Dexmethylphenidate

Dexmethylphenidate is used as a treatment for attention deficit hyperactivity disorder (ADHD), usually along with psychological, educational, behavioral or other forms of treatment. It is proposed that stimulants help ameliorate the symptoms of ADHD by making it easier for the user to concentrate, avoid distraction, and control behavior. Placebo-controlled trials have shown that once-daily dexmethylphenidate XR was effective and generally well tolerated. Improvements in ADHD symptoms in children were significantly greater for dexmethylphenidate XR versus placebo. It also showed greater efficacy than osmotic controlled-release oral delivery system (OROS) methylphenidate over the first half of the laboratory classroom day but assessments late in the day favoured OROS methylphenidate. ==Contraindications==

Hypertension Patients with preexisting high blood pressure or hypertension are at an increased risk of having symptoms worsen due to the use of CNS stimulants. Cardiac disease Sudden death has been reported in patients taking CNS stimulants with cardiac structural abnormalities, arrhythmias, coronary disease, or other forms of cardiac disease. Careful assessment and adjustments to dosage are recommended. Glaucoma Dexmethylphenidate can increase intraocular pressure(IOP) due to dilation of the pupils. In patients with preexisting glaucoma, IOP can cause further damage to the optic nerve. ==Adverse effects==

Products containing dexmethylphenidate have a side effect profile comparable to those containing methylphenidate. == Interactions ==

Methylphenidate (MPH) is widely described in the pharmacological literature as being metabolized primarily, and almost exclusively, by carboxylesterase 1 into its inactive metabolite, ritalinic acid (RA). However, enzyme-induction and inhibition data, together with structural biochemical analyses of MPH and related analogues, challenge this CES1-only framework. Accumulating evidence strongly indicates that CYP2B6, CYP2E1, and CYP3A4 contribute substantially to the clearance and metabolic fate of methylphenidate. Studies examining CYP2B6 show that induction by agents such as carbamazepine produces a marked reduction in circulating methylphenidate concentrations, whereas inhibition—including reports involving turmeric constituents—results in elevated plasma levels and a prolonged duration of action. CYP2E1 has been shown to catalyse α-hydroxylation of the methylphenidate ester side chain, a reaction that promotes its spontaneous degradation to ritalinic acid; inhibition of this isoenzyme, most notably by alcohol, correspondingly increases methylphenidate exposure. CYP3A4 also plays a clinically relevant role, particularly in the presence of ethanol, wherein it mediates the transesterification of methylphenidate to ethylphenidate, an active metabolite. Induction of CYP3A4, including observations associated with glucose-stimulated pathways, increases metabolic flux through this route and can alter drug levels while shortening the duration of effect. Taken together, these findings indicate that the classical view of methylphenidate metabolism as governed solely by CES1 is incomplete. A multi-enzyme model better accounts for observed clinical pharmacokinetics and drug–drug interactions, with CYP2B6 serving as a major clearance pathway, CYP2E1 generating ritalinic acid through α-hydroxylation, and CYP3A4 producing ethylphenidate in ethanol-containing conditions. == Pharmacology==

Pharmacokinetics Dexmethylphenidate has a 4–6 hour duration of effect. A long-acting formulation, Focalin XR, which spans 12 hours is also available and has been shown to be as effective as DL (dextro-, levo-)-TMP (threo-methylphenidate) XR (extended release) (Concerta, Ritalin LA), with flexible dosing and good tolerability. It has also been demonstrated to reduce ADHD symptoms in both children and adults. d-MPH has a similar side-effect profile to MPH CTx-1301 is an experimental medication that is an extended-release formulation of dexmethylphenidate that has a half life more than an hour longer than extended-release dexmethylphenidate (d-MPH-ER). It is under development for ADHD. Mechanism of action Methylphenidate is a catecholamine reuptake inhibitor that indirectly increases catecholaminergic neurotransmission by inhibiting the dopamine transporter (DAT) and norepinephrine transporter (NET), which are responsible for clearing catecholamines from the synapse, particularly in the striatum and meso-limbic system. Moreover, it is thought to "increase the release of these monoamines into the extraneuronal space." In Vitro studies show Methylphenidate possesses weak affinity for 5-HT1A receptors and acts as a partial agonist. Methylphenidate, by acting as a negative allosteric modulator of the DAT transporter, prevents dopamine molecules from being absorbed into DAT. This modulation makes DAT less efficient at coupling sodium and chloride gradients to drive inward dopamine transport. Instead, DAT is shifted to the outward-facing state, making it harder to use the sodium gradient (positive charge that normally pulls dopamine inward) and the chloride gradient (negative charge that normally stabilizes the cycle). In this outward conformation, dopamine is “pulled” from the cytosol into the synapse while reuptake is blocked. By keeping DAT outward-facing, sodium coupling is disrupted, chloride coupling is decreased, and inward turnover destabilized. This biases DAT toward outward release, allowing dopamine to leak out without fully coupling to ions. As a result, dopamine is no longer tightly gated by sodium binding, and the firing rate of dopamine from DAT increases. Methylphenidate increases extracellular dopamine not only by competitively inhibiting reuptake at the dopamine transporter (DAT), but also by modulating DAT conformation through non-substrate-mediated mechanisms. Specifically, methylphenidate acts as a negative allosteric modulator (NAM) at the presynaptic Dopamine Transporter, stabilizing the transporter in its outward-facing conformation. This shift alters the electrochemical gradient and transporter kinetics in a way that promotes dopamine efflux from the presynaptic cytosol into the synaptic cleft even though methylphenidate is not a DAT substrate. This presynaptic Dopamine Transporter Negative allosteric modulation driven efflux amplifies phasic dopamine release and uniquely increases phasic firing rate. This of course in contrast to amphetamines, which reverse DAT via substrate competition and concurrently reduce the dopamine transporter firing rate. Notably, methylphenidate has been shown in studies to induce up to a 500% increase in dopamine release, comparable in magnitude to methamphetamine, though via a non-vesicular, transporter-mediated mechanism. Its 2–3-fold higher DAT binding affinity compared to cocaine may contribute to its more potent and sustained dopaminergic effect. This is identical in process to how cocaine leads to an increase in dopamine firing rate and dopamine release into the synapse. However because methylphenidate binds to the DAT transporter with 2-3 fold higher affinity than cocaine this leads to methylphenidate being more powerful as a DAT negative allosteric modulator. Producing a robust dopamine release of 500% equivalent to methamphetamine. Although four stereoisomers of methylphenidate (MPH) are possible, only the threo diastereoisomers are used in modern practice. There is a high eudysmic ratio between the SS and RR enantiomers of MPH. Dexmethylphenidate (d-threo-methylphenidate) is a preparation of the RR enantiomer of methylphenidate. In theory, D-TMP (d-threo-methylphenidate) can be anticipated to be twice the strength of the racemic product. == Chemistry ==

Dexmethylphenidate a d-threo isomer of methylphenidate which means both chiral centers are in the R configuration. It possesses a Piperidine ring, Phenyl ring and a Methyl Ester group. It is structurally similar to Dopamine and Norepinephrine due to fact that all three molecules contain a Phenethylamine Moiety. It is this similarity that allows Dexmethylphenidate to bind to the Dopamine Transporter (DAT) and the Norepinephrine Transporter (NET). == Notes ==