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Epilepsy is a heterogeneous
symptom complexa chronic
disorder characterized by recurrent
seizures.
The term epilepsy refers to a disorder
of brain function characterized by the
periodic and unpredictable
occurrence of seizures.
Classification of Seizure
Types.
Partial seizures
1. Simple partial seizures
Diverse manifestations determined by the region of cortex
activated by the seizure (e.g., if motor cortex representing
left thumb, clonic jerking of left thumb results; if
somatosensory cortex representing left thumb, paresthesia
of left thumb results), lasting approximating 20-60 seconds.
Key feature is preservation of consciousness.
Conventional drugs used: Carbamazepine, phenytoin,
valproate
RECENTLY DEVELOPED ANTI-SEIZURE DRUGS: Gabapentin,
lacosamide, lamotrigine, levetiracetam, rufinamide,
tiagabine, topiramate, zonisamide
Generalized seizures
1. Generalized tonic-clonic (grand mal)
seizures
As described earlier for partial with secondarily
generalized tonic-clonic seizures except that it is
not preceded by a partial seizure.
CONVENTIONAL ANTI-SEIZURE DRUGS: Gabapentin,
lacosamide, lamotrigine, levetiracetam, rufinamide,
tiagabine, topiramate, zonisamide
Newer agents: Lamotrigine, levetiracetam,
topiramate
Phenytoin
Phenytoin is the oldest nonsedative antiseizure
drug, introduced in 1938 after a systematic
evaluation of compounds such as phenobarbital that
altered electrically induced seizures in laboratory
animals. It was known for decades as
diphenylhydantoin.
Chemistry
Phenytoin is a diphenyl-substituted hydantoin. It has
much lower sedative properties. A more soluble
prodrug of phenytoin, fosphenytoin, is available
for parenteral use; this phosphate ester compound
is rapidly converted to phenytoin in the plasma.
Mechanism of Action
Phenytoin has major effects on several physiologic systems. It
alters Na+, K+, and Ca2+ conductance, membrane potentials, and
the concentrations of amino acids and the neurotransmitters
norepinephrine, acetylcholine, and -aminobutyric acid (GABA).
Studies with neurons in cell culture show that phenytoin blocks
sustained high-frequency repetitive firing of action potentials.
This effect is seen at therapeutically relevant concentrations.
The effect on Na+ conductance, arises from preferential binding
toand prolongation ofthe inactivated state of the Na +
channel. This effect is also seen with therapeutically relevant
concentrations of carbamazepine, lamotrigine, and valproate
and probably contributes to their antiseizure action in the
electroshock model and in partial seizures.
Drug interactions
Drug interactions involving phenytoin are primarily
related to protein binding or to metabolism. Since
phenytoin is 90% bound to plasma proteins, other
highly bound drugs, such as phenylbutazone and
sulfonamides, can displace phenytoin from its binding
site. In theory, such displacement may cause a
transient increase in free drug. A decrease in protein
bindingeg, from hypoalbuminemiaresults in a
decrease in the total plasma concentration of drug
but not the free concentration. Intoxication may occur
if efforts are made to maintain total drug levels in the
therapeutic range by increasing the dose.
Mephenytoin, Ethotoin,
&Phenacemide
Many congeners of phenytoin have been
synthesized, but only three have been marketed
in the USA, and one of these (phenacemide) has
been withdrawn. The other two congeners,
mephenytoin and ethotoin, like phenytoin,
appear to be most effective against generalized
tonic-clonic seizures and partial seizures. No wellcontrolled clinical trials have documented their
effectiveness. The incidence of severe reactions
such as dermatitis, agranulocytosis, or hepatitis
is higher for mephenytoin than for phenytoin.
Carbamazepine
Closely related to imipramine and
other antidepressants,
carbamazepine is a tricyclic
compound effective in treatment of
bipolar depression. It was initially
marketed for the treatment of
trigeminal neuralgia but has proved
useful for epilepsy as well.
Clinical Use
Although carbamazepine has long been
considered a drug of choice for both
partial seizures and generalized tonicclonic seizures, some of the newer
antiseizure drugs are beginning to
displace it from this role. Carbamazepine
is not sedative in its usual therapeutic
range. The drug is also very effective in
some patients with trigeminal neuralgia
Carbamazepine is completely
metabolized in humans to several
derivatives. One of these,
carbamazepine-10,11-epoxide, has
been shown to have anticonvulsant
activity.
Drug Interactions
Drug interactions involving carbamazepine
are almost exclusively related to the drug's
enzyme-inducing properties. As noted
previously, the increased metabolic capacity
of the hepatic enzymes may cause a
reduction in steady-state carbamazepine
concentrations and an increased rate of
metabolism of other drugs, eg, primidone,
phenytoin, ethosuximide, valproic acid, and
clonazepam.
Toxicity
The most common dose-related adverse effects of
carbamazepine are diplopia and ataxia. The
diplopia often occurs first and may last less than
an hour during a particular time of day.
Rearrangement of the divided daily dose can often
remedy this complaint. Other dose-related
complaints include mild gastrointestinal upsets,
unsteadiness, and, at much higher doses,
drowsiness. Hyponatremia and water intoxication
have occasionally occurred and may be doserelated.
Phenobarbital
Aside from the bromides, phenobarbital is
the oldest of the currently available
antiseizure drugs. Although it has long
been considered one of the safest of the
antiseizure agents, the use of other
medications with lesser sedative effects
has been urged. Many consider the
barbiturates the drugs of choice for
seizures only in infants.
Clinical Use
Phenobarbital is useful in the treatment of
partial seizures and generalized tonicclonic seizures, although the drug is often
tried for virtually every seizure type,
especially when attacks are difficult to
control. There is little evidence for its
effectiveness in generalized seizures such
as absence, atonic attacks, and infantile
spasms
Pharmacokinetics
The therapeutic levels of
phenobarbital in most patients range
from 10 mcg/mL to 40 mcg/mL.
Documentation of effectiveness is
best in febrile seizures, and levels
below 15 mcg/mL appear ineffective
for prevention of febrile seizure
recurrence. The upper end of the
therapeutic range is more difficult to
define because many patients
Lamotrigine
Lamotrigine, like phenytoin, suppresses
sustained rapid firing of neurons and produces a
voltage- and use-dependent inactivation of
sodium channels. This action probably explains
lamotrigine's efficacy in focal epilepsy. It appears
likely that lamotrigine also inhibits voltage-gated
Ca2+ channels, particularly the N- and P/Q-type
channels, which would account for its efficacy in
primary generalized seizures in childhood,
including absence attacks. Lamotrigine also
decreases the synaptic release of glutamate
Clinical Use
Gabapentin is effective as an adjunct
against partial seizures and generalized
tonic-clonic seizures at dosages that
range up to 2400 mg/d in controlled
clinical trials. Monotherapy studies also
document some efficacy. Some clinicians
have found that very high dosages are
needed to achieve improvement in seizure
control.
Clinical Use
Valproate is very effective against absence seizures
and is often preferred when the patient has
concomitant generalized tonic-clonic attacks.
Valproate is unique in its ability to control certain
types of myoclonic seizures. The drug is effective in
generalized tonic-clonic seizures, especially those
that are primarily generalized. A few patients with
atonic attacks may also respond, and some evidence
suggests that the drug is effective in partial seizures.
Other uses of valproate include management of
bipolar disorder and migraine prophylaxis.
Infantile spasm
An infantile spasm (IS) is a specific
type of seizure seen in an epilepsy
syndrome of infancy and childhood
known as West Syndrome. West
Syndrome is characterized by
infantile spasms, developmental
regression, and a specific pattern on
electroencephalography (EEG)
testing called hypsarrhythmia
(chaotic brain waves).
Treatment
Courses of corticotropin or corticosteroids can be
given, or other drugs may be tried. Other drugs
widely used are the benzodiazepines such as
clonazepam or nitrazepam; their efficacy in this
heterogeneous syndrome may be nearly as good as
that of corticosteroids. Vigabatrin is effective and is
considered the drug of choice by many pediatric
neurologists. The mechanism of action of
corticosteroids or corticotropin in the treatment of
infantile spasms is unknown but may involve
reduction in inflammatory processes.
Status Epilepticus
SE was defined by its durationthat
is, as continuous seizures occurring
for longer than 1 hour. Clinical and
animal experiences later showed that
pathologic changes and prognostic
implications occurred when SE
persisted for 30 minutes.