Antiseizure Medications

Question 1

Seizure

Answer 1

: Excessive neuronal discharge characterized as brief, involuntary, episodic

Question 2

Convulsion

Answer 2

Violent involuntary contraction of voluntary muscles

Question 3

Epilepsy

Answer 3

Chronic seizure disorder

Question 4

SZ Epi

Answer 4

8% of population have at least 1 seizure in lifetime

About 0.5-1% have epilepsy (chronic seizures)

80% controlled with standard therapy

500,000 with uncontrolled epilepsy

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 by detected by postsynaptic NMDA receptors on neuron B
(6) Subsequent excitation of its own VSSC and so on

Question 6

Widespread input from its dendrites triggers too much axonal flow, mediated by voltage-sensitive sodium channels (VSSC) (__________ target)

Answer 6

valproate

Question 7

This in turn overly activates voltage-sensitive calcium channels (VSCC) linked to glu (___________ target)

Answer 7

lamotrigine

Question 8

Generalized Seizures
Generalized Tonic-Clonic (Grand mal) [30%]
Mechanism

Answer 8

Initiation occurs locally –> loss of GABA inhibitory tone

Propagation due to ↓ GABA tone over large area plus ↑ response to glutamate and Na+-channel excitation

Question 9

Generalized Absence (Petit mal) [10%]
Mechanism

Answer 9

Oscillatory stimulation of thalamic-cortical circuitry - activation of low-threshold T-type Ca++ channels

ethosuxmide

Question 10

Valproic acid in prego

Answer 10

NO

Question 11

Simple Partial [10%]

Answer 11

Key feature is preservation of consciousness

Usually of cortical origin in restricted region (e.g., Jacksonian motor seizures reflect topographic organization of cortex)

Question 12

Complex Partial [35%]

Answer 12

Loss of or impaired consciousness

Psychomotor: Involves limbic as well as temporal / frontal cortex (emotional)

Question 13

Secondary Generalization

Answer 13

Loss of consciousness, include other areas/muscle groups

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

Question 14

Most difficult to treat?

Answer 14

Generalized

intioition

Question 15

Mechanisms of Antiseizure Drugs Treatment

Answer 15

Elevating seizure threshold –> stabilize membrane

Limiting propagation –> reduce synaptic transmission or nerve conduction

Drugs are more effective in limiting propagation (generalized seizures) than in preventing initiation (partial seizures)

Question 16

Status Epilepticus

Answer 16

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 17

Status Epilepticus

Treatment Options:

Answer 17

Initial therapy IV diazepam (lorazepam or midazolam) until seizures stop or 20 mg given

Then start phenytoin or fosphenytoin slow infusion

If seizures persist IV phenobarbital until seizures stop

If seizures still continue, pentobarbital or propofol infusion with pressor support

Question 18

Prego

Answer 18

NOTE: Risk to offspring from antiepileptic drugs generally less than risk from maternal seizures during pregnancy
Risk of birth defects 2-3-fold higher if mother on AEDs
• Cleft palates, skeletal abnormalities, CNS-cardiac problems
• Most (> 90%) deliver normal babies
Difficult to separate medication effect from disease effect, but probably medication
• Valproate and phenobarbital may have highest risk
• Carbamazepine, phenytoin, lamotrigine - lower rates
• Newer agents with low rates include levetiracetam, gabapentin, oxcarbazepine

Monotherapy preferred
• Decreases fetal exposure  minimizes teratogenicity
• Incidence highest with multidrug therapy
Drug levels generally lower during pregnancy
• Enhanced metabolic clearance
• Altered protein binding
• Adjust dosage accordingly, especially for lamotrigine
Vitamin K deficiency and hemorrhage in newborn
• Phenytoin, carbamazepine, and phenobarbital
• Recommend vitamin K supplementation to mother in final month of pregnancy and for the newborn