Gabapentin

Mechanism

Chemical and Commercial Profile

Common trade names: Neurontin, Gabapentin Normon, Gabapentin Kern Pharma.
Group: Second generation antiepileptic, structural analogue of GABA.

Mechanism of Action

Despite being a lipophilic analogue of gamma-aminobutyric acid, gabapentin does not bind to GABA_A or GABA_B receptors, nor does it alter their reuptake or catabolism. It acts by specifically binding to the auxiliary subunit α₂δ-1 of high-threshold voltage-gated calcium channels in presynaptic neurons of the cortex and spinal cord. Upon binding, it decreases calcium entry and blocks the exocytic release of excitatory amino acids such as glutamate and substance P.

Pharmacokinetics

Pharmacokinetics

• Absorption: Exclusively mediated by the intestinal neutral amino acid transporter L (LAT-1). It presents **non-linear saturable absorption kinetics**: the higher the single dose administered, the lower the absorbed fraction of the drug.

Gabapentin Bioavailability Saturation Effect \text{Bioavailability } (F) = \begin{cases} 60\% & \text{at a dose of } 900 \text{ mg/day} \\ 47\% & \text{at a dose of } 1200 \text{ mg/day} \\ 27\% & \text{at a dose of } 4800 \text{ mg/day} \end{cases}

• Distribution: Virtually no binding to plasma proteins (<3%). The volume of distribution is 0.6-0.8 L/kg. It easily crosses the blood-brain barrier.
• Metabolism: Absent. It is not metabolized in the human body. Free of interactions with cytochrome CYP450 enzymes.
• Excretion: Renal exclusively by glomerular filtration, eliminating 100% of the absorbed dose as unchanged drug. It can be cleared by hemodialysis.
• Half-life (t_1/2): 5-7 hours, requiring mandatory dosing in three daily doses to maintain stable effective concentrations in the CNS.

Indicators and dose

Indications

• Adjuvant treatment of focal seizures in adults and children over 6 years of age.
• First-line treatment of Peripheral Neuropathic Pain (diabetic neuropathy, postherpetic neuralgia) in adults.
• Restless legs syndrome (idiopathic).

Dosage and Settings

• Day 1: 300 mg once a day.
• Day 2: 300 mg twice a day.
• Day 3: 300 mg three times a day (900 mg/day total).
• Usual therapeutic range: 900-3600 mg/day divided into three doses.
• Analytical adjustment in Renal Failure (Critical):

  Creatinine Clearance (Cl_Cr)	Daily Dose of Gabapentin	Dosing Interval
  >80 mL/min	900 - 3600 mg	Three doses per day (every 8 hours)
  50-79 mL/min	600 - 1800 mg	Two doses per day (every 12 hours)
  30-49 mL/min	300 - 900 mg	One dose per day (every 24 hours)
  15-29 mL/min	150 - 300 mg	One dose every other day (every 48 hours)
  <15 mL/min (Anuria)	100 - 150 mg	One dose every 48 hours or after each hemodialysis session

Security

Contraindications

• Hypersensitivity to the active ingredient.
• Recent acute pancreatitis (may reflexly delay gallbladder emptying).

Adverse Effects (ADR)

• Very common (>10%): Rotational dizziness, residual daytime sleepiness, generalized fatigue, motor ataxia with gait instability (especially in the elderly).
• Frequent (1%-10%):Moderate body weight gain, symmetrical peripheral edema in the lower extremities (induced by secondary local vasodilation), dry mouth, hostility or transient aggressiveness in pediatrics.
• Rare (<0.1%): Acute withdrawal syndrome after abrupt discontinuation, toxic pancreatitis, myoclonic worsening.

Clinical Interactions

• Antacids: Preparations containing aluminum oxide or magnesium hydroxide decrease the bioavailability of gabapentin by 20% due to absorption competition in the LAT-1 transporter. It is recommended to distance intake by at least two hours.
• Opioids: Coadministration with morphine or fentanyl increases the serum concentration of gabapentin by 40% and doubles the risk of central respiratory depression due to receptor synergy.

Pregnancy and Breastfeeding

FDA Category: C. Limited data; It is not conclusively associated with major malformations retrospectively, but the use of other more tested alternatives is preferred in pregnant women with controlled epilepsy. Breastfeeding: Compatible. It is excreted in milk in reduced proportions with a relative infant dose of ~1-2%. Monitor for lethargy or minor motor delay.