dextroamphetamine

Dextroamphetamine
Systematic (IUPAC) name
(2S)-1-phenylpropan-2-amine
Identifiers
CAS number	51-64-9 51-63-8 (sulfate), 1462-73-3 (hydrochloride)
ATC code	N06BA02
PubChem	5826
DrugBank	APRD00480
ChemSpider	5621
Chemical data
Formula	C9H13N
Mol. mass	135.2062
SMILES	eMolecules & PubChem
Pharmacokinetic data
Bioavailability	oral >75%
Metabolism	Hepatic
Half life	10–28 hours (Average ~12 hours)
Excretion	Renal: ~45%
Therapeutic considerations
Pregnancy cat.	B3(AU) C(US)
Legal status	Controlled (S8)(AU) Schedule III(CA) Class B(UK) Schedule II(US)
Routes	Clinical: Oral, intravenous, sublingual Recreational: Vaporized, insufflated, suppository

"Dexies" redirects here. For the band, see Dexys Midnight Runners.

Dextroamphetamine is a psychostimulant drug which is known to produce increased wakefulness and focus in association with decreased fatigue and decreased appetite. Drugs with similar psychoactive properties can be referred to or described as "amphetamine analogues", "amphetamine-like", or having "amphetaminergic" effects. Enantiomerically pure dextroamphetamine is more potent than racemic amphetamine and has stimulant properties similar to racemic methamphetamine, though less potent and neurotoxic.^[1]

Dextroamphetamine is the dextrorotary or "Right-handed" stereoisomer of the amphetamine molecule. The amphetamine molecule has 2 stereoisomers: levo-amphetamine "left-handed" and dextro-amphetamine "right-handed". Names for dextroamphetamine include d-amphetamine, dexamphetamine, and (S)-(+)-amphetamine, and brand names for dextroamphetamine include Dexedrine and Dextrostat. It is the active metabolite of the 'prodrug' lisdexamfetamine, known by its brand name Vyvanse and makes up approximately 72% of ADHD drug Adderall.^[2] In addition, dextroamphetamine is an active metabolite of several older N-substituted amphetamine prodrugs used as anorectics, such as clobenzorex (Asenlix), benzphetamine (Didrex), and amphetaminil (Aponeuron).^[3]

History

Racemic amphetamine was first synthesized under the chemical name "phenylisopropylamine" in Berlin, 1887 by the Romanian chemist Lazar Edeleanu.^{[citation needed]} It was not widely marketed until 1932, when the pharmaceutical company Smith, Kline, and French (currently 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 dextroamphetamine, and in 1937 Smith, Kline, and French introduced tablets under the tradename Dexedrine.^{[citation needed]} In the United States, Dexedrine was approved to treat narcolepsy, attention disorders, depression, and obesity. 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").^{[citation needed]}

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 recognized medical uses.^{[citation needed]}

Internationally, it has been available under the names AmfeDyn (Italy), Curban (US), Obetrol (Switzerland), Simpamina (Italy), Dexedrine (US), Dextropa (Portugal), and Stild (Spain). ^[4]

Contraindications

Do not use in patients with a history of drug abuse. Do not use during or within 14 days following the administration of MAO inhibitors; hypertensive crises may result. Advanced arteriosclerosis, symptomatic cardiovascular disease, moderate to severe hypertension, hyperthyroidism, known hypersensitivity or idiosyncrasy to the sympathomimetic amines, glaucoma and agitated states. Amphetamines should not be used to combat fatigue or to replace rest.^[5]

Effects

Dextroamphetamine, either for recreational or medicinal use, can induce the effects shown below. In general, adverse effects and their severity are relative to the dosage. Standard therapeutic dosages have relatively few serious adverse effects, unless dextroamphetamine is contraindicated with a pre-existing health condition or drug such as an MAO inhibitor.^{[citation needed]}

Physical effects

Physical effects of dextroamphetamine can include a reduced appetite, anorexia, hyperactivity, dilated pupils, flushing, restlessness, dry mouth, headache, tachycardia, bradycardia, tachypnea, hypertension, hypotension, fever, diaphoresis, diarrhea, constipation, blurred vision, aphasia, dizziness, twitches, insomnia, numbness, palpitations, arrhythmias, tremors, dry and/or itchy skin, acne, pallor, convulsions, coma, stroke, heart attack and death. Stunted growth in childen has been shown to occur with long term use amphetamines. ^{[6][7][8][9][10][11]} Sudden death due to cardiotoxicity occurs in between 1.3 to 8.5 per 100,000 person-year.^[12]

Psychological effects

Psychological effects of dextroamphetamine can include euphoria (via increased dopamine and serotonin), anxiety (via increased norepinephrine), altered libido, increased alertness, increased concentration, increased energy, increased self-esteem, increased self-confidence, increased excitation, increased orgasmic intensity, increased sociability, increased irritability, increased aggression, psychomotor agitation, hubris, excessive feelings of power and/or superiority, repetitive and/or obsessive behaviors, paranoia and amphetamine psychosis can occur. The long term effects of amphetamines use on the neural development of children has not been established.^{[6][13][14][15][16]}

Withdrawal effects

Withdrawal symptoms from dextroamphetamine primarily consist of mental fatigue, mental depression and an increased appetite. Symptoms may last for days with occasional use and weeks or months with chronic use with severity dependent on the length of time and the amount of dextroamphetamine taken. Withdrawal symptoms may also include anxiety, agitation, excessive sleep, vivid or lucid dreams (deep REM sleep), suicidal thoughts and psychosis.^[17][18][19]

Overdose

The Physician's 1991 Drug Handbook reports: "Symptoms of overdose include restlessness, tremor, hyperreflexia, tachypnea, confusion, aggressiveness, hallucinations, and panic." Dilated pupils are common with high doses.

The fatal dose in humans is not precisely known, but in various species of rat generally ranges between 50 and 100 mg/kg, or a factor of 100 over what is required to produce noticeable psychological effects.^[20][21] Although the symptoms seen in a fatal overdose are similar to those of methamphetamine, their mechanisms are not identical, as some substances which inhibit dextroamphetamine toxicity do not do so for methamphetamine.^[22][23] Methamphetamine is often^{[weasel words]} considered to be significantly more neurotoxic than dextroamphetamine in cases of overdose, particularly to serotonergic and dopaminergic neurons in the CNS.^{[citation needed]}

An extreme symptom of overdose is amphetamine psychosis, characterized by vivid visual, auditory, and sometimes tactile hallucinations. Many of its symptoms are identical to the psychosis-like state which follows long-term sleep deprivation, so it remains unclear whether these are solely the effects of the drug, or due to the long periods of sleep deprivation which are often undergone by the chronic user. Amphetamine psychosis, however, is extremely rare in individuals taking oral amphetamines at therapeutic doses; it is usually seen in cases of prolonged or high-dose intravenous (IV) for non-medicinal uses.^[24]

Chemistry

Dextroamphetamine is the dextrorotary stereoisomer of the amphetamine molecule, which can take two different forms. It is a slightly polar, weak base and is lipophilic.^[25]

Formulations

Dextroamphetamine sulfate

5mg d-amphetamine sulfate tablets

A tablet preparation of the salt dextroamphetamine sulfate (brand names: Dexedrine or Dextrostat) is available in 5 mg and 10 mg strengths^{[n 2]} in the United States. Dextroamphetamine sulfate is also available as a capsule preparation of controlled release dextroamphetamine sulfate (brand names: Dexedrine SR or Dexedrine Spansule) in the strengths of 5 mg, 10 mg, and 15 mg.

Lisdexamfetamine

Dextroamphetamine is the active metabolite of the prodrug lisdexamfetamine (L-lysine-d-amphetamine.) Lisdexamfetamine dimesylate is available by the brandname Vyvanse. Vyvanse is marketed as a once-a-day dosing since lisdexamfetamine must be first metabolised to dextroamphetamine because it is inactive, lisdexamfetamine provides a slow release of dextroamphetamine into the body. Vyvanse is available as capsules, in six strengths: 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, and 70 mg. The conversion rate of lisdexamfetamine to dextroamphetamine base is 0.2948, so a 30 mg-strength Vyvanse capsule is molecularly equivalent to 8.844 mg dextroamphetamine base. However, this molecular equivalence would only hold true as a bioequivalence ratio if lisdexamfetamine's salt, dimesylate, was instantly dissolved resulting in the complete dissociation of lisdexamfetamine ions, and then the covalent amide bond of every lisdexamfetamine immediately underwent hydrolysis.^{[citation needed]} Lisdexamfetamine's metabolism differs from dextroamphetamine's metabolism. Lisdexamfetamine is metabolised in the gastrointestinal tract, while dextroamphetamine's metabolism is hepatic.^[26] Vyvanse is being marketed for its lower misuse potential than when compared to similar drugs such as amphetamine, dextroamphetamine, and methylphenidate, though it is still rated as a Schedule II drug by the U.S. Drug Enforcement Administration. Lisdexamfetamine has a significantly slower onset and its route of administration is limited to being taken orally, unlike many^[which?] similar drugs which are commonly nasally insufflated to achieve a much faster onset and higher bioavailability.^{[citation needed]} Since lisdexamfetamine is a prodrug and thus not psychoactive so it must be metabolized into dextroamphetamine first to provide effects. Insufflation of lisdexamfetamine is expected to produce no stimulant property, though this is disputed by the DEA.^{[citation needed]}

Mixed amphetamine salts

Instant Release 30 mg Adderall Tablets

Another pharmaceutical that contains dextroamphetamine is Adderall. The drug formulation of Adderall (both controlled and instant release forms) is:

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

One-quarter dextroamphetamine saccharide

One-quarter dextroamphetamine sulfate

One-quarter racemic (d,l-)amphetamine sulfate

Aspartate, saccharate, and sulfate salts differ pharmacokinetically in the rate at which they are metabolized by the body. For this and other reasons, Adderall's effects are different from pharmaceuticals with dextroamphetamine as an exclusive active ingredient. Adderall is roughly three-quarters dextroamphetamine, with it accounting for 72.7% of the amphetamine base in Adderall (the remaining percentage is levoamphetamine). Adderall’s inclusion of levoamphetamine provides the pharmaceutical with a quicker onset and longer clinical effect compared to pharmaceuticals exclusively formulated of dextroamphetamine.^[27] One study has shown that where the human brain has a preference for dextroamphetamine over levoamphetamine, it has been reported^{[weasel words]} that certain children have a better clinical response to levoamphetamine.^[28]

Uses

Clinical

• Approved for the treatment of ADHD and Narcolepsy.^[29]
• Treatment for depression and weight-loss may be prescribed in rare treatment-resistant cases.^{[30] [31]}
• In all clinical treatment scenarios, the dose of dextroamphetamine should be increased gradually from/by 2.5–5 mg/day every three days-week in order to help prevent misuse by minimizing the initial euphoria and effectively estimate the minimal dose required for each individual in treatment of the relevant condition.^[32]

Experimental

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.^[33] Such alternate uses include reduction of fatigue in cancer patients, antidepressant treatment for HIV patients with depression and debilitating fatigue,^[34] and early stage physiotherapy for severe stroke victims.^[35] 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.^[36]

Military

The U.S. Air Force uses dextroamphetamine as one of its to "go pills," given to pilots on long missions to help them remain focused and alert. (Conversely, the Air Force also issues "no-go pills"; prescription sedatives used after the mission to calm down.) ^[37][38][39] [1] The Tarnak Farm incident was linked by media reports to the use of this drug on long term fatigued pilots. A military tribunal did not accept this explanation, citing the lack of similar incidents. Newer stimulant medications or awakeness promoting agents with fewer side effects, such as modafinil are being investigated and sometimes issued for this reason.^[37]

Recreational

Along with amphetamine and methylphenidate, non-prescription use of dextroamphetamine has been used as a recreational stimulant drug that provides euphoria and is also used as a study aid, social aid and party drug. The National Institute on Drug Abuse stated a large percentage of American college students reported stimulant use for non-medicinal purposes.^[40]

Pharmacology

Scientific findings have established that dextroamphetamine administration increases the activity of the phosphoinositol cycle via an indirect release of dopamine and noradrenaline. These results are the first time that this has been confirmed in humans.^[41] Because dextroamphetamine is a substrate analog at monoamine transporters, at all doses, dextroamphetamine prevents the reuptake of these neurotransmitters by competing with endogenous monoamines for uptake.^[42] Transporter inhibition causes monoamines to remain in the synaptic cleft for a prolonged period (amphetamine inhibits monoamine reuptake in rats with a norepinephrine to dopamine ratio (NE:DA) of about 1:1 and a norepinephrine to 5-hydroxytryptamine ratio (NE:5-HT) of about 1:25).^[43] At higher doses, when the concentration of dextroamphetamine is sufficient,^[42] the drug can trigger direct release of norepinephrine and dopamine from the cytoplasmic transmitter pool, That is, dextroamphetamine will cause norepinephrine and dopamine efflux via transporter proteins, functionally reversing transporter action, such that the transporters "pump out" catecholamines rather than taking them back up. This inversion leads to a release of large amounts of these transmitters from the cytoplasm of the presynaptic neuron into the synapse, causing increased stimulation of post-synaptic receptors and extreme euphoria. Dextroamphetamine releases monoamines in rats with selectivity ratios of about NE:DA = 1:3.5 and NE:5-HT = 1:250, meaning that NE and DA are readily released, but release of 5-HT occurs at a 1/4 ration than of NE:DA.^[44]

Dextroamphetamine does not alter glutamate levels in the prefrontal cortex. Dextroamphetamine increases dopamine release in the prefrontal cortex; activation of the dopamine-2 receptors inhibits glutamate release in the prefrontal cortex. Activation of the dopamine-1 receptors in the prefrontal cortex, however, results in elevated glutamate levels in the nucleus accumbens. An increase of the glutamate levels in the nucleus accumbens is the reason that dextroamphetamine has an ability to increase locomotor activity in rats. Serotonin also plays a role in dextroamphetamine's affect on glutamate levels; however, at therapeutic doses, dextroamphetamine would likely have little (if any) effect on the serotonin transporter (SERT).^[45]

Pharmacokinetics

On average, about one half of a given dose is eliminated unchanged in the urine, while the other half is broken down into various metabolites (mostly benzoic acid).^[46] However, the drug's half-life is highly variable because the rate of excretion is very sensitive to urinary pH. Under alkaline conditions, direct excretion is negligible and 95%+ of the dose is metabolized. Having an alkaline stomach will cause the drug to be absorbed faster through the stomach resulting in a higher blood level concentration of amphetamine. Having an alkaline bladder causes the drug to be excreted very slowly. It is possible with acute doses of sodium bicarbonate dissolved in water during amphetamine's course in the body for the half-life of the drug to last about 24 hours, with after effects lasting another 10 hours. The main metabolic pathway is dextroamphetamine phenylacetone benzoic acid hippuric acid. Another pathway, mediated by enzyme CYP2D6, is dextroamphetamine p-hydroxyamphetamine p-hydroxynorephedrine. Although p-hydroxyamphetamine is a minor metabolite (~5% of the dose), it may have significant physiological effects as a norepinephrine analogue.^[47]

Subjective effects are increased by larger doses, however, over the course of a given dose there is a noticeable divergence between such effects and drug concentration in the blood.^[48] In particular, mental effects peak before maximal blood levels are reached, and decline as blood levels remain stable or even continue to increase.^[49][50][51] This indicates a mechanism for development of acute tolerance, perhaps distinct from that seen in chronic use.^[52]

References

• Poison Information Monograph (PIM 178: Dexamphetamine Sulphate)
• Physician's 1991 Drug Handbook
• Dexamphetamine 1845887055 at GPnotebook
• Package inserts: "New Zealand". http://www.medsafe.govt.nz/Profs/Datasheet/d/Dexamphetaminesulphatetab.htm.  "Canada". http://www.mentalhealth.com/drug/p30-d04.html. 
• Yamada H, Baba T, Hirata Y, Oguri K, Yoshimura H (1984). "Studies on N-demethylation of methamphetamine by liver microsomes of guinea-pigs and rats: the role of flavin-containing mono-oxygenase and cytochrome P-450 systems". Xenobiotica 14 (11): 861–6. PMID 6506758. 

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Notes

1. ^ Free-base form amphetamine is a volatile oil, hence the efficacy of the inhalers.
2. ^ A preperation with a strength of 10 mg dextroamphetamine sulfate is about 7.28 mg dextroamphetamine base.