Phenytoin MOA – voltage-gated sodium channel blocker

Mechanism of Action of Phenytoin

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Introduction

Phenytoin is one of the oldest and most widely used antiepileptic drugs (AEDs), primarily for treating focal seizures and generalized tonic-clonic seizures. It has a well-known profile, acting on voltage-gated sodium channels to reduce high-frequency neuronal firing. Despite newer alternatives, phenytoin remains important, especially in emergency settings like status epilepticus (IV use).

It’s a high-yield topic in USMLE, NCLEX, GPAT, and NEET-PG due to its pharmacokinetics, side effects, and drug interactions.

Stepwise Mechanism of Action of Phenytoin

  1. Voltage-gated Na⁺ channel blockade
    Phenytoin binds to voltage-gated sodium channels in their inactivated state, prolonging inactivation and preventing repetitive neuronal firing.
  2. Use-dependent (state-dependent) blockade
    The drug shows use-dependence, meaning it preferentially acts on active neurons, which fire frequently, making it ideal for suppressing seizure foci.
  3. Inhibition of sustained high-frequency action potentials
    Phenytoin prevents the spread of seizure activity by stopping sustained, rapid depolarization.
  4. Stabilization of neuronal membranes
    By reducing excitability, phenytoin stabilizes neuronal membranes and lowers seizure threshold.
Phenytoin MOA – voltage-gated sodium channel blocker
Phenytoin controls seizures by binding inactivated sodium channels and preventing repetitive firing.

Pharmacokinetic Parameters of Phenytoin

ParameterValue
Bioavailability70–90% (oral)
Half-life7–42 hrs (dose-dependent kinetics)
MetabolismHepatic via CYP2C9, CYP2C19
Protein binding~90%
ExcretionRenal (as inactive metabolites)
Therapeutic range10–20 μg/mL
KineticsZero-order at high doses

Clinical Uses of Phenytoin

  • Generalized tonic-clonic seizures
  • Focal (partial) seizures
  • Status epilepticus (IV form, loading dose)
  • Seizure prophylaxis in head trauma
  • Trigeminal neuralgia (off-label)

Adverse Effects of Phenytoin

  • CNS effects – Nystagmus, ataxia, confusion
  • Gingival hyperplasia
  • Hirsutism
  • Megaloblastic anemia (↓ folate absorption)
  • Peripheral neuropathy
  • Drug-induced lupus
  • Stevens-Johnson Syndrome (SJS)
  • Osteomalacia (↓ vitamin D metabolism)
  • Teratogenicity – Fetal hydantoin syndrome
  • Hepatotoxicity
  • Skin rash

Comparative Analysis: Phenytoin vs Levetiracetam

FeaturePhenytoinLevetiracetam
MOANa⁺ channel blockerSV2A modulation
Drug interactionsMany (CYP inducer)Minimal
SedationLowMild/moderate
Gingival hyperplasiaCommonRare
TeratogenicityFetal hydantoin syndromeSafer in pregnancy
KineticsZero-order at high dosesLinear

Practice MCQs

Q1. Phenytoin primarily acts on which ion channel?
a. Calcium channels
b. Potassium channels
c. Sodium channels ✅
d. Chloride channels

Q2. The kinetics of phenytoin at high doses is:
a. First-order
b. Zero-order ✅
c. Mixed
d. None

Q3. A classical side effect of phenytoin is:
a. Gingival hyperplasia ✅
b. Alopecia
c. Anemia
d. Ataxia

Q4. Phenytoin is indicated for:
a. Absence seizures
b. Myoclonic seizures
c. Status epilepticus ✅
d. Febrile seizures

Q5. Which vitamin deficiency can occur with phenytoin?
a. Vitamin A
b. Vitamin D ✅
c. Vitamin K
d. Vitamin B1

Q6. Phenytoin has high binding to:
a. Globulin
b. Plasma protein ✅
c. Albumin only
d. RBCs

Q7. What happens when phenytoin exceeds its metabolic capacity?
a. Increased absorption
b. Toxicity due to zero-order kinetics ✅
c. Rapid elimination
d. Decreased half-life

Q8. Which of the following is teratogenic with phenytoin use?
a. Spina bifida
b. Neural crest defects
c. Fetal hydantoin syndrome ✅
d. Ebstein anomaly

Q9. Phenytoin-induced anemia is due to:
a. Iron deficiency
b. B12 deficiency
c. Folate deficiency ✅
d. Hemolysis

Q10. Phenytoin is metabolized by:
a. CYP3A4
b. CYP2D6
c. CYP2C9 and CYP2C19 ✅
d. UGT

FAQs

Q1: Can phenytoin be used for absence seizures?
No. It is ineffective and may worsen absence seizures.

Q2: Why does phenytoin require careful dosing?
Because it exhibits zero-order kinetics, small dose changes can cause toxicity.

Q3: How should IV phenytoin be administered?
Slowly, not exceeding 50 mg/min, to avoid cardiac arrhythmias.

Q4: What is fetal hydantoin syndrome?
A congenital syndrome with cleft lip, growth retardation, facial anomalies, and mental retardation due to phenytoin use in pregnancy.

Q5: Why monitor liver function with phenytoin?
It is hepatically metabolized and may cause liver damage with long-term use.

References

NCBI: https://www.ncbi.nlm.nih.gov/books/NBK482370/

KD Tripathi – Essentials of Medical Pharmacology

Goodman & Gilman – The Pharmacological Basis of Therapeutics

Review of Pharmacology – Sparsh Gupta

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