Methylphenidate: Difference between revisions

'''Methylphenidate''' (also known as '''MPH''', '''MPD''', and its brand names '''Ritalin''', '''Concerta''', and '''Methylin''', among others) is a [[psychoactive class::stimulant]] substance of the [[chemical class::phenidate]] class. Methylphenidate is the parent compound of the [[substituted phenidates]], a family of compounds that includes [[ethylphenidate]], [[isopropylphenidate]], and others. It acts primarily by enhancing the activity of the [[neurotransmitters]] [[dopamine]] and [[norepinephrine]] in the brain.

Methylphenidate was first licensed by the U.S. Food and Drug Administration (FDA) in 1955 for treating what was then known as "hyperactivity." Although it was prescribed to patients as early as 1960, it only became heavily prescribed in the 1990s when the diagnosis of ADHD itself became more widely accepted.<ref>Diller, Lawrence (1999). Running on Ritalin. ISBN 978-0553379068.</ref><ref>The history of attention deficit hyperactivity disorder (PubMed.gov / NCBI) | http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3000907/</ref>

Methylphenidate is approved for treatment of attention-deficit hyperactivity disorder (ADHD) and narcolepsy. It is often used by students with or without ADHD to enhance their mental abilities, improve their concentration, and help them study.

Methylphenidate is a synthetic molecule of the [[substituted phenethylamine]] and [[substituted phenidate]] classes. It contains a phenethylamine core featuring a phenyl ring bound to an amino (-NH₂) group through an ethyl chain. It is structurally similar to [[amphetamine]], featuring a substitution at R_α which is incorporated into a [[piperidine]] ring ending at the terminal amine of the phenethylamine chain. Additionally, it contains a methyl acetate bound to R_β of its structure.  

Four isomers of methylphenidate are possible, since the molecule has two chiral centers. One pair of threo isomers and one pair of erythro are distinguished, from which primarily d-threo-methylphenidate exhibits the pharmacologically desired effects.<ref>Heal DJ, Pierce DM (2006). "Methylphenidate and its isomers: their role in the treatment of attention-deficit hyperactivity disorder using a transdermal delivery system". ''CNS Drugs''. '''20''' (9): 713–38. doi:10.2165/00023210-200620090-00002. <nowiki>PMID 16953648</nowiki>. S2CID 39535277.</ref> The erythro diastereomers are ''pressor'' amines, a property not shared with the threo diastereomers. When the drug was first introduced it was sold as a 4:1 mixture of erythro:threo diastereomers, but it was later reformulated to contain only the threo diastereomers. "TMP" refers to a threo product that does not contain any erythro diastereomers, i.e. (±)-threo-methylphenidate. Since the threo isomers are energetically favored, it is easy to epimerize out any of the undesired erythro isomers. The drug that contains only dextrorotatory methylphenidate is sometimes called d-TMP, although this name is only rarely used and it is much more commonly referred to as dexmethylphenidate, d-MPH, or d-threo-methylphenidate. A review on the synthesis of enantiomerically pure (2''R'',2'''R'')-(+)-''threo''-methylphenidate hydrochloride has been published.<ref>Prashad M (2001). "Approaches to the Preparation of Enantiomerically Pure (2R,2′R)-(+)-threo-Methylphenidate Hydrochloride". ''Adv. Synth. Catal''. '''343''' (5): 379–92. doi:10.1002/1615-4169(200107)343:5<379::AID-ADSC379>3.0.CO;2-4.</ref>

While both [[amphetamine]] and methylphenidate are dopaminergic, it should be noted that their methods of action are somewhat distinct. Specifically, methylphenidate is a dopamine reuptake inhibitor while amphetamine is both a releasing agent and reuptake inhibitor of [[dopamine]] and [[norepinephrine]]. Each of these drugs have a corresponding effect on norepinephrine which are weaker than their effects on dopamine. Methylphenidate's mechanism of action at dopamine-norepinephrine release is still debated, but is fundamentally different from most other phenethylamine derivatives as methylphenidate is thought to increase general firing rate, whereas amphetamine reduces firing rate and reverses the flow of the monoamines via TAAR1 activation.<ref>Dopamine transporter occupancies in the human brain induced by therapeutic doses of oral methylphenidate. (PubMed.gov / NCBI) | http://www.ncbi.nlm.nih.gov/pubmed/9766762</ref><ref>Neurotransmitter transporters and their impact on the development of psychopharmacology (PubMed.gov / NCBI) | http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1760736/</ref><ref>Focalin XR review | http://www.pharma.us.novartis.com/product/pi/pdf/focalinXR.pdf</ref><ref>Concerta Xl slow release | http://www.medicines.org.uk/emc/medicine/8382/SPC/Concerta#PHARMACOLOGICAL_PROPSSPC</ref>