Download Current Medications for Seizure Control

Current Medications for
Seizure Control
Nabil J. Azar, M.D.
Assistant Professor of Neurology
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
Is it necessary to treat seizures?
• Usually, but not always
• Exceptions
– provoked seizures, if the provocation is gone
ex: febrile seizures, seizures provoked by medications, by changes in
blood composition
– single unprovoked seizures with a normal EEG and MRI
(the risk of recurrence is about 40%)
– certain very mild forms of epilepsy where life style changes
alone can prevent seizure recurrence
adequate sleep, with consistent hours
avoidance of alcohol and drugs
– certain benign focal epilepsies in children
Why should we treat epilepsy?
• Seizures may result in physical injury
• Seizures usually restrict life style (driving, working
with hazardous equipment or in a hazardous
environment)
• Severe very prolonged seizures may cause brain
damage
• Frequent seizures over a long period of time may cause
cell loss in some parts of the brain and may impair
some brain functions (particularly memory)
• Untreated epilepsy may become more entrenched and
resistant
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
Phenobarbital (Luminal) 1912
Primidone (Mysoline)
Phenytoin (Dilantin)
Methsuximide (Celontin)
Ethosuximide (Zarontin)
Clonazepam (Klonopin)
Carbamazepine (Tegretol,
Carbatrol)
• Valproate (Depakote) 1978
•
•
•
•
•
•
•
Coming soon: Retigabine, Brivaracetam…
new
•
•
•
•
•
•
•
•
•
•
•
•
Felbamate (Felbatol) 1993
Gabapentin (Neurontin)
Lamotrigine (Lamictal)
Topiramate (Topamax)
Tiagabine (Gabitril)
Levetiracetam (Keppra)
Oxcarbazepine (Trileptal)
Zonisamide (Zonegran)
Pregabalin (Lyrica)
Vigabatrin (Sabril)
Rufinamide (Banzel)
Lacosamide (Vimpat) 2009
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
ƒ Some questions have to be asked:
ƒ Is the diagnosis correct?
ƒ
ƒ
ƒ
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?
ƒ Epilepsy may be truly resistant to medication
treatment
ƒ 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 enzymeinducing AED:
lamotrigine, topiramate, tiagabine, oxcarbazepine,
zonisamide
• Combinations with synergistic effects:
• Lamotrigine + valproate
• Levetiracetam + lamotrigine
Pharmacokinetic overview of old AEDs
PHT
bioavailability
VPA
PHB
PMD
ESX
CZP
>90%
>90%
>90%
>80%
45%
<20%
<10%
86%
>95% >96% 65-90% ~80%
<80%
Liver
Liver
Liver
Liver
>90% 75-85% >90%
Protein binding 90%
% Metabolism
CBZ
95%
Metabolism site Liver
75%
90%
Liver
T1/2
7-42
6-20
5-15
65-110
8-15
30-60
Enz. induction
Autoinduction
yes
no
yes
yes
no
no
yes
no
yes
no
no
no
Enz. Inhibition
yes
Liver
30-40
no
no
Pharmacokinetic overview
of new AEDs
FBM GPN LTG TOP
TGB
LEV
no
no
OXC ZNS
PGB
Absorption
dose dependent no
yes
no
no
no
no
no
bioavailability >90% ~60%>98% >80% >89% ~100% 99% ~100% 90%
Tmax (hrs)
1 -4
2-3 1.4-4.8 1-4 0.9-2.6 ~1
4-6*
2-6 1-2.5
0%
Protein binding
25%
0% 55% 15%
96%
0%
T1/2
18-24
5-8 12-70 20-30
2 -9
6 -8
9*
63
5.5-6.7
Autoinduction
no
no slight
no
no
slight
no
no
no
40%* 40%
* applies to monohydroxyderivative (MHD), the main active metabolite
Effect of newer AEDs on blood
concentration of established AEDs
AED serum concentration with add-on
FBM
PGB
GPN
LTG
TPM
TGB
LEV
OXC
ZNS
CBZ
PHT
VPA
* an increase in PHT level may occur at high OXC doses
*
Pharmacological properties
Old AEDs:
New AEDs:
- Liver induction /
- No / mild liver
-
-
-
inhibition
Important autoinduction
High protein binding
Common blood level
monitoring
Prevalent drug-drug
interaction
-
induction / inhibition
No / mild
autoinduction
Low protein binding
Less common blodd
level monitoring
Minimal drug-drug
interaction
Idiosynchratic toxicity of old AEDs
PHT
Rash, enlarged lymph nodes, liver failure, blood abn
CBZ
Rash, other hypersensitivity, liver failure, blood abn
VPA
Liver failure, pancreatitis (rare), blood abn
PHB
Rash, connective tissue disorders, liver failure, blood
PMD
Connective tissue disorders
ESX
Blood abnormalitities
CZP
Rash
Old AEDs: most problematic adverse
effects
PHT
Sedation, gum swelling
CBZ
Sedation, fatigue
VPA
Sedation, weight gain, hair loss, hormonal changes
PHB
Sedation, slow thinking, lower IQ
PMD
Sedation, slow thinking
ESX
Gastrointestinal malaise
CZP
Sedation, constipation, tolerance
Idiosynchratic toxicity of new AEDs
FBM
Aplastic anemia, liver failure
GPN
-
LTG
Skin rash
TPM
acute angle-closure glaucoma, oligohydrosis
TGB
-
LEV
-
OXC
Rash
ZNS
Rash, oligohydrosis
New AEDs: most problematic
adverse effects
FBM
GPN, PGB
GI upset, headache, insomnia
Weight gain, myoclonus
LTG
Insomnia
TPM
Speech disorder, behavior changes, kidney stones
TGB
Confusion, dizziness
LEV
Irritability, nightmares
OXC
Low sodium (hyponatremia)
ZNS
Behavioral changes, kidney stones
Tolerability
• New AEDs compared by large studies
(lowest to highest)
– gabapentin, lamotrigine, levetiracetam
– tiagabine, oxcarbazepine
– topiramate, zonisamide
Tolerability - cognitive profiles of new AEDs
• Best
- Lamotrigine
- Felbamate
- Gabapentin
- Levetiracetam
- Oxcarbazepine
- Pregabalin
- Lacosamide
• 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
Nonepileptic indications
Azar & Abou-Khalil, Sem in Neurol 2008
How other medical conditions influence our
choice
– Migraine: depakote, topamax (? for keppra,
zonegran)
– Bipolar disease: lamictal, depakote( ?
neurontin, topamax, oxcarbazepine)
– Obesity: topamax, zonisamide, felbamate
(lamotrigine, levetiracetam, tiagabine,
oxcarbazepine are weight neutral)
– Obesity + migraine: topamax
– 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
* 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