1 Epilepsy Seizure Brief episode of abnormal electrical activity in nerve cells of the brain Convulsion Involuntary spasmodic contractions of any or all voluntary muscles throughout the body including skeletal and facial muscles ID: 930794
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Slide1
Drugs for Epilepsy
16 October 2017
1
Slide2Epilepsy
SeizureBrief episode of abnormal electrical activity in nerve cells of the brainConvulsionInvoluntary spasmodic contractions of any or all voluntary muscles throughout the body, including skeletal and facial muscles
EpilepsyChronic, recurrent pattern of seizures
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Slide3Epilepsy
The third most common neurologic disorder after
cerebrovascular and Alzheimer’s disease.the
sudden, excessive
, and synchronous discharge of cerebral neurons
.
This abnormal electrical
activity may result in a variety of events, including
loss of
consciousness, abnormal movements, atypical or odd behavior, and distorted perceptions that are of limited duration but recur if untreated.
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Slide4ETIOLOGY OF SEIZURES
Primary (idiopathic)Cause cannot be determined
More than 50% of epilepsy casesSecondary (symptomatic)
Distinct cause is identified
Trauma
, infection, cerebrovascular
disorder
Focal areas that are functionally
abnormal may be triggered
into activity by changes in
physiologic factors
, such as an alteration in blood gases, pH, electrolytes, and blood glucose and changes in environmental factors, such as sleep deficiency, alcohol intake, and stress.
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Slide5Classification of Epilepsy
A. Focal (
Partial-onset seizures) involve only a portion of the brain, typically part
of one
lobe of one hemisphere.
The
symptoms
depend
on the site of neuronal discharge and on the extent
to which the electrical activity spreads to other neurons in the brain.
Focal seizures may progress to become generalized tonic–clonic seizures.
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Slide6A. Focal (Partial-onset seizures)
1. Simple partial: The electrical discharge does not spread, and the patient does not lose
consciousness. The patient often exhibits abnormal activity of a single limb
or muscle group that is controlled by the region of the
brain.
Simple
partial seizures may occur
at any age.
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Slide7A. Focal (Partial-onset seizures
)2. Complex partial:
These seizures exhibit complex sensory hallucinations and mental alteration.
Motor dysfunction may
involve chewing
movements, diarrhea, and/or urination. Consciousness is
altered.
Complex
partial seizures may occur at any age.
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Slide8B. Generalized
May begin locally and then progress to include abnormal electrical discharges throughout both hemispheres of the brain.
It may be convulsive or nonconvulsive
, and the patient usually has
loss of consciousness
.
1. Tonic–clonic: These seizures result in loss of
consciousness, followed
by
tonic (continuous contraction) and
clonic (rapid
contraction and
relaxation
) phases. 16 October 20178
Slide92. Absence: involve a brief,
rapid, and selflimiting loss of consciousness. The onset generally occurs in patients at 3 to 5 years of age and lasts until puberty or beyond.
The
patient
exhibits
rapid
eye-blinking, which lasts for
3 to 5 seconds.
3. Myoclonic:
short
episodes of muscle contractions that may recur for several minutes. Myoclonic seizures occur at any age but usually begin
around puberty
or early adulthood.
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Slide104. Clonic: consist of short episodes of
muscle contractions that may closely resemble myoclonic seizures. Consciousness is more impaired with clonic seizures as compared to myoclonic.
5. Tonic: involve increased tone in the extension muscles
and are generally less than 60 seconds long.
6. Atonic:
also
known as drop attacks and
are characterized
by a sudden loss of muscle tone.
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Slide1116 October 2017
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Slide12Status epilepticus
:A series of seizures (usually tonic-clonic) without recovery of consciousness between attacks; it
is a life-threatening emergency.
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Slide1316 October 2017
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Slide14PHARMACOKINETICS
A. PhenytoinPhenytoin metabolism is nonlinear
; elimination kinetics shift from first-order to zero orderThe
metabolism of
phenytoin
is enhanced in the presence
of inducers
of liver metabolism (
eg, phenobarbital, rifampin) and
inhibited by other drugs (eg,
cimetidine, isoniazid
).
Phenytoin itself induces hepatic drug metabolism, decreasing the effects of other antiepileptic drugs including carbamazepine, clonazepam
, and lamotrigine.
Fosphenytoin
is a water-soluble
prodrug
form of
phenytoin that is used
parenterally
.
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Slide15B. Carbamazepine
Carbamazepine induces formation of liver drug-metabolizing enzymes that increase metabolism of the drug itself and
may increase the clearance of many other anticonvulsant drugs including
clonazepam
,
lamotrigine
, and
valproic
acid.Carbamazepine
metabolism can be inhibited by other drugs (eg, propoxyphene,valproic
acid
). A related drug, oxcarbazepine, is less likely to be involved in drug interactions.
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Slide16C. Valproic
AcidIn addition to competing for phenytoin plasma protein binding sites
, valproic acid inhibits the metabolism of
carbamazepine,
ethosuximide
, phenytoin, phenobarbital
, and
lamotrigine
.
Hepatic biotransformation of valproic
acid leads to formation of a
toxic metabolite
that has been
implicated in the hepatotoxicity of the drug.16 October 2017
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Slide17D. Other Drugs
Gabapentin, pregabalin, levetiracetam, and
vigabatrinEliminated
by the kidney, largely in
unchanged form
.
These
agents have virtually no drug-drug interactions.
Tiagabine
, topiramate
, and zonisamide undergo both hepatic metabolism
and renal elimination of intact drug
.
Lamotrigine is eliminated via hepatic glucuronidation.
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Slide18MECHANISMS OF ACTION
Effect of antiseizure drugs is to suppress repetitive
action potentials in epileptic foci in the brain. A. Sodium Channel Blockade
Phenytoin
,
carbamazepine,
lamotrigine
, and
zonisamide
block voltage-gated sodium channels in
neuronal membranes
.
results in prolongation of the inactivated state of the Na+ channel and the refractory period of the neuron. Phenobarbital and valproic
acid may exert similar effects at high doses.
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Slide19B. GABA-Related Targets
Benzodiazepines interact with specific receptors on the GABAA receptor–chloride ion channel (facilitate the inhibitory
effects of GABA).
Phenobarbital
also
enhance the inhibitory actions of GABA but interact with
a different receptor site on chloride ion channels that results in
an increased
duration of chloride ion channel opening.
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Slide20B. GABA-Related Targets
GABA aminotransaminase
(GABA-T) is an enzyme in the termination of action of GABA. The enzyme is
irreversibly inactivated
by
vigabatrin
and can also
be inhibited by
valproic
acid.
Tiagabine inhibits a GABA transporter (GAT-1) in neurons
and glia
prolonging the action of the neurotransmitter.
Gabapentin is GABA analog, but it does not activate GABA receptors directly.
Felbamate
,
topiramate
, and
valproic
acid
facilitate
the inhibitory
actions of
GABA
.
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Slide21C. Calcium Channel Blockade
Ethosuximide inhibits low-threshold (T type) Ca2+
currents , especially in thalamic neurons.A
similar action is reported for
valproic
acid
, as well as for both
gabapentin
and
pregabalin.
D. Other mechanismsvalproic
acid
causes neuronal membrane hyperpolarization
, possibly by enhancing K+ channel permeability. Phenobarbital , Topiramate, and
Felbamate acts as an antagonist
at
glutamate NMDA
receptors.
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Slide22CLINICAL USES
Up to 80% of patients can expect partial or complete control of seizures with appropriate treatment.
Antiepileptic drugs suppress but do not cure
or prevent
seizures
Antiepileptics
are indicated when there is two or more seizures occurred in short interval (6m -1 y)
An initial therapeutic aim is to use only one drug (
monotherapy)
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Slide23A. Generalized Tonic-Clonic
SeizuresValproic acid, carbamazepine, and phenytoin
are the drugs of choice for generalized tonic-clonic (grand mal) seizures.
Phenobarbital
(
or
primidone
) is now considered to be an alternative agent in
adults but continues to be a primary drug in infants.
Lamotrigine and
topiramate
are also approved drugs for this indication.16 October 2017
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Slide24B. Partial SeizuresThe drugs of first choice are
carbamazepine (or oxcarbazepine) or lamotrigine or
phenytoin. Alternatives include
felbamate
,
topiramate
,
phenobarbital
, and
valproic acid.
Many
of the
newer anticonvulsants can be used adjunctively including gabapentin and pregabalin, a structural congener.
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Slide25C. Absence Seizures
Ethosuximide or valproic acid are the preferred drugs because they cause minimal sedation.
Valproic
acid
is particularly useful
in patients who have concomitant generalized tonic-
clonic
or myoclonic seizures. Clonazepam
is an alternative drug (disadvantages sedation and
tolerance).
Lamotrigine
, levetiracetam, and zonisamide are also effective in absence seizures.
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Slide26D. Status Epilepticus
I.V diazepam or lorazepam
is usually effective providing short-term control. For prolonged therapy
,
I.V
phenytoin
(highly
effective and less
sedating).
Phenytoin may cause
cardiotoxicity, and
fosphenytoin
(
water soluble) is a safer parenteral agent. Phenobarbital used in status epilepticus
, especially in children.
In
very
severe status
epilepticus
that does not respond to these measures,
general anesthesia
may be used.
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Slide27E. Other Clinical Uses
Valproic acid is used as a first-line drug in the treatment of mania.
Carbamazepine and lamotrigine have also been used successfully in
bipolar disorder
.
Carbamazepine
is the drug of choice for
trigeminal
neuralgia
.
Gabapentin and Pregabalin have efficacy in pain
of neuropathic
origin, including
postherpetic neuralgia, and, like phenytoin, may have some value in migraine.
Topiramate
is
also used
in the treatment of
migraine
.
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Slide28TOXICITY:
A. Teratogenicity ; congenital malformations. Neural tube defects (eg,
spina bifida) are associated with the use of valproic
acid
.
carbamazepine
has been implicated as a cause of
craniofacial anomalies
and spina
bifida.A fetal
hydantoin
syndrome
has been described after phenytoin use by pregnant women, also Gingival hyperplasia.
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Slide29B. Overdosage
ToxicityMost of the commonly used anticonvulsants are CNS depressants, and
respiratory depression may occur with overdosage. Management is
primarily supportive (airway management, mechanical ventilation
), and
flumazenil
may be used in benzodiazepine overdose.
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Slide30C. Life-Threatening Toxicity
Fatal hepatotoxicity with valproic acid (risk
to children younger than 2 years and patients taking multiple anticonvulsant drugs).
Lamotrigine
has caused skin rashes
and life-threatening Stevens-Johnson syndrome
or
toxic
epidermal necrolysis. Children are at higher risk (1–2% incidence),
especially if they are also taking valproic
acid
.
Reports of aplastic anemia and acute hepatic failure have limited the use of
felbamate to severe, refractory seizure states.
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