Exam 3- Seizures Flashcards
1
Q
Seizure
A
Characterized by excessive or hypersynchronous discharge of neurons in the cortex. Paroxysmal (sudden, rapid onset)
2
Q
Epilepsy
A
Chronic disorder characterized by recurrent, spontaneous seizures
3
Q
Potential causes for epilepsy
A
Head trauma, stroke, CNS lesion, metabolic disorder, genetic
70-80% of epilepsy has no known cause
4
Q
Can drug withdrawal and overdose cause epilepsy?
A
No, they can precipitate a seizure but not epilepsy.
5
Q
Ion channels and neuronal firing
A
Na channels opening leads to Na influx and depolarization/ action potential. K channels openings leads to K efflux and hyperpolarization.
Na and K impose limits on neuronal firing. They are targets for ASDs.
6
Q
Neuronal networks and surround inhibition: Glutamate- GABA interactions
A
Excitatory neurons (glutamate) activates other excitatory neurons and inhibitory neurons (GABA), which prevent glutamate from activating surrounding circuits.
7
Q
Biochemical properties of K and Na effects on seizures
A
Biochemical properties of K and Na channels limit frequency of neuronal firing, thereby preventing repetitive firing of neurons that characterize seizures.
8
Q
What are brain circuits balanced by?
A
Excitatory (glutamate) and inhibitory (GABA) neurotransmitters
9
Q
Two major categories of seizures
A
Focal onset and generalized onset
10
Q
Focal seizures
A
Begin focally in one hemisphere, often preceded by aura.
11
Q
Focal seizures without altered awareness
A
Motor seizures that cause change in muscle activity
Sensory seizures that cause changes in any one of the senses
Autonomic seizures cause changes in a part of the nervous system that automatically controls body functions.
Psychic seizures can cause changes in how people think, feel, or perceive
12
Q
Focal seizure with altered awareness (complex partial)
A
Usually lasts 1-2 minutes. Starts in an area of the temporal lobe May be preceded by an aura (or warning) Automatisms (involuntary, automatic behaviors) Unaware of surroundings or may wander.
13
Q
Focal seizures with secondarily generalization: loss of consciousness
A
Starts in one area but then spreads to both sides of brain
Short-lasting but may take longer to recover
14
Q
Generalized seizures
A
Begins in central brain (thalamus) region and spreads to both hemispheres. Tonic-clonic Absence (petit mal) Myoclonic Atonic
15
Q
Tonic-clonic (grand mal) seizure
A
Tonic phase- all muscles stiffen. Patient often loses consciousness and falls, Tongue or cheek may be bitten
Clonic phase- arms and legs begin to jerk rapidly. Consciousness returns but patient may be drowsy, confused. May take 30 min for patient to return to normal.
16
Q
Absence seizure
A
Brief lapse in awareness, blank stare, rapid recovery
Bursting activity of calcium channels give rise to abnormality in thalamo-cortical circuit.
17
Q
Myoclonic seizure
A
Consciousness preserved, short muscle jerks
18
Q
Atonic seizure
A
Consciousness preserved. Loss of muscle strength bilaterally, patient falls
19
Q
Status epilepticus
A
An epileptic seizure of longer than 5 minutes or 2 or more seizures within a 5 min period without person returning to normal.
Seizure can be tonic-clonic, complex partial, or absence
Mortality 22%
Causes severe brain inflammation and injury, functional deficits and epilepsy
20
Q
What was the first anti-seizure drug?
A
Phenobarbital in 1912
21
Q
Anti-seizure agents
A
Suppress the rapid and excessive firing of neurons during seizures.
Prevent the spread of seizures within the brain
Only provide symptomatic treatment with many AE
Have not been demonstrated to alter the course of epilepsy
22
Q
Mechanisms of anti-seizure agents
A
Ion channels- drugs that enhance Na channel inhibition, inhibit T-type and voltage-activated calcium channels, activates K channels.
Receptors- GABA, Glutamate
Actions on synaptic vesicle protein (SV2A) or special Ca channels
23
Q
Drugs that enhance Na channel closure
A
Agents prolong refractory period of sodium channel, thereby preventing repetitive neuronal firing
Target sodium channels opening and closing rapidly
Phenytoin, carbamezapine, lamotrigine, valproate, zonisamide, ruflinamide
Strong specificity for focal and secondarily generalized seizures.
24
Q
Drugs that inhibit T-type calcium channels
A
Include ethosuximide, valproic acid
Effective against absence seizures, which involve abnormal calcium currents originating in the thalamus
25
Calcium channel drugs
Pregabalin and Gabapentin inhibit high voltage activated calcium channels. They are structurally related to GABA but their main action is to inhibit calcium channels and glutamate release
26
Potassium channel drugs
Ezogabine (only drug in class)
Activates voltage gated K channels
Stabilizes membrane potential and reduces brain excitability
27
Drugs that facilitate GABA mediated inhibition moa
GABA-A receptor is a chloride channel. Opening this channel hyperpolarizes neuron, making is less likely to fire.
28
Drugs acting on the GABA/ benzodiazepine receptor MOA
Benzodiazepines (diazepam)- bind to receptor and facilitates GABA mediated Cl flux. Positive allosteric modulators.
Barbiturates- also bind to GABA/ Benzo receptor to facilitrate chloride flux. Limited by their sedative properties.
29
Receptor targeting anti-seizure drugs: glutamatergic inhibitors
Drugs that diminish glutamatergic excitation
Felbamate, topiramate
Secondary effects to block glutamate receptor function (less excitation)
Perampanel selectively blocks glutamate receptors. 1st drug in class for tx of epilepsy.
30
Problems with sodium channel drugs
Phenytoin- saturation kinetics. Small increase in dose may lead to large increase in plasma concentrations and AE (hirsutism, cardiac and CNS depression).
Carbamazepine- induces more P450 system thereby decreasing its own 1/2 life and requiring more frequent dosing.
31
Problems with benzos/barbiturates
Limited due to dizziness, sedation, and abuse
Withdrawal- increased seizure frequency w/ abrupt d/c
Diazepam useful for aborting seizure acutely (status epilepticus)
32
Anti-seizure drugs and pregnancy
Possible teratogenic effects of valproate, phenytoin, topiramate
Minimize exposure to pregnant women, but they still need to be treated.
33
Epidiolex
FDA approved for Dravet and Lenox-Gastaut syndromes
| Purified, plant derived cannabidiol (CBD)
34
Abnormal neurophysiology in seizures
Surround inhibition may be overcome, leading to increased neuronal discharge.
- Increased extracellular K, weakening hyperpolarization
- Rapidly firing neurons may activate glutamate receptors
- Decreased GABA inhibition is a major factor. (there is no longer GABA inhibiting glutamate from exciting surrounding neurons)
35
Valproic acid MOA
enhance sodium channel inhibition, inhibit T-type calcium channels, increase GABA synthesis, and inhibit GABA metabolism
36
Gabapentin MOA
Facilitates GABA release (minor) and blocks calcium channels inhibiting neurotransmitter release (major)
37
Vigabatrin MOA
Inhibits GABA metabolism
38
Tiagabine MOA
Inhibits GABA reuptake by neurons and glia
39
Felbamate and Topiramate GABA MOA
Facilitate actions of GABA on receptor site
40
Stiripentol MOA
Facilitates GABA action
41
1st generation ASDs
```
Phenobarbital
Primidone (metabolized into phenobarbital)
Phenytoin
Carbamazepine
Valproate
```
42
1st generation ASDs
```
Phenobarbital
Primidone (metabolized into phenobarbital)
Phenytoin
Carbamazepine
Valproate
```
43
Phenobarbital forms
PO and IV
44
Phenobarbital metabolism
Hepatic
45
Phenobarbital- enzyme induction?
Yes CYP2C9/19 enzyme inducer
46
Phenobarbital half life
Very long 1/2 life (2-5 days)
| Needs loading dose
47
Phenobarbital AE
Drowsiness, sedation, ataxia, CNS depression
Cognitive and behavioral, altered bone metabolism
Respiratory and CV effects with IV use
48
Phenobarbital therapeutic concentrations
19-40mcg/ml
49
How do you increase phenobarbital doses?
Increase every 2-3 weeks by 30-60 mg
50
Phenytoin forms
PO and IV
51
Phenytoin metabolism
Hepatic (CYP2C19)
52
Phenytoin protein bounding
Highly protein bound!
Check free concentration (1-2mcg/mL) in patients with low albumin, on other highly PPB drugs (valproate), patients with decreased renal function
53
Is phenytoin an enzyme inducer?
Yes, STRONG 3a4/5
54
Phenytoin dose-concentration profile
Non-linear
55
Phenytoin AE
Dose related- drowsiness, sedation, ataxia, nystagmus
| Idiosyncratic- gingival hyperplasia, hirsutism, anemia, lymphadenopathy, altered bone metabolism, rash
56
Phenytoin IV administration
Max rate 50 mg/min but slower is safer
57
Phenytoin BBW
CV risk with rapid infusion (hypotension)
58
What should you monitor for for Phenytoin IV LD?
Hypotension and bradycardia
59
Phenytoin therapeutic concentration
10-20 mcg/ml
60
Rules to adjust phenytoin doses to avoid toxicity
7/11 rule
SS plasma level <7 mcg/mL - increase dose by 100 mg/day
SS plasma level 7-11 mcg/mL- increase dose by 50 mg/day
SS plasma level >11 mcg/mL- increase dose by 30 mg/day
61
Phenytoin patient counseling
Need regular dentist visits
Need labs
Do not crush ER capsules
Keep seizure diary
62
Carbamazepine forms
PO and IV
63
Carbamazepine metabolism
Hepatic, auto inducer (induces own metabolism)
64
Carbamazepine enzyme inducer?
Yes, 3A3/4/5
65
Carbamazepine AE
Dose related- drowsiness, sedation, diplopia, N
| Idiosyncratic- hyponatremia, leukopenia, aplastic anemia, rash, decreased calcium absorption
66
Carbamazepine BBW
CV risk w/ rapid infusion
| Fatal skin reactions/ Stevens-Johnson syndrome (HLA-B*1502 predictive)
67
Valproate forms
PO and IV
68
Valproate metabolism
Hepatic
69
Valproate PPB
Highly protein bound (90%)
| PPB is saturable at higher doses
70
Valproate indications
Absence, simple, complex, and complex partial
71
Valproate increasing dose
Doses may be increased weekly by 5-10 mg/kg/day until effective or toxicity occurs
72
Valproate therapeutic concentration
40-120 mcg/ml
73
Valproate AE
Dose related- tremor, drowsiness, sedation, N/V, hepatotoxicity
Idiosyncratic- weight gain, hair loss, pancreatitis, decreased ca absorption
74
Valproate in pregnancy
Teratogen
| Birth defects- spina bifida
75
Valproate brand names
Depakene, Stavzor, Depakote, Depacon
76
Valproate counseling
Lab- liver function tests, CBC, drug levels
| Monitor for weight gain, increased appetite
77
Valproate BBW
CV risk with rapid infusion
| Hepatotoxicity
78
Limitations of first generation ASD
Limited dosage forms available
All are hepatically metabolized
DDI
Significant AE
79
Phenobarbital MOA
GABA receptor agonist
80
Phenytoin MOA
Prolongs Na channel inactivation, thereby preventing repetitive neuronal firing
81
Phenytoin birth defect
Fetal hydantoin syndrome
82
Phenytoin saturation kinetics
Small increase in dose can lead to large increases in concentration and toxicity
83
Carbamazepine MOA
Prolongs Na channel refractory period thereby preventing repetitive neuronal firing
84
Ethosuximide
Inhibits T-type calcium channels
| 1st line for absence seizures
85
Felbamate form
PO
86
Felbamate metabolism
Hepatic
87
Felbamate indication/ when is it used?
Lennox-Gastaut Syndrome (LGS)
and partial seizures (focal)
Only used when benefit outweighs the risk due to hepatotoxicity and aplastic anemia
Informed consent must be signed prior to use
88
Felbamate MOA
Facilitates actions of GABA at receptor site, decreases glutamate excitation
89
Gabapentin form
PO
90
Gabapentin indication
Partial seizures w/wo secondary generalized seizures (tonic-clonic)
91
Gabapentin metabolism
Renal 100%
92
Gabapentin AE
Dizziness, drowsiness, sedation, weight gain
93
Lamotrigine form
PO
94
Lamotrigine metabolism
hepatic
95
Lamotrigine AE
drowsiness, but may be the least sedating
96
Lamotrigine BBW
Rash, serious skin rxns
| Factors associated with rash- age <16, VPA use, high doses
97
Lamotrigine dosing
On EIASD's (phenobarbital, phenytoin, carbamazepine) W/O valproate= 25 mg QD for two weeks, increase after
On EIASD's WITH valproate- 25 mg every other day for 2 weeks, then increase
98
Lamotrigine MOA
Enhances Na channel closure, thereby preventing repetitive neuronal firing.
Acts on high voltage Ca channels
99
Lamotrigine indication
Myoclonic, tonic-clonic
| May be helpful in LG
100
Topiramate MOA
Facilitates actions of GABA at receptor site, decreases glutamate excitation
101
Topiramate forms
PO
102
Topiramate metabolism
Renal
103
Topiramate AE
Mental slowing, drowsiness, ataxia, dizziness, renal calculi, acute glaucoma, weight loss, oligohidrosis, paresthesia`
104
Topiramate indications
Tonic-clonic or partial (focal) seizures
| Adjunct treatment for LGS
105
Topiramate titration
Slower titration for patients with decreased renal function or not on EIASD
106
Tiagabine MOA
Inhibits GABA reuptake
107
Tiagabine forms
PO
108
Tiagabine metabolism
Hepatic metabolism
109
Tiagabine PPB
Highly protein bound (>96%)
110
Tiagabine indications
Adjunct for partial (focal) seizures
111
Tiagabine AE
Dizziness, asthenia/lack of energy, somnolence, Nausea, nervousness
112
Levetiracetam forms
PO and IV
113
Levetiracetam indications
Adjunctive therapy for partial, myoclonic, and generalized tonic-clonic seizures
114
Levetiracetam metabolism
25% hydrolyzed
| 75% renal
115
Levetiracetam AE
headache, dizziness, somnolence, depression
116
Oxcarbazepine indications
monotherapy for adults with partial seizures
| Adjunct therapy for partial seizures in adults and children >4
117
Oxcarbazepine AE
Dizziness, fatigue,. HA, hyponatremia ( more common than with carbamazepine), rash, diplopia/double vision, somnolence
118
Who has the greatest risk of hyponatremia on oxcarbazepine?
Elderly patients on diuretics
119
Zonisamide MOA
Enhance Na channel closure
| T-type calcium channels
120
Zonisamide forms
PO
121
Zonisamide indication
Adjunct for partial seizures
122
Zonisamide PK profile
Extensively bound to erythrocytes
Hepatic metabolism
Very long t1/2 (50-69 hours)
Up to two weeks to reach SS
123
Zonisamide AE
Sulfonamide compound; possible skin reactions, Stevens-Johnson syndroms
Drowsiness, N/V, ataxia, kidney stones, anorexia, paresthesia
124
Fosphenytoin
Phenytoin prodrug
Rapidly converted into PHT
Water soluble, not dissolve din propylene glycol, ethanol
125
Fosphenytoin form
Only IV
126
Fosphenytoin BBW
CV risk with rapid infusion
127
Pregabalin MOA
Inhibit voltage gated calcium channels, inhibiting glutamate release
128
Pregabalin forms
PO
129
Pregabalin PK
Renal metabolism
| >90% bioavailable
130
Pregabalin indication
Adjunctive treatment for partial onset seizures
131
Pregabalin AE
Dizziness, weight gain, edema, somnolence, ataxia, dry mouth, blurred vision
132
Lacosamide (Vimpat) forms
PO and IV
133
Lacosamide PK
Renal
134
Lacosamide indication
Adjunct in partial onset seizures w/ epilepsy
| Adjunct of primary GTC seizures >4 yo
135
Lacosamide AE
Diplopia, HA, dizziness, N, ataxia, syncope, hypersensitivity rxns
136
Lacosamide caution
Caution in patients with cardiac conduction problems (increases PR interval)
137
Ruflinamide MOA
Na channel closure
138
Ruflinamide form
PO
139
Ruflinamide PK
Hydrolysis, not CYP dependent
140
Ruflinamide AE
Somnolence, loss of coordination, dizziness, gait disturbances, QT shortening, ataxia`
141
Ruflinamide indications
Adjunctive for LGS >4 years old
142
Vigabatrin MOA
Inhibit GABA metabolism
143
Vigabatrin form
PO
144
Vigabatrin indications
Adjunct for adults with refractory complex partial seizures who have inadequately responded to other medications
Monotherapy for peds 1 month- 2 years with infantile spasms
145
Vigabatrin PK
Renal excretion
146
Vigabatrin AE
Permanent vision loss, anemia, somnolence, peripheral neuropathy, weight gain, edema
147
Vigabatrin and vision loss
Permanent bilateral concentric visual field loss in 30% or more of patients
Need vision testing at baseline and every 3 months
SHARE rems progam
148
Clobazam form
PO
149
What makes clobazam unique?
It is the only 1,5 benzo available (the rest are 1,4)
150
Clobazam indication
Adjunct for LGS in >2 years old
151
Clobazam PK
Hepatic
152
Clobazam AE
Somnolence, lethargy, dizziness, mood changes, irritability, more behavioral effects in children
Tolerance less likely than with other benzos
153
Perampanel MOA
Selective AMPA type glutamate receptor noncompetitive antagonist
154
Perampanel formn
PO
155
Perampanel Use
Adjunct for partial onset > 12 yo
156
When should you avoid perampanel?
In severe renal or hepatic disease
157
Perampanel PK
70% urine elimination
| Extensively metabolized by CYP then glucuronidation
158
Perampanel AE
Dizziness, somnolence, HA, fatigue
159
Perampanel DDI
Using with EIASDs significantly reduces T1/2. May need to start at higher doses and titrate up faster
160
Eslicarbazepine MOA
Voltage gated sodium channel blocker
161
Eslicarbazepine PK
Hydrolysis
| 90% urine excretion
162
Eslicarbazepine indications
Adjunct for partial onset
163
Brivaracetam MOA
Unknown, displays high affinity for sv2A in brain
164
Brivaracetam uses
Adjunct for partial onset > 16 yo
165
Brivaracetam form
PO, IV
166
Brivaracetam PK
Hepatic metabolism
167
Epidiolex indications
Seizures in LGS or Dravet syndrome >2 years old
168
Epidiolex AE
Somnolence, decreased appetite, diarrhea, transaminase elevations, fatigue, malaise, asthenia, rash, insomnia, infections
169
Stiripentol indications
Pts >2 yo who are taking clobazam for Dravet
170
Stiripentol form
po
171
Stiripentol PK
Hepatic
| Highly PPB
172
Stiripentol admin
Capsules must be swallowed whole with water during a meal
173
Cenobamate moa
modulation of GABA channels and decrease excitatory currents by inhibiting sodium currents
174
Cenobamate indication
partial onset seizures in adults
175
cenobamate form
PO
176
Cenobamate PK
metabolism by glucuronidation and oxidation
| very long t1/2
177
Cenobamate contraindication
Contraindicated in familal short QT syndrome
178
Cenobamate ae
diplopia, N, somnolence, dizzinesss, fatigue, HA
179
Fenfluramine indication
tx of seizures with Dravet syndrome >2 yo
180
Fenfluramine BBW
Valvular HD
| FINTEPLA REMS program
181
Fenfluramine PK
hepatic metabolism
182
Fenlfluramine AE
Decreased appetite, somnolence, sedation, lethargy, diarrhea, constipation, abnormal ECG, fatigue, malaise, asthenia, ataxia, balance disorder, gait disturbances, drooling, HTN, salivary hypersecretion, pyrexia, upper RTI, vomiting, weight loss, fall, status epilepticus
183
Patient counseling: Oxcarbazepine
Dizziness, sedation, N/V
184
Patient counseling: Levetiracetam
Behavioral changes, N/V
185
Patient counseling: Topiramate
dizziness, paresthesias, weight loss, drink fluids
186
Patient counseling: Lamotrigine
Dizziness, rash, N/V
187
Patient counseling: Pregabalin
Peripheral edema, dizziness, weight gain
188
Patient counseling: Lacosamide
Dizziness, HA, irregular heart beat
189
Patient counseling: Ruflinamide
Somnolence, dizziness
190
Patient counseling: Vigabatrin
Permanent vision loss
191
Patient counseling: Clobazam
Sedation
192
What are the default DOC for seizures?
Carbamazepine, phenytoin, oxcarbazepine
193
What ASD do you avoid in bleeding?
Valproate
194
What ASDs do you avoid in a history of a rash, hypersensitivity reaction, S-J syndrome?
Phenytoin, carbamazepine, lamotrigine, oxcarbazepine
195
What ASDs do you use in a patient with hepatic impairment or if DDI are a concern?
Gabapentin, levetiracetam, pregabalin, topiramate, tiagabine, lacosamide
196
What drugs do you use if you use for rapid titration?
Phenytoin, valproate, gabapentin, levetiracetam
197
What is DOC ASD for the elderly?
Gabapentin
198
What is the least sedating ASD
Lamotrigine
199
Non-pharm seizure treatment
Surgery
Vagal nerve stimulation
Ketogenic diet
200
Switching ASD
Start new ASD at a low dose and gradually increase dose. The previous drug should be tapered gradually.
201
Stopping ASDs
Five criteria must be met:
- No seizures for 2-5 years
- Normal neurological examination
- Normal intelligence
- Single type of partial or generalized seizure
- Normal EEG with treatment
202
Methods of contraception and ASDs
Those with 1st pass hepatic metabolism most affected (morning after pill, oral contraceptive)
If choosing to take combined OCP, must contain 50mcg of estrogen at a minimum
203
Levonorgestrol impants and ASDs
Contraindicated with enzyme inducers due to VERY strong failure rate
204
Mirena coil and ASD
Releases progestin and is not affected by hepatic metabolism
205
Depo-provera and ASD
Injections may need more frequent dosing
206
ASDs that do not affect OCPs
```
Gabapentin
Lacosamide
Levetiracetam
Pregabalin
Zonisamide
Valproate
Lamotrigine
```
207
ASDs that affect OCPs
```
Carbamezapine
Oxcarbemazepine
Phenobarbital
Phenytoin
Primidone
Topiramate
Felbamate
```
208
Oral contraceptives decrease the concentrations of which ASDs?
Lamotrigine and valproate
209
ASD use during pregnancy
Use one ASD if possible at the lowest possible dose. Use the most effective ASD.
Administer at least 4-5 mg/day folic acid
210
Breastfeeding and ASD
Depends on protein binding property of ASD
Risk of sedation, irritability, failure to gain weight
Recommend baby nurse prior to taking ASD
Consider monitoring levels, especially for lamotrigine
No effect on cognitive outcomes
211
Phenobarbital and valproate combo AE
Sedation and weight gain
212
Phenytoin and carbamazepine AE
Dizziness and diplopia
| Maintaining therapeutic doses can be difficult
213
Valproate and lamotrigine combo
Requires adjustment of lamotrigine dose because of increased lamotrigine levels
214
Topiramate, Lamotrigine, or zonisamide and enzyme-inducing drugs (carbamazepine, phenytoin)
Doses of the additive drugs to enzyme-inducers will need to be substantially higher because of increased clearance
215
Benozodiazapines AE
Hypotension, CNS depression
216
Emergency therapies for SE
Diazepam, Lorazepam, Midazolam
217
Urgent therapies for SE
Brivaracetam, Fosphenytoin, Lacosamide, Levetiracetam, Phenobarbital, Phenytoin, Topiramate, Valproate
218
Refractory therapies for SE
Ketamine, Midazolam, Pentobarbital, propofol
219
Divalproex ER brand and dose
Depakote 500-750 TID
220
Valproic acid brand and dose
Depakene, Stavzor
| 500-750 BID
221
Phenytoin brand and dose
Dilantin 100-500 mg QD
222
Levetiracetam brand and dose
Keppra, 500-1000mg BID
223
Lamotrigine brand and dose
Lamictal 100-200 BID
224
Pregabalin brand and dose
Lyrica, 100-200 bid
225
Gabapentin brand and dose
Neurontin 300-600 TID
226
Topiramate brand and dose
Topamax 50-100 mg BID
227
Carbamazepine brand and dose
Tegretol XR, Carbatrol/Equestrol
| 200-600 BID
228
Which drugs have renal elimination?
Gabapentin, Topiramate, Levetiracetam, Pregabalin, Lacosamide, Vigabatrin, eslicarbazepine, ezogabine, ruflinamide
