Mechanism of Action and Half-Life of Dextroamphetamine
Dextroamphetamine works by directly stimulating the release of dopamine and norepinephrine from presynaptic terminals while simultaneously blocking their reuptake transporters, and has a half-life of approximately 11-12 hours. 1, 2
Mechanism of Action
Dextroamphetamine operates through multiple complementary pathways in the central nervous system:
Primary Neurotransmitter Effects
- Directly stimulates release of norepinephrine and dopamine from presynaptic terminals, distinguishing it from medications that only block reuptake 3, 1
- Acts directly on the dopamine transporter in the striatum, causing significant increases in synaptic dopamine concentrations 1
- Inhibits dopamine and norepinephrine transporters (preventing reuptake back into neurons), vesicular monoamine transporter 2 (VMAT2), and monoamine oxidase activity 1
- Has agonist activity at serotonin type 1A receptors, contributing to its overall neurochemical profile 1
Peripheral Effects
- Elevates systolic and diastolic blood pressures through sympathomimetic activity 2
- Produces weak bronchodilator and respiratory stimulant effects via adrenergic receptor stimulation 2
- Stimulates both α- and β-adrenergic receptor sites: α-adrenergic stimulation causes vasoconstriction and increased peripheral resistance, while β-adrenergic stimulation increases heart rate and stroke volume 4
Brain Regional Effects
- Significantly enhances executive function, working memory, and inhibitory control in the prefrontal cortex through dopaminergic and noradrenergic modulation 1
- Occupies a high proportion of dopamine transporter sites in the striatum when administered orally at therapeutic doses 1
Pharmacokinetics and Half-Life
Absorption and Distribution
- Peak plasma concentration occurs within 1-3 hours after oral administration 3
- Ingestion of 10 mg produces an average peak blood level of 33.2 ng/mL in healthy volunteers 2
- Low plasma protein binding allows for rapid distribution to target tissues 5
Half-Life
- The plasma half-life is 11-11.75 hours for dextroamphetamine 5, 2
- Immediate-release forms act within 30 minutes with 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 3
Metabolism and Elimination
- Involves multiple metabolic pathways including p-hydroxylation, N-demethylation, deamination, and conjugation 5
- Up to 80% is excreted unchanged in urine, making renal function an important consideration 5
- Average urinary recovery is 38% within 48 hours of administration 2
Important Clinical Considerations
Age-Related Metabolism
- Children aged 4-5 years metabolize stimulants more slowly and require lower starting doses (2.5-5 mg) with smaller incremental increases 3, 5
- Standard adult dosing ranges from 5-60 mg daily, typically divided into twice-daily administration 3, 4
Food Effects
- Food may increase both absorption and bioavailability of dextroamphetamine after meals, potentially affecting timing of administration 5
Prodrug Conversion
- Lisdexamfetamine (Vyvanse) is a prodrug converted to dextroamphetamine only after ingestion when metabolized by erythrocyte cells, providing lower abuse potential 3
Common Pitfalls
- Dosing late in the day causes insomnia; schedule administration at breakfast and lunch to minimize sleep disturbances 3
- Rapid dose escalation increases side effects; titrate by 5 mg weekly increments based on clinical response 5
- Cardiovascular monitoring is essential: avoid use in patients with uncontrolled hypertension, coronary artery disease, or tachyarrhythmias 3