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Image:Dextroamphetamine-2D-skeletal.png Dextroamphetamine
(2S)-1-phenylpropan-2-amine IUPAC name
CAS number 51-64-9	ATC code N06BA01
PubChem 5826	DrugBank APRD00480
Chemical formula	{{{chemical_formula}}}
Molecular weight	135.206 g/mol
Bioavailability	>75%
Metabolism	Hepatic
Elimination half-life	10–28 hours (Average ~12 hours)
Excretion	Renal: ~45%
Pregnancy category
Legal status
Routes of administration	Clinical: Oral, intravenous, sublingual Recreational: Vaporized, insufflated, suppository

Dextroamphetamine is a powerful psychostimulant which produces increased wakefulness, energy and self-confidence in association with decreased fatigue and appetite. It is perhaps the archetypal psychostimulant, and drugs with similar psychoactive properties are often referred to as "amphetamine analogues", or described as having "amphetamine-like", or even "amphetaminergic" effects. Its stimulant properties are similar to those of methylphenidate and methamphetamine, though with a slower onset of action and a duration that lies somewhere between the two.^{[citation needed]}

Dextroamphetamine is the dextrorotary stereoisomer of the amphetamine molecule, which can take two different forms. Other common names for dextroamphetamine include d-amphetamine, dexamphetamine, (S)-(+)-amphetamine, and brand names such as Dexedrine and Dextrostat.

Contents 1 History 2 Chemistry 3 Formulations 3.1 Dextroamphetamine sulfate 3.2 Lisdexamfetamine 3.3 Mixed amphetamine salts 4 Uses 4.1 Clinical 4.1.1 Attention deficit hyperactivity disorder 4.1.2 Narcolepsy 4.1.3 Obesity 4.1.4 Depression 4.1.5 Experimental 4.2 Military 4.3 Illicit 5 Overdose 6 Pharmacology 6.1 Subjective effects 6.2 Effect on neurochemistry 6.2.1 Monoamines 6.2.2 Glutamate 6.3 Time course and elimination 6.4 Chronic Amphetamine Use and Abuse 7 References 8 Footnotes

[edit] History

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, and French (currently known as GlaxoSmithKline) introduced it in the form of the "Benzedrine Inhaler," for combating cold symptoms. Notably, the chemical form of Benzedrine in the inhaler was the purely basic form (i.e., it was not a chloride or sulfate salt). In free-base form, amphetamine is a volatile oil, hence the efficacy of the inhalers.

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 Dexedrine tablets, under the tradename Dexedrine. In the United States, Dexedrine tablets were 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").

It quickly became apparent that Dexedrine and other amphetamines had a high potential for abuse, although they were not heavily controlled until 1970, when the Comprehensive Drug Abuse Prevention and Control Act was passed by the United States Congress. Dexedrine, along with other sympathomimetics, was eventually classified as schedule II, the most restrictive category possible for a drug with recognized medical uses.

[edit] Chemistry

Dextroamphetamine is a slightly polar, weak base and is lipophilic.

[edit] Formulations

[edit] Dextroamphetamine sulfate

A tablet preparation of the salt dextroamphetamine sulfate (pharmaceutical names: Dexedrine or Dextrostat) is available in two strengths: 5 mg and 10 mg. A pharmaceutical with a strength of 30mg dextroamphetamine sulfate is 22.0 mg dextroamphetamine.

Dextroamphetamine sulfate is also available in a controlled release version (pharmaceutical name: Dexedrine SR or Dexedrine Spansule), capsulated in the strengths: 5 mg, 10 mg, and 15 mg.

[edit] Lisdexamfetamine

Main article: Lisdexamfetamine

Dextroamphetamine is also the metabolite of the prodrug lisdexamfetamine dimesylate (pharmaceutical name: Vyvanse). Vyvanse is ment to provide once a day dosing because it regulates a slow release of dextroamphetamine into the brain. Vyvanse is available as capsules, in three strengths: 30 mg, 50 mg, and 70 mg. A 30mg strength Vyvanse capsule is molecularly equivalent to 8.88mg dextroamphetamine. However, this molecular equivalence would only hold true as a bioequivalence ratio if: the dimesylate salt instantly dissolved resulting in the complete dissociation of lisdexamfetamine ions, and then the covalent amide bond of every lisdexamfetamine molecule immediately underwent hydrolysis. In fact, Being a prodrug, lisdexamfetamine has properties than dextroamphetamine; for instantance, lisdexamfetamine is metabolised in the gastrointestinal tract, while dextroamphetamine's metabolism is hepatic.^[1]

[edit] Mixed amphetamine salts

Another pharmaceutical that contains "active ingredients" in addition to 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 saccharate

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. Contrary to the beliefs that Adderall is three-quarters dextroamphetamine, dextroamphetamine accounts for 72.7% of the amphetamine base in Adderall (the remaining precentage 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 .^[2] Although it seems that there the human brain has a preference for dextroamphetamine over levoamphetamine, it has been reported that certain children have a better clinical response to levoamphetamine.^[3]

[edit] Uses

[edit] Clinical

[edit] Attention deficit hyperactivity disorder

Template:List to prose (section) Dextroamphetamine is primarely used for treatment of attention deficit hyperactivity disorder (ADHD). In some localities it has replaced methylphenidate as the first-choice medication for ADHD, a role in which it is considered highly effective.^[3]

Compared to Methylphenidate (Ritalin)

Children with comorbid conduct disorder or oppositional defiant disorder respond better to dextroamphetamine^{[citation needed]}

Dextroamphetamine suppresses the appetite more than methylphenidate because of the drug's duration^{[citation needed]}

Methylphenidate may give children more stomachaches.^{[citation needed]}

Amphetamines produce more insomnia because of the duration of the drug^{[citation needed]}

Methylphenidate causes less euphoric side effects than amphetamine^{[citation needed]}

Children with comorbid tic disorders (for example, Tourette syndrome) tolerate methylphenidate better than dextroamphetamine.^[4]

Dextroamphetamine sulfate is cheaper to produce than methylphenidate

[edit] Narcolepsy

Dextroamphetamine is also used for well-established narcolepsy, generally where non-pharmacological measures have proved insufficient.

[edit] Obesity

It is occasionally prescribed for weight-loss in cases of extreme obesity.

[edit] Depression

Amphetamines are occasionally prescribed off label alongside antidepressants for cases of extreme clinical depression. Although this off label use is not permitted in Australia, other than in Western Australia where the Stimulant Prescription Guidelines specify depression as a legitimite indication for dexamphetamine and methylphenidate (along with ADHD, brain damage and narcolepsy).

[edit] 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.^[5] Such alternate uses include reduction of fatigue in cancer patients, antidepressant treatment for HIV patients with depression and debilitating fatigue,^[6] early stage physiotherapy for severe stroke victims,^[7] If physical therapy patients take dextroamphetamine while they practice their movements for rehabilitation, they learn to move much faster than without dextroamphetamine, and in practice sessions with shorter lengths.^[8]

[edit] Military

The U.S. Air Force uses dextroamphetamine as its "go-pill," given to pilots on long missions to help them remain focused and alert. Other branches of the U.S. military (as well as the armed forces of other nations) commonly use or have dispensed dextroamphetamine to troops to prevent or treat fatigue in combat situations. Because of the propensity of dextroamphetamine to cause behavioral side effects, this use is viewed as controversial; (Friendly Fire incidents are linked sometimes to the use of this drug and its effects on long term fatigued pilots) newer stimulant medications with fewer side effects, like modafinil are being investigated for this reason. NASA has also used dextroamphetamine to combat fatigue in astronauts near the end of a mission.

[edit] Illicit

Along with Ritalin, illicit use of dextroamphetamine has been reported among students, both as a study aid, and for purely recreational purposes. According to the National Institute on Drug Abuse, 4% of American college students reported non-prescription stimulant use in 2004.^[9]

[edit] 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.^[10][11] This suggests a wide therapeutic range, in contrast to such drugs as morphine and heroin, where effective doses may be as much as 50% of a fatal dose. Although the symptoms seen in a fatal overdose are similar to those of methamphetamine, their mechanisms are not identical, as some substances which inhibit d-amphetamine toxicity do not do so for methamphetamine.^[12][13]

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 effect of the drug, or due to the long periods of sleep deprivation which are often undergone by the chronic user or abuser. "In apparently sensitive individuals, psychosis may be produced by 55 to 75 mg of dextroamphetamine. With high enough doses, psychosis can probably be induced in anyone."^[14]

[edit] Pharmacology

[edit] Subjective effects

Dextroamphetamine makes people declare that they are in a friendlier than average mood.^[15] Dextroamphetamine improves self-control for people who have a hard time naturally controlling themselves.^[16] Dextroamphetamine aids a person learning and memory of words, and perhaps makes the brain stronger.^[8] When a person given dextroamphetamine is tested, their brain is extremely active in the brain parts required for the test and radically less active in other parts.^[15] Short practice sessions with dextroamphetamine have a greater effect on learning than sessions without dextroamphetamine.^[8][15] Dextroamphetamine raises decision-making scores, improves choices, and changes beliefs about rewards; at the same time, dextroamphetamine barely—if at all—affects guesses of time.^[16] Those who feel lower amounts of joy from dextroamphetamine have greater impulsivity improvements compared to those who feel extreme happiness.^[16] Clinically signifigant side effects of dextroamphetamine include sleeplessness, reduced appetite, dryness of mouth, and headaches. The Physician's 1991 Drug Handbook reports: "Symptoms of overdose include restlessness, tremor, hyperreflexia, tachypnea, confusion, aggressiveness, hallucinations, and panic." Note that many of the symptoms of Amphetamine psychosis are identical to the psychosis-like state which follows long-term sleep deprivation, so it remains unclear pending further studies whether or not these are solely the effect of the drug(s) themselves, or due to the long periods of sleep deprivation which is often undergone by the use of amphetamines

[edit] Effect on neurochemistry

Dextroamphetamine affects the dynamics neurotransmitter systems, and it's mechanism of action are continously being investigated and discovered.

[edit] Monoamines

Dextroamphetamine affects dopamine and serotonin levels in the caudate, and norepinephrine in the hippocampus. Because dextroamphetamine is a substrate analog at monoamine transports, at all doses, dextroamphetamine prevents the reuptake of these neurotransmitters,^[17] causing them to remain in the synaptic cleft for a prolonged period (inhibiting monoamine reuptake in rats with ratios of about: NE:DA = 1:1, NE:5HT = 1:10^[18]). At some point, when doses are high, and the concentration of dextroamphetamine is high enough,^[17] dextroamphetamine will enter nerve cells and cause release of monoamines from the cytoplasmic dopamine pool (as opposed to 'protected' vesicular stores).^[19] In such high concentrations, dextroamphetamine will cause the norepinephrine, dopamine and, serotonin(5HT) transporters to reverse their direction of flow. This inversion leads to a release of these transmitters from the vesicles to the cytoplasm and from the cytoplasm to the synapse (releasing monoamines in rats with ratios of about NE:DA = 1:3.5, NE:5HT= 1:250), causing increased stimulation of post-synaptic receptors.

[edit] Glutamate

Dextroamphetamine does not alter glutamate levels in the prefrontal cortex. This may be because dextroamphetamine increases dopamine release in the prefrontal cortex; activation of the dopamine-2 recepters in the prefrontal cortex inhibits glutamate release in the prefrontal cortex. However activation of the dopamine-1 receptors in the prefrontal cortex, increases glutamate leves in the in the nucleus accumbens. An increase of the glutamate levels in the nucleus accumbens may be part of the reason that dextroamphetamine has the an ability to increase locomotor activity in rats. Serotonin may also play a role in dextroamphetamines affect on glutamate levels.^[20]

[edit] Time course and elimination

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).^[21] 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. The main metabolic pathway is d-amphetamine phenylacetone benzoic acid hippuric acid. Another pathway, mediated by enzyme CYP2D6, is d-amphetamine p-hydroxyamphetamine p-hydroxynorephedrine. Although p-hydroxyamphetamine is a minor metabolite (~5% of the dose), it may may have significant physiological effects as a norepinephrine analogue.^[22]

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.^[23] In particular, mental effects peak before maximal blood levels are reached, and decline as blood levels remain stable or even continue to increase.^[24][25][26] This indicates a mechanism for development of acute tolerance, perhaps distinct from that seen in chronic use. Its slower onset of action as compared to methamphetamine and methylphenidate is presumably due to a somewhat lower effectiveness in crossing the blood-brain barrier.^[27]

[edit] Chronic Amphetamine Use and Abuse

While continuous abusive dosing with amphetamine can cause tolerance, clinically observed intermittent use in rats has produced "reverse tolerance" or sensitization to some psychological effects.^{[28][29][30][31][32]} As a result, regular abusive doses commonly results in a quick decrease of desired stimulant properties. Interesting decreased or intermittent dosages can lead to an increase in unwanted side effects such as craving. Notably, the sensitization is induced more quickly, and persists far longer than withdrawal-related effects, suggesting a phenomenon more complex than a simple tolerance-induced withdrawal syndrome.

[edit] References

• Poison Information Monograph (PIM 178: Dexamphetamine Sulphate)
• Physician's 1991 Drug Handbook
• Dexamphetamine GPnotebook 1845887055
• Package inserts: New Zealand. Canada.
• 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.

[edit] Footnotes

Stimulants edit
Caffeine Nicotine Modafinil Adrafinil Armodafinil
Sympathomimetic amines edit Benzylpiperazine Cathinone Chlorphentermine Cocaine Diethylpropion Ephedrine Fenfluramine Mazindol Methylone Methylphenidate Pemoline Phendimetrazine Phenmetrazine Phentermine Phenylephrine Propylhexedrine Pseudoephedrine Sibutramine Synephrine Amphetamines edit 4-FMP Amphetamine Benzphetamine Dextroamphetamine dl-Amphetamine MDMA MDA MDEA Methamphetamine Paramethoxyamphetamine

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This page uses content from the English-language version of Wikipedia. The original article was at Dextroamphetamine. The list of authors can be seen in the page history. As with Psychology Wiki, the text of Wikipedia is available under the GNU Free Documentation License.