Anticonvulsants

Question 1

anticonvulsant possible MOAs

Answer 1

• enhancement of inhibition (GABA)
• inhibition of excitation (glutamate or aspartate)
• modulation of voltage-dependent ion channels in propagating AP

all SLOW NT transmission

Question 2

Anticonvulsants: Na channel blockers

Answer 2

• phenytoin

- carbamazepine (and oxcarbazepine)

Question 3

Anticonvulsants: Ca channel blockers

Answer 3

• ethosuximide

- gabapentin

Question 4

Anticonvulsants: GABA modulators

Answer 4

• benzodiazepines (diazepam, lorazepam, midazolam)

- barbiturates (phenobarbital)

Question 5

Anticonvulsants: “other”

Answer 5

valproic acid
lamotrigine
levetiracetam

Question 6

main toxicities of anticonvulsants

Answer 6

CNS (simple sedation to ataxia)
GI (nausea, vomiting, diarrhea)
Dermatologic (rash)
Bone marrow suppression

Drug interactions (possibly CYP450)
Dose titration
Suicide
Pregnancy

Question 7

Phenytoin
MOA?
Side effects?

Answer 7

-binds to voltage-dependent Na channels

-Zero-order kinetics (elimination is by a set amount/unit time, clearance system can be saturated.)
^monitor plasma levels

-CYP450 clearance

Side effects:

• gingival hyperplasia
• hirsutism (female w/ male hair pattern)
• reduced folate levels

Question 8

Carbamazepine
MOA?
Side effects?

Answer 8

• binds to voltage-dependent Na channels
• CYP450 clearance

Side effects:

• CNS (drowsy, dizzy, ataxia, nystagmus)
• GI (nausea, vomiting, diarrhea)
• RASHES (asian)
• Hyponatremia (ADH release)
• BONE MARROW SUPPRESSION (agranulocytosis)
• monitor plasma levels
• monitor active metabolite (10,11 epoxide)

Question 9

ethosuximide
MOA?
Side effects?

Answer 9

• interferes w/ T-type Ca channels
• used for absence seizures

Side effects:
-sleep disturbances, nausea, vomiting

Question 10

benzodiazepines

Answer 10

GABA facilitators. Increase frequency of Cl- channel opening only w/ GABA present –> CNS depression

Side effects:
sedation, cognitive impairment, ataxia

Question 11

barbiturates

Answer 11

Increase duration of Cl- channel opening, don’t need GABA present –> CNS depression

higher risk of OD

Question 12

T/F benzo-like drugs (zolpidem, zalepon, eszopiclone) are used as anticonvulsants.

Answer 12

FALSE.

Used for sleep.

Question 13

possible mechanisms of GABA modulating meds

Answer 13

• mimic GABA/improve effects (benzos/barbs)
• reduce reuptake into neurons/glia
• inc GABA production
• reduce GABA metabolism (valproic acid)

Question 14

valproic acid

MOA?

Answer 14

• interferes w/ Na channels
• blocks T-type Ca channels
• increases GABA levels (inhibits breakdown)

Question 15

valproic acid
Clearance?
Side effects?

Answer 15

-CYP450 clearance

Side effects:

• weight gain
• HEPATOTOXICITY, PANCREATITIS, thrombocytopenia
• NEURAL TUBE DEFECTS
• monitor plasma levels
• LFTs

Question 16

Gabapentin
MOA?
Side effects?

Answer 16

• interferes w/ P/Q type Ca channels
• RENAL clearance (few drug interactions)
• well-tolerated but INFREQUENTLY USED FOR SEIZURES bc not as efficacious

Question 17

lamotrigine
MOA?
Side effects?

Answer 17

• interferes w/ Na channels
• more direct interference w/ glutamate and aspartate (drug binds to postsynaptic AMPA receptors)
• prominent CNS side effects, some GI
• RASHES –> risk of Stevens-Johnson Syndrome (slow taper introduction reduces risk)
• linear kinetics, well-tolerated (don’t need to monitor)

Question 18

levetiracetam

MOA?

Answer 18

• suppresses synaptic vesicle protein SV2A
• -> reduce release of excitatory NT –> CNS depression
• FREQUENTLY USED for seizures
• good oral bioavailibility
• RENAL clearance
• well-tolerated, good efficacy

(looks like gabapentin, but more efficacious)

Question 19

therapeutic considerations for anticonvulsants

Answer 19

• dose titration to therapeutic effect (slowly introduce, don’t want to intro seizure)
• monitor plasma levels
• monotherapy preferred (max dose of drug first. stop drop before moving on to next)

Question 20

anticonvulsants:

common themes for OLDER agents

Answer 20

• phenytoin
• carbamazepine
• valproic acid
• phenobarbital
• narrow therapeutic margins
• HEPATIC metabolism/protein binding
• drug interactions
• good experience

Question 21

anticonvulsants:

common themes for NEWER agents

Answer 21

• gabapentin
• lamotrigine
• levetiracetam
• wider therapeutic margins
• RENAL clearance
• few drug interactions
• improved tolerability
• narrow indications

Question 22

Pt on lamotrigine presents w/ rash on most of upper trunk and arms. What do you do?

Answer 22

Even if mild rash, discontinue lamotrigine b/c rash can progress in unpredictable manner.

Question 23

Tx for status epilepticus seizures

Answer 23

BENZOS (via IV)

diazepam, lorazepam, midazolam

Question 24

If unsure of seizure type, which tx?

Answer 24

Valproic acid (multiple mechanisms)

Question 25

Despite good efficacy of benzos for partial or generalized tonic-clonic seizures, why are these drugs not usually used?

Answer 25

They would work but would cause tolerance (would need higher and higher doses)

Question 26

Oxcarbazepine

Answer 26

carbamazepine derivative

less side effects compared to carbamazepine, doesn’t get metabolized to 10,11-epoxide