Gabapentinoids: Difference between revisions

[[File:GABA.svg|250px|thumbnail|Skeletal structure of the [[GABA|gamma-aminobutyric acid]] (GABA) molecule.]]

Gabapentinoids are close structural relatives, and are all 3-substituted derivatives of [[GABA]], the differences being the addition of a cyclohexyl group on the GABA chain in the case of [[gabapentin]], the substitution of that cyclohexyl group for an isobutyl group in the case of [[pregabalin]], and the substitution of that isobutyl group with a cyclic phenyl ring in the case of [[phenibut]]. Hence, they are GABA analogues, as well as γ-amino acids.<ref>{{cite book | vauthors=((Wyllie, E.)) | date= 2012 | title=Wyllie’s treatment of epilepsy: principles and practice. | isbn=9781451153484}}</ref><ref name="Benzon2014">{{cite book | vauthors=((Benzon, H. T.)), ((Rathmell, J. P.)), ((Wu, C. L.)), ((Turk, D. C.)), ((Argoff, C. E.)), ((Hurley, R. W.)) | date= 2014 | title=Practical management of pain | publisher=Elsevier/Saunders | url=https://www.sciencedirect.com/science/book/9780323083409 | isbn=9780323170802}}</ref>

Gabapentinoids closely resemble the α-amino acids <small>L</small>-leucine and <small>L</small>-isoleucine, and this may be of greater relevance in relation to their pharmacodynamics than their structural similarity to GABA.<ref name=":0">{{cite journal | vauthors=((Dooley, D. J.)), ((Taylor, C. P.)), ((Donevan, S.)), ((Feltner, D.)) | journal=Trends in Pharmacological Sciences | title=Ca2+ channel α2δ ligands: novel modulators of neurotransmission | volume=28 | issue=2 | pages=75–82 | date= February 2007 | url=https://linkinghub.elsevier.com/retrieve/pii/S0165614706002896 | issn=01656147 | doi=10.1016/j.tips.2006.12.006}}</ref>

 

! scope="col" style="width: 50px;" |'''R₃'''

! scope="col" |'''Structure'''

|[[Pregabalin]]||CH₂CH(CH₃)₂||[[File:Pregabalin.svg|200px]]

|[[Gabapentin]]||C₅H₁₀||[[File:Gabapentin.svg|200px]]

|[[Phenibut]]||C₆H₅||[[File:Phenibut.svg|200px]]

|[[F-Phenibut]]||C₆H₄F||[[File:F-Phenibut.svg|200px]]

|[[Baclofen]]||C₆H₄Cl||[[File:Baclofen.svg|200px]]

Gabapentinoids act by inhibiting the α2δ subunit-containing voltage-dependent calcium [[receptor#Ion_channels|channels]] (VGCCs).<ref>{{cite journal | vauthors=((Patel, R.)), ((Dickenson, A. H.)) | journal=Pharmacology Research & Perspectives | title=Mechanisms of the gabapentinoids and α 2 δ -1 calcium channel subunit in neuropathic pain | volume=4 | issue=2 | pages=e00205 | date= April 2016 | url=https://onlinelibrary.wiley.com/doi/10.1002/prp2.205 | issn=20521707 | doi=10.1002/prp2.205}}</ref> While all gabapentinoids block the α2δ channels, they also have unique pharmacological characteristics such as enzyme inhibition.<ref>{{cite journal | vauthors=((Goldlust, A.)), ((Su, T.-Z.)), ((Welty, D. F.)), ((Taylor, C. P.)), ((Oxender, D. L.)) | journal=Epilepsy Research | title=Effects of anticonvulsant drug gabapentin on the enzymes in metabolic pathways of glutamate and GABA | volume=22 | issue=1 | pages=1–11 | date= September 1995 | url=https://linkinghub.elsevier.com/retrieve/pii/0920121195000289 | issn=09201211 | doi=10.1016/0920-1211(95)00028-9}}</ref> The gabapentinoids are selective in their binding to the α₂δ VDCC subunit.<ref name="Benzon2014"/>

Pregabalin has demonstrated significantly greater potency (about 2.5-fold) than gabapentin in clinical studies.<ref>{{cite journal | vauthors=((Schifano, F.)), ((D’Offizi, S.)), ((Piccione, M.)), ((Corazza, O.)), ((Deluca, P.)), ((Davey, Z.)), ((Di Melchiorre, G.)), ((Di Furia, L.)), ((Farré, M.)), ((Flesland, L.)), ((Mannonen, M.)), ((Majava, A.)), ((Pagani, S.)), ((Peltoniemi, T.)), ((Siemann, H.)), ((Skutle, A.)), ((Torrens, M.)), ((Pezzolesi, C.)), ((Kreeft, P. van der)), ((Scherbaum, N.)) | journal=Psychotherapy and Psychosomatics | title=Is there a recreational misuse potential for pregabalin? Analysis of anecdotal online reports in comparison with related gabapentin and clonazepam data | volume=80 | issue=2 | pages=118–122 | date= 2011 | issn=1423-0348 | doi=10.1159/000321079}}

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Gabapentin and pregabalin are absorbed from the intestines by an active transport process mediated via the large neutral amino acid transporter 1 (LAT1, SLC7A5), a transporter for amino acids such as <small>L</small>-leucine and <small>L</small>-phenylalanine.<ref name=":1">{{cite journal | vauthors=((Calandre, E. P.)), ((Rico-Villademoros, F.)), ((Slim, M.)) | journal=Expert Review of Neurotherapeutics | title=Alpha2delta ligands, gabapentin, pregabalin and mirogabalin: a review of their clinical pharmacology and therapeutic use | volume=16 | issue=11 | pages=1263–1277 | date= November 2016 | issn=1744-8360 | doi=10.1080/14737175.2016.1202764}}</ref> The oral bioavailability of gabapentin is approximately 80% at 100 mg administered three times daily once every 8 hours, but decreases to 60% at 300 mg, 47% at 400 mg, 34% at 800 mg, 33% at 1,200 mg, and 27% at 1,600 mg, all with the same dosing schedule.<ref>{{cite journal | vauthors=((Bockbrader, H. N.)), ((Wesche, D.)), ((Miller, R.)), ((Chapel, S.)), ((Janiczek, N.)), ((Burger, P.)) | journal=Clinical Pharmacokinetics | title=A comparison of the pharmacokinetics and pharmacodynamics of pregabalin and gabapentin | volume=49 | issue=10 | pages=661–669 | date= October 2010 | issn=1179-1926 | doi=10.2165/11536200-000000000-00000}}</ref>

Gabapentin, pregabalin, and phenibut all undergo little or no metabolism. Conversely, gabapentin enacarbil, which acts as a prodrug of gabapentin, must undergo enzymatic hydrolysis to become active. This is done via non-specific esterases in the intestines and to a lesser extent in the liver.<ref name=":1" />