CNS Anti-Seizure Drugs - Kelly 6

Question 1

Seizures

Answer 1

Episodes of abnormal electrical activity in the brain that cause involuntary movements, sensations or thoughts
May result from head trauma, broke, brain tumours, hypoxia, fever, brain infections and other conditions
Caused by synchronous neuronal discharged within seizure focus point, may spread

Question 2

Epilepsy

Answer 2

Recurrent seizures that cannot be attributed to any proximal cause

Question 3

Partial seizures

Answer 3

Focal

Question 4

Generalized seizures

Answer 4

Spread

Question 5

Cellular mechanisms of seizure generation

Answer 5

Excitation: ionic inward Na and Ca currents, Glutamate
Inhibition: ionic inward Cl and outward K, GABA

Question 6

Mechanisms of anti-epileptic drugs

Answer 6

1. Block ion channels
2. Augment action of GABAergic neurotransmission
3. Diminish action of excitatory glutaminergic transmission

Question 7

Drugs that block Na channels

Answer 7

Voltage-sensitive Na channels rapidly open when membrane reaches threshold
Rapid depolarization, and NT release
Prolong inactivation state of the Na channel and increase the refractory period of the neutron
Have most effect on neurons that are firing repetitively and less effect on normal neurotransmission
Phenytoin, carbamazepine, valproic acid

Question 8

Phenytoin

Answer 8

Used to treat tonic clonic seizures and partial seizures
Reduces sustained high frequency neon firing by binding to inactivated Na channels
Effects Ca channel
Inhibits the release of NT
Decreases release of glutamate and increases GABA
Variable bioavailability (first pass effect)
Elimination kinetics shift from first order to zero order at moderate to high doses
At higher concentrations, small changes in dose can produce larger changes in phenytoin concentrations

Question 9

Carbamazepine

Answer 9

Prevent opening of Na channels
Closely related in structure of tricyclic antidepressants
Reduces high frequency neuronal firing
Used to treat tonic-clonic and partial seizures

Question 10

Drugs that block Ca channels

Answer 10

T-Type Ca channels in thalamic neurons blocks the rhythmic cortical discharge observed in absence seizures

Question 11

Absence seizure

Answer 11

Caused by self-sustained cycle of activity generated between thalamic and cortical cells
Treated by ethosuximde and valproic acid which book T-Type Ca channels

Question 12

Benzodiazepines

Answer 12

Enhance GABA activation of the GABA-chloride ionophore
Bind to different sites on the ionophore, facilitating GABA binding and increased frequency/duration of channel opening
Leads to hyper polarization and counteracts the depolarization effect of excitatory neurotransmission

Question 13

Barbiturates

Answer 13

Bind to GABA receptors on allosteric site
Prolong GABA-mediated Cl channel openings
Potentiate GABA actions at GABA receptors at low concentrations
Have direct agonist actions at higher concentrations
Some blockade of VD Na channels

Question 14

Clonazepam

Answer 14

BZ used in treatment of absence seizures and mythic seizures

Question 15

Diazepam

Answer 15

BZ

Used intravenous for Status epilepticus

Question 16

GABA transaminase

Answer 16

Terminates actions of GABA
Inhibition of GABA transaminase increases levels of GABA
Blockade og GABA transporters in neurons and glia increases levels of GABA in the synaptic cleft

Question 17

Diminish action of excitatory glutaminergic transmission

Answer 17

Block NMDA or AMPA receptors

Question 18

Topiramate

Answer 18

Blocks voltage-dependent Na channels at high firing frequencies
Antagonizes glutamate action at AMPA/kainate receptor subtype

Question 19

Felbamate

Answer 19

Blocks voltage dependent Na channels at high firing frequencies
Modulates NMDA receptor
Depolarization that allows receptor to be activated

Question 20

Toxicity

Answer 20

Most AEDs are CNS depressants and at high doses, respiratory depression may occur
May be additive with other CNS depressants
Teratogenicity

Question 21

Teratogenicity

Answer 21

Valproic acid associated neural tube defects
Carbamazepine associated craniofacial abnormalities and spina bifida
Phenytoin associated fetal hydrantoin syndrome