Ethylphenidate

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Ethylphenidate
Ethylphenidate.svg
Ethylphenidate-3D-ball-model.png
Clinical data
Trade names EPH
Routes of
administration
Insufflation, vaporized, intravenous, intramuscular, rectal, oral, sublingual
ATC code
  • none
Legal status
Legal status
Pharmacokinetic data
Bioavailability Variable
Protein binding Unknown
Metabolism Hepatic transesterification of prodrugs methylphenidate and ethanol
Excretion Urine, Sweat.
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
Chemical and physical data
Formula C15H21NO2
Molar mass 247.33274 g/mol
3D model (JSmol)
 NYesY (what is this?)  (verify)

Ethylphenidate (EPH) is a psychostimulant and a close analog of methylphenidate.

Ethylphenidate acts as both a dopamine reuptake inhibitor and norepinephrine reuptake inhibitor, meaning it effectively boosts the levels of the norepinephrine and dopamine neurotransmitters in the brain, by binding to, and partially blocking the transporter proteins that normally remove those monoamines from the synaptic cleft.

However, considering the close similarities between ethylphenidate and methylphenidate and the fact that methylphenidate, like cocaine, actually does not primarily act as a "classical" reuptake inhibitor, but rather as an "inverse agonist at the DAT" (also called a "negative allosteric modulator at the DAT"),[1] it is at least very likely that ethylphenidate also primarily acts as an inverse DAT agonist instead of (or at least only secondarily) as a classical reuptake inhibitor (which could be called a "competitive antagonist at the DAT" using a similar terminology as "negative allosteric modulator at the DAT", which per definition means that its mechanism is non-competitive).

There have been anecdotal reports of a perforated septum resulting from even just a few uses of ethylphenidate by insufflation (snorting). Some users also report the drug is extremely painful to insufflate. This is almost certainly due to the ethylphenidate that is sourced from grey market vendors containing caustic impurities. There is absolutely no evidence that pure ethylphenidate would have caustic effects, since ethylphenidate only differs from methylphenidate in that MPH's methyl acetate is replaced with an ethyl acetate in EPH. Methyl acetate and ethyl acetate have exactly the same pKa of 25,[2][3] which means that they are both even less acidic than water, which has a pKa of 14[4] (the lower the pKa the stronger the acid). Considering the fact that methylphenidate has been recreationally insufflated by 4% of the general population[5] without any reports of perforated septums and since ethylphenidate is certainly not more corrosive than methylphenidate, it is clear that the cause for the pain caused can ony be impurities.

Pharmacokinetics[edit]

Ethylphenidate metabolizes into methylphenidate and ritalinic acid.[6]

Tiny amounts of ethylphenidate can be formed in vivo when alcohol (also known formally as ethanol) and methylphenidate are coingested, via hepatic transesterification.[7] Ethylphenidate formation appears to be more common when large quantities of methylphenidate and alcohol are consumed at the same time, such as in non-medical use or overdose scenarios.[8] However, the transesterfication process of methylphenidate to ethylphenidate, as tested in mice liver, was dominant in the inactive (−)-enantiomer but showed a prolonged and increased maximal plasma concentration of the active (+)-enantiomer of methylphenidate.[9] Additionally, only a few percent of the consumed methylphenidate is converted to ethylphenidate.[7]

This carboxylesterase-dependent transesterification process is also known to occur when cocaine and alcohol are consumed together, forming cocaethylene.[10]

Pharmacodynamics[edit]

All available data on ethylphenidate's pharmacokinetics are drawn from studies conducted on rodents. Ethylphenidate is more selective to the dopamine transporter (DAT) than methylphenidate, having approximately the same efficacy as the parent compound,[9] but has significantly less activity on the norepinephrine transporter (NET).[11] Its dopaminergic pharmacodynamic profile is nearly identical to methylphenidate, and is primarily responsible for its euphoric and reinforcing effects.[12]

The eudysmic ratio for ethylphenidate is superior to that of methylphenidate.[9][not in citation given]

The following is ethylphenidate's binding profile in the mouse, alongside methylphenidate's. Figures for both the racemic and the dextrorotary enantiomers are given:[11]

Compound Binding DAT Binding NET Uptake DA Uptake NE
d-methylphenidate 139 408 28 46
d-ethylphenidate 276 2479 24 247
dl-methylphenidate 105 1560 24 31
dl-ethylphenidate 382 4824 82 408

Legality[edit]

  • Ethylphenidate is not controlled internationally; see Convention on Psychotropic Substances
  • Ethylphenidate is not controlled in the Netherlands, as the Opium Law does not cover it, nor is there any law covering analogs of controlled drugs (methylphenidate is covered).
  • Ethylphenidate is not explicitly controlled in US but it could possibly be considered an analog of a Schedule II substance (methylphenidate) under the Federal Analog Act if sold for human consumption.
  • Ethylphenidate is illegal in Sweden as of 15 December 2012.
  • Ethylphenidate is illegal to manufacture, distribute or import in the UK, as of 10 April 2015 it has been placed under a Temporary Class Drug Order which automatically places it in a Class-B-like category.[13] Though ordinarily the TCDO would only last 1 year, the ACMD reported that since its invocation prevalence of MPA had significantly decreased, and that it had been challenging to collect information about the drug. As a result of this, they requested that the TCDO be extended a further year from 26 June 2016.[14]
  • Ethylphenidate is illegal in Jersey under the Misuse of Drugs (Jersey) Law 1978.[15]
  • Australian state and federal legislation contains provisions that mean that analogues of controlled drugs are also covered by the legislation. Ethylphenidate would be an analogue of methylphenidate under this legislation.[citation needed]
  • Ethylphenidate is controlled in Canada under the Controlled Drugs and Substances Act under Schedule III as of 05.05.2017.[16]
  • Ethylphenidate is illegal in Germany as of 05.07.2013 [17]
  • Ethylphenidate is illegal in Austria by the "Neue Psychoaktive Substanzen Gesetz" (=new psychoactive substances act) NPSG since 1 January 2012
  • Ethylphenidate is illegal in Denmark as of 1 February 2013.[18]
  • Ethylphenidate is illegal in Poland by "the Act on Counteracting Drug Addiction" since 1 July 2015 [19]
  • It is illegal in Lithuania to use, buy, possess, transport, sell or import Ethylphenidate from 2015 [20]
  • As of October 2015 Ethylphenidate is a controlled substance in China.[21]

See also[edit]

References[edit]

  1. ^ Heal DJ; Gosden J; Smith SL (Dec 2014). "Dopamine reuptake transporter (DAT) "inverse agonism"--a novel hypothesis to explain the enigmatic pharmacology of cocaine.". Neuropharmacology. 87: 19–14. PMID 24953830. doi:10.1016/j.neuropharm.2014.06.012. In vivo experiments in animals demonstrate that cocaine's monoaminergic pharmacology is profoundly different from that of other prescribed monoamine reuptake inhibitors, with the exception of methylphenidate. These findings led us to conclude that the highly unusual stimulant profile of cocaine and related compounds, eg methylphenidate, is not mediated by monoamine reuptake inhibition alone. We describe the experimental findings which suggest cocaine serves as a negative allosteric modulator to alter the function of the dopamine reuptake transporter (DAT) and reverse its direction of transport. This results in a firing-dependent, retro-transport of dopamine into the synaptic cleft. [...] Because the physiological role of DAT is to remove dopamine from the synapse and the action of cocaine is the opposite of this, we have postulated that cocaine's effect is analogous to an inverse agonist. 
  2. ^ https://owl.oit.umass.edu/departments/OrganicChemistry/appendix/pKaTable.html
  3. ^ https://www.proprofs.com/flashcards/story.php?title=pka-values_1
  4. ^ https://chem.libretexts.org/Core/Organic_Chemistry/Fundamentals/What_is_the_pKa_of_water%3F
  5. ^ Bogle, KE; Smith, BH (2009). "Illicit methylphenidate use: a review of prevalence, availability, pharmacology, and consequences". Curr Drug Abuse Rev. 2: 157–76. PMID 19630746. 
  6. ^ Noelia Negreira; Claudio Erratico; Alexander L.N. van Nuijs; Adrian Covaci (January 2016). "Identification of in vitro metabolites of ethylphenidate by liquid chromatography coupled to quadrupole time-of-flight mass spectrometry". Journal of Pharmaceutical and Biomedical Analysis. 117 (5): 474–484. PMID 26454340. doi:10.1016/j.jpba.2015.09.029. 
  7. ^ a b Markowitz, J. S.; Devane, C. L.; Boulton, D. W.; Nahas, Z.; Risch, S. C.; Diamond, F.; Patrick, K. S. (2000). "Ethylphenidate formation in human subjects after the administration of a single dose of methylphenidate and ethanol". Drug metabolism and disposition: the biological fate of chemicals. 28 (6): 620–624. PMID 10820132. 
  8. ^ Markowitz, J. S.; Logan, B. K.; Diamond, F.; Patrick, K. S. (1999). "Detection of the novel metabolite ethylphenidate after methylphenidate overdose with alcohol coingestion". Journal of Clinical Psychopharmacology. 19 (4): 362–366. PMID 10440465. doi:10.1097/00004714-199908000-00013. 
  9. ^ a b c Patrick, K.; Williard, R.; Vanwert, A.; Dowd, J.; Oatis, J.; Middaugh, L. (2005). "Synthesis and pharmacology of ethylphenidate enantiomers: the human transesterification metabolite of methylphenidate and ethanol". Journal of Medicinal Chemistry. 48 (8): 2876–2881. PMID 15828826. doi:10.1021/jm0490989. 
  10. ^ Bourland, J.; Martin, D.; Mayersohn, M. (1997). "Carboxylesterase-mediated transesterification of meperidine (Demerol) and methylphenidate (Ritalin) in the presence of 2H6ethanol: preliminary in vitro findings using a rat liver preparation". Journal of pharmaceutical sciences. 86 (12): 1494–1496. PMID 9423167. doi:10.1021/js970072x. 
  11. ^ a b 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. PMID 17218796. doi:10.1097/FBP.0b013e3280143226. 
  12. ^ Jatlow, P.; Elsworth, J. D.; Bradberry, C. W.; Winger, G.; Taylor, J. R.; Russell, R.; Roth, R. H. (1991). "Cocaethylene: a neuropharmacologically active metabolite associated with concurrent cocaine-ethanol ingestion". Life Sciences. 48 (18): 1787–1794. PMID 2020260. doi:10.1016/0024-3205(91)90217-Y. 
  13. ^ https://www.gov.uk/government/news/legal-highs-to-be-banned-under-temporary-power
  14. ^ "Re: TCDOs and ACMD position on methylphenidate-based NPS" (PDF). 2016-02-29. Retrieved 2016-11-28. 
  15. ^ http://www.jerseylaw.je/law/Display.aspx?url=/law/lawsinforce/consolidated/08/08.680.60_MisuseofDrugs(GeneralProvisions)Order2009_RevisedEdition_1January2014.pdf
  16. ^ http://gazette.gc.ca/rp-pr/p2/2017/2017-04-05/html/sor-dors44-eng.php
  17. ^ http://www.gesetze-im-internet.de/btmg_1981/anlage_ii_60.html
  18. ^ https://www.retsinformation.dk/Forms/R0710.aspx?id=145195
  19. ^ http://isap.sejm.gov.pl/DetailsServlet?id=WDU20150000875
  20. ^ http://www.vvkt.lt/lit/I-narkotiniu-ir-psichotropiniu-medziagu-saraas/312
  21. ^ "关于印发《非药用类麻醉药品和精神药品列管办法》的通知" (in Chinese). China Food and Drug Administration. 27 September 2015. Retrieved 1 October 2015. 

See also[edit]