Professional Documents
Culture Documents
Generation
Carbamazepine
NS
MOA
-
frequency-dependent
and
voltage-depenent
blockade
of
inactivate
Na+
channels;
interaction
with
other
ion
ch
and
several
NTs
Effects
-
INH
of
post
tetanic
potentiation
(prevents
spread
of
seizure
from
epileptic
focus);
cerebellar
vestibular
stim;
analgesic
actions;
antidiuretic
actions;
antidepressant
actions
PK
-
good
oral
BA;
highly
metab
by
CYP34A,
INC
metab
of
OCs
Uses
-
Epilepsy
(1st
choice
for
partial
seizures
and
gen
tonic-clonic
seizures;
also
DEC
occurance
of
complex
partial
seizure;
Tolerance
in
10-20%);
Trigeminal
neuralgias;
BAD;
Diabetes
insipidus
AE-
dizzines,
drowsiness,
blurred
vision,
diplopia,
ataxia,
neutropenia,
thrombocytopenia,
agranulocytosis,
aplastic
anemia,
confusion,
agitation,
hallucinations,
arrhythmias,
HF
(long
Tx),
water
retention,
liver
failure,
allergic
rxns,
NEURAL
TUBE
DEFECTS
IN
PREGOS!
Phenytoin
NS
MOA
-
frequency-dep
and
voltage-dep
blockade
of
inactivated
Na+
channels
Effects
-
INH
of
post
tetanic
potentiation
(prevents
spread
of
seizure
from
epileptic
focus);
cerebellar
vestibular
stim;
analgesic
actions,
induction
of
hepatic
microsomal
enzymes
PK
-
good
oral
BA;
highly
metab
by
CYP450;
INH
Warfarin
metab;
INC
metab
of
OCs
USES
-
EPILEPSY
(1st
or
2nd
choice
drug
for
partial
and
gen
tonic-clonic
seizures);
Trigeminal
neuralgias;
cardiac
arrhythmias
AE
CNS
-
nystagmus,
diplopia,
ataxia,
dyskinesia,
vertigo,
tremor,
hyperreWlexia,
dystonic
rxns,
hyperactivity,
sedation,
drowsiness,
peripheral
neuropathy,
encephalopathy
GI
-
GINGIVAL
HYPERPLASIA,
hepatitis,
hepatic
necrosis,
INH
of
folate
absorption
(long
Tx)
ENDO
-
hyperglycemia
(b/c
dec
insulin
secretion);
Osteomalacia
HEME
-
megaloblastic
anemia
(Tx
w/
folate),
blood
dyscrasias,
lymphoadenopathy
Skin
hyperpigmentation,
hirsutism,
coarsening
facial
features;
allergic
skin
rxns;
MALFORMATIONS
IN
PREGOS
Phenobarbital
NS
MOA
-
Enhancement
of
GABA-mediated
INH;
Blockade
of
AMPA
receptors;
Direct
opening
of
Cl-
channels;
Blockade
of
Na+
and
Ca++
channels
Effects
-
Suppression
of
excessive
discharge
of
seizure
focus;
prevention
of
spread
of
excitation
ofrom
seizure
focus
PK
-
good
oral
BA;
metab
by
liver;
excreted
by
kidney,
INC
metab
of
OCs
Uses
-
2nd
choice
for
parital
seizures,
Generalized
tonic-clonic
seizures,
Status
epilepticus
AE
-
all
AE
and
CI
of
barbiturate
class;
sedation,
nystamus,
ataxia,
agitation
and
confuision
in
elderly,
birth
defects
in
PREGOS;
hypoprothrombinemia
(prophylaxis
w/
Vit
K);
osteoporosis
([ix
iwth
Vit
D);
megaloblastic
anemia
([ix
w/
folate)
Ethosuximide
NS
MOA
-
Blockade
of
voltage-sensitive
T
type
Ca++
ch
in
thalamic
neurons
Effects
-
suppression
of
oscillating
discharge
of
thalamic
seizure
focus;
prevention
of
spread
of
excitation
through
thalamocortical
and
corticothalamic
circuits;
other
brain
circuits
are
unaffected
at
therapeutic
con'c
PK
-
good
oral
BA;
metab
by
liver;
t1/2
=
45
hrs
Uses
-
DOC
in
absent
seizures;
earlier
the
Tx
the
greater
the
ef[icacy
of
therapy;
2nd
choice
drug
in
myoclonic
and
atonic
seizures
AEs
-
drowsiness,
fatigue,
dizziness,
vertigo,
ataxia,
diplopia,
nystagumus,
restlessness,
agitation,
anxiety,
aggressiveness,
inability
to
con'c,
leukopenia,
agranulocytosis,
aplastic
anemia,
SJ
syndrome
Valproic
acid
BS
MOA
-
Blockade
of
inactivated
Na+
ch;
Blockade
of
NMDA
rec
excitation;
Blockade
of
T
type
Ca++
ch;
INC
GABA
content
in
brain;
Opening
K+
ch
Effects
-
BROAD
spectrum
antiepileptic;
INH
CYP2C9
PK
-
100%
oral
BA;
metab
by
liver
Uses
-
Epilepsy
(best
for
myoclonic
seizures;
1st
line
agent
for
tonic-clonic
seizures
and
ABSENT
seizures;
effective
in
simple
and
complex
partial
seizures;
alternative
drug
in
infantile
spasms);
BAD
(acute
mania
and
prophylactic
Tx);
Migraine
prophylaxis
AE
CNS
-
sedation,
drowsiness,
dizziness,
tremor,
ataxia,
nystagmus,
diplopia,
dysarthria,
nervousness,
agitation
GI
-
N/V,
anorexia,
weight
gain,
hyperammonemia,
hepatitis
HEME
-
Thrombocytopenia
Allergic
rxns;
MENSTRUAL
DISTURBANCES;
INC
risk
of
NTDs
in
PREGOS
Clonazepam
BS
A
benzodiazepine
some
selectivity
for
seizures
and
long-acting.
MOA
increase
the
frequency
of
the
GABA
A
activated
Cl-
channels.
Uses
-
second
line
drug
in
partial
and
generalized
seizures
(including
absence,
myoclonic
seizures,
infantile
spasms
nad
Lennox-Gastaut
syndrome).
Tolerance
can
occur
after
1-6
months.
An
adjunct
therapy
for
partial
seizures.
AEs:
drowsiness,
lethargy.
Cognitive
effects.
2nd
Generation
Oxcarbazepine
NS
Prodrug
that
results
in
less
potent
enzyme
inducer
Uses
-
monotherapy
or
adjunct
therapy
for
partial
seizures
Gabapentin/Pregabalin
NS
MOA
-
unknown
PK
-
intestinal
absorption
by
L-amino
acid
carrier
protein;
elim
by
kidney;
oral
admin
Uses
-
2nd
choice
or
adjenct
for
partial
and
tonic-clonic
seizures;
essential
tremor;
neuropathic
pain
AE
-
fatigue,
drowsiness,
dizziness,
ataxia;
WITHDRAWAL
RXNS
Ezogabine
NS
MOA
-
Targets
neuron
speci[ic
voltage-gated
K
channels
to
dampen
neuronal
hyperexcitability.
Uses
-
Adjunct
treatment
in
drug
resistant
partial
seizures.
Lamotrigine
BS
MOA
-
volt
and
freq.
dep
blockade
of
Na+
ch;
Blockade
of
volt-gated
Ca++
ch
PK
-
good
oral
BA;
metab
by
glucuronidation
(INH
by
valproate
-->
INC
plasma
con'c)
Uses
-
1st
choice
for
simple
and
complex
partial
seizures,
tonic-clonic
seizures;
2nd
choice
form
absent,
myoclonic,
and
infantiie
seizures;
migraine
prophylaxis
AE
-
drowsiness,
dizziness,
fatigue,
ataxia,
diplopia;
gen
skin
rash;
S-J
syndrome
Levetiracetam
BS
MOA
-
unknown
Uses
-
1st
or
2nd
choice
for
parial
and
tonic-clonic
and
myoclonic
seizures
AE
-
drowsiness,
fatigue,
dizziness,
ataxia
Topiramate
BS
MOA
-
Blockade
of
voltage-gated
Na+
and
Ca++
ch;
potentiation
of
inhibitory
effects
of
GABA
at
GABA-A
receptors;
blockade
of
AMPA
glutamate
receptors;
INH
of
CA
PK
-
good
oral
BA;
50%
elim
by
kidney;
DEC
OC
plasma
levels
Uses
-
1st
or
2nd
choice
for
simple
and
complex
partial,
tonic-clonic,
myoclonic,
atonic,
infantile
seizures;
Lennox-Gastaut
syndrome;
Migraine
prevention
AE
-
drosiness,
dizziness,
fatigue,
ataxia,
aphasia,
nystagmus,
parethesias;
ocular
HTN,
CA
glaucoma,
metab
acidosis,
PPT
renal
calculi
CI
-
glaucoma,
COPD,
nephrolithiasis,
porphyria
Felbamate
BS
MOA
-
Blockade
of
NMDA
glutamate
receptors;
potentiation
of
GABA
responses
Uses
-
2nd
choice
drug
for
atonic
seizures,
Lennox-Gastaut
syndrome
AEs
-
drowsiness,
dizziness,
fatigue
HA;
APLASTIC
ANEMIA
AND
SEVERE
HEPATITIS
Zonisamide
BS
MOA
-
Blockade
of
Na+
channels,
Blockade
of
T
type
Ca++
ch;
Enhancement
of
GABAergic
transmissiion,
INH
of
glutamatergic
transmission
Uses
-
2nd
choice
of
adjunct
for
Partial
and
tonic
clonic
seizures,
myoclonic
seizures
AEs
-
drowsiness,
dizziness,
HA,
irritability,
allegic
rxns
(sulfa
drug),
somnolence,
anorexia,
hyperthermia
and
oligohydrosis
in
children
Three Major Categories for Pharmacotherapy: MOA Limit repetitive firing by promoting inactivated state of voltage-gated Na + channels. Excitatory ion channel. Enhance GABA-mediated synaptic inhibition. Inhibitory Cl- ion channel. Inhibition of voltage-activated Ca2+ channels associated with T-type Ca2+ currents. Other: Opens K+ channels and stabilizes the electrical currents, NMDA antagonist Drugs that Work on Reducing the Rate of Na+ Channels Recovery from Inactivation: Neurons can no longer fire at high frequency Drugs that work on simple partial, complex partial and partial with secondary generalized tonic-clonic seizures Carbamazepine, phenytoin, valproic acid ( 1st generation) Lamotrigine, topiramate and zonisamide ( 2nd gen) Drugs that Enhance GABA Inhibition: Raise the Seizure Threshold Benzodiazepines and barbiturates enhance GABA A receptors, enhances Cl- flow and hyperpolarizes the membrane. They work on both partial and tonic-clonic seizures. At high doses can be used for status epilepticus, drugs may also inhibit high frequency firing. Tiagabine inhibits GABA transporter site preventing reuptake back into the presynaptic cell. Drugs Effective Against Generalized-Onset: Absence Seizure There is a presence of thalamic and neocortical discharge of 3/sec generalized spike and wave discharges. T-type Ca2+ channels inhibited by Ethosuximide, valproic acid effective on absence seizures. When do you start treating? Treatment is indicated after at least two unprovoked seizures. After the first, if warranted by abnormal EEG discharges, abnormal neurological exam or other structural abnormality thought responsible for the seizure. First Line Drugs for Partial Seizures Advantages/Disadvantages Carbamazepine high evidence for efficacy, low cost, mood stabilizer/ enzyme inducer, high interaction potential, hyponatremia in elderly. Gabapentin non-enzyme inducer, no interactions, effective in neuropathic pain/ low evidence of efficacy (except in the elderly), weight gain. Lamotrigine high level of efficacy also in the elderly, non- enzyme inducer, effective mood stabilizer (bipolar depression) / slow titration, allergic reaction, drug interactions . Levetiracetam- high level of evidence for efficacy, rapid titration, non-enzyme inducer, no significant interactions/ psychiatric adverse effects. Oxcarbazepine low potential for enzyme induction, lower risk of rashes then carbamazepine/ higher risk of hyponatremia then carbamazepine, reduces blood conc of oral contraceptives.
Phenobarbital extensive experience, low cost, once-daily dosing/ enzyme inducer, high interaction potential, cognitive and behavioral effects Phenytoin high level of evidence of efficacy, rapid titration, extensive experience, low cost, once-daily dosing possible/ complicated PK, enzyme inducer, high interaction potential, cosmetic adverse effects Topiramate effective for migraine prophylaxis, low potential for enzyme induction/ slow titration, cognitive adverse effects Valproate rapid titration, mood stabilizer/ enzyme inhibitor, some interaction potential, weight gain, teratogenic potential
First Line Drugs for Generalized Seizure Advantages/ Disadvantages Lamotrigine non-enzyme inducer, effective in bipolar depression/ slow titration; dose requirements influenced by valproate, enzyme inducers and estrogen-containing contraceptives; can aggravate myoclonic seizures in some patients Levetiracetam non-enzyme inducer, no significant interactions, rapid titration/ psychiatric adverse effects Topiramate effective for migraine prophylaxis, low potential for enzyme induction/ slow titration, cognitive adverse effects Valproate best evidence for efficacy, rapid titration/ enzyme inhibitor, some interaction potential, weight gain, teratogenic potential Other Seizures Absence seizures: ethosuximide, valproate and lamotrigine. Myoclonic convulsions: valproic acid and levetiracetam. Status epilepticus: prolonged seizure, any type (>30mins). Emergency. Give IV: lorazepam or diazepam followed by phenytoin, phenobarbital or valproate. Attend to airway and cardiovascular stability Dosing Gradual dose titration. Improves CNS tolerability and reduces the risk of idiosyncratic adverse effects. Measure serum concentration based on individual response. Dose with the least amount of sedation as possible maintaining blood levels. Dose based on symptoms. Seizures begat seizures, make changes if the seizures are not controlled. If efficacy diminishes, consider changes in enzymes review for drug interactions and adjust the dose. Refractory seizures: 30% Long Term Prognosis Excellent for most children with seizures, particularly if they are cryptogenic/ idiopathic (unknown origin). Long-term mortality increased in childhood-onset epilepsy, especially for those not in remission. With uncontroled Sz, an increased risk in epilepsy-related deaths and sudden unexplained death.