ANTISEIZURE DRUGS

OR

Antiepileptic drugs

Epilepsy Chronic disorder characterized by recurrent seizures

Seizures is a sudden, excessive, abnormal discharge of cerebral neurons

Causes of seizures Heredity – major contributing factor may occur due to infection, neoplasm or head injury Environmental causes-alteration in blood gases, pH,

electrolytes, or glucose availability

Seizure classified into two broad groups

Partial: simple or complex

Generalized: absence, tonic, clonic, tonic-clonic, myoclonic, febrile

PARTIAL SEIZURES

Simple partial seizures (without loss of consciousness) confined to a single locus in brain abnormal activity in one limb or muscles With autonomic symptoms (nausea, blood pressure

changes,...)

Complex partial seizures (with loss of consciousness) Simple partial followed by a loss of consciousness Impaired consciousness from the onset Exhibits complex sensory hallucination Motor dysfunction may involve chewing movements,

diarrhea or urination

Generalized seizures

Electrical discharge spread to both hemisphere May be convulsive (shaken repeatedly) or non

convulsive Immediate loss of consciousness occurs Types

generalized tonic-clonic (grand mal) seizures

absence (petit mal) seizurestonic seizuresatonic seizuresclonic and myoclonic seizuresfebrile seizures

======================= Partial Seizures localized onset of attack ascertained, either by

clinical observation or by EEG – attack begins in a specific locus in brain

Simple Partial seizures – least complicated, characterized by minimal spread of abnormal discharge, normal consciousness and awareness are preserved – pt may have a sudden onset of clonic jerking of an extremity lasting 60-90 secs; residual weakness lasts for 15-30 mins after attack.

Pt completely aware of attack, can describe it in detailEEG may show an abnormal discharge highly localized to the involved portion of brain

=======================Complex Partial seizures – localized onset, discharge becomes more widespread (usually bilateral) and almost always involves limbic systemmost (not all) CPS arise from one of the temporal lobes, possibly because of the susceptibility of this area to insults such as hypoxia or infection

Clinically, pt may have a brief warning followed by an alteration of consciousness during which some pts may stare and others may stagger or even fallMore, however, demonstrate fragments of integrated motor behavior called automatisms for which pt has no memoryafter 30-120 secs, pt makes a gradual recovery to normal consciousness but may feel tired or ill for several hours after attack

Generalized Seizures Tonic-clonic seizures

characterized by tonic phase continuous rigidity of all extremities

clonic phase massive jerking of body ( rapid contraction and relaxation)

Tongue or cheek bitten, urinary incontinence common Seizure followed by period of confusion and exhaustion

due to depletion of energy

Absence seizure (petit mal) Typical absence seizures consists of staring for a

few seconds (altered consciousness) then returning to full function, as if nothing occurred

Brief duration (< 10 secs) ass with mild clonic jerking of eyelids, patient

stares & exhibit rapid eye blinking begin in childhood or adolescence and may occur

up to hundreds of times a day

The patient has no recollection of the event.

Myoclonic seizures Myoclonic jerking – seen in generalized tonic-

clonic seizures, partial seizure, absence seizures, and infantile spasms

Short episode of muscle contractions

Occurs due to permanent nurologic damage due to hypoxia, uremia, encephalitis or drug poisoning

Atonic seizures

sudden loss of postural tone, if standing pt falls suddenly and may be injured, if seated, may suddenly drop forward

Infantile spasms characterized clinically by brief recurrent

myoclonic jerks of body with sudden flexion or extension of the body and limbs

90% of affected pts have their 1st attack before age of 1 yr

Most pts mentally retarded cause infection, kernicterus and hypoglycemia

Febrile fits Frequently occurs in young children (6 months- 6

yrs) during high grade fever Characterized by tonic clonic convulsions of short

duration (1 to 5 min), eye rolling & unresponsiveness

Benign, do not cause death, nurologic damage, injury, or learning disorder

Status epilepticus Continuous, rapid, recurrent seizures

Antiepileptic drugs

Primary drugs Phenytoin Carbamazepine Clonazepam (BZ) Clorazepate (BZ) Diazepam (BZ) Ethosuximide Lorazepam (BZ) Phenobarbital Primidone Valproic acid

Adjunct drugs Fel bamate Gaba pentin Lamo trigine Leve tira cetam Tiaga bine Topira mate Zoni samide Viga batrin

Pathophysiology of Seizures

Increased CNS excitability

Membrane depolarization Increased excitatory input Decreased inhibitory (GABA) input

Strategies in Treatment

Stabilize membrane by blockade of voltage gated channels (Na & Ca) prevent depolarization by action on ion channels

Increase GABAergic transmission

Decrease Excitatory glutamate transmission

Classification of Anticonvulsants

Action on Ion Channels

Enhance GABA

Transmission

Inhibit glutamate

Transmission

Na+:

Phenytoin, Carbamazepine, Lamotrigine

Topiramate

Valproic acid

Ca++:

Ethosuximide

Valproic acid

Benzodiazepines

Barbiturates

Valproic acid

Gabapentin

Vigabatrin

Topiramate

Felbamate

Felbamate

Topiramate

Phenytoin Diphenylhydantoin – oldest antiseizure drug

Mechanism of action. Blocks voltage gated Na+ channels in inactive state,

slows recovery blocks repetitive firing of action potentials, promotes

stabilization of membrane, reduce propagation of abnormal impulse in brain

At higher dose blocks Ca 2+ conductance Interfere with release of neurotransmitters

norepinephrine, acetylcholine Produces drowsiness and lethargy

Phenytoin /Clinical use

Highly effective in Partial seizures (simple and complex) Tonic-clonic seizures Status epilepticus Arrhythmia

Not effective in absence seizures

Phenytoin /Adverse effects Depression of CNS Sedation, Nystagmus,

diplopia and ataxia, confusion & hallucination Reversible Gingival hyperplasia and hirsutism GIT nausea & vomitingLong term use Coarsening of facial features occurs in children Mild peripheral neuropathy deep tendon

reflexes in lower extremities Osteomalacia due to abnormalities of vitamin D

metabolism

Phenytoin /Adverse effects Megaloblastic anemia due to folate

deficiency Inhibition of antidiuretic hormone

secretion Hyperglycemia and glycosuria

insulin secretion Teratogenic effects fetal

hydantoin syndrome includes cleft lip, cleft palate, congenital heart disease, growth retardation and mental deficiency

Phenytoin/ Drug Interactions

Phenytoin metabolism decrease by Cimetidine, isoniazid, Chloramphenicol, dicumarol, sulfonamide

Phenytoin metabolism increase by Carbamazepine

Carbamazepine

M.O.A By blocks sodium channels reduce the

propagation of abnormal impulses inhibits high-frequency repetitive firing in neurons decrease synaptic transmission, inhibits uptake

and release of NE from brain postsynaptic action of GABA potentiated

Carbamazepine /Clinical use

Drug of choice in all partial seizures Highly effective in tonic–clonic seizures Trigeminal neuralgia Use in Manic depressive patient to decrease

the symptoms

Carbamazepine Adverse effects

Respiratory depression Drowsiness, vertigo, diplopia, blurred vision,

ataxia & coma Irritating to stomach n & v may occurs Serious liver toxicity hyponatremia and water intoxication Idiosyncratic blood dyscrasias,including fatal

cases of aplastic anemia and agranulocytosis Is an enzyme inducer

Drugs inhibiting metabolism of Carbamazepine

Cimetidine Diltiazem Erythromycin Isoniazid Propoxyphene

Phenobarbital clinically useful as antiseizure drugs

phenobarbital, mephobarbital, metharbital,

Mechanism of Action Elevate seizure threshold Limits the spread of seizure discharge in brain Binds to a regulatory site on GABA receptor,

prolonging the openings of Cl- channels Blocks excitatory responses induced by glutamate

Phenobarbital/ clinical uses

Doc in children with febrile fits Effective in simple partial seizures Recurrent tonic clonic seizures Relieve anxiety insomnia

Phenobarbital adverse effects Sedation Ataxia Nystagmus Vertigo N &v Morbilliform rash (measles like) Agitation & confusion Rebound seizures can occur on discontinuation of

drug

Primidone

2-deoxyphenobarbital Metabolized to Phenobarbital and phenyl-

ethyl-malonamide All 3 are active anticonvulsants M.O.A. – similar to Phenobarbital Effective against partial and tonic clonic

seizures

Valproic acid

Drug of choice for myoclonic seizures Effective in tonic clonic & absence seizures Block sodium channels & enhance

GABAergic transmission Adverse effects N, V, ataxia, sedation,

tremors, rash & alopecia

Ethosuximide

Inhibit T-type calcium channels in brain reduce propagation of abnormal electrical activity

First choice in absence seizures

Benzodiazepines Benzodiazepines are safest antiepileptic drugs Clonazepam use for chronic treatment of

absence & myoclonic seizures Chlorazepate effective in partial seizures Diazepam & lorazepam drug of choice in

acute treatment of status epilepticus (interrupt repeated seizures)

A/E sedation, drowsiness, fatigue, ataxia, respiratory and cardiac depression

Adjunct antiepileptic drugs

Newer agents Use as add on therapy in refractory

epilepsies Also effective as monotherapy

Lamotrigine

M.O.A. –blocks sodium channels, voltage activated calcium channels & decreased synaptic release of glutamate

Add on therapy, monotherapy for partial seizures, absence and myoclonic seizures in children

Dizziness, headache, diplopia, nausea, somnolence, and skin rash – potentially life-threatening dermatitis develops in 1-2% of pediatric pts

Felbamate

Broad spectrum Use only in refractory cases (may cause

aplastic anemia & hepatic failure) block sodium channels & inhibits glycin &

glutamate transmission Effective in partial seizures

Gabapentin Amino acid, analog of GABA, effective against

partial seizures M.O.A. – in spite of its close structural

relationship to GABA, it appears not to act on GABA receptors, interfere with voltage gated calcium channels

Used in Partial and G tonic clonic seizures, diabetic neuropathic pain, postherpetic neuroralgia in adults

To-pira-mate

Effective in refectory partial and secondary generalized seizures

M.O.A. Blocks voltage dependent sodium channels Potentiate inhibitory effect of GABA,

acting at a site different from BNZs or barbs

Ti-aga-bine M.O.A. – inhibitor of GABA uptake Prolongs inhibitory action of synaptically released

GABA Indicated for adjunctive treatment of partial

seizures

Zonisamide

Primary site of action is on sodium channel Also act on voltage dependent calcium

channels Effective against partial and G tonic clonic

seizures, also against infantile spasms and certain myoclonias

S/E – drowsiness, cognitive impairment, serious skin rashes

Levetiracetam

M.O.A. – unknown Effective for the treatment of refectory

partial seizures S/E – somnolence, asthenia, dizziness

Acetazolamide

Inhibits carbonic anhydrase Mild acidosis in brain – mech by which

drug exerts its antiseizure activity Used for all types of seizures Use severely limited by rapid development

of tolerance usually within weeks