Department of Pharmacology

Shri Ram College of Pharmacy

Banmore

ByYOGENDRA MAVAI

Epilepsy (from the Ancient Greek (epilēpsía) — "seizure") is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or hypersynchronous neuronal activity in the brain. Epilepsy is more likely to occur in young children, or people over the age of 65 years; however, it can occur to anyone at any time..

Epilepsy is usually controlled, but not cured, with medication. However, over 30% of people with epilepsy do not have seizure control even with the best available medications. Surgery may be considered in difficult cases..

Introduction

Epilepsy affects about 0.5% of the population.

The characteristic event is the seizure, which is often associated with convulsion, but may occur in many other forms.

The seizure is caused by an abnormal high-frequency discharge of a group of neurons, starting locally and spreading to a varying extent to affect other parts of the brain.

Seizures may be partial or generalised depending on the location and spread of the abnormal neuronal discharge. The attack may involve mainly motor, sensory or behavioural phenomena. Unconsciousness occurs when the reticular formation is involved.

Partial seizuresThe discharge begins locally, and often remains localised. Produce relatively simple symptoms without loss of consciousness.

• Two major categories, namely partial and generalised seizures; there is some overlap and many varieties of each.

Generalised seizuresInvolve the whole brain, including the

reticular system, thus producing abnormal electrical activity throughout both hemispheres. Immediate loss of consciousness.

Tonic-clonic=stiffening of the limbs-jerking of the limbs and face

Myoclonic seizures are rapid, brief contractions of bodily muscles (1 arm & 1 foot), sudden jerk of a foot during sleep

Atonic seizures (drop attacks, astatic or akinetic seizures )= loss of muscle tone,head drops, loss of posture or sudden collapse

Tonic seizures =stiffness or rigidity in all muscles,a fall with injuries (sleep and are resistant to drug therapy).

Infantile Spasms (myoclonic-tonic seizures) = repetitive seizures by quick, sudden movements

Two common forms of generalised epilepsy are the tonic-clonic fit (grand mal) and the absence seizure (petit mal). Status epilepticus is a life- threatening condition in which seizure activity is uninterrupted.

Repeated epileptic discharge can cause neuronal death (excitotoxicity).

Current drug therapy is effective in 70-80% of patients.

Chemical-induced: Pentylenetetrazole, Kainic Acid,

Maximal electrochock

Kindling

Animal Models of Seizures

Idiopathic: genetic abnormalities

Symptomatic : effects of an epileptic lesion

Cryptogenic: presumptive lesion that is otherwise difficult or impossible to uncover during evaluation.

Epilepsy syndromes are further divided by presumptive cause:

There are over 40 different types of epilepsy, including: benign Rolandic epilepsy, frontal lobe epilepsy, infantile spasms, juvenile myoclonic epilepsy, juvenile absence epilepsy, childhood absence epilepsy (pyknolepsy), hot water epilepsy, Lennox-Gastaut syndrome, Landau-Kleffner syndrome, mitochondrial disorders, progressive myoclonic epilepsy, reflex epilepsy, Rasmussen's syndrome, temporal lobe epilepsy, limbic epilepsy, status epilepticus, abdominal epilepsy, massive bilateral myoclonus, catamenial epilepsy, Jacksonian seizure disorder, Lafora disease, photosensitive epilepsy, etc.

During the neonatal period and early infancy -hypoxic-ischemic encephalopathy, CNS infections, trauma, congenital CNS abnormalities, and metabolic disorders.

During late infancy and early childhood, febrile seizures are fairly common -CNS infections and trauma.

During childhood, well-defined epilepsy syndromes are generally seen.

During adolescence and adulthood-CNS lesion, Other causes are stress, trauma, CNS infections, brain tumors, illicit drug use and alcohol withdrawal.

In older adults, cerebrovascular disease is a very common cause. Other causes are CNS tumors, head trauma, and other degenerative diseases that are common in the older age group, such as dementia.

Etiology

Mutations in several genes have been linked to some types of epilepsy. Several genes that code for protein subunits of voltage-gated and ligand-gated ion channels have been associated with forms of generalized epilepsy and infantile seizure syndromes.

One speculated mechanism for some forms of inherited epilepsy are mutations of the genes that code for sodium channel proteins; these defective sodium channels stay open for too long, thus making the neuron hyper-excitable.

Pathophysiology

Glutamate, an excitatory neurotransmitter, may, therefore, be released from these neurons in large amounts, which — by binding with nearby glutamatergic neurons { located in hippocampus)

— triggers excessive calcium (Ca2+) release in these post-synaptic cells. Such excessive calcium release can be neurotoxic to the affected cell.

Another possible mechanism involves mutations leading to ineffective GABA (the brain's most common inhibitory neurotransmitter) action. Epilepsy-related mutations in some non-ion channel genes have also been identified.

Epileptogenesis is the process by which a normal brain

develops epilepsy after trauma, such as a lesion on the brain.

One interesting finding in animals is that repeated low-level

electrical stimulation to some brain sites can lead to permanent

increases in seizure susceptibility: in other words, a permanent

decrease in seizure "threshold." This phenomenon, known as

kindling (by analogy with the use of burning twigs to start a

larger fire) was discovered by Dr. Graham Goddard in 1967.

The Interictal Spike (paroxysmal depolarization shift)

Increased excitability

Membrane depolarization, potassium buildup

Increased excitatory (EAA, glutamate) input

Decreased inhibitory (GABA) input

In short

Increased EAA•Increased Excitatory Amino Acid Transmission

•Increased sensitivity to EAA

•Progressive increase in glutamate release during kindling

•Increased glutamate and aspartate at start of seizure

•Upregulation of NMDA receptors in kindled rats

Decreased GABA•Decreased binding of GABA and benzodiazepines

•Decreased Cl- currents in response to GABA

•Decreased glutamate decarboxylase activity (synthesizes GABA)

•Interfere with GABA causes seizures

Evidence for the Pathophysiology of Seizures

The mainstay of treatment of epilepsy is anticonvulsant medications. Often, anticonvulsant medication treatment will be lifelong and can have major effects on quality of life. The choice among anticonvulsants and their effectiveness differs by epilepsy syndrome.

Availability - Currently there are 20 medications approved by the Food and Drug Administration for the use of treatment of epileptic seizures in the US

Medications

•Stabilize membrane and prevent depolarization by action on ion channels

•Increase GABAergic transmission

•Decrease EAA transmission

Strategies in Treatment

Current antiepileptic drugs are thought to act mainly by two main mechanisms:

Reducing electrical excitability of cell membranes, possibly through inhibition of sodium channel.

Enhancing GABA-mediated synaptic inhibition. This may be achieved by an enhanced pre- or post- synaptic action of GABA, by inhibiting GABA-transaminase, or by drugs with direct GABA-agonist properties.

A few drugs appear to act by a third mechanism, namely inhibition of T-type calcium channels.

Newer drugs act by other mechanism, yet to be elucidated.

Drugs that block excitatory amino acid receptors are effective in animal models, but not yet developed for clinical use.

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).

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.

Antiseizure: used in the treatment of grand mal epilepsy and tonic-clonic seizure disorders, not in absence seizures.

Antiarrhythmias

Gastrointestinal irritation Ataxia Blood dyscrasias. Gingival hyperplasia, increased collagen

proliferation.

Hepatitis. Drug interactions: increased plasma

concentrations of phenytoin can occur by concurrent administration of chloramphenicol, isoniazid, cimetidine, zdicumarol, et al.

Derivative of tricyclic antidepressants

Similar profile to that of phenytoin, but with fewer unwanted effects

Effective in most forms of epilepsy (except absence seizures); particularly effective in psychomotor epilepsy; also useful in trigeminal neuralgia and mania.

Strong inducing agent; therefore many drug interactions

Low incidence of unwanted effects; principally sedation, ataxia, mental disturbances, water retention

Valproate is very effective against absence seizure.

Mechanism: facilitate glutamic acid decarboxylase; inhibit GABA-transaminase; enhance synaptic responses. some effect on sodium channels

Relatively few unwanted effects: anorexia, nausea, teratogenicity, liver damage (rare, but serious)

The main drug used to treat absence seizures, may exacerbate other forms

Acts by blocking T-type Ca2+-channels Relatively few unwanted effects, mainly

nausea and anorexia. (mental disturbances)

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

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.

Tonic-clonic (grand mal) seizures: carbamazepine preferred because of low incidence of side-effects, phenytoin, valproate. Use of single drug is preferred when possible, because of risk of pharmacokinetic interactions.

Partial (focal) seizures: carbamazepine, valproate; clonazepam or phenytoin are alternatives.

Absence seizures (petit mal): ethosuximide or valproate. Valproate is used when absence seizures coexist with tonic-clonic seizures, since most drugs used for tonic-clonic seizures may worsen absence seizures.

Myoclonic seizures: valproate or clonazepam.

Status epilepticus: must be treated as an emergency, with diazepam intravenously.

Epilepsy surgery is an option for patients whose seizures remain resistant to treatment with anticonvulsant medications who also have symptomatic localization-related epilepsy; a focal abnormality that can be located and therefore removed. The goal for these procedures is total control of epileptic seizures, although anticonvulsant medications may still be required.

Surgery

Methods of anticonvulsant treatment are both currently approved for treatment and investigational uses. A currently approved device is vagus nerve stimulation (VNS). Investigational devices include the responsive neurostimulation system (RNS) and deep brain stimulation (DBS).

Electrical stimulation

Selection of an appropriate antiseizure agent

Use of single drug Withdrawal Toxicity Fetal malformations