FARMAKOTERAPI SISTEM SARAF, UROGENITAL,

DAN MUSKOLOSKELETAL

EPILEPSY
EFTA TRIASTUTI / VALENTINA YURINA
Study Program of Pharmacy
Medical Faculty Brawijaya University
 Kompetensi
Mampu memahami definisi, etiologi, dan patofisiologi epilepsi.

Mampu mengenali tanda dan gejala epilepsi.

Mampu memahami prinsip penatalaksanaan (terapi farmakologi dan

non-farmakologi) epilepsi.

Mampu menjelaskan mekanisme kerja terapi farmakologi epilepsi.

Mampu merekomendasikan kepada dokter spesialis yang relevan.

Mampu menangani dan memutuskan masalah terapi epilepsi secara

mandiri.
Mampu melakukan monitoring dan evaluasi terkait efikasi dan efek
samping terapi epilepsi.
Mampu merekomendasikan pemeriksaan laboratorium (seperti EEG)
untuk mengetahui progresivitas atau perbaikan kondisi epilepsi.
Transmisi Sinaptik Normal

Carl E. Stafstrom Pediatrics in Review 1998;19:342-351 Hiperpolarisasi

©1998 by American Academy of Pediatrics
Transmisi Sinaptik Normal

Depolarisasi

Carl E. Stafstrom Pediatrics in Review 1998;19:342-351

©1998 by American Academy of Pediatrics
Receptors in Action potential
◦ Ionotropic receptors
◦ Very fast post-synaptic action
◦ Binding with various drug: barbiturat (phenobarbital,
pentobarbital), steroids, alcohol, benzodiazepines
◦ Metabotropic receptors
◦ G-proteins coupled receptors
◦ Do not use ion channel in their structure (consist of an
extracellular domain that binds to a neurotransmitter and
an intracellular domain that binds to G-protein)
◦ Activation of G-protein receptors leads its releasing from
the receptors and interacts with ion channel and other
proteins to open or close ion channels through
intracellular messengers
◦ Slow post-synaptic responses
◦ Use potassium channels instead of chloride
Schematic GABA synapse Ch, Ali & W Ol, D & W Olsen, Richard. (2019). 2 G AB A GABA IS
THE MAJOR INHIBITORY NEUROTRANSMITTER IN THE NERVOUS
SYSTEM.
 : Bernard C. Alterations in synaptic function in epilepsy. In: Noebels JL, Avoli M,
Schematic glutamate Rogawski MA, et al., editors. Jasper's Basic Mechanisms of the Epilepsies
[Internet]. 4th edition.
synapse Bethesda (MD): National Center for Biotechnology Information (US); 2012.
DEFINISI
Epidemiology

Approximately 10% of world

population will have a seizure at
some time during their lives, and 1%
of the population suffers from
epilepsy (comparable prevalence
in men vs. women)
Etiology

Seizures occur because a group of cortical

neurons discharge abnormally in synchrony.
Anything that disrupts the normal homeostasis
of neurons and their stability can trigger
hyperexcitability and seizures.
Etiology of seizure
Hyperventilation  absence seizures.

Sleep, sleep deprivation, sensory stimuli, and emotional

stress

Hormonal changes (menses, puberty, or pregnancy)

theophylline, alcohol, high-dose phenothiazines,

antidepressants (especially maprotiline or bupropion), and
street drug

Perinatal injuries and small gestational weight at birth

Immunizations have not been associated with an increased

risk of epilepsy.
Classification of epileptic seizures
•A. Simple (without impairment of consciousness)
•1. With motor symptoms
I. Partial •2. With special sensory or somatosensory symptoms
seizures •3. With psychic symptoms
•B. Complex (with impairment of consciousness)
(seizures •1. Simple partial onset followed by impairment of consciousness—
begin with or without automatisms
locally) •2. Impaired consciousness at onset—with or without automatisms
•C. Secondarily generalized (partial onset evolving to generalized
tonic-clonic seizures)

•A. Absence
II. Generalized •B. Myoclonic
•C. Clonic
seizures (bilaterally •D. Tonic
symmetrical and •E. Tonic-clonic
without local onset) •F. Atonic
•G. Infantile spasms

III. Unclassified IV. Status

seizures epilepticus
Generalized tonic clonic seizure
Signs & symptoms of seizure
 Types & features of seizure
Feature Absence Myoclonic Atonic seizure Tonic-clonic
seizure seizure seizure
Consciousness Impaired Unaffected Impaired Impaired
Duration ≤ 30 seconds 1-5 seconds A few seconds 1-3 minutes
Symptoms & Brief absence, Bilateral Sudden loss of Initial cry, loss
signs blinking, synchronous muscles tone of muscle
chewing jerks in arms & causing tone,
legs severe falls respiratory
arrest,
cyanosis,
tonic-clonic
seizure,
tongue biting,
urinary & fecal
incontinence
Age group Children & Children & Infants & Any age
adolescents adolescents children
 Differences between syncope & epileptic seizure

Clinical feature Syncope Epileptic seizure

Triggers Common No
Time of day Mostly diurnal, does not Day or night, awaken
awaken patients from patient from sleep
sleep
Skin coloration Pale Cyanotic or normal
Premonitory symptoms Tinnitus, visual blurring or None or aura
blackout
Duration Usually < 30 seconds 1-3 minutes or longer
Eyes Open Closed
Urinary incontinence Occasional Common
Confusion Brief or absent Longer-lasting
Tongue-biting Occasional Common
Prolactin, creatine Normal Elevated
kinase
Typical EEG changes Absent Common
EEG
Pathophysiology
 Multiple mechanisms that might
contribute to synchronous hyper
excitability :
◦ alterations in the distribution, number, type and biophysical
properties of ion channels in the neuronal membranes;
◦ biochemical modifications of receptors;
◦ modulation of second messaging systems and gene
expression;
◦ changes in extracellular ion concentrations;
◦ alterations in neurotransmitter uptake and metabolism in glial
cells; and
◦ modifications in the ratio and function of inhibitory circuits.
Diagnosis
THERAPY: Goals of therapy
◦ Complete elimination of seizures and no side effects with
an optimal quality of life.

◦ The best quality of life is associated with a seizure-free state.

◦ Because therapy is continued for many years (often a

lifetime), chronic side effects must be considered.
◦ Providing optimal quality of life goes beyond balancing
seizures and side effects. It involves assessing all the
concerns of a patient with epilepsy, such as, issues about
driving, their future, forming relationships, safety, social
isolation, social stigma, and so on. It is also important to
recognize that patients with epilepsy can have other
neuropsychiatric comorbidities such as depression, anxiety,
and sleep disturbances that need treatment
Neural site of action of Antiepileptics
Antiepileptics site of action in gabanergic synapse
Antiepileptic indications
Algorithm therapy
Carbamazepine
Voltage dependent Na+ channel inactivation

Initial dose 100 mg twice a day

Daily maintenance dose (adults) 400–1600 mg

Dosage interval 3 – 4 times/day

t1/2: 12 – 18 hours

Indication: Partial & secondarily generalized tonic clonic

seizure

Side Effects: ataxia, diplopia, sedation, GI distress (dose related);

skin rash, hepatic dysfuncton, SJS (idiosyncratic)
 clonazepam

Maintenance Indication:
Open GABAA dose: 2-8 absence, partial,
channel mg/day in 2-3 generalized
divided doses tonic-clonic

Side Effect:
ataxia, sedation,
Initial dose: 0,5 diplopia,
mg/day in 2-3 t1/2: 20-40 hours hypersalivation,
divided doses behaviour
disturbance
(dose related)
 Ethosuximide

Maintenance dose: 15-

T-type Calcium Initial dose: 15
40 mg/kg/day in 2-3
channel blocker mg/kg/day
divided doses

Side Effect: ataxia,

headache, GI distress,
sedation (dose
t1/2: 60 hours Indication: absence
related); blood
dyscrasia, skin rash
(idiosyncratic)
Gabapentin
Improve utilization of GABA precursor: glutamate

Initial dose: 300 mg 3 times a day

Maintenance dose: 900-4800 mg/day in 3 divided doses

t1/2: 5-7 hours

Indication: Partial & secondarily generalized tonic clonic seizure

Side Effects: drowsiness, fatigue, loss of libido

Lamotrigine
Voltage dependent Na+ channel inactivation &
glutamate (AMPA/kainate) receptor antagonist

Initial dose: 25 mg twice a day

Maintenance dose: 300-800 mg/day (without

valproate); 100-400 mg/day (with valproate) 1-2
times a day

t1/2: 24 hours

Indication: partial, generalized tonic-clonic,

secondarily generalized tonic-conic

Side Effects: dizziness, ataxia (dose related); skin

rash, SJS (idiosyncratic)
Oxcarbazepine
Voltage Side Effects:
dependent Na+ hyponatremia
channel (dose related); skin
inactivation rash (idiosyncratic)

Indication: Partial &

Initial dose: 300 mg secondarily
twice a day generalized tonic
clonic seizure

Maintenance dose:
600-2400 mg in 2 t1/2: 8-10 hours
divided doses
 Phenobarbital

Voltage Indication:
dependent Maintenanc partial,
Na+ channel e dose: 90- generalized
inactivation 180 mg/day tonic-clonic,
& Open as single secondarily
GABAA dose generalized
channel tonic-conic
Side Effects:
sedation,
Initial dose: ataxia,
t1/2: 2-3
180 mg twice behavioural
days
a day disturbance,
diplopia (dose
related); skin
rash, SJS
(idiosyncratic)
 Phenytoin
Voltage dependent Na+ channel inactivation

Initial dose: 1000 mg in 2-4 divided doses

Maintenance dose: 300-400 mg/day in single or divided dose

Fosphenytoin is prodrug form for IM & IV use

t1/2: 12-24 hours

Indication: partial, generalized tonic-clonic, secondarily generalized

tonic-conic
Side Effects: diplopia, ataxia, gingiva hyperplasia, osteomalacia,
hirsutism, polyneuropathy, megaloblastic anemia (dose related); skin
rash, SJS, blood dyscrasia, hepatic dysfunction (idiosyncratic)
Topiramate
Na+ channel inactivation, open GABAA channel, glutamate receptor
antagonist, calcium channel inhibition

Initial dose: 25 mg/day

Maintenance dose: 100-400 mg twice a day

t1/2: 16-30 hours

Indication: partial, generalized tonic-clonic, secondarily

generalized tonic-conic

Side Effects: ataxia, confusion (dose related); glaucoma, renal stone

(idiosyncratic)
 Valproate

Side Effects: GI distress,

weight gain, hair loss,
Na+ channel sedation, tremor,
inactivation & thrombocytopenia
t1/2: 6-18 hours
open GABAA (dose related); hepatic
dysfunction, peripheral
channel edema, pancreatitis
(idiosyncratic)
Indication:
absence,
Initial & partial,
maintenance generalized
dose: 750-3000 tonic-clonic,
mg/day in 2-3 secondarily
divided doses generalized
tonic-conic,
myoclonus
Vigabatrin
GABA transaminase inhibitor & GABA reuptake
inhibition

Initial dose: 500 mg twice a day

Maintenance dose: 2-4 g/day in two divided

doses

t1/2: 5-8 hours

Indication: partial seizure

Side Effects: sedation, vertigo, psychosis (dose

related); visual constriction (idiosyncratic-
irreversible)
Drug interactions
Drug Level increased by Level decreased by
phenytoin Benzodiazepines Carbamazepine
Chloramphenicol Phenobarbital
Disulfiram Pyridoxine
Ethanol Vigabatrin
Isoniazid
Phenylbutazone
Sulfonamides
Trimetoprim
Warfarin
Carbamazepine Erythromycin Phenobarbital
Isoniazid Phenytoin
Valproic acid Oxcarbazepine
Phenobarbital Valproic acid -
Valproic acid - Topiramate
Lamotrigine
Phenytoin
Carbamazepine
Drug interactions

Drug Level increased by Level decreased by

Ethosuximide Valproic acid -
Gabapentin - -
Lamotrigine Valproic acid Carbamazepine
Phenobarbital
phenytoin
Vigabatrin - -
Topiramate - Carbamazepine
Phenytoin
Valproic acid
Efficacy spectrum of antiepileptic drug

Focal & Valproate

most of Benzodiazepines
generalized
seizure Phenobarbital
Primidone
Lamotrigine
Levetiracetam
Topiramate
Zonisamide
Rufinamide
Felbamate
 Efficacy spectrum of antiepileptic drug
focal seizures, Carbamazepine
with or without
secondary
Phenytoin
generalisation Gabapentin
Lacosamide
Oxcarbazepine
Eslicarbazepine acetate
Pregabalin
Tiagabine
Vigabatrin
absence
seizures Ethosuximide
Antiepileptic advantages & disanvantages
Antiepileptic advantages & disanvantages
Non-pharmacological
therapy
◦ Diet  ketogenic  high in fat and low in
carbohydrates and protein and thus leads to acidosis
and ketosis or modified Atkins diet.
◦ Surgery  lobectomy and lesionectomy
◦ Vagus nerve stimulation (VNS)  implanted medical
device to reduce the frequency of seizure  changes
thecerebrospinal fluid (CSF) concentration of
inhibitory and stimulatory neurotransmitters and
activates specific areas of the brain that generate or
regulate cortical seizure activity through increased
blood flow.
Status
epilepticus
 Status epilepticus

Repetitive
> 20
minutes
SE adalah kejang
yang berlangsung
terus-menerus No normal
mental
selama periode state
waktu tertentu between
atau berulang seizure
tanpa disertai
pulihnya
kesadaran
diantara kejang

true medical emergency,

with a mortality of up to 15%
 Status epilepticus therapy

drugs of
choice 
equally
effective,
but
lorazepam
has the
advantage
of a longer
functional
half-life in
the brain
Status epilepticus therapy algorithm
Status epilepticus therapy algorithm
 Consideration
Sedating agents (diazepam or lorazepam) as a form of chemical
restraint to calm the patient should be avoided. These agents will
prolong the postictal (after the seizure) state of confusion & may
induce respiratory depression
• The pulse and blood pressure usually rise significantly during a
convulsive seizure, but return to normal quickly after the end of
the seizure and usually do not require treatment

Occasionally, patients may become bradycardia or hypotensive,

particularly after a prolonged seizure, this may require treatment with
fluids or atropine if the bradycardia is severe

• Test the blood immediately to determine the blood sugar level, as

hypoglycemia is a common cause of seizures
 Patient evaluation

Carefully examine the patient for

evidence of head injury or serious
injury to any other part of the body

Is there any evidence of drug

abuse, such as track marks or white
powder in the nose?

During the seizure, check the pupils

for size and symmetry
Patient education
Importance of adherence to the
treatments

Potential drug side effects

Potential drug interactions

Help to identify trigger factor &

support to avoid it