Aed new vs old final

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Anti Epileptic Drugs, New Vs. Old

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  • 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.
  • 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.
  • These slides really on a more complicated level than rest of talk
  • Confirm Keppra indications?
  • Aed new vs old final

    1. 1. What’s New In Antiepileptic Drugs
    2. 2. ILAE Classification of Seizures Seizures Partial Generalized Simple Partial Absence Complex Partial Myoclonic Secondarily Generalized Atonic Tonic Tonic-Clonic C-Slide 2
    3. 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. 4. AED Choice by Seizure 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. 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. 6. Idiosyncratic Adverse Effects of AEDs  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. 7. Long-Term Adverse Effects of AEDs  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. 8. Stevens-Johnson Syndrome
    9. 9. Gingival Hyperplasia Induced by Phenytoin New Eng J Med. 2000:342:325. P-Slide 9
    10. 10. After Withdrawal of Phenytoin New Eng J Med. 2000:342:325. P-Slide 10
    11. 11. Trabecular Bone http://www.merck.com P-Slide 11
    12. 12. AED Hypersensitivity Syndrome  Characterized by rash, systemic involvement  Arene oxide intermediates - aromatic ring  Lack of epoxide hydrolase  Cross-reactivity P-Slide 12 – – – – Phenytoin Carbamazepine Phenobarbital Oxcarbazepine
    13. 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. 14. DO WE NEED MORE 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. 15. The Ideal AED Therapy: • 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. 16. New Versus Standard AEDs • Equal efficacy • Differentiated by – Adverse events – Drug interactions – Pharmacokinetics profiles
    17. 17. How do we make 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. 18. Number of Licensed Antiepileptic 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. 19. Number of Licensed Antiepileptic Drugs SINCE 1998 20 Pregabalin 10 Zonisamide Levetiracetam Tiagabine Oxcarbazepine Topiramate 5 Fosphenytoin Lamotrigine Gabapentin Felbamate 0 1990 2000 Calendar Year
    20. 20. AED Choice by Seizure 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. 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. 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. 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. 24. 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)
    25. 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. 26. 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
    27. 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. 28. What’s really new • Two new drugs – Revolutionary • lacosamide • rufinamide • Four drugs in late trials – Evolutionary • brivaracetam • Eslicarbazepine – Revolutionary: • Carisbamate • Retigabine
    29. 29. Lacosamide • Works on sodium 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. 30. Double-Blind Placebo-Controlled Add-on Trial 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. 31. RUFINAMIDE • Also works on 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. 32. Rufinamide AEs With Incidence ≥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. 33. BRIVARACETAM • Similar mechanism to Levetiracetam but much stronger in animal models • Also has sodium channel blocking activity • FDA trials underway
    34. 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. 35. Eslicarbazepine • A “third generation” 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. 36. • • • • Summary of 2nd Generation AEDs Safer More expensive May help with intractable partial seizures Less drug interactions • Not profoundly more potent
    37. 37. ILAE Summary Guidelines Seizure type 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. 38. Summary of AAN evidence-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. 39. Summary of AAN evidence-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. 40. Summary of AAN evidencebased 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. 41. Summary of AAN evidencebased 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. 42. Summary of ILAE guidelines on therapeutic drug levels C-Slide 42
    43. 43. LEVEL OF KNOWLEDGE AT TIME OF APPROVAL What we know What we don’t know
    44. 44. THANK YOU !!!

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