Dextroamphetamine
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| Dextroamphetamine
| |
| Systematic (IUPAC) name | |
| (2S)-1-phenylpropan-2-amine | |
| Identifiers | |
| CAS number | 51-63-8 (sulphate), 1462-73-3 (hydrochloride) |
| ATC code | N06 |
| PubChem | |
| DrugBank | |
| Chemical data | |
| Formula | C9H13N |
| Mol. mass | 135.206 g/mol |
| Pharmacokinetic data | |
| Bioavailability | >75% |
| Metabolism | Hepatic |
| Half life | 10–28 hours (Average ~12 hours) |
| Excretion | Renal: ~45% |
| Therapeutic considerations | |
| Pregnancy cat. | |
| Legal status |
Controlled (S8)(AU) Schedule III(CA) Class B(UK) Schedule II(US) |
| Routes | Clinical: Oral, intravenous, sublingual Recreational: Vaporized, insufflated, suppository |
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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. It is combined with levo-amphetamine in Adderall and other racemic amphetamines.
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 liquid-free base, 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.
Chemistry
Dextroamphetamine is a slightly polar, weak base and is lipophilic.
Formulations
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.
Lisdexamfetamine
Dextroamphetamine is also the metabolite of the prodrug lisdexamfetamine dimesylate (pharmaceutical name: Vyvanse). Vyvanse is meant 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 different properties than dextroamphetamine; for instance, lisdexamfetamine is metabolised in the gastrointestinal tract, while dextroamphetamine's metabolism is hepatic.[1]
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 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.[1] Although it seems that where the human brain has a preference for dextroamphetamine over levoamphetamine, it has been reported that certain children have a better clinical response to levoamphetamine.[1]
Uses
Clinical
- Primarily used to treat 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.
- Treatment of Narcolepsy, generally where non-pharmacological measures have proved insufficient.
- Occasionally prescribed for weight-loss in cases of extreme obesity.
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.[1] Such alternate uses include reduction of fatigue in cancer patients, antidepressant treatment for HIV patients with depression and debilitating fatigue,[1] early stage physiotherapy for severe stroke victims,[1] 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.[1]
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.[1][1] 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; e.g. Tarnak Farm incident) 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.
Illicit
Along with Ritalin, illicit use of dextroamphetamine has been reported among students, both as a study aid, social 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.[1]
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.[1][1] 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[citation needed]. 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.[1][1]
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."[1]
Pharmacology
Subjective effects
Dextroamphetamine makes people declare that they are in a friendlier than average mood.[1] Dextroamphetamine improves self-control for people who have a hard time naturally controlling themselves.[1] Dextroamphetamine aids a person learning and memory of words, and perhaps makes the brain stronger.[1] 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.[1] Short practice sessions with dextroamphetamine have a greater effect on learning than sessions without dextroamphetamine.[1][1] 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.[1] Those who feel lower amounts of joy from dextroamphetamine have greater impulsivity improvements compared to those who feel extreme happiness.[1] Clinically significant side effects of dextroamphetamine include sleeplessness, reduced appetite, dryness of mouth, and headaches.
Effect on neurochemistry
Dextroamphetamine affects the dynamics neurotransmitter systems, and its mechanisms of action are continuously being investigated and discovered.
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,[1] causing them to remain in the synaptic cleft for a prolonged period (inhibiting monoamine reuptake in rats with a norepinephrine to dopamine ratio (NE:DA) of about 1:1 and a norepinephrine to 5-hydroxytryptamine ratio (NE:5HT) of about 1:10[1]). At some point, when doses are high, and the concentration of dextroamphetamine is high enough,[1] dextroamphetamine will enter nerve cells and cause release of monoamines from the cytoplasmic dopamine pool (as opposed to 'protected' vesicular stores).[1] 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 and NE:5HT = 1:250), causing increased stimulation of post-synaptic receptors.
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 receptors inhibits glutamate release in the prefrontal cortex. However activation of the dopamine-1 receptors in the prefrontal cortex, increases glutamate leves in the nucleus accumbens. An increase of the glutamate levels in the nucleus accumbens may be part of the reason that dextroamphetamine has an ability to increase locomotor activity in rats. Serotonin may also play a role in dextroamphetamines affect on glutamate levels.
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).[1]
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.[1]
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.[1] In particular, mental effects peak before maximal blood levels are reached, and decline as blood levels remain stable or even continue to increase.[1][1][1] 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.[1]
References
- Poison Information Monograph (PIM 178: Dexamphetamine Sulphate)
- Physician's 1991 Drug Handbook
- Dexamphetamine 1845887055 at GPnotebook
- 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.
Footnotes
Psychoanaleptics: psychostimulants, agents used for ADHD and nootropics (N06B) | |
|---|---|
| Centrally acting sympathomimetics | Amphetamine - Amphetaminil - Atomoxetine - Dextroamphetamine - Dextromethamphetamine - Fencamfamin - Fenozolone - Fenetylline - Methylphenidate - Mesocarb - Pemoline - Pipradrol - Prolintane |
| Xanthine derivatives | Caffeine - Propentofylline |
| Racetams | Aniracetam - Oxiracetam - Phenylpiracetam - Piracetam - Pramiracetam |
| Ampakines | CX-516 - CX-546 - CX-614 - CX-691 - CX-717 - IDRA-21 - LY-503,430 - PEPA |
| Eugeroics | Adrafinil - Armodafinil - Modafinil |
| Other psychostimulants and nootropics | Acetylcarnitine - Citicoline - Cyprodenate - Idebenone - Deanol - Dimebon - Fipexide - Linopirdine - Meclofenoxate - Nizofenone - Pirisudanol - Pyritinol - Sulbutiamine - Vinpocetine |
nl:Dextro-amfetaminefi:Deksamfetamiini
Acknowledgement and Attribution Regarding Sources of Content
Some of the initial content on this page may be incorporated in part from copyleft sources in the public domain including wikis such as Wikipedia and AskDrWiki. Drug information for patients came from the The National Library of Medicine. Infectious disease information may have come from the Centers for Disease Control (CDC). Differential Diagnoses are drawn from clinicians as well as an amalgamation of 3 sources: 1.The Disease Database; 2. Kahan, Scott, Smith, Ellen G. In A Page: Signs and Symptoms. Malden, Massachusetts: Blackwell Publishing, 2004:3; 3. Sailer, Christian, Wasner, Susanne. Differential Diagnosis Pocket. Hermosa Beach, CA: Borm Bruckmeir Publishing LLC, 2002:7 .
