See Also Ritalin
Dexmethylphenidate (Focalin, Novartis), 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.
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]
Typical daily doses of dexmethylphenidate are around 10–20mg for children and 20–40mg 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.[14]
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.[15]
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.[16]
Side effects
Insomnia, nausea, stomach pain, 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.
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.
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. [17] From there, doctors usually increase dose from 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.[18]
External links
References
- ^ Schweri, MM; Skolnick; Rafferty; Rice; Janowsky; Paul (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): 1062-70.
- ^ Ding, YS; Fowler; Volkow; Dewey; Wang; Logan; Gatley; Pappas (1997). "Chiral drugs: comparison of the pharmacokinetics of 11Cd-threo and L-threo-methylphenidate in the human and baboon brain". Psychopharmacology 131 (1): 71-8.
- ^ 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 (New York, N.Y.) 53 (3): 168–175.
- ^ 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.
- ^ Markowitz, J.; Patrick, K. (2008). "Differential pharmacokinetics and pharmacodynamics of methylphenidate enantiomers: does chirality matter?". Journal of clinical psychopharmacology 28 (3 Suppl 2): S5-S61.
- ^ 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.
- ^ U.S. Patent 5,908,850
- ^ Mcgough, J.; Pataki, C.; Suddath, R. (2005). "Dexmethylphenidate extended-release capsules for attention deficit hyperactivity disorder". Expert review of neurotherapeutics 5 (4): 437-441.
- ^ 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.
- ^ 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.
- ^ Spencer, T.; Adler, L.; Mcgough, J.; Muniz, R.; Jiang, H.; Pestreich, L.; Adult Adhd Research, G. (2007).
- ^ Keating, GM; Figgitt (2002). "Dexmethylphenidate". Drugs 62 (13): 1899-904; discussion 1905-8.
- ^ 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.
- ^ 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.
- ^ "Oral Uses".
- ^ Rader, R; Mccauley; Callen (2009). "Current strategies in the diagnosis and treatment of childhood attention-deficit/hyperactivity disorder". American family physician 79 (8): 657-65.
- ^ "Focalin XR for ADHD".
- ^ "Dexmethylphenidate--Novartis/Celgene. Focalin, D-MPH, D-methylphenidate hydrochloride, D-methylphenidate, dexmethylphenidate, dexmethylphenidate hydrochloride". Drugs in R&D 3 (4): 279-82. 2002.