Anti-seizure Drugs

Question 1

In general, the activity of which neurotransmitters should be decreased or increased to reduce the incidence of seizures in a patient?

Answer 1

Glutamate should be reduced and GABA should be increased.

Question 2

What are the three stages of a seizure?

Answer 2

FOCAL EPILEPTOGENESIS: caused by an unstable neuronal membrane. SYNCHRONIZATION: paroxysmal discharges can recruit and synchronize a large population of cortical or thalamic neurons. PROPAGATION: the spread of abnormal discharges through large numbers of other neurons.

Question 3

What is the mechanism of Tonic-clonic seizures and how does it relate to the treatment strategy?

Answer 3

Initiation occurs locally with loss of GABA inhibitory tone, propagation due to decreased GABA tone over large area/Increased response to Glu/Na+ channel excitation.
Treatment should increase GABA tone, thus Valproic Acid which seems to increase GABA. Also Lamotrigine and Levetiracetam

Question 4

What is the mechanism of Absence seizures and how does it relate to the treatment strategy?

Answer 4

Mechanism is related to oscillatory stimulation of thalamic-cortical circuitry and inappropriate activation of low threshold T-type Ca++ channels. Treatment should decrease Ca++ current at T-type channels, thus Valproic Acid and Ethosuximide.

Question 5

What is the mechanism of Partial seizures and how does it relate to the treatment strategy?

Answer 5

Mechanism involves the initiation phase and is therefor more difficult to treat. Treatments include Carbamazepine which blocks Na+ channels and suppressed repetitive APs, Lamotrigine which may also block repetitive APs, or Levetiracetam.

Question 6

What is the mechanism of status epilepticus seizures and how does it relate to the treatment strategy?

Answer 6

Status epilepticus is the state of recurrent major motor seizures between which patient does not regain consciousness. Initial treatment is lorazepam/diazepam to halt seizures (raises GABA induced Cl- current, raises AP threshold, suppresses seizure focus), then phenytoin/fosphenytoin (blocks Na+ channels

Question 7

What are the drugs of choice for Tonic-clonic (Grand Mal) seizures?

Answer 7

Valproate, Lamotrigine, Levetiracetam

Question 8

What are the drugs of choice for Partial (simple or complex) seizures?

Answer 8

Carbamazepine, Lamotrigine, Levetiracetam

Question 9

What are the drugs of choice for Absence (Petit mal) seizures?

Answer 9

Ethosuximide, Valproate

Question 10

What are the drugs of choice for Status Epilepticus?

Answer 10

Benzodiazepines: diazepam, lorazepam, midazolam

Question 11

What are the four general MOA of anti-seizure medications?

Answer 11

Inhibition of sodium channel function; Decrease low-threshold (T-type) Ca++ current; Inhibition of high-voltage activated (N-type or VSCC) Ca++ channels, Enhancement of GABA action.

Question 12

What does inhibition of sodium channels achieve and which drugs accomplish this?

Answer 12

This blocks the sustained, repetitive firing of APs that can initiate seizures. Blockade is use dependent (like local anesthetics) so seizing neurons are preferentially targeted. Phenytoin, carbamazepine, Lamotrigine, and Topiramate block VSSC.

Question 13

What does decreasing the low-threshold T-type Ca++ current achieve and which drugs accomplish this?

Answer 13

Abnormal T-type currents are involved in Absence seizures (corticothalamic circuit). These are blocked by ethosuximide and valproate.

Question 14

What does inhibition of high-voltage (VSCC/N-type) Ca++ current achieve and which drugs accomplish this?

Answer 14

VSCC channels are involved in regulation of neurotransmitter release. Lamotrigine and Levetiracetam

Question 15

What does enhancement of GABA action achieve and which drugs accomplish this?

Answer 15

Enhancement of GABA inhibits overall neuronal activity.
Benzodiazepines and phenobarbital facilitate the opening of GABA Cl- channels.
Vigabatrin inhibits inactivation of GABA by transaminase.
Tiagabine blocks reuptake of GABA at the synapse.
Gabapentin increases GABA levels in the brain.

Question 16

What is the MOA (cellular target), distinctive side effects, and pregnancy safety of Carbamazepine?

Answer 16

Blocks VS Na+ Channels, suppressing repetitive AP generation.
Drug of choice for partial seizures and tonic clonic
Strong P450 enzyme inducer
Adverse effects: diplopia, ataxia, N/V, drowsiness, hyponatremia, Stevens-Johnson syndrome
Blood dyscrasias, agranulocytosis, hepatotoxicity,

Question 17

What is the MOA (cellular target), distinctive side effects, and pregnancy safety of Phenytoin?

Answer 17

Blocks VS Na+ Channels, suppressing repetitive AP generation.
Used for partial seizures and tonic-clonic, but falling out of favor.
Strong P450 inducer
Adverse effects: nystagmus, diplopia, ataxia, sedation (at higher doses or in combination with other drugs), rash, gingival hyperplasia

Question 18

What is the MOA (cellular target), distinctive side effects, and pregnancy safety of Levetiracetam?

Answer 18

Binds to and disrupts SV2A protein on Ca++ channels, otherwise mechanism is unknown.
First line drug for Tonic-clonic
Minimal DDI
Adverse effects: Somnolence, dizziness, 
Pregnancy: Lower rates of birth defects

Question 19

What is the MOA (cellular target), distinctive side effects, and pregnancy safety of Lamotrigine?

Answer 19

Mechanism is unclear
Used for partial or generalized seizures
DDI: increased 2 fold by valproate
Adverse effects: similar to phenytoin, dizziness, ataxia, diplopia, sedation.
Pregnancy: adjust dose to match higher rate of clearance

Question 20

What is the MOA (cellular target), distinctive side effects, and pregnancy safety of Topiramate?

Answer 20

Blocks Na+ channels (similar to phenytoin)
Used for Partial seizures, adjunctive therapy
Adverse effects: dizziness, somnolence, psychomotor slowing, impaired concentration, interference with memory,
Pregnancy: Do not use