depression and debilitating fatigue,[14] and early-stage physiotherapy for severe stroke victims.[15] If physical therapy patients take dextroamphetamine while they practice their movements for rehabilitation, they may learn to move much faster than without dextroamphetamine, and in practice sessions with shorter lengths.[16]

Contraindications

Sources[3][17][18]

Side effects

By frequency[3][17][18][20][21][22]

Very common (>10% frequency)

  • Appetite loss
  • Insomnia
  • Abdominal pain

Common (1-10% frequency)

  • High heart rate
  • Palpitations
  • Tremors
  • Headache
  • Dizziness
  • Weight loss
  • Dry mouth
  • Diarrhea
  • Fever
  • Fatigue
  • Infection
  • Nausea/vomiting
  • Dyspepsia (indigestion)
  • Nervousness
  • Emotional lability

Unknown frequency adverse effects

  • Urticaria
  • Sexual dysfunction
  • Overstimulation
  • Restlessness
  • Dyskinesia
  • Tremor
  • Exacerbation of motor and phonic tics and Tourette’s syndrome
  • Hyperactivity

Serious adverse effects

Recent studies by the FDA indicate that, in children, young adults, and adults, there is no association between serious adverse cardiovascular events (sudden death, myocardial infarction, and stroke) and the use of dextroamphetamine or other ADHD stimulants in individuals with normal cardiovascular function.[23][24][25]

Overdosage

An amphetamine overdose is rarely fatal with appropriate care.[26] It can lead to different symptoms.[27][27][28] A moderate overdose may induce symptoms including irregular heartbeat, confusion, painful urination, high or low blood pressure, hyperthermia, hyperreflexia, muscle pain, severe agitation, rapid breathing, tremor, urinary hesitancy, and urinary retention.[27][28][29] An extremely large overdose may produce symptoms such as adrenergic storm, amphetamine psychosis, anuria, cardiogenic shock, cerebral hemorrhage, circulatory collapse, edema (peripheral or pulmonary), extreme fever, pulmonary hypertension, renal failure, rapid muscle breakdown, serotonin toxidrome, and stereotypy.[ref-note 1] Fatal amphetamine poisoning usually also involves convulsions and coma.[27][29]

Psychosis

Main article: Stimulant psychosis

Abuse of amphetamines can result in a stimulant psychosis which may present with a variety of symptoms (e.g. paranoia, hallucinations, delusions). A Cochrane Collaboration review on treatment for amphetamine, dextroamphetamine, and methamphetamine induced psychosis[33] states that about 5-15% of users fail to recover completely.[34] The same review asserts that, based upon at least one trial, antipsychotic medications effectively resolve the symptoms of acute amphetamine psychosis.[33] An amphetamine psychosis may also develop occasionally as a treatment-emergent side effect.[35][35][36]

Withdrawal

While addiction is a serious risk with heavy recreational amphetamine use, it is unlikely to arise from typical medical use.[27][29][37] Tolerance is developed rapidly in amphetamine abuse; therefore, periods of extended use require increasing amounts of the drug in order to achieve the same effect.[38] According to a Cochrane Collaboration review on withdrawal in highly dependent amphetamine and methamphetamine abusers, "when chronic heavy users abruptly discontinue amphetamine use, many report a time-limited withdrawal syndrome that occurs within 24 hours of their last dose."[39] This review noted that withdrawal symptoms in chronic, high-dose users are frequent, occurring in up to 87.6% of cases, and persist for 3–4 weeks with a marked "crash" phase occurring during the first week.[39] Amphetamine withdrawal symptoms can include fatigue, dysphoric mood, increased appetite, vivid or lucid dreams, hypersomnia or insomnia, increased movement or decreased movement, anxiety, and drug craving.[39] The review suggested that withdrawal symptoms are associated with the degree of dependence, suggesting that therapeutic use would result in far milder discontinuation symptoms.[39] The USFDA does not indicate the presence of withdrawal symptoms following discontinuation of pharmaceutical amphetamine use after an extended period at therapeutic doses.[40][41][42]

Pharmacology

Pharmacodynamics

Template:Main section

Pharmacodynamics of amphetamine in a dopamine neuron
A pharmacodynamic model of amphetamine and TAAR1
via AADC
The image above contains clickable links
Amphetamine enters the presynaptic neuron across the neuronal membrane or through DAT.[43] Once inside, it binds to TAAR1 or enters synaptic vesicles through VMAT2.[43][44] When amphetamine enters synaptic vesicles through VMAT2, it collapses the vesicular pH gradient, which in turn causes dopamine to be released into the cytosol (light tan-colored area) through VMAT2.[44][45] When amphetamine binds to TAAR1, it reduces the firing rate of the dopamine neuron via G protein-coupled inwardly rectifying potassium channels (GIRKs) and activates protein kinase A (PKA) and protein kinase C (PKC), which subsequently phosphorylate DAT.[43][46][47] PKA phosphorylation causes DAT to withdraw into the presynaptic neuron (internalize) and cease transport.[43] PKC-phosphorylated DAT may either operate in reverse or, like PKA-phosphorylated DAT, internalize and cease transport.[43] Amphetamine is also known to increase intracellular calcium, an effect which is associated with DAT phosphorylation through a CAMKIIα-dependent pathway, in turn producing dopamine efflux.[48][49]


Amphetamine and its enantiomers have been identified as potent full agonists of trace amine-associated receptor 1 (TAAR1), a GPCR, discovered in 2001, that is important for regulation of monoaminergic systems in the brain.[50][51] Activation of TAAR1 increases cAMP production via adenylyl cyclase activation and inhibits the function of the dopamine transporter, norepinephrine transporter, and serotonin transporter, as well as inducing the release of these monoamine neurotransmitters (effluxion).[50][52][43] Amphetamine enantiomers are also substrates for a specific neuronal synaptic vesicle uptake transporter called VMAT2.[44] When amphetamine is taken up by VMAT2, the vesicle releases (effluxes) dopamine, norepinephrine, and serotonin, among other monoamines, into the cytosol in exchange.[44]

Dextroamphetamine (the dextrorotary enantiomer) and levoamphetamine (the levorotary enantiomer) have identical pharmacodynamics, but their binding affinities to their biomolecular targets vary.[29][51] Dextroamphetamine is a more potent agonist of TAAR1 than levoamphetamine.[51] Consequently, dextroamphetamine produces roughly three to four times more central nervous system (CNS) stimulation than levoamphetamine;[29][51] however, levoamphetamine has slightly greater cardiovascular and peripheral effects.[29]

Further information: Trace amines

Amphetamine has a very similar structure and function to the endogenous trace amines, which are naturally occurring molecules produced in the human body and brain.[43][53] Among this group, the most closely related compounds are phenethylamine, the parent compound of amphetamine, and N-methylphenethylamine, an isomer of amphetamine (i.e., identical molecular formula).[43][53] In humans, phenethylamine is produced in the body directly from phenylalanine by the same enzyme that converts L-DOPA into dopamine, aromatic amino acid decarboxylase.[53] In turn, N‑methylphenethylamine is metabolized from phenethylamine by phenylethanolamine N-methyltransferase, which the same enzyme that metabolizes norepinephrine into adrenaline.[53] Like amphetamine, both phenethylamine and N‑methylphenethylamine regulate monoamine neurotransmission via TAAR1;[43] however, unlike amphetamine, both of these substances are broken down by monoamine oxidase, and therefore have a shorter half-life than amphetamine.[53]

Pharmacokinetics

Amphetamine is well absorbed from the gut, and bioavailability is typically over 75% for dextroamphetamine.[54] However, oral availability varies with gastrointestinal pH.[55] Dextroamphetamine is a weak base with a pKa of 9–10;[6] 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.[6][55] Conversely, an acidic pH means the drug is predominantly in its water soluble cationic form, and less is absorbed.[6][55]

Approximately 15–40% of dextroamphetamine circulating in the bloodstream is bound to plasma proteins.[56]

The half-life of dextroamphetamine varies with urine pH.[6] At normal urine pH, the half-life of dextroamphetamine is 9–11 hours.[6] An acidic diet will reduce the half-life to 8–11 hours, while an alkaline diet will increase the range to 16–31 hours.[57][58] The immediate-release and extended release variants of dextroamphetamine salts reach peak plasma concentrations at 3 hours and 7 hours post-dose respectively.[6] Dextromphetamine is eliminated via the kidneys, with 30–40% of the drug being excreted unchanged at normal urinary pH.[6] When the urinary pH is basic, more of the drug is in its poorly water soluble free base form, and less is excreted.[6] When urine pH is abnormal, the urinary recovery of amphetamine may range from a low of 1% to as much as 75%, depending mostly upon whether urine is too basic or acidic, respectively.[6] Amphetamine is usually eliminated within two days of the last oral dose.[57] Apparent half-life and duration of effect increase with repeated use and accumulation of the drug.[59]

CYP2D6, Dopamine β-hydroxylase, and flavin-containing monooxygenase are the only enzymes currently known to metabolize amphetamine in humans.[6][7][8][60] Amphetamine has a variety of excreted metabolic products, including 4-hydroxyamfetamine, 4-hydroxynorephedrine, 4-hydroxyphenylacetone, benzoic acid, hippuric acid, norephedrine, and phenylacetone.[6][57][61] Among these metabolites, the active sympathomimetics are 4‑hydroxyamphetamine,[62] 4‑hydroxynorephedrine,[63] and norephedrine.[64]

The main metabolic pathways involve aromatic para-hydroxylation, aliphatic alpha- and beta-hydroxylation, N-oxidation, N-dealkylation, and deamination.[6][57] The known pathways include:[6][8][61]

Metabolic pathways of amphetamine in humans[sources 1]
Graphic of several routes of amphetamine metabolism
Para-
Hydroxylation
Para-
Hydroxylation
Para-
Hydroxylation
unidentified
Beta-
Hydroxylation
Beta-
Hydroxylation
Oxidative
Deamination
Oxidation
unidentified
Glycine
Conjugation
The image above contains clickable links
The primary active metabolites of amphetamine are 4-hydroxyamphetamine and norephedrine;[61] however, most of an administered dose is excreted as amphetamine itself and the inactive metabolites.[6]

History, society, and culture

Main article: History and culture of amphetamines

Racemic amphetamine was first synthesized under the chemical name "phenylisopropylamine" in Berlin, 1887 by the Romanian chemist Lazar Edeleanu.[73] It was not widely marketed until 1932, when the pharmaceutical company Smith, Kline & French (now known as GlaxoSmithKline) introduced it in the form of the Benzedrine inhaler for use as a bronchodilator. Notably, the amphetamine contained in the Benzedrine inhaler was the liquid free-base,[n 1] not a chloride or sulfate salt.

Three years later, in 1935, the medical community became aware of the stimulant properties of amphetamine, specifically dexamfetamine, and in 1937 Smith, Kline, and French introduced tablets under the tradename Dexedrine.[74] In the United States, Dexedrine was approved to treat narcolepsy, attention disorders, depression, and obesity. In Canada, epilepsy and parkinsonism were also approved indications.[75] Dexamfetamine was marketed in various other forms in the following decades, primarily by Smith, Kline, and French, such as several combination medications including a mixture of dexamfetamine and amobarbital (a barbiturate) sold under the tradename Dexamyl and, in the 1950s, an extended release capsule (the "Spansule").[76]

It quickly became apparent that dexamfetamine and other amphetamines had a high potential for misuse, although they were not heavily controlled until 1970, when the Comprehensive Drug Abuse Prevention and Control Act was passed by the United States Congress. Dexamfetamine, along with other sympathomimetics, was eventually classified as Schedule II, the most restrictive category possible for a drug with a government-sanctioned, recognized medical use.[77] Internationally, it has been available under the names AmfeDyn (Italy), Curban (US), Obetrol (Switzerland), Simpamina (Italy), Dexedrine/GSK (US & Canada), Dexedrine/UCB (United Kingdom), Dextropa (Portugal), and Stild (Spain).[78]

In October 2010, GlaxoSmithKline sold the rights for Dexedrine Spansule to Amedra Pharmaceuticals (a subsidiary of CorePharma).[79]

The U.S. Air Force uses dexamfetamine as one of its "go pills", given to pilots on long missions to help them remain focused and alert. Conversely, "no-go pills" are used after the mission is completed, to combat the affects of the mission and "go-pills".[80][81][82][83] The Tarnak Farm incident was linked by media reports to the use of this drug on long term fatigued pilots. The military did not accept this explanation, citing the lack of similar incidents. Newer stimulant medications or awakeness promoting agents with different side effect profiles, such as modafinil, are being investigated and sometimes issued for this reason.[81]

Formulations

An image of the lisdexamphetamine compound
The skeletal structure of lisdexamfetamine
Brand
name 		United States
Adopted Name 		(D:L) ratio
of salts 		Dosage
form 		Source
Adderall – 3:1 tablet [84][85]
Adderall XR – 3:1 capsule [84][85]
Dexedrine dextroamphetamine sulfate 1:0 capsule [84]
ProCentra dextroamphetamine sulfate 1:0 tablet [84]
Vyvanse lisdexamfetamine dimesylate 1:0 capsule [86]
Zenzedi dextroamphetamine sulfate 1:0 liquid [84]

Dextroamphetamine sulfate

Dexamfetamine 5 mg generic name tablets

In the United States, an instant-release (IR) tablet preparation of the salt dexamfetamine sulfate is approved under the brand names Dexedrine and Dextrostat, in 5 mg and 10 mg strengths,[citation needed] and generic formulations from Teva Pharmaceutical Industries and recently Wilshire Pharmaceuticals. It is also available as a capsule preparation of controlled-release (CR) dexamfetamine sulfate, under the brand names Dexedrine SR and Dexedrine Spansule, in the strengths of 5 mg, 10 mg, and 15 mg. A bubblegum flavored oral solution is available under the brand name ProCentra, manufactured by FSC Pediatrics, which is designed to be an easier method of administration in children who have difficulty swallowing tablets, each 5 mL contains 5 mg dexamfetamine.[87]

In Australia, dexamfetamine is available in bottles of 100 instant release 5 mg tablets as a generic drug.[88] or slow release dexamfetamine preparations may be compounded by individual chemists.[89] Similarly, in the United Kingdom it is only available in 5 mg instant release sulfate tablets under the generic name dexamfetamine sulphate having had been available under the brand name Dexedrine prior to UCB Pharma disinvesting the product to another pharmaceutical company (Auden Mckenzie).[90]

Lisdexamfetamine

Main article: Lisdexamfetamine

Dexamfetamine is the active metabolite of the prodrug lisdexamfetamine (L-lysine-dextroamphetamine), available by the brand name Vyvanse (Lisdexamfetamine dimesylate). Lisdexamfetamine is metabolised in the gastrointestinal tract, while dextroamphetamine's metabolism is hepatic.[91] Lisdexamfetamine is therefore an inactive compound until it is converted into an active compound by the digestive system. Vyvanse is marketed as once-a-day dosing as it provides a slow release of dexamfetamine into the body. Vyvanse is available as capsules, and in six strengths; 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, and 70 mg. The conversion rate of Lisdexamfetamine dimesylate to dextroamphetamine base is 0.2948,[92] thus a 30 mg-strength Vyvanse capsule is molecularly equivalent to 8.844 mg dexamfetamine base.

Adderall

Adderall IR 30 mg tablets
Main article: Adderall

Another pharmaceutical that contains dextroamphetamine is Adderall. The drug formulation of Adderall, including both the immediate release (IR) and extended release (XR) forms, is:

One-quarter racemic (d,l-)amphetamine aspartate monohydrate
One-quarter dextroamphetamine saccharate
One-quarter dextroamphetamine sulfate
One-quarter racemic (d,l-)amphetamine sulfate

Adderall is roughly three-quarters dextroamphetamine, with it accounting for 72.7% of the amphetamine base in Adderall (the remaining percentage is levoamphetamine). The salt ratio, as noted above, is 75%:25% or 3:1 dextroamphetamine to levoamphetamine.

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    Trace amines are metabolized in the mammalian body via monoamine oxidase (MAO; EC 1.4.3.4) (Berry, 2004) (Fig. 2)...It deaminates primary and secondary amines that are free in the neuronal cytoplasm but not those bound in storage vesicles of the sympathetic neurone...
    Thus, MAO inhibitors potentiate the peripheral effects of indirectly acting sympathomimetic amines. It is not often realized, however, that this potentiation occurs irrespective of whether the amine is a substrate for MAO. An α-methyl group on the side chain, as in amphetamine and ephedrine, renders the amine immune to deamination so that they are not metabolized in the gut. Similarly, β-PEA would not be deaminated in the gut as it is a selective substrate for MAO-B which is not found in the gut...
    Brain levels of endogenous trace amines are several hundred-fold below those for the classical neurotransmitters noradrenaline, dopamine and serotonin but their rates of synthesis are equivalent to those of noradrenaline and dopamine and they have a very rapid turnover rate (Berry, 2004). Endogenous extracellular tissue levels of trace amines measured in the brain are in the low nanomolar range. These low concentrations arise because of their very short half-life,...
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  65. ^ a b Glennon RA (2013). "Phenylisopropylamine stimulants: amphetamine-related agents". In Lemke TL, Williams DA, Roche VF, Zito W (eds.). Foye's principles of medicinal chemistry (7th ed.). Philadelphia, US: Wolters Kluwer Health/Lippincott Williams & Wilkins. pp. 646–648. ISBN 9781609133450. The simplest unsubstituted phenylisopropylamine, 1-phenyl-2-aminopropane, or amphetamine, serves as a common structural template for hallucinogens and psychostimulants. Amphetamine produces central stimulant, anorectic, and sympathomimetic actions, and it is the prototype member of this class (39). ... The phase 1 metabolism of amphetamine analogs is catalyzed by two systems: cytochrome P450 and flavin monooxygenase. ... Amphetamine can also undergo aromatic hydroxylation to p-hydroxyamphetamine. ... Subsequent oxidation at the benzylic position by DA β-hydroxylase affords p-hydroxynorephedrine. Alternatively, direct oxidation of amphetamine by DA β-hydroxylase can afford norephedrine.
  66. ^ Taylor KB (January 1974). "Dopamine-beta-hydroxylase. Stereochemical course of the reaction" (PDF). Journal of Biological Chemistry. 249 (2): 454–458. doi:10.1016/S0021-9258(19)43051-2. PMID 4809526. Retrieved 6 November 2014. Dopamine-β-hydroxylase catalyzed the removal of the pro-R hydrogen atom and the production of 1-norephedrine, (2S,1R)-2-amino-1-hydroxyl-1-phenylpropane, from d-amphetamine.
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  68. ^ a b c Sjoerdsma A, von Studnitz W (April 1963). "Dopamine-beta-oxidase activity in man, using hydroxyamphetamine as substrate". British Journal of Pharmacology and Chemotherapy. 20 (2): 278–284. doi:10.1111/j.1476-5381.1963.tb01467.x. PMC 1703637. PMID 13977820. Hydroxyamphetamine was administered orally to five human subjects ... Since conversion of hydroxyamphetamine to hydroxynorephedrine occurs in vitro by the action of dopamine-β-oxidase, a simple method is suggested for measuring the activity of this enzyme and the effect of its inhibitors in man. ... The lack of effect of administration of neomycin to one patient indicates that the hydroxylation occurs in body tissues. ... a major portion of the β-hydroxylation of hydroxyamphetamine occurs in non-adrenal tissue. Unfortunately, at the present time one cannot be completely certain that the hydroxylation of hydroxyamphetamine in vivo is accomplished by the same enzyme which converts dopamine to noradrenaline.
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    The observed lack of a significant accumulation of PHN in brain following the intraventricular administration of (+)-amphetamine and the formation of appreciable amounts of PHN from (+)-POH in brain tissue in vivo supports the view that the aromatic hydroxylation of amphetamine following its systemic administration occurs predominantly in the periphery, and that POH is then transported through the blood-brain barrier, taken up by noradrenergic neurones in brain where (+)-POH is converted in the storage vesicles by dopamine β-hydroxylase to PHN.
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Notes

  1. ^ Free-base form amphetamine is a volatile oil, hence the efficacy of the inhalers.

Reference notes

  1. ^ [26][27][28][29][30][31][32]


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