!Antiepileptic Agents Flashcards
(106 cards)
1
Q
What is a seizure
A
Transient alteration of behavior due to disordered, synchronous, and rhythmic firing or populations of brain neurons
-a disorder of neuronal excitability
2
Q
Epilepsy
A
Acquired or inherited malfunction of neuronal ion channels of neurotransmitter systems disrupting normal electrical activity in the brain
3
Q
Partial seizures
A
Beginning vocally in a cortical site
4
Q
Simple partial seizure
A
Preservation of consciousness
5
Q
Complex partial seizure
A
Impairment of consciousnesss
6
Q
Generalized seizure
A
Can occur after starting as a partial sz
Involves both hemispheres widely from the outset
—thalamus+cerebral cortex propogation
7
Q
Manifestation seizures
A
Determined by functions normally served by cortical site where seizures arises
8
Q
What are the types of generalized seizures
A
Absence seizures
Myoclonic seizure
Tonic clonic seizure
9
Q
Membrane depolarization leads to enhanced __ receptor function and reduced __ function
A
Excitatory (glutamate aspartate)
GABA
10
Q
What happens in the presynaptic terminal of GABA neuron
A
Glutamate is turned to GABA by GAD then stored in vesicles
GABA is turned to succinic semi-aldehyde by GABAT
11
Q
What happens when GABA leaves the presynaptic terminal (either through GAT-1 or vesicle release)
A
Bind GABAA on post synaptic and extrasynaptic on postsynaptic neuron
Also
Enters astrocytes where it is turned to succin semi-aldehyde by GABA-T
12
Q
Antiepileptic drugs (AEDs) act on what
A
Voltage gated Nav channels
13
Q
What happens when AED bind voltage gated Nav channels
A
Generate rapid, transient inward currents driving action potential upstroke (excitable neuronal cells)
Cause neuronal action potential
14
Q
Within a few milliseconds, the Nav channels close form inside the neuron and go into a __ __ state from which they cannot be deactivated..directly or instantly
A
Fast inactivated
15
Q
Nav channels return to resting potential. After depolarization and repetitive neuronal activity, the Nav channel goes into a __ ___ state by closing the pore from the INSIDE
A
Slow inactivated
16
Q
Nav resting state
A
-70 V
Activation gate closed
Inactivation gate open
17
Q
Nav open state
A
Activation gate open
Inactivation gate open
0V
18
Q
Fast inactivated state
A
Open activation gate
Closed inactivation gate
+25 V
19
Q
Inactivated closed state
A
Closed activation gate
Closed inactivation gate
-70V
20
Q
Resting state
A
Closed activation state
Open inactivation state
-70V
21
Q
Where do AED bind the Nav receptor
A
At the interior side channel pore
22
Q
If activation gate is open AED can ___ pore
A
Access
23
Q
If inactivation gate is closed, AED ___ access pore
A
Cannot
24
Q
Open is depolarized or depolarizing
A
Depolarizing
25
Fast inactivated state is depolarized or depolarizing
Depolarized
26
What states is the activation gate closed
Resting and inactivated closed
27
What states is the activation gates open
Resting state, open state, fast inactivated state
28
AED lamotrigine
Holds the fast inactivated state shut
29
The probability of a Nav blockade is proportional to the frequency of Nav channel opening and the _-
Dose
30
Epileptic seizures involve neurons firing at __ frequency than normal
Higher
31
Nav blockers act preferentially on neurons involved in __
Disease
32
Effects of AED
Prolong fast inactivation
Enhance slow inactivation
33
Which AED prolong fast inactivation state of Nav ion channels
Carbamazepine, oxcarbazine, lamotrigine, phenyoin, rufinamide, topiramate, valproic acid, zonisamide, and lacosamide
34
Which AED enhance slow inscativation of Nav chennsl
Lacosamide
(Reduces amplitude and frequency of sustained repetitive firing spikes when stimulus was prolonged to tens of seconds as opposed to less than 1 second (as with fast activators)
35
Lacosamide
Bind Nav
36
Which drugs bind Nav on presynaptic terminal
Phenytoin, carbamazepine, lamotrigine, LACOSAMIDE, zonisamide, oxcarbazepine, topiramate, valproic acid
37
What drugs are AMPA receptor antagonists
Topiramate and perampanel
38
What are AMPA receptors
Ligand gated ion channels Glu binding causes depolarization
39
Name a NMDA receptor antagonist
Felbamate
40
What is NMDA
Ligand gated ion channels Glu binding causes depolarization
41
When the GABA receptor is unoccupied, the Cl channel is___
CLOSED inactivated
42
When GABA receptor is occupied the Cl channel is ___
Open
43
What happens when GABAA receptor occupied
Hyperpolarization blunts AP propagation
44
What drugs stop the biosynthesis of GABA in the presynaptic neuron(L-glu to GABA by glutamic acid decarboxylase)
Vigabatrin
Valproic acid
45
What does vigabatrin do
Stop GABAT
46
What does valproic acid strop
GABA-T and SSD
47
What drug stops the reuptake of GABA by the terminal by GAT-1
Tiagabine
48
What is GAT-1
Actually for reuptake
49
What drugs enhance post synaptic GABA-Eric neuronal transmission
1. barbiturates (phenobarbital/primidone)
2. benxodiazapines (lorazepam/diazepam/clonazepam)
3. Topiramate
50
Benzodiazepines
Bind to a distinct site->allosteric change potentiation GABA binding->Cl channels open with greater frequency
51
Barbiturates
Bind to a distinct site and increases the duration of Cl channel opening
52
Toxicity barbiturates
High doses of barbiturates are GABA independent
Lethality PB>benzodiazepines
53
Lethality PB_BZd
>
54
Barbiturates is ___ and benzodiazepine is ___
GABA independent
| GABA dependent
55
Barbiturates lethality
Respiratory depression
| Coma
56
Topiramate
GABAA agonist-
| Increases frequency of GABAA receptor activation (AND fast inactivation of Nav channels AND AMPA-receptor antagonist)
57
What are neuronal T type Ca channels
Mediate 3 Hz spike and wave activity in the thalamus
58
Hallmark of what is of 3-Hz spike and wave activity in thalamus by T type Ca channels
Absence (Petit mal )seizures
59
AED inhibit T type Ca channels
Useful for controlling absence seizures
60
How treat absence seizures
Antagonist of T type Ca channels to target cortex-thalamus oscillation
61
Ethosuximide
Narrow spectrum
Only used for absence seizures
Only limits Ca excitation (Ca channel)
62
Ethosuximide, valproic acid, zonisamide
Antagonists of T type Ca channels
Prolong fast inactivation of Nav channels (valproic and zonisamide)
GABA-T inhibitor (valproic acid)
63
What does levetiracetam
Books SV2A which allows release of synaptic vesicles of GAB from neuron presynaptic
64
What do gabapentin and pregabalin do
Block a2delta subunit of P/Q-type Ca channel on presynaptic neuron
65
What does retigabine do(only available in EU)
Block KCNQ K channel on pre and post synaptic which causes efflux of K
66
What factors do physicians use to select AED
```
FDA indications
Side effects/toxicity profile
Pharmacokinetics-adherence (prevalence of significant medication non adherence in epilepsy has been reported to vary between 26 and 79%
Drug drug interactions
Routes of administration
Cost
```
67
Broad warning risk of all AED
Abrupt withdrawal of antiepileptic medication may precipitate status epilepticus
Suicidal behavior and ideation
Suggests that the risk apples to all AED used for any indication
68
Phenytoin pharmacokinetics
Zero order-dose titration upward may exceed Vmax of patient
69
Phenytoin serum drug level monitoring
10-20 mg
Come >50 mcg/mL
Circulatory/respiratoy depresssion and death >95 mcg/mL
70
Phenytoin is an inducer go what
CYP-450
Frequent drug drug interactions
71
Toxicities of phenytoin
```
Gingival hyperplasia (oral hygiene vital0
Hypothyroidism
CV risk (arrhythmia/hypotension
Hypocalcemia/vit D deficits/osteoporosis **
```
72
Osteopenia/osteoporosis are SE associated with
Carbamazepine, phenytoin, phenobarbital,valproic acid
73
Why do carbamazepine, phenytoin, phenobarbital, and valproic acid cause osteopenia/osteoporosis
Induce CYP450 dependent vitamin D catabolism, thereby reduce circulating vitamin D levels. Resultant decreased absorption of intestinal Ca can trigger compensatory PTH mediated responses that demineralization bone to maintain systemic Ca homeostasis
74
Carbamazepine serum monitoring level
4-12 mcg/mL
75
Carbamazepine is an inducer of what
CYP 450 enzymes
Frequent drug drug interactions
Induces auto induction (self metabolism)
76
Toxicities carbamazepine
Hematologic also:leukopenia/neutropenia/thrombocytopenia
Hypocalcemia/vitamin D deficit/osteoporosis
77
CBZ induces its own ____
Metabolism (also lamotrigine does this)
78
After 14 days of CBZ (and sometimes lamotrigine) CYP is increased. What does this cause
CBZ more metabolized and decrease in efficacy and could get recurrence of seizures
79
Oxcarbazepine
Analogue of carbamazepine with fewer CNS/hematologic always SE;s due to formation of an alternative active metabolite, and is a less potent CYP450 inducer (dose dependent) (AE cross sensitivity 30%)
80
Ox-CBZ turned into 10-monohydroxy ox-CBZ (s-licarbazine) by what
Reductase
81
10-monohydroxy ox-CBZ (S-licarbazine) is turned to glucuronide with what
Conjugation
82
What happens when CYP3A4 reacts with CBZ
CBZ-10,11 epoxied (active and TOXIC)
83
What happens when CBZ-10,11 epoxied reacts with epoxied hydroplane
10,11-diol and glucuronides
84
Eslicarbazepine
A prodrug converged to S-licarbazine
85
Phenobarbital serum drug level monitoring
10-40mcg.mL
Coma/respiratoy depression >50mcg/mL
Fatality risk >80 mcg.mL
86
Phenobarbital is an inducer of what
CYP-450
| Frequent drug drug interactions
87
Toxicities of phenobarbital
CNS depressant
| Hypocalcemia/vitamin D deficit/osteoporosis
88
Vigabatrin is prescribable only by what
REMS program
89
Toxicities of vigabatrin
Progressive, permanent, bilateral, concentric vision loss
D/C after mac of 3 months if no effective response
90
Drug drug interactions associated with hepatic CYP450 induction
Carbamazepine, phenytoin, phenobarbital, valproate
91
AED inducers can increase clearance of __ __ metabolized by CYP isoenzymes
Oral contraceptives
2-4 fold rise in OHC failure rate risk for unplanned pregnancy
92
What birth control can you use with AED inducers
Long lasting reversible contraceptives including copper or levonorgestrel IUDs and etonogestrel implants
93
AED inducers can increase clearance of ___ metabolized by CYP
Warfarin
Less anticoagulation elevated risk for arterial/venous thrombosis
94
AED inducer can increase clearance of __ medication metabolized by CYP isoenzymes
HIV
| Elevated risk for HIV replication
95
Valproic acid and lamotrigine inhibit what
Conjugation of drugs by glucuronosyltransferases (UGT) causing accumulation of parent drug (espicially each other when used together)
96
Phenytoin, carbamazepine and phenobarbital induce what
Conjugation of drugs by glucuronosyltransferases (UGT) causing reduction or parent drug (when given with valproic acid)
97
Mixed clearance newer AED
Minimize drug interactions
98
Renal clearance of newer AED minimized drug interactions . What drugs
Levetiracetam/topiramate/oxcarbazepine/gabapentin/pregabalin/vigabatrin
99
65-100% renal clearance of these drugs. Renal insuffiency causes what
Dose adjustment
100
Status epilepticus-a medical emergency
A seizure that persists for a sufficient length of time or is repeated frequently enough that recovery between attacks does not occur
101
Causes of status epilepticus
Abrupt withdrawal of AEDs, BZds, opoids, alcohol, brain mass/trauma, infection, fever
102
Initial therapy of epilepticus in adults
In 1st IV
-lorazepam .1mg/kg IV or 4mg IV (max 2 mg/minute)
Alternatives
-diazepam .15 mg/kg IV up to 10 mg per dose (max 5 mg/minute)
Wait 1 minute for response then additional lorazepam PRN
If no IV
Midazolam 10 mg IM is weight >40 kg
In second IV
Fosphenytoin 20mg/kg PE at 100 to 120 mg PE/minute OR
Phenytoin 20mg/kg at 25 to 50 mg/minutes OR
Valproic acid 30 mg/kg at 10 mg/kg/minute
Levetiracetam 40 to 60 mg/kg (maximum 4500 mg) over 15 minutes
103
Second line therapy for treatment of convulsive status
Repeat fosphenytoin if given previously or choose among first line drugs not already given
Intubation, mechanical ventilation
Continuous blood pressure, cardiac monitoring
Prepare for continuous midazolam or propofol infusion
Then midazolam, propofol, pentobarbital
104
Parenteral benzodiazepine choices initial regimen
Lorazepam, diazepam, midazolam, clonazepam
105
Non sedation antiseizure choices (initial regimen )
Phenytoin, fosphenytoin, valproate, levetiracetam, lacosamide
106
How treat status epilepticus
Initial therapy
-lorazepam or diazepam
Wait a minute for response then additional lorazepam
If no IV
Midazolam
In second IV
Fosphenytoin, or phenytoin, or valproic acid, or levetiracetam
Then correct metabolic abnormalities
Then repeat fosphenytoin incubate
Then prepare for continuous midazolam or propofol infusion
Start midazolam, propofol or pentobarbital
