Transcript Introduction to the newest anticonvulsants

Barbara Lynne Phillips, M.D.
Assistant Professor of Neurology
WSU BSOM
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Participated in Phase II and III trials of
lacosamide
No other disclosures
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Mainstay of treatment
Two main targets
Ion channels (Na, K, Ca)
 GABA/Glutamate
 Other
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Despite more than 15 available agents, rate of
sz control is still only about 60% for first drug
tried and up to 75% overall
% of patients who are intractable remains the
same at 25-30%
Multiple new agents available in last few years,
some with unique mechanisms of action
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PO tablet, oral suspension and IV
Indication: first line, monotherapy and
adjunctive, partial onset sz, 17+
Schedule V
Metabolism: Hepatic, CYP 3A4 2C9
Dosing: Start 50 mg bid, max rec 200 mg bid
Mechanism: Slow inactivation Na channel
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Potential SE: Dizziness most common. Others
ataxia, paresthesias, headache, syncope, psych
symptoms reported but rare.
No significant drug interactions
Concerns: Can increase PR interval, more likely
in DM neurop or CV disease. Use with caution
in dysrhythmia pts.
Adjust dose in hepatic and renal pts
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PO: tablet, oral suspension, considered orphan
drug
Indication: Adjunctive in pts with LGS, 2 yo +
Schedule IV
Metabolism: hepatic CYP 2C19, wk 3A4
Dosing: 5 mg bid – 20 mg bid
Mechanism: Benzo, potentiates GABAergic
neurotrans, GABA A receptor, (1,5 benzo)
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Potential SE: somnolence most common.
Ataxia, confusion, psych (8%).SJS rare but
reported. Withdrawal sx possible.
Weak inducer CYP 2C19 – may reduce effect of
some BCPs
Concerns: Etoh raises CLB level by 50%, other
CNS depressants potentiate sedation, caution
with previous psych hx, adj dose in geriatric,
hepatic and renal pts.
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PO tablet, once daily dosing
Indication: adjunctive partial sz, 18+
Not scheduled
Metabolism: Drug is extensively metabolized
to Eslicarbazepine, major active metabolite(?),
no autoinduction. Renal excretion
Dosing: 400 mg qd – 600 mg qd
Mechanism: inhib voltage gated Na channels
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Potential SE: dizzy, drowsy, nausea, h/a,
ataxia, diplopia, blurry vis. NO increase in
psych sx over what is expected in this
population.
Rare SJS, DRESS, rash
Concerns: can’t be given with OXC, dose adj
with CBZ, don’t give if allergic to either. Mild
inducer may affect BCP, decr dose with decr
CrCl. Reported decr T3/T4 only. Unknown sig
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PO tablet, once daily dosing
Indication: Adjunctive, partial onset, 12 yo +
Schedule III. Euphoria, sim to ketamine
Metabolism: hepatic CYP 3A4
Dosing: 2-4 mg/d – max 12 mg/d
Mechanism: non-competitive AMPA glutamate
receptor ANTAGONIST on post-synaptic
neurons
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Potential SE: dizzy, ataxia, drowsy. Has black
box warning for potential psych sx incl hostile,
aggression, anger, anxiety, agitation, suicidal
Psych SE: dose dependent 12% at 8 mg, 20% at
12 mg. (6% placebo). Most w/i 6 wks
Other concerns: enzyme inducers reduce its
effectiveness, may reduce BCP efficacy,
possible euphoria, not rec in severe hep/renal
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PO (tablet and powder)
Indication: Refractory CPS, 10+ (not first line),
infantile spasms 1 m-2 yr, first line
monotherapy
Not scheduled
Metabolism: renal excretion, min metabolized
Dosing: 500 mg bid – 1500 mg bid adults
Mechanism: irreversible inhibitor of GABA transaminase
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Potential SE: Black box for vision loss (periph)
which is gradual, progressive, bilat concentric
field constriction. Higher risk with longer
exposure. Permanent. Req serial VF testing.
Other SE: fatigue, memory, wt gain,
coordination prob, confusion in 16+. 10-16 also
URI. Infants – lethargy, bronchitis, ear infection
incl acute otitis media
Extremely good efficacy, no cardiac or protein
binding
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PO tablet, oral suspension. Take with food.
Indication: adjunctive, sz in LGS 4+.
Particularly effective in reducing Drop Attacks.
Not scheduled
Dosing: 400 bid- 1600 mg bid adults.
10/mg/kg/d up to 1600 mg bid, children
Metabolism: extensively hydrolyzed, renal exc
Mechanism: modulation of Na channel,
prolongs inactive state
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Potential SE: dizzy, drowsy, ataxia, nausea,
infreq mood problems and suicidality
Other: Prolongs QT interval, clinically without
risk unless pre-existing. Contraindicated in
Familial Short QT Syndrome.
May reduce efficacy of BCP. VPA decr its
metab by 70% causing incr level. No change
dosing for renal. Not rec for hepatic disease.
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PO tablet
Indication: Adj partial onset, 18+, not first line
Schedule V
Dosing: 100 mg tid – 400 mg tid
Metabolism:glucuronidated, renal excretion
Mechanism: enhances transmembrane K
currents mediated by KCNQ ion channels.
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Potential SE: Black box for visual disturbance,
retinal pigmentary abnormalities like pigment
dystrophies. Urinary retention – some req
prolonged self-cath. Skin discoloration (bluegrey, brown) nails, lips, mucous membranes,
skin (1/4 with concomitant retinal pigment
abnl)
Other: dizzy, psych (hallucinations, mood,
psychosis)