antiseizure meds

Question 1

Compare seizure vs convulsion

Answer 1

• Seizure: Excessive neuronal discharge characterized as brief, involuntary, episodic • Convulsion: Violent involuntary contraction of voluntary muscles

Question 2

Mechanisms of seizures

Answer 2

• 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

Question 3

Steps in seizure

Answer 3

focal epileptogenesis, synchronization and propagation

Question 4

Seizure consequences

Answer 4

increased oxygen demand > ischemia > subsequent brain damage > “Seizures beget seizures”

Question 5

Model for Unstable - Excessive Neurotransmission Seizures

Answer 5

(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

Question 6

List drugs used for Grand mal [tonic-clonic] seizures

Answer 6

valproate, lamotrigine, levetiracetam

Question 7

List drugs used for Petit mal [absence] seizures

Answer 7

ethosuximide, valproic acid

Question 8

List drugs used for Partial seizures

Answer 8

carbamazepine, lamotrigine, levetiracetam

Question 9

List drugs used for atypical absence,myoclonic or atonic seizures

Answer 9

valproate, lamotrigine, levetiracetam

Question 10

List drugs used for Status epilepticus

Answer 10

benzodiazepines: diazepam-lorazepam-midazolam

Question 11

How are effective drugs identified for tonic-clonic seizures

Answer 11

the maximal electroshock seizure (MES) test

Question 12

Describe Tonic clonic seizure

Answer 12

• 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

Question 13

Tonic clonic seizure mechanism

Answer 13

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

Question 14

How are effective drugs identified for absence seizures

Answer 14

pentylenetetrazol (PTZ) test

Question 15

Describe absence seizures

Answer 15

• EEG: 3 cycles/sec • Normal muscle tone; impaired consciousness with staring spells (with or without eye blinks); function normal after seizure

Question 16

Mechanism of absence seizures

Answer 16

Related to oscillatory stimulation of thalamic-cortical circuitry; inappropriate activation of low-threshold T-type Ca++ channels

Question 17

Describe simple partial seizure and location in brain

Answer 17

Key feature is preservation of consciousness. Usually of cortical origin in restricted region

Question 18

Describe complex partial seizure and location in brain

Answer 18

Loss of or impaired consciousness. Psychomotor: Involves limbic as well as temporal / frontal cortex (emotional

Question 19

Describe secondary general seizure

Answer 19

Loss of consciousness, include other areas/muscle groups.

Question 20

Mechanism of partial seizures

Answer 20

Mechanism: Involves initiation (rather than propagation) - difficult to treat

Question 21

Seizure treatment aims to do what? Which method is most effective?

Answer 21

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)

Question 22

List drugs that inhibit sodium channel function

Answer 22

Phenytoin, carbamazepine, lamotrigine

Question 23

MOA of drugs that inhibit sodium channel function in seizures

Answer 23

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

Question 24

List drugs that decrease low-threshold Ca (T-type) current in seizures and their use

Answer 24

ethosuximide- reduces the abnormal currents seen in absence seizures

Question 25

List drugs that enhance GABA action in seizures

Answer 25

benzodiazepines (increase GABA mediated opening of Cl channels), valproate (acts partially in this mechanism)

Question 26

List drugs that inhibit high-voltage activated Ca channels in seizures

Answer 26

lamotrigine- VSCC (aka N-type) involved in regulation of glutamate neurotransmitter release

Question 27

List drugs that inhibit function of synaptic vesicle protein SV2A

Answer 27

•Impairs Ca++-mediated neurotransmitter release - levetiracetam

Question 28

Carbamazepine- MOA, use, pharmacokinetics and side effects

Answer 28

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

Question 29

Phenytoin- MOA, use, pharmacokinetics and side effects

Answer 29

Blocks Na channels. Partial and tonic clonic seizures. Strong CYP450 inducer. SE: nystagmus, diplopia, rash, gingibal hyperplasia, osteomalacia long term

Question 30

Levetiracetam - MOA, use, side effects

Answer 30

Effects Ca channels and disrupts function of SV2A synaptic vesicle protein. 1st line in generalized tonic-clonic. SE: somnolence, asthenia, minimal DDIs

Question 31

Lamotrigine0 MOA, use, side effects

Answer 31

Effects on VSSCs and VSCCs. 1st line for partial or generalized seizures, better tolerated. SE: diplopia, ataxia, dizziness, rashes, sedation

Question 32

Ethosuximide- MOA, use, side effects

Answer 32

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

Question 33

Valproate- MOA, uses, side effects

Answer 33

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

Question 34

Clonazepam- MOA, uses, side effects

Answer 34

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

Question 35

Diazepam- MOA, uses, side effects

Answer 35

Enhance GABA Cl- influx to raise action potential threshold. Drug of choice for status epilepticus. SE: ineffective after few months, somnolence

Question 36

Phenobarbitol- Uses

Answer 36

neonatal status epilepticus.

Question 37

What is status epilepticus

Answer 37

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

Question 38

Treatment of status epilepticus

Answer 38

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

Question 39

Risk of antiseizure meds during pregnancy

Answer 39

Risk to offspring from antiepileptic drugs generally less than risk from maternal seizures during pregnancy

Question 40

Which antiseizure meds are high risk vs low risk

Answer 40

Valproate and phenobarbital may have highest risk. Carbamazepine, phenytoin, lamotrigine - lower rates

Question 41

Rules for treating seizures in pregnancy

Answer 41

Monotherapy is preferred, drug levels will be lower during pregnancy due to enhanced metabolic clearance so dose must be adjusted

Question 42

Which anti seizure meds have risk of Vitamin K deficiency in newborns

Answer 42

•Phenytoin, carbamazepine, and phenobarbital. Recommend Vit K supplementation to mother in final month of pregnancy