Anticonvulsants Part II
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- 1. Anticonvulsants IIBrian J. Piper, Ph.D., M.S. email@example.comFebruary 8, 2013
2. Objectives Pharmacy students will be able to: describe the MOA of recently developed AEDs. identify and contrast the relative frequency ofadverse events for AEDs. 3. Voltage Sensitive Ion Channels Composed of multiple subunits (,,) subunit, transmembrane 4 = voltometer can exist in open, closed, or inactive states Pore inactivator Stahl (2008). Essential Psychopharmacology, p. 149, 152. 4. Carbamazepine Structure: similar to TCAs Indications: generalized & partial seizures PK: CYP3A4 inducer ( Carb t1/2 from 36 to 10!, birthcontrol) Adverse Events: diplopia, ataxia (not sedation) Pregnancy Category: D MOA: stabilizes the inactivated state of voltage-gated sodiumchannels 5. MOAs of Carbamazepine (& others) Prolong inactive state of voltage sensitive ionchannel for Na+, Ca2+, K+ Bind to subunit of Na+ channel Increase inhibitory effects of GABAStahl (2008). Essential Psychopharmacology. 6. Stevens-Johnson Syndrome Potentially lethal drug induced hypersensitivity Carbamazepine (1/5,000), phenobarbital,phenytoin, lamotrigine Symptoms: fever, sore throat, skin sloughing(mouth/lips, genitals, anus) Adults (Han Chinese) > children Conjunctivitis in SJSBae et al. (2013). Korean Journal of Pain, 26(1), 80 83. 7. Oxcarbazepine (& Eslicarbazepine) Structure: similar to carbamazepine Indications: generalized & partial seizures Adverse Events: diplopia, ataxia, hyponatremia PK: CYP3A4 inducer t1/2 = 2 / 10 AE: SJS (rare)(Europe only) 8. Lamotrigine Indications: partial & generalized seizures Lennox-Gastaut syndrome Bipolar I MOA: voltage gated ion channels, glutamaterelease Adverse Effects: dizziness, headache, somnolence PK: t1/2 = 24 h Pregnancy Category: C 9. Comparative Efficacy & Tolerability AED nave epileptics (age 13-80) randomized tolamotrigine (150 mg/day) or carbamazepine (600mg/day)->->Brodie et al. (1995). Lancet, 345, 476-479. 10. Gabapentin MOA: voltage sensitive Ca2+ channels GABA glutamate Indications: partial seizures, pain, not bipolar Adverse Events: somnolence, ataxia, headache PK: t1/2 = 6 hours not CYP inducer, negligible drug interactionsPorter & Meldrum (2011). In Katzungs Basic & Clinical Pharmacology, p. 413. 11. AED Rash Rashes, commonly minor, are commonly experienced by epileptics (16%). Comparison of rash rates in practices of 13 epileptologists (N = 1,890 adults) Average rate of rash = 2.8% Significantly above average: phenytoin (PHT), lamotrigine (LTG) Average: oxcarbazepine (OXC), carbamazepine (CBZ) Significantly below average: gabapentin (GBP), valproate (VPA)Arif et al. (2007). Neurology, 68, 1701-1709. 12. AED Rash Rashes, commonly minor, are commonly experienced by epileptics (16%). Comparison of rash rates in practices of 13 epileptologists (N = 1,890 adults) AED discontinuation due to rash = 1.3% Significantly above average: phenytoin (PHT), lamotrigine (LTG) Average: oxcarbazepine (OXC), carbamazepine (CBZ) Significantly below average: gabapentin (GBP), valproate (VPA)Arif et al. (2007). Neurology, 68, 1701-1709. 13. No malformations = safe? Prospective study of offspring ofepileptics that received: sodium valproate (VPA, N=42) carbamazepine (CBZ, N=48) lamotrigine (LTG, N=34) -------------------------------------------------- polytherapy (Poly, N=30), * no medications (NoMe, N=27). Offspring of non-epileptics(control, N=230) were alsoexamined Neuropsychological test 1 year Monotherapy < ControlBromley et al. (2010). Epilepsia, 51(10), 2058-2065. 14. Prenatal AEDs & Autism Neurodevelopmental disorders (Autism Spectrum Disorders, ADHD & dyspraxia) at age 6 in a prospective study.Bromley et al. (2013). Journal of Neurology, Neurosurgery, & Psychiatry, in press. 15. Future Pipeline15 16. FDA Approved IndicationsAgent Epilepsy Seizure Type Otherphenobarbital partial & generalizedphenytoin partial & generalizedvalproic acid absence & partial manic episodes, migrainecarbamazepine partial & generalized bipolar I, pain (neuralgia)oxcarbazepine partiallamotrigine partial & generalized bipolar Igabapentinpartial pain (neuralgia) 17. AED & Suicide Suicide rates are 3-fold higher among epileptics relativeto the general population. The FDA issued an alert that all AEDs may increase riskof suicidal thoughts/behavior; monitor for worsening ofdepression and any unusual changes in mood orbehavior. Evidence is currently inconclusive whether increasedsuicide following AEDs (oxcarbazepine, valproate) occursonly in high risk populations (bipolar, chronic pain) or inepileptics without comorbid conditions.Patorno et al. (2010), JAMA, 303(14), 1401-1409; Hecimovic et al. (2011). Epilepsy & Behavior, 22, 77-84. 18. General AED Principles At least 50% of epileptics have a substantial reduction in seizure frequency with AEDs. If one AED doesnt work, the likelihood that a second wont work is greater. Seizures are intractable in 30% of epileptics.Brodie, M. J. (2010). Seizure, 19, 650-655, 19. Summary AEDs target voltage gated channels & GABA. 2nd generation AED are better tolerated thanolder agents but offer limited improvementsin efficacy. Polytherapy is very common for seizurecontrol which presents opportunities tomanage drug interactions.