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Spears CNS 1 B
Epilepsy/ Antiepileptic Medications
| Question | Answer |
|---|---|
| Seizures vs Epilepsy. What are seizures? | Finite episodes of brain dysfunction resulting in abnormal discharge (firing) of cerebral neurons |
| What are some causes of seizures? | Infection; poisoning; fever; electrolyte imbalance; Hypoglycemia; Medication-induced; Drug withdrawal in a dependent addict |
| Seizures vs Epilepsy: What's elpilepsy? | Heterogenous, complex, chronic neurological disorder characterized by recurrent and unpredictable seizures |
| What are some symptomatic causes of Epilepsy? | Structural etilology; Brain damage, TBI, stroke, Brain tumor or lesion, Infection |
| What some idiopathic cauases of epilepsy? | Heredity, Autoimmune/Metabolic cause, Genetic defects |
| Genetic defects in an idiopathic cause of epilepsy can arise in: | GABA-A receptors; NMDA receptors; voltage gated ion-channels; syntaxin binding protein, adhesion molecules, synapse development *defects in certain NT that alter function |
| Classification set by the International League Against Epilepsy classification of seizure types consist of: | 1. Focal Onset seizures (formerly partial onset) 2. Generalized onset seizures |
| Epilepsy pathophysiology is: Abnormal, _______firing of several neurons | synchronous |
| Epilepsy can be caused by an imbalance b/w excitatory ⬆️ Glutamate and inhibitory ⬇️_______ NT | GABA |
| Focal Seizures affects a portion of the brain (usually 1-sided) unilateral in the front of the brain in the _______--> then leads to hyperexcitability | cortex |
| When excitatory occurs, it also ______ the type of change and behavior a person undergoing an epiletpic seizure can experience. | influences |
| In a secondary generalized seizure, main difference b/w primary and secondary is the _____ ______ | focal point |
| in the primary generalized seizure, hyper-excitation starts in the ________ where as in the secondary generalized seizure, it starts in the ________, jumps to the thalamus and then spreads to other areas of the brain | thalamus; cortex |
| RememBer that pin primary generalized seizures, initiating hyper-excitation starts in the _______ | thalamus |
| Epilepsy pathophys: magnetic resonance imaging of brain strucutre is _____ | MRI |
| electroencephalogram to measure brain electrical activity _______ | EEG |
| Partial seizure EEG demonstrates local or partial seizure where: | 1 portion of the brain experiences hyperexcitation |
| What are examples of Non-Pharmtx for epilepsy? | Ketogenic diet ( High-fat, low-carb (3:1 or 4:1 ratio of fat: protein/carb); Adverse effects: dehydration, reduced growth rate, hypercholesterolemia, kidney stone formation); *reserved for pts who have not responded to the typical meds. *shift from glucose to fat—> thought to reduce hyperexcitability and also though to increase GABA activity. Neurostimulation (Deep brain or vagal nerve stimulation; Responsive neurostimulation (RNS); Surgery: Temporal Lobe resection |
| Neurostimulation (non-pharmacological tx for epilepsy delivers an electrical impulse to regulate and normalize the? | activity of the brain |
| Difference between Deep brain stimulation and Responsbve neurostimulation is where? | the probes are applied to in the brain |
| Goals of Tx for epilepsy is to? | -Minimize high-frequency, rapid firing (not to decrease all excitation); -Decrease neuronal excitation (inhibits Na+ and Ca+ channels; inhibits glutamatergic transmission -increase neuronal inhibition (enhances GABAergic transmission |
| Decreasing Neuronal excitation for epilepsy—> By applying drugs to inhibit Ca2+ or Na+ channels is to inhibit release of? | that excitatory NT. I.e. in the case of the rat activity of normal vs epliptiform activity in control vs Lamotrigine. *normal—> notice that its not changing normal activity of AP. But when chemical epipsy is induced in the hippocampus, you see a rapid firing and apply Lamotrigine and we see a loss of rapid firing. Then a wash-period—> we see return of rapid firing activity |
| Na+ channel Inhibition drugs are? | Carbamazepine (Tegretol) Eslicarbazepine (Aptiom) Oxcarbazepinee (Trileptal) Lacosamide (Vimpat) Lamotrigine (Lamictal) + Ca2+ inhibition Phenytoin (Dilantin) Topiramate (Topamax) + GABA enhancement + Miscellaneous Valproic Acid + GABA activitty enhancement + Ca2+ inhibition Zonisamide (Zonegran) + Miscellaneous + Ga2+ inhibition Cenobamate (Xcopri) + GABA enhancement |
| Ca2+ channel inhibitor drugs are? | Ethosuximide (Zarontin) Gabapentin (Neurontin) Pregabalin (Lyrica) |
| GABA activity enhancement drugs are? | Phenobarbital (Luminal) Primidone (Mysoline) Benzodiazepines Tiagabine (Gabitril) + GABA enhancement Vigabitrin ( + GABA enhancement |
| Miscellaneous drugs available are? | Levetiracetam (Keppra) Perampenel (Fycompia) Cannabidiol (Epidiolex) |
| Na+ channel inactivation MOA is? | stabilizes inactive state of Voltage-gated Na+ and reduces Excitatory transmission -inhibits RAPID ACTION POTENTIAL firing (reducing presynaptic glutamate release) |
| Na+ channel inactivators and Ca2+ inactivators are located in the ________ | presynapatic |
| Na+ channel inactivators that are fast acting include which drugs? | Phenytoin, Lamotrigine, Topiramate, Carbamazeppine, Oxcarbazepine (Eslicarbazepine), Zonisamide |
| Na+ channel inactivators that are slow include? | Lacosamide |
| Na+ channel inactivator that is fast and slow is what drug? | Cenobamate |
| Ca2+ channel inhibitors have several different voltage gated subtypes: most important ones are? MOA? | P/Q and T-type -Presynaptic inhibitors of Ca2+ channels leading to decreased NT *most targeted by anti[eplipetic drugs and important for brain function |
| Which Ca2++ channel drugs target the P/Q VG? | Gabappentin; Pregabalin Lamotrigine (P/Q > t-type) |
| Which Ca2+ channel drugs target the T-type VG? | Ethosuximide, Valproate, Zonisamide |
| Antiepileptic medications inhibit all neeuronal firing in the overactive brain region (T/F) | False |
| What is the effect of anti-seizure drugs that inactivate V-G Na+ channels? | Reduced rapid neuronal firing |
| Seizures can be cuased by too much _______ signaling and/or too little _____ signaling in the brain. | Glutamatergic, GABAergic |
| Vigabatrin targets the GABA-T (Transaminase) which is important for metabolizing GABA. | GABA |
| Valproate is also a drug that can inhibit GABA-T and prevent metabolism of GABA by succinic Semialdehyde to _______ | metabolites |
| Blocking GAT-1 means your blocking reuptake of GABA making more bailable to bind to: | post-synaptic receptors |
| Tiagabine is a 3rd GABAergic affecting medication for epilepsy (fucntions by | inhibiting a transport protein called GAT-1 (GABA transporter) -blocking that transporter, cannot be taken back up into the presynapatic cell. And uou get more available to bind to post-synaptic receptoers. |
| The more typical GABAergic drugs that we know are benzodiazepines and barbituates, which function as our: | GABA-a positive modulators (bind to that postsynaptic channel and yio know that the GABA-a receptor is permeable to chloride. And so when those compounds bind to the channel, it opens that pore more to allow more chloride conductance |
| Drugs that enhance inhibitory transmission (Presynaptic) Vigabatrin MOA is? Tiagabine MOA is? | 1. selective, irreversible inhibition of GABA transaminase Reduces GABA metabolism 2. selective GABA transporter (GAT) inhibitor Reduces GABA reuptake (Block GABA transported to allow more GABA for signalling) |
| GABA-A receptor modulation (Postsynaptic) medications that act on the Barbituate site are? (1) Drugs on the Benzodiazepine (alpha) site? (2) Drugs that act on the BZD-independent site? (3) MOA for GABA-a receptor positive allosteric modulators? (4) | 1. Phenobarbital/Primidone 2. Benzodiazepines 3. Cenobamate (has activity to influence the GABA-a receptor but it does bind to a site that is distinct for Benzo’s (*similar effect for allowing Cl- meaning more hyperpolarization and reducing rapid firing 4. Increase GABA-mediated Cl-influx (more chloride—> hyperpolarize post neuron making it less able to carry on an AP |
| Topiramate (multiple MOA. What are they? | *1. Inactivation of VG-Na+ channels *2. Antagonizes AMPA/kainate activity (going to reduce the post signaling of glutamate by blocking these AMPA receptors) *3. Increases (GABA-A) activity 4. Weak carbonic anhydrase inhibitor (side effects) (small effect to increase Cl- in post-synaptic) |
| Zonisamide (multiple MOA). What are they? | *1. Prolongs inactivated state of sodium channels *2. Inhibits T-type calcium channels (decreasing Ca2+ channels will decrease Glu release located in the presynaptic channel) 3. Weak carbonic anhydrase inhibitor (side effects) 4. Free radical scavenger *remember that Na+ channel inactivations decrease AP |
| Valproic acid has multiple MOA) What are they? | *1. Stabilizes sodium channels in the inactive state (reducing repetitive firing) *2. Inhibition of T-type calcium channels (reduces glutamate release) *3. GABA production/biosynthesis (GABAergic—> application on both sides (decrease glutamate and decreases GABA metabolism) ◦ by increasing activity of glutamic acid decarboxylase *4. GABA metabolism ◦ by inhibition of GABA transaminase 5. IP3 formation/ postsynaptic 2nd messenger signaling ◦ by inhibition of inositol phosphatase |
| Levetiracetam MOA? | *Inhibits synaptic vesicle protein (SV2A) *Modulation of neurotransmitter release from presynaptic neurons (influences release of multiple NT) could be Glu or GABA); application tends to reduce the release of Glu |
| Perampanel MOA? | *Postsynaptic selective, non-competitive AMPA receptor antagonist (Blocking post Glu signaling |
| Cannabidiol (Epidiolex) MOA? | *◦Unknown *◦ Perhaps via postsynaptic inhibition of AMPA receptors *◦NOT mediated via CB receptors ◦ antagonists at non-CB1 receptors like GPR55 that regulate intracellular Ca2+ Specified for Lennox-Gastaut or Dravet syndrome patients ≥ 1 year ol |
| AE of Antiepileptic drugs: Phenytoin—> | Double vision • Hirsutism* (not due to increase of androgen (independent) & changes in facial features (coarsening) • Acne • Gingival hyperplasia* (20-40%) Inhibition of (overgrowth of collagen tissue) Pt should brush teeth > 8 times per day |
| GENERAL AE of Antiepileptic drugs are? | Sedation, Dizziness, Dausea, Ataxia |
| AE of Antiepileptic drugs: Carbamazepine/Oxcarbazepine/Eslicarbazepine—> | Hyponatremia* (oxcarbazepine > carbamazepine), Agranulocytosis *• SJS (HLA-B*15:02 testing required for carbamazepine) *importnat to test variant before admin b/c its CI for risk of causing SJS |
| AE of Antiepileptic drugs: Lamotrigine—> | Severe skin rash*, Double vision |
| AE of Antiepileptic drugs: PRegabalin/Gabapentin—> | Peripheral edema*, Weight gain |
| AE of Antiepileptic drugs: Cenobamate—> | Suicidal ideations*, Hypersensitivity, QT interval shortening |
| AE of Antiepileptic drugs: Topiramate & Zonisamide—> | Cognitive impairment, decreased appetite/weight loss, risk of kidney stones & odd taste to carbonated beverages Topiramate → Weight loss medication (when combined with phentermine) |
| AE of Antiepileptic drugs: Levetiracetam—> | Increased blood pressure, aggression, infection, muscle weakness, accidental injury |
| AE of Antiepileptic drugs: Perampenel—> | Fatigue, irritability *Boxed Warning: serious psychiatric and behavioral reactions |
| AE of Antiepileptic drugs: Cannabidiol—> | Fatigue, insomnia, decreased appetite, weight loss, diarrhea, infection |
| AE of Antiepileptic drugs: Vigabatrin | weight gain, vision loss, *may worsen generalized epilepsy |
| AE of Antiepileptic drugs: Tiagabine | Infecction, muscle weakness, reduced conc,, accidental injury, *may worsen generalized epilepsy |
| AE of Antiepileptic drugs: Valproate | GI (N/V), CNS (sedation, ataxia), *hepatotxicity, weight gain, *teratogen (box warning, fetal risk)* |
| Vigabatrin and Tiagabine —> have specific applications for partial or focal seizures. These should NOT be used in your pts that have? | generalized epilepsy and these also lowere seizure threshold |
| (T/F) blocking GAT1 to inhibit GABA reuptake is one way valproic acid enhances GABA activity | F—> only 1 blocks GAT 1 (Tiagabine) |
| What are the effects of Cenobamate on neuronal or seizure activity? | -decreases seizure activity -reduce lutamate release -reduce AP via Na+ channels inactivation -increases post neuron hyperpolarization |
| As a Ca2+ channel inhibitor, Gabapentin helps reduce seizure activity by? | decreasing Presynaptic release of glutamate -*no direct effect on GABA-a receptor, blocking channel decreases efflux of Ca2+ and lowers Glu |
| Neurotransmission Review: Slide 14 Spears | AP (red) right Na+ inactivators will function here to decrease that action potential firing. Ca2+ will work adjacent (expressed on the presynaptic nerve terminal and when you inhibit those, that’s going to impact vesicle release and cause less release of the NT So when you block Ca2+, step 2 can’t occur (Release of NT for hyperexcitement) |
Created by:
Xander635
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