Anti Epileptics Ii & Migraine

‫بسم ال الرحمن الرحيم‬ Drugs for Epilepsies-II & Migraine

Glutamate & GABA, synthesis & metabolism Glutamate Glutamic acid decarboxylase

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Valproic acid

GABA GABATransaminase a-keto glutarate Kreb’s cycle

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Succinic Semi-aldehyde

Succinic acid

Gabapentin Vigabatrin

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