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Pharmacological therapy
Amphetamines
Amphetamine occurs as two stereoisomers referred to as dextroamphetamine (D-(+)-amphetamine) and levoamphetamine (L-(–)-amphetamine).
The two stereoisomers of amphetamine differ slightly in their pharmacokinetic and pharmacodynamic properties, and two IR amphetamine formulations have been developed for use in the treatment of ADHD that differ in the relative proportions of each stereoisomer. Dexamphetamine consists of the purified dex (+)-enantiomer. The other formulation is marketed under the name Adderall®, and is a mixture of purified dex (+)- and racemic salts of amphetamine.1–3
It is believed that amphetamines work by increasing the amount of monoamine neurotransmitters in the synapse during neuronal activation.4 This is similar to the effects of methylphenidates.
The secretion of the monoamine neurotransmitters dopamine, norepinephrine and serotonin at a nerve junction synapse, and the impact of amphetamines on neurotransmitter release and reuptake are illustrated below. The numbers in the Figure are explained in the following text.
Dopamine (DA), norepinephrine (NE) and serotonin (5-HT) transport in the synapse, and the effect of amphetamine on transmitter release.
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Upon depolarization of the presynaptic terminal by a nerve impulse, the neurotransmitters dopamine, norepinephrine and serotonin are released into the synapse.
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These neurotransmitters reversibly bind to the postsynaptic receptor.
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The accumulation of monoamines into the secretory presynaptic vesicles is mediated by transporters within the vesicles: vesicular monoamine transporters (VMATs).5 Several studies have demonstrated a decrease in VMAT-2 function following amphetamine administration, resulting in an increase in cytoplasmic dopamine.5,6 It is believed that amphetamine reverses these transporters, resulting in the accumulation of dopamine and norepinephrine in the synapse, similar to the action of methylphenidate.5-9 However, in contrast to methylphenidate, amphetamine also decreases the activity of the serotonin transporters located on the presynaptic membrane; therefore, serotonin also accumulates in the synapse.5,6,8
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Amphetamine has also been shown to be a reversible inhibitor of the monoamine oxidase enzyme, which is the enzyme responsible for the metabolism of these monoamine neurotransmitters. This contributes to an increase in the availability of dopamine, norepinephrine and serotonin.9
References:
1. Dexedrine tablets SPC, UK. 2005.
2. Dextrostat tablets, prescribing information, USA. 2003.
3. Adderall® XR prescribing information, USA. 2006.
4. Biederman J, Faraone SV. Attention-deficit hyperactivity disorder. Lancet 2005; 366: 237–48.
5. Erickson JD, Schafer MK-H, Bonner TI, Eiden LE, Weihe E. Distinct pharmacological properties and distribution in neurons and endocrine cells of two isoforms of the human vesicular monoamine transporter. Proc Natl Acad Sci USA 1996; 93: 5166–71.
6. Fleckenstein AE, Gibb JW, Hanson GR. Differential effects of stimulants on monoaminergic transporters: Pharmacological consequences and implications for neurotoxicity. Eur J Pharmacol 2000; 406: 1–13.
7. Jones SR, Joseph JD, Barak LS, Caron MG, Wightman RM. Dopamine neuronal transport kinetics and effects of amphetamine. J Neurochem 1999; 73: 2406–14
8. Kuczenski R, Segal DS. Effects of methylphenidate on extracellular dopamine, serotonin, and norepinephrine: Comparison with amphetamine. J Neurochem 1997; 68: 2032–37.
9. Suzuki O, Hattori H, Asano M, Oya M, Katsuma Y. Inhibition of monoamine oxidase by d-methamphetamine. Biochem Pharmacol 1980; 29: 2070–73.