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Flashcards in Ph- Epilepsy Deck (59):
1

What 4 antiepileptics are Na channel inhibitors?

1. phenytoin
2. valproic acid
3. carbamazepine
4. lamotrigine

2

What 5 antiepileptic drugs are used as enhancers of GABAa signaling?

1. phenobarbital
2. clonazepam
3. diazepam
4. lorazepam
5. tiagabine

[also gabapentin- it is mixed action]

3

What antiepileptic drug is used at a T-type Ca channel inhibitor?

ethosuximide

4

What is the difference between a seizure and epilepsy?

Seizure is a transient alteration in behavior due to uncontrolled, hyperexcitable neuron firing. They can be provoked by chemical agents, hypoglycemia, hyponatremia in a normal individual.

Epilepsy is a disorder with periodic and unpredictable episodes of seizure activity. The seizures are UNPROVOKED and are due to an underlying cellular defect

5

What is the difference between a partial and generalized seizure?

Partial - begins focally at one site in the brain [although they may subsequently generalize]

Generalized- begin with wide involvement of the brain including BOTH hemispheres

6

What is the difference between a simple partial seizure and a complex partial seizure?
Where do most complex partial seizures originate?

Simple partial = no loss of consciousness
Complex partial = some impairment of consciousness

Most complex partial occur in the temporal lobe due to a decreased threshold for seizure activity

7

The etiology of most partial seizures is what?
What is the etiology for most generalized seizures?

Partial are frequently due to a lesion in the cortex:
1. tumor
2. developmental malformation
3. trauma
4. stroke

Generalized are thought to have a mutligenic, complex genetic origin

8

What are some well known triggers for partial and generalized seizure activity?

1. emotional distress
2. sleep deprivation
3. drowsiness
4. withdraw from alcohol, anti-seizure, sedative drugs

9

What is a powerful activator of petit mal absence seizures?

Hyperventilation

10

What is status epilepticus?

recurrent seizure activity is so frequent that there is no discernable interictal period.

Generalized convulsive form produces minutes of repeating seizures w/o regaining consciousness that can be life threatening

11

How does a seizure manifest of EEG?

train of brief, high amplitude electrical signals that rhythmically continue through the ictal period.

Evolution in frequency, distribution, morphology

12

Although the exact mechanism has not been discerned, what do we think seizure activity is associated with physiologically?

High-frequency firing of action potentials by single central neurons that is propagated through synaptic transmission

13

Drugs used in the treatment of epilepsy fall into what 3 categories?

1. suppress high frequency neuronal firing by increasing the refractory period of voltage-gated Na channels

2. enhance GABA-mediated synaptic transmission because it is inhibitory

3. inhibit voltage-gated Ca channels [T-type] that are critical for large amplitude spike-wave discharge

14

What is the mechanism of action of phenytoin?

suppresses the recovery of voltage-gated Na channels from inactivation [so they cannot fire again]

15

What is the mechanism of action of phenobarbital?

Phenobarbital increases the duration of GABAa channel opening.
This potentiates GABA inhibitory activity

16

What is the mechanism of action of carbamazepine?

Suppresses the recovery from inactivation of voltage-gated Na channels

17

What is the mechanism of action of ethosuximide?

It blocks conduction through T-type Ca channels

18

What is the mechanism of action of valproic acid?

It suppresses the recovery from inactivation of voltage-gated Na channels

-and-

At higher concentrations it can block conduction through T-type Ca channels

19

What are the 3 benzodiazepines?
What is their mechanism of action?

the "pams" - diazepam, clonazepam, lorazepam

They enhance ion conduction through GABAa receptor channels by directly binding to the gamma subunit and increasing the frequency of channel opening

20

What is the mechanism of action of gabapentin?

1. Enhances release of GABA at inhibitory synapses through an uknown mechanism
2. reduces release of excitatory AA by binding to Ca channels

21

What is the mechanism of action of lamotrigine?

suppresses the recovery of inactive voltage-gated Na channels

22

What is the mechanism of action of topiramate?

1. Na channel blockade
2. Ca channel blockade
3. GABA potentiation
4. glutamate receptor antagonism

23

What is the mechanism of action of tiagabine?

it blocks GABA reuptake in neurons and glia

24

What is the mechanism of action of levetiracetam?

Unknown, but is known to bind presynaptic vesicle protein SV2A

25

Describe briefly the generation of an action potential.

What determines the frequency of action potential generation?


1. Neuronal cell membranes have a resting potential from -90 to -60mV.
2. When they get to -40mV, they mass threshold value and there is rapid opening of voltage gated Na channels that try to depolarize to their Na equlibrium potential of +40
3. Termination of action potential involves:
- inactivation of Na channels
- opening of voltage-gated K channels [resting potential -95] that bring the neuron back to "rest"

Frequency of action potential generation is the time course of recovery of Na channels from inactivation

26

What are the 3 configurations of a voltage-gated Ca channel?
Describe the transition between these states?

What configuration do antiepileptic drugs act on?

1. Closed configuation - at rest the channel is closed, but opens in response to depolarization [voltage-dependent]

2. Open- ions conduct into the cell further depolarizing it

3. Inactivated - the open channel goes through a voltage INDEPENDENT transition to inactivated by "plugging" the pore with a cytoplasmic inactivation domain

AEDs act on the inactivated confirmation, stabilizing the refractory period and regulating the frequency with which AP can fire

27

Why don't phenytoin, lamotrigine, valproic acid and carbamazepine affect low frequency firing of neurons?

Generation of AP at slow rates is not limited by inactivation recovery of the Na channels.

These drugs just extend inactivation recovery

28

The majority of synaptic transmission in the brain is mediated by what 2 AAs?

1. glutamate- excitatory
2. GABA [gamma-aminobutyric acid]- inhibitory

29

Describe the structure of the GABA receptor on the post synaptic cell. How does this account for the effect of GABA?

GABAr is a pentameric Cl- channel.
When it is bound by GABA it causes hyperpolarization of the post-synaptic cell, not allowing neuronal firing to continue

30

What are the 3 different ways that GABA potentiating drugs can work?

1. benzodiazepines [pams] and phenobarbital directly bind to distinct site on the post-synaptic Cl- channel potentiating the effect

2. Tiagabine inhibits the uptake of GABA into glia or neurons increasing the time it is in the synaptic cleft

3. Gabapentin operates somehow at the presynpatic terminal possibly determining the quantity of GABA released per stimulus
[it also binds voltage-gated Ca channels, decreasing presynaptic Ca and releasing glutamate excitation]

31

Where are T-type calcium channels found?
what is the function?
What 2 types of seizures are probably caused by them?
What drugs are used to block ion permeation through these channels?

They are expressed in neurons of the thalamus and seem to be the key regulator of rhythmic electrical activity
1. absence seizures - 3Hz spike and slow wave pattern
2. generalized seizures - alternating rhythms btw cortex and thalamus

It is blocked by:
1. ethosuximide
2. high concentrations of valproic acid

32

What type of seizures are treated by carbamazepine?
What other conditions besides epilepsy is it used for?
What are the pharmacokinetics?
What are the 4 major side effects?

1. simple and complex partial seizures
2. tonic-clonic generalized

It is also used for: trigeminal neuralgia


Pharmacokinetics: it induces enzymes [including the ones that metabolize it] so t1/2 decreases over time

Side effects:
1. diplopia
2. ataxia
3. agranulocytosis
4. aplastic anemia

33

What type of seizures are treated by phenytoin?
What are the pharmacokinetics?
What are the 4 major adverse effects?

1. partial seizures
2. generalized tonic-clonic seizures

Pharmacokinetics: non-linear kinetics results in rapid increases in serum concentration with small increases in dose

Adverse effects:
1. gingival hyperplasia
2. hirsutism
3. stevens-johnson syndrome
4. hepatic failure

34

What 4 types of seizure can valproic acid be used to treat?
What seizure is is the "drug of choice" for?
What are the pharmacokinetics?
What are the 3 major adverse effects?

1. generalized myoclonic [drug of 1st choice]
2. simple/complex partial
3. tonic-clonic
4. absence [esp. if together with gen. tonic-clonic]

It is metabolized in the liver but DOES NOT induce enzymes [like carbamazepine and phenytoin]

Adverse effects:
1. hepatotoxicity-->fulminant hepatitis
2. spina bifida in infants
3. teratogenic

35

What antiepileptic drug can be used for monotherapy of partial seizures, but is more commonly used as an "add-on" agent?
What are side effects of the drug?

Lamotrigine

Side effects:
1. allergic rash--> DIC
2. stevens-johnson syndrome

36

What drug is first line for treating febrile seizures in children?

phenobarbital

37

What 3 seizures can phenobarbital treat>?
What is it first line for?
What are the pharmacokinetics?
What are the adverse effects?

1. febrile seizures in children [1st line]
2. partial
2. generalized tonic-clonic

Pharmacokinetics: induces p450

Side effects:
1. sedative effect

38

What drug is used for treating myoclonic or absence seizures in children?
What is the main side effect?

clonazepam- main side effect of drowsiness

39

What 2 benzodiazepines are used to treat status epilepticus?

1. diazepam
2. lorazepam

40

What GABA drug is used solely as an adjunctive treatment for partial seizures?

tiagabine- inhibits uptake of GABA by neurons and glia

41

What drug is used mainly to treat classic absence seizures?

Ethosuximide- reduces low-threshold T-type Ca current in the thalamus which is responsible for rhythmic current [3Hz spike/wave cortical discharge]

42

What seizures are treated by topiramate?
What non-epilepsy condition is also treated by topiramate?

What are the major side effects?

1. partial and generalized tonic-clonic
2. Lennox-Gastualt syndrome
3. West syndrome

Topiramate is also used to treat migraines

Side effects:
1. visual problems [myopia, glaucoma]
2. urolithiasis

43

What 2 seizures are treated by Levetiracetam?
What is the mechanism of action?

1. partial and generalized tonic-clonic
2. generalized myoclonic

It binds to synaptic vesicle protein SV2A

44

What seizures are gabapentin used as adjunct for?
What other condition can gabapentin be used to treat?

1. partial and generalized tonic-clonic seizures

Also used for neuropathic pain

45

What 2 drugs are used together to be the "drug of choice" for partial seizures?

Phenytoin, carbamazepine

46

The generalized strategy for optimal drug treatment of epilepsy is to achieve the longest seizure-free periods with the minimal risk of drug toxicity.
How is this achieved?

1. start a patient on a single drug and achieve steady state plasma concentration at the lower limit of the therapeutic window
2. Assess dose over sufficient time intervals and characterize the drug behavior.
3. adjust the dose to control seizure and toxicity
4. If the patient is compliant AND the single drug fails, substitute a second SINGLE AGENT and repeat the process
5. if the second single drug fails, try a third monotherapy before switching to 2 drugs

47

_______- and __________ are the first line drugs for partial and generalized tonic-clonic seizures, although _______ and ______ are potentially effective as well.

Carbamazepine and phenytoin are first choice

valproic acid and phenobarbital are also effective

48

What is the drug of choice for generalized myoclonic seizures?

Valproic acid

[clonazepam can also be effective]

49

What drugs should NOT be used for absence seizures due to the fact that they have been known to exacerbate absence epilepsy?

1. carbamazepine
2. phenytoin

50

What percent of patients become seizure-free through medication and will actually be able to stop treatment fully?
How long shoud you wait to begin withdrawing treatment?

60% will become seizure free

Wait 2-5 years without symptoms to start withdrawing drugs

51

Can antiepileptic drugs be used during pregnancy?
What changes need to be made to the regimen?
What 3 drugs absolutely cannot be used?

Drugs can still be used, but they will have altered metabolism so you need to adjust and monitor more frequently.

Increased risk of developmental malformation with:
1. phenytoin
2. valproic acid
3. carbamazepine

52

What is Dravet syndrome?
What antiepileptic drugs exacerbate the condition?

It is severe myoclonic epilepsy in infants

Na channel blockers [phenytoin, carbamazepine, valproic acid] cannot be used because these patients have a mutation in the Na channels of inhibitory interneurons. Blocking flow will actually result in disinhibition of neuronal pathways and CAUSE hyperexcitablitly

53

What are the 2 "functional definitions" of status epilepticus?
How can it be differentiated from serial seizures?

1. seizures for greater than 5 minutes
2. 2 or more seizures between which there is incomplete recovery of consciousness

Serial seizures are 2 or more seizures occuring over a brief period of time but with FULL recovery of consciousness

54

What is the overall mortality rate of adults with status epilepticus?
What does a first episode predispose them to?
What are the 2 categories of initiating conditions for status epilepticus?

Overall mortality = 20%
First episode puts them at a LARGE risk for severe future attacks..

1. Acute triggers
2. Chronic triggers

55

What are the acute triggers of status epilepticus?

1. electrolyte abnormality
2. renal failure
3. sepsis
4. CNS infection
5. trauma
6. stroke
7. drug OD

56

What are chronic triggers of status epilepticus?

1. pre-existing epilepsy
2. seizures due to chronic alcohol use
3. long term consequences of CNS neoplasms

57

What is the first step in the management of status epilepticus?

1. As with any medical emergency, evaluate and stabilize ABCs [airway, breathing, circulation]

58

What is the goal of treatment for status epilepticus?
When should drug therapy be initiated?
What are the steps of treatment?

The goal of drug treatment is to stop the seizure activity and should be initiated as soon as the diagnosis is made.

1. IV Lorazepam [0.1mg]
2. if seizure continues --> IV phenytoin [20mg/kg]
3. if seizure continues --> additional 5 to 10 mg of IV phenytoin at same infusion rate

If seizure continues, evaluate for signs of systemic distress [like hyperthermia].
If this is evident, the patient is in the ICU, or the seizure has been over an hour--> anesthesia

If there is not systemic stress, not the ICU, shorter than an hour--> phenobarbital [and increase as needed via IV]

59

Why is phenobarbital withheld until you have tried lorazepam and phenytoin?

Because it is a potent CNS depressor and has potential synergism with benzodiazepines