Antiseizure Drugs

By Dr Geoffrey Ayebazibwe
MBChB, MSc. Pharmacology, PGDCT

+256771235301
 Epilepsy
• Common neurologic disorder with sudden
and recurring seizures
• Caused by abnormal electrical impulses in
the brain
• In the U.S., 2.5 million people are affected.

• Not all seizure disorders are epilepsy.

 Epilepsy
Seizure
Abnormal electrical discharges in the cerebral cortex
caused by sudden, excessive firing of neurons
– Result in a change in behavior of which the patient is
not aware
– While conscious, the patient may or may not lose
movement control
– Loss of body control may affect one area or the entire
body
 Epilepsy
Causes of Seizures
• Imbalance of excitatory and inhibitory
neurotransmitters:
– Glutamate – inhibitory
– GABA – excitatory
– Other neurotransmitters can be involved
• Neurotransmitter levels are controlled by enzymes
• Disruption in enzymes = disruption of
neurotransmitters
 Epilepsy
Classes of Seizures
• Partial
– Simple-partial
– Complex-partial
• Generalized
– Tonic-clonic or grand mal
– Absence or petit mal
– Myoclonic
– Atonic
 Epilepsy
Partial Seizures
• Localized in a specific area of the brain
• Occurs with 65% of epileptic patients
• Can progress to generalized seizures
 Epilepsy
Partial Seizures
• Simple-Partial
– No loss of consciousness
– May have muscle twitching or sensory
hallucinations
• Complex-Partial
– Impaired consciousness
– With confusion, blank stare, and postseizure
amnesia
 Epilepsy
Generalized Seizures
• Involves both hemispheres of the brain, not
one specific location
• Types
– Tonic-Clonic
– Absense
– Myoclonic
– Atonic
 Generalized Seizures

Tonic-Clonic Seizures
• Tonic – body becomes rigid, lasts a minute
or less
• Clonic – initiated with muscle jerks, and
may be accompanied by shallow breathing,
loss of bladder control, and excess
salivation
 Generalized Seizures

Absence
• Interruption of activities by blank stare, rotating
eyes, uncontrolled facial movements, rapid eye
blinking, and/or jerking of an arm or leg
• No generalized convulsions
• Usually lasts 30 seconds or less
• Many times it progresses to tonic-clonic as the
patient gets older
 Generalized Seizures
Myoclonic
• Occurs with sudden, massive, brief muscle jerks or
non-massive, quick jerks
• Consciousness is not lost
• Can occur during sleep
Atonic
• Begins with sudden loss of muscle tone and
consciousness
• Muscles relax, limbs go limp
• Lasts a few seconds to a minute, then patient can
resume standing and walking
 Antiepileptic Drug Therapy
Goals of Therapy
1. Seizure control or lessen the frequency
2. Prevent emotional and behavioral changes

Abnormal Neuronal Activity

• Depolarization
If excessive neurotransmitters are released it leads to
uncontrollable firing of the neuron = seizure
• Treatment
Block the firing of the neuron by raising the threshold of
depolarization
 Antiepileptic Drug Therapy
• Start with monotherapy at a low dose and
titrate up slowly
• Medication must be maintained at steady
therapeutic levels (no missed doses)
• Polytherapy can be used if sufficient
response is not seen with monotherapy
 Antiepileptic Drug Therapy
Problems with Therapy
• Wrong medication is used for the seizure
type
• Side effects may cause problems with
patient compliance
• If doses are missed, there is an increased
risk of seizure activity
EPILEPSY Affects 5–10% of the general population.
It is due to sudden, excessive depolarization of
some or all cerebral neurons. Common neurologic disorder with
sudden and recurring seizures Caused by abnormal electrical
impulses in the brain

This may be:

• localized (focal or partial seizure);
• spread to cause a secondary generalized seizure;
• may affect all cortical neurons simultaneously
(primary generalized seizure).
Abnormal electrical discharges in the cerebral cortex caused by
sudden, excessive firing of neurons Result in a change in behavior of
which the patient is not aware While conscious, the patient may or
may not lose movement control Loss of body control may affect one
area or the entire body
Causes of Seizures
1. Cardiovascular disease
2. High fever
3. Hypocalcemia
4. High or low blood sugar
5. Hypoxia
6. Infection (meningitis)
7. Metabolic abnormalities
8. Brain tumor
9. Toxic substances
10. Trauma or injury to the
head
11. ETOH withdrawal
EEG

Cortex:
F – frontal
O – occipital
T – temporal

Rang et al.
Pharmacology
– 5th Ed. (2003)

Classification of seizures
 1. Carboxamides (enzyme inductors – CYP450):
Carbamazepine (+ neuropathic pain – n. trigeminus,
postherpetic pain, etc.), Oxcarbazepine
2. Hydantoins: Phenytoin (enzyme inductor), used in digitalis
ANTISEIZURE DRUGS

intoxication too
3. Barbiturates (Phenobarbital – enzyme inductors) and their
analogues (Primidone – prodrug)
4. Succinimides: Ethosuximide (casp. 250 mg – petit mal)
5. Valproates (enzyme inhibitors): Sodium valproate (Depakin®)
6. Benzodiazepines: Clonazepam, Clorazepate, Diazepam
t1/2 43 h, amp. 10 mg/2 ml i.m./i.v., Lorazepam, Nitrazepam
7. GABA analogues: Gabapentin, Tiagabine
8. Hetereogenic anticonvulsants: Lamotrigine, Levetiracetam,
Pregabalin (partial seizures, peripheral neuropathic pain),
Topiramate, Vigabatrin
MECHANISM OF ACTION OF ANTIEPILEPTIC DRUGS
Antiepileptics inhibit the neuronal discharge or its spread in one or
more of the following ways:
(1) Enhancing GABA synaptic transmission: barbiturates, benzo-
diazepines, gabapentin, levetiracetam, tiagabine, vigabatrin, topira-
mate, valproate; the result is increased permeability to chloride ion,
which reduces neuronal excitability. Valproate and topiramate block
GABA transaminase and tiagabine blocks reuptake of GABA.
(2) Reducing cell membrane permeability to voltage-dependent
sodium channels: carbamazepine, lamotrigine, oxcarbazepine,
phenytoin, topiramate, valproate.
(3) Reducing cell membrane permeability to calcium T-channels:
valproate, ethosuximide; the result is diminishing of the generation
of action potential.
(4) Inhibiting excitory neurotransmitter glutamate: lamotrigine.
 GABA
Barbiturates
Benzodiazepines
Gabapentin
Levetiracetam
Tiagabine
Topiramate
Valproate
Vigabatrin

Na+ Ca2+
Carbamazepine
Ethosuximid
Lamotrigine
e
Oxcarbazepine
Levetiraceta
Phenytoin
m
Topiramate
Pregabalin
Valproate
Valproate
Antiseizure drugs enhanced GABA Synaptic
transmission
Goodman & Gilman's
The Pharmacologic Basis of
Therapeutics - 11th Ed. (2006)
Antiseizure drugs, enhanced Na+ channel inactivation
Goodman & Gilman's The Pharmacologic Basis of Therapeutics - 11th Ed. (2006)
 Antiseizure drugs, induced reduction of
current through T-type Ca2+ channels.

Goodman & Gilman's The Pharmacologic Basis of Therapeutics - 11th Ed. (2006)
 Goodman & Gilman's The Pharmacologic Basis of Therapeutics – 11th Ed. (2006)

Effects of three antiseizure drugs on sustained high-frequency firing of action

potentials by cultured neurons. Intracellular recordings were made from
neurons while depolarizing current pulses, approximately 0.75 s in duration,
were applied (on-off step changes indicated by arrows). In the absence of a
drug, a series of high-frequency repetitive action potentials filled the
entire duration of the current pulse. Phenytoin, carbamazepine, and
sodium valproate all markedly reduced the number of action potentials
elicited by the current pulses.
INDIVIDUAL ANTIEPILEPTICS
▼CARBAMAZEPINE blocks voltage-dependent sodium ion channels,
reducing membrane excitability. The t1/2 of the drug falls from 35 to
20 h over the first few weeks of therapy due to the induction of hepatic
enzymes that metabolize it as well as other drugs (including adrenal
corticosteroids, hormonal contraceptives, theophylline and warfarin.
Standard tablets are taken twice a day.

Carbamazepine is a drug offirst choice for focal and secondary

generalized epilepsy but aggravates myoclonic and absence seizure.
It is useful for the treatment of trigeminal neuralgia, postherpetic
pains, etc.
Adverse reactions (ARs): reversible blurring of vision, diplopia,
dizziness, ataxia, depression of AV conduction, skin rashes, liver, and
kidney dysfunction.
Carbamazepine (Epitol, Tegretol)
• Has effect on sodium channels which may
alter synaptic transmission.
• Blood monitoring must be done regularly.
• Be cautious of interactions and side effects.
 Valproic acid (Depakene) and
divalproex (Depakote)
• Increases the availability of GABA
(inhibitory)
• Take with water, not a carbonated drink
• Do not use aspirin
▼VALPROIC ACID (Sodium valproate) acts by inhibiting GABA
transaminase and increases the concentration of inhibitory neuro-
transmitter GABA at its receptors. Valproic acid has t1/2 13 h and
90% bound to plasma albumin. It is a nonspecific inhibitor of meta-
bolism, and inhibits its own metabolism, and that of lamotrigine,
phenobarbital, phenytoin and carbamazepine. Valproic acid is
effective for treatment of generalized and partial epilepsy, febrile
convulsion and post-traumatic epilepsy.

ARs can be troublesome: weight gain, teratogenicity, polycystic

ovary syndrome, and loss of hair which grows back curly.
Nausea can be a problem, rarely, liver failure (risk maximal at
2–12 weeks). Ketone metabolites may cause confusion in urine
testing in diabetes mellitus.
 Phenytoin (Dilantin)
• May be used to prevent seizures
• Promotes sodium outflow from cells –
stabilizes the neuronal membrane
• Be cautious of drug interactions
• Intravenous phenytoin must be mixed
carefully
▼PHENYTOIN
(t1/2 6–24 h) has saturation kinetics. It is extensively
hydroxylated in the liver and this process becomes saturated at the
doses needed for therapeutic effect (therapeutic plasma
concentration range is 10–20 mg/L). Phenytoin is a potent inducer of
hepatic metabolizing enzymes affecting itself and other drugs
(carbamazepine, warfarin, adrenal and gonadal steroids, thyroxine,
tricyclic antidepressant, doxycycline, vitamin D, folate).

Drugs that inhibit phenytoin metabolism include: valproic acid,

cimetidine, co-trimoxazole, isoniazid, chloramphenicol, some
NSAIDs, disulfiram. Phenytoin is 90% bound to plasma
albumin and small changes in binding will result in a higher
concentration of free active drug. It is used to prevent all types of
partial seizure, generalized seizure, and st. epilepticus. It is not used
for absence attacks.
 Phenytoin Side Effects

Dose Related
– Ataxia
– Diplopia
– Dizziness
– Drowsiness
– Encephalopathy
– Involuntary movements
 Phenytoin Side Effects
ARs: impairment of cognitive function (which has led many
physicians to prefer carbamazepine and valproate), sedation,
hirsutism, skin rashes, gum hyperplasia (due to the inhibition of
collagen metabolism),hyperglycemia, anaemia, osteomalacia.

Non-Dose-Related
– Gingival hyperplasia
– Peripheral neuropathy
– Vitamin deficiencies
Saturation kinetics.

Phenytoin is extensively
hydroxylated in the liver and this process becomes
saturated at about the doses needed for therapeutic
effect.

Thus phenytoin at low doses exhibits first-

order kinetics but saturation or zero-order kinetics
develop as the therapeutic plasma concentration
range (10–20 mg/L) is approached, i.e. the dose
increments of equal size produce disproportional rise
in steady-state plasma concentration.
Basic & Clinical
Pharmacology –
10th Ed. (2007)

Nonlinear relationship of phenytoin dosage and plasma concentrations.

Five different patients (identified by different symbols) received increasing
dosages of phenytoin by mouth, and the steady-state serum concentration
was measured at each dosage. The curves are not linear, since, as the
dosage increases, the metabolism is storable. Note also the marked
variation among patients in the serum levels achieved at any dosage.
▼BENZODIAZEPINES
•Diazepam given intravenously or rectally is highly effective for
stopping continuous seizure activity, especially generalized tonic-
clonic status epilepticus.

The drug is occasionally given orally on

a long-term basis, although it is not considered very effective in
this application, probably because of the rapid development of
tolerance. A rectal gel is available for refractory patients who need
acute control of bouts of seizure activity.

•Lorazepam appears in some studies to be more effective and

longer-acting than diazepam in the treatment of status epilepticus
and is preferred by some experts.
 Clonazepam (Klonopin)
Only indication is prophylaxis of seizures
• Depresses nerve transmission in the motor
cortex
• C-IV controlled substance (benzodiazepine)
• Clonazepam (t1/2 25 h) is a benzodiazepine used as
a second line drug for treatment of primary
generalized epilepsy and status epilepticus.
 Clonazepam, Clorazepate,
Diazepam, Lorazepam,
Nitrazepam

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

By Bennett and Brown (2003) Barbiturates

▼BARBITURATES (enzyme inducers)
Antiepilepsy members include phenobarbital (phenobarbitone –
( t1/2 100 h), methylphenobarbital and primidone (which is
largely metabolized to phenobarbital, i.e. it is a prodrug). They are
still used for generalized seizures; sedation is usual.

Primidone and its

active metabolites

Basic & Clinical

Pharmacology –
10th Ed. (2007)
▼LAMOTRIGINE (t1/2 6–24 h) inhibits excitory neurotransmitter
glutamate. Lamotrigine is effective for the treatment of partial and
secondarily generalized tonic-clonic seizure. It is generally well
tolerated but may cause serious ARs of the skin, including
Stevens–Johnson syndrome and toxic epidermal necrolysis.

▼TOPIRAMATE (t1/2 21 h) is used as adjunctive treatment for

partial seizure, with or without secondary generalization. ARs:
sedation, weight loss, acute myopia, raised intraocular pressure.

▼ETHOSUXIMIDE (t1/2 55 h) blocks T-type calcium ion

channels. It is active in absence seizures (petit mal).
ARs: gastric upset, CNS effects and allergic reactions.
PRINCIPLES OF MANAGEMENT
• Any causative factor must be treated (cerebral neoplasm etc).
• Educate the patient about the disease, duration of treatment
and need for compliance.
• Avoid precipitating factor (alcohol, sleep deprivation, emotional
stress, and caffeine).
• Anticipate natural variation: fits may occur around menstrual
periods in women – catamenial (monthly) epilepsy.
• Give antiepileptics only if seizure type and frequency require it
(e.g. more than one fit every 6–12 months).
Grand mal: I choice – valproate or Lamotrigine
Alternative – Carbamazepine, Topiramate or Phenytoin
Petit mal: I choice – Ehosuximide or valproate
Alternative – Clonazepam or Lamotrigine
Partial seizures: I choice – Carbamazepine or valproate
Alternative – Phenytoin, Lamotrigine, Vigabatrin, Topiramaatus epilepticus: I
choice – Diazepam or Lorazepam (i.v.)
Alternative – Phenobarbital (i.m./i/v.)
MAIN INDICATIONS OF ANTIEPILEPTIC DRUGS
 Generalized Seizures

Status Epilepticus
• Continuous tonic-clonic seizures with or
without return to consciousness
• High fever and lack of oxygen severe
enough to cause brain damage or death
Treatment of status epilepticus in adults

Patient in opisthotonus (grand mal)

• Withdrawal from antiseizure drugs should be accomplished

gradually to avoid increased seizure frequency and severity.
• In general, withdrawal from anti-absence drugs is more easily
accomplished than withdrawal from drugs used in partial or
generalized tonic clonic seizure states.
GENERAL GUIDE TO ANTIEPILEPSY PHARMACOTHERAPY

(1) The decision whether or not to initiate drug therapy after a

single seizure remains controversial since approximately 25%
of patients may not have another seizure.
(2) Therapy should start with a single drug (70% of patients can
be controlled on one drug (monotherapy).
(3) Anticonvulsant drug therapy should be appropriate to the type
of seizure.
(4) The choice of drugs is also determined by the patient’s age
and sex.
(5) If the attempt to control epilepsy by use of a single drug is
unsuccessful, it should be withdrawn and replaced by a second
line drug, though these are effective in only 10% of patients.
There is little evidence that 2 or 3 drugs are better than one,
but more drugs often mean more ARs.
(6) Effective therapy must never be stopped suddenly,
only gradually.
(7) After a period of at least 2–3 years free from seizures, with-
drawal of anticonvulsants can be considered. In general, dis-
continuing the antiepileptic drug therapy is associated with
about 20% relapse during withdrawal and a further 20% relapse
over the following 5 years. It is recommended that the antiepi-
leptic drug be withdrawn over a period of 6 months. If a fit
occurs during this time, full therapy must begin again until the
patient has been free from seizure for a further 2–3 years.
• Thank You!!