DRUGS FOR EPILEPSY

EPILEPSY
• It is produced due to abnormal electrical conductivity of the brain characterized by
episodes of Seizures or Convulsion.
• The major neurotransmitters concerned with epilepsy are GABA Glycine and
Glutamate.
• The levels of GABA and Glycine are decreased during development of seizures.
• Levels of Glutamate are increased during Epilepsy.
TYPES OF SEIZURES
A. Focal
Focal seizures involve only a portion of the brain, typically part of one lobe of one hemisphere. The
symptoms of each seizure type 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.

a) Simple partial: These seizures are caused by a group of hyperactive neurons exhibiting abnormal
electrical activity and are confined to a single locus in the brain. The electrical discharge does not
spread, and the patient does not lose consciousness or awareness. The patient often exhibits
abnormal activity of a single limb or muscle group that is controlled by the region of the brain
experiencing the disturbance. The patient may also show sensory distortions. This activity may
spread. Simple partial seizures may occur at any age.
b) Complex partial: These seizures exhibit complex sensory hallucinations and mental distortion.
Motor dysfunction may involve chewing movements, diarrhea, and/or urination. Consciousness is
altered. Simple partial seizure activity may spread to become complex and then spread to a
secondarily generalized convulsion. Complex partial seizures may occur at any age.
B. Generalized
Generalized seizures may begin locally and then progress to include abnormal electrica discharges
throughout both hemispheres of the brain. Primary generalized seizures may be convulsive or
nonconvulsive, and the patient usually has an immediate 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. The seizure may be followed by a
period of confusion and exhaustion due to the depletion of glucose and energy stores.
2. Absence: These seizures involve a brief, abrupt, 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
stares and exhibits rapid eye-blinking, which lasts for 3 to 5 seconds. An absence seizure has a very
distinct three-per-second spike and wave discharge seen on electroencephalogram.
3. Myoclonic: These seizures consist of short episodes of muscle contractions that may recur for
several minutes. They generally occur after wakening and exhibit as brief jerks of the limbs.
Myoclonic seizures occur at any age but usually begin around puberty or early adulthood.
4. Clonic: These seizures consist of short episodes of muscle contractions that may closely resemble
myoclonic seizures. Consciousness is more impaired with clonic seizures as compare to myoclonic.
5. Tonic: These seizures involve increased tone in the extension muscles and are generally less than 60
seconds long.
6. Atonic: These seizures are also known as drop attacks and are characterized by a sudden loss of
muscle tone.
DRUGS FOR EPILEPSY
A. Benzodiazepines
Benzodiazepines bind to GABA inhibitory receptors to reduce firing rate.
Most benzodiazepines are reserved for emergency or acute seizure
treatment due to tolerance. However, clonazepam and clobazam may be
prescribed as adjunctive therapy for particular types of seizures. Diazepam is
also available for rectal administration to avoid or interrupt prolonged
generalized tonic– clonic seizures or clusters when oral administration is not
possible.
B. Carbamazepine
Carbamazepine blocks sodium channels, thereby inhibiting the generation of
repetitive action potentials in the epileptic focus and preventing their
spread. Carbamazepine is effective for treatment of focal seizures and,
additionally generalized tonic–clonic seizures, trigeminal neuralgia, and
bipolar disorder. Carbamazepine is absorbed slowly and erratically following
oral administration and may vary from generic to generic, resulting in large
variations in serum concentrations of the drug. It induces its own
metabolism, resulting in lower total carbamazepine blood concentrations at
higher doses.

Hyponatremia may be noted in some patients, especially the elderly, and

may necessitate a change in medication. Carbamazepine should not be
prescribed for patients with absence seizures because it may cause an
increase in seizures.
C. Eslicarbazepine
Eslicarbazepine acetate is a prodrug that is converted to the active
metabolite eslicarbazepine by hydrolysis. Es licarbazepine is the active
metabolite of oxcarbazepine. It is a voltage-gated sodium channel blocker
and is approved for partial-onset seizures in adults. The side effect profile
includes dizziness, somnolence, diplopia, and headache. Serious adverse
reactions such as rash, psychiatric side effects, and hyponatremia occur
rarely.

D. Ethosuximide
Ethosuximide reduces propagation of abnormal electrical activity in the
brain, most likely by inhibiting T-type calcium channels. It is only effective in
treating absence seizures.
E. Ezogabine
Ezogabine is thought to open voltage-gated M-type potassium channels
leading to stabilization of the resting membrane potential. Possible unique
side effects are urinary retention, QT interval prolongation, blue skin
discoloration, and retinal abnormalities.

F. Felbamate
Felbamate has a broad spectrum of anticonvulsant action with multiple
proposed mechanisms including the blocking of voltage-dependent sodium
channels, competing with the glycine coagonist binding site on the N-
methyl-d-aspartate (NMDA) glutamate receptor, blocking of calcium
channels, and potentiating GABA action. It is reserved for use in refractory
epilepsies (particularly Lennox-Gastaut syndrome) because of the risk of
aplastic anemia (about 1:4000) and hepatic failure.
G. Gabapentin
Gabapentin is an analog of GABA. However, it does not act at GABA
receptors, enhance GABA actions or convert to GABA. Its precise mechanism
of action is not known. It is approved as adjunct therapy for focal seizures
and treatment of postherpetic neuralgia. Reduced dosing is required in renal
disease. Gabapentin is well tolerated by the elderly population with partial
seizures due to its relatively mild adverse effects. It may also be a good
choice for the older patient because there are few drug interactions.

H. Lacosamide
Lacosamide in vitro affects voltage-gated sodium channels, resulting in
stabilization of hyperexcitable neuronal membranes and inhibition of
repetitive neuronal firing. Lacosamide is approved for adjunctive treatment
of focal seizures. It is available in an injectable formulation. The most
common adverse events that limit treatment include dizziness, headache,
and fatigue.
I. Lamotrigine
Lamotrigine blocks sodium channels, as well as high voltage-dependent
calcium channels. Lamotrigine is effective in a wide variety of seizure types,
including focal, generalized, absence seizures, and Lennox-Gastaut
syndrome. It is also used to treat bipolar disorder. Lamotrigine dosages
should be reduced when adding valproate to therapy. Slow titration is
necessary with lamotrigine (particularly when adding lamotrigine to a
regimen that includes valproate) due to risk of rash, which may progress to a
serious, life-threatening reaction.

J. Levetiracetam
Levetiracetam is approved for adjunct therapy of focal onset, myoclonic, and
primary generalized tonic–clonic seizures in adults and children. The exact
mechanism of anticonvulsant action is unknown. Levetiracetam can cause
mood alterations that may require a dose reduction or a change of
medication.
K. Oxcarbazepine
Oxcarbazepine is a prodrug that is rapidly reduced to the 10-monohydroxy (MHD)
metabolite responsible for its anticonvulsant activity. MHD blocks sodium channels,
preventing the spread of the abnormal discharge. It is also thought to modulate
calcium channels. It is approved for use in adults and children with partial-onset
seizures. The adverse effect of hyponatremia limits its use in the elderly.

L. Perampanel
It is approved for adjunctive treatment of partial-onset seizures in patients 12 years or
older. Perampanel is a newer antiepileptic agent, and limited data are available in
patients.

M. Phenobarbital and primidone

The primary mechanism of action of phenobarbital is enhancement of the inhibitory
effects of GABA-mediated neurons. Primidone is metabolized to phenobarbital (major)
and phenylethylmalonamide, both with anticonvulsant activity. Phenobarbital is used
primarily in the treatment of status epilepticus when other agents fail.
N. Phenytoin and fosphenytoin
Phenytoin blocks voltage-gated sodium channels by selectively binding to the channel
in the inactive state and slowing its rate of recovery. It is effective for treatment of
focal and generalized tonic–clonic seizures and in the treatment of status epilepticus.
Phenytoin is an enzyme inducer.

Depression of the CNS occurs particularly in the cerebellum and vestibular system,
causing nystagmus and ataxia. The elderly are highly susceptible to this effect. Gingival
hyperplasia may cause the gums to grow over the teeth. Long-term use may lead to
development of peripheral neuropathies and osteoporosis. Although phenytoin is
advantageous due to its low cost, the actual cost of therapy may be much higher,
considering the potential for serious toxicity and adverse effects.

Fosphenytoin is a prodrug that is rapidly converted to phenytoin in the blood within

minutes. Whereas fosphenytoin may be administered intramuscularly (IM), phenytoin
sodium should never be given IM, as it causes tissue damage and necrosis.
Fosphenytoin is the drug of choice and standard of care for IV and IM administration
of phenytoin.
O. Pregabalin
Pregabalin binds to the α2-δ site, an auxiliary subunit of voltage-gated
calcium channels in the CNS, inhibiting excitatory neurotransmitter release.
The exact role this plays in treatment is not known, but the drug has proven
effects on focal-onset seizures, diabetic peripheral neuropathy, postherpetic
neuralgia, and fibromyalgia. Dosage adjustments are needed in renal
dysfunction. It has no significant metabolism and few drug interactions.
Weight gain and peripheral edema have been reported.

P. Rufinamide
Rufinamide acts at sodium channels. It is approved for the adjunctive
treatment of seizures associated with Lennox-Gastaut syndrome in children
over age 4 years and in adults.
Adverse effects include the potential for shortens QT intervals. Patients with
familial short QT syndrome should not be treated with rufinamide.
Q. Tiagabine
Tiagabine blocks GABA uptake into presynaptic neurons permitting more
GABA to be available for receptor binding, and therefore, it enhances
inhibitory activity. Tiagabine is effective as adjunctive treatment in partial-
onset seizures. Tiagabine should not be used for indications other than
epilepsy.

R. Topiramate
Topiramate has multiple mechanisms of action. It blocks voltage-dependent
sodium channels, reduces high-voltage calcium currents (L type), is a
carbonic anhydrase inhibitor, and may act at glutamate (NMDA) sites.
Topiramate is effective for use in partial and primary generalized epilepsy. It
is also approved for prevention of migraine.
Adverse effects include somnolence, weight loss, and paresthesias. Renal
stones, glaucoma, oligohidrosis (decreased sweating), and hyperthermia
have also been reported.
S. Valproic acid and divalproex
Possible mechanisms of action include sodium channel blockade, blockade
of GABA transaminase, and action at the T-type calcium channels. These
varied mechanisms provide a broad spectrum of activity against seizures. It
is effective for the treatment of focal and primary generalized epilepsies.

Rare hepatotoxicity may cause a rise in liver enzymes, which should be

monitored frequently. Teratogenicity is also of great concern.

T. Vigabatrin
Vigabatrin acts as an irreversible inhibitor of γ-aminobutyric acid
transaminase (GABA-T). GABA- T is the enzyme responsible for metabolism
of GABA. Vigabatrin is associated with visual field loss ranging from mild to
severe in 30% or more of patients.
U. Zonisamide
Zonisamide is a sulfonamide derivative that has a broad spectrum of action.
The compound has multiple effects, including blockade of both voltage-
gated sodium channels and T-type calcium currents. It has a limited amount
of carbonic anhydrase activity. Zonisamide is approved for use in patients
with focal epilepsy. In addition to typical CNS adverse effects, zonisamide
may cause kidney stones. Oligohidrosis has been reported, and patients
should be monitored for increased body temperature and decreased
sweating. Zonisamide is contraindicated in patients with sulfonamide or
carbonic anhydrase inhibitor hypersensitivity.