Phenytoin

• Phenytoin controls generalized tonic-clonic and partial seizures effectively.
• It stabilizes neuronal membranes by blocking voltage-gated sodium channels.

Chemical Formula:

• C₁₅H₁₂N₂O₂

Mechanism of Action:

• Blocks Na⁺ channels in a use-dependent manner → stabilizes hyperexcited neurons.
• Prevents repetitive firing.

Therapeutic Uses:

• Tonic-clonic seizures
• Focal (partial) seizures
• Status epilepticus (IV loading)

Side Effects:

• Gingival hyperplasia
• Hirsutism
• Ataxia, diplopia
• Teratogenicity (fetal hydantoin syndrome)
• Enzyme inducer (CYP450)
• Skin rash (rare: SJS)

SAR of Phenytoin:

1. Hydantoin nucleus (imidazolidine-2,4-dione):

   • Required for anticonvulsant activity.

2. Two phenyl rings at C5:

   • Critical for activity.
   • Provide lipophilicity and help in binding to sodium channels.

3. Substitutions on phenyl rings:

   • Modulate activity, duration, and toxicity.

4. Poor water solubility:

   • Limits parenteral formulations.

5. Tautomerism:

   • Exists in keto-enol forms, which may influence receptor binding.

Synthesis of Phenytoin:

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