Pharmacology of Dexamphetamine
Dexamphetamine is a sympathomimetic central nervous system stimulant that directly stimulates adrenergic receptors as an agonist and indirectly causes the release of dopamine and norepinephrine from presynaptic terminals. 1, 2
Mechanism of Action
Dexamphetamine functions through dual mechanisms:
- Direct action: Acts as an agonist at adrenergic receptors throughout the central and peripheral nervous systems
- Indirect action: Promotes the release of dopamine and norepinephrine from presynaptic nerve terminals, increasing synaptic concentrations of these monoamine neurotransmitters 1, 2
The enhanced availability of dopamine and norepinephrine in key brain regions, particularly the prefrontal cortex, contributes to improvements in attention, focus, impulse control, and alertness 3, 4.
Pharmacokinetics
Peak plasma concentrations occur approximately 3 hours after oral administration of immediate-release formulations, with an average half-life of approximately 12 hours 2. Following administration of three 5 mg immediate-release tablets, average maximal plasma concentrations (Cmax) of 36.6 ng/mL are achieved at approximately 3 hours 2.
Key pharmacokinetic parameters:
- Bioavailability: Well absorbed orally; extended-release formulations show similar bioavailability to immediate-release forms 2
- Time to peak effect: 1-3 hours for immediate-release; approximately 8 hours for sustained-release formulations 2
- Duration of action: Immediate-release formulations require dosing 2-3 times daily; sustained-release formulations provide 8+ hours of clinical action 1
- Food effects: Rate and extent of absorption remain similar in fed versus fasted states for sustained-release formulations 2
Clinical Dosing
Starting dose is 2.5-5 mg once or twice daily, with a typical therapeutic range of 5-30 mg/day divided into 2-3 doses 1, 5, 1. The first dose should be administered in the morning after breakfast, with subsequent doses at 4-6 hour intervals to minimize insomnia 5, 2.
Titration schedule:
- Week 1: Start with 2.5 mg once or twice daily
- Week 2: Increase to 5 mg if needed
- Week 3: Increase to 7.5 mg if needed
- Week 4: Increase to 10 mg if needed 5
Maximum recommended doses vary by population:
- Children weighing <25 kg: Generally should not exceed 10 mg single doses 5
- Children and adolescents: Up to 40 mg total daily dose 5
- Adults: Up to 40 mg total daily dose, though some may require up to 0.9 mg/kg 5
Peripheral Effects
Beyond CNS stimulation, dexamphetamine produces peripheral sympathomimetic effects including:
- Elevation of systolic and diastolic blood pressure (increases SBP by ~2 mmHg and DBP by ~2 mmHg) 6
- Increased heart rate (increases by ~4 beats per minute) 6
- Weak bronchodilator effects
- Respiratory stimulant action 2
Controlled Substance Status
Dexamphetamine is classified as a Schedule II federally controlled substance due to its high potential for abuse and dependence 7, 2. The rapid onset of action, immediate behavioral effects, and tendency to develop tolerance with continued use contribute to increased risk for abuse in vulnerable individuals 1.
The FDA black box warning specifically states that dexamphetamine has a high potential for abuse, and prolonged administration may lead to dependence 7, 2.
Important Clinical Considerations
Dexamphetamine should be avoided in patients with uncontrolled hypertension, underlying coronary artery disease, and tachyarrhythmias 1. Sudden death has occurred in patients with heart defects or serious heart disease 2.
The medication may cause fetal harm based on animal data, though human data are insufficient to determine risk 7, 2. Dexamphetamine passes into breast milk and breastfeeding is not recommended during treatment 2.
Contraindications include:
- Current or recent (within 14 days) use of monoamine oxidase inhibitors (MAOIs)
- Known hypersensitivity to amphetamine products
- Advanced arteriosclerosis, symptomatic cardiovascular disease
- Moderate to severe hypertension 2