Download Epilepsy is a chronic brain disorder of various etiologies

EPILEPSY
Epilepsy
is
a
chronic
brain
disorder
of
various
etiologies
characterized by recurrent, unprovoked seizures.
Traditionally,
patients with single or only provoked seizures are not
considered to have epilepsy. Epilepsy is not a single disease but is
divided into various epileptic syndromes.
Epileptic
syndromes are groups of epileptic patterns, consisting of
one or more seizure types.
Convulsions are seizures with prominent motor activity (eg,
generalized
tonic-clonic
seizures).
Seizures
may
also
be
nonconvulsive, manifested only by altered consciousness (eg, absence
or complex partial seizures).
A seizure may be defined as a periodic attack of disturbed cerebral
function due to disturbance in the electrical activity in one or more
areas of the brain.
 Seizures may be classified as partial (focal) or generalized. Each
different type of seizure disorder is characterized by a specific
pattern of events, as well as a different pattern of motor or sensory
SEIZURE TYPE
FEATURES
Partial seizures:
Simple partial
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 to 60 seconds. Key
feature is preservation of consciousness.
Complex partial
Impaired consciousness lasting 30 seconds to
2 minutes, often associated with purposeless
movements such as lip smacking or hand
wringing.
Partial with secondarily generalized tonic- Simple or complex partial seizure evolves
clonic seizure
into a tonic-clonic seizure with loss of
consciousness and sustained contractions
(tonic) of muscles throughout the body
followed by periods of muscle contraction
alternating with periods of relaxation (clonic),
Generalized seizures:
Absence seizure
Myoclonic seizure
Tonic-clonic seizure
Abrupt onset of impaired consciousness
associated with staring and cessation of
ongoing activities typically lasting less
than 30 seconds.
A brief (perhaps a second), shock-like
contraction of muscles which may be
restricted to part of one extremity or may
be generalized.
As described above for partial with
secondarily generalized tonic-clonic
seizures except that it is not preceded by
a partial seizure.
In contrast to partial seizures, which arise from localized regions of
the cerebral cortex, generalized- seizures arise from the reciprocal
firing of the thalamus and cerebral cortex
ETIOLOGY
Seizure disorders are generally categorized as idiopathic or acquired.

Idiopathic seizures have no known cause.

Acquired seizure disorders have a known cause, including high fever,
electrolyte imbalances, uremia, hypoglycemia, hypoxia, brain tumors.
Once the cause is removed (if it can be removed), the seizures
theoretically cease.
The known causes of epilepsy

include brain injury at birth, head injuries, and

inborn errors of metabolism.

In some patients, the cause of epilepsy may be genetic basis.
Familial epilepsy usually presents as childhood onset epilepsy
without evidence of underlying brain disease. A genetic basis is more
likely in patients with generalized rather than partial epilepsies.
The genetic defects cause abnormalities of ion channels and/or key
structural membrane proteins.
Meningitis,
encephalitis
including
herpes
simplex,
abscess,
cysticercosis, toxoplasmosis, rubella, neurosyphilis, tuberculosis.
MECHANISM

The pivotal role of synapses in mediating communication among
neurons in the mammalian brain suggested that defective synaptic
function might lead to a seizure.
That
is, a reduction of inhibitory synaptic activity or enhancement of
excitatory synaptic activity might be expected to trigger a seizure;
The
neurotransmitters mediating the bulk of synaptic transmission in the
mammalian brain are amino acids, with Gama -aminobutyric acid (GABA)
and
glutamate
being
the
neurotransmitters, respectively
principal
inhibitory
and
excitatory
Generally, anticonvulsants reduce the excitability of the neurons
(nerve cells) of the brain.
When neuron excitability is decreased, seizures are theoretically
reduced in intensity and frequency of occurrence or, in some
instances, are virtually eliminated.
For some patients, only partial control of the seizure disorder may
be obtained with anticonvulsant drug therapy.
THERAPEUTIC ASPECTS
The ideal antiseizure drug would suppress all seizures without causing
any unwanted effects.
The drugs used currently not only fail to control seizure activity in some
patients, but frequently cause unwanted effects that range in severity
from minimal impairment of the CNS to death from aplastic anemia or
hepatic failure.
The clinician who treats patients with epilepsy is thus faced with the
task of selecting the appropriate drug or combination of drugs that best
controls seizures in an individual patient at an acceptable level of
untoward effects.
The degree of success varies as a function of seizure type, cause,
and other factors.
To minimize toxicity, treatment with a single drug is preferred.
 If seizures are not controlled with the initial agent at adequate
plasma concentrations, substitution of a second drug is preferred to
the concurrent administration of another agent.
 However, multiple-drug therapy may be required, especially when
two or more types of seizure occur in the same patient.
Measurement
of
drug
concentrations
in
plasma
optimizing antiseizure medication, especially when
facilitates
The event of therapeutic failure,
Toxic effects appear, or
Multiple-drug therapy is instituted.
Clinical effects of some drugs do not correlate well with their
concentrations in plasma, and recommended concentrations are only
guidelines for therapy.
The ultimate therapeutic regimen must be determined by clinical
assessment of effect and toxicity.
The general principles of the drug therapy of the epilepsies are
summarized below.
CHEMICALSUMMARY
CLASSIFICATION
AND
CLINICAL USES
DRUG
TABLE
CLINICAL ASPECTS OF ANTI EPILEPTIC DRUGS AVAILABLE IN INDIA
Mechanism of action of anticonvulsant
drugs that act on sodium channels. The
sodium channel can normally exist in a
closed (A), open (B), or inactivated (C)
state.
A. An activation gate is closed and sodium
ions cannot pass through the channel.
B. The channel activation gate opens
rapidly
following
depolarization
and
sodium enters freely.
Soon after opening, an inactivation gate
(C) closes, preventing further entry of
sodium ions into the cell.
Drugs
sharing
carbamazepine
this
mechanism
include
(Tegretol), oxcarbazepine
phenytoin
(Dilantin),
(Trileptal), topiramate
(Topamax), valproic acid (Depakene), zonisamide (Zonegran), and
lamotrigine (Lamictal).
All of these agents have the capacity to block sustained highfrequency repetitive firing (SRF) of action potentials.
This is accomplished by reducing the amplitude of sodium-
dependent action potentials through an enhancement of steady-state
inactivation.
CARBAMAZEPINE
PHARMACOLOGY AND MECHANISM OF ACTION
The exact mechanism by which carbamazepine suppresses seizure
spread is obscure, although it is believed to act primarily through
inhibition of voltage gated sodium channels. In addition, interaction
with voltage-gated calcium and potassium channels can also
contribute to its activity.
Pharmacokinetics
The absorption of carbamazepine from immediate- release tablets is
slow and erratic because of its low watersolubility.
No first-pass metabolism.
Fat, may enhance the bioavailability of carbamazepine.
The suspension dosage form is absorbed faster than the tablets.
Compared with immediate-release
carbamazepine, both these
formulations have decrease side effects and improve seizure control.
The enzyme-induction effect begins within 3 to 5 days of the initiation
of therapy and takes 21 to 28 days to complete.
Carbamazepine also displays diurnal variation in its serum level with
the evening level lower than the morning level.
Adverse Effects
Side effects of carbamazepine can fluctuate daily, paralleling the rise
and decline of serum concentrations.
Neurosensory side effects (e.g., diplopia, blurred vision, nystagmus,
ataxia, unsteadiness, dizziness, and headache) are the most common,
occurring in 35% to 50% of patients.
These side effects are more common during initiation of therapy and
can dissipate with continued treatment.
Carbamazepine can also cause nausea, which can either be caused
by a local effect of the drug on the GI tract, in which case food may
help, or caused by an effect on the brainstem, which may ultimately
require discontinuation of the drug.
Drug Interactions
Because of concentration-dependent efficacy and side effects, drug
interactions with carbamazepine often are very significant.
Drugs that inhibit CYP 3A4 potentially may increase carbamazepine
Serum Conc Dosage manipulation, including the use of the
controlled- or sustained-release preparations, should be tried before
the patient is considered to be intolerant of carbamazepine.
Leukopenia is the most common hematologic side effect.
Leukopenia usually is transient, even when the drug is continued, and
can be caused by a redistribution of white blood cells (WBCs) rather
than a decrease in their production. In about 2% of patients, the
leukopenia is persistent, but even patients with WBC counts of
3,000/mm3 or less do not seem to have an increased incidence of
infection.
A clinical guide is to continue carbamazepine therapy unless the
WBC count drops to less than 2,500/mm3 and the absolute neutrophil
Carbamazepine
can
cause
hyponatremia, the incidence of which
count drops to less
than
1,000/mm3.
increases with age, however, its occurrence is lower than that seen
with oxcarbazepine.
Periodic
determinations
of
serum
sodium
concentration
are
Dosing and Administration
The variable contributions of the 10,11-epoxide metabolite and freecarbamazepine concentrations have restricted a precise definition of
the therapeutic range.
Loading doses of carbamazepine are indicated only for critically ill
patients. During dosage titration, it should be remembered that
carbamazepine clearance increases with time.
Doses may be started at onefourth to one-third the anticipated
maintenance dose and increased every 2 to 3 weeks. Because of the
auto- and heteroinduction of carbamazepine metabolism, it is
necessary to administer the drug two to four times per day.
The controlled- and sustained release formulations provide fewer
peak-to-trough fluctuations, which can improve adherence, reduce
side effects, and improve seizure control.
Carbamazepine tablets should not be stored in places where they
would be exposed to high heat and high humidity.
Advantages
Carbamazepine has been well studied. Oral immediate- and
extended-release solid and liquid dosage forms are available.
The oral solid dosage form is available as an immediate-release tablet
and as a sustained-release capsule and a controlled-release tablet as
twice-daily dosing Compared with other first-generation AEDs,
carbamazepine causes minimal cognitive impairment.
DISADVANTAGES
Carbamazepine has an active metabolite that can contribute to efficacy and toxicity.
Other drugs can alter the concentration of this metabolite without changing the
concentration of the parent carbamazepine.
It induces its own metabolism, which requires careful dosage titration.
It also induces the metabolism of other medications, and other drugs
may interact with it and/ or the active metabolite.
There is no parenteral formulation.
There are clinically meaningful CNS side effects including sedation
and nausea. When ingested during the first trimester by pregnant
women, carbamazepine has been associated with a 1% risk of spina
bifida.
Chronic carbamazepine use also has been associated with alterations
in bone mineral density in some studies and decreases in 25-hydoxy
(OH) vitamin D.
PLACE IN THERAPY
Carbamazepine should be considered a firstline therapy for patients
with newly diagnosed partial seizures and for patients with primary
GABAPENTIN
PHARMACOLOGY AND MECHANISM OF ACTION
Gabapentin was designed to be a GABA agonist but does not react at
the GABA receptor, alter GABA uptake, or interfere with GABA
transaminase.
Gabapentin appears to bind to an amino acid carrier protein and
appears to act at a unique receptor. Gabapentin inhibits high-voltage
activated calcium channels.
It elevates human brain GABA levels, possibly via alterations in GABA
synthesis or reversal of the neuronal GABA transporter, resulting in
nonvesicular release of GABA.
PHARMACOKINETICS
Gabapentin is a substrate of the L-amino acid carrier protein in the
gut (system L), as well as in the CNS.
This amino acid carrier protein transports the drug across the gut
membrane by an active process.
The binding of gabapentin to this system is saturable, and gabapentin
therefore displays dose-dependent bioavailability that appears to
vary considerably between individuals.
Food, including protein-rich meals, does not appear to interfere with
gabapentin oral absorption.
Concentrations in human CSF are 5% to 35% of plasma levels, and
tissue concentrations are approximately 80% of plasma levels.
Because gabapentin is eliminated exclusively by the kidneys, dosage
adjustments are necessary in patients with significantly impaired
renal function. In anuric patients, 35% of gabapentin is removed by
Adverse Effects
Fatigue, somnolence, dizziness, and ataxia are the most frequently
reported side effects. Aggressive behavior has been reported in
children.
The CNS effects of gabapentin are generally less than those of
traditional AEDs.
A withdrawal reaction characterized by anxiety, insomnia, nausea,
sweating, and increased pain has also been reported with abrupt
discontinuation in patients taking it for pain.
Drug Interactions
Gabapentin does not induce or inhibit liver enzymes; therefore, drug
interactions are not likely to occur with gabapentin.
There is a 10% reduction in the clearance of gabapentin in patients
taking cimetidine and a 20% reduction in the bioavailability if
Dosing and Administration
Typical starting doses of gabapentin are 300 mg at bedtime on the first
day, increasing to 900 mg/day over 3 days.
Pharmacokinetic study suggest gabapentin should be given at least four
times a day when the total daily dose is 3,600 mg or greater.
Gabapentin does not appear to be absorbed rectally. Patients with endstage renal disease maintained on hemodialysis should receive an initial
300- to 400-mg dose with 200 to 300 mg gabapentin given after every 4
hours of hemodialysis.
Advantages
Gabapentin has multiple mechanisms of action and is mechanistically
different from first-generation AEDs. It is not metabolized and is excreted
unchanged by the kidney.
Gabapentin has the additional advantages of a broad therapeutic index
Disadvantages
Gabapentin is absorbed by an active process that saturates at higher doses.
This may require more frequent daily dosing for patients who need doses
greater than 3,600 mg/day. Doses exceeding the 3,600 mg/day maximum
listed in the package insert may be required in some patients to achieve
seizure remission. There is no parenteral formulation.
Place in Therapy
Gabapentin is a second-line agent for patients with partial seizures who have
failed initial treatment. In addition, although monotherapy trials have no
proven efficacy in previously treated patients.
CONTRAINDICATIONS, PRECAUTIONS, INTERACTIONS
Barbiturates

The barbiturates are used cautiously in patients with liver or kidney
disease and those with neurological disorders.

The barbiturates (eg, phenobarbital) are used with caution in patients with
pulmonary disease and in hyperactive children.

When barbiturates are used with other CNS depressants (eg, alcohol, narcotic
analgesics, and antidepressants), an additive CNS depressant effect may occur.
BENZODIAZEPINES

The
benzodiazepines
are
contraindicated
in
patients
with
known
hypersensitivity to the drugs.

The benzodiazepines are used cautiously during pregnancy (Category D) and in
patients with psychoses, acute narrow angle glaucoma, liver or kidney disease,
and neurologic disorders.

The benzodiazepines are used cautiously in elderly patients.

When the benzodiazepines are used with other CNS depressants (eg, alcohol,
narcotic analgesics, and antidepressants), an additive CNS depressant effect
may occur.

Increased effects of the benzodiazepines are seen when the drugs are
administered with cimetidine, disulfiram, and oral contraceptives.

When the benzodiazepines are administered with theophylline, there is a
decreased effect of the benzodiazepines.
HYDANTOINS

The hydantoins are contraindicated in patients with known hypersensitivity to
the drugs.

Phenytoin is contraindicated in patients with sinus bradycardia, sinoatrial
block, second and third degree AV block, and Adams-Stokes syndrome; it also
is contraindicated during pregnancy (ethotoin and phenytoin are Pregnancy
Category D) and lactation.

Ethotoin is contraindicated in patients with hepatic abnormalities.

When the hydantoins are used with other CNS depressants (eg, alcohol,
narcotic analgesics, and antidepressants), an additive CNS depressant effect
may occur. The hydantoins are used cautiously in patients with liver or kidney
disease and neurologic disorders.

Phenytoin is used cautiously in patients with hypotension, severe myocardial
insufficiency, and hepatic impairment.

Phenytoin interacts with many different drugs. For example, isoniazid,
chloramphenicol,
sulfonamides,
benzodiazepines,
succinimides,
and
cimetidine all increase phenytoin blood levels.

The barbiturates, rifampin, theophylline, and warfarin decrease phenytoin
blood levels.

When administering the hydantoins with meperidine, the analgesic effect of
meperidine is decreased.

Phenytoin has been shown to induce microsomal enzymes responsible for the
metabolism of a number of drugs.

Autostimulation of its own metabolism, however, appears to be insignificant.
Other drugs, notably phenobarbital and carbamazepine, cause decreases in
phenytoin
steady-state
concentrations
through
induction
of
hepatic
microsomal enzymes.

On the other hand, isoniazid inhibits the metabolism of phenytoin, resulting in
increased steady-state concentrations when the two drugs are given together.
OXAZOLIDINEDIONES

The Oxazolidinediones are contraindicated
in patients with
known
hypersensitivity to the drugs.

Trimethadione is classified as a Pregnancy Category D drug and is
contraindicated during pregnancy and lactation.

Trimethadione is used with caution in patients with eye disorders (eg, retinal or
optic nerve disease), liver or kidney disease, and neurologic disorders.

When trimethadione is used with other nervous system (CNS) depressants (eg,
alcohol, narcotic analgesics, and antidepressants), an additive CNS depressant
effect may occur.
SUCCINIMIDES

The succinimides are contraindicated in patients with known hypersensitivity
to the drugs.

The succinimides are contraindicated in patients with bone marrow depression
or hepatic or renal impairment and during lactation.

Ethosuximide is classified as a Pregnancy Category C drug and is used with
caution during pregnancy.

As with all anticonvulsants, when the succinimides are used with other CNS
depressants (eg, alcohol, narcotic analgesics, and antidepressants), an additive
CNS depressant effect may occur.

When the hydantoins are administered with the succinimides there may be an
increase in the hydantoin blood levels. Concurrent administration of valproic
acid and the succinimides may result in either a decrease or an increase in
succinimide blood levels.

When primidone in administered with the succinimides, lower primidone
levels may occur.

When the hydantoins are administered with the succinimides there may be an
increase in the hydantoin blood levels. Concurrent administration of valproic
acid and the succinimides may result in either a decrease or an increase in
succinimide blood levels.

When primidone in administered with the succinimides, lower primidone
levels may occur.
UNITED STATES FDA PHARMACEUTICAL PREGNANCY CATEGORIES

PREGNANCY CATEGORY A Adequate and well-controlled studies have failed
to demonstrate a risk to the fetus in the first trimester of pregnancy (and there
is no evidence of risk in later trimesters).

PREGNANCY CATEGORY B
Animal reproduction studies have failed to
demonstrate a risk to the fetus and there are no adequate and well-controlled
studies in pregnant women or animal studies which have shown an adverse
effect, but adequate and well-controlled studies in pregnant women have failed
to demonstrate a risk to the fetus in any trimester.

PREGNANCY CATEGORY C Animal reproduction studies have shown an
adverse effect on the fetus and there are no adequate and well-controlled
studies in humans, but potential benefits may warrant use of the drug in
pregnant women despite potential risks.

PREGNANCY CATEGORY D There is positive evidence of human fetal risk
based on adverse reaction data from investigational or marketing experience or
studies in humans, but potential benefits may warrant use of the drug in
pregnant women despite potential risks.

PREGNANCY CATEGORY X
Studies in animals or humans have
demonstrated fetal abnormalities and/or there is positive evidence of human
fetal risk based on adverse reaction data from investigational or marketing
experience, and the risks involved in use of the drug in pregnant women clearly
outweigh potential benefits. One characteristic of the FDA definitions of the
pregnancy categories is that the FDA requires a relatively large amount of highquality data on a pharmaceutical for it to be defined as Pregnancy Category A.
As a result of this, many drugs that would be considered Pregnancy Category A
in other countries are allocated to Category C by the FDA.