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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)