antiseizure pharm

Question 1

1. Relate the postulated mechanisms underlying seizure pathophysiology for simple and complex partial, absence, tonic-clonic, and status epilepticus seizure disorders to the mechanisms of actions of the drugs of choice for their treatment. Focus on neurotransmitter systems and ion channels as drug targets.

Answer 1

➢ Grand Mal Seizures: Propagation carried out through
• DECREASE in GABA tone
• INCREASE in response to Glutamate
• INCREASE in sodium channel conduction
o Most drugs BLOCK the Na+ channels that propagate the spread throughout the brain in a use-dependent manner
• This use-dependence is important because when a seizure is not occurring, these drugs will have little effect on the brain
➢ Petit Mal Seizures: Related to strong coupling and oscillatory stimulation of thalamic and cortical neurons
• Generated by activation of low threshold-T type Ca++ channels (depolarization)

Simple Partial [10%]

• preservation of consciousness
• cortical origin in restricted region

Complex Partial [35%]
-Loss of or impaired consciousness

Secondary Generalization

• Loss of consciousness, include other areas/muscle groups
• Mechanism: Involves initiation (rather than propagation) - *difficult to treat

Question 2

2. List drugs of choice for the following seizure types: partial

Answer 2

(carbamazepine, lamotrigine, levetiracetam),

Question 3

what is drug choice for grand mal/tonic clonic

Answer 3

(valproate, lamotrigine, levetiracetam)

Question 4

what is drug choice for petit mal [absence]

Answer 4

(ethosuximide, valproic acid)

Question 5

what is drug choice forstatus epilepticus

Answer 5

(benzodiazepines: diazepam-lorazepam-midazolam)

Question 6

carbamazepine

Answer 6

drug of choice for partial seizures
Strong inducer of CYP450 
S/E
-Diplopia-ataxia-sedation  dose-related
-GI upset
-Rare but serious
-Aplastic anemia-agranulocytosis  monitor CBC
-Hepatotoxicity  monitor liver function tests

Question 7

lamotrigine

Answer 7

Mechanism- Effects on VSSCs (suppress repetitive APs) and VSCCs ( Glu release) - broad spectrum

1st line for partial or generalized seizures - better tolerated than phenytoin or carbamazepine

ADRs
Similar to phenytoin (lower incidence): diplopia, ataxia, dizziness, skin rashes, sedation

Question 8

levetiracetam (Keppra)

Answer 8

Mechanism - Efficacy
Precise mechanism unknown - affects Ca++ channels
1st line in treatment of generalized tonic-clonic seizures

ADRs
Somnolence, asthenia, dizziness
Low incidence of cognitive effects

Question 9

valproate

Answer 9

Broad spectrum agent with efficacy against the most common seizure types
Inhibits metabolism of other AEDs: phenytoin, lamotrigine, carbamazepine, phenobarbital, ethosuximide

Adverse Drug Reactions
Dose-related GI upset (nausea-vomiting, pain)
Weight gain common
Black Box Warnings
-Hepatic failure  deaths [increased risk

Question 10

levetiracetam

Answer 10

Inhibits function of synaptic vesicle protein SV2A

Impairs Ca++-mediated neurotransmitter release - levetiracetam

Question 11

ethosuximide

Answer 11

Decrease in low-threshold Ca++ (T-type) current
block abnormal Oscillatory currents in thalamic neurons in absence seizures
Drug of choice in absence seizures

Adverse Drug Reactions – generally few side effects
Dose-related gastric distress most common (nausea-vomiting, pain)
Less common: transient lethargy-fatigue, dizziness, headache

Question 12

Phenobarbital

Answer 12

Neonatal status epilepticus
Adjunct for partial and tonic-clonic seizures

Metabolized slowly by P450 system - t1/2 of 4-5 days
Classic enzyme inducer

Adverse Drug Reactions
Irritability - overactivity in many children, sedative effects in others
Mild ataxia, nystagmus, skin rash, osteomalacia
May interfere with learning (cognitive deficits)

Question 13

benzodiazepines (diazepam-lorazepam-midazolam)

Answer 13

Clonazepam (Klonopin)
Effective against absence seizures plus difficult cases: myoclonic seizures, infantile spasms, atonic seizures
ADRs: Sedation (> 50%), behavioral problems (25%)

Diazepam (Valium)
Drug of choice for status epilepticus [lorazepam (Ativan) and midazolam (Versed) also used]

Adjunctive therapy in atonic and absence seizures and infantile spasms
Ineffective after a few months (tolerance development)
ADRs: Somnolence - tolerance are limiting factors in chronic use

Question 14

Which anticonvulsant drug is INCORRECTLY matched with its mechanism of action?

Valproic acid  enhancement of GABA activity
Levetiracetam  block of Ca++-mediated release of glutamate activity
Carbamazepine  enhancement of GABA activity
Phenytoin  block of VSSC  suppress repetitive action potential
Ethosuximide  block of T-type Ca++ channels in thalamocortical pathways
Diazepam  block of VSSC  suppress repetitive action potential

Answer 14

Diazepam  block of VSSC  suppress repetitive action potential
Carbamazepine  enhancement of GABA activity

Question 15

Patients should be carefully monitored for gingival hyperplasia if they are taking:

Clozapine (Clozaril)
Alprazolam (Xanax)
Carbamazepine (Tegretol)
Phenytoin (Dilantin )
Valproic acid (Depakote)
Zolpidem (Ambien)
Phenelzine (Nardil)

Answer 15

Phenytoin (Dilantin)

Question 16

Phenytoin

Answer 16

Very effective against partial and tonic-clonic seizures
IM absorption erratic (better with prodrug Fosphenytoin)
Strong inducer of CYP450 enzymes
Adverse Drug Reactions
-Nystagmus-diplopia-ataxia-sedation  dose-related
-Rash; gingival hyperplasia-hirsutism develop gradually
-Long-term use  osteomalacia, peripheral neuropathy

Question 17

Which of the following anticonvulsive agents does NOT result in additive CNS depression (increased somnolence) when given with opioid analgesics?

Phenytoin (Dilantin)
Carbamazepine (Tegretol)
Phenobarbital (Luminal)
Diazepam (Valium)
Levetiracetam (Keppra)
All of the above will produce additive CNS depression

Answer 17

all of the above

Question 18

how to treat status epilepticus

Answer 18

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

Treatment Options:
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 19

is risk to offsrping from AED more or less than risk from maternal seizures?

Answer 19

less than

Question 20

what are the two drugs with highest risk during pregnancy

Answer 20

phenobarbital, valproate

Question 21

which drugs cause vit k deficiency and hemmorhage in newborns

Answer 21

phenytoin, carbamazepine, phenobarbital

Question 22

Of the currently available anticonvulsant agents listed below, which is the preferred agent for the initial treatment of status epilepticus or local anesthetic-induced seizures?

Carbamazepine (Tegretol)
Diazepam (Valium )
Ethosuximide (Zarontin)
Phenobarbital (Luminal)
Phenytoin (Dilantin)
Valproic acid (Depakote)
Midazolam (Versed )

Answer 22

Diazepam (Valium )

Midazolam (Versed )