Rontin Mechanism of Action

Pharmacology: Pharmacodynamics: Gabapentin is structurally related to the neurotransmitter GABA (gamma amino butyric acid) but its mechanism of action is different from that of several other drugs that interact with GABA synapses including valproate, barbiturates, benzodiazepines, GABA transaminase inhibitors, GABA uptake inhibitors, GABA agonists, and GABA prodrugs. In vitro studies with radiolabeled gabapentin have characterized a novel peptide binding site in rat brain tissues including neocortex and hippocampus that may relate to anticonvulsant activity of gabapentin and its structural derivatives. However, the identification and function of the gabapentin binding site remains to be elucidated.
In animals, gabapentin readily enters the brain and prevents seizures from maximal electroshock, from chemical convulsants including inhibitors of GABA synthesis, and in genetic models of seizures.
The mechanism by which gabapentin exerts its analgesic action is unknown.
ln particular, gabapentin presents pain related responses in several models of neuropathic pain in rats or mice.
Gabapentin also decreases pain-related responses after peripheral inflammation. However, the drug has not altered immediate pain-related behaviors. The clinical relevance of these findings is not known.
Pharmacokinetics: Gabapentin bioavailability is not dose-proportional. That is, as the dose is increased, bioavailability decreases. Following oral administration peak plasma gabapentin concentrations are observed with 2 to 3 hours.
Bioavailability of gabapentin is approximately 60%, 47%, 34%, and 27% following 900, 1200, 2400, 3600, and 4800 mg/day given in 3 divided doses, respectively. Food has only a slight effect on rate and extent of absorption of gabapentin.
Gabapentin is not bound to plasma proteins and has a volume of distribution equal to 57.7 liters. In patients with epilepsy, gabapentin concentration in CSF are approximately 20% of corresponding steady-state trough plasma concentrations.
Gabapentin is eliminated from the systemic circulation by renal excretion as unchanged drug.
Gabapentin does not induce hepatic mixed function oxidase enzymes responsible for drug metabolism. Gabapentin elimination rate constant, plasma clearance, and renal clearance, are directly proportional to creatinine plasma clearance. In elderly patients, and in patients with impaired renal function, gabapentin plasma clearance is reduced. Dosage adjustment in patients undergoing hemodialysis is necessary and dose should be adjusted based on creatinine clearance values in these patients. Gabapentin can be removed from plasma by hemodialysis.