Gabapentin & Pregabalin

GABAPENTIN & PREGABALIN

Gabapentin is an amino acid, an analog of GABA, that is effective against partial seizures. Originally planned as a spasmolytic, it was found to be more effective as an antiseizure drug. Pregabalin is another GABA analog, closely related to gabapentin. This drug has been approved for both antiseizure activity and for its analgesic properties.

Mechanism of Action

In spite of their close structural resemblance to GABA, gabapentin and pregabalin do not act directly on GABA receptors. They may, however, modify the synaptic or nonsynaptic release of GABA. An increase in brain GABA concentration is observed in patients receiving gabapentin. Gabapentin is transported into the brain by the L-amino acid transporter. Gabapentin and pregabalin bind avidly to the α₂δ subunit of voltage-gated Ca²⁺ channels. This appears to underlie the main mechanism of action, which is decreasing Ca²⁺ entry, with a predominant effect on presynaptic N-type channels. A decrease in the synaptic release of glutamate provides the antiepileptic effect.

Clinical Uses

Gabapentin is effective as an adjunct against partial seizures and generalized tonic-clonic seizures at dosages that range up to 2400 mg/d in controlled clinical trials. Open follow-up studies permitted dosages up to 4800 mg/d, but data are inconclusive on the effectiveness or tolerability of such doses. Monotherapy studies also document some efficacy. Some clinicians have found that very high dosages are needed to achieve improvement in seizure control. Effectiveness in other seizure types has not been well demonstrated. Gabapentin has also been promoted for the treatment of neuro-pathic pain and is now indicated for postherpetic neuralgia in adults at doses of 1800 mg and above. The most common adverse effects are somnolence, dizziness, ataxia, headache, and tremor.

Pregabalin is approved for the adjunctive treatment of partial seizures, with or without secondary generalization; controlled clinical trials have documented its effectiveness. It is available only in oral form, and the dosage ranges from 150 to 600 mg/d, usually in two or three divided doses. Pregabalin is also approved for use in neuropathic pain, including painful diabetic peripheral neu-ropathy and postherpetic neuralgia. It is the first drug in the USA approved for fibromyalgia. In Europe it is approved for general-ized anxiety disorder.

Pharmacokinetics

Gabapentin is not metabolized and does not induce hepatic enzymes. Absorption is nonlinear and dose-dependent at very high doses, but the elimination kinetics are linear. The drug is not bound to plasma proteins. Drug-drug interactions are negligible. Elimination is via renal mechanisms; the drug is excreted unchanged. The half-life is relatively short, ranging from 5 to 8 hours; the drug is typically administered two or three times per day.

Pregabalin, like gabapentin, is not metabolized and is almost entirely excreted unchanged in the urine. It is not bound to plasma proteins and has virtually no drug-drug interactions, again resembling the characteristics of gabapentin. Likewise, other drugs do not affect the pharmacokinetics of pregabalin. The half-life of pregabalin ranges from about 4.5 hours to 7.0 hours, thus requir-ing more than once-daily dosing in most patients.