Dextroamphetamine

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Dextroamphetamine
INN: Dexamfetamine
D-amphetamine.svg
Names
Pronunciation/ˌdɛkstræmˈfɛtəmn/
Trade namesDexedrine, DextroStat, Metamina, Attentin, Zenzedi, ProCentra, Amfexa, Tentin
Other namesD-Amphetamine
  • (2S)-1-Phenylpropan-2-amine
Clinical data
Dependence riskModerate-high[1][2]
Addiction riskModerate-high [1][2]
Pregnancy
category
  • AU: B3
  • US: C (Risk not ruled out)
Routes of
use
By mouth
Onset of actionIR dosing: 0.5–1.5 hours[3]
Duration of actionIR dosing: 3–6 hours[4][5]
XR dosing: 8–12 hours[2][4][5]
External links
AHFS/Drugs.comMonograph
US NLMDextroamphetamine
MedlinePlusa605027
Legal
License data
Legal status
Pharmacokinetics
BioavailabilityOral: 75–100%[6]
Protein binding15–40%[7]
MetabolismCYP2D6,[8] DBH,[12] FMO3[13]
Elimination half-life9–11 hours[8][9]
pH-dependent: 7–34 hours[10]
ExcretionRenal (45%);[11] urinary pH-dependent
Chemical and physical data
FormulaC9H13N
Molar mass135.210 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](Cc1ccccc1)N
  • InChI=InChI=1S/C9H13N/c1-8(10)7-9-5-3-2-4-6-9/h2-6,8H,7,10H2,1H3/t8-/m0/s1 ☒N
  • Key:KWTSXDURSIMDCE-QMMMGPOBSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Dextroamphetamine (D-AMP)[note 1] is a medication used to treat attention deficit hyperactivity disorder (ADHD) and narcolepsy.[17][18] It is also used as an athletic performance and cognitive enhancer, and recreationally as an aphrodisiac and euphoriant. Dextroamphetamine was also used in the past by some countries' military forces to fight fatigue during extended combat operations.

It is a central nervous system (CNS) stimulant and an amphetamine enantiomer.[note 2] The amphetamine molecule exists as two enantiomers,[note 2] levoamphetamine and dextroamphetamine. Dextroamphetamine is the dextrorotatory, or 'right-handed', enantiomer and exhibits more pronounced effects on the central nervous system than levoamphetamine.

Pharmaceutical dextroamphetamine sulfate is available as both a brand name and generic drug in a variety of dosage forms. Dextroamphetamine is sometimes prescribed as the inactive prodrug lisdexamfetamine dimesylate, which is converted into dextroamphetamine after absorption.

Uses

Medical

Dextroamphetamine 5mg tablets
Dexedrine Spansule 5, 10 and 15 mg capsules, a sustained-release dosage form of dextroamphetamine

Dextroamphetamine is used to treat attention deficit hyperactivity disorder (ADHD) and narcolepsy (a sleep disorder), and is sometimes prescribed off-label for its past medical indications, such as depression and obesity.[17][18]

Performance

Recreational

Dextroamphetamine is also used recreationally as a euphoriant and aphrodisiac, and like other amphetamines is used as a club drug for its energetic and euphoric high. Dextroamphetamine is considered to have a high potential for misuse in a recreational manner since individuals typically report feeling euphoric, more alert, and more energetic after taking the drug.[20][21][22] Large recreational doses of dextroamphetamine may produce symptoms of dextroamphetamine overdose.[22] Recreational users sometimes open dexedrine capsules and crush the contents in order to insufflate it or subsequently dissolve it in water and inject it.[22] Injection into the bloodstream can be dangerous because insoluble fillers within the tablets can block small blood vessels.[22] Chronic overuse of dextroamphetamine can lead to severe drug dependence, resulting in withdrawal symptoms when drug use stops.[22]

Contraindications

{{#section-h:Amphetamine|Contraindications}}

Side effects

{{#section-h:Amphetamine|Adverse effects}}

Overdose

{{#section-h:Amphetamine|Overdose}}

Interactions

Many types of substances are known to interact with amphetamine, resulting in altered drug action or metabolism of amphetamine, the interacting substance, or both.[8][23] Inhibitors of the enzymes that metabolize amphetamine (e.g., CYP2D6 and FMO3) will prolong its elimination half-life, meaning that its effects will last longer.[13][23] Amphetamine also interacts with MAOIs, particularly monoamine oxidase A inhibitors, since both MAOIs and amphetamine increase plasma catecholamines (i.e., norepinephrine and dopamine);[23] therefore, concurrent use of both is dangerous.[23] Amphetamine modulates the activity of most psychoactive drugs. In particular, amphetamine may decrease the effects of sedatives and depressants and increase the effects of stimulants and antidepressants.[23] Amphetamine may also decrease the effects of antihypertensives and antipsychotics due to its effects on blood pressure and dopamine respectively.[23] Zinc supplementation may reduce the minimum effective dose of amphetamine when it is used for the treatment of ADHD.[note 3][27]

Pharmacology

Dextroamphetamine, like other amphetamines, elicits its stimulating effects via several distinct actions: it inhibits or reverses the transporter proteins for the monoamine neurotransmitters (namely the serotonin, norepinephrine and dopamine transporters) either via trace amine-associated receptor 1 (TAAR1) or in a TAAR1 independent fashion when there are high cytosolic concentrations of the monoamine neurotransmitters[28] and it releases these neurotransmitters from synaptic vesicles via vesicular monoamine transporter 2.[29] It also shares many chemical and pharmacological properties with human trace amines, particularly phenethylamine and N-methylphenethylamine, the latter being an isomer of amphetamine produced within the human body.

Pharmacodynamics

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.[28] Once inside, it binds to TAAR1 or enters synaptic vesicles through VMAT2.[28][29] 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.[29][30] When amphetamine binds to TAAR1, it reduces the firing rate of the dopamine neuron via potassium channels and activates protein kinase A (PKA) and protein kinase C (PKC), which subsequently phosphorylates DAT.[28][31][32] PKA-phosphorylation causes DAT to withdraw into the presynaptic neuron (internalize) and cease transport.[28] PKC-phosphorylated DAT may either operate in reverse or, like PKA-phosphorylated DAT, internalize and cease transport.[28] 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.[33][34]

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.[35][36] 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).[28][35][37] Amphetamine enantiomers are also substrates for a specific neuronal synaptic vesicle uptake transporter called VMAT2.[29] When amphetamine is taken up by VMAT2, the vesicle releases (effluxes) dopamine, norepinephrine, and serotonin, among other monoamines, into the cytosol in exchange.[29]

Dextroamphetamine (the dextrorotary enantiomer) and levoamphetamine (the levorotary enantiomer) have identical pharmacodynamics, but their binding affinities to their biomolecular targets vary.[36][38] Dextroamphetamine is a more potent agonist of TAAR1 than levoamphetamine.[36] Consequently, dextroamphetamine produces roughly three to four times more central nervous system (CNS) stimulation than levoamphetamine;[36][38] however, levoamphetamine has slightly greater cardiovascular and peripheral effects.[38]

Related endogenous compounds

{{#section-h:Amphetamine|Related endogenous compounds}}

Pharmacokinetics

{{#section-h:Amphetamine|Pharmacokinetics}}

History, society, and culture

Racemic amphetamine was first synthesized under the chemical name "phenylisopropylamine" in Berlin, 1887 by the Romanian chemist Lazar Edeleanu. 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,[note 4] not a chloride or sulfate salt.

Three years later, in 1935, the medical community became aware of the stimulant properties of amphetamine, specifically dextroamphetamine, and in 1937 Smith, Kline, and French introduced tablets under the tradename Dexedrine.[39] In the United States, Dexedrine was approved to treat narcolepsy, attention disorders, and obesity. In Canada indications once included epilepsy and parkinsonism.[40] Dextroamphetamine 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 dextroamphetamine and amobarbital (a barbiturate) sold under the tradename Dexamyl and, in the 1950s, an extended release capsule (the "Spansule").[41] Preparations containing dextroamphetamine were also used in World War II as a treatment against fatigue.[42]

It quickly became apparent that dextroamphetamine 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. Dextroamphetamine, 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.[43] 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).[44] It became popular on the mod scene in England in the early 1960s, and carried through to the Northern Soul scene in the north of England to the end of the 1970s.

In October 2010, GlaxoSmithKline sold the rights for Dexedrine Spansule to Amedra Pharmaceuticals (a subsidiary of CorePharma).[45]

The U.S. Air Force uses dextroamphetamine 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 effects of the mission and "go-pills".[46][47][48][49] 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.[47]

Formulations

Dextroamphetamine pharmaceuticals and prodrugs[note 5]
Brand
name
United States
Adopted Name
(D:L) ratio Dosage
form
Marketing
start date
US consumer
price data
Sources
Adderall 3:1 (salts) tablet 1996 GoodRx [18][58]
Adderall XR 3:1 (salts) capsule 2001 GoodRx [18][58]
Mydayis 3:1 (salts) capsule 2017 GoodRx [59]
Adzenys XR-ODT amphetamine 3:1 (base) ODT 2016 GoodRx [60][61]
Dyanavel XR amphetamine 3.2:1 (base) suspension 2015 GoodRx [62][63]
Evekeo amphetamine sulfate 1:1 (salts) tablet 2012 GoodRx [64] [65]
Dexedrine dextroamphetamine sulfate 1:0 (salts) capsule 1976 GoodRx [18][58]
Zenzedi dextroamphetamine sulfate 1:0 (salts) tablet 2013 GoodRx [58]
Vyvanse lisdexamfetamine dimesylate 1:0 (prodrug) capsule 2007 GoodRx [18][66]
tablet

Dextroamphetamine sulfate

Dexamphetamine 5 mg generic name tablets

In the United States, immediate release (IR) formulations of dextroamphetamine sulfate are available generically as 5 mg and 10 mg tablets, marketed by Barr (Teva Pharmaceutical Industries), Mallinckrodt Pharmaceuticals, Wilshire Pharmaceuticals, Aurobindo Pharmaceutical USA and CorePharma. Previous IR tablets sold by the brand names of Dexedrine and Dextrostat have been discontinued but in 2015 IR tablets became available by the brand name Zenzedi, offered as 2.5 mg, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg and 30 mg tablets.[67] Dextroamphetamine sulfate is also available as a controlled-release (CR) capsule preparation in strengths of 5 mg, 10 mg, and 15 mg under the brand name Dexedrine Spansule, with generic versions marketed by Barr and Mallinckrodt. 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 dextroamphetamine.[68] The conversion rate between dextroamphetamine sulfate to amphetamine free base is .728.[69]

In Australia, dexamphetamine is available in bottles of 100 instant release 5 mg tablets as a generic drug.[70] or slow release dextroamphetamine preparations may be compounded by individual chemists.[71] In the United Kingdom, it is available in 5 mg instant release sulfate tablets under the generic name dexamfetamine sulfate as well as 10 mg and 20 mg strength tablets under the brand name Amfexa. It is also available in generic dexamfetamine sulfate 5 mg/ml oral sugar-free syrup.[72] The brand name Dexedrine was available in the United Kingdom prior to UCB Pharma disinvesting the product to another pharmaceutical company (Auden Mckenzie).[73]

Lisdexamfetamine

Dextroamphetamine is the active metabolite of the prodrug lisdexamfetamine (L-lysine-dextroamphetamine), available by the brand name Vyvanse (Elvanse in the European market) (Venvanse in the Brazil market) (lisdexamfetamine dimesylate). Dextroamphetamine is liberated from lisdexamfetamine enzymatically following contact with red blood cells. The conversion is rate-limited by the enzyme, which prevents high blood concentrations of dextroamphetamine and reduces lisdexamfetamine's drug liking and abuse potential at clinical doses.[74][75] Vyvanse is marketed as once-a-day dosing as it provides a slow release of dextroamphetamine into the body. Vyvanse is available as capsules, and chewable tablets, and in seven strengths; 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, and 70 mg. The conversion rate between lisdexamfetamine dimesylate (Vyvanse) to dextroamphetamine base is 29.5%.[76][77][78]

Adderall

Adderall tablets
Adderall 20 mg tablets, some broken in half, with a lengthwise-folded US dollar bill along the bottom

Another pharmaceutical that contains dextroamphetamine is commonly known by the brand name Adderall. It is available as immediate release (IR) tablets and extended release (XR) capsules. Adderall contains equal amounts of four amphetamine salts:

Adderall has a total amphetamine base equivalence of 63%.[79] While the enantiomer ratio by dextroamphetamine salts to levoamphetamine salts is 3:1, the amphetamine base content is 75.9% dextroamphetamine, 24.1% levoamphetamine. [note 6]

Amphetamine base in marketed amphetamine medications
drug formula molecular mass
[note 7]
amphetamine base
[note 8]
amphetamine base
in equal doses
doses with
equal base
content
[note 9]
(g/mol) (percent) (30 mg dose)
total base total dextro- levo- dextro- levo-
dextroamphetamine sulfate[81][82] (C9H13N)2•H2SO4
368.49
270.41
73.38%
73.38%
22.0 mg
30.0 mg
amphetamine sulfate[83] (C9H13N)2•H2SO4
368.49
270.41
73.38%
36.69%
36.69%
11.0 mg
11.0 mg
30.0 mg
Adderall
62.57%
47.49%
15.08%
14.2 mg
4.5 mg
35.2 mg
25% dextroamphetamine sulfate[81][82] (C9H13N)2•H2SO4
368.49
270.41
73.38%
73.38%
25% amphetamine sulfate[83] (C9H13N)2•H2SO4
368.49
270.41
73.38%
36.69%
36.69%
25% dextroamphetamine saccharate[84] (C9H13N)2•C6H10O8
480.55
270.41
56.27%
56.27%
25% amphetamine aspartate monohydrate[85] (C9H13N)•C4H7NO4•H2O
286.32
135.21
47.22%
23.61%
23.61%
lisdexamfetamine dimesylate[66] C15H25N3O•(CH4O3S)2
455.49
135.21
29.68%
29.68%
8.9 mg
74.2 mg
amphetamine base suspension[62] C9H13N
135.21
135.21
100%
76.19%
23.81%
22.9 mg
7.1 mg
22.0 mg

Notes

  1. Synonyms and alternate spellings include: (2S)-1-phenylpropan-2-amine (IUPAC name), dexamfetamine (INN),[16] dexamphetamine, (S)-amphetamine, (+)-amphetamine, and D-amphetamine.
  2. 2.0 2.1 Enantiomers are molecules that are mirror images of one another; they are structurally identical, but of the opposite orientation.[19]
  3. The human dopamine transporter contains a high affinity extracellular zinc binding site which, upon zinc binding, inhibits dopamine reuptake and amplifies amphetamine-induced dopamine efflux in vitro.[24][25][26] The human serotonin transporter and norepinephrine transporter do not contain zinc binding sites.[26]
  4. Free-base form amphetamine is a volatile oil, hence the efficacy of the inhalers.
  5. These represent the current brands in the United States, except Dexedrine instant release tablets. Dexedrine tablets, introduced in 1937, is discontinued but available as Zenzedi and generically;[50][51] Dexedrine listed here represents the extended release "Spansule" capsule which was approved in 1976.[52][53] Amphetamine sulfate tablets, now sold as Evekeo (brand), were originally sold as Benzedrine (brand) sulfate in 1935[54][55] and discontinued sometime after 1982.[56][57]
  6. Calculated by dextroamphetamine base percent / total amphetamine base percent = 47.49/62.57 = 75.90% from table: Amphetamine base in marketed amphetamine medications. The remainder is levoamphetamine.
  7. For uniformity, molecular masses were calculated using the Lenntech Molecular Weight Calculator[80] and were within 0.01g/mol of published pharmaceutical values.
  8. Amphetamine base percentage = molecular massbase / molecular masstotal. Amphetamine base percentage for Adderall = sum of component percentages / 4.
  9. dose = (1 / amphetamine base percentage) × scaling factor = (molecular masstotal / molecular massbase) × scaling factor. The values in this column were scaled to a 30 mg dose of dextroamphetamine sulfate. Due to pharmacological differences between these medications (e.g., differences in the release, absorption, conversion, concentration, differing effects of enantiomers, half-life, etc.), the listed values should not be considered equipotent doses.
Image legend

Reference notes

References

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    Table 9.2 Dextroamphetamine formulations of stimulant medication
    Dexedrine [Peak:2–3 h] [Duration:5–6 h] ...
    Adderall [Peak:2–3 h] [Duration:5–7 h]
    Dexedrine spansules [Peak:7–8 h] [Duration:12 h] ...
    Adderall XR [Peak:7–8 h] [Duration:12 h]
    Vyvanse [Peak:3–4 h] [Duration:12 h]
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