Seizures Cpc Kuma

Front 1

Epidemiology of seizures

Back 1

Third most common neurological disorder
10% of the population will experience a seizure
1/100 adults have a diagnosis of epilepsy
~ 1 - 2 % of the population
40 million worldwide
2.3 million in the USA
Estimated annual burden on society: $12.5 billion

Front 2

at what number of seizures are patient put on meds

Back 2

2

Front 3

what is the fastest growing population to have seizures

Back 3

the elderly (>65)

Front 4

where is the most common area in the brain that seizures start in

Back 4

temporal lobe

Front 5

occipital lobe

Back 5

visual preception
the cells are more tightly packed here so it is hard to propagate a seizure

Front 6

parietal lobe

Back 6

primary somatosensory

not easy to propagate a seizure in this area

Front 7

temporal lobe

Back 7

memory, language, emotion

most common area to propagate a seizure

there is direct access to this area of the brain throught the nose

stimulants increase the risk of seizures

auras:
smell, taste, emotions can preceed a seizre and they will always be the same (ie: same smell or taste)

Front 8

what is the most important asspect of seizures

Back 8

where they start

Front 9

charateristics of seizures

Back 9

Length: seconds to minutes
Biochemical changes: last minutes to days
Aura: time immediately prior to seizure (simple partial seizure SPS)
Ictal: the seizure
Post-ictal: time after a seizure (may have no recolection of what happened during time of seizure)
Areas of susceptibility: temporal and frontal
EEG: electroencephalograph test

Front 10

EEG phase I and II

Back 10

phase I: electrodes on the skull monitoring electrical impulses

phase II: underneath the skull

looking for abnormal or slowing impluses

Front 11

5 types of generalized seizures

Back 11

absence
myoclonic
tonic-clonic
tonic
atonic

Front 12

what is characteristic of generalized seizures

Back 12

they start on both sides of the brain at the same time

Front 13

tonic=

Back 13

increased tone

Front 14

clonic phase

Back 14

movement

Front 15

atonic seizures

Back 15

these seizures are with out tone so the patient either falls forward or backwards

Front 16

can partial seizures become generalized

Back 16

yes

Front 17

what are the most common seizures in adults

Back 17

partial seizures

Front 18

3 types of partial seizures

Back 18

secondarily generlized
complex
simple (an aura)

Front 19

complex partial seizures

Back 19

the most common form of seizures

awareness is impaired
this seizure can progress to generlized seizures

Front 20

International Seizure Classification

Back 20

Primary Generalized
Tonic-Clonic
Tonic
Clonic
Atonic
Absence
Myoclonic

Front 21

partial seizures

Back 21

Simple (SPS) - awareness, mentation not impaired
Complex (CPS) - awareness, mentation impaired
Secondary Generalization

Front 22

epilepsy syndromes

Back 22

Juvenile Myoclonic Epilepsy (JME)
Lennox-Gastaut Syndrome (LGS)

Front 23

Juvenile Myoclonic Epilepsy (JME) know!!

Back 23

characteristic onset at puberty
jerks upon awakening
a lot of jerks may indicate a big seizure that day
will not out grow

depekote treates will (it was used in the past but is associated with a lot of weight gain)

Front 24

Lennox-Gastaut Syndrome (LGS)

Back 24

difficult to treat consists of every seizure type

Front 25

absence seizure

Back 25

starts at 5-7 years old and do not necessarily out grow

lapses of awareness

consist of staring

Front 26

Primary Generalized Epilepsy

Back 26

Begins in both hemispheres
Hereditary link
Onset associated with age
Often an abnormal EEG all the time not just during a seizure
Generally no structural lesion
Typically normal IQ & neurological exam

Front 27

Partial Seizures (Acquired)

Back 27

Begin focally
No hereditary link
Onset has a bimodal distribution (<20 y/o & >60 y/o)
EEG generally normal inter-ictally (unless having a seizure)
May or may not have a structural lesion on MRI
may have a shrunken temporal lobe

Front 28

most common types of seizures

Back 28

complex partial 36%
simple partial 14%
generalized tonic clonic 23%
other generalized (in peds mainly) 8%

Front 29

biggest etiology of epilepsy

Back 29

idiopathic 66%

Front 30

traditional AEDs (know)

Back 30

Phenobarbital (PB) - 1912
Primidone (Mysoline) (PRM) - 1938
Phenytoin (Dilantin) (PHT) – 1938
Ethosuximide (Zarontin) (ESX) - 1960
Carbamazepine (Tegretol, Carbatrol) (CBZ) – 1974
Valproate (Depakote, Depakene) (VPA) - 1978

Front 31

New AEDs

Back 31

Felbamate (Felbatol) (FBM) - 1993
Lamotrigine (Lamictal) (LTG) - 1993
Gabapentin (Neurontin) (GBP) - 1994
Topiramate (Topamax) (TPM) - 1996
Tiagabine (Gabitril) (TGB) – 1997
Oxcarbazepine (Trileptal) (OXC) - 1999
Levetiracetam (Keppra ) (LEV) - 2000
Zonisamide (Zonegran) (ZNS) – 2000
Pregabalin (Lyrica) (PGB) – 2006
Lacosamide (Vimpat) (LCM) – 2009
Rufinamide (Banzel) (RFN) – 2009
Vigabatrin (Sabril) (VGB) - 2009

Front 32

do traditional or new AEDs have more drug interactions

Back 32

traditional because they are potent inducers and inhibitors

Front 33

what are SE of all AEDS (know)

Back 33

they can decrease WBC, RBC and platelets

Front 34

10% of patients will develop a _____ with AEDs

Back 34

rash
it is ok unless systemic issues such as SJS or TEN

Front 35

what AED is indicated for absence seizures (know)

Back 35

zarontin/ethosuximide

Front 36

treatment considerations for seizures

Back 36

compliance
type of seizures
efficacy
AEDs toxicity
drug drug interactions
patient's hx of seizures
patient age
comorbidities

Front 37

what is the percentage of success in monotherapy for first AED

Back 37

47%

Front 38

after monotheray what happens to success of additional AEDs

Back 38

2nd--> 13%
3rd-->1%

Front 39

seizure free ____% polytherapy

Back 39

3

Front 40

What is the Reality of AEDs?

Back 40

First AED monotherapy fails in ~50% of patients with epilepsy
Chance of seizure freedom with substitution monotherapy after failure of initial AED is low ~ 13%
Many patients with epilepsy will require adjunctive therapy
The rate of seizure freedom is ~ 26% with adjunctive therapy
Adjunctive AED therapy may be more effective when initiated immediately after failure of first AED
Better efficacy and safety profiles of newer AEDs may translate into combination therapy that improves seizure control without increased toxicity

Front 41

what is the benefit of adjunct therapy over monotherapy in seizures

Back 41

Chance of seizure freedom with substitution monotherapy after failure of initial AED is low ~ 13%
Many patients with epilepsy will require adjunctive therapy
The rate of seizure freedom is ~ 26% with adjunctive therapy
Adjunctive AED therapy may be more effective when initiated immediately after failure of first AED

also develops a bond between the patient and the doctor because if the seizures are decreasing the goals of therapy are being met

Front 42

Major Receptors in Epilepsy

Back 42

GABA (inhibitory NT)
Ion Channels
Na+ channels
Ca++ channels (t type important in absence seizures)
Amino Acid
Glutamate (excititory so try to diminish)

Front 43

Ion channels

Back 43

Na+ channel: voltage controlled “gating”
Maintains intracellular Na+ concentration much lower (more negative) than extracellular
Accomplished by the Na+/K+ ATPase pump
Channels open via membrane depolarization, which allows a transient influx of Na+ ions

Ca and Na channels are not just in the heart

Front 44

amino acid receptors: glutamate

Back 44

want to inhibit
Glutamate is an excitatory neurotransmitter
Receptor subtypes:
NMDA: fluxes Na+ and Ca2+
AMPA/Kainate: fluxes Na+

Front 45

AEDs/Receptor: GABA (know!!!)

Back 45

Vigabatrin: enhances GABA levels by inhibiting GABA transaminase
Tiagabine: blocks the reuptake of GABA
Gabapentin/pregabalin: promote accumulation and synthesis of GABA; however, this may not be the direct mechanism of action
Barbiturates (phenobarbital and primidone)/ Benzodiazepines/Valproate/Felbamate/Topiramate:enhance Cl- conductance through GABA-A receptors, thereby enhancing GABA

increasing GABA

Front 46

Vigabatrin and GABA

Back 46

enhances GABA levels by inhibiting GABA transaminase

Front 47

Tiagabine and GABA

Back 47

blocks the reuptake of GABA

Front 48

Gabapentin/pregabalin and GABA

Back 48

promote accumulation and synthesis of GABA; however, this may not be the direct mechanism of action

Front 49

AEDs/Receptor and Sodium channels (know!!)

Back 49

Phenytoin/Fosphenytoin/Carbamazepine/ Valproate/Felbamate/ Lamotrigine/Topiramate/ Oxcarbazepine/Zonisamide/Rufinamide: block Na+ channels (fast)

Lacosamide
Selective enhancement of sodium channel slow inactivation
Binds to collapsin response mediator protein 2 (CRMP-2)

Front 50

Phenytoin/Fosphenytoin/Carbamazepine/ Valproate/Felbamate/ Lamotrigine/Topiramate/ Oxcarbazepine/Zonisamide/Rufinamide and Na channels

Back 50

block fast Na channels

Front 51

Lacosamide and Na channels

Back 51

Selective enhancement of sodium channel slow inactivation
Binds to collapsin response mediator protein 2 (CRMP-2)

very unique MOA

Front 52

AEDs/Receptor and Ca channels (know!!)

Back 52

Ethosuximide/Valproate/Zonisamide: reduce T-type calcium current in the thalamic-cortical pathway
Felbamate/oxcarbazepine/lamotrigine: affect calcium channels in an unknown fashion
Topiramate: reduces L-type calcium current
Pregabalin: binds to the alpha-2-delta subunit of the voltage-gated calcium channel, modulating the release of glutamate, noradrenaline, and substance P
Gabapentin: binds to the alpha-2-delta auxiliary subunit of voltage-sensitive calcium channels and reduces excitatory inward L-type calcium current

Front 53

Ethosuximide/Valproate/Zonisamide and Ca channels

Back 53

reduce T-type calcium current in the thalamic-cortical pathway

Front 54

Felbamate/oxcarbazepine/lamotrigine and Ca channels

Back 54

affect calcium channels in an unknown fashion

Front 55

Topiramate and Ca channels

Back 55

reduces L-type calcium current

Front 56

Pregabalin and Ca channels

Back 56

binds to the alpha-2-delta subunit of the voltage-gated calcium channel, modulating the release of glutamate, noradrenaline, and substance P

Front 57

Gabapentin and Ca channels

Back 57

binds to the alpha-2-delta auxiliary subunit of voltage-sensitive calcium channels and reduces excitatory inward L-type calcium current

Front 58

AEDs/Receptor: glutamate

Back 58

Felbamate: blocks NMDA
Topiramate: blocks Kainate
Lamotrigine: blocks Glutamate release
Pregabalin:
Binds to the alpha-2-delta subunit of calcium channels
Enhances the activity of glutamic acid decarboxylase
Therefore reducing release of excitatory neurotransmitters (glutamate, noradrenaline, substance P)

Front 59

what is Kepra/Levetiracetam MOA

Back 59

Levetiracetam acts by enhancing the function of SV2A that inhibits abnormal bursting in epileptic circuits

Front 60

general treatment principles of seizures and pregnancy

Back 60

Pregnancy: metabolic clearance is usually increased during the last trimester
Monotherapy is best
Monitor serum levels

want to avoid high peaks therefore give smaller doses more frequently

high peaks are more teratogenic

sometimes may have to increase the dose by 3x due to increase Vd, but make sure to decrease the dose after delivery

Front 61

seizures and pregnancy

Back 61

Having seizures > 5 GTCS during pregnancy was independently predictive of a lower verbal IQ score in the child*
Poor cognitive outcomes are associated with valproate use during pregnancy and potentially with phenobarbital and phenytoin**
Fetal malformation has been reported with AED use/ exposure during 1st trimester**
2 to 4% risk in the general population
4 to 6% in infants exposed to AEDs in utero
Carbamazepine 2.2%, Valproate 6.2%, Lamotrigine 3.2%, Phenytoin 3.7% (absolute values)

Front 62

if a patient becomes pregnant and is taking valproate and is stable what should you do

Back 62

don't switch the drug

Front 63

Reproductive Endocrine Disorders and AEDs

Back 63

Menstrual disorders
Amenorrhea, oligomenorrhea, abnormal menstrual cycle interval
Polycystic ovarian syndrome (PCOS)
High androgens/normal estrogens (LH/FSH >2)
Associated with increased risk of diabetes, CV disease, and endometrial cancer
There is an increased rate of PCOS in women with epilepsy

Front 64

First-order pharmacokinetics

Back 64

Constant amount of drug removed per time (concentration dependent)

Front 65

Zero-order pharmacokinetics

Back 65

As saturation is approached, small changes in dosage produce disproportionately large changes in serum concentrations

phenytion
alcohol
heparin

Front 66

enzyme induction (know)

Back 66

Phenobarbital, phenytoin, primidone, carbamazepine, felbamate, topiramate (birth control pills) above 200 mg per day, oxcarbazepine at higher doses, vigabatrin

Front 67

enzyme inducers and birth control

Back 67

decrease the levels of birth control so increase the risk of unplanned pregnancy so need higher dose of estrogen

Front 68

enzyme inducers and warfarin

Back 68

warfarin levels would be altered

Front 69

Autoinduction

Back 69

Within 2 weeks: carbamazepine

don't start with normal dose (titrate0 to determine toleration because it takes 2 weeks to build up enough enzymes to metabolize the med.

it induces it's own enzymes

Front 70

at what dose is topiramate become and inducer

Back 70

> 200 mg/day

Front 71

SV2A and AED/receptors

Back 71

The synaptic vesicle protein SV2A is the binding site for levetiracetam
SV2A is found in the brain
Levetiracetam acts by enhancing the function of SV2A that inhibits abnormal bursting in epileptic circuits
Lack of function of SV2A would cause seizures

decreasing seizure activity by binding the site

Front 72

enzyme inhibitors

Back 72

Valproic acid (phase II metabolism and glucuranidaiton so increase serum concentration), felbamate, oxcarbazepine (mild), topiramate (mild), vigabatrin

Front 73

what are the effects of enzyme inhibitors

Back 73

the increase serum concentrations of other drugs

Front 74

what AED is the last choice because of aplastic anemia

Back 74

felbamate

Front 75

AED Effects on Drug Metabolizing Isozymes

Back 75

Older
Enzyme inducers (CYP1A2, 2C, 3A, UGTs)
CBZ
PHT
PB/PRM
Enzyme inhibitor
VPA (CYP2C19, UGT, EH)

Newer

No effects on CYP:
LEV
LTG
ZNS
TIA
GBP
PGB
LCM
Modest inducer
OXC, TPM (CYP3A), VGB
Inhibitors
TPM, OXC (CYP2C19), VGB

Front 76

AEDs & Drug Interactions: The Obvious & The Hidden

Back 76

When can PK Interactions Occur?
When initiating a new medication
Induction of drug metabolizing enzymes
Inhibition
When removing an existing medication
De-induction
Reversal of inhibition
serum concentrations of other drugs will change

Front 77

Protein Binding

Back 77

Affected by two factors
Binding affinity of drug and plasma proteins
Number of available binding sites
Clinical significance
A highly bound drug with a free fraction of 10% or less is altered
Conditions that alter plasma protein binding (PPB)
Cirrhosis, CRF, malnutrition, pregnancy, age, drugs, hypoalbuminemia

Front 78

is there a cross sensitivity reaction across all AEDs with aromatics (know!)

Back 78

yes

Front 79

AED Hypersensitivity

Back 79

Aromatics: potential for cross-reactivity?
Phenytoin
Phenobarbital
Carbamazepine
Oxcarbazepine
Lamotrigine*
Zonisamide
Rufinamide
Lacosamide
Characterized by
Rash
Systemic involvement e.g. diarrhea, N/V
Potentially due to lack of epoxide hydrolase

a more life threatening rash occurs with an aromatic ring

starts with a rash that looks like a sunburn not in typical places such as the palms, soles of feet, around the mouth and on the tongue

starts becoming sores and the skin sloughs off (SJS and TEN)

Front 80

Breakthrough Seizures can be caused by(know)

Back 80

Nonadherence
Sleep deprivation
Major emotional stress
Major physical stress

Front 81

Goals of Therapy of seizure treatment

Back 81

Stop seizures (#1 may not be realistic)
Minimize side effects (adjunctive therapy because can use lower doses with 2 different drugs with different MOA)
Consider cost of therapy
Quality of life (QOL)
Match seizure disorder with AED
Monotherapy (best overall unless 1st drug fails) > Polytherapy

Front 82

Monitoring AED Therapy

Back 82

Prior to starting AED and periodically as needed
Liver enzyme tests: alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, gamma-glutamyl transpeptidase (GGT)
Comprehensive metabolic panel, CBC, platelet count
Neurological exam and patient report
AED serum level = trough (short t½)

Front 83

are AEDS expected to increase LFTs

Back 83

yes because they are inducing enzymes so it is expected that they increase </= 3x ULN

Front 84

nagstagmis

Back 84

indicates a drug toxicity
fast eye movements in the lateral gaze
indicates neurological toxicity

Front 85

______ levels really indicates liver function

Back 85

platelets

Front 86

1st Generation/Traditional AEDs

Back 86

Phenobarbital (Luminal®)
Primidone (Mysoline®)
Phenytoin (Dilantin®)
Ethosuximide (Zarontin®)
Carbamazepine (Tegretol®)
Valproate (Depakote®)

all are inducers except valproate

Front 87

half lives of
CBZ
PB
PHT
VPA

Back 87

6-15
72-124
12-60
6-18

Front 88

Other Formulations of AEDs

Back 88

Carbamazepine (Tegretol XR®)
Carbamazepine (Carbatrol®)
Diazepam (Diastat®) (rectal gel)
Valproate (Depacon®) (IV)
Fosphenytoin (Cerebryx®) (injectable)
Valproate (Depakote ER®)
Phenytoin (Phenytek®)
Levetiracetam (Keppra XR®)
Lamotrigine (Lamictal XR®)

will make absence seizures worse

Front 89

Phenobarbital (Luminal®)

Back 89

MOA: enhances GABA
Indications: GTCS*, PS*, SE*
Metabolism: hepatic (Phase 1), inducer
t½: 24 to 110 hours
Dosage forms: tablet, liquid, injectable
Blood levels: 15 to 45 mcg/ml
Controlled substance: Schedule IV

*Generalized Tonic-Clonic Seizures, Partial Seizures, Status Epilepticus (not used for absence seizures)

the long half life makes it hard to asses patients

phenobarbital is a barbiturate and therefore has a withdrawal component so it is hard to get off of

Front 90

does phenobarbital come in an IV form (know)

Back 90

yes

Front 91

Phenobarbital (Luminal®) SE and drug interactions

Back 91

Side effects: sedation, rash, blood dyscrasias, hepatotoxicity, aggression
Drug interactions:
Increase phenobarbital: valproate
Decrease phenobarbital: phenytoin
Other medications decreased: birth control pills

Front 92

all inducers cause ________ so supplement ___ and ____

Back 92

osteopenia
vitamin D
Ca

Front 93

Barbiturates (phenobarbital and primidone)/ Benzodiazepines/Valproate/Felbamate/Topiramate and GABA

Back 93

enhance Cl- conductance through GABA-A receptors, thereby enhancing GABA

Front 94

at what point are drug concentrations taken

Back 94

AED serum level = trough (short t½)

Front 95

Phenytoin (Dilantin®) (know MOA, Inducer, protein, binding, blood level)

Back 95

MOA: sodium channel blockade
Indications: GTCS, PS, SE
Metabolism: zero-order, hepatic (phase1), inducer
Protein binding: 90 to 95%
t½: 7 to 42 hours
Dosage forms: suspension, liquid, kapseals, injectable, chewable tablet
Blood levels: 10 to 20 mcg/ml

Front 96

Phenytoin (Dilantin®) blood levels

Back 96

Blood levels: 10 to 20 mcg/ml

Front 97

does Phenytoin (Dilantin®) have an IV formulation (know)

Back 97

yes

Front 98

with highly protein bound meds in the elderly with decreased albumin what happens

Back 98

total concentrations would be fine, but the free fraction would be increased and therefore they are at a greater risk of toxicity

Front 99

Phenytoin (Dilantin®) dose (know)

Back 99

Dose: 200 to 400 mg/day

Front 100

SE Phenytoin (Dilantin®)

Back 100

Side effects: sedation, rash, osteomalacia, gingival hyperplasia, hirsutism, blood dyscrasias, hepatotoxicity

Front 101

drug interactions and Phenytoin (Dilantin®)

Back 101

Drug interactions:
Increase phenytoin:
Felbamate, cimetadine, phenobarbital, warfarin
Decrease phenytoin:
Carbamazepine, phenobarbital
Other medications decreased:
Birth control pills

Front 102

what AED causes gingival hyperplasia

Back 102

Phenytoin (Dilantin®)

so brush teeth QID use dental floss
and go to dentist 4x a year

Front 103

Phenytoin (Dilantin®) used in _____

Back 103

Used in status epilepticus

Front 104

Phenytoin (Dilantin®) limitations

Back 104

Limitations due to propylene glycol and ethanol
Infusion rate: maximum 50 mg/min
Cardiac arrhythmias
Monitor patient with a loading dose
Diluent 0.9% normal saline, short stability
Must pass through a final filter
Side effects: cardiac arrhythmias, tissue necrosis, pain at injection site, cording of vein

Front 105

what does Phenytoin (Dilantin®) have to be mixed with

Back 105

propylene glycol and ethanol

it has to be mixed with the above to get into solution and to prevent microcrystals from forming

Front 106

at what rate should Phenytoin (Dilantin®) be administered at

Back 106

1000 mg load is standard but do not want to give too quickly because the patient can flat line

Front 107

should Phenytoin (Dilantin®) be refrigerated

Back 107

no it increases the possibility of forming microcrystals

Front 108

what must be monitored with Phenytoin (Dilantin®)

Back 108

monitor for hypotension

Front 109

Fosphenytoin (Cerebyx®)

Back 109

Used in status epilepticus
No propylene glycol added
Diluent either D5W or NaCl
Causes less venous and tissue irritation
Given faster than phenytoin: up to 150 mg/min
Converted into phenytoin immediately
Indications:
Adults: PS, GTCS
Not recommended <4 y/o
IM or IV (available 50 mg/ml: 2 or 10 ml vial, refrigerate)
Serum levels 2 hrs after IV, 4 hrs after IM

Front 110

what is added to Fosphenytoin (Cerebyx®) to increase solubility

Back 110

a phosphate tail making it more water soluble

Front 111

at what rate is Fosphenytoin (Cerebyx®)

Back 111

Given faster than phenytoin: up to 150 mg/min

it is a prodrug so want to mirror phenytoin curve

Front 112

when Fosphenytoin (Cerebyx®) is given too quickly what is the se

Back 112

groin itching

Front 113

when do you take serum levels of Fosphenytoin (Cerebyx®)

Back 113

Serum levels 2 hrs after IV, 4 hrs after IM

because it has to be converted to the active metabolite it is a prodrug

Front 114

what formulations does Fosphenytoin (Cerebyx®) come in

Back 114

IM or IV

Front 115

Phenytoin (Phenytek®)

Back 115

Extended phenytoin
200 or 300 mg capsules
Erodible-Matrix Delivery System
Used for noncompliance

Front 116

Primidone (Mysoline®)

Back 116

MOA: enhances GABA
Indications: GTCS, PS
Metabolism: hepatic (inducer)
Active metabolites
Phenylethylmalonamide (PEMA)
Phenobarbital (most potent component)
Protein binding: ~80%
Dosage form: tablet
Side effects: sedation, irritability, aggression, rash, hepatotoxicity, blood dyscrasias
Drug interactions: see phenobarbital

Front 117

injectable AEDs

Back 117

phenobarbital
phenytion
fosphenytion
valproate
levetiracetam

Front 118

Ethosuximide (Zaronitin®)

Back 118

MOA: Inhibits T-type calcium channels
Indication: absence
Metabolism: hepatic
t½: 30 hours (P), 60 hours (A)
Dosage forms: capsule, liquid
Side effects: sedation, GI, hiccoughs, blood dyscrasias, aggression, nightmares, rash, hepatotoxicity

Front 119

what is an unusual SE of Ethosuximide (Zaronitin®) (know)

Back 119

hiccoughs and nightmares

Front 120

Valproate (Depakote®)

Back 120

MOA: increases GABA, blocks sodium channels, inhibits T-type calcium channels
Indications: broad spectrum, PS, GTCS, pain, migraine prophylaxis, bipolar, absence
Metabolism: hepatic (phase 1), inhibitor
t½: 5 to 20 hours
Dosage forms: tablet, capsule liquid, injectable, sprinkle form
Blood levels: 50 to 100 mcg/ml, psych uses up to 150 mcg/ml
Protein binding: 90 to 95%

Front 121

is valproate an inhibitor or an inducer

Back 121

inhibitor

Front 122

what is the dose of valproate

Back 122

Dose: ~15 mg/kg/day = 1000 to 1500 mg per day
typical dose is 500 mg TID

Front 123

is valproate a broad spectrum AED

Back 123

yes

Front 124

SE of valproate

Back 124

Side effects: tremor, weight gain, hair thinning, hepatotoxicity, mild sedation

multiple drugs and children <2 will increase risk of hepatoxicity

Front 125

drug interactions with valproate

Back 125

Increase valproate:
Cimetadine, salicylates
Decrease valproate:
Phenobarbital, phenytoin, carbamazepine
Other medications increased:
Lamotrigine

Front 126

what does valproate do to the half like of lamotrigine

Back 126

increases it

Front 127

Valproate (Depakote ER®)

Back 127

Smoother blood levels
Bioavailability: ~90%
Less weight gain
Less hair thinning
Dose starting at 500 mg up to 1000 mg total daily dose (TDD)
Additional indications:
Migraine prophylaxis
Mania

Front 128

Valproate (Depacon ®)

Back 128

New formulation of Valproate
For intravenous use only
Use when oral route not accessible (migraine abortion)
May be useful in status epilepticus
Well tolerated
Rapid infusion 1.5 - 3 mg/kg/min, 100 mg/ml, 5 ml vial
Indicated for children > 2 y/o

no cardiac arrhythmias or decrease in BP

only IV use because because bad necrosis

Front 129

Carbamazepine (Tegretol ®)

Back 129

MOA: sodium channel blockade
Indications: PS, GTCS, bipolar, pain, *makes absence worse
Metabolism: hepatic (auto-induction)
Active metabolite: CBZ 10,11 epoxide
t½: 12 to 72 hours (I), ~ 18 hours(C)
Dosage forms: tablet, chewable tablet, liquid
Blood levels: 4 to 12 mcg/ml
Protein binding: ~ 85%
Dose: 400 to 1200 mg/day

Front 130

dose of Carbamazepine (Tegretol ®)

Back 130

Dose: 400 to 1200 mg/day

Front 131

blood levels of Carbamazepine (Tegretol ®)

Back 131

Blood levels: 4 to 12 mcg/ml

Front 132

SE of Carbamazepine (Tegretol ®)

Back 132

Side effects: visual distortion, mild sedation, SIADH, rash, blood dyscrasias, hepatotoxicity, cardiac arrhythmias

Front 133

drug interactions with Carbamazepine (Tegretol ®)

Back 133

Increase carbamazepine:
Fluoxetine, erythromycin, cimetidine
Decrease carbamazepine:
Phenytoin, phenobarbital
Decrease other medications:
Birth control pills, warfarin

Front 134

does Carbamazepine (Tegretol ®) have an IV formulation

Back 134

no

Front 135

Carbamazepine (Tegretol XR®)

Back 135

More consistent blood levels
Take less frequently than Tegretol®
Works by an osmotic pump
Ghost tablet in feces
Caution with pro-kinetic drugs: Reglan®
Absorbed best with fatty meal
Dosage forms: 100, 200, and 400 mg tablets

works by osmotic release
best absorbed with a fatty meal

a prokinetic drug will cause it to pass through the gut faster and decrease absorption

Front 136

what are the affects of inducers on bone

Back 136

cause bone loss so Ca and vitamin D needs to be supplemented

Front 137

bone health and AEDs

Back 137

Gradual decline in bone mass and bone mineral density (BMD) with advancing age
Increased risk of osteoporosis and fractures with some AEDs by interfering with Vitamin D metabolism
PHT, PB, CBZ and possibly VPA increase risk for osteopenia/osteoporosis
Limited data with newer AEDs

Front 138

sexual function and AEDs

Back 138

Sexual dysfunction described in 30-60% of men and women with epilepsy
Older AEDs (phenytoin, carbamazepine, phenobarbital & primidone) induce hepatic drug metabolism
Cytochrome P450 isozymes participate in metabolism of estradiol and testosterone
Increased hepatic synthesis of sex hormone binding globulin (SHBG) → ↓ concentrations of bioactive androgen

men and women there is a decrease in estrogen and testosterone

Front 139

do first generation or new AEDs cause more sedation

Back 139

first genertation

Front 140

GABA receptor

Back 140

GABA is formed within axon terminals by decarboxylation of glutamate
GABA is an inhibitory neurotransmitter
GABA receptors: regulate Cl- flux

benzos and barbituates bind the GABA receptor

Front 141

Carbamazepine (Carbatrol®)

Back 141

Extended-release capsule
3 different beads within capsule
Immediate release
Delayed release
Extended release
More consistent blood levels
Given less frequently than Tegretol®
Dosage forms: 100, 200 and 300 mg capsules
Can sprinkle on food

more consistant blood levels so dosed BID and there is better absorption as well than the XR formulation

Front 142

what AED causes weight gain, tremor, and hair loss

Back 142

valproate

Front 143

what AED casues hyponatermia, cardiotoxicity, and visual distortion

Back 143

carbamazepine

Front 144

2nd Generation/New AEDs

Back 144

Felbamate (Felbatol®)
Lamotrigine (Lamictal®)
Gabapentin (Neurontin®)
Topiramate (Topamax®)
Tiagabine (Gabitril®)
Levetiracetam (Keppra®)
Oxcarbazepine (Trileptal®)
Zonisamide (Zonegran®)
Pregabalin (Lyrica®)
Vigabatrin (Sabril®)
Lacosamide (Vimpat®)
Rufinamide (Banzel®)

Front 145

what AED is 100% renally eliminated

Back 145

gabapentin

Front 146

what AED is 100% hepatically eliminated

Back 146

lamotrigine

Front 147

Felbamate (Felbatol®)

Back 147

MOA: blocks sodium channels, interacts with glutamate, enhances GABA
Indications: LGS*, GTCS, PS
Metabolism: 50% hepatic (inducer/inhibitor), 50% renal
t½: 20 to 23 hours
Dosage forms: 400 and 600 mg tablets and liquid
Blood levels: 30 to 100 mcg/ml

3rd line because of aplastic anemia
Therapy restricted to patients unresponsive to other AEDs

Front 148

__________ is a potent inducer and inhibitor

Back 148

Felbamate (Felbatol®)

Front 149

SE of Felbamate (Felbatol®)

Back 149

Side effects: insomnia, weight loss, headache, nausea, aplastic anemia 1/3600, liver failure 1/24,000-34,000 (not as common in children), rash (SJS)

Front 150

does Lamotrigine (Lamictal®) decrease birth control

Back 150

yes

Front 151

SE of Lamotrigine (Lamictal®)

Back 151

Visual distortion, ataxia, sedation, weight neutral, headache, blood dyscrasias, nausea
Rash (up to 10%):
Higher in children including
Stevens-Johnson Syndrome
Toxic epidermal necrolysis
0.3% in adults
Rash greatest with rapid dosage titration of <8 weeks to maintenance levels

Front 152

Lamotrigine (Lamictal®) drug interations

Back 152

Decrease in lamotrigine
Phenytoin
Carbamazepine
Phenobarbital
Primidone
Oral contraceptives
Increase in (increases half life from 24 hours to 72)
Valproate (inhibitor)

Front 153

Lamotrigine (Lamictal®) and bipolar disorders

Back 153

Positive clinical evidence for bipolar depression efficacy
Negative efficacy for mania
decrease dose by 50% if given with valproate which inhibits metabolism of lamotrigine
Double dose if given with carbamazepine

Front 154

Lamotrigine (Lamictal XR®)

Back 154

QD dosing

Front 155

Gabapentin (Neurontin®)

Back 155

MOA: enhances GABA through glutamate
Indications: add-on therapy for PS in adults, pain, post-herpetic neuralgia
Children > 12 y/o
Metabolism: renal elimination (less drug interactions)
t½: 5 to 7 hours
Dosage forms: 100, 300, 400 mg capsules; 100, 300, 400, 600, 800 mg tablet; liquid
Blood levels: 4 to 20 mcg/ml

more sedation
mainly used for pain

Front 156

SE of Gabapentin (Neurontin®)

Back 156

Side effects: ataxia, headache, irritability, edema, weight gain, thinking problems in pediatrics, myoclonus

Front 157

Topiramate (Topamax®)

Back 157

MOA: blocks sodium channels, attenuates glutamate, enhances GABA, weak carbonic anhydrase inhibitor
Indications: >2 y/o add on therapy: LGS, PS, GTCS, myoclonus; >10 y/o monotherapy: PS, primary GTCS, migraine prophylaxis
Add-on therapy for adults with PS, LGS, myoclonus
Metabolism: hepatic (mild >200 mg/day)
t½: 21 hours
Dosage forms: 15 and 25 mg sprinkle capsule; 25, 50, 100, and 200 mg tablet
Blood levels: 3 to 25 mcg/ml

broad spectrum because lots of MOA

Front 158

if a person has had kidney stones in the past don't use drugs with _________ MOA

Back 158

carbonic anhydrase inhibitors

Front 159

Topiramate (Topamax®) a weak carbonic anhydrase inhibitor

Back 159

Weak carbonic anhydrase inhibitor
Side effects:
Paresthesias, weight loss, ataxia
Kidney stones (1.5%, ~2-4x> usual)
decrease urinary citrate, increase urinary p H
recommend 6-8 glasses water/day for all pts, especially h/o nephrolithiasis
Decreased sweating (oligohidrosis), metabolic acidosis

Front 160

SE of Topiramate (Topamax®)

Back 160

decrease cognition (word finding, concentration) (if start too quickly)
Behavioral changes, irritability in children
Dose-dependent weight loss:
2-8% of baseline
Plateaus after ~1 yr
May gradually return to pretreatment weight
Ataxia
Acute myopia & secondary angle closure glaucoma: 30/935,000 exposures

Front 161

Topiramate (Topamax®) drug interactions

Back 161

Decrease in topiramate
Phenytoin 50%
Carbamazepine 40%
Decrease in other medications (dose dependent) >200 mg/day
Oral contraceptives, injection

Front 162

other uses of Topiramate (Topamax®)

Back 162

bipolar disorder
tremor
diabetic neuropathy
migraines

Front 163

Tiagabine (Gabitril®)

Back 163

MOA: enhances GABA
Indications: add-on therapy for adults with PS
Decreased efficacy in children with generalized seizures (Spasticity?)
Recommended ≥ 12 y/o
Metabolism: hepatic, inducible, but does not induce or inhibit other drugs
Short t½ (6.7 hours): dose 2-4/day, but longer pharmacodynamic effect
Dosage form: 2, 4, 12, 16, and 20 mg tablet

not a great seizure drug

if abruptly withdraw get static epilepticus

Front 164

Lamotrigine (Lamictal®)

Back 164

MOA: blocks sodium channels, inhibits glutamate
Indications: LGS, GTS, PS, absence, myoclonic add-on or convergence monotherapy
Not recommended <2 y/o
Metabolism: liver (glucuronidation)
t½: ~20 hours
Dosage forms: 5 to 25 mg chewable tablet and 25 to 200 mg tablet
Blood levels: 3 to 20 mcg/ml

Front 165

anything that is gabanergic helps with ___________

Back 165

spasticity

Front 166

SE of Tiagabine (Gabitril®)

Back 166

Abnormal thinking
Encephalopathy
Sedation
Depression
Ataxia
Tremor
Reflux
Knee buckling

Front 167

Levetiracetam (Keppra®)

Back 167

MOA: SV2A binding in the brain
Indications: adjunctive treatment of PS, myoclonic, and GTCS
Metabolism: renal elimination
t½: 6 to 8 hours
Dosage forms: 250, 500, 750, and 1000 mg tablets; 100 mg/ml oral solution; 100 mg/ml intravenous solution
Dose: 1000 - 3000 mg/d
Blood levels: 5 to 50 mcg/ml

good drug to use in combination because unique MOA

has an IV formulation
can get to therapeutic levels in 1 week

Front 168

SE of Levetiracetam (Keppra®)

Back 168

Somnolence, fatigue, incoordination, (resolve after 1st month of tx)
Behavioral changes, dizziness
Sedation, mental disturbances

unmasks psychosis, so don't give to patients with a history of

Front 169

drug interactions with Levetiracetam (Keppra®)

Back 169

Not metabolized by CYP450 pathways
No clinically significant drug-drug interactions (DDI)

Front 170

other uses of Levetiracetam (Keppra®)

Back 170

Migraine
Bipolar?
Pain
Spasticity

Front 171

Levetiracetam (Keppra XR®)

Back 171

Available in 500 and 750 mg tablets
Once daily dosing

Front 172

Oxcarbazepine (Trileptal®)

Back 172

Indications:
Adults: add-on and monotherapy for PS
Children 4 and above: monotherapy for PS
Children 2 and above: add-on therapy
Metabolism: 70% reduction to monohydroxy derivative (MHD) then hepatic glucuronidation
>1200 mg/day: mild inducer/inhibitor
Inhibits CYP2C19; induces CYP3A4 & 3A5
Decreases efficacy of BCP by ~50%

similar to carbamazapine
it is a prodrug that is converted to MHD

Front 173

SE Oxcarbazepine (Trileptal®)

Back 173

Headache
Dizziness, fatigue, sedation
Hyponatremia (2.5%): higher than with CBZ, but mild
Rash < than CBZ, cross allergy 25-30%

Front 174

half life of Oxcarbazepine (Trileptal®)

Back 174

9 hours

Front 175

Zonisamide (Zonegran®)

Back 175

broad spectrum
One of top 3 AEDs used in Japan & Korea
MOA: blocks sodium channels, blocks T-calcium channels, carbonic anhydrase inhibitor
Indication: add-on treatment of PS in adults
Metabolism: hepatic-glucuronidation, kidney elimination, sulfonamide derivative
t½: 27 hours
Dosage forms: 25, 50, and 100 mg capsules
Blood levels: 10 to 30 mcg/ml

if have a sulfa allergy use with caution

therapeutic levels reached in first couple of weeks

Front 176

infusion rates of phenytoin and fosphenytoin for status epliepticus

Back 176

> We also need to know the loading dose and infusion rates of Phenytoin
> and Fosphenytoin in the case of status epilepticus...
> Load with 18-20 mg (or 18-20 mg of phenytoin equivalents) per kg
> Then infuse at a max infusion rate of 50 mg/min for Phenytoin (using
> only normal saline) or max of 150 mg/min for Fosphenytoin (using any
> solution

Front 177

Zonisamide (Zonegran®)

Back 177

One of top 3 AEDs used in Japan & Korea
MOA: blocks sodium channels, blocks T-calcium channels, carbonic anhydrase inhibitor
Indication: add-on treatment of PS in adults
Metabolism: hepatic-glucuronidation, kidney elimination, sulfonamide derivative
t½: 27 hours
Dosage forms: 25, 50, and 100 mg capsules
Blood levels: 10 to 30 mcg/ml

Front 178

inducers and inhibitors

Back 178

felbamate
oxcarbazepin
topiramate

Front 179

drug interactions of Zonisamide (Zonegran®)

Back 179

Metabolized via CYP3A4
May increase [CBZ] as the dose is increased
Phenytoin, carbamazepine and phenobarbital decrease zonisamide clearance
CYP3A4 inhibitors mayincrease [Zonisamide]: antifungals, erythromycin, cyclosporine

Front 180

SE of Zonisamide (Zonegran®)

Back 180

Kidney stones – 4% in clinical trials
Dizziness, somnolence
Parasthesias
Weight loss, anorexia, nausea
Agitation/irritability
Rash, sulfa derivative
Metabolic acidosis

Front 181

Pregabalin (Lyrica®)

Back 181

MOA: binds to the alpha-2-delta subunit of calcium channels
Indication:
Adults: add-on for PS
Metabolism: renal elimination
t½: 5 to 7 hours

membrane stabilization effects glutamate, which affects GABA

Front 182

SE Pregabalin (Lyrica®)

Back 182

Side effects: dizziness, dry mouth, edema, blurred vision, weight gain, somnolence, abnormal thinking

Front 183

drug interactions with Pregabalin (Lyrica®)

Back 183

none

Front 184

other FDA labeled indications of Pregabalin (Lyrica®)

Back 184

Other FDA labeled indications: postherpetic neuralgia, painful diabetic peripheral neuropathy, fibromyalgia

Front 185

schedule of Pregabalin (Lyrica®)

Back 185

V

Front 186

Vigabatrin (Sabril®)

Back 186

MOA: GABA-transaminase inhibitor
Indications:
Adjunctive therapy for refractory complex partial seizures in adults
Infantile spasm
Pharmacokinetics:
Absorption not affected by food
Renally eliminated (adjust dose for CrCl <60ml/min)
Dosage forms:
Powder: Sabril® 500 mg
Tablet: Sabril® 500 mg

Front 187

SE Vigabatrin (Sabril®)

Back 187

Irreversible visual fields defects, drowsiness, fatigue, hyperactivity - children

can lose visual field in 22-25% of the population so it is not first line

Front 188

what is Vigabatrin (Sabril®) used for and the dose(know)

Back 188

Infantile spasm: 50-100mg/kg/day, divided twice daily

Front 189

SACCADES

Back 189

HAVING A PATIENT FOLLOW YOUR FINGER WITH THEIR EYES AND THERE WILL BE SLIGHT JERKS IN THE EYE MOVEMENT
BREAK OF SMOOTH PERSUIT
JUST SHOWS THAT THE PATIENT IS TAKING THE MEDICAITON

Front 190

what AEDS are easily titrated in 1 week

Back 190

lacosamide
zonisamide
levetiracetam

Front 191

completely renally eliminated AEDs

Back 191

pregabalin
vigabatrin
lacosamide
gabapentin

Front 192

what AEDs are emzymatically hydrolyzed

Back 192

Rufinamide
levetiracetam

Front 193

AEDS that are inducers

Back 193

phenobarb
primidone
phhenytoin
forsphenytoin
carbamaepine

topiratate >/=200mg per day

Front 194

AEDs inducers and inhibitors

Back 194

felbamate
oxcarbazepine >/= 1200 mg/day (,ild)

Front 195

AEDs inhibitors

Back 195

valproate

Front 196

levetiracetam dose starting and titration

Back 196

500 mg ORALLY or IV twice daily; increase daily doses by 1000 mg every 2 weeks to reach a target dose of 3000 mg/day

Front 197

topiramate dose

Back 197

■Tonic-clonic seizure, Primary generalized (initial monotherapy): 1st week, 25 mg ORALLY twice daily (morning and evening); 2nd week, 50 mg ORALLY twice daily; 3rd week, 75 mg ORALLY twice daily; 4th week, 100 mg ORALLY twice daily; 5th week, 150 mg ORALLY twice daily; 6th week (maximum dose) 200 mg ORALLY twice daily

■Tonic-clonic seizure, Primary generalized; Adjunct: begin at 25 to 50 mg/day ORALLY; may increase dosage by 25 to 50 mg/day at 1-week intervals to the usual maintenance dose of 400 mg/day in two divided doses

Front 198

valporate dose

Back 198

500 mg PO TID

Front 199

carbamazepin dose

Back 199

400-1200 mg/day

typically 200 mg BID

Front 200

drug interactions with Vigabatrin (Sabril®)

Back 200

Inhibits carbamazepine (major intxn),
Induces phenytoin and fosphenytoin (moderate intxn)

Front 201

Lacosamide (Vimpat®)

Back 201

MOA:
Selective enhancement of sodium channel slow inactivation
Binds to collapsin response mediator protein 2 (CRMP-2)
Indication:
Adjunctive therapy for partial-onset seizures in patients with epilepsy aged 17 years and older

unique

Front 202

PK of Lacosamide (Vimpat®)

Back 202

Not affected by food
Renally eliminated; 300mg/day max for CrCl<30ml/min and mild-moderate liver disease
IV formulation: pH 3.5-5 (possible interface at y-site)

Front 203

does Lacosamivde (Vimpat®) have an injectable form (know)

Back 203

yes

Front 204

SE of Lacosamivde (Vimpat®)

Back 204

headache, nausea, diplopia, PR interval increase (minimal)

affects 3rd degree heart block

Front 205

what schedule is Lacosamivde (Vimpat®)

Back 205

V

Front 206

Rufinamide (Banzel®)

Back 206

MOA: Prolongation of the inactive state of sodium channels
Food increases bioavailability
Protein bound: 34%
Metabolized via enzymatic hydrolysis (not CYP 450 dependent)
Elimination is 85% renal
Plasma half-life is 6-10 hrs
Gastaut syndrome in adults and children ≥4 years old

Front 207

PK of Rufinamide (Banzel®)

Back 207

Food increases bioavailability
Protein bound: 34%
Metabolized via enzymatic hydrolysis (not CYP 450 dependent)
Elimination is 85% renal
Plasma half-life is 6-10 hrs

Front 208

indications of Rufinamide (Banzel®) (know)

Back 208

Adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in adults and children ≥4 years old

Front 209

SE of Rufinamide (Banzel®) (know)

Back 209

Shortened QT interval, headache, somnolence

Front 210

is Rufinamide (Banzel®) better absorbed with food or without (know)

Back 210

with

Front 211

Diazepam (Diastat®)

Back 211

Pre-measured rectal gel in syringe
Indications: selected refractory patients on stable AED regimens who require intermittent use of Diazepam, used to abort cluster seizures
Watch breathing and sedation
NOT intended for maintenance therapy
Dosage forms: 2.5, 10, 20 mg syringe
Onset: ~10 min similar to IV
Side effects: somnolence

works great for children with cluster seizures

shuts of CNS

watch for breathing and sedation

Front 212

Status Epilepticus (know)

Back 212

Life threatening event
Seizures persisting > 30 minutes
Patient does not regain consciousness in between seizures
Status epilepticus can occur with any seizure type

ER situation
can occur with any seizure type

Front 213

Status Epilepticus: First line Treatment (know)

Back 213

First Line Therapy
Benzodiazepines
Lorazepam 0.1 mg/kg or Diazepam 0.5 mg/kg
Slow IV push or IV drip
Rectal suppositories
Phenytoin or Fosphenytoin
Load with 18 to 20 mg or mg PE/kg
Phenytoin: NTE 50 mg/min, only NS
Fosphenytoin: NTE 150 mg/min, any solution
Repeat at ½ of dose if no results

Front 214

what are the differences between lorazepam and diazepam

Back 214

lorazepam is first s choice for status epilepticus

diazepam is more lipid soluble so works more quickly but stops more quickly

Front 215

Phenytoin or Fosphenytoin
and status epileticus

Back 215

Load with 18 to 20 mg or mg PE/kg
Phenytoin: NTE 50 mg/min, only NS (because of microcrystals)
Fosphenytoin: NTE 150 mg/min, any solution
Repeat at ½ of dose if no results

fosphenytoin 20 mg PE/kg (about 1 g)

Front 216

Status Epilepticus: second line Treatment

Back 216

Second Line Therapy
Phenobarbital
20 mg/kg
give at < 100 mg/min IV
has a long half life and is sedating so do not use as often because want to be able to asses the patient
Another barbiturate

Front 217

Status Epilepticus: third line treatment

Back 217

Paraldehyde (not used anymore), lidocaine, IV valproate, IV levetiracetam, valproic acid rectally, general anesthesia

can possible be used as second line instead of phenobarbital,

Front 218

Benefits of Generic Antiepileptic Drugs (AEDs)

Back 218

Decrease cost
Patient
Third party payor
Increase availability
Multiple manufacturing sources
Potential better adherence

can get more patients treated

Front 219

problem with generic AEDS

Back 219

there is a difference in bioequivalence from 80-125% therefore this may be too big of a difference for some patients and lead to loss of seizure control

Front 220

when to obtain Serum Concentrations of AEDs

Back 220

Toxicity
Increased seizures
Documentation of therapeutic levels
Deciphering PK interactions

Don’t treat the level, treat the patient – the patient serves as their own control

very expensive to do