DRUGS FOR

SEIZURE /EPILEPSY / CONVULSAN

Farmakoterapi III
Jurusan Farmasi FKIK
UIN Maulana Malik Ibrahim Malang
2018
 Convulsion: Sudden attack of involuntary
muscular contractions and relaxations.

 Seizure: Abnormal central nervous system

electrical activity.

 Epilepsy: A group of recurrent disorders of

cerebral function characterized by both seizures
and convulsions.
 Epilepsy is a chronic brain disease of diverse etiology 
it is characterized by recurrent paroxysmal episodes of
uncontrolled excitation of brain neurons
 Epilepsy is a disease of the brain defined by any of the
following conditions

1. A least two unprovoked (or reflex) seizures occurring >24 h

apart
2. One unprovoked (or reflex) seizure and a probability of
further seizures similar to
the general recurrence risk (at least 60%) after two
unprovoked seizures, occurring
over the next 10 years
3. Diagnosis of an epilepsy syndrome
TYPE OF A SEIZURE IN THE ABSENCE OF A PRECIPITATING
FACTOR  NOT EPILEPTIC DISORDER

 Febrile seizures in children age 0.5 – 6 years

 Alcohol-withdrawal seizure

 Metabolic seizures (sodium, calcium, magnesium,

glucose, oxygen)
 Toxic seizures (drug reactions or withdrawal, renal
failure)
 Convulsive syncope  aritmia
 Acute concussive convulsion brain injury

 Seizures within first week after brain trauma,

infection or stroke
ETIOLOGY
 Structural
 Genetic

 Infectious

 Metabolic

 Immune

 Unknown
VOLTAGE GATED CHANNELS
 Depolarizing conductances
– Excitatory
– Inward sodium and Ca currents
 Hyperpolarizing conductances
– Inhibitory
– Primarily mediated by potassium channels
LIGAND GATED SYNAPTIC TRANSMISSION 
NEUROTRANSMITTER
 These neurotransmitters modulate and regulate the electrical
activity  action potential
- Excitatory Neurotransmitter  Glutamat, Aspartat
- Inhibitory Neurotransmiter  GABA
 The action potential is an electrical signal that travels down
the axon, and is created using sodium ions (Na+), and inhibited
by potassium ions (K+).

 Usually these processes work synergistically to produce normal

behavior and activity.

 When dysfunctional, abnormal electrical activity occurs and

can produce seizures
 Excitation (too much)  Ionic : inward Na and Ca
+ ++
currents

 Inhibition (too little)  Ionic: inward CI-, outward K+

currents
 There are multiple mechanisms that might contribute
to synchronous hyperexcitability including:
 (1) alterations in the distribution, number, type and
biophysical properties of ion channels in the
neuronal membranes;
 (2) biochemical modifications of receptors;
 (3) modulation of second messaging systems and gene
expression;
 (4) changes in extracellular ion concentrations;
 (5) alterations in neurotransmitter uptake and metabolism
in glial cells; and
 (6) modifications in the ratio and function of inhibitory
circuits..
• Cognitive seizures
• impaired language
• other cognitive domains
• positive features eg déjà vu,
hallucinations, perceptual
distortions
• Emotional seizures: anxiety, fear, joy,
etc
Note
When a seizure type begins with
”focal, generalized or absence” then
the word “onset” can be presumed
PARTIAL (FOCAL) SEIZURES

 Excessive electrical activity in one cerebral

hemisphere.
 Affects only part of the body  1 minute.

 Simple Partial:
 Motor
 Sensory
 Autonomic
PARTIAL (FOCAL) SEIZURES
 Complex Partial  Psychomotor Seizures)
Initial subjective feeling (aura), loss of
consciousness, abnormal behavior (perioral
and hand automatisms)
Focal seizures
• Originate within
networks limited
to one
hemisphere
• May be discretely
localized
or more widely
distributed.…
GENERALIZED SEIZURES

 Excessive electrical activity in both cerebral

hemispheres.
 Usually originates in the thalamus or brainstem.
 Affects the whole body.
 Loss of consciousness is common.
Generalized
seizures
• Originate at some
point within and
rapidly engage
bilaterally distributed
networks
• Can include cortical
and subcortical
structures
but not necessarily the
entire cortex
GENERALIZED SEIZURES
 Tonic-clonic (grand mal):
 Tonic phase followed by clonic phase

 Myoclonic: Brief shock-like muscle jerks generalized or restricted to

part of one extremity.

 Atonic: Sudden loss of muscle tone.

 Tonic Seizures: sudden stiffening of the body, arms, or legs

 Clonic Seizures: rhythmic jerking movements of the arms and legs

without a tonic component

http://www.nlm.nih.gov/medlineplus/ency/images/ency/fullsize/19076.jpg
GENERALIZED SEIZURES

 Absence (petit mal): Person appears to “blank out” -

“Daydreaming”
 Simple Absence (primarily effects consciousness only)
 Complex Absence
 Atypical Absence (Includes physical symptoms like eye blinking or lip
movements)

 Status Epilepticus: A seizure lasting longer than 30 min, or 3

seizures without a normal period in between
 May be fatal
 Emergency intervention required
THERAPY
 Monotherapy with anticonvulsant
 Increase dose gradually until seizures are controlled
or adverse effects become unacceptable.

 Multiple-drug therapy may be required.

 Achieve steady-state kinetics

 Monitor plasma drug levels
 Avoid sudden withdrawal
MECHANISM ACTION OF ANTIEPILEPTIC DRUGS

(1) Enhancing GABA synaptic transmission:

barbiturates, benzodiazepines, gabapentin, levetiracetam, tiagabine,
vigabatrin, topiramate, valproate the result is increased
permeability to chloride ion reduces neuronal excitability.
Valproate and topiramate block GABA transaminase
Tiagabine blocks reuptake of GABA.

(2) Reducing cell membrane permeability to voltage-

dependent Na channels:
carbamazepine, lamotrigine, oxcarbazepine, phenytoin, topiramate,
valproate, lacosamide, zonisamide

(3) Reducing cell membrane permeability to Ca channels:

valproate, ethosuximide, Levetiracetam, Pregabalin, the result is
diminishing of the generationof action potential.

(4) Inhibiting excitory neurotransmitter glutamate:

lamotrigine.
 GABA
Barbiturates
Benzodiazepines
Gabapentin
Levetiracetam
Tiagabine
Topiramate
Valproate
Vigabatrin

Na+ Ca2+
Carbamazepine
Ethosuximide
Lamotrigine
Levetiracetam
Oxcarbazepine
Pregabalin
Phenytoin
Valproate
Topiramate
Valproate
Antiseizure drugs
enhanced
GABA
synaptic
transmission

Goodman & Gilman's

The Pharmacologic
Basis of
Therapeutics - 11th
Ed. (2006)
Antiseizure drugs, enhanced Na+ channel inactivation
Antiseizure drugs, induced reduction of
current through T-type Ca2+ channels.
CARBAMAZEPINE

•The t1/2 of the drug falls from 35 -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.

•Carbamazepin XR 15-18 mg/kgBB bid

•Adverse reactions (ARs): reversible blurring of vision,

diplopia, dizziness, ataxia, depression of AV conduction,
skin rashes, liver, and kidney dysfunction.
VALPROIC ACID

 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.
 Dose 20-60 mg/kgBB od/bid

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

 (t1/2 6–24 h) has saturation kinetics.

Dose 4-6 mg/kgBB bid
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 gonad
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.
 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.