Chemistry:Dexmethylphenidate

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Dexmethylphenidate, sold under the brand name Focalin among others, is a central nervous system (CNS) stimulant used in the treatment of attention deficit hyperactivity disorder (ADHD) in those over the age of five years.[1] It is taken by mouth.[1] The immediate-release formulation lasts up to five hours while the extended-release formulation lasts up to twelve hours.[2] It is the more active enantiomer of methylphenidate.[1] Methylphenidate has been shown to be more effective than atomoxetine and superior in treating ADHD symptoms when compared.[3]

Common side effects include abdominal pain, loss of appetite, and fever.[1] Serious side effects may include psychosis, sudden cardiac death, mania, anaphylaxis, seizures, and priapism.[1] Safety during pregnancy and breastfeeding is unclear.[4]

Dexmethylphenidate was approved for medical use in the United States in 2001.[5] It is available as a generic medication.[1] In 2023, it was the 127th most commonly prescribed medication in the United States, with more than 4 million prescriptions.[6][7]

Medical uses

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.[8]

Improvements in ADHD symptoms in children were significantly greater for dexmethylphenidate XR versus placebo.[8] 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.[8]

Contraindications

This section is transcluded from Methylphenidate. (edit | history)

{{#section-h: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.[9]

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.[10]

Adverse effects

Part of this section is transcluded from Methylphenidate. (edit | history)

Products containing dexmethylphenidate have a side effect profile comparable to those containing methylphenidate.[11] {{#section-h:Methylphenidate|Adverse effects}}

Interactions

This section is transcluded from Methylphenidate. (edit | history)

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. {{#section-h:Methylphenidate|Interactions}}

Pharmacology

Pharmacokinetcs

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.[12][13] It has also been demonstrated to reduce ADHD symptoms in both children[14] and adults.[15] d-MPH has a similar side-effect profile to MPH[11] and can be administered without regard to food intake.[16]

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.[17][18][19][20][21]

Mechanism of action

Methylphenidate is a catecholamine reuptake inhibitor that indirectly increases catecholaminergic neurotransmission by inhibiting the dopamine transporter (DAT) and norepinephrine transporter (NET),[22] which are responsible for clearing catecholamines from the synapse, particularly in the striatum and meso-limbic system.[23] Moreover, it is thought to "increase the release of these monoamines into the extraneuronal space."[24]

In Vitro studies show Methylphenidate possesses weak affinity for 5-HT1A receptors and acts as a partial agonist.[25]

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.[26]

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.[27]

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.[28][29] In theory, D-TMP (d-threo-methylphenidate) can be anticipated to be twice the strength of the racemic product.[22][30]

Compd[31] DAT (Ki) DA (IC50) NET (Ki) (IC50)
D-TMP 161 23 206 39
L-TMP 2250 1600 >10K 980
DL-TMP 121 20 788 51

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.[32] It is this similarity that allows Dexmethylphenidate to bind to the Dopamine Transporter (DAT) and the Norepinephrine Transporter (NET).[33]

Notes

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 "Dexmethylphenidate Hydrochloride Monograph for Professionals". American Society of Health-System Pharmacists. https://www.drugs.com/monograph/dexmethylphenidate-hydrochloride.html. 
  2. ↑ Mosby's Drug Reference for Health Professions - E-Book. Elsevier Health Sciences. 2013. pp. 455. ISBN 978-0-323-18760-2. https://books.google.com/books?id=41z07XtCfa0C&pg=PA455. 
  3. ↑ "Comparative efficacy and acceptability of methylphenidate and atomoxetine in treatment of attention deficit hyperactivity disorder in children and adolescents: a meta-analysis". BMC Psychiatry 11 (1). 2011-11-10. doi:10.1186/1471-244x-11-176. ISSN 1471-244X. PMID 22074258. 
  4. ↑ "Dexmethylphenidate Use During Pregnancy". https://www.drugs.com/pregnancy/dexmethylphenidate.html. 
  5. ↑ "Focalin- dexmethylphenidate hydrochloride tablet". 24 June 2020. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7c552f11-e24a-4d9b-bb8d-be10c928eca8. 
  6. ↑ "Top 300 of 2023". https://clincalc.com/DrugStats/Top300Drugs.aspx. 
  7. ↑ "Dexmethylphenidate Drug Usage Statistics, United States, 2013 - 2023". https://clincalc.com/DrugStats/Drugs/Dexmethylphenidate. 
  8. ↑ 8.0 8.1 8.2 "Dexmethylphenidate extended release: a review of its use in the treatment of attention-deficit hyperactivity disorder". CNS Drugs 23 (12): 1057–1083. December 2009. doi:10.2165/11201140-000000000-00000. PMID 19958043. 
  9. ↑ "Dexmethylphenidate Disease Interactions" (in en). https://www.drugs.com/disease-interactions/dexmethylphenidate.html. 
  10. ↑ "Dexmethylphenidate Disease Interactions" (in en). https://www.drugs.com/disease-interactions/dexmethylphenidate.html. 
  11. ↑ 11.0 11.1 "Dexmethylphenidate". Drugs 62 (13): 1899–904; discussion 1905–8. 2002. doi:10.2165/00003495-200262130-00009. PMID 12215063. 
  12. ↑ "Dexmethylphenidate extended-release capsules for attention deficit hyperactivity disorder". Expert Review of Neurotherapeutics 5 (4): 437–441. July 2005. doi:10.1586/14737175.5.4.437. PMID 16026226. 
  13. ↑ "Open-label study of dexmethylphenidate hydrochloride in children and adolescents with attention deficit hyperactivity disorder". Journal of Child and Adolescent Psychopharmacology 14 (4): 555–563. 2004. doi:10.1089/cap.2004.14.555. PMID 15662147. 
  14. ↑ "A double-blind, placebo-controlled withdrawal trial of dexmethylphenidate hydrochloride in children with attention deficit hyperactivity disorder". Journal of Child and Adolescent Psychopharmacology 14 (4): 542–554. Winter 2004. doi:10.1089/cap.2004.14.542. PMID 15662146. 
  15. ↑ "Efficacy and safety of dexmethylphenidate extended-release capsules in adults with attention-deficit/hyperactivity disorder". Biological Psychiatry 61 (12): 1380–1387. June 2007. doi:10.1016/j.biopsych.2006.07.032. PMID 17137560. 
  16. ↑ "A single-dose, two-way crossover, bioequivalence study of dexmethylphenidate HCl with and without food in healthy subjects". Journal of Clinical Pharmacology 44 (2): 173–178. February 2004. doi:10.1177/0091270003261899. PMID 14747426. 
  17. ↑ "New directions in psychiatric drug development: promising therapeutics in the pipeline". Expert Opinion on Drug Discovery 18 (8): 835–850. 3 August 2023. doi:10.1080/17460441.2023.2224555. PMID 37352473. 
  18. ↑ "Reviewing the role of emerging therapies in the ADHD armamentarium". Expert Opinion on Emerging Drugs 26 (1): 1–16. March 2021. doi:10.1080/14728214.2020.1846718. PMID 33143485. 
  19. ↑ "An updated safety review of the current drugs for managing ADHD in children". Expert Opinion on Drug Safety 22 (11): 1025–1040. 2023. doi:10.1080/14740338.2023.2271392. PMID 37843488. 
  20. ↑ "Industry update: what is new in the field of therapeutic delivery?". Therapeutic Delivery 9 (3): 155–161. 1 February 2018. doi:10.4155/tde-2017-0117. 
  21. ↑ "An update on the pharmacokinetic considerations in the treatment of ADHD with long-acting methylphenidate and amphetamine formulations". Expert Opinion on Drug Metabolism & Toxicology 15 (11): 937–974. November 2019. doi:10.1080/17425255.2019.1675636. PMID 31581854. 
  22. ↑ 22.0 22.1 "Differential pharmacokinetics and pharmacodynamics of methylphenidate enantiomers: does chirality matter?". Journal of Clinical Psychopharmacology 28 (3 Suppl 2): S54–S61. June 2008. doi:10.1097/JCP.0b013e3181733560. PMID 18480678. 
  23. ↑ "[3H]Threo-(+/-)-methylphenidate binding to 3,4-dihydroxyphenylethylamine uptake sites in corpus striatum: correlation with the stimulant properties of ritalinic acid esters". Journal of Neurochemistry 45 (4): 1062–1070. October 1985. doi:10.1111/j.1471-4159.1985.tb05524.x. PMID 4031878. 
  24. ↑ "Focalin XR- dexmethylphenidate hydrochloride capsule, extended release". 27 June 2020. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1a1da905-42a0-4748-9c39-67eca45deccc. 
  25. ↑ "Unravelling the effects of methylphenidate on the dopaminergic and noradrenergic functional circuits". Neuropsychopharmacology 45 (9): 1482–1489. August 2020. doi:10.1038/s41386-020-0724-x. PMID 32473593. 
  26. ↑ "5-HT1B Receptor-Mediated Serotoninergic Modulation of Methylphenidate-Induced Locomotor Activation in Rats" (in en). Neuropsychopharmacology 33 (3): 619–626. February 2008. doi:10.1038/sj.npp.1301445. ISSN 1740-634X. PMID 17487226. https://www.nature.com/articles/1301445. 
  27. ↑ "Atomic models for the polypeptide backbones of myohemerythrin and hemerythrin". Biochemical and Biophysical Research Communications 66 (4): 1349–1356. 1975-10-27. doi:10.1016/0006-291x(75)90508-2. ISSN 1090-2104. PMID 5. Bibcode: 1975BBRC...66.1349H. 
  28. ↑ "Chiral drugs: comparison of the pharmacokinetics of [11Cd-threo and L-threo-methylphenidate in the human and baboon brain"]. Psychopharmacology 131 (1): 71–78. May 1997. doi:10.1007/s002130050267. PMID 9181638. https://zenodo.org/record/1232627. 
  29. ↑ "Brain kinetics of methylphenidate (Ritalin) enantiomers after oral administration". Synapse 53 (3): 168–175. September 2004. doi:10.1002/syn.20046. PMID 15236349. 
  30. ↑ "Stereoselective effects of methylphenidate on motor hyperactivity in juvenile rats induced by neonatal 6-hydroxydopamine lesioning". Psychopharmacology 160 (1): 92–98. February 2002. doi:10.1007/s00213-001-0962-5. PMID 11862378. 
  31. ↑ "Methylphenidate and its ethanol transesterification metabolite ethylphenidate: brain disposition, monoamine transporters and motor activity". Behavioural Pharmacology 18 (1): 39–51. February 2007. doi:10.1097/FBP.0b013e3280143226. PMID 17218796. 
  32. ↑ "Dexmethylphenidate" (in en). PubChem. U.S. National Library of Medicine. https://pubchem.ncbi.nlm.nih.gov/compound/154101. 
  33. ↑ "Dexmethylphenidate hydrochloride in the treatment of attention deficit hyperactivity disorder". Neuropsychiatric Disease and Treatment 2 (4): 467–473. December 2006. doi:10.2147/nedt.2006.2.4.467. PMID 19412495. 
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