Dexmethylphenidate


Dexmethylphenidate
Dexmethylphenidate
Systematic (IUPAC) name
(R,R)-(+)-Methyl 2-phenyl-2-(2-piperidyl)acetate
Clinical data
AHFS/Drugs.com monograph
MedlinePlus a603014
Pregnancy cat. C
Legal status Controlled (S8) (AU) Schedule III (CA) ? (UK) Schedule II (US)
Routes oral
Pharmacokinetic data
Bioavailability 11 – 52%
Protein binding 30%
Metabolism hepatic
Half-life 2 – 4 hours
Excretion renal
Identifiers
CAS number 40431-64-9 N
ATC code N06BA11
PubChem CID 154101
DrugBank APRD00657
ChemSpider 135807 YesY
UNII M32RH9MFGP YesY
KEGG D07806 YesY
ChEBI CHEBI:51860 YesY
ChEMBL CHEMBL827 YesY
Chemical data
Formula C14H19NO2 
Mol. mass 233.31 g/mol
SMILES eMolecules & PubChem
 N(what is this?)  (verify)

Dexmethylphenidate, otherwise known as d-threo-methylphenidate (D-TMP), is the dextrorotatory enantiomer of methylphenidate. It is a norepinephrine-dopamine reuptake inhibitor (NDRI) and releasing agent and thus a psychostimulant, which affects the CNS. Dexmethylphenidate is sold as Focalin by Novartis, as Attenade by Celgene and as a generic drug by Teva.

Contents

Mode of activity

Methylphenidate is a catecholamine reuptake inhibitor that indirectly increases catecholaminergic neurotransmission by inhibiting the dopamine transporter (DAT) and norepinephrine transporter (NET),[1] which are responsible for clearing catecholamines from the synapse, particularly in the striatum and meso-limbic system.[2] Moreover, it is thought to act as a releasing agent by increasing the release of dopamine and norepinephrine.[3]

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" is a preparation of the RR enantiomer of MPH.[4][5] In theory, d-TMP can be anticipated to be twice the strength of the racemic product.[6] However, certain authors recommend that the ratio is ~70% increase in potency upon enantiopurification of the racemate.[1]

Compd[7] DAT (Ki) DA (IC50) NET (Ki) NE (IC50)
D-TMP 161 23 206 39
L-TMP 2250 1600 >10K 980
DL-TMP 121 20 51 788

Therapeutic use

Dexmethylphenidate is used as a treatment for ADHD, ideally in conjunction 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. Dexmethylphenidate may also improve listening skills and organization of tasks, and may help prevent tic disorders. Because it is a psychostimulant, dexmethylphenidate may also help with narcolepsy and in certain cases of major depression.

Importantly, the propensity for "abuse" with d-TMP is much less than for the corresponding racemic product.[8]

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-TMP XR (Concerta, Ritalin LA), with flexible dosing and good tolerability.[9][10]) It has also been demonstrated to reduce the symptoms of childhood ADHD,[11] as well as ADHD in adults.[12] d-MPH has a similar side-effect profile to MPH[13] and can be administered without regard to food intake.[14]

Dexmethylphenidate has a chemical structure similar to a family of key brain neurotransmitters called monoamines, which include norepinephrine and dopamine. The increase in dopamine which occurs with the use of this medication can create a sense of euphoria, and therefore may make the user subject to abuse of the drug.[15]

Typical daily doses of dexmethylphenidate are around 10–20 mg for children and 20–40 mg for adults. As with all psychostimulant compounds, certain individuals may respond to a small dose and certain individuals may require a larger than average dose, hence, dosing is usually initiated at a typical range and then titrated to suit the patient.[16]

There is a possibility of withdrawal symptoms if dexmethylphenidate use is discontinued suddenly. As with other stimulants, withdrawal symptoms may include emotional or behavioral depression. Tapering off is recommended, under the supervision of a doctor. Addiction, which involves compulsive or harmful drug-seeking behavior, is rare but not impossible.[17]

Efficacy

Placebo-controlled trials have shown that once-daily dexmethylphenidate XR was effective and generally well tolerated.[18] Improvements in ADHD symptoms in children were significantly greater for dexmethylphenidate XR versus placebo.[18] It also showed greater efficacy than osmotic release oral system (OROS) methylphenidate over the first half of the laboratory classroom day but assessments late in the day favoured OROS methylphenidate.[18]

Concerns

The same concerns that apply to other stimulant drugs should be considered: Reports of sudden heart death in children caused Canada to stop marketing Adderall XR (another stimulant used to treat Attention-Deficit Hyperactivity Disorder) for a period in 2005, however it was returned to the market in that same year after it was demonstrated that cardiac risk is low in patients free of congenital heart defects. Heart problems have been reported, predominantly in young people taking ADD stimulants, though the FDA has not concluded that psychostimulants increase risk of cardiac problems for a person without a heart condition. Suicidal thinking has been reported in young people who are taking antidepressants at the same time they are taking an ADHD stimulant and many antidepressants carry a "black box warning" label concerning a possible increase in suicidal ideation in patients under 18 years of age.[19]

Side effects

Insomnia, dizziness, nausea, stomach pain, euphoria, headache, anxiety, anorexia, and weight loss are common side effects.

Rare but much more serious side effects include uncontrolled muscle movements (e.g., stiffness, twitching, shaking), hyperthermia, tics, edema of the feet/hands, blurred vision, mental/mood/behavior changes (e.g., agitation, aggression, mood swings, depression, hallucinations, abnormal thoughts/behavior), extreme tiredness, and severe sweating, easy bleeding/bruising, shortness of breath, fainting, chest/jaw/left arm pain, sudden vision changes, signs of infection (fever, persistent sore throat), tachycardia, weakness, seizures, confusion, slurred speech, and severe headaches and in some very rare cases death.[citation needed]

Also, there is a potential for a severe allergic reaction, but it is extremely rare. Trouble breathing, itching, a rash, swelling, or dizziness are all signs/symptoms of this allergic reaction.[citation needed]

Interactions

Dexmethylphenidate should not be used in combination with a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), phenelzine (Nardil), rasagiline (Azilect), selegiline (Eldepryl, Emsam), or tranylcypromine (Parnate) that has been used in the past 14 days. Serious, life-threatening side effects can occur if dexmethylphenidate is taken with an MAOI.[citation needed]

Usage

The Focalin XR capsules are sometimes prescribed over other extended release stimulants because the capsules can be opened and their contents mixed with applesauce or pudding to help children who cannot, or will not, swallow large capsules. This is possible due to the SODAS (Spheroidal Oral Drug Absorption System) delivery system, also used in Ritalin LA. Focalin XR comes in five, ten, fifteen, twenty, thirty, and forty milligram capsules. To determine appropriate dosage doctors first prescribe one to four 5 mg capsules. An appropriate treatment plan is then based on the patient's reaction to the initial dose.[20] From there, doctors usually increase dose by 5 mg to 10 mg until finding the right dosage.

Legal status

Dexmethylphenidate, due to its abuse potential is classed as a Schedule II controlled drug in the United States.[21]

External links

References

  1. ^ a b Markowitz, J. .; Patrick, K. . (2008). "Differential pharmacokinetics and pharmacodynamics of methylphenidate enantiomers: does chirality matter?". Journal of clinical psychopharmacology 28 (3 Suppl 2): S54–S61. doi:10.1097/JCP.0b013e3181733560. PMID 18480678.  edit
  2. ^ Schweri, M. M.; Skolnick, P.; Rafferty, M. F.; Rice, K. C.; Janowsky, A. J.; Paul, S. M. (1985). "3HThreo-(+/-)-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. doi:10.1111/j.1471-4159.1985.tb05524.x. PMID 4031878.  edit
  3. ^ Novartis: FOCALIN XR Overview PDF: FOCALIN XR - Full Prescribing Information
  4. ^ Ding, Y. S.; Fowler, J. S.; Volkow, N. D.; Dewey, S. L.; Wang, G. J.; Logan, J.; Gatley, S. J.; Pappas, N. (1997). "Chiral drugs: comparison of the pharmacokinetics of 11Cd-threo and L-threo-methylphenidate in the human and baboon brain". Psychopharmacology 131 (1): 71–78. doi:10.1007/s002130050267. PMID 9181638.  edit
  5. ^ Ding, Y.; Gatley, S.; Thanos, P.; Shea, C.; Garza, V.; Xu, Y.; Carter, P.; King, P. et al. (2004). "Brain kinetics of methylphenidate (Ritalin) enantiomers after oral administration". Synapse 53 (3): 168–175. doi:10.1002/syn.20046. PMID 15236349.  edit
  6. ^ Davids, E.; Zhang, K.; Tarazi, F.; Baldessarini, R. (2002). "Stereoselective effects of methylphenidate on motor hyperactivity in juvenile rats induced by neonatal 6-hydroxydopamine lesioning". Psychopharmacology 160 (1): 92–98. doi:10.1007/s00213-001-0962-5. PMID 11862378.  edit
  7. ^ Williard, R.; Middaugh, L.; Zhu, H.; Patrick, K. (2007). "Methylphenidate and its ethanol transesterification metabolite ethylphenidate: brain disposition, monoamine transporters and motor activity". Behavioural pharmacology 18 (1): 39–51. doi:10.1097/FBP.0b013e3280143226. PMID 17218796.  edit
  8. ^ U.S. Patent 5,908,850
  9. ^ Mcgough, J.; Pataki, C.; Suddath, R. (2005). "Dexmethylphenidate extended-release capsules for attention deficit hyperactivity disorder". Expert review of neurotherapeutics 5 (4): 437–441. doi:10.1586/14737175.5.4.437. PMID 16026226.  edit
  10. ^ Silva, R.; Tilker, H.; Cecil, J.; Kowalik, S.; Khetani, V.; Faleck, H.; Patin, J. (2004). "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. doi:10.1089/cap.2004.14.555. PMID 15662147.  edit
  11. ^ Arnold, L.E., et al. (2004). "A double-blind, placebo-controlled withdrawal trial of dexmethylphenidate hydrochloride in children with attention deficit hyperactivity disorder". J Child Adolesc Psychopharmacol. 2004 Winter;14(4):542-54.
  12. ^ Spencer, T.; Adler, L.; Mcgough, J.; Muniz, R.; Jiang, H.; Pestreich, L.; Adult Adhd Research, G. (2007). "Efficacy and safety of dexmethylphenidate extended-release capsules in adults with attention-deficit/hyperactivity disorder". Biological psychiatry 61 (12): 1380–1387. doi:10.1016/j.biopsych.2006.07.032. PMID 17137560.  edit
  13. ^ Keating, G. M.; Figgitt (2002). "Dexmethylphenidate". Drugs 62 (13): 1899–1904; discussion 1904–8. doi:10.2165/00003495-200262130-00009. PMID 12215063.  edit
  14. ^ Teo, S.; Scheffler, M.; Wu, A.; Stirling, D.; Thomas, S.; Stypinski, D.; Khetani, V. (2004). "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. doi:10.1177/0091270003261899. PMID 14747426.  edit
  15. ^ "[1]".
  16. ^ Quinn, D. (2008). "Does chirality matter? Pharmacodynamics of enantiomers of methylphenidate in patients with attention-deficit/hyperactivity disorder". Journal of clinical psychopharmacology 28 (3 Suppl 2): S62–S66. doi:10.1097/JCP.0b013e3181744aa6. PMID 18480679.  edit
  17. ^ "Oral Uses".
  18. ^ a b c Moen M, Keam S.Dexmethylphenidate Extended Release: A Review of its Use in the Treatment of Attention-Deficit Hyperactivity Disorder. CNSDrugs 2009; 23(12):1057-1083.doi:10.2165/11201140-000000000-00000.
  19. ^ Rader, R.; Mccauley, L.; Callen, E. C. (2009). "Current strategies in the diagnosis and treatment of childhood attention-deficit/hyperactivity disorder". American family physician 79 (8): 657–665. PMID 19405409.  edit
  20. ^ "Focalin XR for ADHD".
  21. ^ "Dexmethylphenidate--Novartis/Celgene. Focalin, D-MPH, D-methylphenidate hydrochloride, D-methylphenidate, dexmethylphenidate, dexmethylphenidate hydrochloride". Drugs in R&D 3 (4): 279–282. 2002. PMID 12455205.  edit

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