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Gabapentinoids, also known as α2δ ligands, are a class of drugs that are chemically derivatives of the inhibitory neurotransmitter gamma-Aminobutyric acid (GABA) (i.e., ) which bind selectively to the α2δ protein that was first described as an auxiliary subunit of voltage-gated calcium channels (VGCCs).
Clinically used gabapentinoids include gabapentin, pregabalin, and mirogabalin, as well as a gabapentin prodrug, gabapentin enacarbil. Further analogues like imagabalin and atagabalin have been tested in but their development has been halted. Other gabapentinoids which are used in scientific research but have not been approved for medical use include 4-methylpregabalin and PD-217,014.
Additionally, phenibut has been found to act as a very low affinity gabapentinoid in addition to its action as a GABAB receptor agonist.
The gabapentinoid drugs do not bind significantly to other known drug receptors and so the α2δ VGCC subunit has been called the gabapentin receptor. Recently, the same α2δ-1 protein has been found closely associated not with VGCCs but with other proteins such as presynaptic NMDA receptor, cell adhesion molecules such as thrombospondin and others. Gabapentinoids alter the function of these additional α2δ binding proteins, and these have been proposed as mediators of drug actions.
Despite the fact that gabapentinoids are , gabapentin and pregabalin do not bind to , do not convert into or GABA receptor agonists in vivo, and do not modulate GABA transport or metabolism. Conversely, GABA does not bind appreciably to the α2δ protein. Furthermore, gabapentinoids do not act directly as inhibitors or blockers of VGCC. Instead, they reduce the release of excitatory neurotransmitters including Glutamic acid, monoamine neurotransmitters and Substance P. Although not thought to be a major site of action, gabapentinoids such as gabapentin, but not pregabalin, have been found to activate Kv voltage-gated potassium channels (KCNQ).
The endogenous α-amino acids L-leucine and L-isoleucine, which resemble the gabapentinoids in chemical structure (see figure) are ligands of the α2δ VDCC subunit with similar affinity as gabapentin and pregabalin (e.g., IC50 = 71 nM for L-isoleucine), and are present in human cerebrospinal fluid at micromolar concentrations (e.g., 12.9 μM for L-leucine, 4.8 μM for L-isoleucine). It has been hypothesized that they may be endogenous ligands of the subunit and that they may competitively antagonize the effects of gabapentinoids in brain tissues. In accordance, while gabapentin and pregabalin have nanomolar binding affinities for the α2δ subunit, their potencies in vivo are in the low micromolar range, and competition for binding by endogenous L-amino acids is likely responsible for this discrepancy.
In one study, the affinity (Ki) values of gabapentinoids for the α2δ subunit expressed in rat brain were found to be 0.05 μM for gabapentin, 23 μM for ( R)-phenibut, 39 μM for ( S)-phenibut, and 156 μM for baclofen. Their affinities (Ki) for the GABAB receptor were >1 mM for gabapentin, 92 μM for ( R)-phenibut, >1 mM for ( S)-phenibut. Baclofen does not have relevant actions at α2δ receptors and so it is not regarded as a gabapentinoid.
Pregabalin has demonstrated significantly greater potency (about 2.5-fold) than gabapentin in clinical studies and mirogabalin is even more potent in vivo.
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. Conversely, the oral bioavailability of pregabalin is greater than or equal to 90% across and beyond its entire clinical dose range (75 to 900 mg/day). Food does not significantly influence the oral bioavailability of pregabalin. Conversely, food increases the area-under-curve levels of gabapentin by about 10%. Drugs that increase the transit time of gabapentin in the small intestine can increase its oral bioavailability; when gabapentin was co-administered with oral morphine (which slows intestine peristalsis), the oral bioavailability of a 600 mg dose of gabapentin increased by 50%. The oral bioavailability of gabapentin enacarbil (as gabapentin) is greater than or equal to 68%, across all doses assessed (up to 2,800 mg), with a mean of approximately 75%. In contrast to the other gabapentinoids, the pharmacokinetics of phenibut have been little-studied, and its oral bioavailability is unknown. However, it would appear to be at least 63% at a single dose of 250 mg, based on the fact that this fraction of phenibut was recovered from the urine unchanged in healthy volunteers administered this dose.
Gabapentin at a low dose of 100 mg has a Tmax (time to peak levels) of approximately 1.7 hours, while the Tmax increases to 3 to 4 hours at higher doses. The Tmax of pregabalin is generally less than or equal to 1 hour at doses of 300 mg or less. However, food has been found to substantially delay the absorption of pregabalin and to significantly reduce peak levels without affecting the bioavailability of the drug; Tmax values for pregabalin of 0.6 hours in a fasted state and 3.2 hours in a fed state (5-fold difference), and the Cmax is reduced by 25–31% in a fed versus fasted state. In contrast to pregabalin, food does not significantly affect the Tmax of gabapentin and increases the Cmax of gabapentin by approximately 10%. The Tmax of the instant-release (IR) formulation of gabapentin enacarbil (as active gabapentin) is about 2.1 to 2.6 hours across all doses (350–2,800 mg) with single administration and 1.6 to 1.9 hours across all doses (350–2,100 mg) with repeated administration. Conversely, the Tmax of the extended-release (XR) formulation of gabapentin enacarbil is about 5.1 hours at a single dose of 1,200 mg in a fasted state and 8.4 hours at a single dose of 1,200 mg in a fed state. The Tmax of phenibut has not been reported, but the onset of action and peak effects have been described as occurring at 2 to 4 hours and 5 to 6 hours, respectively, after oral ingestion in recreational users taking high doses (1–3 g).
Gabapentin and pregabalin are not significantly bound to plasma proteins (<1%). The phenibut analogue baclofen shows low plasma protein binding of 30%.
Recently, a detailed three dimensional molecular structure of the α2δ-1 protein with gabapentin and alternatively with L-leucine bound at the gabapentinoid binding site has been published . These show that drugs bind to the first calcium channel and chemotaxis (Cache domain) domain in the α2 part of the α2δ-1. A very similar study shows the structure of α2δ-1 structure with mirogabalin bound. These studies also suggests that the L-leucine bound structure is slightly different than the drug bound structure, consistent with L-leucine acting as an antagonist to gabapentinoid drugs.
The gabapentinoids also closely resemble the α-amino acids L-leucine and L-isoleucine, and this may be of greater relevance in relation to their pharmacodynamics than their structural similarity to GABA.
Pregabalin, under the brand name Lyrica, was approved in Europe in 2004 and was introduced in the United States in September 2005 for the treatment of epilepsy, postherpetic neuralgia, and neuropathic pain associated with diabetic neuropathy. It was subsequently approved for the treatment of fibromyalgia in the United States in June 2007. Pregabalin was also approved for the treatment of generalized anxiety disorder in Europe in 2005, though it has not been approved for this indication in the United States.
Gabapentin enacarbil, under the brand name Horizant, was introduced in the United States for the treatment of restless legs syndrome in April 2011 and was approved for the treatment of postherpetic neuralgia in June 2012.
Phenibut, marketed under the brand names Anvifen, Fenibut, and Noofen, was introduced in Russia in the 1960s for the treatment of anxiety, insomnia, and a variety of other conditions. It was not discovered to act as a very weak (3.5 orders of magnitude less potent) gabapentinoid until 2015.
Baclofen marketed under the brandname of Lioresal was introduced in the United States in 1977 for the treatment of spasticity is chemically similar to phenibut but is usually not considered a gabapentinoid.
Mirogabalin, under the brand name Tarlige, was approved for the treatment of neuropathic pain and postherpetic neuralgia in Japan in January 2019.
A longitudinal trend study analyzed multinational sales data, revealing an overall increase in gabapentinoid consumption across 65 countries and regions from 2008 to 2018. This comprehensive analysis underscores the widespread use of gabapentinoids beyond their initial antiseizure applications, reflecting their role in treating a broad spectrum of conditions.
Drug tolerance to gabapentinoids is reported to develop very rapidly with repeated use, although to also dissipate quickly upon discontinuation, and drug withdrawal such as insomnia, nausea, headache, and diarrhea have been reported. More severe withdrawal symptoms, such as severe rebound anxiety, have been reported with phenibut. Because of the rapid tolerance with gabapentinoids, users often escalate their doses, while other users may space out their doses and use sparingly to avoid tolerance.
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