ANTIEPILEPTIC

EPILEPSY

Epilepsy is a very common disorder. affecting approximately 0.5% of the population.

Cause: Usually there is no recognizable cause, although it may develop as a consequence of various kinds of brain damage, such as trauma, infection or tumor growth.

The characteristics event in epilepsy is the seizure, which is associated with the episodic high frequency discharge of impulses by a group of neurons in the brain; spread to other areas of the brain.

Classification of Epilepsy

The site of the primary discharge and the extent of its spread determines the symptoms that are produced. Depending on the symptoms epilepsy is classified into two broad groups: namely, partial seizures and  generalized seizures.

A. Generalized seizures:

Site: Generalized seizures involve the whole brain , including the reticular system (center of consciousness), thus producing abnormal electrical activity throughout both hemispheres (of cortex). Immediate loss of consciousness is characteristic of generalized seizure.

(i)Grand mal (major epilepsy or tonic-clonic seizures)

Symptoms:

Tonic phase

·         A Tonic-clonic seizure consist of an initial, strong contraction of the whole musculature, causing a rigid-extensor spasm.

·         Respiration stops and defecation, micturation and salivation often occur.

·         This toxic phase lasts for about 1 minute.

Clonic phase:

Tonic phase is followed by a series of violent, synchronous jerks gradually dies out in 2-4 minutes.

The patient stays unconscious for a few minutes and then gradually recovers, feeling ill and confused.

Electro-encephalogram of brain:

                                                normal

                                                tonic

                                                clonic

(ii) Petit mal (minor epilepsy / absence seizures)

Absence seizures occur in children. They are much less dramatic, but may occur more frequently (many seizures a day).

Symptoms:

The patients abruptly ceases whatever he was doing, sometimes stopping speaking in mid-sentence, and stares vacantly for a few seconds, with little or no motor disturbances (i.e. no convulsion).

The patient is unaware of his surrounding ( a kind of unconsciousness) and recovers abruptly with no after effects.

EEG (Electro Encephalogram) pattern:

                                                normal

                                                petitmal

(iii) Akinetic (atonic seizures)

Unconscious with relaxation of all muscles due to excessive inhibitory discharges. Patient may fall.

B. Partial Seizures:

Partial seizures are those in which the discharge begins locally, and often remain localized. These may produce  relatively simple symptoms without loss of consciousness.

(i) Cortical focal epilepsy: (Jacksonial epilepsy)

Symptoms:

Repetitive jerking of a particulate muscle groups which spreads and may involve much of the body within 2 minutes. No voluntary control over the body.

No loss of consciousness.

(ii) Psychomotor epilepsy

Site: the focus is in the temporal lobe.

Symptoms: The attack may consist of stereotyped purposive movements such  as rubbing or patting movements, or much more complex behavior such as dressing or walking or hair-combing.

the seizure usually lasts for a few minutes, after which the patient recovers with no recollection of the events.

Mode of action of antiepileptic drugs:

Two main mechanisms appear to be important:

(i) enhancement of GABA action (e.g. barbiturates, benzodiazepines)

(ii) inhibition of sodium channel function.

A. Enhancement of GABA action:

(i) Many of the clinically effective anticonvulsants (e.g. phenobarbitone and benzodiazepine) when binds with the GABA-benzodiazeoine-chloride-channel receptor complex

®        enhance the affinity for GABA to its receptor site

®        opens chloride channel

®        inhibitory impulse is prolonged

(ii) A recently introduced drug, Vigabatrin acts by inhibiting GABA-transaminase which is responsible for inactivating GABA - thereby  increasing the GABA content of the brain.

Valproate also has GABA-transaminase-inhibiting effects.

B. Inhibition of sodium channel function

(e.g. phenytoin and carbamazepine)

They affect membrane excitability by an action on voltage-dependent sodium channel which carry the inward membrane current necessary for the generation of action potential.

Their blocking action shows the property of use-dependent i.e. they block preferentially the excitation of cells that are firing respectively, and the higher the frequency of firing, the greater the block produced.

Hence, these drugs block the high frequency discharge that occurs in an epileptic fit without unduly interfering with the low frequency firing of neurons in the normal state.

There are three state of sodium channels - resting, open and inactivated states. Phenytoin and carbamazepine bind preferentially to the channels inactivate state, thus preventing them from returning to the resting state, and thus reducing the number of functional channels available to generate action potentials.

They limits spread of seizure activity.

CLASSIFICATION OF ANTIEPILEPTIC DRUGS

Classification is base on chemical structure:

1.      Barbiturates:                      Phenobarbitone, Mephobarbitone, Primidone

2.      Hydantoin:                         Phenytoin, Mephenytoin

3.      Iminostilbine:                     Carbamazepine

4.      Oxazoladinedione:             Trimethodione (Troxidone)

5.      Succinimide:                      Ethosuximide

6.      Aliphatic carboxylic acid:  Valproic acid

7.      Benzodiazepines:               Clonazepam, diazepam

8.      Newer drugs:                     Progabide, Vigabatrin, Gabapentin, Lomotrigine.

PHENYTOIN

Pharmacology:

On CNS

Phenytoin is not a CNS depressant; some sedation occurs at therapeutic doses, but this does not increase further with dose; rather toxic doses produce excitement.

It abolishes tonic phase generated by electric shock but have no effect on clonic phase. It limits the spread of seizure activity.

On CVS

It is found to produce bradycardia (heart going slow), prolong PR interval, and produce T-wave abnormalities on electrocardiogram (ECG). Phenytoin is used in digitalis-induced arrhythmias. It causes depression of ventricular automaticity produced by digitalis, without adverse intraventricular conduction. Because it also reverses the prolongation of AV conduction by digitalis, phenytoin is useful in supraventricular tachycardias caused by digitalis intoxication.

Adverse effects:

These are numerous.

At therapeutic levels:

(a)    Hyperplasia of gums which is disfiguring rather than harmful, often develops gradually - occurs more in young patients, can be minimized by maintain oral hygiene.

(b)   Hirsutism (abnormal hair growth) coarsening of face (troublesome in young girls), acne - etc. which probably results from increased androgen activity.

(c)    Hypersensitivity reactions are - rashes, neutropenia is rare but requires discontinuous of therapy.

(d)   Megaloblastic anaemia - phenytoin decreases folate absorption and increases its excretion. This can be connected by giving folic acid.

(e)    Osteomalacia desensitizes target tissues to Vit D and interferes with calcium metabolism.

(f)    It may inhibit insulin release and cause hyperglycemia.

(g)    Used during pregnancy- may produce foetal malformations in children born to epileptic mother.

At high plasma levels (dose related toxicity):

(a)    Cerebellar and vestibular manifestations:- e.g. ataxia, vertigo etc.

(b)   Drowsiness, behavioral alterations, rental confusions and hallucination.

(c)    nausea, vomiting - it can be minimized by taking with meal.

(d)   Intravenous injection can cause local vascular injury edema and discoloration of injected limb. Rate o injection should not exceed 25 mg/min.

(e)    Fall in blood pressure and cardiac arrhythmias occur only on i.v. injection.

Uses

1.      Grand mal, cortical focal and psychomotor epilepsy. It is ineffective in petit mal.

2.      Status epilepticus: Occasionally used by slow i.v injection.

3.      Trigeminal neuralgia - second by a carbamazepine.

4.      Cardia arrhythmias - specially digitalis induces.

N.B. Status epilepticus

It is the continuous clinical manifestation of an epileptic discharge without intermission. Recurrent tonic-clonic convulsions without recovery of consciousness is an emergency; fits have to be controlled as quickly as possible.

Treatment:

(a)    Diazepam 10 mg i.v. bolus injection (2 mg/min) followed by slow infusion titrated to control the fits is the therapy of choice. Clonazepam (1-2 mg i.v.) is an alternative.

(b)   Phenobarbitone (100-200 mg i.m.) or phenytoin (25 mg/min i.v., maximum 1 g) act more slowly; may be substituted after the convulsions have been controlled.

(c)    Paraldehyde (5-10 m deep i.m. or 16 ml per rectum) may be used if i.v. injection is difficult.

(d)   a general anaesthetic and curarization with positive pressure respiration may be required in cases not responding to the above drugs.

(e)    General measures including maintenance of air way, oxygenation, fluid and electrolyte balance, BP, normal cardiac rhythm and care of the unconscious must be taken.

TREATMENT OF EPILEPSIES

The choice of anti-convulsant drug and dose is given according to the seizure type(s) and need of the individual patient.

Type of seizures	First choice	Second choice	Alternatives
1.       Generalized tonic-clonic (grand mal) & simple partial (cortical focal) 2.       Absence (petit mal) 3.       Complex partial (Psychomotor) 4.       Akinetic 5.       Febrile seizures 6.       Status epilepticus	Phenytoin, Carbamazepine Valproate Carbamazepine Valproate Diazepam(rectal) Diazepam(i.v.)	Phenobarbitone, Valproate Ethosuximide Valproate, Phenytoin Primidone - Phenytoin(i.v.) Phenobarbitone(i.m.)	Primidone, Vigabatrin Clonazepam, Troxidone Primidone, Vigabatrin Clonazepam Phenobarbitone Clonazepam, Paraldehyde