Farmakologi dari obat

anti kejang atau epilepsi

Dr.Datten Bangun MSc.SpFK

Dept.Farmakologi & Therapeutik
Fak.Kedokteran UHN
MEDAN
 Definitions
 Seizure
• The clinical manifestation of an abnormal
hypersynchronized discharge in a population of
cortical excitatory neurons

 Epilepsy:
• A tendency toward recurrent seizures
unprovoked by acute systemic or neurologic
insults

P-Slide 2
 Etiology

• Congenital defects, head injuries, trauma,

hypoxia
• Infection e.g. meningitis, brain abscess, viral
encephalitis
• Concussion, depressed skull, fractures.
• Brain tumors (including tuberculoma), vascular
occlusion.
• Drug withdrawal, e.g. CNS depressants .
• Fever in children (febrile convulsion).
• Hypoglycemia
• PKU
• Photo epilepsy
 TRIGGERS::
Fatigue, stress, poor nutrition, alcohol and sleep
deprivation.
Caution: Repetitive stimulation:
- aliran air
- sinar lampu dikaraoke
- mengejar Pokemon
 Seizure Facts

• Seizures are not usually life threatening.

• The brain almost always stops the seizure on
its own.
• Breathing may cease for a few seconds, and
the patient may turn blue.
• People don’t feel pain during a seizure;
muscles may be sore afterward.
• Person may be “different” for a while after the
seizure.
 Treatment
• Try to find a cause. (e.g. fever, head trauma, drug
abuse)
– Recurrent seizures that cannot be attributed to any
cause are seen in patients with epilepsy.
• Therapy is aimed at control
– drugs do not cure.
• The type of seizure determines the choice of
drug!
• More than 80% of patients with epilepsy can
have can have their seizures controlled with
medications.
 Treatment
• 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
 Mechanisms of Action
• 3 main categories of therapeutics:
1. Inhibition of voltage-gated Na+ channels to slow
neuron firing.
2. Enhancement of the inhibitory effects of the
neurotransmitter GABA.
3. Inhibition of calcium channels.
 Benefits of AED
Goals of Therapy
o Stop seizures

o No unwanted side effects

 Side Effects of AED
• Fatigue, abdominal discomfort, dizziness, or
blurred vision during the first weeks
• Rash, inflammation or failure of the liver or
pancreas, a serious reduction in the number of
white blood cells (needed to fight infection), a
serious reduction in the number of platelets
(needed to control bleeding)
• Osteomalacia with certain AED
Anti-epileptic Drugs and Osteomalacia

• Adverse effects on bone density reported since the

early 1960’s

• Phenytoin and carbamazepine most frequently

associated with osteomalacia

• Newer agents (e.g. topiramate, lamotrigine,

gabapentin) appear to be less causitive of
osteomalacia
Types of Seizures
s

(focal) Primary
 A) Focal or partial

1) Simple partial( Jacksonian )

2) Complex partial( psychomotor )

- The electrical discharge is confined in certain parts
of the temporal lobe concerned with mood as well
as muscle.
 B) Primary generalized
1) Tonic- clonic. Pt fall in convulsion & may bite his
tongue & may lose control of his bladder or bowel.
2) Tonic. Some pts, after dropping unconscious
experience only the tonic or clonic phase of seizure.
3) Atonic ( akinetic). Starts between the ages 2-5 yrs.
The pt’s legs simply give under him & drops down.
4) Myoclonic . Sudden, brief shock like contraction
which may involve the entire body or be confined to
the face, trunk or extremities.
5) Absence . Loss of consciousness without involving
motor area. Most common in children ( 4-12 yrs ).
6) Status epilepticus ( re-occuring seizure ). Continuous
seizure without intervening return of consciousness
 Antiepileptic Drug
• An antiepileptic drug (AED) is a drug which decreases
the frequency and/or severity of seizures in people
with epilepsy
 Treats the symptom of seizures, not the underlying
epileptic condition
 Does not prevent the development of epilepsy in
individuals who have acquired a risk for seizures
(e.g., after head trauma, stroke, tumor)
• Goal of therapy is to maximize quality of life by
eliminating seizures (or diminish seizure frequency)
while minimizing adverse drug effects

P-Slide 15
 TREATMENT OF SEIZURES
Seizure disorder Drugs
Tonic-clonic(Grand mal) Carbamazepine or
Drug of Choice Valproate or
Phenytoin or
Phenobarbital
Alternatives: Topiramte
Lamotrigine (as adjunct or
alone)
Gabapentin (as adjunct)

Partial (simple or complex) Carbamazepine or Topiramte

Drug of choice or
Phenytoin or
Valproate
Alternatives: Phenobarbital
Lamotringine (as adjunct or alone)
Gabapentin (as adjunct )
 Treatment cont,d
Absence ( petit mal) Valproate or
Drug of choice Ethosuximide

Alternatives: Clonazepam
Lamotrigine
Myoclonic, Atonic Valproate
Drug of choice
Alternatives: Clonazepam

Status Epilepticus Diazepam, i.v.

Drug of choice or Phenytoin, i.v. or Vaproate
Alternatives: Phenobarbital, i.v
Febrile Seizures Diazepam, rectal*
Diazepam ,i.v
Valproate
* Preferred
 Treatment:
• Up to 80% of pts can expect partial or complete
control of seizures with appropriate treatment.
• Antiepileptic drugs suppress but do not cure
seizures
• Antiepileptics are indicated when there is two or
more seizures occurred in short interval (6m -1 y)
• An initial therapeutic aim is to use only one drug
(monotherapy)
 Treatment ( Cont. )
• Advantage of monotherapy:
• fewer side effects, decreased drug-drug interactions,
better compliance, lower costs
• Addition of a second drug is likely to result in significant
improvement in only approx. 10 % of patients.
 Treatment ( Cont. )
• when a total daily dose is increased, sufficient time (about
5 t 1l2) should be allowed for the serum drug level to reach
a new steady-state level.

• The drugs are usually administered orally

• The monitoring of plasma drug levels is very useful

• Precipitating or aggravating factors can affect seizure

control by drugs
 Treatment ( Cont. )

• The sudden withdrawal of drugs should be avoided

withdrawal may be considered after seizure- free
period of 2-3 or more years

• Relapse rate when antiepileptics are withdrawn is

20 -40 %
When to Withdraw Antiepileptic Drugs?

Normal neurological examination

Normal IQ
Normal EEG prior to withdrawal
Seizure- free for 2-5 yrs or longer
NO juvenile myoclonic epilepsy

Pts not meeting this ideal profile in all points,

withdrawal may be encouraged after careful
assessement of the individual patient.
 The Major Antiepileptic Drugs
• The main drugs in current use are:
= phenytoin,
= carbamazepine,
= valproate and
= ethosuximide.

• Secondary drugs include:

– Phenobarbitone: highly sedative
– Various benzodiazepines (e.g. clonazepam);
Diazepam used in treating status epilepticus.
Na+ Channel Inhibitors
 Phenytoin
Mechanism of Action: acts by stabilizing membranes
(1) Blocking voltage-dependence Na+ channel
(2) Blocking voltage-dependence Ca2+ channel
(3) Inhibiting calcium-induced secretory processes,
including release of hormones and
neurotransmitters.
(4) Inhibiting post tetanic potentiation (PTP).
 PHARMACOKINETICS

• Because phentoin is a weak acid, its intestinal

absorption is variable and plasma
concentration can vary widely. Monitoring is
therefore needed
• It is metabolized by the microsomal system
and is excreted first in the bile and then in
the urine.
 Therapeutic uses
• Antiseizure: used in the treatment of grand
mal epilepsy and tonic-clonic seizure
disorders, not in absence seizures.
• Treatment on peripheral neuralgia .
• Antiarrhythmias
 Adverse effects
• Gastrointestinal irritation
• Ataxia and diplopia.
• Blood dyscrasias.
• Gingival hyperplasia, hirsutism, increased collagen
proliferation.

• Hepatitis.
• Fetal malformations: fetal hydantion syndrome
• Drug interactions: increased plasma concentrations of
phenytoin can occur by concurrent administration of
chloramphenicol, isoniazid, cimetidin, dicumarol, et al.
Phenytoin Induced Gingival Hyperplasia

17 year old boy treated

with 300mg/day
phenytoin for 2 years
(unsupervised)

Partial recovery at 3
months after
discontinuation

Images in Clinical Medicine (Feb 2000) 342:325

 Na+ Channel Inhibitors

• Carbamzepine (Tegretol, Carbatrol):

– Indications:
• First choice for complex partial and generalized
tonic-clonic seizures.
– Contraindications:
• May exacerbate absence or myoclonic seizures.
• Blood disorders
• Liver disorders
 Na+ Channel Inhibitors
• Carbamazepine (Tegretol, Carbatrol):

– Drug Interactions:
• CBZ metabolism is affected by many drugs, and
CBZ affects the metabolism of many drugs.
– Adverse Effects:
• Mild leukopenia or hyponatremia
• Circulating concentrations of thyroid hormones
may be depressed; TSH remains normal.
 CARBAMAZEPINE
Its mechanism of action and clinical uses are similar to that
of phenytoin.
However, it is also commonly used for Rx of mania and
trigeminal neuralgia.

Pharmacokinetics
-available as an oral form only
-Well absorbed
-80 % protein bound
-Strong inducing agent including its own (can lead to failure
of other drugs e.g. oral contraceptives, warfarin, etc.
er
 Pharmacokinetics of CBZ( Cont. )

• Metabolized by the liver

• Excreted in urine as glucuronide conjugate

• Plasma t1/2 approx. 30 hours

• Therapeutic plasma concentration 6-12 µg/ml

(narrow).

• Dose 200-800 mg/day (given BID as sustained

release form)
Pharmacokinetic interactions of CBZ

• Inducers of liver enzymes reduce its

plasma level
e.g. Phenytoin; Phenobarbital; Rifampicin

• inhibitors of liver enzymes elevate its

plasma levels
e.g. erythromycin,INH ,verapamil;
Cimetidine
• Side Effects of Carbamazepine:

• G.I upset
• Drowziness, ataxia and headache; diplopia
• Hepatotoxicity- rare
• Congenital malformation (craniofacial anomalies & neural
tube defects).
• Hyponatraemia & water intoxication.
• Late hypersensitivity reaction (erythematous skin rashes,
mouth ulceration and lymphadenopathy.
• Blood dyscrasias as fetal aplastic anemia (stop
medication); mild leukopenia (decrease the dose)
 Na+ Channel Inhibitors

• Oxcarbazepine (Trileptal):
– FDA approved in 2000 for partial seizures
• Complex partial seizures
• Primary & secondarily generalized tonic-clonic
seizures
• No effect on absence or myoclonic seizures

– Fewer adverse effects than CBZ, phenytoin

 Na+ Channel Inhibitors
• Valproic Acid (Valproate; Depakene, Depakote):

– Other Mechanisms of Action:

• 1) Some inhibition of T-type Ca2+ channels.
• 2) Increases GABA production and decreases
GABA metabolism.
 Sodium Valproate or Valproic Acid

• Pharmacokinetics :
• Available as capsule, Syrup, I.V
• Metabolized by the liver ( inactive )
• High oral bioavailability
• Inhibits metabolism of several drugs such as
Carbamazepine; phenytoin, Topiramate and
phenobarbital.
• Excreted in urine ( glucuronide )
• Plasma t1/2 approx. 15 hrs
 Valproic Acid (Valproate; Depakene,
Depakote):

– Indications:
• Simple or complex partial, & primary
generalized tonic-clonic
• Also used for absence, myoclonic, and atonic
seizures.
• Highly effective for photosensitive epilepsy and
juvenile myoclonic epilepsy.
– Contraindications:
• Liver disease
 Sodium Valpraote ( cont. )

• Clinical Use:
– Very effective against absence, myoclonic
seizures.
– Also, effective in gen. tonic-clonic siezures
(primarly Gen)
– Less effective as compared to carbamazepine for
partial seizures
– Like Carbamazepine also can be used for Rx of
mania
 Side Effects of Sod. valproate:

• Nausea, vomiting and GIT disturbances (Start with

low doses)
• Increased appetite & weight gain
• Transient hair loss.
• Hepatotoxicity
• Thrombocytopenia
• Neural Tube defect (e.g. Spina bifida) in the
offspring of women. (contraindicated in pregnancy)
Enhancement of GABA Inhibition
 Newer Antiepileptic Drugs
( Second- Generation )
1. Vigabatrin 1989
2. Gabapentin 1993**
3. Lamotrigine 1994**
4. Topiramate 1996**
5. Tiagabine 1997
6. levetiracetam 1999
7. Oxcarbazepine 2000 (safety profile similar to CBZ).
Hyponatremia is also problem, however it is less
likely to cause rash than CBZ.
8. Zonisamide 2000
 Voltage-Gated Ca2+ Channel T Currents

• Ethosuximide (Zarontin):

– Mechanism of Action:
• Reduces low threshold Ca2+currents (T currents) in
the thalamic neurons.
• Half-life is ~60 hr in adults; ~30hr in children.
– Indications:
• First line for absence seizures
– Contraindications:
• May exacerbate partial & tonic-clonic seizures
 Voltage-Gated Ca2+ Channel T Currents

• Ethosuximide (Zarontin):
– Adverse Effects:
• Psychotic behavior
• Blood dyscrasias
• Persistent headaches
• Anorexia
• Hiccups
• Lupus-like syndromes

– Toxicity:
• parkinson-like symptoms
• photophobia
 Blockade of Calcium Channels ()
• Gabapentin (Neurontin):

– Mechanism of Action:
• Originally designed to be a centrally acting GABA agonist.
• Selective inhibition of v-g Ca2+ channels containing the
α2δ1 subunit.

– Indications:
• adjunct therapy in adults and children with partial &
secondarily generalized seizures.
• Also effective as monotherapy.
 Blockade of Calcium Channels ()
• Gabapentin (Neurontin):

– Contraindications:
• Can exacerbate myoclonic & absence seizures.
– Adverse Effects:
• Weight Gain (5%) with ankle edema
• Irritability
• Behavioral problems in children (6%)
• Has been associated with movement disorders.
 Blockade of Calcium Channels ()
• Pregabalin (Lyrica):
Mechanism of Action:
• Same as gabapentin
– Indications:
• Approved in 2005
• Adjunct therapy for partial & secondarily
generalized seizures
– Contraindications:
• No effect on absence, myoclonic, or primary
generalized tonic-clonic seizures
– Other uses:
• Prescribed for neuropathic pain, fibromyalgia
 Other/Unknown MOA
• Levetiracetam (Keppra):

– Mechanism of Action:
• Not exactly known
• Binding affinity to Synaptic Vesicle Protein 2A
correlates with its anticonvulsant activity.
• Also blocks calcium channel N-currents, increases
intracellular Ca2+ levels, modulates GABA channel
currents
– Indications:
• Approved in 1999 as an adjunct therapy for adults with
partial seizures.
• Some patients have success with monotherapy
• NEWER AGENTS DIFFER FROM OLDER DRUGS
BY:

= Relatively lack of drug-drug interaction (simple

pharmacokinetic profile)---- Improved
tolerability

HOWEVER THEY ARE:

---- Costly with limited clinical experience
 Lamotrigine

Pharmacological effects:

= Resembles phenytoin in its pharmacological effects

= Well absorbed from GIT
=Metabolised primarily by glucuronidation
= Does not induce or inhibit C. P-450 isozymes ( its
metabolism is inhibitted by valproate )
= Plasma t 1/2 approx. 24 hrs.
 Lamotrigine (cont’d)
• Mechanism of Action:
Inhibits excitatory amino acid release (glutamate &
aspartate ) by blockade of Na channels.

• Uses: As add-on therapy or as monotherapy

• Side effects:
• Skin rash, somnolence, blurred vision, diplopia,
ataxia, headache, aggression, influenza – like
syndrome
 Gabapentin
• Structural analogue of GABA .May increase the
activity of GABA or inhibits its re-uptake.

Pharmacokinetics:
Not bound to proteins
Not metabolized and excreted unchanged in urine
• Does not induce or inhibit hepatic enzymes (similar
to lamotrigine)
• Plasma t ½ 5-7 hours
 Gabapentin ( Cont. )

• Side effects:
• Somnolence, dizziness, ataxia, fatigue and
nystagmus.

• Uses:
• As an adjunct with other antiepileptics
 Topiramate
Pharmacological Effects:
-Well absorbed orally ( 80 % )
-Food has no effect on absorption
-Has no effect on microsomal enzymes
-9-17 % protein bound ( minimal )
-Mostly excreted unchanged in urine
-Plasma t1l2 18-24 hrs
 Topiramate ( Cont. )
• Mechanism of Action:
• Blocks sodium channels (membrane stabilization)
and also potentiates the inhibitory effect of
GABA.

Clinical Uses:
Recently, this drug become one of the safest
antiepileptics which can be used alone for partial
and generalized tonic-clonic, and absence
seizures.
 Topiramate (cont’d)
Side effects:
• Psychological or cognitive dysfunction
• Weight loss
• Sedation
• Dizziness
• Fatigue
• Urolithiasis
• Paresthesias (abnormal sensation )
• Teratogenecity (in animal but not in human)
 Benzodiazepine
• Diazepam: preferred drugs for Status
epilepticus.
• Nitrazepam: petit mal ,especially myoclonic
seizures and infantile spasms.
• Clonazepam: is one of the most effective in
some cases of myoclonic seizures. Used in
petit mal and status epilepticus
 Barbiturates
• Phenobarbital, Luminal: is useful in the treatment
of generalized tonic-clonic seizures and statue
epilepticus.
• Mechanism:(1) block Ca2+ currents presynaptic
membrane and decrease neurotransmitter
release.(2) prolong the openings of the Cl- channel
in postsynaptic membrane and decrease it’s
response.
• Adverse effects: sedation, depression, drug
interaction.
 Drugs and Other Substances that Can
Cause Seizures
Drugs of abuse Psychotropics
• Amphetamine • Antidepressants
• Cocaine • Antipsychotics
• Phencyclidine • Li
• Methylphenidate
Sedative-hypnotic drug
Anesthetics and analgesics withdrawal
• Meperidine • Alcohol
• Tramadol • Barbiturates
• Local anesthetics • Benzodiazepines
 Pharmacokinetic Factors
in the Elderly
 Absorption - little change
 Distribution
– Decrease in lean body mass important for highly
lipid-soluble drugs
– Fall in albumin leading to higher free fraction
 Metabolism - decreased hepatic enzyme
content and blood flow
 Excretion - decreased renal clearance
 Pharmacokinetic Factors
in Pediatrics

 Neonate - often lower per kg doses

– Low protein binding
– Low metabolic rate

 Children - higher, more frequent doses

– Faster metabolism
 Antiepileptics and Pregnany:

– Seizure very harmful for pregnant women.

– Monotherapy usually better than drugs
combination.
– Folic acid is recommended to be given for every
pregnant women with epilepsy
– Phenytoin, sodium valproate are absolutely
contraindicated and oxcarbamazepine is better
than carbamazepine.
– Experience with new anticonvulsants still not
reliable to say that are better than old ones.
 Pharmacokinetics in Pregnancy
 Increased volume of distribution

 Lower serum albumin

 Faster metabolism

 Higher dose, but probably less than predicted by

total level (measure free level)

 Consider more frequent dosing

 Return to pre-pregnancy conditions rapidly (within 2

weeks) after delivery
 Common Causes of Failure of
Antiepileptics
1. Improper diagnosis of the type of seizures
2. Incorrrect choice of drug
3. Inadequate or excessive dosage
4. Poor compliance
Thank you for your attention
 Na+ Channel Drugs
• Phenytoin (Dilantin, Phenytek)
• Cabamazepine (Tegretol, Carbatrol)
• Valproic Acid (Depakene, Depakote)
• Lamotrigine (Lamictal)
• Topiramate (Topamax)
• Zonisamide (Zonegran)
• Lidocaine
 GABA Drugs
• Barbiturates: •Tiagabine (Gabitril)
– Phenobarbital (Luminal)
– Pimidone (Mysoline)
•Valproic Acid (Depakene, Depakote)
• Benzodiazepines: •Topiramate (Topamax)
– Diazepam (Valium)
– Lorazepam (Ativan) •Zonisamide (Zonegran)
– Clonazepam (Klonopin)
– Clorazepate (Tranxene-SD)
Ca2+ Channel Drugs
• Ethosuximide (Zarontin)

• Valproic Acid (Depakene, Depakote)

• Zonisamide (Zonegran)
• Gabapentin (Neurontin)
• Pregabalin (Lyrica)
• Levetiracetam (Keppra)
Primary Generalized Tonic-Clonic (Grand
Mal) Seizures

•Alternatives
• Drugs of Choice:
•Lamotrigine
• Phenytoin •Topiramate
• Carbamazepine •Zonisamide
• Oxcarbazepine •Levetiracetam
• Valproate •Primidone
•Phenobarbital
•Diazepam
 Partial, Including Secondarily
Generalized Seizures

• Drugs of Choice: •Alternatives

• Phenytoin •Lamotrigine
• Carbamazepine •Topiramate
• Oxcarbazepine •Zonisamide
• Valproate •Levetiracetam
•Primidone
•Phenobarbital
•Gabapentin
•Pregabalin
•Tiagabine
 Absence (Petit Mal)

• Drugs of Choice: •Alternatives

• Ethosuximide •Clonazepam
• Valproate •Zonisamide
Atypical Absence, Myoclonic, Atonic Seizures

• Drug of Choice: •Alternatives

• Valproate •Clonazepam
•Topiramate
•Zonisamide
•Levetiracetam