Dexmethylphenidate Explained

Dexmethylphenidate, sold under the brand name Focalin among others, is a potent central nervous system (CNS) stimulant used to treat 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.

Common side effects include abdominal pain, loss of appetite, and fever.[1] Serious side effects may include abuse, psychosis, sudden cardiac death, mania, anaphylaxis, seizures, and dangerously prolonged erection.[1] Safety during pregnancy and breastfeeding is unclear.[3] Dexmethylphenidate is a central nervous system (CNS) stimulant.[1] How it works in ADHD is unclear.[1]

Dexmethylphenidate was approved for medical use in the United States in 2001.[4] It is available as a generic medication.[1] In 2021, it was the 121st most commonly prescribed medication in the United States, with more than 4million prescriptions.[5] [6]

Medical uses

Dexmethylphenidate is used as a treatment for 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.[7]

Improvements in ADHD symptoms in children were significantly greater for dexmethylphenidate XR versus placebo.[7] 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.[7]

Adverse effects

Products containing dexmethylphenidate have a side effect profile comparable to those containing methylphenidate.[8]

Mode of activity

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.[9] Moreover, it is thought to "increase the release of these monoamines into the extraneuronal space."[10]

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.[11] [12] In theory, D-TMP (d-threo-methylphenidate) can be anticipated to be twice the strength of the racemic product.[13] [14]

Compd[15] DAT (Ki)DA (IC50)NET (Ki)NE (IC50)
D-TMP1612320639
L-TMP22501600>10K980
DL-TMP1212078851

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 DL (dextro-, levo-)-TMP (threo-methylphenidate) XR (extended release) (Concerta, Ritalin LA), with flexible dosing and good tolerability.[16] [17] It has also been demonstrated to reduce ADHD symptoms in both children[18] and adults.[19] d-MPH has a similar side-effect profile to MPH[8] and can be administered without regard to food intake.[20]

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.[21] [22] [23] [24] [25]

Notes and References

  1. Web site: Dexmethylphenidate Hydrochloride Monograph for Professionals . Drugs.com . American Society of Health-System Pharmacists . 15 April 2019 .
  2. Book: Mosby's Drug Reference for Health Professions - E-Book . 2013 . Elsevier Health Sciences . 9780323187602 . 455 .
  3. Web site: Dexmethylphenidate Use During Pregnancy . Drugs.com . 15 April 2019 .
  4. Web site: Focalin- dexmethylphenidate hydrochloride tablet . DailyMed . 24 June 2020 . 15 November 2020.
  5. Web site: The Top 300 of 2021 . ClinCalc . 14 January 2024 . 15 January 2024 . https://web.archive.org/web/20240115223848/https://clincalc.com/DrugStats/Top300Drugs.aspx . live .
  6. Web site: Dexmethylphenidate - Drug Usage Statistics . ClinCalc . 14 January 2024.
  7. Moen MD, Keam SJ . Dexmethylphenidate extended release: a review of its use in the treatment of attention-deficit hyperactivity disorder . CNS Drugs . 23 . 12 . 1057–83 . December 2009 . 19958043 . 10.2165/11201140-000000000-00000 . 24975170 .
  8. Keating GM, Figgitt DP . Dexmethylphenidate . Drugs . 62 . 13 . 1899–904; discussion 1905–8 . 2002 . 12215063 . 10.2165/00003495-200262130-00009 . 249894173 .
  9. Schweri MM, Skolnick P, Rafferty MF, Rice KC, Janowsky AJ, Paul SM . [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 . 1062–70 . October 1985 . 4031878 . 10.1111/j.1471-4159.1985.tb05524.x . 28720285 .
  10. Web site: Focalin XR- dexmethylphenidate hydrochloride capsule, extended release . DailyMed . 27 June 2020 . 15 November 2020.
  11. Ding YS, Fowler JS, Volkow ND, Dewey SL, Wang GJ, Logan J, Gatley SJ, Pappas N . Chiral drugs: comparison of the pharmacokinetics of [11C]d-threo and L-threo-methylphenidate in the human and baboon brain ]. Psychopharmacology . 131 . 1 . 71–8 . May 1997 . 9181638 . 10.1007/s002130050267 . 26046917 .
  12. 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 . Brain kinetics of methylphenidate (Ritalin) enantiomers after oral administration . Synapse . 53 . 3 . 168–75 . September 2004 . 15236349 . 10.1002/syn.20046 . 10.1.1.514.7833 . 11664668 .
  13. Markowitz JS, Patrick KS . Differential pharmacokinetics and pharmacodynamics of methylphenidate enantiomers: does chirality matter? . Journal of Clinical Psychopharmacology . 28 . 3 Suppl 2 . S54-61 . June 2008 . 18480678 . 10.1097/JCP.0b013e3181733560 .
  14. Davids E, Zhang K, Tarazi FI, Baldessarini RJ . Stereoselective effects of methylphenidate on motor hyperactivity in juvenile rats induced by neonatal 6-hydroxydopamine lesioning . Psychopharmacology . 160 . 1 . 92–8 . February 2002 . 11862378 . 10.1007/s00213-001-0962-5 . 8037050 .
  15. Williard RL, Middaugh LD, Zhu HJ, Patrick KS . Methylphenidate and its ethanol transesterification metabolite ethylphenidate: brain disposition, monoamine transporters and motor activity . Behavioural Pharmacology . 18 . 1 . 39–51 . February 2007 . 17218796 . 10.1097/FBP.0b013e3280143226 . 20232871 .
  16. McGough JJ, Pataki CS, Suddath R . Dexmethylphenidate extended-release capsules for attention deficit hyperactivity disorder . Expert Review of Neurotherapeutics . 5 . 4 . 437–41 . July 2005 . 16026226 . 10.1586/14737175.5.4.437 . 6561452 .
  17. Silva R, Tilker HA, Cecil JT, Kowalik S, Khetani V, Faleck H, Patin J . Open-label study of dexmethylphenidate hydrochloride in children and adolescents with attention deficit hyperactivity disorder . Journal of Child and Adolescent Psychopharmacology . 14 . 4 . 555–63 . 2004 . 15662147 . 10.1089/cap.2004.14.555 .
  18. Arnold LE, Lindsay RL, Conners CK, Wigal SB, Levine AJ, Johnson DE, West SA, Sangal RB, Bohan TP, Zeldis JB . 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 . 542–54 . Winter 2004 . 15662146 . 10.1089/cap.2004.14.542 .
  19. Spencer TJ, Adler LA, McGough JJ, Muniz R, Jiang H, Pestreich L . Efficacy and safety of dexmethylphenidate extended-release capsules in adults with attention-deficit/hyperactivity disorder . Biological Psychiatry . 61 . 12 . 1380–7 . June 2007 . 17137560 . 10.1016/j.biopsych.2006.07.032 . 45976373 . free .
  20. Teo SK, Scheffler MR, Wu A, Stirling DI, Thomas SD, Stypinski D, Khetani VD . A single-dose, two-way crossover, bioequivalence study of dexmethylphenidate HCl with and without food in healthy subjects . Journal of Clinical Pharmacology . 44 . 2 . 173–8 . February 2004 . 14747426 . 10.1177/0091270003261899 . 20694072 .
  21. Brady LS, Lisanby SH, Gordon JA . New directions in psychiatric drug development: promising therapeutics in the pipeline . Expert Opinion on Drug Discovery . 18 . 8 . 835–850 . 3 August 2023 . 37352473 . 10.1080/17460441.2023.2224555 . 259240509 .
  22. Childress AC, Beltran N, Supnet C, Weiss MD . Reviewing the role of emerging therapies in the ADHD armamentarium . Expert Opinion on Emerging Drugs . 26 . 1 . 1–16 . March 2021 . 33143485 . 10.1080/14728214.2020.1846718 . 226251694 .
  23. Ryst E, Childress A . An updated safety review of the current drugs for managing ADHD in children . Expert Opinion on Drug Safety . 22 . 11 . 1025–1040 . 2023 . 37843488 . 10.1080/14740338.2023.2271392 . 264144450 .
  24. Harris E . Industry update: what is new in the field of therapeutic delivery? . Therapeutic Delivery . 1 February 2018 . 9 . 3 . 155–161 . 10.4155/tde-2017-0117. free .
  25. Childress AC, Komolova M, Sallee FR . 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 . 31581854 . 10.1080/17425255.2019.1675636 . 203660100 . free .

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