Current Medications for Seizure Control Nabil J. Azar, M.D. Assistant Professor of Neurology Director, Clinical Neurophysiology Training Program Medical Director, Intra-operative Neuromonitoring Vanderbilt University Medical Center Nashville, TN
Current Medications for
Seizure Control
Nabil J. Azar, M.D. Assistant Professor of Neurology
Director, Clinical Neurophysiology Training Program
Medical Director, Intra-operative Neuromonitoring
Vanderbilt University Medical Center
Nashville, TN
Outline • General principles of antiepileptic (AED) drugs use • AED selection: a. Depends on type of seizures and epilepsy
syndrome b. Old vs. new AEDs c. Safety and ease of use d. Presence of other medical conditions e. Titration rate and dosing f. Special populations: - Children - Women of child bearing age - elderly • Limitations of AED drug therapy
Goal of epilepsy treatment
Seizure freedom and no side effects
Efficacy and tolerability
Initiation of AED therapy • Diagnosis: seizure type (s), epilepsy syndrome and
etiology (if possible). • Selection of best (or ideal) AED: - Efficacy: one AED (monotherapy) is the goal - Safety - Tolerability - Pharmacokinetic advantages - Titration rate - Dosing - Comorbidities
Newly treated epilepsy- outcome of AED treatment
470 patients with epilepsy who had never received AED treatment: 64% were seizure-free at follow-up
Kwan & Brodie, Epilepsia 2001
Antiepileptic drugs (AEDs) old new
• Phenobarbital (Luminal) 1912 • Primidone (Mysoline) • Phenytoin (Dilantin) • Methsuximide (Celontin) • Ethosuximide (Zarontin) • Clonazepam (Klonopin) • Carbamazepine (Tegretol,
Carbatrol) • Valproate (Depakote) 1978
• Felbamate (Felbatol) 1993 • Gabapentin (Neurontin) • Lamotrigine (Lamictal) • Topiramate (Topamax) • Tiagabine (Gabitril) • Levetiracetam (Keppra) • Oxcarbazepine (Trileptal) • Zonisamide (Zonegran) • Pregabalin (Lyrica) • Vigabatrin (Sabril) • Lacosamide (Vimpat) • Clobazam (Onfi) • Rufinamide (Banzel) • Ezogabine (Potiga) 2012
Coming soon: Eslicarbazepine, brivaracetam…
Azar & Abou-Khalil; Sem in Neurol 2008
Azar & Abou-Khalil; Sem in Neurol 2008
Failed therapy due to lack of efficacy
• Option 1: substitution therapy- best if first AED has failed completely
• Option 2: add-on therapy- best if there has been some benefit • all new AEDs
Questions to be answered when AEDs fail
Some questions have to be asked: Is the diagnosis correct?
Are we dealing with a different seizure type than we thought? are seizures non-epileptic?
Are seizure medications used optimally? Is the patient taking the medication consistently? Are there other factors such as stress, sleep deprivation,
alcohol, drug abuse, another medication that worsens seizures?
Epilepsy may be truly resistant to medication treatment
Epilepsy surgery, VNS, ketogenic diet, new drug trials
Advantageous combinations
• Advantages can be based on lack of interaction • no significant interaction in either direction:
gabapentin, levetiracetam, pregabalin • do not significantly affect others, but have
shorter half-life when added to an enzyme-inducing AED:
lamotrigine, topiramate, tiagabine, oxcarbazepine, zonisamide
• Combinations with synergistic effects: • Lamotrigine + valproate • Levetiracetam + lamotrigine
Pharmacokinetic overview of old AEDs
PHT
bioavailability
Protein binding
T1/2
Autoinduction
>90% 75-85% >90% >90%
90% 75% 90% 45%
7-42 6-20 5-15 65-110
no yes no no
CBZ VPA PHB PMD
>90%
<20%
8-15
no
ESX
>90%
<10%
30-60
no
CZP
>80%
86%
30-40
no
% Metabolism 95% >95% >96% <80%
Metabolism site Liver Liver Liver Liver Liver Liver Liver
65-90% ~80%
Enz. induction yes yes yes yes no no no
Enz. Inhibition yes
Pharmacokinetic overview
of new AEDs
FBM
Absorption
dose dependent
bioavailability
Tmax (hrs)
Protein binding
T1/2
Autoinduction
no yes no no
>90% ~60% >98% >80%
1-4 2-3 1.4-4.8 1-4
25% 0% 55% 15%
18-24 5-8 12-70 20-30
no no slight no
GPN LTG TOP TGB
no
>89%
0.9-2.6
96%
2-9
no
LEV
no
~100%
~1
0%
6-8
no
OXC
no
99%
4-6*
40%*
9*
slight
ZNS
no
~100%
2-6
40%
63
no
* applies to monohydroxyderivative (MHD), the main active metabolite
PGB
no
90%
1-2.5
0%
no
5.5-6.7
Pharmacological properties Old AEDs: - Liver induction /
inhibition - Important auto-
induction - High protein binding - Common blood level
monitoring - Prevalent drug-drug
interaction
New AEDs: - No / mild liver
induction / inhibition - No / mild
autoinduction - Low protein binding - Less common blodd
level monitoring - Minimal drug-drug
interaction
Idiosynchratic toxicity of old AEDs
PHT
CBZ
VPA
PHB
PMD
Rash, enlarged lymph nodes, liver failure, blood abn
Rash, other hypersensitivity, liver failure, blood abn
Liver failure, pancreatitis (rare), blood abn
Rash, connective tissue disorders, liver failure, blood
Connective tissue disorders
ESX Blood abnormalitities
CZP Rash
Old AEDs: most problematic adverse effects
PHT
CBZ
VPA
PHB
PMD
Sedation, gum swelling
Sedation, fatigue
Sedation, weight gain, hair loss, hormonal changes
Sedation, slow thinking, lower IQ
Sedation, slow thinking
ESX Gastrointestinal malaise
CZP Sedation, constipation, tolerance
Idiosynchratic toxicity of new AEDs
FBM
GPN
LTG
TPM
TGB
Aplastic anemia, liver failure
-
Skin rash
acute angle-closure glaucoma, oligohydrosis
-
LEV -
OXC Rash
ZNS Rash, oligohydrosis
New AEDs: most problematic adverse effects
FBM
GPN, PGB
LTG
TPM
TGB
GI upset, headache, insomnia
Weight gain, myoclonus
Insomnia
Speech disorder, behavior changes, kidney stones
Confusion, dizziness
LEV Irritability, nightmares
OXC Low sodium (hyponatremia)
ZNS Behavioral changes, kidney stones
Tolerability - cognitive profiles of new AEDs
• Best - Lamotrigine - Gabapentin - Levetiracetam - Oxcarbazepine - Pregabalin - Lacosamide - Ezogabine
• Intermediate - Tiagabine - Zonisamide
• Worst - Topiramate
Prevalence of comorbidity
• Depression (50%) • Bipolar disorder (10%) • Panic attacks 50 % • Migraine: 25 % • Sleep disturbances: >25% • Restless leg syndrome: 10 % • Obesity 30 % • Spasticity: cerebral palsy, multiple sclerosis • Peripheral neuropathy • Chronic pain syndromes
Azar & Abou-Khalil, Sem in Neurol 2008
Nonepileptic indications
How other medical conditions influence our choice
– Migraine: valproate, topiramate(? for levetiracetam, zonisamide)
– Bipolar disease: lamotrigine, valproate( ? gabapentin, topiramate, oxcarbazepine)
– Obesity: topiramate, zonisamide, felbamate – Obesity + migraine: topiramate – Peripheral neuropathy, chronic pain
syndromes: pregabalin, gabapentin
Titration rates: initiation at therapeutic doses
• Rapid titration: - Most of old AEDs - Felbamate - Gabapentin - Zonisamide - Levetiracetam * - Pregabalin - Lacosamide *
• Slow titration: - Lamotrigine - Topiramate - Tiagabine - Vigabatrin - Ezogabine
* Available in intravenous form
Special considerations in Children
• General rules: - Avoid sedating AEDs because of comorbid
disorders (autism, mental retardation…) - Go slower and lower • Specifics: - Rash with lamictal is more serious - Psychosis with keppra is more common - Oligohydrosis with topamax and zonegran
more lethal - Fulminant liver failure with depakote is more
likely (2 years<)
Nadkarni et a; Neurology 2005
Bryant & Dreifuss; Neurology 1996
Pellock & Brodie; Epilepsia 1997
Women of childbearing potential • Infertility: more common than normal population
• Reproductive and sexual dysfunction: • Deapkote causing PCOS reversible with lamotrigine
• Oral contraceptive pills (OCP): - Lowered efficacy by enzyme inducing AEDs; PHB, PHT, CBZ,
PMD, TPM (>200 mg) and OXC (>900 mg) - estradiol (OCP, pregnancy) lowers efficacy of lamotrigine • Developmental abnormalities in exposed fetus: VPA has the highest risk (7- 8 %) especially in polytherapy and high
dosages, followed by CBZ and PHT (5-6 %). Some new AEDs appear safer in event of unexpected pregnancy
(ex: LTG, OXC, ? LEV ?, TPM ?, ZNS ?) Folic acid (1-4 mg daily)
Lofren et al; Epilepsy Res 2007
Artama et al; Neurology 2005
Special considerations in the elderly • General rules: - Avoid sedating AEDs because of comorbid disorders (polytherapy,
dementia…) - Go slower and lower: respond better to low doses - Avoid enzyme-inducing and highly protein-bound AEDs (i.e AEDs) - Anaylze blood levels with caution (ask for free levels) - Use extended release formulation (especially with CBZ, VPA) - Use new AEDs • Specifics: - Hyponatremia with trileptal is common (especially when taking
diuretics) - Reversible Parkinsonism with chronic VPA is not rare - Renal calculi with TPM and ZNS are more likely - Osteopenia and osteaporosis with PB, PHT and CBZ are very
common
Armaon et al; Neurology 1996
Perucca et al; Epilepsy Res 2006
Saetre et al; Epilepsia 2007
New versus old AEDs- summary • Old - Established efficacy - Poor tolerability: more
sedation - Safety issues - Fast titration - Major interactions - Blood level monitoring - Disrupt hormonal milieu - Reduce bone density
• New - Similar efficacy - Better tolerability - Better safety - Slower titration - Less interactions - More expensive - Less teratogenicity - High in breast milk
Limitations of AED therapy
• Treats the symptoms or seizures and not the disease or epilepsy – Does not prevent the development or progression
of epilepsy – Does not cure epilepsy
• We need drugs with: - Better efficacy and tolerability - Prevent epilepsy - Reverse the process of epileptogenesis