ANTISEIZURE

DRUGS
1
Dr. Saman Omer
Pharmacology Dept.
 LEARNING OUTCOMES
At the end of lecture students should be able to
• Define epilepsy
• Discuss pathogenesis and etiology of epilepsy
• Describe various types of epilepsy
• Classify antiseizure drugs
• Discuss the pharmacokinetics and
pharmacodynamics of antiseizure drugs
• Discuss the treatment of status epilepticus
 EPILEPSY
• Chronic disorder of brain function characterized
by recurrent & unpredictable occurrence of
seizures

• 1 % of world population

• Due to sudden, excessive depolarization of

some or all cerebral neurons
 PATHOGENESIS

• Defect in inhibitory feedback mechanisms

• Synchronized firing of neurons

 ETIOLOGY OF EPILEPSY
• Idiopathic
• Genetic (hereditary)
• Congenital defects, head injuries, trauma, hypoxia

• Infection ( bacteria or virus ) e.g. meningitis, brain

abscess, viral encephalitis
• Concussion, depressed skull, fractures
• Brain tumors , vascular occlusion, stroke

• Fever in children (febrile convulsion)

• Hypoglycemia
 EPILEPSY
Focal onset (local cortical site)
– Spread to cause a sec. generalized seizure
2. Generalized onset (both hemispheres)
 FOCAL ONSET SEIZURE
(PARTIAL SEIZURE)
• Seizure activity is restricted to discrete areas of
the cerebral cortex

• Associated with structural abnormalities

(Organic lesions) of brain

• Symptoms depend upon the site of epileptic

focus
• May progress to become generalized
 FOCAL AWARE SEIZURES
(SIMPLE PARTIAL SEIZURES)
• Cause motor, sensory, autonomic, or psychic
symptoms
• No alteration in consciousness
• Can occur at any age
• Abnormal electrical activity is confined to single
focus in brain minimal spread
• Convulsions may remain confined to single limb
• Sensory abnormalities may be present
 FOCAL IMPAIRED AWARENESS
SEIZURE (COMPLEX PARTIAL
SEIZURE)
• Have localized onset
• Discharge become widespread, involve limbic
system

• Brief period of alteration of consciousness

• Patients have purposeless movements

• Patients may have hallucinations, mental

retardation
 GENERALIZED ONSET
SEIZURE
• There is diffuse involvement of both
hemispheres

• Patient has sudden transient loss of

consciousness

• May result from biochemical, or structural

abnormalities
 GENERALIZED TONIC-CLONIC
SEIZURE (GRAND MAL EPILEPSY)
• Most common type of epilepsy
• Characterized by sudden transient loss of
consciousness

• Tonic spasm of whole body followed by clonic

jerking movements
• The entire fit last about 1–3 minutes

• Convulsions are followed by generalized

depression of central nervous system
 GENERALIZED TONIC-CLONIC
SEIZURE (GRAND MAL EPILEPSY)
• Attack can occur at any age

• Tongue biting, incontinence of urine and feces

may be occur

• May be preceded by auditory or visual aura

• May occur alone or in association with absence

seizure
 GENERALIZED ABSENCE
SEIZURE (PETIT MAL EPILEPSY)
• Most commonly occur in children

• Brief episodes of unconsciousness (4-20 secs,

usually ˂ 10 secs)

• No warning and immediate resumption of

consciousness
 MYOCLONIC SEIZURES

• Sudden, brief, involuntary

• Single or multiple contractions of muscles

or muscle groups of variable topography
 ATONIC SEIZURES
• Sudden loss of postural muscle tone

• Consciousness is briefly impaired

• Quick head drop, patient may collapse

• High risk of head injury

 TREATMENT OF EPILEPSY
• Orally
• Goal…prevent occurrence of seizures
• Choice of drug…. Type of seizures

• Monotherapy…. Preferred
• Treatment should not be stopped abruptly

• In some cases life long drug treatment is

required
 TREATMENT OF EPILEPSY
• Treat the known underlying cause, e.g. cerebral
neoplasm
• Avoid precipitating factors
• If patient has no seizures in past 2–3 years,
antiepileptic therapy may be discontinued
gradually over a period of 6 months
• “PHARMACORESISTANT”
• Surgical resection
CHEMICAL CLASSIFICATION
Cyclic ureides
Hydantoins:
• Phenytoin
• Fosphenytoin
• Primidone

Barbiturates: Phenobarbital; Primidone

Succinimides: Ethosuximide
Tricyclics
Carboxamides:
• Carbamazepine; Oxcarbazepine

Benzodiazepines
• Diazepam
• Clonazepam

GABA Derivatives (analogues)

• Gabapentin
• Pregabalin
• Vigabatrin
Others
• Valproate :Sodium valproate
• Lamotrigine
• Levetiracetam
• Retigabine
• Rufinamide
• Tiagabine
• Topiramate
• Zonisamide
• Lacosamide
• Perampanel
 THERAPEUTIC
CLASSIFICATION
• FOCAL ONSET (SIMPLE & COMPLEX):

Phenytoin Carbamazepine
Phenobarbibital Valproic acid
Gabapentin Lamotrigine
 THERAPEUTIC
CLASSIFICATION

• GENERALIZED TONIC CLONIC:

Phenytoin Carbamazepine
Phenobarbital Valproic acid
Primidone
 THERAPEUTIC
CLASSIFICATION

• GENERALIZED ABSENCE SEIZURE:

Ethosuximide Valproic acid

Lamotrigine Clonazepam
THERAPEUTIC CLASSIFICATION

• MYOCLONIC SEIZURE:
Valproic acid
• STATUS EPILEPTICUS
Diazepam Lorazepam
Phenobarbital Phenytoin
• FEBRILE SEIZURES
Phenobarbital Primidone
 CLASSIFICATION ACCORDING
TO MECHANISM OF ACTION
• Inhibit the neuronal discharge or its spread in
one or more of the following ways:
(1) Enhancing GABA synaptic transmission:

• Barbiturates Benzodiazepines Tiagabine

• Vigabatrin Gabapentin Valproate
Levetiracetam Topiramate
 ENHANCING GABA SYNAPTIC
TRANSMISSION

• GABAA receptors

• GAT-1 (GABA transporter 1)

• GABA transaminase (GABA-T)

ENHANCEMENT OF INHIBITION
(2) Reducing cell membrane permeability to
voltage-dependent sodium channels:

• Lamotrigine
• Oxcarbazepine
• Carbamazepine
• Phenytoin
• Topiramate
• Valproate
Antiseizure drugs, enhanced Na+ channel inactivation
Goodman & Gilman's The Pharmacologic Basis of Therapeutics - 11th Ed. (2006)
(3) Reducing cell membrane permeability to
calcium T-channels:
• Valproate
• Ethosuximide
• Levitracetam
• Pregabalin

The result is diminishing of the generation of action

potential
 Antiseizure drugs, induced reduction of
current through T-type Ca2+ channels.

Goodman & Gilman's The Pharmacologic Basis of Therapeutics - 11th Ed. (2006)
(4) Inhibiting excitory neurotransmitter
glutamate:
Levetiracetam
Gabapentin & pregablin
Felbamate
Perampanel
 MOLECULAR TARGETS AT
GLUTAMATERGIC SYNAPSE
 GABA
Barbiturates
Benzodiazepines
Gabapentin
Levetiracetam
Tiagabine
Topiramate
Valproate
Vigabatrin

Na+ Ca2+
Carbamazepine
Ethosuximide
Lamotrigine
Levetiracetam
Oxcarbazepine
Pregabalin
Phenytoin
Valproate
Topiramate
Valproate
 CLASSICAL
• Phenytoin NEWER
• Phenobarbital • Lamotrigine
• Primidone • Felbamate

• Carbamazepine • Topiramate
• Gabapentin
• Ethosuximide
• Tiagabine
• Valproate (valproic • Vigabatrin

acid) • Oxycarbazepine
• Levetiracetam
• Trimethadione (not
• Fosphenytoin
currently in use)
 PHARMACOKINETICS
• Narrow therapeutic window

• Special factors affecting dose:

– Nonlinear relationships between dose & drug
exposure
– Influence of hepatic/renal impairment on clearance
– Drug-drug interactions

• Levetiracetam, gabapentin, pregablin…no drug

interactions
• Must have reasonable BA..MUST enter CNS
• Medium to long acting
 PHENYTOIN
• Oldest non sedating drug

• Analog of hydantoin

• Available as
– Extended release capsule
– Prompt capsule
– I/V solution
 PHENYTOIN
• I/M route is not recommended
– Absorption is unpredictable
– Drug precipitation in muscle occurs

• With I/V administration

– Risk of “purple glove syndrome”

• Fosphenytoin
– water soluble prodrug
– Less incidence of purple glove syndrome
 PHENYTOIN
MECHANISM OF ACTION

• Alters Na + , K + & Ca 2+ conductance,

membrane potentials & conc of amino acids and
neurotransmitters NE, Ach, GABA

• Blocks sustained high-frequency repetitive firing

of action potentials
 PHENYTOIN

• Potent inducer of hepatic metabolizing enzymes

• 90% bound to plasma albumin

• Low volume of distribution

• Prone to displacement….if dec albumin….inc

levels
 PHENYTOIN

• Some drugs that compete with phenytoin for

binding to plasma proteins

– Valproic acid
– Phenylbutazone
– Sulfonamides

• Valproic acid….inhibits phenytoin metabolism

 PHENYTOIN
• t1/2 12–36 hrs

• Metabolized by liver to inactive metabolite, which

are excreted in urine

• Elimination depends on the dose

• At low blood levels…. 1st order kinetics

• At high levels…. Zero order kinetics
 USES
• Focal onset seizure

• Tonic clonic seizure

• Not used for absence seizures

• Non-seizure indications include

- Trigeminal neuralgia
- As antiarrhythmic
 ADVERSE EFFECTS

• Impairment of cognitive function

• Nystagmus

• Diplopia & Ataxia

• Sedation (high doses only)

• Hirsutism
 ADVERSE EFFECTS

• Gum hyperplasia (due to the inhibition of

collagen metabolism)

• Coarsening of facial features(increased

androgen secretion)

• Mild peripheral neuropathy

• Low folate levels & megaloblastic anemia

• Osteomalacia (abnormality of Vit D met)

 ADVERSE EFFECTS
• Idiosyncratic reactions
– Skin rash
– Lymphadenopathy
– Hepatitis

• Teratogenic; Fetal hydantoin syndrome

PHENYTOIN INDUCED GINGIVAL
HYPERPLASIA
 CARBAMAZEPINE
• Iminostilbene….tricyclic compound

• Most widely used antiseizure drug- first line

MECHANISM OF ACTION
Blocks voltage-dependent Na+ ion channels,
reducing membrane excitability- use dependent
 CARBAMAZEPINE
PHARMACOKINETICS

• 100% BA

• Peak levels …6-8 hrs

• Slow distribution

• 70 % PPB
 CARBAMAZEPINE
PHARMACOKINETICS

• Induces its own metabolism

• Metabolized in liver

• Active metabolite carbamazepine-10,11-epoxide

 CARBAMAZEPINE
DRUG INTERACTIONS

• Stimulates transcriptional up regulation of

CYP3A4 & CYP2B6

– Reduction in CMZ conc

– Inc metabolism of concomitant anti seizure drugs
 CARBAMAZEPINE
DRUG INTERACTIONS

• Valproic acid inhibit CMZ clearance

• Phenytoin & phenobarbital…. Decrease steady

state conc of CMZ
 ADVERSE EFFECTS
• Dose dependent mild GI discomfort
• Reversible blurring of vision
• Diplopia or ataxia
• Dizziness
• Rarely weight gain
• Benign leukopenia (10%-disappears in 4
months)
• Rash & hyponatremia
 OXCARBAZEPINE
• Chemically related to carbamazepine

• Less potent than carbamazepine

• Produces less side effects

• Induces hepatic microsomal enzymes to lesser

extent than carbamazepine
 ETHOSUXIMIDE
• First line drug.. Generalized absence seizures
PHARMACOKINETICS
• Complete absorption

• Not protein bound

• t1/2 40 hrs approx

• Metabolized in liver by CYP3A hydroxylation

 ETHOSUXIMIDE
MECHANISM OF ACTION
• Inhibits low-voltage activated T-type calcium
channels
• Other channels affected
– Voltage gated Na channels
– Calcium activated potassium channels
– Inward rectifier potassium channels
 ETHOSUXIMIDE
DRUG INTERACTIONS
• Ethosuximide + Valproic acid…. Dec ethosuximide
clearance
TOXICITY (dose related)
• Gastric distress, pain, nausea, vomiting
• Transient lethargy
• Headache, dizziness, hiccup, euphoria
USES
• Childhood generalized absence seizures
 TRIMETHADIONE
• Oxazolidinedione antiseizure drug

• Effective in generalized absence seizures

• Was DOC until ethosuximide wasn’t introduced

• Hemeralopia (day blindness)

 LAMOTRIGINE
PHARMACOKINETICS
• Completely absorbed
• 55 % protein bound
• Metabolized by glucoronidation in liver
• Half life 24 hrs approx.
• Use-dependent inhibition of Na+ channels,
glutamate release, may inhibit Ca++ channels
 LAMOTRIGINE
USES
• Focal seizures
• Generalized tonic clonic seizures
• Generalized absence epilepsy
ADVERSE REACTIONS
• Stevens–Johnson syndrome
• Toxic epidermal necrolysis
• Lowest risk of major congenital malformations
Stevens–Johnson syndrome
 TOPIRAMATE
• Broad spectrum anti-seizure drug

PHARMACOKINETICS

• Rapidly absorbed

• BA 80 %

• Minimal plasma protein binding… 15 %

• Moderate metabolism
 TOPIRAMATE
MECHANISM OF ACTION

Several cellular targets

1) Voltage gated Na channels

2) GABAA receptor subtypes
3) AMPA or kainate receptors
 TOPIRAMATE
USES
• Focal seizures

• Primary generalized tonic-clonic seizures

• Lennox-Gastaut syndrome

• Juvenile myoclonic epilepsy

• Infantile spasms
 TOPIRAMATE
TOXICITY
• Dysnosmia & diminished verbal fluency

• Impaired verbal memory

• Paresthesia

• Somnolence, fatigue, dizziness, nervousness,

confusion

• Acute myopia & angle closure glaucoma

 TOPIRAMATE
TOXICITY

• Oligohydrosis, elevation in body temperature

• Significant weight loss

• Oral cleft formation in new borns

 BENZODIAZEPINES
• Positive allosteric modulators of GABAA
receptors

LIMITATIONS

• Pronounced sedative effects

• Tolerance
 BENZODIAZEPINES

DIAZEPAM

• I/V or rectally

• Highly effective for stopping continuous seizure

activity, especially status epilepticus
 BENZODIAZEPINES
LORAZEPAM
• More effective
• Longer-acting than diazepam in the treatment of
status epilepticus

CLONAZEPAM
• t1/2 25 h
• Second line drug for treatment of primary
generalized epilepsy & status epilepticus
 BARBITURATES

• Phenobarbital
• Methylphenobarbital
• Primidone

• Generalized seizures

• Sedation is usual
 Clonazepam, Clorazepate,
Diazepam, Lorazepam,
Nitrazepam

GABAA-
site
GABAA- + +
benzo-
diazepine Cl−
+ Barbitu-
receptor rate sate
complex

By Bennett and Brown (2003) Barbiturates

 PRIMIDONE
• Derivative of phenobarbital

• Primidone is converted to two active metabolites

i.e. phenobarbital and phenyl ethyl malonamide
(PEMA)

• All three compounds are active anti seizure

agents
 PRIMIDONE
• Effective against focal seizures & generalized
tonic clonic seizures

• Drowsiness, dizziness

• Ataxia

• Nausea , vomiting
 GABAPENTIN
• It is an amino acid, which structurally resembles
GABA
• Modifies the release of GABA, inhibits release of
glutamate - also binds with Ca+2 channeluptake
• May interfere with GABA uptake
• Add-on therapy for partial seizures, evidence
that it is also effective as monotherapy in newly
diagnosed epilepsies (partial)
 GABAPENTIN
PHARMACOKINETICS
• BA > 90 %
• Not bound to plasma proteins
• Negligible drug interactions
• Absorption: Non-linear. Saturable (amino acid
transport system), no protein binding.
• Metabolism: none, eliminated by renal excretion
• Half-life: 5-9 hours, administered 2-3 times daily
• Drug interactions: none known
 GABAPENTIN
ADVERSE EFFECTS:
• Somnolence, dizziness
• Ataxia, headache
• Tremor
• Weight gain
• Peripheral edema
• Less CNS sedative effects than classic AEDs
 GABAPENTIN
USES:
• Focal seizures
• Neuropathic pain
– Postherpetic neuralgia
– Painful diabetic neuropathy
• Anxiety disorders
• Fibromyalgia
 TIAGABINE
• Analog of nipecotic acid…a GABA uptake
inhibitor
• Interferes with GABA reuptake
• Highly selective for GAT-1
• Causes prolongation of GABA-mediated
inhibitory synaptic response and potentiation of
tonic inhibition
 TIAGABINE
• 90-100 % BA
• Highly protein bound
• Half-life: 5-8 hours (short)
• Oxidized by liver by CYP3A
• Elimination is primarily in the feces (60-65%)
and urine (25%)
 TIAGABINE

• Second line treatment for focal seizures

• Contraindicated in generalized onset seizures
• Adverse effects: CNS sedative
• Drug interactions: minimal
 TIAGABINE
ADVERSE EFFECTS:

• Nervousness, dizziness, tremor

• Difficulty concentrating, depression
• Excessive confusion, somnolence, ataxia
• Psychosis, rash
 VALPROATE
PHARMACOKINETICS
• Well absorbed
• BA > 80 %
• Food may delay absorption
• t1/2 9 to 18 hrs
• Highly protein bound
 VALPROATE
MECHANISM OF ACTION
• Inhibits GABA transaminase…..blocking degradation of
GABA & ↑ GABA
• Facilitate glutamic acid decarboxylase (GAD) enzyme
responsible for GABA synthesis
• Blocks sustained high-frequency repetitive firing of
neurons
• Blocks NMDA receptor-mediated excitation
 VALPROATE
DRUG INTERACTIONS
• Inhibits metabolism of drugs…. Phenobarbital &
ethosuximide

• Displaces phenytoin from plasma proteins

• Levels of carbamazepine epoxide may be increased

• Dec clearance of lamotrigine

 VALPROATE
USES
• Generalized tonic clonic seizure
• Absence seizures
• Myoclonic
• Atonic
• Status epilepticus (IV)
• Migraine prophylaxis
• Mood stabilizer in Bipolar disorder
 VALPROATE
TOXICITY
GIT
Nausea, vomiting, abdominal pain, heartburn

CNS
Fine tremor

OTHER REVERSIBLE A/E

Weight gain, increased appetite, hair loss
 VALPROATE
TOXICITY

IDIOSYNCRATIC A/E

Hepatotoxicity
Thrombocytopenia

• Interferes with conversion of ammonia to urea

• Fatal hyperammonemic encephalopathy
 VALPROATE
TOXICITY

TERATOGENIC EFFECTS

• Neural tube effects…. Spina bifida

• Cardiovascular, orofacial & digital abnormalities

• Cognitive impairment
 ZONISAMIDE
• Sulfonamide derivative
• Inhibit sodium channels- may also inhibit voltage
dependent calcium channels
• High BA, low plasma protein binding
• Excreted in urine
• Half-life is 1–3 days
• Can cause drowsiness and may produce
potentially serious skin rashes
• Drug interactions: minimal
 ZONISAMIDE
• Effective for
– Focal seizures
– Generalized tonic–clonic seizures
– Infantile spasms
– Myoclonic seizures
 LEVETIRACETAM
• Analog of piracetam
• Broad spectrum anti-seizure
• Most commonly prescribed
– Favorable adverse effect profile
– Broad therapeutic window
– Favorable pharmacokinetic properties
– Lack of drug-drug interactions
 LEVETIRACETAM
PHARMACOKINETICS
• Oral absorption rapid & complete
• Linear kinetics
• Half-life: 6-8 hours (short)
• Protein binding less than 10 %
• Metabolism occurs in blood
 LEVETIRACETAM
MECHANISM OF ACTION
• Levetiracetam binds selectively to
SV2A….synaptic vesicle integral membrane
protein

• Function as a positive effector of synaptic

vesicle exocytosis

• Binding reduces the release of the excitatory

neurotransmitter glutamate during trains of high-
frequency
 LEVETIRACETAM
CLINICAL USES
• Focal seizures
• Primary generalized tonic-clonic seizures
• Myoclonic seizures of juvenile myoclonic
epilepsy
 LEVETIRACETAM
ADVERSE EFFECTS
• Somnolence
• Asthenia, ataxia
• Infection (colds), and dizziness
• Behavioral and mood changes
– irritability, aggression, agitation
– anger, anxiety, apathy
– Depression and emotional lability
 FELBAMATE
• Blocks N-methyl-d-aspartate (NMDA) receptors

• Also produces a barbiturate like potentiation of

GABA receptor responses

• Focal seizures
• Lennox-Gastaut syndrome
 FELBAMATE
• Cause aplastic anemia & severe hepatitis

• Used only in patients with refractory seizures

who respond poorly to other medications
 VIGABATRIN
• Analog of GABA
MECHANISM OF ACTION
• Specific, irreversible inhibitor of GABA-T

– producing a sustained increase in the extracellular

concentrations of GABA

– prolongs the activation of extrasynaptic GABAA

receptors that mediate tonic inhibition.
 VIGABATRIN
CLINICAL USES
• Focal seizures

• Infantile spasms

• Reserved for pts with refractory seizures

 VIGABATRIN
ADVERSE EFFECTS
• Irreversible retinal dysfunction

• Somnolence, headache, dizziness

• Weight gain

• Agitation, confusion, psychosis

Other use of antiepileptic drugs
• Cardiac arrythmias(phenytoin)not used
clinically though
• Bipolar disorder(valproate,
carbamezapine, oxcarbazepine,
lamotrigine, topiramate)
• Migraine prophylaxis(valproate,
gabapentine, topiramate)
• Anxiety disorders(gabapentin)
• Neuropathic pain(carbamezapine,
gabapentin, pregabalin, lamotrigine0
 STATUS EPILEPTICUS
More than 30 minutes of either

– Continuous seizure activity

– Two or more sequential seizures without full
recovery of consciousness between seizures

FORMS:
1. Convulsive status epilepticus
2. Non convulsive status epilepticus
3. Focal status epilepticus
 STATUS EPILEPTICUS
TREATMENT:
INITIAL TREATMENT

• Benzodiazepine
– I/V Lorazepam or Diazepam
– IM midazolam

PREHOSPITAL SETTING

• Rectal Diazepam
• Intranasal Midazolam
• Buccal Midazolam
 STATUS EPILEPTICUS
TREATMENT:

IF SEIZURES CONTINUE (SECOND THERAPY)

• I/V Fosphenytoin or Phenytoin

• Phenobarbital

IF SECOND THERAPY FAILS

 STATUS EPILEPTICUS
TREATMENT:
REFRACTORY STATUS EPILEPTICUS

• Anesthetic dose of
– Pentobarbital
– Propofol
– Midazolam
– Thiopental

SUPER REFRACTORY
• Reinstitute general anesthesia