Editing Dexmethylphenidate

{{Short description|Central nervous system stimulant}}
{{Use dmy dates|date=October 2022}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{Drugbox
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 460779887
| image = Dexmethylphenidate structure.svg
| image_class = skin-invert-image
| width = 200
| alt = 
| image2 = Dextromethylphenidate-based-on-hydrochloride-xtal-1995-3D-balls.png
| alt2 = 

<!--Clinical data-->
| tradename =  Focalin, Focalin XR, others
| Drugs.com = {{drugs.com|monograph|dexmethylphenidate-hydrochloride}}
| MedlinePlus = a603014
| DailyMedID = Dexmethylphenidate
| pregnancy_AU      = <!-- A / B1 / B2 / B3 / C / D / X -->
| pregnancy_AU_comment = 
| pregnancy_category = 
| dependency_liability = [[Physical dependence|Physical]]: None<br />[[Psychological dependence|Psychological]]: Moderate<ref name="Stahl's Essential Psychopharmacology">{{cite book | vauthors=Stahl SM | title=Prescriber's Guide: Stahl's Essential Psychopharmacology | date=April 2024 | publisher=Cambridge University Press | location=Cambridge, United Kingdom | isbn=9781108228749 | pages=503–510 | edition=8th | chapter=Methylphenidate (D,L) }}</ref>
| addiction_liability = Moderate <!-- PLEASE NOTE: countless sources state that methylphenidate has a "High" abuse liability. This term is not synonymous with "addiction liability", which is the relative risk (compared to other addictive drugs) of developing an addiction (aka "substance use disorder") when it's used as prescribed or recreationally. -->
| routes_of_administration = [[Oral administration|By mouth]]
| ATC_prefix = N06
| ATC_suffix = BA11
| ATC_supplemental =

| legal_AU = Schedule 8
| legal_CA = Schedule III
| legal_DE = Anlage III
| legal_UK = Class B
| legal_US = Schedule II
| legal_US_comment = <ref name="Focalin FDA label" /><ref name="Focalin XR FDA label" />
| legal_UN = P II
| legal_status = Rx-only

<!--Pharmacokinetic data-->
| bioavailability = 11–52%
| protein_bound = 30%
| metabolism = [[Liver]]
| elimination_half-life = 4 hours
| excretion = [[Kidney]]

<!--Identifiers-->
| index2_label = hydrochloride
| CAS_number_Ref = {{cascite|changed|??}}
| CAS_number = 40431-64-9
| CAS_number2 = 19262-68-1
| PubChem = 154101
| PubChem2 = 154100
| IUPHAR_ligand = 7554
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB06701
| DrugBank2 = DBSALT001458
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 135807
| ChemSpiderID2 = 135806
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = M32RH9MFGP
| UNII2 = 1678OK0E08
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D07806
| KEGG2_Ref = {{keggcite|correct|kegg}}
| KEGG2 = D03721
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 51860
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 827
| ChEMBL2 = 904
| synonyms = d-threo-methylphenidate (D-TMP)

<!--Chemical data-->
| IUPAC_name = (''R'',''R'')-(+)-Methyl 2-phenyl-2-(2-piperidyl)acetate
| C=14 | H=19 | N=1 | O=2 
| SMILES = O=C([C@@H]([C@@H]1NCCCC1)C2=CC=CC=C2)OC
| SMILES2 = Cl.[H][C@@](C(=O)OC)(C1=CC=CC=C1)[C@@]1([H])CCCCN1
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C14H19NO2/c1-17-14(16)13(11-7-3-2-4-8-11)12-9-5-6-10-15-12/h2-4,7-8,12-13,15H,5-6,9-10H2,1H3/t12-,13-/m1/s1
| StdInChI2 = 1S/C14H19NO2.ClH/c1-17-14(16)13(11-7-3-2-4-8-11)12-9-5-6-10-15-12;/h2-4,7-8,12-13,15H,5-6,9-10H2,1H3;1H/t12-,13-;/m1./s1
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = DUGOZIWVEXMGBE-CHWSQXEVSA-N
| StdInChIKey2 = JUMYIBMBTDDLNG-OJERSXHUSA-N
}}

<!-- Definition and medical uses -->
'''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.<ref name=AHFS2019>{{cite web |title=Dexmethylphenidate Hydrochloride Monograph for Professionals |url=https://www.drugs.com/monograph/dexmethylphenidate-hydrochloride.html |website=Drugs.com |publisher=American Society of Health-System Pharmacists |access-date=15 April 2019}}</ref> It is taken [[Oral administration|by mouth]].<ref name=AHFS2019/> The immediate-release formulation lasts up to five hours while the [[extended-release]] formulation lasts up to twelve hours.<ref>{{cite book |title=Mosby's Drug Reference for Health Professions - E-Book |date=2013 |publisher=Elsevier Health Sciences |isbn=9780323187602 |page=455 |url=https://books.google.com/books?id=41z07XtCfa0C&pg=PA455}}</ref> It is the more active [[enantiomer]] of [[methylphenidate]].<ref name="AHFS2019" />  

<!-- Side effects and mechanism -->
Common side effects include [[abdominal pain]], [[loss of appetite]], and [[fever]].<ref name=AHFS2019/> Serious side effects may include [[psychosis]], [[sudden cardiac death]], [[mania]], [[anaphylaxis]], [[seizures]], and [[priapism]].<ref name=AHFS2019/> Safety during [[pregnancy]] and [[breastfeeding]] is unclear.<ref name=Preg2019>{{cite web |title=Dexmethylphenidate Use During Pregnancy |url=https://www.drugs.com/pregnancy/dexmethylphenidate.html |website=Drugs.com |access-date=15 April 2019}}</ref>

<!-- History and culture -->
Dexmethylphenidate was approved for medical use in the United States in 2001.<ref name="Focalin FDA label">{{cite web | title=Focalin- dexmethylphenidate hydrochloride tablet | website=DailyMed | date=24 June 2020 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7c552f11-e24a-4d9b-bb8d-be10c928eca8 | access-date=15 November 2020}}</ref> It is available as a [[generic medication]].<ref name=AHFS2019/> In 2022, it was the 109th most commonly prescribed medication in the United States, with more than 5{{nbsp}}million prescriptions.<ref>{{cite web | title=The Top 300 of 2022 | url=https://clincalc.com/DrugStats/Top300Drugs.aspx | website=ClinCalc | access-date=30 August 2024 | archive-date=30 August 2024 | archive-url=https://web.archive.org/web/20240830202410/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status=live}}</ref><ref>{{cite web | title = Dexmethylphenidate Drug Usage Statistics, United States, 2013 - 2022 | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Dexmethylphenidate | access-date = 30 August 2024}}</ref>
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==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.<ref name=Moen2009>{{cite journal | vauthors = Moen MD, Keam SJ | title = Dexmethylphenidate extended release: a review of its use in the treatment of attention-deficit hyperactivity disorder | journal = CNS Drugs | volume = 23 | issue = 12 | pages = 1057–83 | date = December 2009 | pmid = 19958043 | doi = 10.2165/11201140-000000000-00000 | s2cid = 24975170}}</ref>

Improvements in ADHD symptoms in children were significantly greater for dexmethylphenidate XR versus placebo.<ref name=Moen2009/> 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.<ref name=Moen2009 />

==Contraindications==
{{transcluded section|source=Methylphenidate}}
{{trim|{{#section-h:Methylphenidate|Contraindications}}}}

==Adverse effects==
{{transcluded section|source=Methylphenidate|part=yes}}
Products containing dexmethylphenidate have a side effect profile comparable to those containing methylphenidate.<ref name="Dexmethylphenidate">{{cite journal | vauthors = Keating GM, Figgitt DP | title = Dexmethylphenidate | journal = Drugs | volume = 62 | issue = 13 | pages = 1899–904; discussion 1905–8 | year = 2002 | pmid = 12215063 | doi = 10.2165/00003495-200262130-00009 | s2cid = 249894173}}</ref>
{{trim|{{#section-h:Methylphenidate|Adverse effects}}}}

== Interactions ==

{{transcluded section|source=Methylphenidate}}
{{trim|{{#section-h:Methylphenidate|Interactions}}}}

== Pharmacology==
{{main|Methylphenidate#Pharmacology}}
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 <small>DL (dextro-, levo-)</small>-TMP (threo-methylphenidate) XR (extended release) (Concerta, Ritalin LA), with flexible dosing and good tolerability.<ref>{{cite journal | vauthors = McGough JJ, Pataki CS, Suddath R | title = Dexmethylphenidate extended-release capsules for attention deficit hyperactivity disorder | journal = Expert Review of Neurotherapeutics | volume = 5 | issue = 4 | pages = 437–41 | date = July 2005 | pmid = 16026226 | doi = 10.1586/14737175.5.4.437 | s2cid = 6561452}}</ref><ref>{{cite journal | vauthors = Silva R, Tilker HA, Cecil JT, Kowalik S, Khetani V, Faleck H, Patin J | title = Open-label study of dexmethylphenidate hydrochloride in children and adolescents with attention deficit hyperactivity disorder | journal = Journal of Child and Adolescent Psychopharmacology | volume = 14 | issue = 4 | pages = 555–63 | year = 2004 | pmid = 15662147 | doi = 10.1089/cap.2004.14.555}}</ref> It has also been demonstrated to reduce ADHD symptoms in both children<ref>{{cite journal | vauthors = Arnold LE, Lindsay RL, Conners CK, Wigal SB, Levine AJ, Johnson DE, West SA, Sangal RB, Bohan TP, Zeldis JB | title = A double-blind, placebo-controlled withdrawal trial of dexmethylphenidate hydrochloride in children with attention deficit hyperactivity disorder | journal = Journal of Child and Adolescent Psychopharmacology | volume = 14 | issue = 4 | pages = 542–54 | date =Winter 2004 | pmid = 15662146 | doi = 10.1089/cap.2004.14.542}}</ref> and adults.<ref>{{cite journal | vauthors = Spencer TJ, Adler LA, McGough JJ, Muniz R, Jiang H, Pestreich L | title = Efficacy and safety of dexmethylphenidate extended-release capsules in adults with attention-deficit/hyperactivity disorder | journal = Biological Psychiatry | volume = 61 | issue = 12 | pages = 1380–7 | date = June 2007 | pmid = 17137560 | doi = 10.1016/j.biopsych.2006.07.032 | s2cid = 45976373 | doi-access = free}}</ref> d-MPH  has a similar side-effect profile to MPH<ref name="Dexmethylphenidate" /> and can be administered without regard to food intake.<ref>{{cite journal | vauthors = Teo SK, Scheffler MR, Wu A, Stirling DI, Thomas SD, Stypinski D, Khetani VD | title = A single-dose, two-way crossover, bioequivalence study of dexmethylphenidate HCl with and without food in healthy subjects | journal = Journal of Clinical Pharmacology | volume = 44 | issue = 2 | pages = 173–8 | date = February 2004 | pmid = 14747426 | doi = 10.1177/0091270003261899 | s2cid = 20694072}}</ref>

'''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.<ref>{{cite journal | vauthors = Brady LS, Lisanby SH, Gordon JA | title = New directions in psychiatric drug development: promising therapeutics in the pipeline | journal = Expert Opinion on Drug Discovery | volume = 18 | issue = 8 | pages = 835–850 | date = 3 August 2023 | pmid = 37352473 | doi = 10.1080/17460441.2023.2224555 | s2cid = 259240509}}</ref><ref>{{cite journal | vauthors = Childress AC, Beltran N, Supnet C, Weiss MD | title = Reviewing the role of emerging therapies in the ADHD armamentarium | journal = Expert Opinion on Emerging Drugs | volume = 26 | issue = 1 | pages = 1–16 | date = March 2021 | pmid = 33143485 | doi = 10.1080/14728214.2020.1846718 | s2cid = 226251694}}</ref><ref>{{cite journal | vauthors = Ryst E, Childress A | title = An updated safety review of the current drugs for managing ADHD in children | journal = Expert Opinion on Drug Safety | volume = 22 | issue = 11 | pages = 1025–1040 | date = 2023 | pmid = 37843488 | doi = 10.1080/14740338.2023.2271392 | s2cid = 264144450}}</ref><ref>{{cite journal | vauthors = Harris E |title=Industry update: what is new in the field of therapeutic delivery? |journal=Therapeutic Delivery |date=1 February 2018 |volume=9 |issue=3 |pages=155–161 |doi=10.4155/tde-2017-0117|doi-access=free}}</ref><ref>{{cite journal | vauthors = Childress AC, Komolova M, Sallee FR | title = An update on the pharmacokinetic considerations in the treatment of ADHD with long-acting methylphenidate and amphetamine formulations | journal = Expert Opinion on Drug Metabolism & Toxicology | volume = 15 | issue = 11 | pages = 937–974 | date = November 2019 | pmid = 31581854 | doi = 10.1080/17425255.2019.1675636 | s2cid = 203660100 | doi-access = free}}</ref>

=== Mechanism of action ===
Methylphenidate is a [[catecholamine]] reuptake inhibitor that indirectly increases catecholaminergic neurotransmission by inhibiting the [[dopamine transporter]] (DAT) and [[norepinephrine transporter]] (NET),<ref name="MarkowitzPatrick2008">{{cite journal |vauthors=Markowitz JS, Patrick KS |date=June 2008 |title=Differential pharmacokinetics and pharmacodynamics of methylphenidate enantiomers: does chirality matter? |journal=Journal of Clinical Psychopharmacology |volume=28 |issue=3 Suppl 2 |pages=S54-61 |doi=10.1097/JCP.0b013e3181733560 |pmid=18480678}}</ref> which are responsible for clearing catecholamines from the [[synapse]], particularly in the [[striatum]] and [[limbic system|meso-limbic system]].<ref>{{cite journal |vauthors=Schweri MM, Skolnick P, Rafferty MF, Rice KC, Janowsky AJ, Paul SM |date=October 1985 |title=[3H]Threo-(+/-)-methylphenidate binding to 3,4-dihydroxyphenylethylamine uptake sites in corpus striatum: correlation with the stimulant properties of ritalinic acid esters |journal=Journal of Neurochemistry |volume=45 |issue=4 |pages=1062–70 |doi=10.1111/j.1471-4159.1985.tb05524.x |pmid=4031878 |s2cid=28720285}}</ref> Moreover, it is thought to "increase the [[releasing agent|release]] of these monoamines into the extraneuronal space."<ref name="Focalin XR FDA label">{{cite web |date=27 June 2020 |title=Focalin XR- dexmethylphenidate hydrochloride capsule, extended release |url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1a1da905-42a0-4748-9c39-67eca45deccc |access-date=15 November 2020 |website=DailyMed}}</ref>

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.<ref>{{cite journal |vauthors=Ding YS, Fowler JS, Volkow ND, Dewey SL, Wang GJ, Logan J, Gatley SJ, Pappas N |date=May 1997 |title=Chiral drugs: comparison of the pharmacokinetics of [11C]d-threo and L-threo-methylphenidate in the human and baboon brain |url=https://zenodo.org/record/1232627 |journal=Psychopharmacology |volume=131 |issue=1 |pages=71–8 |doi=10.1007/s002130050267 |pmid=9181638 |s2cid=26046917}}</ref><ref>{{cite journal |vauthors=Ding YS, Gatley SJ, Thanos PK, Shea C, Garza V, Xu Y, Carter P, King P, Warner D, Taintor NB, Park DJ, Pyatt B, Fowler JS, Volkow ND |date=September 2004 |title=Brain kinetics of methylphenidate (Ritalin) enantiomers after oral administration |journal=Synapse |volume=53 |issue=3 |pages=168–75 |citeseerx=10.1.1.514.7833 |doi=10.1002/syn.20046 |pmid=15236349 |s2cid=11664668}}</ref> In theory, ''D''-TMP (d-threo-methylphenidate) can be anticipated to be twice the strength of the [[racemic]] product.<ref name="MarkowitzPatrick2008" /><ref>{{cite journal |vauthors=Davids E, Zhang K, Tarazi FI, Baldessarini RJ |date=February 2002 |title=Stereoselective effects of methylphenidate on motor hyperactivity in juvenile rats induced by neonatal 6-hydroxydopamine lesioning |journal=Psychopharmacology |volume=160 |issue=1 |pages=92–8 |doi=10.1007/s00213-001-0962-5 |pmid=11862378 |s2cid=8037050}}</ref>

{| class="wikitable"
|-
! Compd<ref name="Williard">{{cite journal |vauthors=Williard RL, Middaugh LD, Zhu HJ, Patrick KS |date=February 2007 |title=Methylphenidate and its ethanol transesterification metabolite ethylphenidate: brain disposition, monoamine transporters and motor activity |journal=Behavioural Pharmacology |volume=18 |issue=1 |pages=39–51 |doi=10.1097/FBP.0b013e3280143226 |pmid=17218796 |s2cid=20232871}}</ref>
! DAT (K<sub>i</sub>)
! DA (IC<sub>50</sub>)
! NET (K<sub>i</sub>)
! (IC<sub>50</sub>)
|-
|<small>D</small>-TMP||161||23||206||39
|-
|<small>L</small>-TMP||2250||1600||>10K||980
|-
|<small>DL</small>-TMP||121||20||788||51
|-
|}

== Notes ==
{{notelist}}

== References ==
{{Reflist|refs=

<ref name="Daytrana FDA label">{{cite web | title=Daytrana- methylphenidate patch | website=DailyMed | date=15 June 2021 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2c312c31-3198-4775-91ab-294e0b4b9e7f | access-date=26 March 2022}}</ref>

<!--ref name="Concerta FDA label">{{cite web |title=Concerta- methylphenidate hydrochloride tablet, extended release |website=DailyMed |date=1 July 2021 |url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1a88218c-5b18-4220-8f56-526de1a276cd |access-date=26 March 2022 |archive-date=26 March 2017 |archive-url=https://web.archive.org/web/20170326230808/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1a88218c-5b18-4220-8f56-526de1a276cd |url-status=live}}</ref-->

}}

{{ADHD pharmacotherapies|state=expanded}}
{{Drug use}}
{{Stimulants}}
{{Monoamine reuptake inhibitors}}
{{Sigma receptor modulators}}
{{Phenethylamines}}
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[[Category:Enantiopure drugs]]
[[Category:Stimulants]]
[[Category:2-Benzylpiperidines]]
[[Category:Drugs developed by Novartis]]
[[Category:Norepinephrine–dopamine reuptake inhibitors]]
[[Category:Nootropics]]
[[Category:Methyl esters]]
[[Category:Methylphenidate]]
[[Category:2-Piperidinyl compounds]]
[[Category:Attention deficit hyperactivity disorder management]]
[[Category:Wikipedia medicine articles ready to translate]]