EPILEPSY

AND
ANTICONVULCSANT
(ANTIEPILEPTIC) DRUGS
Pharmacotherapy of the epilepsies
Seizure: Transient alteration of behaviour Due to
Disordered synchronous rhythmic of Brain
neurones
Epilepsy: Disorder of brain function characterized
by periodic, unpredictable occurrence of seizures
Seizures Non-epileptic- Evoked in normal brain
by electroshock or chemical convulsants
Seizures Epileptic- When occuring without
provocation*
CAUSES OF EPILEPSY
- Genetic Factors
- Antenatal and birth factors congenital
abnormalities
- Infection meningitis, viral encephalitis
- Toxic factors lead and mercury poisoning
- Drug withdrawal abrupt cessation of CNS
depressants
- Cerebral injury
- Metabolic disorders
- Hypoxia, hyperpyrexia, hypoglycemia


CLASSIFICATION of Epipepsy : Major Seizure Types
I. Partial (focal, local) seizures
A. Simple partial seizures - Seizures may be limited to a
single limb or muscle group, may show
sequential involvement of body parts.
Consciousness is usually preserved;
B. Complex partial - seizures (psychomotor epilepsy,
temporal lobe epilepsy)
Impairment of consciousness, may have autonomic
activity such as pupil dilation, flushing, piloerection,
etc.
C. Partial seizures (evolving to secondary generalized
seizures)

May generalize to tonic, clonic, or tonic-clonic
II. Generalized seizures
A. Absence seizures (Petitmal epilepsy) - Brief loss of
consciousness, with or without motor
involvement; occurs in childhood with a
tendency to disappear following adolescence
B. Myoclonic seizures (Myoclonus)
Sudden, brief, shock like contractions of musculature
(myoclonic jerks) usually of the upper extremities.
C. Clonic seizures - Repetitive muscle jerks
D. Tonic seizures - Rigid, violent muscular contraction with
limbs fixed
TONIC-CLONIC - Generalized seizures usually start with tonic
and thereafter progress to clonic rhythmic contractions.
Clonic subsides after several min. Regain consciousness.

E. Tonic-clonic seizures (grand mal epilepsy)-
Loss of consciousness; sudden sharp tonic
contractions of muscles, falling to ground,
followed by clonic convulsive movements; depression
and incontinence
F. Atonic seizures (astatic) - Sudden diminution in
muscle tone affecting isolated muscle groups, or
loss of all muscle tone; may have extremely brief
loss of consciousness
STATUS EPILEPTICUS- dogs

II. Generalized seizures
EPSP &IPSP
EPSP
Opening-Na+ channels
Cond. Of Cl-channels
Cond.of K+channels
Changes in int.metabolism
IPSP
Opening Cl-channels
Cond. K+chnnels
Activation of enzymes-those
inhibitory rec. or that Exc.rec.
ANTICONVULSANT DRUGS

Mechanism of action of anticonvulsant drugs

1. Reduce excitability of cell membranes via use-
dependent block of sodium channels

2. Enhance inhibitory GABAergic transmission

3. Inhibition of calcium channels

CNS DEP: Sedation Sleep Unconciousness SA Dep. Of CVS & RS
Death
Clinical classification of anti-seizure drugs
Seizure type Conventional New drugs
1. SPS





2. CPS

3. Partial.
generalized
1. Carbamazapine
2. Phenytoin
3. Valproate



Same as above

Carbamazapine
Phenobarbitone
Phenytoin
Primidone
Valproate

Gapapentine
Lamotrigine
Levetiracetam
Tiagabine
Topiramate
Zonisamide
Same as above


Same as above

Clinical classification of anti-seizure drugs
Seizure type Conventional New drugs
Absence


Myoclonic


Tonic-clonic
Ethosuximide
Valproate

Valproate

Carbamazapine
Phenobarbitone
Phenytoin
Primidone
Valproate
Lamotrigine


Lamotrigine
Topiramate

Lamotrigine
Topiramate
Clinical classification of anti-seizure drugs
Seizure Drugs Second choice
Febrile


Status
epilepticus
Diazepam rectal


Diazepam i.v.
Lorazepam i.v.



Fosphenytoin i.v.
Pheno i.v.
Movie!
MOA of antiseizure drugs
Reduce excitationReduce EPSP Enhance Na
or Ca channel inactivation

Carbamazapine Lamotrigine
Phenytoin Valproate
Topiramate Zonisamide
Valproate
Ethosuximide
Trimethadione
MOA of antiseizure drugs
Promote inhibition Promote IPSP Enhance
GABA transmission [Cl channels]
BZD
GABA
binding sites

Barbiturates
GABA
GABA-T
Succinic semialdehyde
Dehydrogenase
Metabolites
GAT-1
GABA
Vigabatrine
Valproate
Tiagabine
Guidelines to drug therapy
Start with single, well tried safe drug
According to type of seizure
Age, sex-Hirsutism, terratogenicity, hepatitis
Single drug Failure SUBSTITUTE with
second[difft.MOA] withdrawal of First gradual
Three drug hardly useful
Dosage increased at particular time*
BARBITURATES and BENZODIAZEPINES
Phenobarbitione, pentobarbitone, Mephobarbitone,
Secobarbitone
Potentiate inhibitory GABAergic transmission
increasing the duration or frequency of chloride
channel opening.
used for the treatment of status epilepticus.
Treatment must be initiated rapidly.
Intravenous diazepam is the treatment of choice
Other possibilities if benzodiazepines fail include
intravenous phenytoin, Phenobarbital or general
anaesthesia.
Benzodiazepines
Clonazepam Absence & Myoclonic
Diazepam & Lorazepam S tatus epilepticus
Clobazam, Clorazepate + Other drugs Partial seizures
Diazepam:
Not used in long term[Sedation, tolerance]
Control of convulsions[Epilepsy & others]
0,2-0.5mg/kg slow i.v. 100mg/day
ADE-Fall of BP, Resp.dep.,
Rectally in children-Febrile
Lorazepam: 0.1mg/kg-i.v.-Long duration*
PHENYTOIN
This is the oldest non-sedative anticonvulsant drug
and is still one of the most widely used.
Mechanism of action: At therapeutic levels, the
main action of phenytoin is to block sodium
channels and inhibit the generation of repetitive
action potentials.
Pharmacokinetics: Effective after oral administration.
Absorption is almost complete in most patients. It is
highly bound to plasma proteins. Metabolism in
the liver is by hydroxylation followed by conjugation
with glucuronic acid. The metabolites are
excreted in the urine.
PHENYTOIN
Drug Interactions-Phenytoin
Pheno & Phenytoin: Both induce enzymes metabolism of each
other Result unpredictable
CBMZP & Phenytoin Induce each others metabolism
Valproate Displaces phenytoin Also decreases metabolism!
Phenytoin toxicity
Chloromphenicol, Cimetidine etc. inhibit Phenytoin metabolism
Phenytoin inhibits Warfarin metabolism
OCP and Phenytoin*
Uses:
1. Treatment of generalized tonic-clonic seizures
and partial seizures
2. Treatment of disturbed psychotic patients
without epilepsy
3. Cardiac arrhythmias
Side effects:
These are usually dose-related.
1. Gingival hyperplasia, hirsutism, nystagmus, ataxia
2. Coarsening of facial features and osteomalacia
3. Blood dyscrasias eg aplastic anaemia

PHENYTOIN
PRIMIDONE
2-deoxy analogue of phenobarbitone
hepatotoxic withdrawn

BROMIDES
Sodium, Potassium, Ammonium bromide salts
Bromism- bromide accumulation toxicity
adverse effect



Ethosuximide
Reduces Ca flow in T type Ca channels
Reduces 3Hz spikes[EEG] from thalamus
neurones
Effective in absence seizures only[ No action
on Na and GABA]
ADE- GI, Behavioral effects[Anxiety, inability
to concentrate)
CARBAMAZEPINE
Acts by blocking voltage-gated sodium channels (binds to
sodium channels in the inactive state).
orally active and bound (75%) to plasma proteins. It has
antidepressant properties.
Slows rate of recovery of inactivated Na channels Prevents
repetitive firing of AP.
Ph.effects: Similar to phenytoin
Antidiuretic effect*
Uses: Carbamazepine is used for tonic-clonic and partial
seizures. It is also used in pain and manic depression.
Side effects include:
1. induction of liver enzymes
2. ataxia
3. diplopia
4. aplastic anaemia (not very common)
VALPROIC ACID
Valproic acid acts by:
1. Hyperpolarizing neuronal membranes through an
action on potassium channels.
2. Blocking sodium channels (in the inactive state).
3. Increasing GABA levels by inhibiting GABA-T
It is used for tonic-clonic and partial seizures
Side effects include:
1. ataxia
2. diarrhea
3. induction of liver enzymes and hepatic failure
4. Gastric irritation
5. teratogenicity

NEWER ANTICONVULSANT DRUGS
Lamotrigine:
Developed as antifolate agent, Anticonvlsant axction-not
related to antifolate
Suppresses repetitive action potentials by blocking sodium
channels in a use-dependent manner.
inhibits the release of glutamate.
used for tonic-clonic and partial seizures.
Side effects- blurred vision and GIT upset.
Tiagabine:
prevents reuptake of GABA thus raising GABA levels.
used for partial Seizures.
Others: Levetiracetam, Topiramate, Felbamate, Zonisamide
NEWER ANTICONVULSANT DRUGS
Vigabatrin:
Acts as an irreversible inhibitor of GABA-T and therefore
prevents degradation of GABA leading to elevated
levels of GABA.
It is used for Partial and infantile seizures.
Gabapentin:
Increases neuronal release of GABA.
It is used as an adjunct in patients with partial seizures.
Side effects include ataxia, dizziness and fatigue.