Anti-Epileptics

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General Terms

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Epilepsy

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chronic disorder characterized by recurrent seizures

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Seizures

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finite episodes of brain dysfunction resulting from abnormal discharge of cerebral neurons

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Focal (Partial) Seizures

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local origin; high frequenzy and synchronous firing one hemisphere, No LOC

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Generalized (Tonic Clonic)

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Spread of excitation to normal brain tissue, including motor pathways. Preceeded by an aura. Both hemispheres, Positive LOC

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Convultions

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involuntary skeletal muscle contractions. Abnormal discharge of motor neurons. Not all seizures are convulsions.

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Partial seizures

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one region of the brain, one side

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Secondary generalized seizure

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spread to the thalamus

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Primary generalized seizure

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starts in thalamus, spreads to other parts of brain

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MOA of Seizures (2)

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1. Loss of GABAergic Function: GABA interneurons are responsible for maintaining Tonic inhibitory control over surrounding internerurons near ectopic focus. Epilectics have increased cortical activity.$$$2. Increased Excitatory Glutamate Transmission: Increase in glutamate levels in some epileptics by causing a “depolarization shift”

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MOA of Anti Epileptic Meds:$$$General (2)

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1. Action of neurons on seizure foci to prevent excessive discharge$$$2. Action to reduce spread of excitation from seizure foci into normal aggregates of neurons.

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MOA of Anti Epileptic Meds:$$$Molecular (3)

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1. Inhibiting Na+ or Ca++ influx responsible for neuronal depolarization$$$2. Increase GABA-mediated inhibition; maintains tonic inhibitory control$$$3. Decrease excitatory glutamate neurotransmission; linked to CA++ channels

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Animal Screens for Antiepileptic Drugs

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1. Pentylenetetrazol (Metrazol) test: generalized seiures/absence seizures$$$2. Maximal electroshock test: partial seizures

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Status Epilepticus

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DOC Diazepam, Lorazepam, Phenytoin (IV-longer), Phenobarbital (resistant), Carbamazepine

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Absence Seizures

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DOC Ethosuximide; (other) Valproic Acid, Lamotrigine

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Partial Seizures and General Clonic-Tonic Seizures

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DOC: Phenytoin, Carbamazepine, Gabapentin (adjunctive), Phenobarbitol, Lamotrigine

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Trigeminal Neuralgia

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Carbamazepine

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Manic Episodes in Bipolar Disorder

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Carbamazepine, Valproic Acid

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Myoclonic Seizures

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DOC Valproic Acid,

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Lennox-Gastraut Sx

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Valproic Acid, Felbamate (refractory)

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Migraine Prophylaxis

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Valproic Acid, Topiramate

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Fibromyalgia

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Gabapentin

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Febrile Seizures

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Phenobarbitol

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Partial Seizures

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Topiramate, Tigabine, Levetiracetam, Felbamate (refractory)

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Drugs

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Sodium Channel Blockers

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MOA: binds and prolongs the inactivated state of Na+ channel; decreases Na+ influx, use-dependent block, prefers high-frequency neurons

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Phenytoin (Dilantin)

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MOA: binds and prolongs the inactivated state of Na+ channel; decreases Na+ influx, use-dependent block, prefers high-frequency neurons$$$ (Fosphenytoin: Prodrug for status epilepticus, emergency IM)$$$Intake: Oral: variable, IM: not recommended, IV: status epilepticus$$$Kinetics: Rate: dose-dependent, at high concentrations saturation is zero-order$$$Clinical Use: DOC Partial seizures and Generalized Tonic-Clonic Seizures, Status epilepticus (IV)$$$SE: ataxia, nystagmus, gingival hyperplasia (20% kids), Hirsutism (male-patterned hair growth), VN, Hypersensitivity$$$Contra: don’t discontinue abruptly, teratogenic$$$Drug interactions: cimetadine, valproic acid, PB, carbamazepine, dicumarol, oral contraceptives

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Carbamazepine (Tegretol)

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MOA: binds and prolongs the inactivated state of Na+ channel; decreases Na+ influx, use-dependent block, prefers high-frequency neurons$$$Kinetics: produces microsomal enzyme induction, need to adjust dose during therapy$$$Clinical Use: Partial seizures and Generalized Tonic-Clonic Seizures, Status epilepticus (IV), Trigeminal neuralgia, Manic episodes in bipolar dx$$$SE: diplopia, ataxia, Steven Johnson Syndrome, Rash, BBW: aplastic anemia$$$Contra: Teratogenic, CBC count, Asian! (Genetic Test: Incidence of CBZ-induced SJS is 10x higher in ASIAN pts bc have HLA B*1502 allele)$$$Drug Interactions: Enzyme induction, cimetidine, Phenobarbital, phenytoin$$$

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Lamotrigine (Lamictal)

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MOA: binds and prolongs the inactivated state of Na+ channel; decreases Na+ influx, use-dependent block, prefers high-frequency neurons$$$Pharm: glucoronidation of the liver$$$Clinical Use: broad-spectrum: partial seizures, generalized seizures$$$SE: somnolence, diplopia, allergic rxns, rash , SJS (in kids, ONLY pts 16yrs or older!)$$$Drug interactions: change metabolism (as above)

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T-Type Calcium Channel Inhibitors

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MOA: Inhibits low-threshold Ca++ currents (T-type calcium channels) in the thalamic neurons

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Ethosuximide (Zarontin)

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MOA: Inhibits low-threshold Ca++ currents (T-type calcium channels) in the thalamic neurons$$$Clinical Use: DOC Absence seizures in children$$$SE: Gastric distress (ANV)

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Valproic Acid (Dapekene)

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MOA: Unknown? Blocks the Ca++ and Na+ channels, Increases GABA $$$Kinetics: conjugated in liver$$$Clinical Use: Absence seizures, DOC Myoclonic Seizures, Lennox-Gastaut Sx, Manic Episodes of Bipolar dx, Migraine Prophylaxis$$$SE: NVA (common), hepatotoxicity (children), MOTINOR LIVER$$$Contra: liver function tests, teratogenic$$$Drug Interactions: MONITOR serum level, changes metabolim of many

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GABA Channel Potentiators

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MOA: Increases GABA inhibitory activity$$$

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Gabapentin

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MOA: Unknown? Increase GABE release$$$Kinetics: Not metabolized in liver, NO drug interaction, excreted unchanged in liver$$$Clinical Use: Adjunctive therapy: Partial and generalized seizures, neuropathic pain (DPN, PHN), Fibromyalgia$$$SE: somnolence, weight gain

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Pregabalin

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Diazepam (Valium)

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MOA: Increases GABA inhibitory activity$$$Kinetics: short duration of action$$$Clinical Use: DOC status epilepticus (IV)$$$SE: frequent recurrence of seizures (short duration of action), dizziness, ataxia, drowsiness

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Lorazepam (Ativan)

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MOA: Increases GABA inhibitory activity$$$Kinetics: intermediate acting BZD, less lipid soluble, longer acting$$$Clinical Use: Status Epilepticus

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Clonazepam (Klonzepam)

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MOA: Increases GABA inhibitory activity$$$Kinetics: Long acting$$$SE: sedation

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Phenobarbital (Mysoline)

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MOA: ? Increases GABA mediated Cl- influx$$$Kinetics: liver microsomal enzymes$$$Clinical Use: Tonic-clonic and partial seizures, Febrile seizures in infants$$$SE: drowsiness, sedation, respiratory depression

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Adjunct Drugs for Partial Seizures

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Topiramate (Topamax)

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Clinical Use: Partial seizures, Migraine prophylaxis

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Tigabine (Gabitril)

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MOA: inhibitor of GAGA reuptake$$$Clinical Use: Partial seizures$$$SE: dizziness, nervousness

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Levetiracetam (Keppra)

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Clinical Use: Partial seizures (Piracetam analog)

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Zonisamide (Zonegran)

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Kinetics: sulfonamide derivative$$$SE: hyperthermia (in kids-caution!)

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Misc Antiepileptic Drugs

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Felbamate

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MOA: Broad spectrum; blocks Na+ channes, blocks glycine coactivatio of NMDA glutamate R, blocks Ca++ channels$$$Clinical Use: Refractory cases of Partial Seizures and

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LGS, Lennox-Gestaut Sx$$$SE: Aplastic Anemia

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