4.2

Anti-Seizure Drugs: Old Agents

• Hydantoins: Phenytoin and Fosphenytoin
  • SAR: Activity increased by bulky C5 group, phenytoin's 5,5-diphenyl structure leads to maximum activity
  • Metabolism: Primarily via CYP3A4 (N-demethylation, N-oxidation), also CYP2D6 (aromatic hydroxylation)
  • Adverse Effects: Sedation, associated with 5-HT2 and 5-HT3 antagonism

Oxazolidinedione (Trimethadione)

• SAR: Lack of bulky C5 groups eliminates grand mal activity, but increases petit mal (absence seizure) activity
  • High toxicity limits its therapeutic use.

Succinimide (Ethosuximide)

• Drug of choice for absence seizures (petit mal)
  • SAR: No bulky C5 group, replaces -O- (in oxazolidinedione) with -CH2, resulting in safer drug with retained activity
  • Metabolism: ~20% excreted unchanged, via CYP 3A4 and 2E1

Valproic acid

• Used for both grand and petit mal seizures
  • MOA: Promotes GABA transmission by inhibiting GABA metabolism; blocks VGSC, decreasing neuronal firing
  • Adverse Effects: Limited use due to rare hepatotoxicity and teratogenicity

Anti-Seizures: New Agents

Iminostilbene (Carbamazepine)

• SAR: 2 phenyl groups are essential for activity, substitutions at C10 (keto, hydroxy, acetate ester) result in less potent but still active compounds
  • MOA: Inactivation of excessive neuronal firing by VGSC blockade
  • Note: Derivatives of TCAs (tricyclic antidepressants)

GABA Analogs (Gabapentin and Pregabalin)

• SAR: Both are analogs of GABA (inhibitory neurotransmitter)
  • MOA: Regulates Ca+2 influx via VGCC, activating GAD (glutamic acid decarboxylase) to inhibit glutaminergic neurotransmission
  • Metabolism: Minimal

Phenyltriazine (Lamotrigine)

• Useful for grand mal, petit mal, and partial seizures in adults
  • MOA: Blocks VGSC and VGCC, stabilizing presynaptic neurons; inhibits glutamate release, preventing excitatory response
  • Metabolism: Glucuronidation

Dicarbamate (Felbamate)

• Potent and widely used, but associated with severe adverse effects: aplastic anemia and hepatic failure
  • MOA: Interacts with NMDA, decreasing glutamate transmission and reducing neuronal excitation
  • Metabolism: Via ester hydrolysis and oxidation

CNS Stimulants

Methylxanthines

• Xanthine derivatives found in plants, act as CNS stimulants.

Epilepsy

• Disorder characterized by recurrent seizures, not caused by identifiable factors.

Seizures

• Symptom of disturbed electrical activity in the brain

Generalized Seizures

• Absence (petit mal): Brief loss of awareness, blank stare, postseizure amnesia, no loss of motor activity.
• Myoclonic: Short duration, no loss of consciousness, involves muscular jerks.
• Tonic-Clonic (grand mal): Bilateral muscle jerking, loss of consciousness, tonic-clonic spasms

Partial Seizures

• Simple: Affects an entire hemisphere or a lobe of the brain.
• Complex: Temporal/psychomotor seizures, can be mistaken for psychotic behavior.

MOA of Anti-Seizure Drugs

• Drugs alter ion channel or receptor function to promote synaptic inhibition or modulate synaptic excitation.

Sites of Action for Anti-Seizure Drugs

Glutamate Presynaptic Neuron

• Lamotrigine
• Ezogabine
• Ethosuximide
• Valproate
• Zonisamide
• Benzodiazepines
• Carbamazepine
• Lamotrigine
• Lacosamide
• Oxcarbazepine
• Phenobarbital
• Phenytoin
• Rufinamide
• Topiramate
• Valproate
• Zonisamide

GABA Presynaptic Neuron

• SSAH
• GAD
• GABA-T
• Vigabatrin
• Benzodiazepines
• Phenobarbital
• Topiramate
• Valproate
• Tiagabine
• Topiramate
• Felbamate

Partial and Generalized Tonic-Clonic Seizures

• Benzodiazepines
• Carbamazepine
• Ezogabine
• Lacosamide
• Felbamate
• Oxcarbazepine
• Phenobarbital
• Phenytoin
• Pregabalin
• Primidone
• Rufinamide
• Tiagabine
• Topiramate
• Vigabatrin

Myoclonic Seizures

• Felbamate
• Lamotrigine
• Levetiracetam
• Valproate
• Zonisamide
• Gabapentin
• Clonazepam
• Topiramate

Absence Seizures

• Ethosuximide
• Methosuximide
• Trimethadione

Anti-Parkinson Drugs

• Parkinson's Disease (PD): Slowly progressive, neurodegenerative disorder affecting the extrapyramidal dopaminergic pathway

• Clinical Manifestations:

  • Resting tremor (improved by voluntary activity)
  • Bradykinesia (slow initiation and paucity of voluntary movements)
  • Muscle and joint rigidity (postural disturbances)

• Treatment:

  • L-A-B-A-S-E drugs and related substances: Levadopa, Amantadine, Bromocriptine, Anticholinergics, Selegiline, Entacapone

Normal vs Parkinsonism

• Normal: Substantia nigra, Corpus striatum, Dopamine, Acetylcholine, GABA
• Parkinsonism: Lack of dopamine, resulting in deficient DA neurotransmitter; lack of direct stimulation for thalamus modulation (responsible for excitatory outflow to motor cortex).

Anti-Parkinsonism

• Drugs and Mechanism of Action:
  • Lipophilic DA Precursor: Levadopa (dopamine precursor)
  • DA Agonist and Reuptake Inhibitor: Amantadine
  • DA Agonists: Bromocriptine, Pergolide, Pramipexole
  • Anticholinergics: Treat tremor (Benztropine, Biperiden, Trihexypeħnidyl)
  • MAO-B Inhibitors: (Without hypertensive crisis): Selegeline and Rasagiline
  • COMT Inhibitors: Entacapone and Tolcapone

cns drugs