Reinin Mechanism of Action





United Lab
Full Prescribing Info
Pharmacology: Gabapentin is structurally related to the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). It has sufficient lipid solubility to cross the blood-brain barrier.
Despite its structural relationship to GABA and demonstrable antiepileptic activity, gabapentin's precise mechanism of action remains unknown. It does not modify GABAA or GABAB radioligand binding, it is not converted metabolically into GABA or a GABA agonist, and it is not an inhibitor of GABA uptake or degradation. Gabapentin also has no affinity for binding sites on common neuroreceptors such as benzodiazepine, glutamate, N-methyl-D-aspartate (NMDA), quisqualate, kainite, strychnine-insensitive or strychnine-sensitive glycine, alpha1, alpha2, or beta adrenergic, adenosine A1 or A2, cholinergic muscarinic or nicotinic, dopamine D1 or D2, histamine H1, serotonin S1 or S2, opiate mµ, delta or kappa, cannabinoid, voltage-sensitive calcium channel sites labeled with nitrendipine or diltiazem, or at voltage-sensitive sodium channel sites labeled with batrachotoxin in A20-alpha-benzoate. Furthermore, gabapentin does not alter the cellular uptake of dopamine, noradrenaline or serotonin.
The mechanism of gabapentin's anticonvulsant action is unknown. Gabapentin exhibits antiseizure activity in mice and rats in both the maximal electroshock and pentylenentetrazole seizure models and other preclinical models (e.g., strains with genetic epilepsy, etc).
The mechanism of gabapentin's analgesic action is unknown. In animal models, gabapentin prevents allodynia (pain-related behavior in response to a normally innocuous stimulus) and hyperalgesia (exaggerated response to painful stimuli). It prevents pain-related responses in neuropathic pain models and decreases pain-related responses after peripheral inflammation in rats or mice.
Pharmacokinetics: Gabapentin is absorbed from the gastrointestinal tract by means of a saturable mechanism. Bioavailability is not dose-proportional, i.e., bioavailability decreases as dose increases. Mean peak plasma gabapentin concentrations (Cmax) occur at approximately three hours after single oral doses of gabapentin regardless of dose size or formulation. Mean time to reach peak plasma concentration (tmax) values after multiple-dose administration are approximately one hour shorter than the values after a single dose administration. Food has only a slight effect on the rate and extent of gabapentin absorption (14% increase in AUC and Cmax).
Less than 3% of gabapentin circulates bound to plasma protein. Gabapentin has a volume of distribution of 57.7 liters. In patients with epilepsy, gabapentin concentrations in cerebrospinal fluid (CSF) are approximately 20% of corresponding plasma concentrations. Gabapentin is distributed in breast milk.
There is no evidence of gabapentin metabolism in humans. The elimination half-life of gabapentin is independent of dose and averages five to seven hours.
Gabapentin is eliminated solely by renal excretion. It does not induce hepatic mixed function oxidase enzymes responsible for drug metabolism.
Special Population: Renal Insufficiency: In subjects with renal insufficiency (mean creatinine clearance ranging from 13-114 mL/min) who were given single 400 mg oral doses of gabapentin, the mean gabapentin half-life ranged from about 6.5 hours (creatinine clearance >60 mL/min) to 52 hours (creatinine clearance <30 mL/min) and gabapentin renal clearance from about 90 mL/min (>60 mL/min) to about 10 mL/min (>30 mL/min). Mean plasma clearance decreased from approximately 190 to 20 mL/min. Dosage adjustment in adult patients with compromised renal function is necessary.
Hemodialysis: In anuric adult subjects, the apparent elimination half-life of gabapentin on nondialysis days was about 132 hours; during dialysis the apparent half-life of gabapentin was reduced to 3.8 hours. Hemodialysis had a significant effect on gabapentin elimination in anuric subjects. Dosage adjustment in patients undergoing hemodialysis is necessary.
Age: Gabapentin's apparent oral clearance (CL/F) decreased as age increased from about 225 mL/min in subjects 30 years old to about 125 mL/min in subjects 70 years and older. Renal clearance (CLr) and CLr adjusted for body surface area also declined with age; however, the decline in the renal clearance of gabapentin with age can be attributed to the decline in renal function. Reduction of gabapentin dose may be required in patients who have age-related compromised renal function.
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