Dextroamphetamine
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Dextroamphetamine
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| Systematic (IUPAC) name | |
| (2S)-1-phenylpropan-2-amine | |
| Identifiers | |
| CAS number | 51-63-8 (sulfate), 1462-73-3 (hydrochloride) |
| ATC code | N06 |
| PubChem | |
| DrugBank | |
| Chemical data | |
| Formula | C9H13N |
| Mol. mass | 135.206 g/mol |
| SMILES | & |
| 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 |
Dextroamphetamine is a psychostimulant which produces increased wakefulness, energy and self-confidence in association with decreased fatigue and appetite. It is perhaps the archetypal psycho-stimulant, and drugs with similar psychoactive properties are often referred to as "amphetamine analogues", or described as having "amphetamine-like", or even "amphetaminergic" effects. As a CNS stimulant, enantiopure dextroamphetamine is more powerful than racemic amphetamine (Benzedrine) and has stimulant properties that are similar to those of methamphetamine, but is slightly less potent.
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 racemic-amphetamine in the ADHD drug Adderall. It is the active metabolite of the recently introduced prodrug lisdexamfetamine, known by its brand name Vyvanse. In addition, it is an active metabolite of several older N-substituted amphetamine prodrugs used as anorectics, such as clobenzorex (Asenlix), benzphetamine (Didrex) and amphetaminil (Aponeuron).
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[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 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 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.
Internationally, it has been available under the names AmfeDyn (Italy), Curban (US), Obetrol (Switzerland), Simpamina (Italy) and Stild (Spain). [1]
[edit] Contraindications
The drug should be avoided for those who have: hypersensitivity to amphetamines, a history of drug abuse, cardiovascular diseases, hypertensive disease, hyperthyroidism, or in those with glaucoma.
[edit] Adverse effects
[edit] Side effects
Cardiovascular: Palpitations, tachycardia, elevation of blood pressure.
Central Nervous System: Psychotic episodes at recommended doses (rare), overstimulation, restlessness, dizziness, insomnia, euphoria, dyskinesia, dysphoria, tremor, headache, exacerbation of motor and phonic tics and Tourette's syndrome.
Gastrointestinal: Dryness of the mouth, unpleasant taste, diarrhea, constipation, other gastrointestinal disturbances. Anorexia or weight loss may occur as undesirable effects when amphetamines are used for other than the anorectic effect.
Allergic: Urticaria.
Endocrine: Impotence, changes in libido.
[edit] Withdrawal
Withdrawal from Dextroamphetamines can have various psychological and physical effects if halted mid-course due to an induced dependency. Such symptoms may include fatigue, increased tiredness and depression. It is recommended that prescription users consult their doctor before attempting to stop or limit their dosage of daily amphetamine intake. [3][4][5][6]
[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.[7][8] This suggests a wide therapeutic range[citation needed], 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.[9][10] Methamphetamine is often considered to be significantly more neurotoxic than d-amphetamine in cases of overdose, particularly to serotonergic and dopaminergic neurons in the CNS.
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 extraordinarily sensitive individuals--such as those with a pre-existing neuropsychiatric disorder--psychosis may be produced by 55 to 75 mg of dextroamphetamine. With high enough doses, psychosis can probably be induced in anyone." 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) abuse.[11]
[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 5mg and 10mg strengths in the United States. A pharmaceutical with a strength of 10 mg dextroamphetamine sulfate is 7.33mg 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
Dextroamphetamine is also the active 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 30 mg-strength Vyvanse capsule is molecularly equivalent to 8.88 mg 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.[12]
Vyvanse is also being marketed for its lower abuse and misuse potential than when compared to similar drugs such as Adderall, Dexedrine, and the methylphenidate preparations, though it is still rated as a Schedule II drug by the U.S. Drug Enforcement Administration. Vyvanse significantly slower onset and its route of administration is limited to being taken orally, unlike many similar drugs which are commonly nasally insufflated to achieve a much faster onset and higher bioavailability. Since Vyvanse is a prodrug and thus not psychoactive it must be metabolized into dextroamphetamine first before having psychoactive effects. Insufflation of Vyvanse is expected to produce no stimulant property, though this is disputed by the DEA.
[edit] Mixed amphetamine salts
Another pharmaceutical that contains dextroamphetamine is Adderall. The drug formulation of Adderall (both controlled and instant release forms) is:
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- 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. 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.[13] 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.[14]
[edit] Uses
[edit] 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 treatment-resistant obesity.
[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.[15] Such alternate uses include reduction of fatigue in cancer patients, antidepressant treatment for HIV patients with depression and debilitating fatigue,[16] early stage physiotherapy for severe stroke victims,[17] 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.[18]
[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.[19][20][21] (Friendly fire incidents have been linked 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 and sometimes issued for this reason.[22]
[edit] Illicit
Along with Ritalin and Adderall, 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.[23]
[edit] Pharmacology
[edit] Effect on neurochemistry
Dextroamphetamine affects the dynamics neurotransmitter systems, and its mechanisms of action are continuously 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,[24] 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[25]). At some point, when doses are high, and the concentration of dextroamphetamine is high enough,[24] dextroamphetamine will enter nerve cells and cause release of monoamines from the cytoplasmic dopamine pool (as opposed to 'protected' vesicular stores).[26] 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.
[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 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 dextroamphetamine's affect on glutamate levels; however, at therapeutic doses, dextroamphetamine would likely have little (if any) effect on the serotonin transporter (SERT).[27]
[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).[28] 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 blader cause 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 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 have significant physiological effects as a norepinephrine analogue.[29]
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.[30] In particular, mental effects peak before maximal blood levels are reached, and decline as blood levels remain stable or even continue to increase.[31][32][33] 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.[34]
[edit] Dextroamphetamine in popular culture
- In the best selling Left Behind series of christian novels, dextroamphetamine (as Benzedrine or Dexedrine) is mentioned as a drug used to aid characters in regaining consciousness or staying awake after injury or fatigue.
- The English pop group Dexys Midnight Runners were named after Dexedrine, a brand of dextroamphetamine popularly used as a recreational drug among Northern Soul fans at the time.
- The main character, Case, in the William Gibson novel Neuromancer takes "Brazilian dex" in the form of octagon shaped pills.
- In the American television program Boston Legal, Denny Crane, a character with Alzheimer's disease, says he is taking dextroamphetamine.
[edit] 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.
[edit] Footnotes
- ^ PHARMACEUTICAL MANUFACTURING ENCYCLOPEDIA Second Edition, Marshall Sittig, Volume 1, NOYES PUBLICATIONS
- ^ Side Effects of Dexedrine (amphetamines; Biphetamine, Desoxyn dextroamphetamine sulfate)
- ^ DEXAMPHETAMINE - CMI.
- ^ What should I watch for while taking dextroamphetamine?.
- ^ Tolerance Page 2.
- ^ What are the possible side effects of dextroamphetamine?.
- ^ Miczek K (1979). "A new test for aggression in rats without aversive stimulation: differential effects of d-amphetamine and cocaine." (Abstract). Psychopharmacology (Berl) 60 (3): 253-9. doi:. PMID 108702.
- ^ Grilly D, Loveland A (2001). "What is a "low dose" of d-amphetamine for inducing behavioral effects in laboratory rats?". Psychopharmacology (Berl) 153 (2): 155-69. doi:. PMID 11205415.
- ^ Derlet R, Albertson T, Rice P (1990). "Antagonism of cocaine, amphetamine, and methamphetamine toxicity.". Pharmacol Biochem Behav 36 (4): 745-9. doi:. PMID 2217500.
- ^ Derlet R, Albertson T, Rice P (1990). "The effect of SCH 23390 against toxic doses of cocaine, d-amphetamine and methamphetamine.". Life Sci 47 (9): 821-7. doi:. PMID 2215083.
- ^ LS Goodman, A Gilman (1970). The Pharmacological Basis of Therapeutics, 7th Ed., New York: Macmillan Co..
- ^ FDA Approval of Vyvanse Pharmacological Reviews Pages 18 and 19
- ^ Glaser, et al. (2005). "Differential Effects of Amphetamine Isomers on Dopamine in the Rat Striatum and Nucleus Accumbens Core". Psychopharmacology 178: 250-258 (Pages: 255,256). doi:.
- ^ Arnold (2000). "Methylphenidate vs Amphetamine: Comparative Review". Journal of Attention Disorders 3 (4): 200-211. doi:.
- ^ Warneke L (1990). "Psychostimulants in psychiatry.". Can J Psychiatry 35 (1): 3-10. PMID 2180548.
- ^ Wagner G, Rabkin R (2000). "Effects of dextroamphetamine on depression and fatigue in men with HIV: a double-blind, placebo-controlled trial.". J Clin Psychiatry 61 (6): 436-40. PMID 10901342.
- ^ Martinsson L, Yang X, Beck O, Wahlgren N, Eksborg S (Sep-Oct 2003). "Pharmacokinetics of dexamphetamine in acute stroke.". Clin Neuropharmacol 26 (5): 270-6. doi:. PMID 14520168.
- ^ Butefisch CM et al. (2002). "Modulation of Use-Dependent Plasticity by D-Amphetamine". Annals of Neurology 51 (1): 59–68. doi:. PMID 11782985.
- ^ Air Force scientists battle aviator fatigue
- ^ U.S. Pilots Stay Up Taking 'Uppers'
- ^ Emonson DL, Vanderbeek RD. (1995) The use of amphetamines in U.S. Air Force tactical operations during Desert Shield and Storm. 66(8):802
- ^ Air Force scientists battle aviator fatigue
- ^ NIDA Notes Volume 20, Number 4 (March 2006)
- ^ a b Kuczenski R et al. (1995). "Hippocampus Norepinephrine, Caudate Dopamine and Serotonin, and Behavioral Responses to the Stereoisomers of Amphetamine and Methamphetamine". The Journal of Neuroscience 15 (2): 1308–1317. PMID 7869099. Free full text (PDF)
- ^ Rothman, et al. "Amphetamine-Type Central Nervous System Stimulants Release Norepinephrine more Potently than they Release Dopamine and Serotonin." (2001): Synapse 39, 32–41 (Table V. on page 37)
- ^ Patrick, and Markowitz (1997). "Pharmacology of Methylphenidate, Amphetamine Enantiomers and Pemoline in Attention-Deificit Hyperacitivty Disorder". Human Psychopharmacology 12: 527-546 (Page:530).
- ^ Shoblock J, Sullivan E, Maisonneuve I, Glick S (2003). "Neurochemical and behavioral differences between d-methamphetamine and d-amphetamine in rats". Psychopharmacology (Berl) 165 (4): 359-69. PMID 12491026.
- ^ Mofenson H, Greensher J (1975). "Letter: Physostigmine as an antidote: use with caution.". J Pediatr 87 (6 Pt 1): 1011-2. PMID 1185381.
- ^ Rangno R, Kaufmann J, Cavanaugh J, Island D, Watson J, Oates J (1973). "Effects of a false neurotransmitter, p-hydroxynorephedrine, on the function of adrenergic neurons in hypertensive patients." (Scanned copy). J Clin Invest 52 (4): 952-60. doi:. PMID 4348345.
- ^ Asghar S, Tanay V, Baker G, Greenshaw A, Silverstone P (2003). "Relationship of plasma amphetamine levels to physiological, subjective, cognitive and biochemical measures in healthy volunteers". Hum Psychopharmacol 18 (4): 291–9. PMID 12766934.
- ^ Angrist B, Corwin J, Bartlik B, Cooper T (1987). "Early pharmacokinetics and clinical effects of oral D-amphetamine in normal subjects.". Biol Psychiatry 22 (11): 1357-68. doi:. PMID 3663788.
- ^ Brown G, Hunt R, Ebert M, Bunney W, Kopin I (1979). "Plasma levels of d-amphetamine in hyperactive children. Serial behavior and motor responses." (Abstract). Psychopharmacology (Berl) 62 (2): 133-40. doi:. PMID 111276.
- ^ Brauer L, Ambre J, De Wit H (1996). "Acute tolerance to subjective but not cardiovascular effects of d-amphetamine in normal, healthy men.". J Clin Psychopharmacol 16 (1): 72-6. doi:. PMID 8834422.
- ^ MacKenzie R, Heischober B (1997). "Methamphetamine". Pediatr Rev 18 (9): 305–9. doi:. PMID 9286149.
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