‫بسم ال الرحمن الرحيم‬

Drugs for Epilepsies-II

&
Migraine
Glutamate & GABA, synthesis & metabolism

Glutamate
Glutamic acid
decarboxylase + Valproic acid

GABA
GABA- Gabapentin
Transaminase -
Vigabatrin
Succinic
a-keto
Semi-aldehyde
glutarate

Kreb’s
cycle Succinic acid
 Gabapentin
• An analog of GABA, does not act on GABA receptors
• Mechanism of action:
• Inhibit GABA metabolism & re-uptake
• Also inhibit voltage-sensitive Ca-channels
• Uses:
• Partial seizures & generalized tonic-clonic seizures
• Post herpetic neuralgia
• Toxicity: Drowsiness, dizziness, ataxia & tremors
• Kinetics: Plasma t-1/2 6-8 hrs, excreted unchanged in
urine, no liver enzyme induction, no drug interactions
 Lamotrigine
• Mechanism of action:
• Inhibits voltage & use dependent Na-channels
• Also inhibits voltage dependent Ca-channels
• Uses:
• Partial seizures & generalized tonic-clonic seizures
• Absence seizures
• Toxicity:
• Drowsiness, dizziness, diplopia & skin rash
• Metabolized in liver. Drug interactions with enzyme
inducers & inhibitors
 Topiramide
• Mechanism of action:
• Block voltage dependent Na-channels
• Potentiate inhibitory effect of GABA
• Blocks excitation of AMPA receptors
• Uses:
• Partial seizures & generalized tonic-clonic seizures
• Absence seizures, West’s & Lennox-Gestaut syndromes
• Toxicity:
• Drowsiness, dizziness, fatigue, confusion & paresthesias
• Acute myopia & glaucoma. Urolithiasis. Teratogenicity
• Can induce liver enzymes & cause drug interaction
 Felbamate
• Mechanism of action:
• Inhibits action of glycine on NMDA receptors
Uses:
• Partial seizures & Lennox-Gestaut syndrome
• Toxicity:
• Aplastic anemia & hepatiits
• Kinetics:
• Partial liver metabolism & partial renal excretion
• Phenytoin & carbabmazepine increase its metabolism
• Can inhibit liver enzymes & Cause drug-interactions
 Tiagabine
• Mechanism of action:
• Inhibits GABA uptake by neurons & glia.
• Preferably, ↓ gama-amino transfease (GAT-I) in
forebrain & hippocampus
• Uses:
• Partial seizures, in combination with other drugs
• Toxicity:
• Dizziness, nervousness, tremors & depression
• Kinetics:
• Liver metabolism, affected by enzyme inducers
• Itself does not inhibit or induce liver enzymes
 Vigabatrin
• Mechanism of action:
• Irreversible inhibitor of GABA aminotransferase
(GABA-T), responsible for metabolism of GABA
• Also inhibit GABA re-uptake
• Uses:
• Partial seizures & West’s syndrome
• Toxicity:
• Visual defects in 1/3 of patients
• Agitation, confusion & psychosis, not suitable for
psychiatric patients
• Drowsiness dizziness & weight gain
 Migraine
• Classic form
• Prodromal symptoms (aura), 15 minutes
• Visual disturbances (scotomas, hemianopia, flashes)
• Speech abnormalities (aphrasia)
• Weakness of one side
• (↑ 5-HT levels in brian)
• Acute attack (headache), few hours to 1-2 days
• Hemicranial, throbbing, may spread all over head
• Nausea & vomiting. Irritability, likes dark room
• Vasodilatation (due to calcitonin gene-related peptides)
 Drugs for migraine
• For acute attack of migraine
• 5-HT agonists: (Triptans & ergotamine)
• Ca-channel blockers (flunarizine & verapamil)
• NSAIDs: Aspirin, ibuprofen, paracetamol
• Anti-emetics: metoclopramide, domperidone
• For prophylaxis:
• Beta blockers (Proprnolol)
• Antidepressants: TCAs (amitriptyline), SSRIs
(fluvoxamine)
• Antiseizure agents (valproic acid, carbamazepine)
• Pizotifen & clonidine
 5-HT agonists
• A. Triptans: Specific & first line drugs for migraine
• Sumatriptan (short half-life, 2-3 hours)
• Naratriptan (intermediate half-life, 6 hours) Frovatriptan
(long half-life, 25 hours)
• Mechanism of action:
• Agonists for 5-HT1D & 5-HT1B receptors, found in
cerebral & meningeal blood vessels
• Cause vasoconstriction & ↓ release of peptides
• Adverse effects:
• Tingling, dizziness, muscle weakness & chest pain
• Contraindications: cardiac & peripheral vascular disease
 5-HT agonists (Cont.)
• Ergotamine tartarate (oral, sublingual & rectal)
• Mechanism of action:
• Causes vasoconstriction: agonist of 5-HT receptors &
partial agonists on a-receptors
• Specific for migraine, otherwise not analgesic
• More effective when given during prodrome
• Tolerance develops after repeated use
• Accumulates: < 6 mg per attack & < 10 mg per week
• Combination with caffeine, facilitates absorption
• Toxicity: Gangrene, chest pain, abortion
• Contraindications: cardiac & peripheral vascular disease