Eti Nurwening Sholikhah

Department of Pharmacology & Therapy

Faculty of Medicine
Universitas Gadjah Mada
Anticonvulsants
Drugs are clinically used to control seizures in people with
epilepsy or other seizures
Groups Drugs (Examples)
hydantoins phenytoin
mephenytoin
succimides Ethosuximide, methosuccimide

benzodiazepines Clonazepam, clorazepate

as tranquilizers and sedatives diazepam

not related to larger groups

iminostilbene carbamazepine

a branched-chain carboxylic valproic acid

acid
phenyltriazine lamotigrine
cyclic analog of GABA gabapentin
sulfamate-substituted topiramate
monosaccharide
nipecotic acid derivative tiagabine
pyrrolidine derivative levetiracetam
Drugs
acting
on motor
system
Non-depolarizing
muscle relaxants

Cause a flaccid paralysis of

skeletal muscle by binding to
motor end plate
cholinoceptors, thus blocking
neurotransmission

Pancuronium
Alcuronium
Rocuronium
Gallamine
Mivacurium
Atracurium
BENZODIAZEPINES
The benzodiazepines are used primarily as sedative-antianxiety
drugs but also have broad antiseizure properties.

Clonazepam and clorazepate

have been approved in the U.S. for the long-term treatment of
certain types of seizures.

Diazepam and lorazepam have well-defined roles in the

management of status epilepticus.

Mechanism of Action

Antiseizure actions of the benzodiazepines largely result from their

capacity to enhance GABAmediated synaptic inhibition

At therapeutic concentrations, benzodiazepines act

at GABAA receptors and increase the frequency, but not duration,
of openings at GABA-activated Cl– channels.
PHARMACOKINETIC PROPERTIES

Benzodiazepines are well absorbed orally, and peak plasma

concentrations are usually reached within 1–4 hours.

After intravenous administration, they redistribute in a manner

typical of highly lipid-soluble agents.
CNS effects develop rapidly but wane quickly as the drugs move to
other tissues.

Diazepam redistributes rapidly (t1/2 of redistribution, ∼1 hour).

The extent of binding of benzodiazepines to plasma proteins
correlates with lipid solubility, ranging from 99% for diazepam to
∼85% for clonazepam.
TOXICITY
The principal side effects of long-term oral therapy with clonazepam are
drowsiness and lethargy. These occur in ∼50% of patients initially, but
tolerance often develops with continued administration.

Muscular incoordination and ataxia are less frequent. Although these

symptoms usually can be kept to tolerable levels by reducing the dosage or
the rate at which it is increased, they sometimes force drug discontinuation.

Other side effects include hypotonia, dysarthria, and dizziness.

Behavioral disturbances (aggression, hyperactivity, irritability, difficulty
in concentration), especially in children, can be very troublesome.
Anorexia and hyperphagia have been reported. Increased salivary and
bronchial secretions may cause difficulties in children.
Seizures are sometimes exacerbated and status epilepticus may be
precipitated if the drug is discontinued abruptly.

Cardiovascular and respiratory depression may occur after the intravenous

administration of diazepam, clonazepam, or lorazepam, particularly if other
antiseizure agents or central depressants have been administered
previously.
A cronic brain disease of diverse etiology,
charactherisized by recurrant paroxysmal episodes of
uncontrolled exitation of brain neuron
Antiepileptics are used to prevent seizures and
therefore need to be given chronically

Only in the case of status epilepticus (a succession

of several tonic-clonic seizures) is acute
anticonvulsant therapy indicated —usually with
benzodiazepines given i.v. or, if needed, rectally.

The ultimate goal of treatment for epilepsy is no

seizures and no side effects with an optimal quality of
life
Classification of epileptic Seizures
 Antiseizure drug–enhanced Na+ channel inactivation

Prolong the inactivation of the Na+ channels, thereby reducing the

ability of neurons to fire at high frequencies. Note that
the inactivated channel itself appears to remain open, but is
blocked by the inactivation gate (I). A, activation gate.
 GENERAL APPROACH TO TREATMENT
1. Identification of goals, assessment of seizure type and frequency,
development of a care plan, and a follow-up evaluation
2. Appropriate initial AEDs
3. Plans. Patient characteristics such as age, medical condition, ability
to comply with a prescribed regimen, and insurance coverage also
should be explored because these may influence AED choices or
help to explain a lack of response or unexpected adverse effects.
4. If a decision is made to start AED therapy, monotherapy is preferred.
5. Once the care plan is established, a prescription is generated fora
specific AED. Usually this includes a dose-titration schedule. Atthis
point, patient education and assurance of patient understandingof
the plan are essential
6. The AEDs used initially to control seizures may not need to begiven
for a lifetime. Polypharmacy may be reduced, and some patients can
discontinue AEDs
7. Selection and optimization of AED therapy require not only an
understanding of drug mechanism(s) of action and spectrum of
clinical activity but also an appreciation of pharmacokinetic
variability as well as patterns of drug-related adverse effects.
Aim of therapeutic intervension:
To stabilize neuronal resting potential
And to lower exitability

Drugs:
inhibiting excitatory (Most: glutamate) or
activating inhibitory neurons (most: GABA)
Usually with benzodiazepins given iv:
Diazepam iv, 10-20 mg over 3-6 min.
Adverse effect

Phenobarbital, primidone, Osteomalacia (give vit D

phenytoin prophylaxis)
Megaloblastic anemia (folate
prophylaxis)

Valproic acid (less sedating Tremor, gastrointestinal

than other anticonvulsants) upset, weight gain, reversible
hair loss, hepatotoxicity

Carbamazepine Nystagmus, ataxia, diplopia,

gastrointestinal problem, skin
rash
 Phenobarbital
The T max is 8 to 12 h (oral).
Rapidly distributed to all tissues and fluids with high
concentrations in the brain, liver, and kidneys. Lipid
solubility plays a dominant factor in distribution. Protein
binding is 20% to 45%.
Detoxified in liver by microsomal enzyme system.

Onset of action is 30 min.

Duration is 5 to 6 h (oral).

Indications and Usage

Short-term treatment of insomnia; long-term treatment of
generalized tonic-clonic and cortical focal seizures; emergency
control of acute convulsions; preanesthetic sedation.

Unlabeled Uses
Treatment of febrile seizures in children; treatment and prevention of
hyperbilirubinemia in newborns; management of chronic cholestasis.
Contraindications
Hypersensitivity to barbiturates; history of addiction to
sedative/hypnotic drugs; history of porphyria; severe liver
impairment; respiratory disease with dyspnea; nephritic patients.
Dosage and Administration
Insomnia Adults PO / IM / IV 100 to 320 mg.
Sedation Adults PO 30 to 120 mg/day in 2 to 3 divided doses.
Epilepsy Adults PO 60 to 250 mg/day.
Convulsions Adults IV 100 to 320 mg. Repeat if needed (max, 600 mg
per 24 h).

Status Epilepticus Adults IV 10 to 20 mg/kg. Repeat if needed.

Children IV 15 to 20 mg/kg over 10 to 15 min.

Preoperative Sedation
Children PO / IM / IV 1 to 3 mg/kg.

Anticonvulsant Children
IM / IV 4 to 6 mg/kg/day. For 10 days, then adjust to blood level.
Alternatively, use IM / IV 10 to 15 mg/kg/day to reach therapeutic level
more quickly. Max IV rate 60 mg/min. Max adult IM dose is 500 mg or 5
mL volume regardless of concentration.
For oral administration, tablets may be crushed and mixed with
fluid or food.
For IM administration, inject deeply into large muscle. Do not
exceed max IM dose of 500 mg or 5 mL of volume (regardless
of concentration).
For IV administration, inject into large vein. Do not exceed max
IV rate of 60 mg/min; respiratory depression, apnea and
hypotension may result.
Avoid inadvertent intra-arterial injection; arterial spasm,
thrombosis, and gangrene may result.
 Topiramate
Precise mechanism is unknown, but topiramate may block
repetitively elicited action potentials, affect ability of chloride ion
to move into neurons, and antagonize an excitatory amino acid
receptor.

Topiramate absorption is rapid.

T max is 2 h. Bioavailability is about 80% and is not affected by food.
Steady state is reached in about 4 days.
Topiramate is 15% to 41% bound to plasma proteins.

Renal Function Impairment

Cl is reduced 42% in moderately impaired and 54% in severely
impaired patients.

Hepatic Function Impairment

Cl may be decreased.
Pediatric patients have a 50% higher Cl and shorter t ½ than adults.
Consequently, plasma concentrations for the same mg/kg dose may be
lower in children than adults.

Indications and Usage

Initial monotherapy for partial onset or primary generalized tonic-
clonic seizures; adjunctive therapy for partial onset seizures, primary
generalized tonic-clonic seizures, seizures associated with Lennox-
Gastaut syndrome, prophylaxis of migraine headache.

Unlabeled Uses
Adjunctive therapy for bipolar disorder, alcohol and cocaine
dependence, binge eating disorder, bulimia nervosa, cluster
headaches, infantile spasms, weight loss or obesity, and smoking.
Dosage and Administration

Epilepsy, adjunctive therapy

Adults 17 yr of age and older
PO 200 to 400 mg daily in 2 divided doses in adults with partial
seizures and 400 mg daily in 2 divided doses in adults with primary
generalized tonic–clonic seizures. Initiate therapy at 25 to 50 mg daily
and titrate to an effective dose in increments of 25 to 50 mg weekly.
Doses over 400 mg do not improve response. Daily doses above 1,600
mg have not been studied.

Children 2 to 16 yr of age
PO 5 to 9 mg/kg/day in 2 divided doses. Initiate therapy at 25 mg
or less (based on range of 1 to 3 mg/kg/day) nightly for first wk
and titrate to an effective dose at 1- to 2-wk intervals by
increments of 1 to 3 mg/kg/day in 2 divided doses.
Epilepsy, monotherapy
Adults and Children 10 yr of age and older
PO 400 mg daily in 2 divided doses. Initiate therapy at 50 mg
daily and titrate to an effective dose in increments of 25 to 50
mg weekly.

Migraine
Adults
PO 50 mg in the morning and evening. Clinical outcome guides
dose and titration rate; however, the recommended titration rate
is:
Week 1: 25 mg in the evening.
Week 2: 25 mg in the morning and evening.
Week 3: 25 mg in the morning and 50 mg in the evening.
Week 4: 50 mg in the morning and evening.

Renal Function Impairment (Ccr less than 70 mL/min)

Dosage adjustment of 50% of the usual adult dose is
recommended.
 Benzodiazepine
All benzodiazepines in clinical use have the capacity to promote the
binding of the major inhibitory neurotransmitter g-aminobutyric acid
(GABA) to GABAA receptors, thereby enhancing the GABAinduced
ionic currents through these channels

A number of distinct mechanisms of action are thought to contribute

to the sedative-hypnotic, muscle-relaxant, anxiolytic, and
anticonvulsant effects of the benzodiazepines, and specific subunits
of the GABAA receptor are responsible for specific pharmacological
properties of benzodiazepines.

Although benzodiazepines exert qualitatively similar clinical effects,

quantitative differences in their pharmacodynamic spectra and
pharmacokinetic properties have led to varying
patterns of therapeutic application.
Novel Benzodiazepine-Receptor Agonists: Zolpidem and Zalephon
Hypnotics that are structurally dissimilar to benzodiazepines include
zolpicone (not available in the U.S.), zolpidem (AMBIENT), zaleplon
(SONATA), and indiplon (under review by the FDA); presumably,
their therapeutic efficacies are due to agonist effects at the
benzodiazepine site of the GABAA receptor.
Phenytoin
is effective against all types of partial and tonic-clonic seizures but
not absence seizures.

PHARMACOLOGICAL EFFECTS
Central Nervous System Phenytoin exerts antiseizure activity
without causing general CNS depression. In toxic doses, phenytoin
may produce excitatory signs and, at lethal levels, a type of
decerebrate rigidity.

MECHANISM OF ACTION
Phenytoin limits the repetitive firing of action potentials evoked by a
sustained depolarization. This effect is mediated by a slowing of the
rate of recovery of voltage-activated Na+ channels from
inactivation.

At therapeutic concentrations, the effects on Na+ channels are

selective, without changes in spontaneous activity or in responses
to GABA or glutamate.
Carbamazepine
Carbamazepine is a primary drug for the treatment of partial and
tonic-clonic seizures and is also used for the treatment of trigeminal
neuralgia.
Although effects of carbamazepine resemble those of phenytoin,
the drugs exhibit some important differences. For example,
carbamazepine will produce therapeutic responses in manic-
depressive patients, including some in whom lithium carbonate is
not effective. The mechanisms responsible for these effects
of carbamazepine are not clearly understood.

Mechanism of Action
Like phenytoin, carbamazepine appears to limit the repetitive firing
of action potentials evoked by a sustained depolarization by slowing
the rate of recovery of voltage-activated Na+ channels.
At therapeutic concentrations, carbamazepine is selective in that
there are no effects on spontaneous activity or on responses to
GABA or glutamate. The carbamazepine metabolite, 10,11-
epoxycarbamazepine, has similar effects and may contribute to the
antiseizure efficacy of carbamazepine.
THERAPEUTIC USES
Carbamazepine is useful in patients with generalized tonic-clonic
and both simple and complex partial seizures. Renal and hepatic
function and hematological parameters should be monitored.

Carbamazepine is the primary agent for treatment of trigeminal

and glossopharyngeal neuralgias.

It is also effective for lightning tabetic pain associated with bodily

wasting.

Most patients with neuralgia benefit initially, but only 70% obtain
continuing relief. Adverse effects require discontinuation
of medication in 5–20% of patients.
Oxcarbazepine
Oxcarbazepine (10,11-dihydro-10-oxocarbamazepine) is a keto analog
of carbamazepine.

Oxcarbazepine is a prodrug: it is rapidly converted to its active

metabolite, a 10-monohydroxy derivative, which is inactivated by
glucuronidation and eliminated by renal excretion.

Its mechanism of action is similar to that of carbamazepine.

Oxcarbazepine is a less potent enzyme inducer than is carbamazepine,
and substitution of oxcarbazepine for carbamazepine is associated
with increased levels of phenytoin and valproic acid, presumably
because of reduced induction of hepatic enzymes.

Although oxcarbazepine does not appear to reduce the anticoagulant

effect of warfarin, it does induce CYP3A4 and thus reduces plasma
levels of oral contraceptives.
Oxcarbazepine is approved for monotherapy or adjunct therapy for
partial seizures in adults and as adjunctive therapy for partial seizures
in children ages 4–16.
Ethosuximide
Ethosuximide is a primary agent for the treatment of absence
seizures.

Mechanism of Action
Ethosuximide reduces low threshold Ca2+ currents (T currents) in
thalamic neurons and thus modulates thalamic 3-Hz spike-and-wave
activity.
At clinically relevant concentrations, ethosuximide inhibits the T
current without modifying the voltage dependence of steady-state
inactivation or the time course of recovery from inactivation.

Therapeutic concentrations of ethosuximide do not inhibit sustained

repetitive firing or enhance GABA responses.
VALPROIC ACID

Its efficacy in animal models parallels its efficacy

against absence as well as partial and generalized tonic-clonic
seizures in humans.

Mechanism of Action
At therapeutic concentrations, valproic acid inhibits sustained
repetitive firing induced by depolarization of mouse cortical or
spinal cord neurons, an effect apparently mediated by prolonging
the recovery phase of voltage-activated Na+ channels.

Valproic acid does not modify neuronal responses to GABA.

Valproic acid also reduces the T Ca2+ current at clinically relevant
but slightly higher concentrations than those that limit sustained
repetitive firing; this effect on T currents in thalamic neurons is
similar to that of ethosuximide.

Limiting sustained repetitive firing and reducing T currents may

contribute to the efficacy of valproic acid against partial and tonic
clonic seizures and absence seizures, respectively.
Gabapentin

Gabapentin is an antiseizure drug that consists of a GABA molecule

covalently bound to a lipophilic cyclohexane ring. Gabapentin was
designed to be a centrally active GABA agonist.

Efficacy in animal models parallels that of valproic acid and

distinguishes gabapentin from phenytoin and carbamazepine.
Despite its design as a GABA agonist, gabapentin does not mimic
GABA when applied to neurons in primary culture. Gabapentin may
promote release of GABA.

The drug binds a protein in cortical membranes with an amino acid

sequence identical to that of the a2d subunit of the L type voltage-
sensitive Ca2+ channel but does not affect Ca2+ currents of the T,
N, or L types in dorsal root ganglion cells.
THERAPEUTIC USES

When combined with other antiseizure drugs, gabapentin is effective

for partial seizures, with or without secondary generalization.

Gabapentin (900 or 1800 mg/day) monotherapy is equivalent

to carbamazepine (600 mg/day) for newly diagnosed partial or
generalized epilepsy.
Gabapentin also is used off-label for the treatment of migraine,
chronic pain, and bipolar disorder.

Gabapentin usually is effective at 900–1800 mg daily in three divided

doses, although 3600 mg may be required in some patients. Therapy
usually is begun with a low dose (300 mg once on the
first day), which is increased in daily increments of 300 mg until an
effective dose is reached.

Overall, gabapentin is well tolerated. The most common adverse

effects are somnolence, dizziness, ataxia, and fatigue. These effects
usually are mild and resolve within 2 weeks of onset during continued
treatment.
Lamotrigine
Lamotrigine was developed as an antifolate agent, based on the
model that reducing folate would combat seizures. The antiseizure
effect of lamotrigine is unrelated to its antifolate properties.

Lamotrigine
blocks sustained repetitive firing of neurons and delays recovery
from inactivation of recombinant Na+ channels, mechanisms
similar to those of phenytoin and carbamazepine that may explain
lamotrigine’s actions on partial and secondarily generalized
seizures.
However, lamotrigine is effective against a broader spectrum of
seizures than phenytoin and carbamazepine, suggesting additional
actions that may include inhibiting synaptic release of glutamate.
Levetiracetam

Levetiracetam exhibits clinical effectiveness against partial and

secondarily generalized tonic-clonic seizures.
The mechanism by which levetiracetam exerts these antiseizure
effects is unknown.

Levetiracetam is rapidly and almost completely absorbed after oral

administration and is not bound to plasma proteins. Ninetyfive
percent of the drug and its inactive metabolite are excreted in the
urine, 65% of which is unchanged drug; 24% of the drug is
metabolized by hydrolysis of the acetamide group.

Levetiracetam neither induces nor is a high-affinity substrate for

CYPs or glucuronidases and thus does not
interact with other antiseizure drugs, oral contraceptives, or
anticoagulants.
Tiagabine
Tiagabine inhibits the GABA transporter, GAT-1, and thereby
reduces GABA uptake into neurons and glia.
Tiagabine is rapidly absorbed after oral administration, extensively
bound to serum or plasma proteins, and metabolized in the liver by
CYP3A. Its t1/2 (∼8 hours) is shortened by 2–3 hours when the drug
is coadministered with hepatic enzyme–inducers such as
phenobarbital, phenytoin, or carbamazepine.
Tiagabine is effective as add-on therapy of refractory partial
seizures, with or without secondary generalization. Its efficacy as
monotherapy for newly diagnosed or refractory partial and
generalized epilepsy has not been established.
Adverse effects include dizziness, somnolence, and tremor, which
are mild to moderate in severity and appear shortly after initiation
of therapy.
Tiagabine-enhanced effects of synaptically released GABA can
facilitate spike-and-wave discharges in animal models of absence
seizures, suggesting that tiagabine may be contraindicated in
patients with generalized absence epilepsy; patients with a history
of spike-and-wave discharges have been reported to have
exacerbations of their EEG abnormalities.
Zonisamide
Zonisamide is a sulfonamide derivative.

Zonisamide inhibits both the T-type Ca2+ currents and the sustained,
repetitive firing of spinal cord neurons, presumably by prolonging the
inactivated state of voltage-gated Na+ channels in a manner similar to
that of phenytoin and carbamazepine.
Interactions of Antiseizure Drugs with Hepatic Microsomal
Enzymes