Term
| the clinical manifestation (sensory, motor, emotional, autonomic) of an abnormal, excessive synchronous discharge of a population of cortical neurons |
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Definition
seizure
can be caused by drugs, head trauma, brain tumors, epilepsy |
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Term
| chronic recurrence of seizures occurring spontaneously |
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Definition
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Term
| seizure originating in one area of the cortex; remains ipsilateral |
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Definition
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Term
| seizure involving areas of both hemispheres |
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Definition
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Term
| a process (development of a hyperexcitable neuron network) that results in chronic seizures |
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Definition
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Term
| neuron damage or death associated with excessive/repeated neuron activation (for example, during status epilepticus) |
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Definition
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Term
| drug binding is dependent on the conformation of the target receptor associated with "use" |
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Definition
use dependent mechanism
AED bind the REFRACTORY state of the Na channel |
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Term
| symptoms of a simple partial seizure |
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Definition
symptoms vary depending on location of abnormal activity in the brain: motor cortex, sensory cortex, visual cortex
CONSCIOUSNESS IS PRESERVED
spread to ipsilateral regions within the cortex
abnormal brain activity starts in one functional area and may spread ipsilateral (on the same side, does not spread to other hemisphere) |
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Term
| symptoms of a complex partial seizure |
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Definition
symptoms typically result from abnormal activity in the temporal lobe or frontal lobe
ALTERED CONSCIOUNESS (IMPAIRED MEMORY OF ICTAL PHASE)
often associated with automatism (lip smacking, hand wringing) while maintaining a highly skilled activity
ictal phase = phase of active seizure (preictal and postictal are terms meaning before and after seizure
the main different between simple and complex is preservation of consciousness |
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Term
| symptoms of partial seizure with secondary generalization |
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Definition
initially manifests with symptoms of simple or complex partial seizure
may evolve into a tonic-clonic seizure with sustained contraction (tonic) followed by rhythmic movements (clonic - alterations of muscle contraction and relaxation) of all limbs
LOSS OF CONSCIOUSNESS
preceded by aura |
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Term
| symptoms of primary generalized absence seizures (petit mal) |
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Definition
sudden, brief interruption of consciousness
blank stare
occasional motor symptoms such as lip smacking, rapid blinking
not preceded by an aura
pathophysiology is thought to involve T type Ca channels in the thalamus |
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Term
| symptoms of primary generalized myoclonic seizures |
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Definition
| brief (1 second or less) muscle contractions; symptoms may occur in individual muscle or generalized to all muscle groups of the body (the latter can result in falling) |
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Term
| symptoms of primary generalized tonic clonic seizures (grand mal) |
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Definition
sustained contraction (tonic) followed by rhythmic movements (clonic) of all limbs
LOSS OF CONSIOUSNESS
preceded by aura
NOT preceded by symptoms of partial or complex seizure |
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Term
| factors affecting neuron excitability |
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Definition
1) type, number, and distribution of voltage (Na and K) and ligand gated ion channels (Cl)
these channels regulate membrane voltage potential
the number and distribution of these channels on the membrane surface will determine excitability
2) biochemical modification of receptor
for example: phosphorylation of the NMDA receptor increases Ca conductance
NMDA receptors are a type of glutamate receptor that mediate Ca flux, phosphorylation opens this channel
3) activation of cell signaling pathways
for example: activation of alpha receptors by NE results in increased K channel conductance favoring hyperpolarization
4) changes in extracellular ion concentration through altering membrane voltage potential or ion flux
5) remodeling of synaptic contacts
for example: an axon terminus closer to cell body increases probability of target neuron reaching threshold
6) neurtransmitter (GABA) metabolism by glial cells
glial cells can uptake and metabolize NT
increased uptake and metabolism of the inhibitory NT, GABA, would in principle promote excitability of neuron networks |
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Term
| mechanism of surround inhibition |
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Definition
[image]
(A) a neuron sends excitatory projections (via axons) to proximal neurons
in addition to activating nearby neurons, the neuron also activates GABAergic interneurons (C) that send inhibitory projections to surrounding neurons (D)
this type of circuit creates an "inhibitory surround", so that action potential generated by neurons, even if rapid and robust, are unable to activate surrounding circuits
neuron networks in the cerebral cortex are complex; a single neuron makes many contacts with other neurons (this complex integration is a fundamental requirement for normal brain function)
surround inhibition is an arrangement of neurons that prevents uncontrolled action potential spread to other neurons outside the circuit
loss of surround inhibition is thought to be a contributing factor in seizure spread in the cortex
this network will control spreading of electrical activity so that surrounding cortical neurons are not activated
this type of network controls localization of electrical activity
loss of the GABAergic interneuron would allow uncontrolled action potential spread (seizure production) |
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Term
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Definition
[image]
A) when activity is confined to one region of the cortex that serves a basic function, such as motor movement or sensation, and there is no change in the patients mental status, the seizure is referred to as a SIMPLE PARTIAL SEIZURE (one area serving a single brain function is affected i.e. one motor region, sensory or visual region)
in complex partial more than one functional region can be affected often serving more complex brain function (i.e. language, memory, emotion)
B) in a secondary generalized seizure, activity begins in a focus, but then spreads to subcortical areas.
diffuse connections from the talamus then synchronize the spread of activity to both hemispheres
C) absence seizures (a type of primary generalized seizure) result from abnormal synchronization between thalamic and cortical cells |
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Term
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Definition
[image]
absence seizure loop:
1) HYPERPOLARIZATION ACTIVATES T-type Ca channels (normally is inhibitory but this is an EXCEPTION)
2) cortex excitation transmitted back to thalamus
3) activation of GABAergic neuron
the absence seizure is generated by a self-sustaining cycle of activity between the thalamus and the cortex
1) hyperpolarization of relay neurons induces burst activity of the T-type Ca channel resulting in synchronous depolarization in the cortex via excitatory connections; cortical neurons become activated
2) excitatory input from the cortex activates the reticular thalamaic neurons
3) the activated GABAergic reticular neurons hyperpolarize the thalamic relay neurons (neuron 1) and reinitiate the cycle (T type Ca channels opening)
NOTE: usually hyperpolarization is inhibitory, but in absence seizures hyperpolarization activates T type Ca channels; activating mutations in the channel are thought to play a role in absence seizure devlopment |
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Term
| summary of mechanisms of anti-seizure drugs |
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Definition
1) prolong the inactivated state (refractory period ) of Na channels
2) inhibit Ca channels (T type and high voltage activated (HVA))
HVA Ca channels cause the release of NTs
3) enhance GABAergic transmission
4) decrease glutamate transmission |
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Term
| mechanisms of anti-seizure drugs |
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Definition
[image]
this figure illustrates a PARTIAL SEIZURE and 4 drug targets (NMDA receptor, high voltage Ca channel, GABA-A receptor, and Na channel)
1 and 2) a simple partial seizure is initiated by loss of surround inhibition
3) 4 molecular drug targets for seizure treatment
a) GABA-A receptor is Cl permeable making it inhibitory (causes hyperpolarization)
AEDs (phenobarbital and benzodizepines) open this channel thus blocking action potential transmission and neurtoransmitter release
b) some drugs act by binding Na channels in the inactive state
the drug stabilizes (holds) the channel in the inactive state
action potential transmission is blocked
c) NMDA receptor activation is excitatory (causes depolarization)
the receptor is ionotropic (a receptor that acts as a ion channel)
felbamate inhibits NMDA receptors
d) the HVA Ca channel is important for regulating NT release (here it is shown closer to the cell body, but it is better to think of it as located closer to the axon terminal where NT is released
gabapentin blocks this channel thus blocking NT release
[image]
this shows the loop pathway involved in an ABSENCE SEIZURE:
the site of action of drugs that are effective against absence seizure is the loop circuit between the talamus and cortex
HYPERPOLARIZATION activates the T type Ca channels, which in turn causes short bursts of action potentials to be sent to the cortex (ethosuximide and valproic acid block the T type Ca channel)
in the absence seizure loop the inhibitory GABAergic neuron hyperpolarizes the next neuron and activates (opens) the T type Ca channel, thus supporting the cycle
BZDs open Cl channels on GABAergic neurons thus inhibitng GABA release onto the next neuron |
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Term
| differences between older and newer AEDs |
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Definition
older drugs introduced before 1979:
phenytoin
carbamazepine
clonazepam
diazepam
ethosuximide
phenobarbital
primidone
valproic acid
newer drugs introduced since 1993:
gabapentin
lamotrigine
felbamate
topiramate
levetiracetam
fosphenytoin
tiagabine
zonisamide
oxcarbazepine
lacosamide
rufinamide
OLDER: usually more dose-dependent side effects and undergo more hepatic metabolism
NEWER: usually less side effects and undergo less hepatic metabolism; some based on rational design (GABA analogs); often used as "add on" or adjunctive therapy to older drugs |
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Term
| mechanistic classification of AEDs |
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Definition
1) primary action on ion channels (Ca and/or Na)
2) drugs that have main effect on the GABAergic neurotransmission
3) drugs with mixed action (ion channel and GABA system activity and/or glutamate antagonism) |
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Term
| drugs with main action on ion channels (Na and Ca) |
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Definition
phenytoin
carbamazepine
lamotrigine
xonisamide
ehtosuximide
rufinamide
lacosamide |
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Term
| mechanism of Na channel inactivation |
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Definition
[image]
some antiseizure drugs (carbamazepine, phenytoin, topiramate, lamotrigine, valproate, zonisamide, rufinamide, lacosamide) prolong the inactivation of the Na channels, there by reducing the ability of neurons to fire at high frequencies
the inactivated channel itself appears to remain open, but is blocked by the inactivation gate
when a neuron membrane is depolarized the Na channels open (active state) allowing Na influx
after a period of depolarization Na channels change to the inactivated state (Na influx is stopped)
the channel remains in this state for a defined period of time before it returns to the resting state
some AEDs selectively bind to the inactivated state
drug binding holds the channel in the activated state for longer time periods thus preventing repetitive production of action potentials
the name "use dependent" comes from the fact that drug binding depends on participation (use) of the Na channel in an action potential |
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Term
| experiment demonstrating effect of drugs on action potential production |
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Definition
[image]
effects of 3 anti-seizure drugs on sustained high frequency firing of action potentials by cultured neurons
intracellular recorders were made from neurons while depolarizing current pulses were applied
in the absence of drug, a series of high frequency repetitive action potentials filled the entire duration of the current pulse
phenytoin, carbamazepine, and valproate all markedly reduced the number of action potentials elicited by the current pulses
why don't these drugs interfere with normal depolarization?
only active on seizure activity b/c of use dependent mechanism
neurons that are firing at the fastest rate will be the ones in the seizure focus and will be the ones that bind more drug |
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Term
| mechanism of T type and high voltage activated (HVA) Ca channel blockage by AEds |
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Definition
[image]
antiseizure drug induced reduction of current through T type Ca channels thus reducing the pacemaker current that underlies the thalamic rhythm in spikes and waves seen in generalized absence seizure
if a drug works on T type Ca channels: think it is used for ABSENCE SEIZURES!!
HVA Ca channels:
Ca influx through these channels cause NT release (not certain how this lowers seizure activity) |
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Term
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Definition
slows recovery from Na channel inactivation at therapeutic concentrations
binding to Na channel is state dependent (use dependent)
phenytoin can prevent the PDS (paroxysmal depolarizing shift), a depolarizing event in neurons that precedes a partial seizure (and potentially secondary generalized seizures) that consists of slower wave Ca influx superimposed with action potentials spikes (Na influx, K efflux) |
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Term
| Na channel blockers interference with initial spike component (the PDS) |
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Definition
[image]
SURFACE EEG:
the PDS is recorded as a single spike by the surface EEG
a silent (no activity in the recording) period follows
after the silent period the tonic-clonic phase follows
Na channel blockers (phenytoin and others) inhibit PDS
the PDS is an initiating factor in seizures
the whole recording is approximately 3 seconds
INTRACELLULAR RECORDING:
at the beginning is a paroxysmal depolarization shift (PDS) comprised of slower Ca influx superimposed by fast action potentials
spikes in the intracellular recording correspond to spikes in the EEG reading |
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Term
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Definition
effective against partial and tonic-clonic seizures
NOT absence seizures |
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Term
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Definition
Pharmacokinetics:
low plasma concentration (first order)
higher plasma concentration (zero order)
HEPATIC METABOLISM SATURABLE
at low doses the relationship is linear, but at high doses the relationship is nonlinear (a small increase in dosage causes a large increase in serum concentration; this represents a transition from first order elimination kinetics to zero order elimination kinetics)
ADRS:
nystagmus, diplopia, ataxia, GINGIVAL HYPERPLASIA (prevention with good oral hygiene), hirsutism
Interactions:
highly plasma protein bound (90%, can displace other drugs); hypersensitivity cross reaction with barbiturate metabolites |
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Term
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Definition
slows Na channel reactivation, use dependent
STOPS PDS, like other Na channel blockers |
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Term
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Definition
| effective for partial and tonic-clonic seizures |
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Term
| PK, ADRs of carbamazepine |
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Definition
Pharmacokinetics:
70-75% plasma protein binding
metabolites have anti-seizure activity
VARIABLE T1/2
ADRs:
most commonly diplopia and ataxia
APLASTIC ANEMIA AND AGRANULOCYTOSIS
STEVENS-JOHNSON SYNDROME AND TOXIC EPIDERMAL NECROLYSIS
strong hepatic enzyme inducer (AUTOINDUCER) - carbamazepine plasma t1/2 decreases over time with constant administration of drug b/c of auto-induction |
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Term
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Definition
slows Na channel reactivation
use dependent
STOPS PDS like other Na channel blockers |
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Term
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Definition
| partial and tonic clonic seizures (LESS ACTIVE THAN CARBAMAZEPINE) |
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Term
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Definition
improved toxicity profile compared to carbamazepine, but can cause HYPOTATREMIA
no hematologic problems
less hepatic enzyme induction compared to carbamazepine |
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Term
| mechanism of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) |
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Definition
mucocutaneous drug induced or idiopathic reaction patterns characterized by skin tenderness, and erythema of skin and mucosa which may progress to extensive separation of epidermis from dermis
TEN is considered a more severe form of SJS; otherwise they are the same pahtological process
prescription drugs are a major precipitating factor of SJS and TEN
exact mechanism is uncertain; drug metabolites may bind tissue proteins causing the tissue protein-metabolite complex to become antigenic which can lead to apoptosis of keratinocytes
a hapten (for example, a drug metabolite) is a small molecule that must bind a larger molecule (usually a protein) to become antigenic
[image]
after the immunogenic drug-protein complex is formed CD8 T cells are activated and attack keratinocytes in the skin and mucosa
massive and wides spread apoptosis of keratinocytes occurs in the most severe cases, resulting in separation of the epidermal layer from the dermal layer of skin
at the onset of SJS, sFasL is released from activated, drug specific lymphocytes
circulating sFasL mediates keratinocyte apoptosis, resulting in skin erosions and widespread ulcerations
amount of soluble FasL in the serum precedes the symptoms of SJS (detachment, erythema)
[image]
detachment and erythematous areas enlarged rapidly, but subsequently gradually improved
soluble FasL in serum was elevated before peak skin effects |
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Term
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Definition
use dependent blockage of Na channels
inhibits high voltage activated (HVA) Ca channels
other mechanisms possible: anti-folate
developed with thought that antifolate compounds may have antiseizure activities (phenytoin has weak antifolate activity) and observation that folic acid is convulsive
it was found that the antifolate activity (inhibiting dihydrofolate reductase) is not likely responsible for the antiseizure effects of this drug |
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Term
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Definition
effective for partial and tonic-clonic seizures
adjunctive therapy |
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Term
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Definition
skin rashes, sometimes severe including SJS (associated with valproic acid coadministration)
interactions:
coadministration of phenytoin, phenobarbital or carbamazepine reduces lamotrigine t1/2 |
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Term
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Definition
prolongs Na channel inactivation
weak inhibitor of T type Ca channels |
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Term
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Definition
| adjunctive therapy for partial seizures |
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Term
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Definition
well tolerated
most common ADRs include somnolence, ataxia, anorexia, nervousness, and fatigue
WEAK CARBONIC ANHYDRASE INHIBITION
carbonic anhydrase is responsible for converting CO2 and H2O into H+ and bicarbonate
inhibition causes metabolic acidosis (less bicarb)
renal function tests are necessary
interactions:
phenobarbital, phenytoin, and carbamazepine decrease zonisamide t1/2
CROSS HYPERSENSITIVITY DUE TO SULFONAMIDE GROUP |
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Term
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Definition
reduces low threshold Ca currents (transient, T type) in THALAMIC NEURONS
the thalamus plays an important role in generation of "spike-and-wave" rhythms (as recorded from thalamic neurons which is produced in part by T type Ca influx) typical of absence seizures
this drug blocks the absence seizure loop between the thalamus and cortex |
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Term
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Definition
FIRST LINE for ABSENCE SEIZURES
not effective against tonic clonic |
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Term
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Definition
| PRINCIPALLY GI EFFECTS and some CNS effects (drowsiness, lethargy, euphoria, dizziness, HA, and hiccup) |
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Term
| MOA of lacosamide and rufinamide |
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Definition
prolongs inactivation of voltage gated Na channels
other mechanisms possible |
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Term
| uses of lacosamide and rufinamide |
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Definition
| adjunctive therapies for partial and Lennox-Gastaut syndrome (a severe and often intractable form of epilepsy) |
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Term
| ADRs of lacosamide and rufinamide |
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Definition
CARDIAC CONDUCTION PROBLEMS
include PR and QT interval prolongation
likely arise from Na channel blockage on cardiac myocytes |
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Term
| drugs with primary effects on GABA system |
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Definition
benzodizepines
tiagabine
vigabatrin
each effect the GABA system by a different sub-mechanism |
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Term
| enhancement of GABAergic transmission |
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Definition
drugs action: receptor binding, reuptake, metabolism
[image]
GABA is synthesized in the nerve terminal and stored in vesicles
GABA is released and binds the receptor causing channel opening (Cl influx)
reuptake is mediated by transporter (GAT-1)
GABA is metabolized by sequential action of GABA transaminase (GABA-T) and dehydrogenase
1) benzodiazepines bind GABA-A receptor and increases GABA affinity for the receptor; Cl influx is increased
2) tiagabine inhibits the GABA reuptake transporter (GAT-1) increasing synaptic concentration of GABA
3) vigabatrin inhibits GABA metabolism inside the presynaptic terminal (inhibits GABA-T) resulting in more GABA release from vesicles |
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Term
| MOA of BZDs (diazepam, lorazepam, clonazepam, clorazepate) |
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Definition
increase frequency of Cl channel opening
increased stimulus is required for neuron to reach threshold
employed clinically as anti-anxiety and sedative, but are also used to treat seizures |
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Term
| uses of diazepam and lorazepam |
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Definition
IV FOR STATUS EPILEPTICUS
sustained seizure activity for 30 minutes or more
very fast distribution into the CNS |
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Term
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Definition
atonic, myoclonic, and absence seizures
used alone or adjunctively |
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Term
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Definition
| adjunct for partial seizures |
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Term
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Definition
2 major limitations are sedative effects and TOLERANCE
hyperactivity and aggression in children
cardiovascular and respiratory depression may occur after IV administration
SLEEP STAGES AFFECTS
dependence
MIXED REPORTS ON INTRAOCULAR PRESSURE (may increase)
abrupt withdrawal can precipitate seizures |
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Term
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Definition
rationally designed drug
INHIBITS GABA REUPTAKE transporter (GAT-1)
GAT-1 located presynaptically
inhibiting these transporters will increase the synaptic concentrations of GABA |
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Term
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Definition
BASED ON "ADD-ON" DATA
adjunctive therapy for partial seizures with or without secondary generalization
monotherapy not established |
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Term
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Definition
more common than other adjunctive therapy drugs
principal ADRs include dizziness, somnolence, and tremor |
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Term
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Definition
rationally designed drug
IRREVERSIBLE inhibitor of GABA transaminase (GABA-T)
RESTRICTED DISTRIBUTION
[image]
the krebs cycle and glutamate metabolism are intertwined with GABA synthesis and metabolism
GABA-T is irreversibly inhibited by vigabatrin
by blocking the conversion of GABA to succinic semialdehyde this drug increases the amount of GABA available for release at inhibitory synapses
decreased production of glutamate may also contribute to anti-seizure activity |
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Term
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Definition
permanent vision loss can occur
retina changes and loss of peripheral vision can be very common
prescribed only through special program |
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Term
| drugs with mixed mechanisms (ion channel and GABA or glutamate system) |
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Definition
valproic acid
gabapentin
levetiracetam
topiramate
felbamate
phenobarbital |
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Term
| 3 main types of glutamate receptors |
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Definition
AMPA, kainate, and NMDA receptors
[image]
in addition to the ion channels and GABAergic system, some anti-seizure drugs act on ionotropic glutamate receptors
the main difference between the receptors is the tissue expression and the ion permeability of the channel
1) AMPA: mediate Na influx and some K efflux
2) Kainate: mediate Na influx and some K efflux
3) NMDA: mediates Ca influx and K efflux
the main point to remember is that glutamate receptors are excitatory and antiseizure drugs are antagonists of these channels |
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Term
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Definition
several modes of action
prolongs Na channel recovery from inactivation
blocks T type Ca channels
enhances GABA mediated transmission |
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Term
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Definition
effective against absence seizures
also for generalized, partial, and myoclonic types |
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Term
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Definition
valproate (ionized species) plasma protein binding is saturable at high therapeutic plasma concentrations (this may affect interaction with other protein bound drugs)
relationship between total plasma concentration (protein bound + fee) and dose is nonlinear because after plasma protein binding is saturated more free drug is available for metabolism and clearance
[image] |
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Term
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Definition
GI most common
rare but serious hepatotoxicity, especially in children under 2 yo receiving other AEDs
TERATOGENIC - neural tube development
toxic metabolites |
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Term
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Definition
designed to act as GABA mimetic but does not bind to GABA receptor
thought to work through increasing synaptic GABA concentration and decreasing HVA Ca currents |
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Term
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Definition
| adjunct therapy for partial and tonic-clonic seizures |
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Term
| PK and ADRs of gabapentin |
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Definition
PK:
eliminated in the urine unchanged
GI absorption dependent on AMINO ACID TRANSPORTER - high protein diet will effect absorption; utilization of amino acid transporter may also help CNS entry
ADRs:
low toxicity (HIGH TI)
overall well tolerated
no effect on metabolism of other drugs, does not induce hepatic enzymes |
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Term
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Definition
evidence for GABA and HVA Ca mechanisms; also binds VESICLE PROTEIN (this could alter NT release)
[image] |
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Term
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Definition
| mostly for adjunct treatment for partial seizures |
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Term
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Definition
minimal ADRs
somnolence, ASTHENIA and dizziness most frequently reported |
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Term
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Definition
several modes of action
Na channel inhibition
activates hyperpolarizing K CURRENT
AMPA antagonist
enhances GABA transmission
HVA Ca action |
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Term
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Definition
| as initial monotherapy in patients 2 year and older with partial onset or primary generalized tonic-clonic seizures |
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Term
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Definition
well tolerated
somnolence, fatigue, weight loss, and PARESTHESIA common
may precipitate renal calculi (CARBONIC ANHYDRASE ACTION)
weak carbonic anhydrase inhibition -> metabolic acidosis (low plasma bicarbonate) |
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Term
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Definition
targets include Na channel inactivation, NMDA RECEPTOR SUBTYPE inhibition and slight GABA enhancement
HVA Ca current decrease |
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Term
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Definition
LIMITED TO INTRACTABLE CASES (i.e. Lennox-Gastaut)
when other drugs are ineffective |
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Term
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Definition
| rare but serious APLASTIC ANEMIA and ACUTE LIVER FAILURE limits use |
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Term
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Definition
enhances GABA mediated tranmission (ALLOSTERIC AND DIRECT ACTIVATION); other mechanisms proposed
unlike BZDs which have allosteric activity only
evidence for glutamate and HVA Ca mechanisms |
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Term
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Definition
sedation, tolerance, dependence
decreased cognitive function
may WORSEN ABSENCE SEIZURES
OVERDOSE RISK
[image]
the barbiturates exhibit a linear dose-response effect, which progresses from sedation to respiratory depression, coma, and death
BZDs exhibit a ceiling effect, which preccludes severe CNS depression following oral administration
BZDs are allosteric activators and depend on GABA to have action
phenobarbital is a DIRECT agonist, can open channels on their own
SJS and TEN
hyperactivity in children
hepatic enzyme INDUCER |
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