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.