Pharmacodynamics +Binding profile Neurotransmittertransporter Measure(units) DAT Ki () 121 161 2250 IC50 () 20 23 1600 NET Ki (nM) 788 206 >10000 IC50 (nM) 51 39 980 SERT Ki (nM) >10000 >10000 >6700 IC50 (nM) >10000 >10000 GPCR Measure(units) 5-HT1A Ki () 5000 3400 >10000 IC50 () 10000 6800 >10000 5-HT2B Ki (nM) >10000 4700 >10000 IC50 (nM) >10000 4900 >10000<unk>  primarily acts as a norepinephrine–dopamine reuptake inhibitor (NDRI). It is a benzylpiperidine and phenethylamine derivative which also shares part of its basic structure with catecholamines.<unk>  is a psychostimulant and increases the activity of the central nervous system through inhibition on reuptake of the neurotransmitters norepinephrine and dopamine. As models of ADHD suggest, it is associated with functional impairments in some of the brain's neurotransmitter systems, particularly those involving dopamine in the mesocortical and mesolimbic pathways and norepinephrine in the prefrontal cortex and locus coeruleus. Psychostimulants like<unk>  and amphetamine may be effective in treating ADHD because they increase neurotransmitter activity in these systems. When reuptake of those neurotransmitters is halted, its concentration and effects in the synapse increase and last longer, respectively. Therefore,<unk>  is called a norepinephrine–dopamine reuptake inhibitor. By increasing the effects of norepinephrine and dopamine,<unk>  increases the activity of the central nervous system and produces effects such as increased alertness, reduced fatigue, and improved attention.<unk>  is most active at modulating levels of dopamine (DA) and to a lesser extent norepinephrine (NE).<unk>  binds to and blocks dopamine transporters (DAT) and norepinephrine transporters (NET). Variability exists between DAT blockade, and extracellular dopamine, leading to the hypothesis that<unk>  amplifies basal dopamine activity, leading to nonresponse in those with low basal DA activity. On average,<unk>  elicits a 3–4 times increase in dopamine and norepinephrine in the striatum and prefrontal cortex. Magnetic resonance imaging (MRI) studies suggest that long-term treatment with ADHD stimulants (specifically, amphetamine and<unk>  decreases abnormalities in brain structure and function found in subjects with ADHD. Both amphetamine and<unk>  are predominantly dopaminergic drugs, yet their mechanisms of action are distinct.<unk>  acts as a norepinephrine–dopamine reuptake inhibitor, while amphetamine is both a releasing agent and reuptake inhibitor of dopamine and norepinephrine.<unk> 's mechanism of action in the release of dopamine and norepinephrine is fundamentally different from most other phenethylamine derivatives, as<unk>  is thought to increase neuronal firing rate, whereas amphetamine reduces firing rate, but causes monoamine release by reversing the flow of the monoamines through monoamine transporters via a diverse set of mechanisms, including TAAR1 activation and modulation of VMAT2 function, among other mechanisms. The difference in mechanism of action between<unk>  and amphetamine results in<unk>  inhibiting amphetamine's effects on monoamine transporters when they are co-administered.<unk>  has both dopamine transporter and norepinephrine transporter binding affinity, with the dextromethylphenidate enantiomers displaying a prominent affinity for the norepinephrine transporter. Both the dextrorotary and levorotary enantiomers displayed receptor affinity for the serotonergic 5HT1A and 5HT2B subtypes, though direct binding to the serotonin transporter was not observed. A later study confirmed the d-threo-methylphenidate (dexmethylphenidate) binding to the 5HT1A receptor, but no significant activity on the 5HT2B receptor was found.<unk>  may protect neurons from the neurotoxic effects of Parkinson's disease and methamphetamine use disorder. The hypothesized mechanism of neuroprotection is through inhibition of methamphetamine-DAT interactions, and through reducing cytosolic dopamine, leading to decreased production of dopamine-related reactive oxygen species. The dextrorotary enantiomers are significantly more potent than the levorotary enantiomers, and some medications therefore only contain dexmethylphenidate. The studied maximized daily dosage of OROS<unk>  appears to be 144 mg/day. Pharmacokinetics<unk>  taken by mouth has a bioavailability of 11–52% with a duration of action around 2–4 hours for instant release (i.e. Ritalin), 3–8 hours for sustained release (i.e. Ritalin SR), and 8–12 hours for extended release (i.e. Concerta). The half-life of<unk>  is 2–3 hours, depending on the individual. The peak plasma time is achieved at about 2 hours.<unk>  has a low plasma protein binding of 10-33% and a volume of distribution of 2.65 L/kg. Dextromethylphenidate is much more bioavailable than levomethylphenidate when administered orally, and is primarily responsible for the psychoactivity of racemic<unk> . The oral bioavailability and speed of absorption for immediate-release<unk>  is increased when administered with a meal. The effects of a high fat meal on the observed Cmax differ between some extended release formulations, with combined IR/ER and OROS formulations showing reduced Cmax levels while liquid-based extended release formulations showed increased Cmax levels when administered with a high fat meal, according to some researchers. A 2003 study, however, showed no difference between a high fat meal administration and a fasting administration of oral<unk> .<unk>  is metabolized into ritalinic acid by CES1A1, enzymes in the liver. Dextromethylphenidate is selectively metabolized at a slower rate than levomethylphenidate. 97% of the metabolised drug is excreted in the urine, and between 1 and 3% is excreted in the faeces. A small amount, less than 1%, of the drug is excreted in the urine in its unchanged form.
Methylphenidate
Dexmethylphenidate
Ethylphenidate
Atomoxetine
Guanfacine
Psychotherapy
Imipramine
Fluoxetine