ANTICONVULSANTSANTICONVULSANTS

SAMUEL AGUAZIM (MD)SAMUEL AGUAZIM (MD)

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What is a Epilepsy?What is a Epilepsy?

EpilepsyEpilepsy is a chronic disorder is a chronic disorder characterized by recurrent episodes characterized by recurrent episodes in which the brain is subject to in which the brain is subject to abnormal excessive discharges abnormal excessive discharges ((seizuresseizures) synchronized throughout ) synchronized throughout a population of neurons.a population of neurons.

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EPILEPSYEPILEPSY

PRIMARY or IDIOPATHICPRIMARY or IDIOPATHIC

SECONDARYSECONDARY

KNOWN CAUSES:KNOWN CAUSES: HEAD INJURY HEAD INJURY TUMORSTUMORS MENINGITISMENINGITIS HYPOGLYCEMIAHYPOGLYCEMIA DRUG WITH DRAWALDRUG WITH DRAWAL

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The two main categories of seizures The two main categories of seizures includeinclude

Partial seizures Partial seizures – – no loss of consciousnessno loss of consciousness

and and Generalized seizures Generalized seizures – – loss of consciousness loss of consciousness

A partial seizure can evolve to a A partial seizure can evolve to a generalized seizure. generalized seizure.

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Partial Seizures Partial Seizures The site of origin is a The site of origin is a localized or discreet localized or discreet area in one hemisphere of the brainarea in one hemisphere of the brain. .

Symptoms depend on the site of neuronal Symptoms depend on the site of neuronal dischargedischarge

The two most common types of partial The two most common types of partial seizure are seizure are

Simple partial and Simple partial and Complex partial. Complex partial.

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Simple PartialSimple Partial These produce symptoms associated with the These produce symptoms associated with the

area of abnormal neural activity in the brain area of abnormal neural activity in the brain confined to confined to single locussingle locus: :

The electrical discharge The electrical discharge does notdoes not spreadspread Can occur at any ageCan occur at any age

motor signs, sensory symptoms, autonomic motor signs, sensory symptoms, autonomic signs and symptoms signs and symptoms

There is There is no impairment of consciousness in no impairment of consciousness in simple partial seizures. simple partial seizures.

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Complex PartialComplex Partial Impairment of consciousness, Impairment of consciousness,

characteristic of complex partial seizures characteristic of complex partial seizures (CPS)(CPS)

Results in the inability to respond to or Results in the inability to respond to or carry out simple commands or to execute carry out simple commands or to execute willed movement, and a lack of awareness willed movement, and a lack of awareness of one’s surroundings and events. of one’s surroundings and events.

Exhibit complex sensory hallucinations, Exhibit complex sensory hallucinations, mental distortion and motor dysfunctionmental distortion and motor dysfunction

Experience initial seizures before age of 20 Experience initial seizures before age of 20 yrsyrs

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Generalized SeizuresGeneralized Seizures At the onset, At the onset, seizure activity occurs seizure activity occurs

simultaneously in large areas of the brain, simultaneously in large areas of the brain, often in both hemispheresoften in both hemispheres..

Begin locally and rapidly spread to both the Begin locally and rapidly spread to both the hemispheres.hemispheres.

Loss of consciousnessLoss of consciousness

Seizures can be convulsive or non-convulsive.Seizures can be convulsive or non-convulsive. The two most common types are The two most common types are tonic-tonic-

clonic (grand mal) and Absence (Petit clonic (grand mal) and Absence (Petit mal). mal).

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Tonic-clonic (grand mal). Most Tonic-clonic (grand mal). Most commoncommon

There is loss of consciousness during There is loss of consciousness during the seizurethe seizure. .

The tonic phaseThe tonic phase, , consisting of consisting of increased muscle tone (rigidity), increased muscle tone (rigidity), is is followed by followed by The Clonic phaseThe Clonic phase, which , which involves jerking of the extremitiesinvolves jerking of the extremities..

Followed by confusion and exhaustion. Followed by confusion and exhaustion.

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Absence (petit mal) Absence (petit mal) This type occurs This type occurs most most often in children, usually beginning between often in children, usually beginning between the ages of 5 and 12 years the ages of 5 and 12 years and often stopping and often stopping spontaneously in the teens.spontaneously in the teens.

The loss of consciousness is so brief that the The loss of consciousness is so brief that the child usually does not even change positionchild usually does not even change position..

Typically described as a blank stare Typically described as a blank stare and and often misinterpreted as often misinterpreted as daydreamingdaydreaming..

Most absence seizures last 10 seconds or less. Most absence seizures last 10 seconds or less.

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Myoclonic seizuresMyoclonic seizures are are rapid, brief rapid, brief contractions of bodily muscles, contractions of bodily muscles, sudden jerks or clumsiness. sudden jerks or clumsiness.

Infantile Spasms a.k.a West Infantile Spasms a.k.a West SyndromeSyndrome sudden spasm or sudden spasm or bending (flexion) of the body either bending (flexion) of the body either at the waist or neck. at the waist or neck.

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Status EpilepticusStatus Epilepticus was defined as was defined as 30 30 minutes of continuous seizure activity or minutes of continuous seizure activity or a series of seizures without return to full a series of seizures without return to full consciousness between the seizuresconsciousness between the seizures

Febrile seizuresFebrile seizures are are convulsions convulsions brought on by a fever in infants or small brought on by a fever in infants or small children. children.

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CLASSIFICATIONCLASSIFICATION Seizures Seizures

PARTIAL / FOCALPARTIAL / FOCAL• SIMPLESIMPLE• COMPLEXCOMPLEX

GENERALIZEDGENERALIZED• GRAND MAL ( tonic clonic)GRAND MAL ( tonic clonic)• PETIT MAL ( Absence)PETIT MAL ( Absence)• MYOCLONICMYOCLONIC• FEBRILE FEBRILE • STATUS EPILEPTICUSSTATUS EPILEPTICUS

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ANTIEPILEPTIC DRUGSANTIEPILEPTIC DRUGS PHENYTOINPHENYTOIN CARBAMAZEPINECARBAMAZEPINE VALPROIC ACIDVALPROIC ACID ETHOSUXIMIDEETHOSUXIMIDE BENZODIAZEPINESBENZODIAZEPINES BARBITURATESBARBITURATES LAMOTRIGINE - NEWER AGENTSLAMOTRIGINE - NEWER AGENTS GABAPENTIN - NEWER AGENTSGABAPENTIN - NEWER AGENTS TIAGABINE - NEWER AGENTS TIAGABINE - NEWER AGENTS TOPIRAMATE - NEWER AGENTSTOPIRAMATE - NEWER AGENTS VIGABATRIN - NEWER AGENTSVIGABATRIN - NEWER AGENTS

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BARBITURATESBARBITURATES - - PHENOBARBITALPHENOBARBITAL

PRIMIDONEPRIMIDONE

BENZODAIZEPINESBENZODAIZEPINES - DIAZEPAM - DIAZEPAM

CLONAZEPAM, CLORAZEPATECLONAZEPAM, CLORAZEPATE

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ANTI EPILEPTIC DRUGS -ANTI EPILEPTIC DRUGS -MECHMECH

INHIBIT ELECTRICAL DISCHARGEINHIBIT ELECTRICAL DISCHARGE

INHIBIT SPREAD OF DISCHARGEINHIBIT SPREAD OF DISCHARGE

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PHENYTOINPHENYTOIN

MECH: MECH: DECREASES Na INFLUXDECREASES Na INFLUX STABILIZES CELL MEMBRANESTABILIZES CELL MEMBRANE

DECREASES INFLUX OF CaDECREASES INFLUX OF Ca DECREASES FIRING RATEDECREASES FIRING RATE

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ACTION :ACTION :

DECREASES PROPAGATION OF DECREASES PROPAGATION OF ABNORMAL IMPULSESABNORMAL IMPULSES

USES: USES: First line treatment for tonic-clonic First line treatment for tonic-clonic

seizuresseizures First line prophylaxis for status First line prophylaxis for status

epilepticusepilepticus Treatment for simple and complex Treatment for simple and complex

seizures.seizures. Drug of choice for initial therapy in adultsDrug of choice for initial therapy in adults

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DROWSINESS – LITTLEDROWSINESS – LITTLE HYPNOSIS – NOHYPNOSIS – NO

KINETICS : KINETICS : ROUTE – ORAL, IV – ST. EPILEPTICUS ROUTE – ORAL, IV – ST. EPILEPTICUS MET : LIVER, EASILY SATURATEDMET : LIVER, EASILY SATURATED EXCRETION : URINE.EXCRETION : URINE.

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PHENYTOIN - SEPHENYTOIN - SE Side effects of phenytoin include:Side effects of phenytoin include: CNS DepressionCNS Depression Gingival hyperplasiaGingival hyperplasia HirsutismHirsutism Osteomalacia Osteomalacia from decreased vitamin Dfrom decreased vitamin D Megaloblastic anemia Megaloblastic anemia from decreased folate from decreased folate

(decreased GI absorption from inhibition of conjugases)(decreased GI absorption from inhibition of conjugases) Aplastic anemiaAplastic anemia Stevens-Johnson syndromeStevens-Johnson syndrome NystagmusNystagmus Yellow-browning of skinYellow-browning of skin NeuropathyNeuropathy (vertigo, ataxia, headache) (vertigo, ataxia, headache) SLE-like syndromeSLE-like syndrome

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FETAL HYDANTOIN SYNDROME FETAL HYDANTOIN SYNDROME IF GIVEN IN PREGNANCYIF GIVEN IN PREGNANCY

CLEFT LIP, CLEFT PALATECLEFT LIP, CLEFT PALATE GROWTH RETARDATIONGROWTH RETARDATION LOW IQLOW IQ CONGENITAL HEART DISEASESCONGENITAL HEART DISEASES

TERATOGENIC EFFECTTERATOGENIC EFFECT

Phenytoin's teratogenic effects Phenytoin's teratogenic effects usually result usually result

in in cleftcleft  liplip and  and palatepalate..

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CARBAMAZEPINECARBAMAZEPINE MECH : BLOCKS Na CHANNELSMECH : BLOCKS Na CHANNELS USED MAINLY -USED MAINLY -All partial, grand All partial, grand

mal epilepsymal epilepsy Drug of choice in Trigeminal Drug of choice in Trigeminal

neuralgianeuralgia

ORAL ROUTEORAL ROUTE

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SE :SE : MC : GITMC : GIT

Chronic use can cause :Chronic use can cause : STUPOR, RESP DEPRESSION, COMASTUPOR, RESP DEPRESSION, COMA APLASTIC ANEMIA, APLASTIC ANEMIA,

THROMBOCYTOPENIA, THROMBOCYTOPENIA, AGRANULOCYTOSIS,AGRANULOCYTOSIS,

LIVER FAILURELIVER FAILURE Steven-Johnson syndromeSteven-Johnson syndrome TeratogenicityTeratogenicity Cleft lip and palateCleft lip and palate Spina bifidaSpina bifida

Steven-Johnson syndromeSteven-Johnson syndrome

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Carbamazepine's teratogenic effects usually Carbamazepine's teratogenic effects usually result in result in cleftcleft  liplip, , cleft palatecleft palate, and , and spina spina

bifidabifida..

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BARBITURATESBARBITURATES PHENOBARBITALPHENOBARBITAL PRIMIDONEPRIMIDONE

MECH MECH May be due to GABA activationMay be due to GABA activation USES ; USES ; FEBRILE CONVULSIONS, CAN ALSO BE FEBRILE CONVULSIONS, CAN ALSO BE

USED FOR SIMPLE & GRAND MAL EPILEPSYUSED FOR SIMPLE & GRAND MAL EPILEPSY Not effective in complex partial Not effective in complex partial Induced CYP450Induced CYP450 SE : SEDATION, ATAXIA, NYSTAGMUS, VERTIGOSE : SEDATION, ATAXIA, NYSTAGMUS, VERTIGO CHR: PSYCHOSIS.CHR: PSYCHOSIS. Rebound seizures occur on discontinuanceRebound seizures occur on discontinuance

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PRIMIDONEPRIMIDONE Also effective in complex partialAlso effective in complex partial SESE Same as phenobarbitalSame as phenobarbital

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BENZODIAZEPINESBENZODIAZEPINES

DIAZEPAM, CLONAZEPAM, DIAZEPAM, CLONAZEPAM, CLORAZEPATECLORAZEPATE

SAFEST DRUGS OF ALL THE SAFEST DRUGS OF ALL THE ANTIEPILETPTIC DRUGSANTIEPILETPTIC DRUGS

Diazepam - Diazepam - Slow I. V. – Status Slow I. V. – Status Epilepticus Epilepticus

SE : Resp depression, CVS depression SE : Resp depression, CVS depression with i.v. administration of high doseswith i.v. administration of high doses

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CLONAZEPAM, CLORAZEPATECLONAZEPAM, CLORAZEPATE For Chronic treatmentFor Chronic treatment

DIAZEPAM, LORAZEPAMDIAZEPAM, LORAZEPAM For For acute conditions Status EPIacute conditions Status EPI Lorazepam longer duration than Lorazepam longer duration than

diazepamdiazepam

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VALPROIC ACID(Divalproex)VALPROIC ACID(Divalproex)

MECH : GABA action increasedMECH : GABA action increased Blocks Na ChannelsBlocks Na Channels Broad spectrum antiepileptic drugBroad spectrum antiepileptic drug Inhibitor of CYP45OInhibitor of CYP45O USES :USES : MYOCLONIC SEIZURESMYOCLONIC SEIZURES and and Bipolar Bipolar

disorderdisorder Absent seizures – 2Absent seizures – 2ndnd drug of choice. drug of choice.

(hepatotoxicity)(hepatotoxicity)

SE : hepatotoxicitySE : hepatotoxicity GIT , TREMOR, ATAXIA,SEDATIONGIT , TREMOR, ATAXIA,SEDATION THROMBOCYTOPENIATHROMBOCYTOPENIA

CI : CI : LIVER FAILURE LIVER FAILURE

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ETHOSUXIMIDE ( zarontin)ETHOSUXIMIDE ( zarontin) Mech: Reduces propagation of abnormal electrical Mech: Reduces propagation of abnormal electrical

activity in the brain by inhibiting Calcium channels activity in the brain by inhibiting Calcium channels

USES: Drug of choice for ABSENCE USES: Drug of choice for ABSENCE SEIZURESSEIZURES

SE:SE: MC : GIT distressMC : GIT distress CONFUSION, CONFUSION, LACK OF CONCENTRATIONLACK OF CONCENTRATION STEVEN JOHNSON SYNDROME.( skin reaction)STEVEN JOHNSON SYNDROME.( skin reaction) Headache, Headache, Itching Itching Fatigue Fatigue

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Adjunct Antiepileptic drugsAdjunct Antiepileptic drugs

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LAMOTRIGINE ( lamictal) LAMOTRIGINE ( lamictal)

Broad spectrumBroad spectrum IHIBITS GLUTAMATE, ASPARTATEIHIBITS GLUTAMATE, ASPARTATE Blocks Na channels and high voltage Blocks Na channels and high voltage

ca channelsca channels Prevents firing Prevents firing Can be Can be tonic-clonic, simple partial, tonic-clonic, simple partial,

complex partial and absence seizures complex partial and absence seizures and Lennox-Gastaut Syndromeand Lennox-Gastaut Syndrome

SE : SE : RASH, Drowsiness, ataxiaRASH, Drowsiness, ataxia, , confusion, blood dyscrasiasconfusion, blood dyscrasias

Lennox-Gastaut Lennox-Gastaut syndrome (LGSsyndrome (LGS), or ), or childhood epileptic childhood epileptic encephalopathy, is a encephalopathy, is a pediatric epilepsy pediatric epilepsy syndrome characterized syndrome characterized by by multiple seizure multiple seizure types; mental types; mental retardation or retardation or regressionregression; and ; and abnormal findings on abnormal findings on electroencephalography electroencephalography (EEG).(EEG).

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GABAPENTIN.( neurontin)GABAPENTIN.( neurontin)

Analogue of GABAAnalogue of GABA Mech – Not knownMech – Not known May interfere with ca channelsMay interfere with ca channels Can be used for Simple and partial Can be used for Simple and partial

seizures, seizures, peripheral neuropathy andperipheral neuropathy and Postherpetic neuralgiaPostherpetic neuralgia

SE; SE; Sedation, Ataxia, Sedation, Ataxia, Drowsiness, Drowsiness, ataxia, fatigueataxia, fatigue

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TIAGABINETIAGABINE

Blocks GABA uptake into presynaptic Blocks GABA uptake into presynaptic neurons neurons

More GABA for receptor bindingMore GABA for receptor binding Exe: BILE ( Major), small amt in UrineExe: BILE ( Major), small amt in Urine It is effective in decreasing the It is effective in decreasing the

number of seizures in patients with number of seizures in patients with partial onset epilepsy.partial onset epilepsy.

SE: Drowsiness, ataxia, tremor,SE: Drowsiness, ataxia, tremor, GI upset dizziness GI upset dizziness

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TOPIRAMATETOPIRAMATE Many actions, Broad spectrumMany actions, Broad spectrum Blocks Na channelsBlocks Na channels Increases GABA activityIncreases GABA activity Block Ca channelsBlock Ca channels Prevent Phosporylation of proteinsPrevent Phosporylation of proteins Has shown reduction in seizures in refractory Has shown reduction in seizures in refractory

cases when used with other Anti-epileptic cases when used with other Anti-epileptic drugs.drugs.

Can be used Can be used tonic-clonic, simple and tonic-clonic, simple and complex seizurescomplex seizures as well as for migraine  as well as for migraine prophylaxis.prophylaxis...

Exe: UrineExe: Urine SE: Drowsiness, ataxia, SE: Drowsiness, ataxia, NephrolithiasisNephrolithiasis, taste , taste

alteration, confusionalteration, confusion

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VIGABATRINVIGABATRIN Inhibit enzyme GABA transaminaseInhibit enzyme GABA transaminase Increases the GABA levelsIncreases the GABA levels Can be used for Can be used for Partial, General tonic Partial, General tonic

clonic seizures & sometimes for clonic seizures & sometimes for Infantile Infantile spasmsspasms

Exe: UrineExe: Urine Adv: very less drug interactionsAdv: very less drug interactions SE: Aggression, Alopecia, Skin rash, SE: Aggression, Alopecia, Skin rash,

drowsiness.drowsiness.