What is the mechanism of action of Phenytoin?

Phenytoin Mechanism of Action

Phenytoin primarily works by blocking voltage-dependent sodium channels in neuronal membranes, resulting in stabilization of hyperexcitable neurons and inhibition of sustained high-frequency neuronal discharges. 1, 2

Primary Mechanism

• Voltage-dependent sodium channel blockade: Phenytoin selectively blocks voltage-gated sodium channels in their inactive state, which:

  • Promotes sodium efflux from neurons 1
  • Stabilizes the threshold against hyperexcitability 1
  • Prevents the spread of seizure activity, particularly in the motor cortex 1
  • Acts in a use-dependent and frequency-dependent manner 3

• Selective inhibition of high-frequency firing: This mechanism allows phenytoin to:

  • Filter out sustained high-frequency neuronal discharges 3
  • Preserve normal brain activity that occurs at lower firing rates 3
  • Block the positive feedback loop that underlies seizure development 3

Cellular Effects

• Membrane stabilization: By blocking sodium channels, phenytoin:

  • Reduces posttetanic potentiation at synapses 1
  • Prevents cortical seizure foci from activating adjacent cortical areas 1
  • Reduces activity in brain stem centers responsible for tonic-clonic seizures 1

• State-dependent binding: Phenytoin preferentially binds to sodium channels in their inactive state, which:

  • Allows normal neuronal firing while blocking ictal activity 4
  • Makes its efficacy dependent on the resting membrane potential of neurons 4
  • Results in greater effects on rapidly firing neurons involved in seizure activity 3

Clinical Implications

• The selective action on high-frequency neuronal activity explains why phenytoin can control seizures without significantly impairing normal neurological function 3

• Phenytoin's effects are dependent on both the intrinsic properties of neural networks and their behavioral state, which may explain why its efficacy can be unpredictable in some patients 4

• The drug's resting membrane potential dependency means its effectiveness may vary based on the overall level of activity in neural networks 4

Additional Considerations

• While the voltage-gated sodium channel is the primary target for phenytoin's antiepileptic effects, research suggests it may have additional mechanisms that contribute to its clinical effects in various disorders 5

• Phenytoin is ineffective against absence (petit mal) seizures, which is consistent with its mechanism of action being more effective against high-frequency neuronal discharges rather than the thalamocortical oscillations seen in absence seizures 6

• Phenytoin's antiarrhythmic effects in cardiac tissue further support that sodium channel blockade is its primary mechanism of action 6

Understanding phenytoin's mechanism helps explain both its therapeutic efficacy in controlling seizures and its limitations in certain seizure types, as well as its potential applications beyond epilepsy.