ANTISEIZURE DRUGS

Medical Pharmacology
Randal A. Skidgel, Ph.D.
Dept. of Pharmacology

HISTORY

Ancient Times: Seizure may have originated from belief that epileptics were seized by the
devil. Epilepsy is derived from the Greek epilambanein meaning to seize or attack.

1850 : Bromides discovered

1870: John Hughlings Jackson proposed first rational mechanism for seizures.

1912: First clinical use of phenobarbital to treat epilepsy

1929 - 1938: Hans Berger developed the EEG and showed the relationship between discharges
in the brain and the clinical manifestations of epileptic seizures.

1938: Merritt and Putnam systematically studied 746 compounds and discovered phenytoin as
effective antiseizure drug.

DEFINITIONS:

Seizures: result from abnormal neuronal discharge in the central nervous system produced by
either focal or generalized disturbances of brain tissue. They result in abnormal phenomena of
motor (convulsion), sensory, autonomic, or psychic origin.

Epilepsy: A condition characterized by recurrent seizures of a particular pattern unprovoked by

any immediate identified cause. Incidence = 1/300 to 1/100

Epileptic Syndromes: A cluster of symptoms frequently occurring together, including seizure

types, precipitating factors, age of onset, family history, prognosis, etc..

ETIOLOGY AND MECHANISMS:

Epileptic seizures are result from hyperexcitable neurons caused by:

1. Increased activity of voltage-gated ion channels (e.g., Na+, K+ & Ca++ channels)
2. Decreased inhibitory (i.e., GABA) neurotransmission
3. Increased excitatory neurotransmission (i.e., glutamate receptors)
4. Alteration of extracellular ion concentration (e.g., potassium, calcium).

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 Classification of Seizures
Loss of
Seizure Type Frequency Consciousness Duration Features

PARTIAL (FOCAL)
Simple partial 10 % No 20 - 60 sec Focal motor (specific muscle groups), sensory (e.g., tingling, hot
or cold sensations) or speech disturbances

Complex partial 35 % Impaired 30 sec to Complex symptoms; confused behavior, dreamy state, amnesia;
2 min often associated with automatisms (purposeless movements).

Partial with 10 % Yes 1 - 2 min Simple or complex partial seizure evolves into loss of
secondarily consciousness, rigid extension of trunk and limbs (tonic), then
generalized tonic- rhythmic contraction of arms and legs (clonic).
clonic seizure

GENERALIZED

Tonic-Clonic 30 % Yes 1 - 5 min Loss of consciousness; massive contraction of skeletal muscle;

(grand mal) rigid extension of trunk and limbs (tonic; posture called
opisthotonos), then rhythmic contraction of arms and legs (clonic).

Absence (petit mal) 10 % Impaired < 30 sec Abrupt brief onset of impaired consciousness, cessation of
activities and staring. Characteristic 3 per second spike and wave
pattern on EEG. Commonly in children (3 - 15 years old).

Myoclonic <3% No 1 - 5 sec Brief, shocklike contraction of muscles; may be restricted to part
of extremity or may be generalized. Can occur in clusters for
several min.

Atonic/Akinetic <2% Yes 5 sec - mins Sudden loss of postural tone leading to sagging of the head or
falling. Sudden freezing of motion (called akinetic)

Status Epilepticus 7% Usually >5 min A state of continuous seizure (of any type) of > 5 min or 2 or more
discrete seizures between which baseline consciousness is not
regained. This is a medical emergency that can be fatal up to
35% of the time.

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Pathways of seizure spread. A, Focal seizure with spread to adjacent and contralateral cortical regions. B, Focal
seizure with secondary generalization. Seizure discharge activates subcortical centers (A), which then activate entire
cortex (B). C, Primary generalized absence seizure in which thalamocortical relays are believed to act on a diffusely
hyperexcitable cortex.

Relationship between cortical EEG, extracellular and intracellular recordings in a seizure focus. A, Seizure was
induced by local application of a convulsant agent. The extracellular recording was made through a high-pass filter. Note
the high-frequency firing of the neuron evident in both extracellular and intracellular recording during the paroxysmal
depolarization shift (PDS). This seizure is representative of a partial with secondarily generalized tonic-clonic seizure. B,
Recording during an absence seizure, demonstrating the characteristic generalized spike and wave discharges at a
frequency of 3 per second.

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DRUG THERAPY OF EPILEPSY AND SEIZURES

A. Identification of antiseizure drugs:

The following animal models of epilepsy have been helpful in drug development:
1. Electro-convulsant shock model:
identifies drugs effective against tonic/clonic seizures

2. Pentylenetetrazole model:
identifies drugs effective against myoclonic or absence seizure

3. Kindling model
identifies drugs useful against partial and secondarily generalized seizures

4. Genetic Models
Animal models developed with primary emphasis on mutations in voltage-
and ligand gated ion channels.

B. Mechanisms of action of antiseizure drugs:

Major known mechanisms by which antiseizure drugs work:

1. Prolong Inactivation state of voltage-dependent Na+ channels in a use-dependent fashion.

2. Increase the effectiveness of inhibitory GABA transmission via the GABAA receptor.
3. Inhibition of Ca++ currents through T-type Ca++ channels.
4. Inhibition of excitatory glutamate transmission via ionotropic receptors.

Prolongation of Na+ channel inactivation state by antiseizure drugs. A, resting state in which Na+ channel activation
gate (A) is closed. B, Arrival of an action potential causes depolarization and opening of activation gate (A) and Na+ flows
into the cell. C, As depolarization continues, an inactivation gate (B) moves into the channel. Some antiseizure drugs
(black box; e.g., phenytoin) prolong the inactivated state of the channel, presumably by preventing reopening of the
inactivation gate.

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 +
Valproic Acid
-

Clobazam

Enhancement of GABA transmission by antiseizure drugs. In the presence of the transmitter GABA, the GABAA
receptor opens, allowing an influx of Cl-, which in turn, increases membrane polarization (hyperpolarizes), reducing the
likelihood of firing of the neuron. Some antiseizure drugs (top) work by reducing the metabolism of GABA. Others act at
the GABAA receptor, enhancing Cl- influx in response to GABA.

Reduction of current through T-type Ca++ channels by antiseizure drugs. Some drugs reduce the flow of Ca++
through T-type Ca++ channels, thus reducing pacemaker current that underlies the thalamic rhythm in spikes and waves
seen in generalized absence seizures.

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 Pregabalin

Figure 7. Effect of Antiseizure Drugs on Glutamate Receptors. Antiseizure drugs that reduce sodium channel
transmission will indirectly affect glutamate transmission by decreasing the amount of transmitter released from the
presynaptic terminal. Felbamate and Topiramate are weak antagonists directly on the postsynaptic glutamate receptors.

Antiseizure Drugs with Novel or Unknown Mechanisms of Action

Additional
DRUG Known Target Unknown Mechanism?

Gabapentin 2 subunit of L-type Ca++ channel Yes

Pregabalin 2 subunit of L-type Ca++ channel Yes

Lamotrigine Prolonged inactivation of Na+ channel Yes

Levetiracetam SV2A, a 90 kDa synaptic vesicle protein Yes

Ezogabine Enhances K+ currents through KCNQ ion channel No

Clobazam Binds to GABAA receptors Yes

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C. General Principles of Drug Therapy

Objective: To control seizures completely without causing intolerable side effects..

Important Concepts:

- Choice of drug depends on seizure type

- Single drug therapy tried first

- Titration of dose necessary

- Monitor plasma drug concentrations

- Therapy tailored to individual

- Drugs treat symptoms; do not cure underlying cause

-Therapeutic failure can be due to many causes (poor compliance most common)

V. CLASSICAL DRUGS USED TO TREAT EPILEPSY AND SEIZURES (Introduced before

1979).

Common Characteristics:

-Absorption good
-cleared by hepatic metabolism
-clearance relatively slow (T1/2 > 12 hours)
-complex pharmacokinetics
-Side effects common
-Drug interactions common

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VI. NEWER ANTISEIZURE DRUGS (Introduced since 1993)

Ezogabine
Rufinamide (Retigabine) Clobazam
Pregabalin Lacosamide

Common Characteristics (except Fosphenytoin and Oxcarbazepine that are derivatives of

classical drugs ):

-Broader spectrum of activity

-Fewer drug interactions
-Less complex Pharmacokinetics
-More expensive

VII. SIDE EFFECTS AND DRUG INTERACTIONS

A. Adverse Reactions

1. Minor Reactions (common)

-gastrointestinal disturbances (most drugs)
-sedative effects (most drugs)
-ataxia (many drugs)
-visual disturbances (several drugs)
-weight gain/loss (several drugs)

2. Drug- Specific Reactions

-gingival hyperplasia (phenytoin)
-hirsutism (phenytoin)
-inhibition of platelet aggregation (valproic acid)
-altered behavior in children and elderly (barbiturates)
-kidney stones & hypohidrosis (sweating) (zonisamide, tiagabine)

3. Serious reactions (rare)

-skin eruptions (hypersensitivity) (most drugs)
-blood dyscrasias (most drugs) very rare
-hepatitis (phenytoin, valproic acid, carbamazepine)
-alopecia (valproic acid) rare

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 -absence status epilepticus (rare; clonazepam + valproic acid; tiagabine?)
-serum sickness (immune reaction)
-teratogenic (most established drugs; probably new drugs as well?)

B. Drug Interactions

1. Induction of Hepatic Drug metabolizing enzymes

Some antiseizure drugs induce hepatic drug-metabolizing enzymes:

Phenytoin
Phenobarbital and Primidone
Carbamazepine and Oxcarbazepine (less effect)

This results in a decrease the plasma concentration of a variety of other drugs such as
antibiotics, other antiseizure drugs, oral anticoagulants, oral contraceptives, etc.

2. Competition for the same drug metabolizing enzyme

Many drugs can increase the plasma concentration of other drugs by inhibiting
their metabolism (i.e., they compete for the same metabolizing enzyme).

Examples:
Phenytoin, valproic acid, phenobarbital and primidone are all metabolized by the
same Cyt P450 and affect the metabolism of each other as well as other drugs
such as dicoumarol or sulfonamides.

3. Displacement of drugs bound to Plasma Proteins

Some drugs are highly bound to plasma proteins and can increase the plasma
concentration of other drugs by displacing them from plasma protein binding
sites.
Example: Phenytoin and valproic acid are highly bound to plasma proteins and
can increase the concentration of each other or drugs like diazepam or warfarin
that are also bound to plasma protein

Relationship between dose and steady state

plasma concentration of phenytoin. Results for
two patients are illustrated. In both patients, there is a
linear relationship between dose and plasma
concentration at low doses. As the dose increases,
there is a transition to a non-linear relationship. This
transition occurs at different doses in each patient,
illustrating the need to start at low doses and increase
them gradually, tailoring the therapy to each patient.

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 SUMMARY OF DRUGS USED FOR ANTISEIZURE THERAPY

Seizure Type Drug(s) of Choice Alternate Drugs

Partial Seizures Carbamazepine Phenobarbital

(including simple, Valproic Acid Primidone
complex and secondarily Phenytoin Gabapentin*
generalized tonic-clonic Lamotrigine**
seizures) Levetiracetam
Tiagabine
Topiramate*
Zonisamide
Oxcarbazepine*
Rufinamide
Lacosamide
Ezogabine
Generalized Tonic- Valproic Acid Phenobarbital
Clonic (Grand Mal) Phenytoin Primidone
Carbamazepine Lamotrigine
Topiramate
Levetiracetam

General Absence (petit Ethosuximide Valproic Acid (first choice if tonic-clonic

mal) seizures present)
Lamotrigine*
Clonazepam (not first choice because of
tolerance)

Myoclonic Valproic Acid Clonazepam

Lamotrigine

Status Epilepticus Lorazepam (i.v.) Phenytoin or Fosphenytoin, (i.v.)

Diazepam (i.v.) (alone or in combination with
diazepam)
*On the basis of an evidence-based review of literature and trials of their efficacy, these agents were recommended as
potential drugs to be prescribed as monotherapy for newly diagnosed cases of epilepsy by subcommittees of the
American Academy of Neurology and American Epilepsy Society (see French et al., Neurology, 62:1252-1260, 2004). Of
these agents, only Oxcarbazepine is FDA approved for this purpose.

**Based on a recent randomized, unblinded large clinical trial (SANAD study) of 1721 patients in the U.K., Lamotrigine
was significantly better than Carbamazepine in treating partial-onset seizures and proposed as the drug of choice for this
class of seizure. See Marson et al., Lancet, 369:1000-10015, 2007.

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