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| | seealso = [[Dextroamphetamine]], [[Lisdexamfetamine]], [[Methylphenidate]], [[Dexmethylphenidate]], [[Modafinil]], [[Atomoxetine]], [[Methamphetamine]] | | | seealso = [[Dextroamphetamine]], [[Lisdexamfetamine]], [[Methylphenidate]], [[Dexmethylphenidate]], [[Modafinil]], [[Atomoxetine]], [[Methamphetamine]] |
| | references = | | | references = |
| }}<h2 id="Pharmacokinetics">Pharmacokinetics</h2><span></span> | | }} |
| '''Absorption:''' Excellent oral bioavailability — sources report ">75%" to "~90%". Food does not significantly affect total absorption but can delay peak concentration. '''Distribution:''' Volume of distribution ~4 L/kg; plasma protein binding less than 20%. Crosses the blood–brain barrier and placenta. '''Metabolism:''' Amphetamine is oxidized to 4-hydroxyamphetamine, α-hydroxyamphetamine, or norephedrine. Norephedrine and 4-hydroxyamphetamine are active metabolites and are further metabolized to 4-hydroxy-norephedrine. Deamination of α-hydroxyamphetamine yields phenylacetone, which is metabolized to benzoic acid and conjugated to its glucuronide and hippuric acid. '''CYP2D6''' is crucial for amphetamine metabolism; genetic polymorphism causes significant inter-patient variability in clearance. Amphetamine itself inhibits monoamine oxidase (MAO), and both CYP1A2 and CYP3A4 contribute to its metabolism.<ref>https://www.ncbi.nlm.nih.gov/sites/books/NBK507808/</ref> '''Elimination:''' Primarily renal — ~30–40% recovered as unchanged amphetamine, the rest as metabolites. Due to its pK<sub>a</sub> of 9.9, urinary elimination is highly pH-dependent: alkaline urine reduces ionization and decreases renal clearance, while acidic urine and high flow rates accelerate clearance via active tubular secretion. '''Half-life:''' The D-enantiomer has a half-life of 9 hours in children (6–12 y), 11 hours in adolescents (13–17 y), and 10 hours in adults. The L-enantiomer is consistently longer-lived: 11 hours in children, 13–14 hours in adolescents, 13 hours in adults.<h2 id="Pharmacodynamics">Pharmacodynamics</h2><span></span>
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| Amphetamine produces its effects through several converging mechanisms at monoaminergic terminals:
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| *'''Trace amine-associated receptor 1 (TAAR1) agonism''' — activates TAAR1 in monoaminergic neurons, triggering PKA/PKC signaling that phosphorylates the dopamine and norepinephrine transporters (DAT, NET), causing them to internalize and reverse direction.
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| *'''VMAT2 substrate''' — enters the presynaptic terminal, displaces dopamine and norepinephrine from vesicles into the cytoplasm.
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| *'''Reverse transport via DAT/NET''' — the elevated cytoplasmic monoamine pool is then ejected into the synaptic cleft via the now-reversed transporters. '''This is the primary mechanism of action — release, not reuptake inhibition.'''
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| *'''Weak reuptake inhibition''' at DAT and NET (secondary to release).
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| *'''MAO inhibition''' at higher concentrations, slowing presynaptic catabolism of monoamines.
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| *'''Serotonergic effects''' at high or supratherapeutic doses (relevant to overdose and serotonin syndrome risk).
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| The net result is a robust increase in synaptic dopamine and norepinephrine in prefrontal cortex, striatum, and nucleus accumbens — underlying both therapeutic (attention, executive function, wakefulness) and reinforcing (euphoria, abuse liability) effects.<h2 id="Indications">Indications</h2>
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| *Attention-deficit hyperactivity disorder (ADHD) in children, adolescents, and adults
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| *Narcolepsy
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| *Off-label: treatment-resistant depression (augmentation), excessive daytime sleepiness in shift-work disorder, cognitive symptoms in chronic illness<h2 id="Titration">Titration strategies</h2>
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| <span></span><titration slug="typical-adult" title="Typical Adult" author="MDElliottMD">
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| Start at 5 mg XR; may increase by 5 mg each day until the desired effect is reached, up to 30 mg XR to start, and up to 60 mg XR eventually if necessary, in 10 mg increments.
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| Occasionally can go higher if no notable effects (good or bad) at 60 mg — proceed with caution.
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| If not long enough acting: add a tail dose of Adderall IR at [XR dose]/2.
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| If too long acting (e.g. disrupting sleep): switch to IR entirely (again at half the XR dose).
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| </titration>
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