Dexamphetamine

 

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Dextroamphetamine

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.

Dextroamphetamine is the dextrorotary or "Right-handed" stereoisomer of the amphetamine molecule. The amphetamine molecule has 2 stereoisomers: levo-amphetamine and dextro-amphetamine. Names for dextroamphetamine include d-amphetamine, dexamphetamine, dexamfetamine, and (S)-(+)-amphetamine, and brand names for dextroamphetamine include Dexedrine and Dextrostat. It is the active metabolite of the 'prodrug' lisdexamfetamine, which is known by its brand name Vyvanse, and makes up approximately 72% of ADHD drug Adderall.^[1] 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).^[2]

History

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 (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. 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").

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.

Internationally, it has been available under the names AmfeDyn (Italy), Curban (US), Obetrol (Switzerland), Simpamina (Italy), Dexedrine (US), Dextropa (Portugal), and Stild (Spain).^[3]

Contraindications

Advanced arteriosclerosis, symptomatic cardiovascular disease, moderate to severe hypertension, hyperthyroidism, known hypersensitivity or idiosyncrasy to the sympathomimetic amines, glaucoma. Agitated state. Patients with a history of drug abuse. During or within 14 days following the administration of monoamine oxidase inhibitors (hypertensive crisis may result).^[4]

Effects

Physical effects

Physical effects of dextroamphetamine can include 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. ^{[5][6][7][8][9][10]} Sudden death due to cardiotoxicity occurs in 13 to 85 out of every 1,000,000 users per year.^[11]

Psychological effects

Psychological effects of dextroamphetamine can include euphoria (via increased dopamine), 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.^{[5][12][13][14][15]}

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.^[16][17][18]

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. Repeated high doses may lead to manifestations of acute psychosis.

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.^[19][20] 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.^[21][22] Methamphetamine is often considered to be significantly more neurotoxic than dextroamphetamine 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 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.^[23]

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.^[24]

Formulations

Dextroamphetamine sulfate

Dexamphetamine Sulphate 5 mg tablets (AU)

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. Lisdexamfetamine's metabolism differs from dextroamphetamine's metabolism. Lisdexamfetamine is metabolised in the gastrointestinal tract, while dextroamphetamine's metabolism is hepatic.^[25] 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 other similar drugs, such as dextroamphetamine and methamphetamine, which are commonly nasally insufflated to achieve a much faster onset and higher bioavailability. Since lisdexamfetamine is a prodrug, and thus not psychoactive, 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.

Mixed amphetamine salts

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.^{[citation needed]} Adderall is roughly three-quarters dextroamphetamine, with it accounting for 72.7% of the amphetamine base in Adderall (the remaining percentage is levoamphetamine). An experiment with rats suggested, Adderall’s inclusion of levoamphetamine provides the pharmaceutical with a quicker onset and longer clinical effect compared to pharmaceuticals exclusively formulated of dextroamphetamine. One study has shown that although the human brain usually has a preference for dextroamphetamine over levoamphetamine, certain children have a better clinical response to levoamphetamine.^[26] Dextroamphetamine induces more euphoria, whereas levoamphetamine induces more depression. The overall greater potency of the dextro form to central actions suggests that this form may have a higher potential for abuse.^[27]

Uses

Clinical

• Approved for the treatment of ADHD and narcolepsy.^[28]
• Treatment for depression and weight-loss may be prescribed in rare treatment-resistant cases.^{[29] [30]}
• 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.^[31]

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.^[32] Such alternate uses include reduction of fatigue in cancer patients, antidepressant treatment for HIV patients with depression and debilitating fatigue,^[33] and early stage physiotherapy for severe stroke victims.^[34] 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.^[35]

Military

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, the Air Force also issues "no-go pills"; prescription sedatives used after the mission to calm down.) ^[36][37][38] [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.^[36]

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 recreational drug. The National Institute on Drug Abuse stated a large percentage of American college students reported stimulant use for non-medicinal purposes.^[39]

Pharmacology

Molecular structure of amphetamine. (Methamphetamine has the same structure, with the addition of a methyl group attached to the nitrogen).

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.^[40] Because dextroamphetamine is a substrate analog at monoamine transporters, at all doses, dextroamphetamine prevents the re-uptake of these neurotransmitters by competing with endogenous monoamines for uptake.^[41] 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 1:1 and a norepinephrine to 5-hydroxytryptamine ratio (NE:5-HT) of about 1:25).^[42]

At higher doses, when the concentration of dextroamphetamine is sufficient,^[41] 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, which triggers a cascading release of catecholamines. This inversion leads to a release of large amounts of these neurotransmitters from the cytoplasm of the presynaptic neuron into the synapse, causing increased stimulation of post-synaptic receptors, inducing 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.^[43]

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 effect on glutamate levels; however, at therapeutic doses, dextroamphetamine has minuscule effect on the serotonin transporter (SERT).^[44]

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).^[45] 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.^[46]

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.^[47] In particular, mental effects peak before maximal blood levels are reached, and decline as blood levels remain stable or even continue to increase.^[48][49][50] This indicates a mechanism for development of acute tolerance, perhaps distinct from that seen in chronic use.^[51]

References

1. ^ N-PSYkelopedia / Dextroamphetamine
2. ^ Amazines Dexamphetamine
3. ^ PHARMACEUTICAL MANUFACTURING ENCYCLOPEDIA Second Edition, Marshall Sittig, Volume 1, NOYES PUBLICATIONS
4. ^ RxList - Dexedrine (Dextroamphetamine)
5. ^ ^{a b} Erowid Amphetamines Vault : Effects
6. ^ Amphetamine; Facts
7. ^ Amphetamines - Better Health Channel
8. ^ adderall xr, adderall medication, adderall side effects, adderall abuse
9. ^ Side Effects of Dexedrine (amphetamines; Biphetamine, Desoxyn dextroamphetamine sulfate)
10. ^ Dextroamphetamine (Oral Route) - MayoClinic.com
11. ^ Vitiello B (April 2008). "Understanding the risk of using medications for attention deficit hyperactivity disorder with respect to physical growth and cardiovascular function" (PDF). Child Adolesc Psychiatr Clin N Am 17 (2): 459–74, xi. doi:10.1016/j.chc.2007.11.010. PMID 18295156. PMC: 2408826. http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=2408826&blobtype=pdf. 
12. ^ Dexedrine | ADD ADHD Information Library
13. ^ Dextroamphetamine
14. ^ http://www.drugs.com/sfx/amphetamine-side-effects.html Side Effects drugs.com
15. ^ Fone KC, Nutt DJ (February 2005). "Stimulants: use and abuse in the treatment of attention deficit hyperactivity disorder". Curr Opin Pharmacol 5 (1): 87–93. doi:10.1016/j.coph.2004.10.001. PMID 15661631. http://linkinghub.elsevier.com/retrieve/pii/S1471-4892(04)00201-2. 
16. ^ Symptoms of Amphetamine withdrawal - WrongDiagnosis.com
17. ^ Dextroamphetamine Withdrawals
18. ^ Drug Abuse Help: Dexedrine Information
19. ^ 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:10.1007/BF00426664. PMID 108702. http://www.springerlink.com/content/v11jj22163t30326/. 
20. ^ 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:10.1007/s002130000580. PMID 11205415. 
21. ^ Derlet R, Albertson T, Rice P (1990). "Antagonism of cocaine, amphetamine, and methamphetamine toxicity". Pharmacol Biochem Behav 36 (4): 745–9. doi:10.1016/0091-3057(90)90071-O. PMID 2217500. 
22. ^ 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:10.1016/0024-3205(90)90555-6. PMID 2215083. 
23. ^ LS Goodman, A Gilman (1970). The Pharmacological Basis of Therapeutics (7th ed.). New York: Macmillan Co.. 
24. ^ DrugBank: Showing Dextroamphetamine
25. ^ FDA Approval of Vyvanse Pharmacological Reviews Pages 18 and 19
26. ^ Arnold (2000). "Methylphenidate vs Amphetamine: Comparative Review". Journal of Attention Disorders 3 (4): 200–211. doi:10.1177/108705470000300403. 
27. ^ 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:10.1007/s00213-004-2012-6. 
28. ^ GlaxoSmithKline Prescribing Information
29. ^ Amphetamine; Dextroamphetamine extended-release capsules
30. ^ Dexedrine Addiction
31. ^ Dexedrine (dextroamphetamine sulfate)
32. ^ Warneke L (1990). "Psychostimulants in psychiatry". Can J Psychiatry 35 (1): 3–10. PMID 2180548. 
33. ^ 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. 
34. ^ 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:10.1097/00002826-200309000-00012. PMID 14520168. 
35. ^ Butefisch CM et al. (2002). "Modulation of Use-Dependent Plasticity by D-Amphetamine". Annals of Neurology 51 (1): 59–68. doi:10.1002/ana.10056. PMID 11782985. 
36. ^ ^{a b} Air Force scientists battle aviator fatigue
37. ^ U.S. Pilots Stay Up Taking 'Uppers'
38. ^ Emonson DL, Vanderbeek RD. (1995) The use of amphetamines in U.S. Air Force tactical operations during Desert Shield and Storm. 66(8):802
39. ^ NIDA Notes Volume 20, Number 4 (March 2006)
40. ^ InterScience :: Dextroamphetamine increases phosphoinositol cycle activity in volunteers: an MRS study
41. ^ ^{a b} Kuczenski R et al. (01 Feb 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. http://www.jneurosci.org/cgi/reprint/15/2/1308. 
42. ^ 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)
43. ^ Patrick, and Markowitz (1997). "Pharmacology of Methylphenidate, Amphetamine Enantiomers and Pemoline in Attention-Deificit Hyperacitivty Disorder". Human Psychopharmacology 12: 527–546 (Page:530). doi:10.1002/(SICI)1099-1077(199711/12)12:6<527::AID-HUP932>3.0.CO;2-U. 
44. ^ 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. doi:10.1007/s00213-002-1288-7. PMID 12491026. 
45. ^ Mofenson H, Greensher J (1975). "Letter: Physostigmine as an antidote: use with caution". J Pediatr 87 (6 Pt 1): 1011–2. doi:10.1016/S0022-3476(75)80946-2. PMID 1185381. 
46. ^ 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:10.1172/JCI107260. PMID 4348345. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=302343. 
47. ^ 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. doi:10.1002/hup.480. PMID 12766934. 
48. ^ 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:10.1016/0006-3223(87)90070-9. PMID 3663788. 
49. ^ 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:10.1007/BF00427126. PMID 111276. http://www.springerlink.com/content/w14m559771164631/. 
50. ^ 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:10.1097/00004714-199602000-00012. PMID 8834422. 
51. ^ MacKenzie R, Heischober B (1997). "Methamphetamine". Pediatr Rev 18 (9): 305–9. doi:10.1542/pir.18-9-305. PMID 9286149.