Pregabalin

pregabalin (also known as 3-isobutyl gaba and by the trade-name lyrica) is a depressant substance of the gabapentinoid class. pregabalin is a common prescription drug, which is typically used to treat neuropathic pain, anxiety, restless leg syndrome, and as an adjunct drug in the treatment of seizures.

pregabalin has a pharmacological profile comparable to that of gabapentin as they both share similar mechanisms of action and induce similar subjective effects. the advantages pregabalin has over gabapentin include greater bioavailability and potency, as well as a wider variety of accepted medical applications for pregabalin not seen with gabapentin, such as its successful use in the treatment of anxiety, in which the use of gabapentin was not successful, excluding some more severe cases.

chemistry

pregabalin is a structural analog of gaba (gamma-aminobutyric acid), with an isobutyl group substituted on the beta carbon of the aminobutyric chain. pregabalin is similar in structure to other gabapentinoids, such as gabapentin and phenibut. pregabalin contains a carboxylated chain of hexane called hexanoic acid. this carbon chain is substituted with an amine group through a methyl bridge in (s) conformation at r₃ and a methyl group at r₅.

pharmacology

pharmacodynamics

the pharmacological action of pregabalin is mediated by binding to the α2δ-1 site of voltage-gated calcium channels. this site has also been referred to as the gabapentin receptor, as it is the target of the related substance gabapentin (also developed by pfizer). advantages to pregabalin over gabapentin include higher bioavailability and potency.

although pregabalin is a chemical derivative of gaba, it displays no activity at any gaba receptors, including gaba_a, gaba_b and the benzodiazepine site. pregabalin, despite its gaba backbone, does not appear to alter gaba levels in the brain, so its pharmacological activity is presumed to be unrelated to gaba. instead, it is its binding to the α2δ-1 site of voltage-gated calcium channels which appears to be the source of its subjective effects. by binding to this site, pregabalin reduces the release of several excitatory neurotransmitters, including glutamate, substance p, acetylcholine and norepinephrine.

one study has also shown that pregabalin promotes deep sleep, thus enhancing sleep quality. this may be substantial because reductions in slow-wave sleep have been associated with anxiety and fibromyalgia.
also, an independent action of the gabapentin site on the neurogenesis of excitatory synapses has been discovered. the endogenous neurochemical thrombospondin also binds to this site and is important for the generation of new excitatory synapses. gabapentin and pregabalin, having a high affinity for this site, block this action and result in lower levels of excitatory synapses in animal models.

as pregabalin treats conditions and neurotransmitters associated with overexcitability of the brain (anxiety, epilepsy, neuropathic pain), its modulation results in the sedating (or calming) effects of pregabalin on the nervous system.

pharmacokinetics

pregabalin is rapidly absorbed when administered on an empty stomach, with peak plasma concentrations occurring within 1 to 1.5 hours. pregabalin oral bioavailability is estimated to be greater than or equal to 90%. the rate of pregabalin absorption is decreased when given with food, resulting in delay of approximately 3 hours to reach peak plasma concentrations, with peak levels themselves, decreased by about 25 to 30%. administration with food, however, has no clinically significant effect on the extent of absorption.

pregabalin undergoes negligible metabolism in humans. in experiments using nuclear medicine techniques, it was revealed that approximately 98% of the radioactivity recovered in the urine was unchanged pregabalin. the primary metabolite is n-methyl pregabalin.

pregabalin is eliminated from the systemic circulation primarily by renal excretion as unchanged substance. renal clearance of pregabalin is 73 ml/minute.