Mechanism of Action of Gabapentin

Introduction

Gabapentin is an antiepileptic drug and one of the most widely prescribed medications for neuropathic pain, postherpetic neuralgia, and partial seizures. Originally developed as a GABA analog, it surprisingly does not act directly on GABA receptors. Instead, it binds to voltage-gated calcium channels, altering neurotransmitter release. It is also used off-label for conditions like anxiety, fibromyalgia, and hot flashes.

Gabapentin is a favorite topic in USMLE, NCLEX, GPAT, and NEET-PG due to its dual role in epilepsy and pain management.

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Stepwise Mechanism of Action of Gabapentin

1. Binding to α2δ subunit of voltage-gated Ca²⁺ channels
   Gabapentin binds to the α2δ-1 subunit of voltage-gated calcium channels in the CNS, particularly in presynaptic neurons.
2. Reduction in calcium influx
   This reduces Ca²⁺ entry into neurons upon depolarization, thereby limiting the release of excitatory neurotransmitters like glutamate, norepinephrine, and substance P.
3. Decreased excitatory transmission
   The inhibition of neurotransmitter release leads to dampened neuronal hyperexcitability, especially in epileptic foci and pain pathways.
4. No direct action on GABA receptors
   Although structurally similar to GABA, it does not bind to GABA-A or GABA-B receptors, nor does it affect GABA synthesis or uptake.

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Pharmacokinetic Parameters of Gabapentin

Parameter	Value
Bioavailability	Decreases with dose (non-linear, 60–30%)
Half-life	5–7 hours
Metabolism	Not metabolized
Excretion	Renal (unchanged drug)
Protein binding	Negligible
Therapeutic range	Not routinely monitored

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Clinical Uses of Gabapentin

• Partial seizures (adjunct therapy)
• Postherpetic neuralgia
• Diabetic neuropathy
• Fibromyalgia
• Generalized anxiety disorder (off-label)
• Restless legs syndrome (off-label)
• Hot flashes (off-label)

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Adverse Effects of Gabapentin

• Sedation and drowsiness
• Dizziness and ataxia
• Fatigue
• Peripheral edema
• Weight gain
• Tremor
• Behavioral changes (children)
• Rare: Suicidal ideation, mood swings

⚠️ Dose adjustment is required in renal impairment due to renal clearance.

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Comparative Analysis: Gabapentin vs Pregabalin

Feature	Gabapentin	Pregabalin
Ca²⁺ channel target	α2δ-1 subunit	α2δ-1 subunit
GABA receptor binding	No	No
Bioavailability	Variable, non-linear	High, linear
Onset of action	Slower	Faster
Indications	Similar, with more off-label use	Approved for more indications

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Practice MCQs

Q1. Gabapentin exerts its action by binding to:
a. GABA-A receptor
b. Sodium channels
c. α2δ subunit of calcium channels ✅
d. NMDA receptor

Q2. What is the effect of gabapentin on calcium influx?
a. Increases Ca²⁺ influx
b. No effect
c. Reduces Ca²⁺ influx ✅
d. Blocks calcium reuptake

Q3. Gabapentin is structurally similar to:
a. Glycine
b. GABA ✅
c. Glutamate
d. Serotonin

Q4. Gabapentin is most commonly used for:
a. Myoclonic seizures
b. Status epilepticus
c. Neuropathic pain ✅
d. Absence seizures

Q5. Which neurotransmitter’s release is reduced by gabapentin?
a. Dopamine
b. Acetylcholine
c. Glutamate ✅
d. Serotonin

Q6. Gabapentin metabolism occurs in:
a. Liver
b. Kidney
c. Brain
d. Not metabolized ✅

Q7. Protein binding of gabapentin is:
a. High
b. Moderate
c. Negligible ✅
d. Variable

Q8. Which condition is gabapentin ineffective in?
a. Neuropathic pain
b. Tonic-clonic seizures ✅
c. Anxiety
d. Diabetic neuropathy

Q9. What is a common side effect of gabapentin?
a. Hyperthermia
b. Peripheral edema ✅
c. Hypoglycemia
d. Insomnia

Q10. In renal failure, gabapentin dose should be:
a. Increased
b. Doubled
c. Reduced ✅
d. Unchanged

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FAQs

Q1: Is gabapentin a GABA agonist?
No, it does not act on GABA receptors despite its structural similarity.

Q2: Is gabapentin a controlled substance?
In the US, it is not federally controlled, but some states regulate it.

Q3: Can gabapentin be used as monotherapy in epilepsy?
It is not preferred as monotherapy, used mainly as adjunctive therapy.

Q4: How is gabapentin eliminated?
Unchanged by the kidneys, requiring dose adjustment in renal impairment.

Q5: Does gabapentin interact with other drugs?
Minimal drug interactions, since it is not metabolized by the liver.

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References

• KD Tripathi – Essentials of Medical Pharmacology
• Goodman & Gilman – The Pharmacological Basis of Therapeutics
• Sparsh Gupta – Review of Pharmacology
• NCBI: https://www.ncbi.nlm.nih.gov/books/NBK459127/