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NEWER VS OLDER AEDDr.B.PRAKASH.MD.DM.,

PSGIMS & RKasturi Neuro Diagnostic Centre

prakashneuro@yahoo.co.in, 978 948 1179

14th July 2013 Neuro Club Meet Black Thunder

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INTRODUCTION

• AEDs : Commonly prescribed, centrally active drugs

• Also used for conditions other than epilepsy (HA, Psy etc., )

• Most of AEDs have more than one MOA

• Newer AEDs have claimed to possess innovative action

• Clinical prediction of therapeutic & Ad.E are limited

• We need to update the post-marketing articles

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Development of AED

• Only Six AED were available before 1978• No single drug has been introduced between 1978 – 1993• About 15 drugs were launched in the last ten years

By 75 years of age, ten percent of population will have experienced some type of seizure.

Population Statistics

AED Statistics

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DRIVE TO DEVELOP NEW AED • The drive is the need • We have a need of ideal AED• The ideal AED is with no AdE / drug IA

CHARACTERISTICS OF IDEAL AED

Sustained Efficacy No Adverse Effects

Favorable Tolerability Once-daily Dosing

Broad Spectrum Of Activity Should Not Interact With Other

Linear Pharmacokinetics Easy monitoring of serum level

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WHY TO LOOK BACK ? • Now ten newer AED are available

• Why to weigh them against older AED

– Even now some older AED are not replaceable

– Newer AED brings out newer Ad.E even after marketing

– Combination requires knowledge on Drugs IA

– Most trials are done as add-on basis /against Placebo rather

than head to head basis

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• Randomized mono therapy trials• In newly diagnosed epilepsy• Seizure freedom is the primary end point

IDEAL DRUG TRIALS

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IDEAL DRUG TRIALS

• Only OXC, LTG, VGB, GBP, TPM, TGB underwent in such trials

• Newer AED have not found to be more efficacious against older AED

• VGB, GBP, TGB are less efficacious than CBZ

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• Only positive newer AED trial was – VGB vs Hydrocortisone – In patients with – Infantile Spasm associated with Tuberous Sclerosis

• However in Infantile Spasm due other etiologies, – VGB is less efficacious than ACTH

DRUG TRIALS

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• Despite the above facts, – pts refractory to older AED may become seizure free – with a newer AED (20-50%) or – add on newer AED (>50%)

• These observation signifies the importance of search for more efficacious newer AED

DRUG TRIALS

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MECHANISM OF ACTION

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BLOCKAGE OF VOLTAGE DEPENDENT SODIUM CHANNELS (VDSC)

• PHT, CBZ, OXC, LTG, TPM, ZNS, FBM• Selectively block high freq repetitive neuronal firing• Seizure spread is inhibited – without interfering physiological neuro transmission

• Useful both for focal and generalized seizures • Not useful for MC / ABS and may even aggravate it• Combination is not useful / sometimes harmful• Blocks (glu) transmission at Nerve terminal also

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POTENTIATION OF GABA ergic INHIBITION

• GABA is the main inhibitory transmitter

• In some brain areas, GABA has pro-epileptic effect

• VGB & TGB potentiates GABA mediated inhibition

• May aggravate seizures, especially MC/ABS

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BLOCK OF T-TYPE CA+ CHANNELS IN THALAMUS• Main MOA in preventing absence seizures

• ESX, ZNS, also VPA, LTG

• Blockade of L-Ca channels aggravate ABS (CBZ)

• Block of N/P/Q type Calcium channels is useful in

management of neuropathic pain.(GBP, PGB)

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OTHER MECHANISMS • TPM – AMPA / Kinase Receptors

• FBM – NMDA Receptors

• LTG – Modulates serotonergic transmission

• LTG / LEV – Affects Potassium currents

• LEV – Modulation of SV2A Protein (Synaptic vesicle protein)

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MECHANISMS FOR ADVERSE EFFECTS • OXC / CBZ : – Anti diuresis Hypo natremia

• TPM / ZNS : – Carb. Anhydrase inhibition Paresthesia / Urolithiasis

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NEWER AED - PHARMACOKINETICS

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NEWER AED - PHARMACOKINETICS

Have linear pharmacokinetics in clinical dose

• Clearance• Volume of distribution• Half life

DoseRate of absorptionRoute of admission

are not affected by

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NEWER AED - PHARMACOKINETICS• GBP, PGB, VGB : Only excreted in urine (unchanged )• LEV, TPM : Mainly excreted in urine

• TPM, TGB, ZNS : Affected by enzyme induction (PB,PHT,CBZ)

• FBM, LTG, OXC, TGB, ZSM • are eliminated by P450 medicated glucuronidation• Subject to drug IA (enzyme induction / inhibition)

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NEWER AED - PHARMACOKINETICS

• CBZ CBZ + VPA ↑ CBZ + ↓ VPA levels Less Efficacy• LTG LTG + VPA ↑ LTG + ↑ VPA More Teratogenic

• GBP, LEV, LCS, PGN, TCB No drug IA

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EFFICACY

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EFFICACY SPECTRUM

• VPA, BZD, LTG, TPM, PB, LEV, ZNS – Broad spectrum activity (Partial)

• ESM– Only ABS / ME/ Continuous spike wave during slow sleep

(CSWS)

• Ineffective / Aggravate seizures– PB : Absence seizures– LTG : Myoclonic epilepsy of infancy

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ADVERSE EFFECT

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ADVERSE EFFECT PROFILE PLAYS AN IMPORTANT ROLE IN AED SELECTION

1. Reversible / Dose dependent– Ataxia / Sedation / Dizziness /Cognitive Dysfunction

2. Slowly Reversible / Chronic– Body weight / Hirsuitism /Gingival hyperplasia

3. Idio-syncratic– Rashes / Blood Sugar / Liver Toxicity

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ADVERSE EFFECT PROFILE

• Drugs with serious Adverse Effects :– FBM: Aplastic Anemia(1:60,000) /Fatal liver tox(1: 26,000)– VBG : Filed defect (1:3.3)- First line treatment for Inf.Spsm

• Narrow Therapeutic Ratio Ad.E Occur in Therapeutic Range

• To prevent S/E– Introduce gradually(TPM, TGB)– Titrate slowly– Avoid totally (PHT, CBZ)

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ADVERSE EFFECT PROFILE• Most newer AED trials have come out with favorable Ad.Effect

profile

• Only VGB & FBM were found to be associated with serious toxicity

• Study design, comparator, dose scheme might have been biased to favor newer AED

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ADVERSE EFFECTS

• Main Adv. Effects– Hyper sensitivity– Weight Gain / Loss– Drug IA– CNS Toxicity

• No routine monitoring– CBZ

• CBC every month x 1 year• If ↓ WBC Stop the drug

– SVP• LFT every 3 months x 1 year• If ↑ SGPT / ammonia > two

times stop the drug

• To minimize Adverse effects– Avoid enzyme inducing drugs– Avoid poly-pharmacy– Well tolerated Newer AED

• For over dose– Decrease the dose

• For poisoning– Emesis, Actvtd.Charcoal– Lavage (Saline, Mg Cit)– Hemo Dialysis– Stop the Drug &– Start new drug simultaneously

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• Varying Ad.E profile makes us to select AED carefully

– GBP Weight gain

– TPM Weight loss

– GBP / LEV / TPM / TGB

• No imm mediated Ad. E noted, hence can be given for pts with drug

allergies

– Epilepsy in elderly : LTG is better tolerated

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ADVERSE EFFECT PROFILE

• Tailor Expected Adverse Effect Profile – Obese : Drugs causing weight loss– Hirsuitism : Avoid in women– Teratogenicity : Avoid in child bearing age women

• Never make a patient to suffer from Ad.E more than consequences of disease – Especially in polytherapy / difficult to treat epilepsy

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DRUG INTERACTIONS

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DRUG INTERACTIONS

• Why is it important ?

– Chronic use is needed

– Partly overlapping MOA

– Polypharmacy is common

– Many AED are enzyme inducers

– Preexisting or New Co-morbid illnesses

– Co-administration of medication often needed

– Drug interaction Change In Sr. Level Toxicity due to

narrow therapeutic window

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DRUG INTERACTIONSENZYME INDUCTION • Mainly by Older drugs (Less by Newer AED)• CBZ, PHT, PB, PRM

↓ of Sr. Conc of other AED, Chemotherapy, OCP, Psy Drug etc., ↑ dose requirement

ENZYME INHIBITION• Esp. VPA ↑ PB, LTG, CBZ epoxide concentration• OXC, FBM ↑ PHT

DISPLACEMENT FROM PLASMA PROTEIN• Clinical response will differ

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DRUG INTERACTIONS• Older AED have more interaction• Easily subject to induction / inhibition

• CBZ,PHT,PB are enzyme inducers• VPA is enzyme inhibitor

• GBP, LEV, VGB are excreted unchanged in urine – No drug interactions

• GBP, LEV, TPM, ZSM have little / no effect on the Pharmacokinetics of other drugs

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DRUG INTERACTIONS

• TPM, OXC, FBM may stimulate metabolism of steroids/ OCP

• VPA Inhibit metabolism of LTG

• Enzyme inducing AED↑Bio transformation of TGB, LTG, OXC,

TPM, ZSM, FBM

• At any Serum concentrations, tolerability is better with

monotherapy

• Some combinations work well like VPA + LTG

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THERAPEUTIC DRUG MONITORING

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THERAPEUTIC DRUG MONITORING

NEWER AED:• Drug monitoring of newer AED – limited• Therapeutic response window is larger• Monitoring facilities are not widely available• Monitoring is unfavorable for marketing

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THERAPEUTIC DRUG MONITORING

OLDER AED:• Monitoring is to guide dose adjustment

– Inadequate response– Poor compliance– Toxicity

• Literature coated values are not ideal– Age, Co-medication, Type of seizure, Underlying Pathology

may alter the response– Useful for difficult to treat epilepsy– Not for milder variants– Any value below the quoted upper limit is therapeutic range

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SEIZURE AGGRAVATION

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AED’S AGGRAVATING SEIZURES

• CBZ, OXC, PHT, VGB, TGB, GBP

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SEIZURE AGGRAVATION• Absences : CBZ, VGB, TGB (less with PHT)• JME : CBZ (less with PHT)• NCSE : TGB• Myoclonus : GBP

• IGE– GTCS Respond to one AED– Others Aggravated by same AED

• LGS– Tonic Respond to CBZ– Absences Aggravated

• Myclonic epilepsy of infancy : LTG

• Only broad spectrum AED do not aggravate seizures– VPA, LTG, TPM– VPA has Longest Clinical Experience / Largest Published Data

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OTHER FACTORS

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TOLERANCE ( Loss of effect)

• Reduction in Drug response / Ad.effect after repeated use• Depends on Drug / Genetic factors• Types

– Metabolic tolerance• Due to enzyme induction• Mainly in older AED• Overcome by increasing the dose

– Functional tolerance• Due to loss of receptor sensitivity• For all AED after prolonged treatment• Causes total loss of AED activity and cross tolerance

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EASE OF USE

• Broad Spectrum• Good tolerability• OD / BD dosage

• High response rate• Lack of interaction• Feasible rapid titration

• Older AED have non-linear phar.kinetics (PHT, CBZ, VPA)• Newer AED have linear kinetics(except GBP)• Most newer AED can be given twice daily

o TGB,GBP, FBM,OXC need more frequent dose• Rapid up titration is possible with GBP, LEV• Slow titration is needed to decrease S/E in LTG, TPM,

TGB, ZSM

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CO-MORBIDITY• Many AEDs precipitate Porphyria– GBP is the DOC

• GBP is useful in PNP with Epilepsy• LTG is useful for Bipolar depression• TPM is useful for Binge eating disorder

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COST

• Newer AED are much more expensive

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SELECTING AED

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OLDER AED NEWER AED NEWEST AED

Primidone

Phenobarbitone

Phenytoin Fosphenytoin

Valproate Divalproate

Carbamazepine Oxcarbazepine Eslicarbaepine

Levitiracetam Briveracetam

Gabapentin

Pregabalin

Lamotrigene

Tiagabine

Topiramate

Zonisamide Lacosamide

Vigabatrin

Felbemate

Perampinal

Rufinamide

Stiripentol

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NARROW SPECTRUM DRUGS

• Vigabatrin for infantile spasm with TS even if it causes irreversible field defects

• Felbamate if the patient is refractory to all drugs

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BROAD SPECTRUM OF ACTIVITY

• Newer AED are preferred as these are better tolerated

OLDER NEWER

VALPROATE LAMOTRIGENE

BENZODIAZEPINE TOPIRAMATE

PHENOBARBITAL ZONISAMIDE

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FACTORS AFFECTING THE SELECTION

BETTER CHOICE NOT BETTER

1. Spectrum of activity VALPROATE VIGABATRIN

2. Efficacy VALPROATE ZONISAMIDE

3. Side effect profile LEVETIRACETAM FELBAMATE

4. Drug interaction LEVETIRACETAM CARBAMAZEPINE

5. Ease of use DIVALPROEX PHENYTOIN

6. Co-morbidity LEVETIRACETAM CARBAMAZEPINE

7. Cost PHENOBARB LEVETIRACETAM

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SHORT COMINGS OF OLDER AED

PHT, CBZ :Bio-availability / bio equivalence problem

PHT : Non linear pharmokinetics

CBZ : Time dependent

CBZ, VPA :Short half life

PB, PHT, CBZ : Enzyme inducer

VPA : Enzyme inhibitor

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CHOICE OF AEDPartial seizures

Newer AED have more advntgs

• LEV, OXC, TOP, LTG are first line

• LSM, ZSM are for 2nd line add

• CLB, PB, PHT, TGB 3rd line

• ACZ, BRM, FBM, Sulthm, VGB are

used as last resort

• GBP is less efficacious

• CBZ / VPA efficacy > Newer AED

Generalized Seizures

Older AED have more advntgs

• VPA 1st DOC for IGE despite wt gain, terat’gty

• VPA controls - ABS: 75%, GTCS: 70%, MC: 75 %

• VPA, ESX, LTG are DOC for absences

• ESX Controls 70% of ABS but not suitable as

monotherapy

• PHT,CBZ,OXC,GBP induces myoclonic seizures

• VGB,TGB induces absences (C/I in IGE)

• LTG, TPM, LEV : Less efficacious

• LTG controls ABS & GTCS by 50% but

– Worsens MC jerks / Causes Skin rashes

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FIRST LINE AED (Older and Newer)• PARTIAL SEIZURES

– CBZ– LEV– OXC– VLP– TPM– LTG

• REFRACTORY PARTIAL – ABOVE– LSM– ZSM– CLB

• GENERALISED SEIZURES– VLP– LTG– TPM

• REFRACTORY GENERALISD– ABOVE– LEV– CLB

• Newer AED occupies important place in all types of Seizures• Among Older AED Only VLP makes success in all areas

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CONCLUSION

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CONCLUSIONS• VPA is the first line of therapy in IGE• CBZ is the first line of therapy in partial seizures• Inspite of several advantages Newer AEDs have not replaced Older

agents• On average, Newer drugs are not much efficacious than Older

agents• There is a trend towards Newer AED, in view of better tolerability• Newer generation AED does not cause serious morbidity in

overdose.• LEV & GBP can be used safely in hepatic diseases.• Older AED as base line and adding a Newer AED, we can achieve a

better seizure control in refractory epilepsy• In selected subgroup of patients (Age, co-medication, co-

morbidity) Newer AED are opted as first line therapy

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THANK YOU