Anti-epilepsy Agents

Epilepsy
 Neurologic disorder characterize by
recurring seizures
 Due to sudden, excessive and synchronous
discharge of cerebral neurons
 Seizure is a brief, temporary disturbance in
electrical activity of brain
 Seizure is symptom of epilepsy
Neurological dysfunction
 Begin at birth(hypoxia,
CNS infections)
 Childhood(trauma)
 Adolescence(stress,
illicit drug use)
 Older adult(CNS tumors,
degenerative diseases)
Epilepsy
 1 person in 20 will have an epileptic seizure at some
time in their life

 Epilepsy is diagnosed on the basis of two or more

epileptic seizures.

 A seizure is triggered by a sudden interruption in the

brain's highly complex electro-chemical activity
Age/Incidence
Structure
Synapse Activity
Normal Synaptic transmission
Symptoms of epilepsy
Symptoms depends on site of origin.

Motor cortex

Occipital lobe
Symptoms of epilepsy

Frontal lobe

Parietal lobe
 Types of epilepsy
1- Idiopathic epilepsy
2- Symptomatic epilepsy

Idiopathic epilepsy:
• When no specific anatomic cause for the seizure.
• Such as trauma or neoplasm is evident.
• Also called as Cryptogenic (primary) epilepsy.
• These seizures may result from an inherited abnormality
in CNS.
• Most cases of epilepsy are idiopathic.
Symptomatic epilepsy
• When two or more seizures occur, the patient may be
diagnosed with symptomatic epilepsy.
• Also called as secondary epilepsy.
Causes
• Illicit drug use, tumor, head injury, hypoglycemia
• Meningeal infection
• Rapid withdrawal of alcohol from an alcoholic
Treatmet
• Chronic treatment with antiseizure medication
• Vagal nerve stimulation
• Surgery
These treatments may be used alone or in combination.
 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
 Photo epilepsy
 TRIGGERS:
• Fatigue
• Stress
• Poor nutrition
• Alcohol
• Sleep deprivation
Seizures
 Seizures are a symptom of an underlying
CNS dysfunction
 It is an abnormal, uncontrolled electrical
discharge from neurons
 Cell membrane disruptions (permeability)
 Altered ion distributions (chemical balance)
 Decreased neurotransmitters (Ach and GABA)
 Everyone has seizure threshold
A) Focal or partial
1) Simple partial( Jacksonian )- The electrical discharge is cofined to the
motor area.
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.
Basis of Pharmacological Rx
Most anti-epileptic agents act either by blockade
of depolarisation channels (Na+ and Ca++)

OR

Enhancing the activity of GABA

(neurotransmission inhibition)
 Phenytoin
Pharmacokinetics
 Well absorbed when given orally, however, it is also available as iv. (for emergency)

 80-90% protein bound

 Induces liver enzymes (Very Important)

 Metabolized by the liver to inactive metabolite

 Excreted in urine as glucuronide conjugate

 Plasma t ½ approx. 20 hours

 Therapeutic plasma concentration 10-20 µg/ml (narrow)

 Dose 300-400 mg/day

 Phenytoin ( Cont. )
Mechanism of Action:
Membrane stabilization by blocking Na & Ca influx
into the neuronal axon.
or inhibits the release of excitatory amino acids via
inhibition of Ca influx
Clinical Uses:
Used for partial Seizures & generalized tonic-clonic
seizures. But not effective for absence Seizures .
Also can be used for Rx of ventricular fibrillation.
Side effects of phenytoin (Cont.)

Dose Related:
 G.I.T upset
 Neurological like headache, vertigo,
ataxia, diplopia, nystagmus
 Sedation
Side effects of Phenytoin ( Cont. )
Non-dose related:
 Gingival hyperplasia
 Hirsutism
 Megaloblastic anaemia
 Hypersensitivity reactions (mainly skin rashes and lesions,
mouth ulcer)
 Hepatitis –rare
 Fetal malformations- esp. cleft palate
 Bleeding disorders (infants)
 Osteomalacia due to abnormalities in vit D metabolism
 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.
Metabolized by the liver to CBZ 10.11-epioxide(active) and
CBZ -10-11-dihydroxide (inactive)
 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)
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
 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
Sodium valproate ( cont. )

Mode of action
 May be due to increase in GABA content of the brain
 Blockade of Na+ and T-type calcium channels
 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)
Newer Antiepileptic Drugs
( Second- Generation )
1. Gabapentin
2. Lamotrigine
3. Topiramate
4. Tiagabine
5. levetiracetam
6. Oxcarbazepine
7. Felbamate
8. Ethosuximide
9. Pregabalin
10. Primidone
11. Zonisamide
 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 inhibited by valproate )
Plasma t 1/2 approx. 24 hrs.
 Mechanism of Action:
blocks sodium channels as well as calcium channels
 Uses: As add-on therapy or as monotherapy

 Side effects:
 Skin rash, 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
 Mechanism of Action:
 Blocks sodium channels (membrane stabilization)
and also potentiates the inhibitory effect of GABA.
Topiramate ( Cont. )
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)
Zonisamide
sulfonamide derivative that has a broad spectrum
of action.
Pharmacokinetics:
 Well absorbed from GIT (100 %)
 Protein binding 40%
 Extensively metabolized in the liver
 No effect on liver enzymes
 Plasma t 50 -68 hrs
½
Mechanism
blockade of both voltage-gated sodium channels and T-type
calcium currents
Zonisamide
Clinical Uses:
Add-on therapy for partial seizures
Side Effects:
Drowsiness, ataxia , headache, loss of appetite,
nausea& vomiting
 Tiagabine
 Adjunctive therapy in partial and generalized tonic-clonic seizures

 Pharmacological effects
 Bioavailability > 90 %

 Highly protein bound ( 96% )

 Metabolized in the liver

 Plasma t ½ 4 -7 hrs


Mode of action:
 inhibits GABA uptake and increases its level
Tiagabine cont’d
 Side effects:
 Asthenia
 Sedation
 Dizziness
 Mild memory impairment
 Abdominal pain
Ethosuximide
 inhibits T-type calcium channels
 effective in treating only primary generalized
absence seizures
 Use of ethosuximide is limited because of this
very narrow spectrum
Felbamate
 It has broad spectrum of anticonvulsant action
 multiple proposed mechanisms including 1)
blocking voltage-dependent sodium channels,
2) competing with the glycine-coagonist
binding site on the N-methyl-D-aspartate
(NMDA) glutamate receptor, 3) blocking
calcium channels, and 5) potentiation of
GABA actions
Felbamate
 reserved for use in refractory epilepsies
(particularly Lennox-Gastaut syndrome)
because of the risk of aplastic anemia (about
1:4000) and hepatic failure
Levetiracetam
 is used as adjunct therapy of partial onset
seizures, myoclonic seizures, and primary
generalized tonic-clonic seizures in adults and
children
 exact mechanism of anticonvulsant action is
unknown
 high affinity for a synaptic vesicle protein
(SV2A)
Levetiracetam
 drug binds to a synaptic vesicle glycoprotein, SV2A,
and inhibits presynaptic calcium channels 
 impede impulse conduction across synapse
 Pharmacokinetics:
 well absorbed orally, and excretion is urinary
 does not interact with CYP or UGT metabolism
systems
 Side effects include dizziness, sleep disturbances,
headache, and weakness
Oxcarbazepine
 is a prodrug that is rapidly reduced to the 10-
monohydroxy (MHD) metabolite which is
responsible for its anticonvulsant activity
 MHD blocks sodium channels preventing the
spread of the abnormal discharge
 May also blocks calcium channel
 approved for use in adults and children with
partial onset seizures
Common Causes of Failure of
Antiepileptics
1. Improper diagnosis of the type of seizures
2. Incorrect choice of drug
3. Inadequate or excessive dosage
4. Poor compliance
Lacosamide
 In-vitro affects voltage-gated sodium channels,
resulting in stabilization of hyperexcitable neuronal
membranes and inhibition of repetitive neuronal
firing.
 Binds to collapsin response mediator protein2
(CRMP-2), a phosphopro-growth.
 Role of (CRMP-2) binding in seizure control is
[Link] is approved for adjunctive
treatment of focal [Link] in injectable
formulation.
Benzodiazepines
 Bind to GABA inhibitory receptors to reduce firing
rate. Most benzodiazepines are reserved for
emergency or acute seizure treatment due to
tolerance.
 However, clonazepam and clobazam may be
prescribed as adjunctive therapy for particular types
of seizures.
 Diazepam is also available for rectal administration
to avoid or interrupt prolonged generalized tonic-
clonic seizures when oral administration is not
possible.
Phenobarbital
 Primary mechanism of action of
phenobarbital is enhancement of the
inhibitory effects of GABA-mediated
neurons.
 Phenobarbital is used primarily in the
treatment of status epilepticus when other
agents fail.
Pregabalin
 Binds to the alpha2-gamma site, an auxiliary subunit
of voltage-gated calcium channels in the CNS,
inhibiting excitatory neurotransmitter release.
 The exact role that it plays is unknown, but the drug
has proven effects on focal-onset seizures, diabetic
peripheral neuropathy, postherpetic neuralgia, and
fibromyalgia.
 More than 90% of pregabalin is eliminated renally.
Dosage adjustments are needed in renal dysfunction.
 Few drug interactions. Weight gain and peripheral
odema have been reported
Rufinamide
 Acts at sodium channels. Approved for the adjuctive
treatment of seizures associated with Lennox-
Gastuat syndrome in children over 4 years and in
adults.
 Weak inhibitor of CYP2E1 and aweak inducer of
CYP3A4 enzymes. Food increases absorption and
peak serum concentrations. Serum concentrations
are affected by other antiepilepsy medications.
 Adverse effects include the potential for shortened
QT intervals. Patients with familial short QT
syndrome should not be treated with rufinamide
Vigabatrin
 Acts as an irreversible inhibitor of gabba-
aminobutyric acid transaminase (GABA-T), is the
enzyme responsible for metabolism of GABA.
 Vigabatrin is associated with visual field loss
ranging from mild to severe in 30% or more of
patients.
 Only available through physicians and pharmacies
that participate in the restricted distribution SHARE
program
 Antiepeliptics 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.
Vagal Nerve Stimulation
What is VNS Therapy?
The VNS Therapy System consists
of an implanted pacemaker-like
generator and nerve stimulation
electrodes, which deliver
intermittent stimulation to the
patient’s left vagus nerve that sends
signals to the brain.
 It is an alternative for patients who have been
refractory to multiple drugs, who are sensitive
to the many adverse effects of antiseizure
drugs, and who have difficulty adhering to
medication schedules
 Vagal nerve stimulation requires invasive
procedure and is expensive
What is the pulse generator?