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Classic AEDs John M. Pellock, MD Professor and Chairman Division of Child Neurology Virginia Commonwealth University Medical College of Virginia Hospitals Richmond, Virginia Older AEDs Phenobarbital (1912) Phenytoin (1938) Ethosuximide (1960) Carbamazepine (1974) Valproic acid (1978) Bromides Benzodiazepines First-Line Therapy Early 20th Century VA Cooperative Study Mattson RH et al. N Engl J Med 313:145, 1985 Toxicity of Classic AEDs M de Silva (Lancet 1996) randomized 167 children with partial or tonic-clonic seizures 6 of 10 children assigned to phenobarbital had behavioral or cognitive adverse events Only 15 children had adverse effects requiring withdrawal Phenytoin: 2 with drowsiness; 1 each skin rash, hirsutism and blood dyscrasia Carbamazepine: 1 each drowsiness and blood dyscrasia VPA: 1 each behavioral and tremor Classic Drugs are Equally Effective AED Selection Seizure type and syndrome Neonatal seizures Infantile spasms Generalized epilepsies Partial-onset AED efficacy AED toxicity Need for monitoring Ease of dosing and compliance issues Underlying medical conditions Medication interactions Urgency of initiating therapy Cost Carbamazepine Carbamazepine Dose: 10-35 mg/kg/day (bid-qid) Elimination >85% hepatic Major pathway CYP3A4 Active metabolite 10-11 epoxide, metabolized by epoxide hydrolase (may be increased out of proportion to total level) Autoinduction Clearance can increase by 300% over first 3-5 wks May need 3 to 4x / day dosing in children Carbamazepine: Adverse Effects 10% with transient leukopenia Risk of aplastic anemia and agranulocytosis 5-8x risk in general population Mid-1980s, 31 cases thrombocytopenia 10 cases agranulocytosis 27 cases aplastic anemia 8 cases pancytopenia Rash reported in 17% pts; 10% have been life-threatening Incidence of rash increased with age: 5% at 0-6 yrs, 15.4% at >7 yrs Hepatotoxicity 20 cases of clinical significance reported by mid-1980s Hepatotoxicity reversible, but recurs with re-administration of drug Dose related neurotoxic effects: dizziness, somnolence, ataxia, diplopia, blurred vision, nausea Carbamazepine: Drug Interactions Enzyme inducer Effects on thyroid and sex hormones Effects on vitamin D metabolism Multiple drug interactions Increase CBZ Azole antifungals, cimetidine, delaviridine, diltiazem, clarithromycin, erythromycin, fluoxetine, INH, NNRTIs, omeprazole, PIs, propoxyphene, verapamil, caffeine, grapefruit juice Decrease CBZ FBM, desmethyldiazepam, PB, PHT, loxapine Increase epoxide levels FBM, VPA Carbamazepine: Drug Interactions Levels rise with CBZ Chlorothiazide, MAO inhibitors, lithium, perphenazine, acenocoumarol, digitalis glycosides, furosemide and INH No significant clinical interaction Phenobarbital, primidone Levels decrease with CBZ Antipsychotics (haloperidol, alprazolam, clozapine, trazadone – clinically insignificant with olanzapine) Azole antifungals, calcium chennel blockers, cyclosporine, FBM, VPA, narcotics, neuromuscular blockers, NNRTIs, oral contraceptives, PIs, theophylline, TGB, tricyclics, VPA, warfarin, ZNS Benzodiazepines Oxcarbazepine Metabolic Pathway: No Epoxide, No Autoinduction O OH Gluc O Reduction Conjugation N N O O NH2 N NH2 O NH2 MHD Oxcarbazepine O Oxidation N O No autoinduction Hydrolysis OH N NH2 Carbamazepine O N NH2 10, 11-Epoxide Schachter S. Exp Opin Invest Drugs 8:1, 1999 OH O NH2 Autoinductio n Oxcarbazepine: Pediatric Adjunctive Therapy Trial 60 Oxcarbazepine (n=135) % of Patients 45 Placebo (n=128) 41% 30 27% 22% 15 7% 4% 1% 0 >50% >75% Decrease in Seizure Frequency Glauser TA et al. Neurology 54:2237, 2000 100% Safety of Oxcarbazepine: Hyponatremia Incidence of clinically significant hyponatremia (Na <125 mmol/L) in clinical trials: 2.5% Most (79%) were receiving concomitant Na-depleting medications Hyponatremia usually asymptomatic TRILEPTAL® prescribing information Safety of Oxcarbazepine: Hypersensitivity 25-30% hypersensitive to CBZ will experience similar reaction to OXC Prevention of hypersensitivity reactions Ask about prior adverse experiences with CBZ If patient has history of hypersensitivity with CBZ, use OXC only if benefit justifies risk Discontinue OXC immediately if signs or symptoms of hypersensitivity develop TRILEPTAL® prescribing information Dosing Guidelines: Pediatric Adjunctive Therapy Approved product labeling recommendations Starting dose: 8-10 mg/kg/day (not to exceed 600 mg/day); titrate to target dose over 2 wks Target dose based on weight 20-29 kg 29.1-39 kg 1200 mg/day >39 kg 1800 mg/day 900 mg/day Clinical experience Improved tolerability with lower starting dose and slower titration Starting dose: 4-5 mg/kg/day increased weekly by 4-5 mg/kg/day to target dose of 20 mg/kg/day in approximately 4 wks Phenobarbital Used in neonatal seizures, and potentially useful for severe epilepsy acknowledging its cognitive, depressive, and behavioral side effects Formulations: 30, 60, and 100 mg tabs; 20 mg / 5 mL elixir Doses Half-life Neonates, 3-4 mg/kg/day Infants, 4-5 mg/kg/day Children, 2-3 mg/kg/day Adults, 0.5-1 mg/kg/day 43-217 hrs Slow taper to discontinue 35-73 hrs 56-140 hrs Phenobarbital: Adverse Effects Neurotoxic effects Sedation, dizziness, mood change, insomnia, hyperkinesia (children, elderly) Cognitive dysfunction Others Osteomalacia Peripheral neuropathy Dupuytren’s contraction Frozen shoulder Idiosyncratic Skin rash Hepatotoxicity Blood dyscrasia Phenobarbital: Drug Interactions Increase PB levels: FBM, MSM, VPA Phenytoin may increase or decrease levels Phenobarbital decreases blood levels Antipsychotics, azole antifungals, CB, CBZ, cyclosporine, FBM, LTG, narcotics, NNRTIs, oral contraceptives, PHT, PIs, steroids, TGB, theophylline, TPM, tricyclics, VPA, warfarin, ZNS Dosing Guidelines: Pediatric Adjunctive Therapy Approved product labeling recommendations Starting dose: 8-10 mg/kg/day (not to exceed 600 mg/day); titrate to target dose over 2 wks Target dose based on weight 20-29 kg 29.1-39 kg 1200 mg/day >39 kg 1800 mg/day 900 mg/day Clinical experience Improved tolerability with lower starting dose and slower titration Starting dose: 4-5 mg/kg/day increased weekly by 4-5 mg/kg/day to target dose of 20 mg/kg/day in approximately 4 wks Phenytoin Phenytoin Pediatric doses Neonate Poor absorption 3 mo-3 yr 4-6 yrs 7-9 yrs >10 yrs mg/kg/day 4-6 15-20 6-10 5-7 4-7 4-6 Half-life, hrs 3-140 1.2-31.5 6-60 Volume of distribution: 0.7-1.2 (neonates) Saturable metabolism, does not follow linear kinetics Oral load can be divided into increments of 300-400 mg given every 2-4 hrs Highly protein bound VPA can increase free fraction by 0.1% for each mg/mL At VPA levels of 100, free phenytoin can be 20% of total Phenytoin: Adverse Effects and Drug Interactions Side effects: nystagmus, ataxia, dizziness, hirsuitism, gingival hyperplasia, peripheral neuropathy, osteomalacia, folate deficiency Idiosyncratic Skin rash Hepatotoxicity Blood dyscrasia Lymphadenopathy Increase PHT levels: amiodarone, cimetidine, diltiazem, FBM, fluconazole, fluoxetine, INH, MSM, omeprazole, OXC, PB, ritonavir, ticlopidine, TPM, VPA Decrease PHT levels: antacids, CBZ, ciprofloxacin, PB, sucralfate R. DeLorenzo, in Antiepileptic Drugs, 4th Edition Ethosuximide Useful for absence attacks of childhood absence epilepsy and for atypical absence Formulations: 250 mg capsule and 250 mg/5 mL solution Common pediatric dose: 10-15 mg/kg/day (initial); 15-40 mg/kg/day (maintenance) qd – tid Increased doses can decrease GI side effects Adverse effects: GI distress, nausea, anorexia, drowsiness, HA, dizziness, hiccups, behavioral changes (rare psychotic reactions) Idiosyncratic: skin rash, blood dyscrasia VPA may increase levels; CBZ, PB, PHT decrease levels Valproic Acid Valproic Acid Different spectrum of usefulness (generalized, absence, atonic, myoclonic [Lennox-Gastaut] seizures) Used in bipolar and schizoaffective disorders Common pediatric doses: 15-60 mg/kg/day Elimination: hepatic metabolism (>95%), glucuronidation (20-50%), beta-oxidation (40%), CYP (minor) Adverse reactions: hepatotoxicity (highest risk in those <2 yrs and on multiple AEDs), pancreatitis, and blood dyscrasia Bleeding with and without thrombocytopenia Osteomalacia Polycystic ovary syndrome (anovulatory cycles) Teratogenicity Valproate: Drug Interactions High protein binding Inhibits biotransformation of PB, ethosuximide, LTG, carbamazepine epoxide, free PHT Increased levels of CCB, FBM, zidovudine Increase VPA levels: ASA, FBM, fluoxetine, INH Decrease VPA levels: CBZ, LTG, PB, PHT, ritonavir Ethosuximide, Valproic Acid, and Lamotrigine in Childhood Absence Epilepsy Glauser TA, et al. NEJM 362;9, March 4, 2010 Benzodiazepines Highly protein bound: 80-90% Used to treat status Rectal dizaepam and oral Intensol used to treat prolonged seizures in intractable seizure disorders and clusters; also available for patients with infrequent seizures Tolerance precludes broad use for chronic seizures Care must be taken to prevent psychosis and seizure exacerbation during withdrawal Use of Drug Level Monitoring: Always Have a Question! Establish “baseline” effective concentrations Evaluate potential causes for lack of efficacy “Fast metabolizers” Noncompliance Evaluate potential causes for toxicity Altered drug utilization as consequence of physiological conditions (puberty, geriatrics) “Slow metabolizers” Altered drug utilization as consequence of pathological conditions (renal failure, liver failure) Drug-drug interactions Switching AED preparations Use of Drug Level Monitoring: Always Have a Question! Evaluate potential causes for loss of efficacy Altered drug utilization as consequence of physiological conditions (e.g. neonates, infants, young children) Altered drug utilization as consequence of pathological conditions Change in formulation Drug-drug interaction Judge “room to move” or when to change AEDs Minimize predictable problems (PHT, VPA)