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Dexmethylphenidate

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Dexmethylphenidate
File:Focalin.png
Clinical data
Pregnancy
category
  • C
Routes of
administration		oral
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability11 – 52%
Protein binding30%
Metabolismhepatic
Elimination half-life2 – 4 hours
Excretionrenal
Identifiers
  • (R,R)-(+)-Methyl 2-phenyl-2-(2-piperidyl)acetate
CAS Number
PubChem CID
DrugBank
ChemSpider
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC14H19NO2
Molar mass233.31 g/mol g·mol−1
3D model (JSmol)
  • O=C(OC)[C@H](c1ccccc1)[C@@H]2NCCCC2

Dexmethylphenidate (trade name Focalin, Novartis, generic by Teva also available), otherwise known as d-threo-methylphenidate (D-TMP), is the dextrorotatory enantiomer of methylphenidate. It is a norepinephrine-dopamine reuptake inhibitor (NDRI) and thus a psychostimulant, which affects the CNS.

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.[1]

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.[2][3] In theory, d-TMP can be anticipated to be twice the strength of the racemic product.[4] However, certain authors recommend that the ratio is ~70% increase in potency upon enantiopurification of the racemate.[5]

Compd[6] 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. Although its has many beneficial effects, because it is a stimulant there is a considerable chance for abuse of the drug. Doctors are advised to closely monitor a patient's intake of Dexmethlphenidate.

Importantly, the propensity for "abuse" with d-TMP is much less than for the corresponding racemic product.[7]

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.[8][9]) It has also been demonstrated to reduce the symptoms of childhood ADHD,[10] as well as ADHD in adults.[11] d-MPH has a similar side-effect profile to MPH[12] and can be administered without regard to food intake.[13]

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.[14]

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.[15]

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.[16]

Efficacy

Placebo-controlled trials have shown that once-daily dexmethylphenidate XR was effective and generally well tolerated.[17] Improvements in ADHD symptoms in children were significantly greater for dexmethylphenidate XR versus placebo.[17] 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.[17]

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.[18]

Side effects

Insomnia, 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 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 severe 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.

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 come in five, ten, fifteen, and twenty 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.[19] From there, doctors usually increase dose by 5 mg to 10 mg until finding the right dosage.

Dexmethylphenidate, due to its abuse potential is classed as a Schedule II controlled drug in the United States.[20]

References

  1. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 4031878, please use {{cite journal}} with |pmid=4031878 instead.
  2. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 9181638, please use {{cite journal}} with |pmid=9181638 instead.
  3. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 15236349, please use {{cite journal}} with |pmid=15236349 instead.
  4. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 11862378, please use {{cite journal}} with |pmid=11862378 instead.
  5. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 18480678, please use {{cite journal}} with |pmid=18480678 instead.
  6. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 17218796, please use {{cite journal}} with |pmid=17218796 instead.
  7. ^ U.S. patent 5,908,850
  8. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 16026226, please use {{cite journal}} with |pmid=16026226 instead.
  9. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 15662147, please use {{cite journal}} with |pmid=15662147 instead.
  10. ^ 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.
  11. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 17137560, please use {{cite journal}} with |pmid=17137560 instead.
  12. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 12215063, please use {{cite journal}} with |pmid=12215063 instead.
  13. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 14747426, please use {{cite journal}} with |pmid=14747426 instead.
  14. ^ "[1]".
  15. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 18480679, please use {{cite journal}} with |pmid=18480679 instead.
  16. ^ "Oral Uses".
  17. ^ 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.
  18. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 19405409, please use {{cite journal}} with |pmid=19405409 instead.
  19. ^ "Focalin XR for ADHD".
  20. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 12455205, please use {{cite journal}} with |pmid=12455205 instead.
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