What is the mechanism of action of Dexedrine (dextroamphetamine)?

Mechanism of Action of Dexedrine (Dextroamphetamine)

Dextroamphetamine directly stimulates the release of dopamine and norepinephrine from presynaptic terminals while simultaneously blocking their reuptake transporters, creating a dual mechanism that powerfully increases synaptic catecholamine concentrations in the striatum and prefrontal cortex. 1

Primary Mechanisms

Neurotransmitter Release

• Dextroamphetamine causes direct release of dopamine and norepinephrine from presynaptic nerve terminals, distinguishing it from reuptake inhibitors like methylphenidate that only block transporters. 1, 2
• The drug facilitates release of newly synthesized dopamine rather than simply redistributing stored neurotransmitter, which is critical for its sustained therapeutic effects. 3
• Dextroamphetamine redistributes catecholamines from synaptic vesicles to the cytosol through a non-exocytic mechanism, representing an unusual molecular pathway compared to typical neurotransmitter release. 4

Transporter Inhibition

• Dextroamphetamine inhibits both dopamine and norepinephrine transporters, preventing reuptake back into presynaptic neurons and prolonging synaptic neurotransmitter availability. 1
• The drug acts directly on the dopamine transporter in the striatum, causing significant increases in synaptic dopamine concentrations that exceed those produced by reuptake inhibition alone. 1
• This dual action—both releasing and blocking reuptake—creates more robust catecholaminergic effects than methylphenidate, making dextroamphetamine a more potent psychostimulant. 5, 6

Reverse Transport Mechanism

• Dextroamphetamine induces reverse transport of neurotransmitter through plasma membrane uptake carriers, essentially forcing transporters to work backward and pump dopamine and norepinephrine into the synapse. 4

Additional Neurochemical Effects

• Dextroamphetamine has agonist activity at serotonin type 1A receptors, contributing to its overall neurochemical profile beyond pure catecholaminergic effects. 1
• The drug inhibits monoamine oxidase activity and affects vesicular monoamine transporter 2, providing additional mechanisms that distinguish it from methylphenidate. 6
• Secondary effects include alterations in acetylcholine and serotonin dynamics in the brain, though these are not the primary therapeutic mechanisms. 3

Regional Brain Effects

Striatal Actions

• The locomotor stimulant effects of low doses depend on mesolimbic dopaminergic neurons, while higher doses produce stereotyped behaviors through nigrostriatal dopaminergic neurons. 3
• Acute administration reduces functional connectivity in the cortico-striatal-thalamic network, with these connectivity changes positively associated with the magnitude of dopamine release. 7

Prefrontal Cortex Modulation

• Dextroamphetamine significantly enhances executive function, working memory, and inhibitory control in the prefrontal cortex through dopaminergic and noradrenergic modulation. 1
• In cortical regions, the drug releases both dopamine and noradrenaline, whereas striatal effects are predominantly dopaminergic. 7

Clinical Pharmacology

Pharmacokinetic Profile

• Peak plasma concentration occurs within 1-3 hours after oral administration, with rapid distribution to target tissues due to low plasma protein binding. 1
• The plasma half-life is 11-12 hours, though immediate-release forms act within 30 minutes with clinical effects lasting 3-4 hours despite the longer elimination half-life. 1
• Extended-release formulations provide 8+ hours of clinical action through modified delivery mechanisms. 1

Metabolism and Elimination

• Metabolism involves multiple pathways including p-hydroxylation, N-demethylation, deamination, and conjugation. 1
• Up to 80% is excreted unchanged in urine, making renal function an important consideration for dosing and drug interactions. 1

Key Distinctions from Methylphenidate

• Unlike methylphenidate, which primarily blocks reuptake, dextroamphetamine's direct release mechanism produces more pronounced effects and explains why it is considered more potent. 5, 6
• When dextroamphetamine and methylphenidate are coadministered, methylphenidate can antagonize the neurochemical changes produced by dextroamphetamine, suggesting different and potentially competing mechanisms of action. 8
• The dopaminergic stimulation from dextroamphetamine produces robust behavioral arousal responses that are blocked by D1 dopamine receptor antagonists, confirming dopamine as the primary mediator of clinical effects. 2