Drugs Used to Treat Epilepsy

Epilepsy
It is a family of different recurrent seizure disorders that have in common
the sudden, excessive, and disorderly discharge of cerebral neurons which
results in abnormal movements or perceptions that are of short duration but
tend to recur.
Seizures
Finite episodes of brain dysfunction resulting from abnormal discharge of
cerebral neurons.

Etiology of Seizures
Birth and perinatal injuries
Vascular insults
Head trauma
Congenital malformations
Metabolic disturbances
Drugs or alcohol, including withdrawal from barbiturates and CNS
depressants
Neoplasia
Infection
Hyperthermia in children

Classification According to Etiology

Primary or idiopathic epilepsy
No specific anatomical cause for the seizure.
May be produced by an inherited abnormality in the CNS.
Treatment chronically with anti-epileptic drugs for life.
Secondary epilepsy
When seizures are triggered by a number of reversible disturbances, such
as tumors, head injury, hypoglycemia, meningeal infection, or rapid
withdrawal of alcohol in an alcoholic.
Anti-epileptic drugs are given until the primary cause can be corrected.

Classification According to Its Nature

Partial or focal seizures
Arise in a part of one cerebral hemisphere and are accompanied by focal
EEG abnormalities.
1. Simple partial
2. Complex partial
Generalized onset seizures
Simultaneous involvement of all or large part of both cerebral
hemispheres seen by EEG or clinically.
1. Tonic-clonic (grand mal)
2. Absence (petit mal)
3. Others, including myoclonic, atonic

Febrile Seizures
Occur in young children, 3 months to 5 years of age, accompanying an
illness with a high temperature.
Consists of a generalized tonic-clonic convulsions of short duration.
Drug of choice: Phenobarbital.

Status Epilepticus
When seizures recur with increasing frequency such that baseline
consciousness is not regained between seizures.
Lasts at least 30 minutes.
Leads to hypoxia, acidemia, hyperpyrexia, CV collapse, renal shutdown.
A medical emergency with mortality of 15% or less.

Seizure Sequence
Focal epileptogenesis (Initiation)
Abnormal voltage-operated ion channel.
Abnormal receptor-operated channels.
1. Decreased GABA-ergic inhibition that causes neural excitation
and depolarization
2. Increased excitatory neurotransmission by glutamate receptor as
NMDA (N-methyl-D-aspartate)
Synchronization of surrounding neurons
Abnormal receptor-operated channel.
Alterations in extracellular ionic environment (increased K+,
decreased Ca++).
Recruitment of normal neurons via anatomical circuits.
Propagation of seizure discharge to other areas of the brain.
Alterations in extracellular ionic environment leading to neuronal
excitability
Recruitment of normal neurons via anatomical circuits

Goal of Therapy
To keep the patient free of seizures without causing any unwanted effects
that might interfere with his normal function.

Monodrug therapy
1. Low incidence of adverse effects.
2. Avoidance of drug interactions.
3. Improved patient compliance.
4. Lower medical cost.

Success with monotherapy depends on:

1. Correct seizure classification and diagnosis.
2. Appropriate drug choice for the seizure type.
3. Optimal drug administration and serum monitoring.

Mechanisms of Drug Action

Use-dependent blockade of sodium channels, reducing the repetitive firing
of neurons.
Phenytoin, Primidone, Carbamazepine, Lamotrigine
Increasing the inhibitory activity of GABA that causes increased influx of
chloride ions that, in turn, decreases neural excitation by hyperpolarization
and elevated seizure threshold.
Clonazepam, Valproic acid, Phenobarbital, Vigabatrin, Tiagabine,
Felbamate, Gabapentin, Pregabalin, Topiramate
Reducing the propagation of abnormal electrical activity in the brain by
inhibiting the T-type calcium channels.
Ethosuximide

Primary Drugs for Epilepsy

Clonazepam(Rivotril)
A BZD which suppresses seizure spread from the epileptogenic foci by

enhancing GABA action.

Valproic acid (Depakene)
A carboxylic acid derivative that acts by increasing the inhibitory activity

of GABA by inhibiting 2 enzymes that inactivates GABA: (1) GABA-

transaminase and (2) succinic semialdehyde dehydrogenase.
Phenytoin (Dilantin)
Also known as diphenylhydantoin or DPH.

Oldest non-sedating drug that acts by inhibiting sodium channel function

and increasing GABA action.

Phenobarbital (Luminal)
A derivative of barbituric acid that inhibits initiation of discharge,
elevates seizure threshold, and potentiates inhibitory pathways in the
brain by enhancing GABA action.
Drug of choice for neonatal and febrile seizures.
Primidone (Mysoline)
Also known as 2-desoxyphenobarbital.
A derivative of barbituric acid which is metabolized to active
anticonvulsants: phenobarbital and phenylethylmalonamide (PEMA).
Acts by inhibition of sodium channel function.
Carbamazepine (Tegretol)
A tricyclic compound used also in treating bipolar depression.
Acts by inhibiting sodium channel function, thus inhibiting the generation
of repetitive action potentials in the epileptic focus.
Ethosuximide (Zarontin)
A succinimide, pure petit mal drug.
Reduces the propagation of abnormal electrical activity in the brain by
inhibiting the T-type calcium channels.

Newer Anti-epileptic drugs

Vigabatrin
♦gamma-vinyl-substituted analogue of GABA.
¨Irreversibly inhibits the GABA metabolizing enzyme, GABA
aminotransferase (GABA-T), thereby enhancing the inhibitory effect of
GABA.
Lamotrigine
Acts by inhibiting sodium channels.
Felbamate
 MOA: 1. Use-dependent blockade of the NMDA receptor; 2. Potentiation of
GABA receptor responses.
Gabapentin and Pregabalin
Analogue of GABA that increases the synaptic release of GABA 
increased GABA concentration.
Tiagabine
Blocks GABA uptake into the presynaptic neuron, permitting more GABA
to be available for receptor binding, thus causing enhanced inhibitory
activity.
Topiramate
A chemical relative of fructose that causes blockade of the sodium
channels, increased GABA activity at GABA receptors, and blockade of
some glutamate receptors.
Levetiracetam
A piracetam analogue effective against seizures induced by maximum
electroshock or pentylenetetrazole.
Modifies the synaptic release of glutamate and GABA.
Zonisamide
A sulfonamide derivative that inhibits the sodium channel and the
voltage-gated calcium channels.

Secondary Drugs for Epilepsy

Methosuximide (Celontin)
Acetazolamide (Diamox)
Mephobarbital (Mebaral)
Mephenytoin (Mesantoin)
Phensuximide (Milontin)
Paramethadione (Paradione)
Ethotoin (Peganone)
Phenacemide (Phenurone)
Tridione (Trimethadione)
Chlorazepate (Tranxene)
Drugs for Status Epilepticus
Lorazepam (Ativan)
Diazepam (Valium)

Chemistry of Anti-epileptic drugs

Phenyl group at the R1 position produces activity against partial seizures.
Alkyl group at the R1 position produces activity against certain generalized
seizures.

Pharmacokinetics
Absorption is good following oral administration.
They cross the BBB, hence have the potential of producing neurologic
toxicity.
They are not highly protein-bound except Phenytoin, BZD, and Valproic acid
which may displace other drugs owing to their being highly protein-bound.
They are cleared chiefly by hepatic mechanism.
Interactions Among Anti-epileptic Drugs
Carbamazepine
With Phenobarbital: Increased metabolism to epoxide, thus
decreasing Carbamazepine effect.
With Phenytoin: Increased metabolism, thus decreasing
Carbamazepine effect.
Phenytoin
With Primidone: Increased conversion of Primidone into Phenobarbital,
thus increasing the blood conc.
Valproic acid
With Clonazepam: Precipitate convulsive status epilepticus.

With Phenobarbital: Decreased metabolism of Phenobarbital, thus

producing toxicity.
With Phenytoin: Increased Phenytoin toxicity due to displacement from
binding.

Interactions with Other Drugs

Antibiotics: Increased serum conc. of Phenytoin,
Phenobabrbital, or Carbamazepine that may cause toxicity.
Anticoagulants: Decreased effect of Coumadin because of increased
metabolism by Phenytoin or Phenobarbital.
Cimetidine: Increased BZD effect due to its displacement from binding.
Isoniazid: Increased toxicity of Phenytoin because its
metabolism is reduced.
Oral contraceptives: Increased failure rate because of increased
metabolism.
Salicylates: Phenobarbital or Valproic acid toxicity because they are
displaced from binding.
Theophylline: Carbamazepine and Phenytoin decrease its effects.

Adverse Drug Reactions

Carbamazepine
Mild GI upset, drowsiness, granulocyte suppression and aplastic anemia

in the elderly, diplopia and ataxia, erythematous skin rashes.

Phenytoin
Ataxia and nystagmus (dose-related), cognitive impairment and sedation,

osteomalacia due to an abnormality in vit. D metabolism.

Hirsutism, gingival hyperplasia, coarsening of facial features, and

peripheral neuropathy on long-term use.

Phenobarbital and Primidone
Sedation and cognitive impairment, behavioral changes (hyperactivity

and short-term memory), induction of liver enzymes.

Valproic acid
Tremors; GI symptoms (NAV, abd. pain, heartburn); hepatotoxicity; spina

bifida; CV, orofacial, and digital abnormalities in offsprings of mothers

taking this drug.
Ethosuximide
Gastric distress, NAV, transient lethargy or fatigue, headache, dizziness,

hiccup.
Clonazepam
  Sedation and lethargy, ataxia, tolerance to anti-epileptic effects.

Withdrawal from Anti-epileptic Treatment

Withdrawal of these drugs can cause increased seizure frequency and
severity. In general, withdrawal of anti-absence drugs is easier than
withdrawal of drugs for partial of grand mal types.
Barbiturates and BZD are the most difficult to discontinue, requiring weeks
or months with very gradual dosage decrements.
Children whose seizures have always been infrequent and whose EEG are
normal are candidates for gradual removal of drugs after 4 seizure-free years.

Anti-epileptic therapy and pregnancy

1. The rates of stillbirth and infant mortality are higher for epileptic
mothers.
2. Children of epileptic mothers who received anticonvulsant
medications during the early months of pregnancy have an increased
incidence of a variety of birth defects.
3. Formation of epoxide intermediates during the metabolism of
carbamazepine and phenytoin may induce fetal malformations.
4. Valproic acid is cited as causing neural tube defects in 1-2% of
offsprings of epileptic mothers.
5. Phenytoin is implicated in fetal hydantoin syndrome characterized
by cleft lip, cleft palate, congenital heart disease, slowed growth, and
mental deficiency.
6. The incidence of malformations is increased with the combination of
carbamazepine, valproic acid, and phenytoin or phenobarbital.

General Principles for Therapy

Early diagnosis and treatment of seizure disorders with a single appropriate
agent offers the best prospect of achieving prolonged seizure-free periods
with the lowest risk of toxicity. Complete control of seizures can be achieved
in up to 50% of cases and that another 25% can improve significantly.
An attempt should be made to ascertain the cause of the epilepsy with the
hope of discovering a correctable lesion, either structural or metabolic.
The degree of success is greater in newly-diagnosed cases and is dependent
on the type of seizure, family history, and extent of associated neurological
abnormalities.
The goal of therapy is to keep the patient free of seizures without interfering
with normal function.
Medication should be initiated with a single dose. Dosage is increased
gradually at appropriate intervals as required for control of seizures or
decreased in the presence of toxicity, and such adjustment is preferably
assisted by monitoring the drug concentration in the plasma.
If a single drug fails to provide adequate control of seizures, substitution
with a second drug is generally preferred to the concurrent administration of
another drug.
Dosage should always be reduced gradually when drug is to be discontinued
in order to minimize risk of precipitating status epilepticus.
No drug should be discarded as useless unless toxicity prevents increased
dosage.
The frequency and severity of toxicity are reduced by avoiding regimens
with 2 or more drugs. However, multiple drug therapy may be required
especially when 2 or more types of seizures occur in the same patient.
Most crucial for successful management is the regularity of medication since
faulty compliance is the most frequent cause of failure in therapy.
Measurement of plasma drug concentrations at appropriate intervals greatly
facilitates the initial adjustment of dosage to minimize dose-related adverse
effects without sacrificing seizure control.
Many patients appear to be resistant to medications or develop unnecessary
side effects because the medications chosen are not appropriate for the kind
of seizure or are not in the optimum doses.