ANTI-EPILEPTIC

DRUGS

ANTI-EPILEPTIC DRUG ANTI-EPILEPTIC DRUG (AED)(AED)

A drug which A drug which decreases the frequency decreases the frequency and/or severity of seizures and/or severity of seizures in people in people with epilepsywith epilepsy

Treats the symptom of seizures, Treats the symptom of seizures, notnot the underlying epileptic condition the underlying epileptic condition

Goal: Goal: maximize quality of life maximize quality of life by by minimizing seizures and adverse drug minimizing seizures and adverse drug effectseffects

Currently no “anti-epileptogenic” Currently no “anti-epileptogenic” drugs availabledrugs available

Current Current PharmacotherapyPharmacotherapy

Just under 60% of all people with Just under 60% of all people with epilepsy epilepsy can become can become seizure free seizure free with with drug therapydrug therapy

In another 20%, the seizures In another 20%, the seizures can can be drastically reducedbe drastically reduced

In ~ 20% of epileptic patients, In ~ 20% of epileptic patients, seizures are seizures are refractory refractory to currently to currently available AEDsavailable AEDs

Choosing Choosing the the right AEDright AED

Seizure typeSeizure type

Epilepsy syndromeEpilepsy syndrome

Pharmacokinetic profilePharmacokinetic profile

Interactions/other medical conditionsInteractions/other medical conditions

EfficacyEfficacy

Expected adverse effectsExpected adverse effects

CostCost

Classification of AEDsClassification of AEDsClassicalClassical

PhenytoinPhenytoin PhenobarbitalPhenobarbital PrimidonePrimidone CarbamazepineCarbamazepine EthosuximideEthosuximide Valproate (valproic Valproate (valproic

acid)acid) Trimethadione (not Trimethadione (not

currently in use)currently in use)

NewerNewer LamotrigineLamotrigine FelbamateFelbamate TopiramateTopiramate Gabapentin/Gabapentin/

PregabalinPregabalin TiagabineTiagabine VigabatrinVigabatrin OxycarbazepineOxycarbazepine LevetiracetamLevetiracetam FosphenytoinFosphenytoin

General Facts About General Facts About AEDsAEDs

Good oral absorption and bioavailabilityGood oral absorption and bioavailability Most metabolized in liver Most metabolized in liver but some excreted but some excreted

unchanged in kidneysunchanged in kidneys Classic AEDs generally have Classic AEDs generally have more severe more severe

CNS sedation than newer drugs CNS sedation than newer drugs (except (except ethosuximide)ethosuximide)

Because of overlapping mechanisms of Because of overlapping mechanisms of action, action, best drug best drug can be chosen based on can be chosen based on minimizing side effectsminimizing side effects in addition to in addition to efficacyefficacy

Targets for AEDsTargets for AEDs

Increase inhibitory neurotransmitter Increase inhibitory neurotransmitter system—GABAsystem—GABA

Decrease excitatory neurotransmitter Decrease excitatory neurotransmitter system—glutamatesystem—glutamate

Block voltage-gated inward positive Block voltage-gated inward positive currents—Nacurrents—Na++ or Ca or Ca++++

Increase outward positive current—KIncrease outward positive current—K++

Many AEDs pleiotropic—act via multiple Many AEDs pleiotropic—act via multiple mechanismsmechanisms

A = activation gateI = inactivation gate

McNamara JO. Goodman & Gilman’s. 9th ed. 1996:461-486.

AEDs: AEDs: Mechanisms of ActionMechanisms of Action

Na+ Na+

CarbamazepinePhenytoin

LamotrigineValproateNa+ Na+

I I

Voltage-gated sodium channel

Open Inactivated

X

AEDs:AEDs: Mechanisms of ActionMechanisms of Action

Calcium channel blockadeCalcium channel blockade

AEDs:AEDs: Mechanisms of ActionMechanisms of Action

GABAGABA

Side effect issuesSide effect issues

SedationSedation - especially with barbiturates - especially with barbiturates CosmeticCosmetic - phenytoin - phenytoin Weight gainWeight gain – valproic acid, gabapentin – valproic acid, gabapentin Weight loss Weight loss - topiramate- topiramate Reproductive function Reproductive function – valproic acid– valproic acid CognitiveCognitive - topiramate - topiramate BehavioralBehavioral – felbamate, leviteracetam – felbamate, leviteracetam Allergic Allergic - many- many

END OF INTROEND OF INTRO

CarbamazepineLamotrigineOxcarbazepinePhenytoinTopiramateValproate

EthosuximideLevetiracetamPregabalinValproate

BarbituratesBenzodiazepinesGabapentinLevetiracetamTiagabineTopiramateValproateVigabatrin

Na+ Na+ Ca2+ Ca2+

GABA GABA

CLINICAL USESCLINICAL USES Generalized Tonic-Clonic Generalized Tonic-Clonic

SeizuresSeizures Partial SeizuresPartial Seizures Absence SeizuresAbsence Seizures Myoclonic & Atypical Myoclonic & Atypical

Absence SyndromesAbsence Syndromes Status EpilepticusStatus Epilepticus Other Clinical UsesOther Clinical Uses

GENERALIZED TONIC-CLONIC SEIZURES

PARTIAL SEIZURES

ABSENCE SEIZURES

MYOCLONIC & ATYPICAL SYNDROMES

STATUS EPILEPTICUS

Drugs of Choice

Valproic AcidCarbamazepinePhenytoin

CarbamazepineLamotriginePhenytoin

EthosuximideValproic

Valproic AcidClonazepam

DiazepamLorazepam

Alternative Agents

Phenobarbital FelbamatePhenobarbitalTopiramateValproic Acid

Clonazepam LevetiracetamTopiramateZonisamide

PhenytoinPhenobarbital

Adjunctive Drugs

LamotrigineTopiramate

GabapentinPregabalin

LamotrigineLevetiracetamZonisamide

LamotrigineFelbamate

Other Clinical UsesOther Clinical Uses Valproic acid Valproic acid –mania–mania CarbamazepineCarbamazepine, , Lamotrigine Lamotrigine –bipolar –bipolar

disorderdisorder CarbamazepineCarbamazepine –trigeminal neuralgia –trigeminal neuralgia Gabapentin Gabapentin –pain of neuropathic origin–pain of neuropathic origin TopiramateTopiramate –migraine –migraine PregabalinPregabalin –neuropathic pain –neuropathic pain

MAIN INDICATIONS OF ANTIEPILEPTIC MAIN INDICATIONS OF ANTIEPILEPTIC DRUGSDRUGS

TOXICITYTOXICITY

TeratogenicityTeratogenicity Overdosage ToxicityOverdosage Toxicity Life-Threatening Toxicity Life-Threatening Toxicity

TeratogenicityTeratogenicity

Valproic acid Valproic acid –neural tube defects–neural tube defects CarbamazepineCarbamazepine –craniofacial –craniofacial

anomalies, spina bifidaanomalies, spina bifida PhenytoinPhenytoin –fetal hydantoin –fetal hydantoin

syndromesyndrome

Overdosage ToxicityOverdosage Toxicity

Respiratory depressionRespiratory depression

Management: supportiveManagement: supportive Airway managementAirway management Mechanical ventilationMechanical ventilation

Life-Threatening Life-Threatening ToxicityToxicity

Valproic acid Valproic acid –fatal hepatoxicity–fatal hepatoxicity LamotrigineLamotrigine –Stevens-Johnson –Stevens-Johnson

syndromesyndrome ZonisamideZonisamide –severe skin reactions –severe skin reactions FelbamateFelbamate –aplastic anemia, acute –aplastic anemia, acute

hepatic failurehepatic failure

GENERALIZED GENERALIZED TONIC-CLONIC TONIC-CLONIC

SEIZURE DRUGSSEIZURE DRUGS

Drug Name Indication Mechanism of Action

Pharmacokinetics

Therapeutic Levels and Dosage

Drug Interaction

Side effects/ Adverse Reactions

Contra-indications

Carbama-zepine

Indicated for complex partial seizures, generalized tonic-clonic seizures, mixed seizure patterns or other partial or generalized seizures. Not indicated for Absence seizures.

It blocks sodium channels at therapeutic concentrations and inhibits high frequency repetitive firing in neurons Acts presynaptically to decrease synaptic transmission

Absorption- varies widely among patients

Peak levels: 6-8 hours after administration Distribution-slowVolume distribution: 1L/kg Systemic clearance-1L/kg/d

70% bound to plasma proteins

Half-life – 36hrs

Maintenance dose range: 800-1200 mg/day PO in divided doses

Therapeutic range: 4-12 mg/L (16.9-50.8 micromoles/L)

Maximum dose of 1600 mg/day recommended (rarely, some patients have required 1.6-2.4 g/day)

Interactions are related to the drug’s enzyme-inducing properties Propoxyphene, troleandomycin, valproic acid – inhibit carbamazepine clearance and increase steady-state carbamazepine blood levels Phenytoin, phenobarbital – decrease steady state concentration of carbamazepine

Common: Diplopia and ataxia (most common), gastrointestinal disturbances; sedation at high doses

Occasional: Retention of water and hyponatremia; rash, agitation in children

Rare: Idiosyncratic blood dyscrasias and severe rashes

•Hypersensitivity• Kidney disease• Cardiovascular disease• Seizure disorder, myasthenia gravis• Dehydration• hypothyroidism                      

Drug Name

Indication Mechanism of Action

Pharmacokinetics

Therapeutic Levels and Dosage

Drug Interaction

Side effects/ Adverse Reactions

Contra-indications

Phenytoin Control of grand mal & complex partial seizure, prevention & treatment of seizure during or following neurosurgery, migraine, trigeminal neuralgia, certain psychoses, cardiac arrhythmias, digitalis intoxication, post-event treatment of MI.

Blocks sodium channels

Prevents nerve conduction

Absorption after oral ingestion may be slow, variable and occasionally incomplete

T1/2 = 20-30 hrs Rapidly distributed to all tissues

Metabolized primarily by liver P450 Highly bound to plasma proteins

Adult Initially 100 mg tid. Maintenance: 300-400 mg daily in equally divided doses. Childn ≥6 yr Initially 100 mg tid, subsequent dosage should be adjusted according to therapeutic response. Pedia Initially 5 mg/kg/day in 2-3 equally divided doses. Max: 300 mg daily. Maintenance: 4-8 mg/kg/day. Susp Initially 125 mg/5 mL tid, subsequent dosage adjusted according to therapeutic response.

induces P450s in liver

increases metabolism of many drugs

reduces action of other drugs

Generally, this will increase action of other drugsThe combination of metabolism and protein binding means that phenytoin can both increase and decrease drug action, even of the same drug

Hirsutism & coarsening of facial featuresAcneGingival hyperplasia (20-40%)Decreased serum concentrations of folic acid, thyroxine, and vitamin K with long-term use.“Fetal hydantoin syndrome”:includes growth retardation, microencephaly, and craniofacial abnormalities

History of hypersensitivity to phenytoin or other hydantoins. Sinus bradycardia, SA block, 2nd- & 3rd-degree AV block. Patients w/ Adams-Stokes syndrome. Lactation.

COST AND PRESENTATION COST AND PRESENTATION (Dilantin)(Dilantin)

Drug Name

Indication

Mechanism of Action

Pharmacokinetics

Therapeutic Levels and Dosage

Drug Interaction

Side effects/ Adverse Reactions

Contra-indications

Valproic acid

Indicated for partial seizures, generalized tonic-clonic seizures, myoclonic seizure , absence seizure .

Valporic acid produces effect on isolated neurones.Therapeutically relevant concentration .Valporic inhibits sustain repetitive firing induce by depolarization cortic and spinal cord neurones. Prolonged recovery of old age activated sodium Na+ channels from inactivation. 

Absorption- Raidly and compeletly after oral administrationPeak levels: 1-4hours . Volume of distribution: 0.2L/kgt-1/2 =15 hoursMetabolism-Hepatic metabolism 95% with less than 5% excreted unchanged.

Initially 15mg/kg/d Childrens : 15-30mg/kg/d Adult:start with 200mg TDS.Maximum daily dose 60mg/kg/d

Valporate increases plasma level of phenobarbitone by inhibiting its metabolism.Volporic acid and cabamazepine induce each other metabolism.Concurrent administration of colonazapam and valporate is contraindicated.

Anorexia, nausea, vomiting, heart burn, drowsiness, atxia, and tremers –dose side effects.Alopasia , rashes , thrombocytophenia

Used during pregnancy it has produced spinabifida and other neural tube defect in the off spring.                      

DRUG NAME INDICATION MOA PHARMOKINETICS

THERAPEUTIC LEVELS AND DOSAGE

DRUG INTERACTION

SIDE EFFECTS SPECIAL PRECAUTIONS

LEVETIRACETAM

PREPARATIONS:tablets (immediate release) 250, 500,750 and 1000mg. Tablets (extended release) 500 and 750 mg.Oral solution:100mg/mlInjection solution:100mg/ml

STORAGE:It should be stored at 25 C. Brief storage at 15-30 C is acceptable.

Used in combination with other antiseizure medications to treat myoclonic, partial onset, or tonic clonic seizures in children and adults

Binds to synaptic vesicle protein SV2A which is involved in synaptic vesicle exocytosis

Absolute oral bioavailability is nearly 100%. peak plasma concentration achieved in about an hour and steady state concentration achieved in 48 hours.It is not significantly bound to plasma. It exhibits linear, dose proportional,kinetics, with low intrasubject and intersubject variability and a half life of 6-8 hrs.It does not undergo hepatic metabolism nor induce or inhibit cytochrome P450 enzymes.It is excreted through the kindneys unchanged as inactive metabolites.

Recommended daily dose:Adults:3000 mgInitiated with 1000mg daily (500 mg twice daily) and increased by 1000 mg/day every 2 weeks up to the maximum recommended dose of 3000mg/dayChildren:60 mg/kg .initiated with 20 mg/kg (10mg/kg twice daily) and increased by 20mg/kg every 2 weeks until the recommended daily dose is reached.

PROBENECID reduces the elimination of levetiracetam by the kidneys, potentially doubling the concentration of levetiracetam in the body

• Headache• sleepiness• Weakness• Dizziness• Difficulty

walking• Mood swings• Anxiety

It should not be discontinued suddenly because of increased seizure activity

It has been associated with increased risk of suicidal thinking and behavior

The medication will make you feel dizzy or drowsy. Do not drive a car or operate machinery.

Nursing mothers: breastfeeding mothers should not consider breastfeeding while taking lebvetiracetam.

DRUG NAME INDICATION MOA PHARMOKINETICS

THERAPEUTIC LEVELS AND DOSAGE

DRUG INTERACTION

SIDE EFFECTS

SPECIAL PRECAUTIONS

LAMOTRIGINE

PREPARATIONS:Tablets:Tablets are supplied for oral administration as 25 mg (white), 100 mg (peach), 150 mg (cream), and 200 mg (blue) tablets. 

STORAGE:Store lamotrigine at 77 degrees F (25 degrees C). Brief storage at temperatures between 59 and 86 degrees F (15 and 30 degrees C) is permitted. Store away from heat, moisture, and light. Do not store in the bathroom. 

Adjunctive Therapy: indicated as adjunctive therapy for the following seizure types in patients ≥ 2 years of age:partial seizuresprimary generalized tonic-clonic seizuresgeneralized seizures of Lennox-Gastaut syndromeMonotherapy:indicated for conversion to monotherapy in adults ( ≥ 16 years of age) with partial seizures who are receiving treatment with carbamazepine, phenytoin, phenobarbital, primidone, or valproate as the single antiepileptic drug (AED).Bipolar DisorderLAMICTAL is indicated for the maintenance treatment of Bipolar I Disorder

Prolongation of Na chanel inactivation nd suppression of high frequency firing. In adddition it may directly block voltage sensitive Na cahnnels thus stabilizing the presynaptic memnbrane and preventing the release of excitatory neurotransmitters mainly glutamate and aspartae.

WELL ABSORBED orally. It is metabolized completely in the liver .Half life is 24 hr. reduced to 16 hr in patients receiving phenytoin, carbazepine and valproate inhibits glucorinidation of lamotrigine and doubles the blood level.

Recommended daily dose:Adults:50 mg/daily initially, increase up to 300 mg/day.

Levels increaed by valproate, decreased by carbamazepine,PB, phenytoin.

Get emergency medical help if you have any of these signs of an allergic reaction: hives; fever; swollen glands; painful sores in or around your eyes or mouth; difficulty breathing; swelling of your face, lips, tongue, or throat.Report any new or worsening symptoms to your doctor, such as: mood or behavior changes, depression, anxiety, or if you feel agitated, hostile, restless, hyperactive (mentally or physically), or have thoughts about suicide or hurting yourself.

Before taking lamotrigine, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your doctor or pharmacist your medical history, especially of: kidney disease, liver disease.This drug may make you dizzy or drowsy or cause blurred vision. Do not drive, use machinery, or do any activity that requires alertness or clear vision until you are sure you can perform such activities safely. Limit alcoholic beverages.