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![Gabapentin
• Mechanism
– designed, yet unknown
• Dose (900 to 4800 mg/day [TID to QID])
• Side Effects
– fatigue, dizziness, ataxia
• Drug Interactions
– None with AEDs [only Antacids]
• Renal Elimination - CrCl
• Clinical Pearl
– non-Epilepsy uses](https://image.slidesharecdn.com/aednewvsoldfinal-140130012303-phpapp02/85/Aed-new-vs-old-final-21-320.jpg)
![Lamotrigine
• Mechanism
– Na+ Channels, Glutamate
• Dose (100 to 500 mg/day [QD or BID])
• Side Effects
– Sedation, Diplopia, Ataxia, Nausea - Rash
• Drug Interactions
• “one way street”
• Contraceptives
• Clinical Pearl
• Slow taper - (esp. VPA)
• Incidence of severe rash may by overestimated
• Pediatric approval](https://image.slidesharecdn.com/aednewvsoldfinal-140130012303-phpapp02/85/Aed-new-vs-old-final-22-320.jpg)
![Topiramate
• Mechanisms - many
– Na+ Channels, Glutamate, GABA, CAI
• Dose (200 to 400 mg/day [BID - QDrenal])
• Side Effects
• Sedation, Difficulty Concentrating, Kidney Stones, Glaucoma
• Drug Interactions
– “one way street”
• Clinical Pearl
– ceiling dose, fluids, visual changes, use outside of
epilepsy](https://image.slidesharecdn.com/aednewvsoldfinal-140130012303-phpapp02/85/Aed-new-vs-old-final-23-320.jpg)
![Tiagabine
• Mechanism
– Blocks re-uptake of pre-synaptic GABA
• Dose (32 to 56 mg/day [BID to QID])
• Side Effects
– Fatigue, Dizziness, Weakness
• Drug Interactions
– “one-way street”
• Clinical Pearl
• different mechanism of action
• take with food to decrease side effects (same AUC)](https://image.slidesharecdn.com/aednewvsoldfinal-140130012303-phpapp02/85/Aed-new-vs-old-final-24-320.jpg)
![Oxcarbazepine
• Mechanism - Na+ Channels
• Dose
• Adjunctive (600 to 1,200 mg/day [BID])
• Mono (up to 2,400 mg/day)
• Side Effects
• Dizziness, Somnolence, Diplopia, N/V, Ataxia
• Drug Interactions
• Inhibit/Induce - OCs, PHT
• Clinical Pearl
• Prodrug (OCBZ to MHD)](https://image.slidesharecdn.com/aednewvsoldfinal-140130012303-phpapp02/85/Aed-new-vs-old-final-25-320.jpg)
![Levetiracetam
• Mechanism
– SV 2 inhibitor
• Dose: (1,000 to 3,000 mg/day [BID])
• Side Effects
– Somnolence, Asthenia, Infection, Dizziness
• Drug Interactions
– PK
• None with AEDs, probenecid - metabolite
– PD ?
• Clinical Pearl
– Adjust dose for renal function](https://image.slidesharecdn.com/aednewvsoldfinal-140130012303-phpapp02/85/Aed-new-vs-old-final-26-320.jpg)
Uploaded byRahul Kumar
Aed new vs old final
This document provides a summary of new and standard antiepileptic drugs (AEDs) in 3 sentences or less: Two new AEDs, lacosamide and ru
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Aed new vs old final
- 1. What’s New InAntiepileptic Drugs
- 2. ILAE Classification ofSeizures Seizures Partial Generalized Simple Partial Absence Complex Partial Myoclonic Secondarily Generalized Atonic Tonic Tonic-Clonic C-Slide 2
- 3. Complex Partial Seizures Impaired consciousness Clinical manifestations vary with site of origin and degree of spread – Presence and nature of aura Seizures Partial Generalized – Automatisms – Other motor activity Duration typically < 2 minutes Complex Partial C-Slide 3
- 4. AED Choice bySeizure Type Partial Simple Complex Secondary generalized Generalized Tonicclonic Tonic Myoclonic PHT, CBZ, PB, GBP, TGB, LVT, OCBZ Atonic Infantile Spasms ACTH TPM? TGB? VGB? VPA, LTG, TPM, (FBM) ZNS Absence ESX
- 5. 1st Generation AEDs •Vast Clinical Experience • Incomplete Efficacy • Unfavorable Kinetics (M-M, protein binding) • Narrow Therapeutic Range – Small window between efficacy & toxicity • Adverse CNS Effects • Adverse Non-CNS Effects • Drug-Interactions
- 6. Idiosyncratic Adverse Effects ofAEDs Hematologic damage – Marrow aplasia, agranulocytosis – Early symptoms: abnormal bleeding, acute onset of fever, symptoms of anemia – Laboratory monitoring probably not helpful in early detection – Felbamate aplastic anemia approx. 1:5,000 treated patients – Patient education P-Slide 6
- 7. Long-Term Adverse Effects ofAEDs Endocrine/Metabolic Effects • Osteomalacia, osteoporosis • Carbamazepine • Phenobarbital • Phenytoin • Oxcarbazepine • Valproate • Folate (anemia, teratogenesis) • Phenobarbital • Phenytoin • Carbamazepine • Valproate • P-Slide 7 Altered connective tissue metabolism or growth (facial coarsening, hirsutism, gingival hyperplasia or contractures) • Phenytoin • Phenobarbital Neurologic • Neuropathy • Cerebellar syndrome phenytoin Sexual Dysfunction - 3060% • Phenytoin • Carbamazepine • Phenobarbital • Primidone
- 8.
- 9. Gingival Hyperplasia Induced by Phenytoin NewEng J Med. 2000:342:325. P-Slide 9
- 10. After Withdrawal of Phenytoin NewEng J Med. 2000:342:325. P-Slide 10
- 11.
- 12. AED Hypersensitivity Syndrome Characterizedby rash, systemic involvement Arene oxide intermediates - aromatic ring Lack of epoxide hydrolase Cross-reactivity P-Slide 12 – – – – Phenytoin Carbamazepine Phenobarbital Oxcarbazepine
- 13. Influence on Hepatic Metabolism •1st Generation antiepileptic drugs – Inducers • Phenobarbital • Phenytoin • Carbamazepine – Inhibitor • Valproate • Therefore, affect the kinetics and dynamics of nonCNS drugs as well…
- 14. DO WE NEEDMORE NEW ANTIEPILEPTIC DRUGS? • Problem with conventional AEDs: – Seizure control • Newly diagnosed well treated • Still 40% with therapy resistance • New AEDs over last 20 years are slowly changing this equation!
- 15. The Ideal AEDTherapy: • Improved efficacy → no seizures • Few side effects → no new problems in patient’s daily life • Easy dosing scheduling → no chance for dosing mistakes • Minimal drug interactions → no need to adjust other medicines • Expense not prohibitive → cost will not prevent taking the AED • Maximizing quality of life
- 16. New Versus StandardAEDs • Equal efficacy • Differentiated by – Adverse events – Drug interactions – Pharmacokinetics profiles
- 17. How do wemake progress? • Revolutionary Drugs – Drugs that work with new mechanisms never tried before – Expectation: They will control seizures that existing drugs can’t control • Evolutionary Drugs – Improve on existing drugs – Expectation: We can eliminate some of the problems/side effects of good drugs, without reducing their effect on seizures
- 18. Number of LicensedAntiepileptic Drugs ANTIEPILEPTIC DRUG DEVELOPMENT ? 20 Pregabalin Zonisamide Levetiracetam Oxcarbazepine Tiagabine 15 Fosphenytoin Topiramate Lamotrigine Gabapentin 10 Felbamate Sodium Valproate Carbamazepine Ethosuximide 5 Phenobarbital Phenytoin Benzodiazepines Primidone Bromide 0 1840 Retigabine Rufinamide Lacosamide Brivaracetam 1860 1880 1900 1920 1940 Calendar Year 1960 1980 2000
- 19. Number of LicensedAntiepileptic Drugs SINCE 1998 20 Pregabalin 10 Zonisamide Levetiracetam Tiagabine Oxcarbazepine Topiramate 5 Fosphenytoin Lamotrigine Gabapentin Felbamate 0 1990 2000 Calendar Year
- 20. AED Choice bySeizure Type Partial Simple Complex Secondary generalized Generalized Tonicclonic Tonic Myoclonic PHT, CBZ, PB, GBP, TGB, LVT, OCBZ Atonic Infantile Spasms ACTH TPM? TGB? VGB? VPA, LTG, TPM, (FBM) ZNS Absence ESX
- 21. Gabapentin • Mechanism – designed,yet unknown • Dose (900 to 4800 mg/day [TID to QID]) • Side Effects – fatigue, dizziness, ataxia • Drug Interactions – None with AEDs [only Antacids] • Renal Elimination - CrCl • Clinical Pearl – non-Epilepsy uses
- 22. Lamotrigine • Mechanism – Na+Channels, Glutamate • Dose (100 to 500 mg/day [QD or BID]) • Side Effects – Sedation, Diplopia, Ataxia, Nausea - Rash • Drug Interactions • “one way street” • Contraceptives • Clinical Pearl • Slow taper - (esp. VPA) • Incidence of severe rash may by overestimated • Pediatric approval
- 23. Topiramate • Mechanisms -many – Na+ Channels, Glutamate, GABA, CAI • Dose (200 to 400 mg/day [BID - QDrenal]) • Side Effects • Sedation, Difficulty Concentrating, Kidney Stones, Glaucoma • Drug Interactions – “one way street” • Clinical Pearl – ceiling dose, fluids, visual changes, use outside of epilepsy
- 24. Tiagabine • Mechanism – Blocksre-uptake of pre-synaptic GABA • Dose (32 to 56 mg/day [BID to QID]) • Side Effects – Fatigue, Dizziness, Weakness • Drug Interactions – “one-way street” • Clinical Pearl • different mechanism of action • take with food to decrease side effects (same AUC)
- 25. Oxcarbazepine • Mechanism -Na+ Channels • Dose • Adjunctive (600 to 1,200 mg/day [BID]) • Mono (up to 2,400 mg/day) • Side Effects • Dizziness, Somnolence, Diplopia, N/V, Ataxia • Drug Interactions • Inhibit/Induce - OCs, PHT • Clinical Pearl • Prodrug (OCBZ to MHD)
- 26. Levetiracetam • Mechanism – SV2 inhibitor • Dose: (1,000 to 3,000 mg/day [BID]) • Side Effects – Somnolence, Asthenia, Infection, Dizziness • Drug Interactions – PK • None with AEDs, probenecid - metabolite – PD ? • Clinical Pearl – Adjust dose for renal function
- 27. Zonisamide • Mechanism – Na+and T-calcium channels, CAI • Dose: 100 to 600 mg/day (BID or QD) • Side Effects: – somnolence, dizziness, nausea, headache, agitation/irritation, kidney stones, weight loss • Drug Interactions • No effect on others • Clinical Pearl • Appr. Japan & Korea ‘89, Sulfonamide • Use outside of epilepsy
- 28. What’s really new •Two new drugs – Revolutionary • lacosamide • rufinamide • Four drugs in late trials – Evolutionary • brivaracetam • Eslicarbazepine – Revolutionary: • Carisbamate • Retigabine
- 29. Lacosamide • Works onsodium channels, like Carbamazepine and Phenytoin • However, It selectively enhances slow inactivation of sodium channels, whereas the older drugs work on fast inactivation • Approved in Europe and USA
- 30. Double-Blind Placebo-Controlled Add-onTrial of Lacosamide (LCS) in Refractory Partial Epilepsy: 50% Responder Rates (n=418) % Patients 41%* 38%* 33% (* P<0.05 vs PL) 22% Placebo LCS 200mg LCS 400mg LCS 600mg Ben-Menachem, E et al Efficacy and Safety of Oral Lacosamide as Adjunctive Therapy in Adults with Partial-Onset Seizures Epilepsia. 2007
- 31. RUFINAMIDE • Also workson sodium channels with new mechanism • Approved in Europe for treatment of a severe form of epilepsy (Lennox-Gastaut syndrome) – “Orphan drug” • In Front of FDA for Lennox-Gastaut and Partial seizures
- 32. Rufinamide AEs WithIncidence ≥3% vs Placebo: All Treated Subjects With Epilepsy (Doubleblind Only) Rufinamide N (%) Placebo N (%) 1465 635 1180 (80.5) 497 (78.3) 36 (17) 16 (8.1) Vomiting 35 (16.5) 14 (7.1) Headache 34 (16.0) 16 (8.1) Nausea 16 (7.5) 7 (3.6) Ataxia 10 (4.7) 1 (0.5) Diplopia 10 (4.7) 1 (0.5 Subjects Subjects with an AE Somnolence
- 33. BRIVARACETAM • Similar mechanismto Levetiracetam but much stronger in animal models • Also has sodium channel blocking activity • FDA trials underway
- 34. Efficacy of Brivaracetam(5, 20 and 50 mg/day) Add-on Treatment in Refractory Partial-Onset Epilepsy RESPONDER RATES p = 0.001 55.8% 60 8.0% 4/50 p = 0.047 32.0% 40 7.7% 4/52 7.7% 4/52 BRV5 (n=50) BRV20 (n=52) BRV50 (n=52) % Patients % Respondents 10 p = 0.002 44.2% 50 30 20 SEIZURE-FREEDOM RATES 16.7% 1.9% 1/54 10 0 PBO (n=54) BRV5 (n=50) BRV20 (n=52) BRV50 (n=52) ITT population: n=208; 110M, 98F; age range 16–65 y 0 PBO (n=54)
- 35. Eslicarbazepine • A “thirdgeneration” Carbamazepine • Improves on second generation – Less effect on sodium – Smoother release may produce less side effects • Hopefully will work equally as well • Ready to submit to FDA
- 36. • • • • Summary of 2ndGeneration AEDs Safer More expensive May help with intractable partial seizures Less drug interactions • Not profoundly more potent
- 37. ILAE Summary Guidelines Seizuretype or epilepsy syndrome Class I Studies Class II Studies Class III Studies Level of efficacy and effectiveness evidence (in alphabetic order) Adults with partial-onset seizures 2 1 30 Level A: CBZ, PHT Level B: VPA Level C: GBP, LTG, OXC, PB, TPM, VGB Children with partial-onset Seizures 1 0 17 Level A: OXC Level B: None Level C: CBZ, PB, PHT, TPM, VPA Elderly adults with partialonset seizures 1 1 2 Level A: GBP, Level B: None Level C: CBZ Adults with generalized onset tonic–clonic seizures 0 0 23 Level A: None Level B: None Level C: CBZ, LTG, OXC, PB, PHT, TPM, VPA Children with generalized onset tonic–clonic seizures 0 0 14 Level A: None Level B: None Level C: CBZ, PB, PHT, TPM, VPA Children with absence Seizures 0 0 6 Level A: None Level B: None Level C: ESM, LTG, VPA BECTS 0 0 2 Level A: None Level B: None Level C: CBZ, VPA JME 0 0 0 Levels A, B, C: None LTG Reference: Epilepsia 2006:47; 1094-1120.
- 38. Summary of AANevidence-based guidelines level A or B recommendations AED Newly Diagnosed Monotherapy Partial/mixed Newly Diagnosed Absence Gabapentin Yes* No Lamotrigine Yes* Yes* Topiramate Yes No Tiagabine No No *Not FDA approved for this indication Reference: Neurology 2004, 62:1252-1260. C-Slide 38
- 39. Summary of AANevidence-based guidelines level A or B recommendations AED Newly Diagnosed Monotherapy Partial/mixed Newly Diagnosed Absence Oxcarbazepine Yes No Levetiracetam No No Zonisamide No No *Not FDA approved for this indication Reference: Neurology 2004, 62:1252-1260. C-Slide 39
- 40. Summary of AANevidencebased guidelines level A or B recommendation AED Partial adjunctive adult Partial Monotherapy Primary generalized Symptomatic generalized Pediatric partial Gabapentin Yes No No No Yes Yes Yes Yes*(only absence) Yes Yes Yes No No No No Lamotrigine Levetiracetam * Not FDA approved for this indication References: Neurology 2004, 62:1252-1260. | Neurology 2004, 62:1261-1273. C-Slide 40
- 41. Summary of AANevidencebased guidelines level A or B recommendation AED Partial adjunctive adult Partial Monotherapy Primary generalized Symptomatic generalized Pediatric partial Oxcarbazepin e Yes Yes No No Yes Tiagabine Yes No No No No Topiramate Yes Yes* Yes Yes Yes Zonisamide Yes No No No No * Not FDA approved for this indication References: Neurology 2004, 62:1252-1260. | Neurology 2004, 62:1261-1273. C-Slide 41
- 42. Summary of ILAEguidelines on therapeutic drug levels C-Slide 42
- 43. LEVEL OF KNOWLEDGEAT TIME OF APPROVAL What we know What we don’t know
- 44.
Editor's Notes
- #4 Complex partial seizures impair consciousness. Typically, staring is accompanied by impaired responsiveness, cognitive function, and recall, although some degree of responsiveness may be preserved (e.g., orienting toward a stimulus). Automatic movements (automatisms) are common and involve the mouth (e.g., lip smacking, chewing, swallowing), upper extremities (e.g., fumbling, picking), vocalization/verbalization (e.g., grunts, repeating a phrase), or complex acts (e.g., shuffling cards). More dramatic automatisms occasionally occur (e.g., screaming, running, disrobing, pelvic thrusting). Complex partial seizures usually last from 15 seconds to 3 minutes. After the seizure, postictal confusion is common, usually lasting less than 15 minutes, although other symptoms, such as fatigue, may persist for hours.
- #10 17 yo boy with h/o generalized tonic clonic seizures for 4 years on phenytoin 300mg/day for 2 years WITHOUT SUPERVISION. Found to have severe gingival hyperplasia and cerebellar ataxia.
- #40 These slides really on a more complicated level than rest of talk
- #41 Confirm Keppra indications?