Anti-Epileptic Drugs (Week 5--DeGiorgio)

Question 1

First choice treatment for epilipsy

Answer 1

Anti-epileptic drugs (AEDs)

Chosen based on type of epilepsy, efficacy, side effect profile, risk or allergy and birth defects

60% become seizure free with first drug

Response rates decline with repeated trials of AEDs

Question 2

How many people develop drug resistant epilepsy?

Answer 2

30-40%

Question 3

Partial onset seizures

Answer 3

Simple partial

Complex partial

Partial with secondary generalization

Question 4

Primary generalized seizures

Answer 4

Absence (petit mal)

Myoclonic

Generalized tonic-clonic

Question 5

Antiepileptic drugs for partial onset seizures

Answer 5

Carbamazepine

Phenytoin

Valproate

New generation: lamotrigine, topiramate, levetiracetam, pregabalin, lacosamide, potiga

Question 6

Antiepileptic drugs for primary generalized seizures

Answer 6

Ethosuccimide

Valproate

New generation: topiramata, lamotrigine, ONFI (for drop attacks)

Question 7

Drugs that act on the Na channel

Answer 7

Phenytoin

Carbamazepine

Oxcarbazepine

Lamotrigine

Lacosamide (Vimpat)

Mechanism: promote closure of ball and chain of Na+ channel; except lacosamide which squeezes Na+ channel so can’t depolarize!

Question 8

Phenytoin

Answer 8

Blocks Na channels

Non-linear kinetics, 24h half-life, dose is 5/kg and therapeutic range is 10-20 ug/ml; high doses cause ataxia and nystagmus; metabolized by CYP2C and induces CYP metabolized drugs (activates the CYP so can lower level of other drugs)

Side effects: imbalance, nystagmus, depression, gingival hyperplasia, rash up to 10%, induces vitamin D (causes low vitamin D levels), hepatitis rarely, birth defects (pregnancy class D)

Question 9

Carbamazepine

Answer 9

Gold standard

Blocks Na+ channels

8-12h half life, metabolized by CYP

Side effects: double vision, ataxia, rash 5-10%, frequent low Na+, rare marrow suppression, rare hepatitis, fetal malformations pregnancy class D

Start at 200mg once a day

Question 10

Lamotrigine

Answer 10

For either partial seizures or primary generalized seizures

24h half life, hepatic metabolism, major drug interactions with valproate (CYP inhibitor)

10% risk of rash, pregnancy class C (lower risk than other AEDs)–use this for women who want to get preggers!

Start 25 mg/day then titrate slowly to 300-500 mg/day

Question 11

Where do phenytoin, carbamazepine and lamotrigine bind?

Answer 11

Common receptor on extracellular side of Na+ channel

Question 12

Drugs acting on Cl- channel

Answer 12

Benzodiazepines bind specific receptors on Cl- channel to cause it to open (and hyperpolarize)

Phenobarbital binds barbituate specific receptor at different site of Cl- channel to cause it to open (and hyperpolarize)

Valproate decreases GABA degradation in presynaptic terminal so more GABA to bind GABA-binding site on Cl- channel to cause it to open (and hyperpolarize)

Question 13

Valproate

Answer 13

For primary generalized seizures

Broad spectrum, increases GABA by inhibiting degradation in presynaptic terminal

Starting dose is 15-20 mg/kg

Side effects: GI, tremor, elevates ammonia, neural tube defects in fetus (“pregnancy class DD” because so bad), obesity (makes you fat!)

Question 14

Drugs that affect Ca2+ channels

Answer 14

Gabapentin

Pregabalin

Question 15

Side effects of gabapentin and pregabalin (affect Ca2+ channels)

Answer 15

Low risk of rash, obesity, imbalance, sedation

Pregnancy class C

(Renal metabolism)

Question 16

Drugs that affect Na+, AMPA, kainate and Ca2+ channels

Answer 16

Topiramate

Zonisamide

Note: both of these “zone you out”

Question 17

Topiramate

Answer 17

Multiple mechanisms

Effective against both partial and generalized epilepsy

Minimal hepatic metabolism

Start at 25 mg/day and titrate to 300-500 mg/day

Disadvantages: behavioral and cognitive problems

Advantages: high potency, rash is rare, weight loss

Pregnancy class C

Question 18

Drugs that affect synaptic vesicle protein

Answer 18

Levetiracetam

Question 19

Levetiracetam

Answer 19

SV2A overexpressed by epileptic neurons but levetiracetam binds SV2A vesicle protein to reduce excitability

Broad spectrum, renal metabolism/clearance, rapid Tm, high effectiveness

Side effects except: insomnia, headache, fatigue, depression and psychosis (in 8-10% of people)

Question 20

Ethosuccimide

Answer 20

Used in children with absence seizures (petit mal)

Blocks inward Ca2+ currents in thalamic neurons

Long half life

Side effects: nausea, vomiting, drug-induced SLE

Question 21

Retigabine (Potiga)

Answer 21

Newest drug

For partial seizures

Binds and activates K+ channels to hyperpolarize neurons and reduce excitability

Question 22

EEG pattern for partial vs. generalized seizure

Answer 22

Partial seizure: spike

Generalized seizure: spike and wave

Question 23

Paroxysmal depolarizing shift

Answer 23

Hundreds/thousands of neurons depolarizing at same time

Origin of an epileptic discharge?

Question 24

Effects of Na+ blocker on the paroxysmal depolarizings shift (PDS)

Answer 24

Prevents the standard electrical signature of epileptic neuron by blocking repetitive action

Reduce number of repetitive action potentials

However, still have some excitability

Question 25

Where is the most common place for a complex seizure (partial onset seizure)?

Answer 25

Temporal lobe

Then, frontal lobe

Question 26

Petit mal vs. complex partial seizure

Answer 26

Petit mal seizure (absence seizure) comes on quickly and ends quickly and has no confusion afterward

Complex partial seizure has post-ictal confusion