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Newer vs older aed (1)

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  • 1. NEWER VS OLDER AED Dr.B.PRAKASH.MD.DM., PSGIMS & R Kasturi Neuro Diagnostic Centre prakashneuro@yahoo.co.in, 978 948 1179 14th July 2013 Neuro Club Meet Black Thunder 1
  • 2. 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 2
  • 3. 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 3
  • 4. 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 4
  • 5. 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 5
  • 6. • Randomized mono therapy trials • In newly diagnosed epilepsy • Seizure freedom is the primary end point 6 IDEAL DRUG TRIALS
  • 7. IDEAL DRUG TRIALS • Only OXC, LTG, VGB, GBP, TPM, TGB underwent in such trials • Newer AED have notfound to be more efficacious against older AED • VGB, GBP, TGB are less efficacious than CBZ 7
  • 8. • 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 8 DRUG TRIALS
  • 9. • 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 9 DRUG TRIALS
  • 10. MECHANISM OF ACTION 10
  • 11. 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 11
  • 12. 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 12
  • 13. 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) 13
  • 14. 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) 14
  • 15. MECHANISMS FOR ADVERSE EFFECTS • OXC / CBZ : – Anti diuresis  Hypo natremia • TPM / ZNS : – Carb. Anhydrase inhibition  Paresthesia / Urolithiasis 15
  • 16. 16 NEWER AED - PHARMACOKINETICS
  • 17. NEWER AED - PHARMACOKINETICS Have linear pharmacokinetics in clinical dose • Clearance • Volume of distribution • Half life Dose Rate of absorption Route of admission are not affected by 17
  • 18. 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) 18
  • 19. 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 19
  • 20. EFFICACY 20
  • 21. 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 21
  • 22. ADVERSE EFFECT 22
  • 23. 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 23
  • 24. 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) 24
  • 25. 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 25
  • 26. 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 26
  • 27. • 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 27
  • 28. 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 28
  • 29. DRUG INTERACTIONS 29
  • 30. 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 30
  • 31. DRUG INTERACTIONS ENZYME 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 31
  • 32. 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 32
  • 33. 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 33
  • 34. 34 THERAPEUTIC DRUG MONITORING
  • 35. 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 35
  • 36. 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 36
  • 37. SEIZURE AGGRAVATION 37
  • 38. AED’S AGGRAVATING SEIZURES • CBZ, OXC, PHT, VGB, TGB, GBP 38
  • 39. 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 39
  • 40. OTHER FACTORS 40
  • 41. 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 41
  • 42. 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 42
  • 43. 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 43
  • 44. COST • Newer AED are much more expensive 44
  • 45. SELECTING AED 45
  • 46. 46 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
  • 47. 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 47
  • 48. BROAD SPECTRUM OF ACTIVITY • Newer AED are preferred as these are better tolerated OLDER NEWER VALPROATE LAMOTRIGENE BENZODIAZEPINE TOPIRAMATE PHENOBARBITAL ZONISAMIDE 48
  • 49. 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 49
  • 50. 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 50
  • 51. CHOICE OF AED Partial 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 51
  • 52. 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 52 • Newer AED occupies important place in all types of Seizures • Among Older AED Only VLP makes success in all areas
  • 53. 53 CONCLUSION
  • 54. 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 54
  • 55. THANK YOU 55

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