Antiepileptic drugs and seizure types

DRUGS USED IN DISORDERS OF THE
CENTRAL NERVOUS SYSTEM AND
TREATMENT OF PAIN
Lecture 3:
Seizures Disorders and Anticonvulsants
Marc Imhotep Cray, M.D. (Antiepileptic Agents)

Marc Imhotep Cray, M.D.
CNS Pharmacology
Lecture 3
Learning Objectives:
2
1. Recognition of the different seizure types
2. The concept that the seizure type determines the selection of a specific
antiepileptic drug
3. The spectrum of action of the most commonly used antiepileptic drugs
4.For a given seizure type, an understanding of the selection process of an
antiepileptic drug based on its: a) Mechanism of action, b) Efficacy,
c) Clinical pharmacokinetics (ease of use), d) Drug-drug interaction
potential, e) Tolerability (common side-effects), f) Serious toxicity
(idiosyncratic reactions)
5. Role of co-morbidities in selection of an antiepileptic drug

CNS Pharmacology
Lecture 3
Classification Schema:
Anticonvulsants (Antiepileptic Agents)
3
“Classic” antiepileptic drugs:
Benzodiazepines
Carbamazepine (Tegretol)
Ethosuximide (Zarontin)
Phenobarbital
Phenytoin (Dilantin)
Primidone (Mysoline)
Valproic acid
Na Valproate (Depakote)
Divalproex Na
“Newer” antiepileptic drugs:
Felbamate (Felbatol)
Gabapentin (Neurontin)
Lamotrigine (Lamictal)
Levetiracetam (Keppra)
Oxcarbazepine (Trileptal)
Pregabalin (Lyrica)
Tiagabine (Gabitril)
Topiramate (Topamax)
Zonisamide (Zonegran)

CNS Pharmacology
Lecture 3
Overview of Epilepsy
4
 Approximately 10% of population will have at least one seizure in their
lifetime
 Globally, epilepsy is the third most common neurologic disorder after
cerebrovascular and Alzheimer’s disease
 Epilepsy is not a single entity but an assortment of different seizure types
and syndromes originating from several mechanisms that have in common
the sudden, excessive, and synchronous discharge of cerebral neurons
 Abnormal electrical activity may result in a variety of events, including loss
of consciousness, abnormal movements, atypical or odd behavior, and
distorted perceptions that are of limited duration but recur if untreated

CNS Pharmacology
Lecture 3
Overview of Epilepsy
5
 Site of origin of abnormal neuronal firing determines symptom produced
 For example, if motor cortex is involved, patient may experience abnormal
movements or a generalized convulsion
 Seizures originating in parietal or occipital lobe may include visual, auditory, and
olfactory hallucinations
 Medications are the most widely used mode of treatment
 In general, seizures can be controlled with one medication in
approximately 75% of patients
 Patients may require more than one medication in order to optimize seizure control
 some patients may never obtain total seizure control

CNS Pharmacology
Lecture 3ELECTROENCEPHALOGRAPHY
6
 EEG permits recording of
collective electrical activity
of cerebral cortex as a
summation of activity
measured as a difference
between two recording
electrodes
 Recording electrodes (leads)
are placed on the scalp on
at least 16 standard sites,
and recordings of potential
differences between key
electrodes are obtained

CNS Pharmacology
Lecture 3
EEG (2)
7
Examples are provided of a
1. normal EEG taken when
client is awake with eyes
closed and
2. normal EEG sleeping
Abnormal patterns of activity
can be seen in presence of
3. tumors and
4. seizures

CNS Pharmacology
Lecture 3
Etiology of Seizures
8
 In most cases, epilepsy has no identifiable cause
 Focal areas that are functionally abnormal may be triggered into
activity by changes in physiologic factors, such as alteration in
blood gases, pH, electrolytes, and blood glucose and changes in
environmental factors, such as sleep deprivation, alcohol intake,
and stress
 The neuronal discharge results from firing of a small population
of neurons in a specific area of the brain referred to as the
“primary focus”
 Neuroimaging techniques, such as magnetic resonance imaging,
positron emission tomography scans, and single photon
emission coherence tomography, may identify areas of concern

CNS Pharmacology
Lecture 3
Etiology of Seizures (2)
9
Intracranial:

CNS Pharmacology
Lecture 3
Etiology of Seizures (3)
10
Extracranial:

CNS Pharmacology
Lecture 3
Classification of Seizures:
11
 It is important to correctly classify seizures to
determine appropriate treatment
 Seizures have been categorized by site of
origin, etiology, electrophysiologic correlation,
and clinical presentation
 The nomenclature developed by the
International League Against Epilepsy is
considered the standard way to classify
seizures and epilepsy syndromes
 Seizures have been classified into two broad
groups: focal and generalized

CNS Pharmacology
Lecture 3
A. Focal Seizures (simple, complex)
12
 Involve only a portion of brain, typically part of one lobe of
one hemisphere
 Symptoms depend on site of neuronal discharge and on
extent to which electrical activity spreads to other neurons
in brain
 Focal seizures may progress to become generalized tonic-
clonic seizures

CNS Pharmacology
Lecture 3
Focal Seizures, Simple partial:
13
 Caused by a group of hyperactive neurons exhibiting abnormal
electrical activity and confined to a single locus in brain
 Electrical discharge does not spread, and patient does not lose
consciousness or awareness
 Pt. often exhibits abnormal activity of a single limb or muscle group
controlled by region of the brain experiencing disturbance
 Pt. may also show sensory distortions
 May occur at any age

CNS Pharmacology
Lecture 3
14

CNS Pharmacology
Lecture 3
Focal Seizures, Complex partial:
15
 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
 May occur at any age

CNS Pharmacology
Lecture 3
16

CNS Pharmacology
Lecture 3
B. Generalized Seizures
17
 May begin locally and then progress to include abnormal
electrical discharges throughout both hemispheres of brain
 Primary generalized seizures may be convulsive or
nonconvulsive, and
 Patient usually has an immediate loss of consciousness (LOC)

CNS Pharmacology
Lecture 3
Generalized Seizures, 1. Tonic-clonic
18
 These seizures result in loss of consciousness (LOC), followed by
tonic (continuous contraction) and clonic (rapid contraction and
relaxation) phases
 So-called “Ictal phase”
 May be followed by a period of confusion and exhaustion due to
depletion of glucose and energy stores
 “Postictal phase”
(Grand Mal seizures)

CNS Pharmacology
Lecture 3
19

CNS Pharmacology
Lecture 3
Status Epilepticus- An unbroken cycle of seizures 20

CNS Pharmacology
Lecture 3
Generalized Seizures, 2. Absence
21
 These seizures involve a brief, abrupt, and self-limiting loss of
consciousness
 Onset generally occurs in patients at 3 to 5 years of age and lasts until
puberty or beyond
 Patient stares and exhibits rapid eye-blinking, which lasts 3 to 5
seconds
 Has a very distinct three-per-second spike and wave discharge seen on
electroencephalogram
(Petit Mal seizures)

CNS Pharmacology
Lecture 3
22

CNS Pharmacology
Lecture 3
Generalized Seizures, 3. Myoclonic
23
 Consist of short episodes of muscle contractions that may recur for
several minutes
 Generally occur after wakening and exhibit as brief jerks of limbs
 Occur at any age but usually begin around puberty or early
adulthood

CNS Pharmacology
Lecture 3
Generalized Seizures cont.
24
4. Clonic: Consist of short episodes of muscle
contractions that may closely resemble myoclonic seizures
 Consciousness is more impaired compared to myoclonic
5. Tonic: Involve increased tone in extension
muscles and are generally less than 60 seconds long
6. Atonic: Also known as drop attacks and are characterized by a
sudden loss of muscle tone

CNS Pharmacology
Lecture 3
Scientific foundations for antiepilepsy
medications screening:
25
ANIMAL MODELS are useful in screening of potential drugs for
treatment of epilepsy
1. The convulsant pentylenetetrazol induces convulsions that have
drug sensitivities similar to absence seizures
2. Maximal electrical shock induces convulsions with drug
sensitivities similar to tonic–clonic seizures
3. Kindling from weak, long-term stimulation of the cortex or
amygdala induces generalized seizures
 Ref: He XP, Kotloski R, Nef S, et al. Conditional deletion of TrkB but not BDNF prevents
epileptogenesis in the kindling model. Neuron, 2004, 43:31–42.

CNS Pharmacology
Lecture 3
General Mechanism of action (MOA) of
antiepilepsy medications
26
 Drugs reduce seizures through such mechanisms as:
 blocking voltage-gated channels (Na+ or Ca2+),
 enhancing inhibitory γ-aminobutyric acid (GABA)-ergic impulses
and
 interfering with excitatory glutamate transmission
 Some antiepilepsy medications have multiple targets within the CNS,
whereas MOA for some agents is poorly defined
Antiepilepsy medications suppress seizures but do not “cure” or
“prevent” epilepsy

CNS Pharmacology
Lecture 3
Medication selection considerations:
27
 Choice of drug treatment is based on:
 Classification of the seizures,
 Patient-specific variables (for example, age, comorbid medical conditions,
lifestyle, and personal preference), and
 Characteristics of the drug (such as cost and drug interactions)
o For example, focal-onset seizures are treated with a different set of
medications than primary generalized seizures, although the list of effective
agents overlaps
 Toxicity of agent and characteristics of patient are major considerations
in drug selection
 In newly diagnosed patients, monotherapy is instituted with a single agent
until seizures are controlled or toxicity occurs

CNS Pharmacology
Lecture 3
Features Common to Antiepileptics:
28
 Many features are common to most antiepileptics:
 None of these drugs are curative
 They tend to be highly bound to plasma proteins
 They are usually cleared by hepatic metabolism
o They may inhibit metabolism of other drugs (valproic acid)
o They may induce metabolism of other drugs (e.g., the effectiveness of
oral contraceptives can be reduced [phenobarbital, phenytoin,
carbamazepine])
o For older “classic” agents, it is important to measure serum
anticonvulsant concentration
 (Low TI / Low Safety Margin/ Narrow Therapeutic Window)

CNS Pharmacology
Lecture 3
Features Common to Antiepileptics (2):
29
Side effects that usually occur include:
1. CNS depression (even phenytoin induces lethargy)
2. Skin rashes (lamotrigine and carbamazepine can cause Stevens–
Johnson syndrome, a life-threatening skin condition that is
thought to be immune complex mediated)
3. Nystagmus
4. Teratogenicity
5. GI effects (nausea, vomiting)

CNS Pharmacology
Lecture 3
First-line Treatments and MOA:
30
Drugs for Treatment of: Mechanism of Action

CNS Pharmacology
Lecture 3
First-line Treatments and MOA (2):
31
Drugs for Treatment of: Mechanism of Action

CNS Pharmacology
Lecture 3
Unique Features of Individual Agents:
32
Each anticonvulsant has some unique features:
 Phenobarbital (Luminal) has a half-life of 4 days
 Patients develop some tolerance to sedative–hypnotic effect, but not to
antiepileptic effect
 Primidone (Mysoline) is an active drug and is also partially
metabolized to phenobarbital; thus, it has properties that are very
similar to phenobarbital
 Phenytoin (Dilantin) is an effective antiepileptic with less sedative
activity
 Elimination follows zero-order kinetics. After saturation of hepatic enzymes, small
increases in dose can lead to large increases in blood concentration
 Gingival hyperplasia, megaloblastic anemia, and cardiac arrhythmias are important
side effects.
 It is often used in new-onset status epilepticus

CNS Pharmacology
Lecture 3
Unique Features of Individual Agents (2):
33
 Carbamazepine (Tegretol) is a tricyclic anticonvulsant that has mood
stabilization activity
 It is also used to treat restless leg syndrome and shingles
 It induces MFOs in the liver
 Potential side effects liver toxicity, syndrome of inappropriate
antidiuretic hormone (SIADH), and aplastic anemia
 Oxcarbazepine (Trileptal) is an analog that has less toxicity
 Valproic acid (Depakene) is useful for many types of seizures
 It can be hepatotoxic, but it does not induce cytochrome P450
enzymes

CNS Pharmacology
Lecture 3
Unique Features of Individual Agents (3):
34
Ethosuximide (Zarontin) is the drug of choice for absence seizures
 It also does not induce cytochrome P450 enzymes
Clonazepam (Klonopin) is a benzodiazepine, which produces considerable
sedation
 Tolerance can occur with long-term use
Tiagabine (Gabitril), levetiracetam (Keppra), and gabapentin (Neurontin)
are useful as adjunct therapies for partial seizures
 Gabapentin and levetiracetam are also used to treat neuropathic pain
Topiramate (Topomax) is useful as an adjunct in treating refractory
seizures
 Felbamate (Felbatol) can also be used to treat refractory seizures, but
they are not first-line therapy due to severe side effects (risk of aplastic
anemia (about 1:4000) and hepatic failure.)

CNS Pharmacology
Lecture 3
Lamotrigine
35
 Lamotrigine blocks sodium channels, as well as high voltage-dependent calcium
channels
 Effective in a wide variety of seizure types, including focal, generalized, absence
seizures, and Lennox-Gastaut syndrome
 Also used to treat bipolar disorder
Pharmacokinetics:
 Metabolized primarily to the 2-N-glucuronide metabolite through the UGT1A4
pathway
 As with other antiepilepsy medications, CYP450 inducers increase lamotrigine
clearance leading to lower lamotrigine concentrations, whereas
 Divalproex results in a significant decrease in lamotrigine clearance (higher
lamotrigine concentrations)
 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

CNS Pharmacology
Lecture 3
Status Epilepticus:
36
STATUS EPILEPTICUS is a life-threatening disorder that must be treated
rapidly:
1. An intravenous benzodiazepine, such as diazepam (Valium) or
lorazepam (Ativan), is the treatment of choice
 MOA: Allosterically modulate GABA action at GABAA receptors, which
increases frequency of Cl– influx and hyperpolarizes neurons
2. If BDZ is ineffective, other measures must be tried, including:
 Phenytoin, given intravenously as fosphenytoin (Cerebyx)
 Phenobarbital, given intravenously
 General anesthesia

CNS Pharmacology
Lecture 3
THE END
37

CNS Pharmacology
Lecture 3
38
Lectures/discussions to follow:
4. Antidepressants
5. Antipsychotic Agents
6. Drugs Affecting Bipolar Disorder
7. Drugs Affecting Movement Disorders and
Other Neurodegenerative Disorders
8. Analgesics
9. Anesthetics
Further study (SDL):
MedPharm Digital Guidebook: Unit 3-Drugs Used for CNS Disorders
Companion eNotes: CNS- Central Nervous System Pharmacology
Textbook Reading: Porter RJ & Meldrum BS. Ch. 24 Antiseizure Drugs
In: Katzung BG, ed. Basic & Clinical Pharmacology. 12th ed. Pgs. 403-25
Online resource center: Medical Pharmacology Cloud Folder

Antiepileptic drugs and seizure types

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