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pharmacology - antiepileptics


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classified by type, eitilogy, and syndrome
Epilepsy eitiology
idiopathic epilepsy = undefined influences on fetal brain develpment, no lesions

symptomatic epilepsy - structural damage to brain
causes: trauma, neoplasia, infection, developmental abnormalities, stroke, vascular malformations
Syndrome characteristics
EX: childhood absence, status epilepticus

Includes: age, prognosis, response to TRT, onset
Properties of a SZ
abnormal brain fcn, 1+ of:

excessive glutaminergic excitation
insufficient gabanergic inhibition
combination of the two

EEG: excessive, hypersynchronous discharge of cerebral cortical neurons
Symptoms of SZ
change in state of consciousness
sensory, psychic, or autonomic disturbances
behavioral change
loss of muscle tone
sz genesis
single focus with spread to adjacent, contralateral

single focus with generalization

primary generalized
SZ focus
small groups of neurons
abnormal discharge
high EFQ bursting
SZ propagation
recruitment of normal neurons (local or distant)
gradual or instantaneous
simple partial sz's
no change in concsciousness

symptoms depend on area of brain that is affected
complex partial sz
Most common type
hardest to treat

confused behavior --> impaired/lost consciousness


often begin as simple partial
partial sz secondarily generalized
loss of consciousness

tonic, clonic, or TC

ALWAYS begin as simple or complex partial
abrupt, breif loss of consciousness

3-per second spike and wave EEG

often symmetircal clonic motor activity --> blinking, jerking of body
Tonic sz's
violent continuous contraction of all muscles

loss of consciousness
clonic sz
rhythmic clonic contractions of all muscles, mostly in arms and legs

loss of consciousness
tonic/clonic sz
begins with sudden loss of consciousness and tonic sz

followed by clonic contractions

usually lasts a few minutes
atonic sz
suddne loss/decrease in muscle tone

breif loss of consciousness
Generalized sz
no sz focus in cortex

problem is sub-cortical
unclassified sz
dont fit any of the other types
status epilepticus
lorazepam/diazepam IV followed by phenytoin/phenobarbital IV
>1hr of status epilepticus

glutamate release --> excess!
lots of NMDA activation
--> lots of Ca released
--> lethal to neurons = brain damage
Animal models of epilepsy
maximal electroshock sz test
kindled sz
maximal electroshock sz test
breif shock thru ear

produces tonic clonic

drugs that block tonic phase may be used in TC sz in humans

rats or mice

clonic sz

effective drugs may be good for absence
kindled sz
in rats

complex partial?

screen for drugs that treat/prevent development of sz FOCUS

put electrode in amygdala or hippocampus

short train of shocks - subthreshold --> post-discharges = focus development
kindled sz development pathway
repeated shocks -->stronger, widespread sz -->propogates to other hemi --> overt complex partial sz --> spontaneous
Pharm treatment of sz disorder
parital - 65% total control, 35% no control
primary gen.: 80% total, 20% no control

right dx is crucial

after 2-3 tries, may go to polytherapy

monitor serum levels

sz-free for 2-4 yr = slowly titrate out
basis of AED resistance
over-expression of efflux pumps in BBB

multi-drug resistance protein - resistance to one means resistance to all
AED pregnancy issues
increased sz risk during preg
pregnancy = down Cp (down absorption, up fu, up CL, up Vd)

Some AEDs decrease OC efficacy
Drugs of Choice: parital
Drugs of Choice: primary TC
Drugs of Choice: absence
General mech of action for AEDs
prevent development of sz foci or revert to non-path state (none work this way)

down excitability

inhibit spread of excitation
Specific mech's of AED
-modulate voltage-dependant ion channels involved in action potential propagation/burst
-enhance GABA-mediated inhibition
- attenuate glutamate excitation
Specific mech's of AED:
change voltage dependent ion channel
1. block Na channels
- EFQ dependent blockade = only affects rapidly firing neurons
-stabilizes inactive state of channels
-at high dose --> complete block, incomplete at low dose

2. open K+ channels -->hyperpolarization --> inhibition

3. block low threshold T-type Ca channels --> decrease burst firing in thalamocortical neurons
Specific mech's of AED:
up GABA-mediated inhibition
up GABA release/synthesis (glutamic acid decarboxylase)
down GABA metabolism (GABA transaminase, succinic semi-aldehyde)
down GABA uptake (GABA uptake carrier)
Specific mech's of AED:
attenuate glutamate
down glutamate synthesis/release

glutamate receptor blockade
ADE's of AED's
cerebellar effects - intention tremor, nystagmus, ataxic gait, diplopia, hyperreflexia

Drug interactions general mech's
induction/inhibition/ of P450 enzymes

change in fu

pharmacodynamic interactions in CNS
2nd generation AEDs
not more effective, but down SE's may up compliance

often developed with mechanism in mind --> commonly GABA
Mech(s) of Action:
Na Channel block
Mech(s) of Action:
Na channel block
Mech(s) of Action:
up GABA levels by up synth and/or down breakdown

Na block

T-type Ca block
Mech(s) of Action:

up GABA action by action on GABA-A receptors

up inhibition by direct action on Cl- channel

down glutamate action thru non-NMDA receptors
Mech(s) of Action:

inhibit thalmic pacemaker --> block T-type Ca channel
Mech(s) of Action:
up GABA action thru GABA-A receptors
Mech(s) of Action:

down glutamate action on NMDA because it occupies the glycine binding site
Mech(s) of Action:
up GABA levels by up GABA synth or up non-vesicular release
Mech(s) of Action:

up GABA by GABA-T block
Mech(s) of Action:

down GABA uptake
Mech(s) of Action:
Alternative uses of AEDs:
neuropathic pain
carbamazepine, gabapentin, lamotrigine
Alternative uses of AEDs:
migraine prophylaxis
valproate, gabapentin
Alternative uses of AEDs:
acute mania
valproate, carbamazepine, lamotrigine
Alternative uses of AEDs:
Alternative uses of AEDs:
mood stabilization
carbarmezepine, topiramate

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