Epilepsy Pharmacology

Seizure: Definition

-Physical findings or changes in behavior that occur after an episode of abnormal electrical activity in the brain

Epilepsy: Definition

-A group of neurological diseases that are characterized by recurrent seizures

Seizure: Newborn Etiology

-Lack of oxygen during birth-Brain malformations-Intracranial Hemorrhage-Maternal drug use

Seizure: Infants and Children Etiology

-Fever-Pediatric Brain Tumor-Infection

Seizure: Children and Adult Etiology

-Congenital Conditions-Genetic Factors-Head Trauma

Seizure: Senior Etiology

-Stroke-AD-Trauma-Brain Tumor

Seizure: Neurophysiology

-Sudden discharge from a group of neurons synchronously

AED: Limitations

-Ineffective in 30-40% of patients with refractory epilepsy-Broad neurotoxic ADE-Symptomatic relief only

AED: Voltage-Gated Mechanisms

-Block Na+ Channels-Inhibit T-type Ca Channels-One drug that activates K+ channels

AED: Ligand-Gated Mechanisms

-Gaba-Glutamate

AED: Na+ Channel Agents

-Phenytoin-Carbamazepine-Oxcarbazepine-Lamotrigine-Valproate

AED: Na+ Channel Agents Use

-Focal Seizures-Generalized Seizures (Secondary)

AED: T-type Ca Channel Agents

-Ethosuximide-Valproate

AED: T-type Ca Channel Agents Use

-Absence Seizures

AED: Valproate MOA

-Block Na+ channels-Inhibit T-type Ca channels-Increase brain levels of GABA

AED: K+ Channel Agents

-Ezogabine

AED: K+ Channel Agents Use

-Discontinued in 2017 due to severe side effects

AED: GABAnergic Agents

-Gabapentin-Benzodiazepines-Barbiturates-Valproate-Vigabatrin-Tigabine-Topiramate

AED: Gabapentin MOA

-Analog of GABA but does not bind to GABA receptors-Binds to voltage-gated Ca2+ channel-Unknown MOA, but might increase GABA biosynthesis and release

AED: Diazepam MOA

-Bind to receptor and facilitates GABA mediated Cl- influx

AED: Barbiturate MOA

-Bind to GABA receptor to facilitate chloride influx

AED: Barbiturate Use

-When other agents fail-Limited by sedative properties that cause overdose concern

AED: Vigabatrin MOA

-Inhibits GABA Metabolism

AED: Tiagabine MOA

-Blocks GABA reuptake by neurons and glia

AED: Topiramate MOA

-Potentiate actions of GABAa Receptor-Block glutamate receptor function

AED: Anti-Glutamatergic Agents

-Topiramate-Perampanel

AED: Perampanel MOA

-A selective non-competitiveantagonist for AMPA-type glutamate receptors

AED: SV2A Targeting Agents

-Levetiracetam-Brivaracetam

AED: SV2A Targeting Agents MOA

-Bind synaptic vesicle membrane protein-Inhbit presynaptic Ca channels-Reduces neurotransmitter release-Decreased neuronal excitability

Pregnancy: Phenytoin

-Fetal Hydantoin Syndrome

Pregnancy: Valproate

-Spina Bifida

Pregnancy: Topiramate

-Teratogenicity-Growth retardation-Delayed mental development

Pregnancy: Agents to Use

-Lamotrigine-Levetiracetam

Common ADE: Dose Related

-Sedation-Ataxia-Diplopia

Common ADE: Osteoporosis Causative Agents

-Carbamazepine-Phenytoin-Phenobarbital-Oxcarbazepine-Valproate

Common ADE: Osteoporosis Prevention

-Supplemental Calcium and Vitamin D

Common ADE: Chronic Phenytoin Use

-Coarsening of Facial Features-Hirsutism-Gingival Hyperplasia

Kinetics: Phenytoin

-Non-Linear relationship between plasma concentration and dose-Rate of metabolism is close to the max for enzymes involved

Kinetics: Phenytoin Impact

-Small increase in dose may lead to large increase in concentration

Kinetics: Gabapentin

-Gut absorption is mediated by system L-amino acid transporters-Saturation is possible

Kinetics: Gabapentin Impact

-Oral bioavailability decreases with increasing dose

DDI: Carbamazepine Interaction Mechanism

-Stimulates up-regulation of 3A4 and 2B6-Autoinduction

DDI: Carbamazepine Impact

-Reduces plasma concentration-Increases metabolism of other AED-Plasma half-life shortens with repeated dose

DDI: Carbamazepine Strategy

-Lower starting dose-Increase gradually over time