Anticonvulsant Agents

Question 1

What neurotransmitters are affected by a seizure?

Answer 1

1. Enhanced excitatory neurotransmitters = glutamate
2. Deficiency of inhibitory neurotransmitters = GABA

Can spread or propagate abnormal activity.

1. focal epileptogenesis
2. synchronization
3. propagation

Recall that seizures need lots of O2. Too little O2 = ischemia in brain. Seizures beget seizures.

Question 2

Tonic-clonic seizures (grand mal):

Answer 2

30%

Initiation: local loss of GABA inhibitory tone

Propagation: due to decreased GABA tone and increased response to glutamate channel excitation

Valproate is drug of choice. Can also use carbamazepine, phenytoin (these block sodium channels).

Question 3

Absence seizures (petit mal):

Answer 3

10%

In youngins.

Inappropriate activation of low-threshold T-type Ca2_ channels (thalamic-cortical circuitry)

Drug of choice is valproate.

Question 4

Simple partial seizures:

Answer 4

10%

Preserve consciousness

Cortical origin

Drug of choice is carbamazepine

Question 5

Complex partial seizures:

Answer 5

35%

Los/impaired consciousness

Psychomotor: limbic, temporal, frontal cortex (emotional)

Question 6

How do anticonvulsant drugs work?

Answer 6

Try to elevate seizure threshold and stabilize membranes or by limiting propagation.

It’s very hard to prevent initiation, like in partial seizures.

1. Block sodium channels to stop the sustained repetitive firing action potentials. Use dependent.
2. Decrease T-type current (Ca2+ channel for low voltage). Involved in absence (petit mal) seizures.
3. Inhibit N-type current (Ca2+ channel for high voltage).
4. Enhance GABA action (like benzos and phenobarbital)

Question 7

Phenobarbital:

Answer 7

Mainly targets GABA,

Targets
VSCC
GABA
Glutamate

Selectively suppresses firing by enhancing GABA inhibition and antagonizing glutamate excitation.

Classic CYP450 enzyme inducer. Significant drug-drug interactions are possible.

Side effects: sedative, interfere with learning, tolerance can develop

Only for adjunctive role (excessive sedation). Good for partial seizures and tonic-clonic. Good for neonatal status epilepticus.

Question 8

Phenytoin:

Answer 8

Mainly targets ion channels:

Targets:
VSSC

Suppress repetitive action potential, block Na+ channels.

Oral, take with food, there are different formulations.

Strong inducer of P450 enzymes. Also has zero order kinetics.

Side effects: Nystagmus, ataxia, sedation (additive!), rash, gingival hyperplasia, hirsutism

Very effective for partial seizures and tonic-clonic seizure BUT not recommended due to unpredictability and side effects.

Question 9

Carbamazepine:

Answer 9

Mainly targets ion channels:

Targets:
VSSC

Suppress repetitive action potential, block Na+ channels.

Oral absorption

P450 enzyme inducer

Side effects: Diplopia, ataxia, nausea, drowsiness, hyponatremia, hepatotoxicity

For partial seizures.

Question 10

Valproic acid:

Answer 10

Has a mixed action:

Targets:
VSSC,
T-type Ca2+,
GABA

Potentiates GABA function. Limits activity of T-type Ca2+ channels.

Take tablets whole, can take with food. Can have IV or oral.

Few side effects. GI complaints, weight gain, bruising, rarely hepatotoxic, BAD FOR PREGNANCY

Additive with alcohol and CNS depressants, anticonvulsants, aspirin and warfarin.

Drug of choice for tonic-clonic seizures.

Can use for absence seizures

Question 11

Diazepam:

Answer 11

Mainly effects on GABA:

Targets:
GABA

Enhance GABA Cl- influx and suppresses seizures.

Given slow IV.

Additive with phenobarbital for respiratory depression.

Develop tolerance.

Drug of choice for status epilepticus.

Question 12

What is status epilepticus, what to treat it with?

Answer 12

No break between seizures. Can die.

Initial treatment: IV diazepam until seizures stop.

Then give phenytoin.

If seizures persist, IV phenobarbital.

Question 13

If pregnant and have seizures, what to take?

Answer 13

Valproate and phenobarbital have highest risk for malformations.

Use monotherapy to decrease exposure.

Use lower levels. Use vit K supplements.

Question 14

Dental patient with seizures:

Answer 14

Treatment plan to avoid stress and missed meds.

Have an emergency plan.

Drug-drug interactions:

1. Be careful of CNS depressants and anticonvulsant agents
2. Avoid gastic irritants like aspirin and NSAIDs (especially for phenytoin and valproic acid)
3. don’t use valproic acid with NSAIDs - interferes with platelet function.
4. Monitor for gingival hyperplasia if on phenytoin.
5. Check for dry mouth (carbamazepine)