Anti-Seizure Medications Flashcards
Characteristics/types of partial seizures
- Simple partial – 10%
- Key feature is preservation of consciousness
- Usually of cortical origin in a restricted region
- Complex partial – 35%
- Loss of or impaired consciousness
- Often psychomotor with involvement of limbic regions
- Secondary generalized
- Loss of consciousness; includes other areas/muscle groups
Characteristics of tonic-clonic seizures
- Tonic-clonic (grand mal) – 30%
- Presentation: tonic phase (rigid extension of trunk and limbs) + clonic phase (rhythmic contraction of arms and legs), loss of postural control, LOC, abnormal behavior, confusion
- Mechanism: Initiation occurs locally with loss of GABA inhibitory tone; propagation due to decreased GABA tone over a large area / increased response to glutamate
Characteristics of absence seizures
- Absence (Petit mal) – 10%
- Presentation: usually begin in childhood and cease by age 20; normal muscle tone, impaired consciousness with staring spells
- Mechanism: Oscillatory stimulation of thalamic-cortical circuitry with inappropriate activation of low-threshold _T-type Ca2+ channels _
General MOA of anti-seizure drugs
- elevating seizure threshold = membrane stabilization
- decrease T-type Ca2+ channel currents
- enhancement of GABA action
- limiting propogation (reduced synaptic transmission)
Pathophysiology of seizures (opportunities for pharmacotherapeutic intervention)
- Traceable to unstable neuronal membrane (focal epileptogenesis ==> initiation).
- Paroxysmal discharges that can recruit and synchronize a large population of cortical neurons or neurons in thalamic region.
- Enhancement of excitatory neurotransmitters (primarily glutamate) OR
- deficiency of inhibitory neurotransmitters (primarily GABA) ==> propagation of abnormal activity
Antiepileptic drugs used in Primary generalized tonic-clonic seizures
- Valproate
- Lamotrigine
- Levetiracetam
- alternative: phenytoin
Antiepileptic drugs used in partial seizures (including secondarily general)
- Carbamazepine (or Oxcarazepine)
- Lamotrigine
- Levetiracetam
Antiepileptic drugs used in absence seizures
- Ethosuximide
- Valproate
Antiepileptic drugs used in atypical absence, myoclonic, atonic seizures
- Valproate
- Lamotrigine
- Levetiracetam
Characteristics/examples of drugs that inhibit sodium channel [VSSC] fxn
- use-dependent blockade of excited cells via binding of inactivated state to prolong refactoriness
- Phenytoin, carbamazepine, lamotrigine, and topiramate block voltage dependent sodium channels and reduce repetitive firing, thus better at controlling tonic-clonic seizures
Example of drug that decreases T-type currents
- ethosuximide
Examples of drugs that enhance GABA action
- Benzodiazepines and phenobarbital
- Vigabatrin [Sabril] inhibits inactivation of GABA by GABA-transaminase
- Tiagabine [Gabatril] blocks the reuptake of GABA at the synapse
- Gabapentin alters GABA neurochemistry (metabolism, release, or reuptake) increasing GABA levels in brain.
Drugs used in status epilepticus
- diazepam
- lorazepam
- midazolam
- Treatment
- Initial therapy = IV Lorazepam until seizures stop, then phenytoin
- If seizures persist, IV phenobarbital, then pentobarbital until seizures stop
- If seizures persist, then pentobarbital or propofol with pressor support
Definition of status epilepticus
A state of recurrent, major motor seizures between which the patient does not regain consciousness; death occurs in 5-20% of untreated cases from respiratory arrest or circulatory collapse
Characteristics of Carbamazepine
Mechanism
Suppresses repetitive action potential firing by blocking Na2+ channels
Use
Drug of choice for partial seizures; also useful in tonic-clonic seizures
May make absence or myoclonic seizures worse
Side effects
CYP450 inducer; clearance can increase 2-fold in the first month of treatment due to self-induction of metabolism
Dose-related: Diplopia, Ataxia, nausea/vomiting, drowsiness, hyponatremia
Rare: Stevens-Johnson Syndrome – risk associated with HLA-B1502 allele and Asian ancestry, aplastic anemia, agranulocytosis, hepatotoxicity
Characteristics of Phenytoin
Mechanism
Blocks Na+ channels, inhibits generation of repetitive action potentials in epileptogenesis focus
Pharmacokinetics
Bioavailability varies between manufacturers
Food enhances absorption and reduces GI upset
Adverse Reactions
Strong inducer of CYP450 enzyme system
Zero-order kinetics – at high therapeutic range, maximum metabolic capacity is saturated and small dose changes can result in toxicity
Dose-related: Nystagmus, ataxia, sedation, rash, gingival hyperplasia
Overdose: Nystagmus, ataxia, diminished mental capacity, death from respiratory and circulatory depression
Uses
NOT first line due to side effects and DDIs
However, one of the most effective drugs against partial and generalized tonic-clonic seizures
Characteristics of Levetiracetam
Mechanism
Binds to and disrupts synaptic vesicle protein; some Ca2+ channel effects
Adverse Reactions
NO P450 drug interactions
Dose-related effects are generally mild: Fatigue, somnolence, dizziness
Uses
First line drug for generalized tonic-clonic
Characteristics of Lamotrigine
Mechanism
Broad spectrum, mechanism unclear
Side effects
Dizziness, ataxia, diplopia, sedation; similar to phenytoin but lower rate of occurrence
DDIs – levels increased by valproate, decreased by estrogens in OC or hormone replacement therapy
Uses
Monotherapy of partial or generalized seizures; as effective as carbamazepine and phenytoin AND better tolerated
Prevention of mania in bipolar disorder
Characteristics of ethosuximide
Mechanism
Inhibition of T-Type Ca2+ current that generates the rhythmical cortical discharge of absence seizures; suppresses brain activity associated with lapses of consciousness common in absence seizures
Adverse Effects
Dose related: GI upset, headache, dizziness
Uses
Drug of choice in absence (petit mal) seizures
Characteristics of Valproic Acid
Mechanism
GABA potentiation via inhibition of GABA-transaminase; reduces activity of T-type Ca2+ channels
Adverse Effects
Inhibits metabolism of phenytoin, lamotrigine, phenobarbital, carbamazepine, ethosuximide
Dose-related: GI complaints, weight gain
Rare: Hepatotoxicity, contraindicated in pregnancy
Uses
First line treatment of generalized, tonic-clonic seizures
Effective against absence seizures but utility is limited by hepatotoxicity
Characteristics of Phenobarbitol
Mechanism
Suppresses firing and spread from abnormal foci by enhancing GABA inhibition and antagonizing glutamate excitation
Adverse Reactions
Classic CYP450 inducer ==> DDIs
Dose-related: Ataxia, nystagmus, rash, sedative effects; sedation limits use
Contraindicated in pregnancy
Uses
Adjunctive treatment of partial and generalized tonic-clonic seizures
Used for neonatal status epilepticus
Characteristics of Gabapentin
Mechanism
Binds to voltage-sensitive Ca2+ channels, decreasing synaptic release of glutamate
Pharmacokinetics
GI absorption is saturable ==> little risk of OD
Adverse Effects
Dose-dependent: sedation, ataxia, dizziness
Few/no DDIs
Uses
Treatment-resistant epilepsy
Characteristics of benzodiazepines
Mechanism
Enhance GABA Cl- influx to raise AP threshold, suppress seizure focus, and strengthen surrounding inhibition
Agents
Clonazepam (Klonipin)
Inhibits T-type Ca2_ channels in thalamocortical circuits
Effective against absence seizures
Risk of sedation (>50%)
Diazepam (Valium)
Drug of choice for status epilepticus, given IV; also used as adjunctive therapy in atonic and absence seizures and infantile spasms
Tolerance develops over a few months
Antiepileptics in pregnancy
- valproate and phenobarbital = higher risk for fetal malformations
- newer agents = levetiracetam, oxcarbazepine, and gabapentin have lower rates
- monotherapy preferred to decrease fetal exposure
- may need to adjust dosage, esp. for lamotrigine
