antiseizure meds Flashcards
Compare seizure vs convulsion
• Seizure: Excessive neuronal discharge characterized as brief, involuntary, episodic • Convulsion: Violent involuntary contraction of voluntary muscles
Mechanisms of seizures
• Paroxysmal discharges 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) can promote spread or propagation of abnormal activity
Steps in seizure
focal epileptogenesis, synchronization and propagation
Seizure consequences
increased oxygen demand > ischemia > subsequent brain damage > “Seizures beget seizures”
Model for Unstable - Excessive Neurotransmission Seizures
(1) Excessive activity in neuron A (2) Widespread input from its dendrites triggers too much axonal flow, mediated by voltage-sensitive sodium channels (VSSC) (valproate target) (3) This in turn overly activates voltage-sensitive calcium channels (VSCC) linked to glu (lamotrigine target) (4) Triggering of excessive, chaotic, unpredictable neurotransmission from neuron A to neuron B (5) Seizure activity is then detected by postsynaptic NMDA receptors on neuron B (6) Subsequent excitation of its own VSSC and so on
List drugs used for Grand mal [tonic-clonic] seizures
valproate, lamotrigine, levetiracetam
List drugs used for Petit mal [absence] seizures
ethosuximide, valproic acid
List drugs used for Partial seizures
carbamazepine, lamotrigine, levetiracetam
List drugs used for atypical absence,myoclonic or atonic seizures
valproate, lamotrigine, levetiracetam
List drugs used for Status epilepticus
benzodiazepines: diazepam-lorazepam-midazolam
How are effective drugs identified for tonic-clonic seizures
the maximal electroshock seizure (MES) test
Describe Tonic clonic seizure
• EEG: High amplitude spikes, 15-40 cycles/sec • Loss of postural control; loss of consciousness; tonic phase (rigid extension of trunk and limbs), clonic phase (rhythmic contraction of arms and legs) • Abnormal behavior, confusion continues even after myoclonus
Tonic clonic seizure mechanism
Initiation occurs locally with loss of GABA inhibitory tone, propagation due to decreased GABA tone over large area / increased response to glutamate / Na+-channel excitation
How are effective drugs identified for absence seizures
pentylenetetrazol (PTZ) test
Describe absence seizures
• EEG: 3 cycles/sec • Normal muscle tone; impaired consciousness with staring spells (with or without eye blinks); function normal after seizure
Mechanism of absence seizures
Related to oscillatory stimulation of thalamic-cortical circuitry; inappropriate activation of low-threshold T-type Ca++ channels
Describe simple partial seizure and location in brain
Key feature is preservation of consciousness. Usually of cortical origin in restricted region
Describe complex partial seizure and location in brain
Loss of or impaired consciousness. Psychomotor: Involves limbic as well as temporal / frontal cortex (emotional
Describe secondary general seizure
Loss of consciousness, include other areas/muscle groups.
Mechanism of partial seizures
Mechanism: Involves initiation (rather than propagation) - difficult to treat
Seizure treatment aims to do what? Which method is most effective?
Elevate seizure threshold (by stabilizing membrane) or limit propagation (by reducing synaptic transmission or nerve conduction). Drugs are more effective at limiting propagation (generalized seizures) than in preventing initiation (partial seizures)
List drugs that inhibit sodium channel function
Phenytoin, carbamazepine, lamotrigine
MOA of drugs that inhibit sodium channel function in seizures
Block of sustained high-frequency repetitive firing of APs that can initiate seizure formation. Blockade is use-dependent > block excitation of cells firing repetitively (epileptic foci) leaving low frequency firing neurons (normal) unaffected. Prolongs the inactivated state of the sodium channel and prolongs refractoriness
List drugs that decrease low-threshold Ca (T-type) current in seizures and their use
ethosuximide- reduces the abnormal currents seen in absence seizures
List drugs that enhance GABA action in seizures
benzodiazepines (increase GABA mediated opening of Cl channels), valproate (acts partially in this mechanism)
List drugs that inhibit high-voltage activated Ca channels in seizures
lamotrigine- VSCC (aka N-type) involved in regulation of glutamate neurotransmitter release
List drugs that inhibit function of synaptic vesicle protein SV2A
•Impairs Ca++-mediated neurotransmitter release - levetiracetam
Carbamazepine- MOA, use, pharmacokinetics and side effects
Blocks Na channels. Partial seizure drug of choice, often tried first in tonic clonic. Strong CYP450 inducer. SE: diploplia, ataxia, sedation, GI upset, aplastic anemia, hepatotoxicity
Phenytoin- MOA, use, pharmacokinetics and side effects
Blocks Na channels. Partial and tonic clonic seizures. Strong CYP450 inducer. SE: nystagmus, diplopia, rash, gingibal hyperplasia, osteomalacia long term
Levetiracetam - MOA, use, side effects
Effects Ca channels and disrupts function of SV2A synaptic vesicle protein. 1st line in generalized tonic-clonic. SE: somnolence, asthenia, minimal DDIs
Lamotrigine0 MOA, use, side effects
Effects on VSSCs and VSCCs. 1st line for partial or generalized seizures, better tolerated. SE: diplopia, ataxia, dizziness, rashes, sedation
Ethosuximide- MOA, use, side effects
Inhibits Na channel function via enhancement of slow inactivation without blocking channel directly. Drug of choice in absence seizure. SE: few- DDI with CYP inhibitors, gastric distress, lethargy, dizziness
Valproate- MOA, uses, side effects
some potentiation of GABA function, Limits activity of T-type Ca++-channels. Broad spectrum agent with efficacy against the most common seizure types- first line in tonic clonic, effective against absence but hepatotoxicity prevnets it from being drug of choice. SE: hepatotoxicity, contraindicated in pregnancy
some potentiation of GABA function, Limits activity of T-type Ca++-channels. Broad spectrum agent with efficacy against the most common seizure types- first line in tonic clonic, effective against absence but hepatotoxicity prevnets it from being drug of choice. SE: hepatotoxicity, contraindicated in pregnancy
Clonazepam- MOA, uses, side effects
Enhance GABA Cl− influx to raise action potential threshold and inhibition of T-type Ca++-channels in thalamocortical circuits. Effective in absence seizures. SE: sedation
Diazepam- MOA, uses, side effects
Enhance GABA Cl- influx to raise action potential threshold. Drug of choice for status epilepticus. SE: ineffective after few months, somnolence
Phenobarbitol- Uses
neonatal status epilepticus.
What is status epilepticus
State of recurrent major motor seizures between which patient does not regain consciousness. Mortality of 20-25% - death can occur from respiratory arrest or circulatory collapse
Treatment of status epilepticus
Initial IV diazepam (or larazepam) until seizures stop > then start phenytoin slow infusion > if seizures persist, phenobarbital until stop > if seizures still continue pentobarbital or propofol
Risk of antiseizure meds during pregnancy
Risk to offspring from antiepileptic drugs generally less than risk from maternal seizures during pregnancy
Which antiseizure meds are high risk vs low risk
Valproate and phenobarbital may have highest risk. Carbamazepine, phenytoin, lamotrigine - lower rates
Rules for treating seizures in pregnancy
Monotherapy is preferred, drug levels will be lower during pregnancy due to enhanced metabolic clearance so dose must be adjusted
Which anti seizure meds have risk of Vitamin K deficiency in newborns
•Phenytoin, carbamazepine, and phenobarbital. Recommend Vit K supplementation to mother in final month of pregnancy
