Dextroamphetamine
From Wikipedia, the free encyclopedia
Categories: All articles with unsourced statements | Articles with unsourced statements since September 2007 | Amphetamines
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 sympathomimetic amine, its stimulant properties are similar to those of methylphenidate and methamphetamine. 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).
HistoryAmphetamine 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] IndicationsDextroamphetamine is useful for those with ADHD and Narcolepsy. It improves self-control for people who have a hard time naturally controlling themselves.[2] Dextroamphetamine aids a person learning and memory of words, and perhaps makes the brain stronger.[3] 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.[4] Short practice sessions with dextroamphetamine have a greater effect on learning than sessions without dextroamphetamine.[3][4] 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.[2] Those who feel lower amounts of joy from dextroamphetamine have greater impulsivity improvements compared to those who feel extreme happiness.[2] ContraindicationsThe 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. Adverse effectsSide effectsCardiovascular: 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. WithdrawalWithdrawal 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. [6][7][8][9] OverdoseThe 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[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.[12][13] 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. The neurotoxic effects of methamphetamine are similar to those of its chemical cousin MDMA (3,4-methylenedioxymethamphetamine; Ecstasy). 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.[14] ChemistryDextroamphetamine is a slightly polar, weak base and is lipophilic. FormulationsDextroamphetamine sulfateImage:Dexamphetamine sulfate 5 mg tablets.jpg
5mg dexamphetamine sulfate tablets
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 30 mg dextroamphetamine sulfate is 22.0 mg dextroamphetamine. Image:Dexedrine Spansules.jpg
Sustained-Release 15 mg Dexedrine Spansules
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. LisdexamfetamineDextroamphetamine 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.[15] 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. Mixed amphetamine saltsImage:Adderall 30mg small.jpg
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:
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.[16] 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.[17] UsesClinical
ExperimentalThough 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.[18] Such alternate uses include reduction of fatigue in cancer patients, antidepressant treatment for HIV patients with depression and debilitating fatigue,[19] early stage physiotherapy for severe stroke victims,[20] 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.[3] MilitaryThe U.S. Air Force uses dextroamphetamine as its "go pill," given to pilots on long missions to help them remain focused and alert.[21][22][23] (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.[24] IllicitAlong 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.[25] PharmacologyEffect on neurochemistryDextroamphetamine affects the dynamics neurotransmitter systems, and its mechanisms of action are continuously being investigated and discovered. MonoaminesDextroamphetamine 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,[26] 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[27]). At some point, when doses are high, and the concentration of dextroamphetamine is high enough,[26] dextroamphetamine will enter nerve cells and cause release of monoamines from the cytoplasmic dopamine pool (as opposed to 'protected' vesicular stores).[28] 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. GlutamateDextroamphetamine 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).[29] Time course and eliminationOn 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).[30] 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 Failed to parse (Missing texvc executable; please see math/README to configure.): \rightarrow \; phenylacetone Failed to parse (Missing texvc executable; please see math/README to configure.): \rightarrow \; benzoic acid Failed to parse (Missing texvc executable; please see math/README to configure.): \rightarrow \; hippuric acid. Another pathway, mediated by enzyme CYP2D6, is d-amphetamine Failed to parse (Missing texvc executable; please see math/README to configure.): \rightarrow \; p-hydroxyamphetamine Failed to parse (Missing texvc executable; please see math/README to configure.): \rightarrow \; p-hydroxynorephedrine. Although p-hydroxyamphetamine is a minor metabolite (~5% of the dose), it may have significant physiological effects as a norepinephrine analogue.[31] Dextroamphetamine in popular culture
References
Footnotes
gl:Dextroanfetamina | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
