ANTIEPILEPTIC DRUGS
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HISTORY
Hippocrates(400 B C)- On the sacred disease
Bromides(1957)
Phenobarbital(1912)
Ketogenic Diet(1920)
Phenytoin (1938)- H Houston Meritt and Tracy Putnam
Carbamazepine(Trigeminal Neuralgia-1962, Seizure-
1965)
Valproate(1967)
Levetiracetam (1998)
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DEFINITIONS
Antiepileptic drug : decreases the frequency
and/or severity of seizures in people with epilepsy
Antiepileptic drug : Treats the symptom of
seizures, not the underlying epileptic condition
Goal of therapy : maximize quality of life by
minimizing seizures and adverse drug effects
American Epilepsy Society 2010
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DEFINITIONS
Seizure: the clinical manifestation of anΠSeizure:
the clinical manifestation of an abnormal
synchronization and excessive excitation of a
population of cortical neurons
Epilepsy: a tendency toward recurrent seizures
unprovoked by acute systemic or neurologic
insults.
American Epilepsy Society 2010
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DEFINITIONS
Status Epilepticus
Convulsive Status Epilepticus : continuous
convulsive seizures lasting > 5 min, or two or more
seizures- and patient’s does not return to baseline
consciousness
Non-Convulsive Status Epilepticus : change in
mental status from baseline >30 min, with
evidence of ictal discharges on EEG
Refractory Status Epilepticus : seizure activity
continues after 1st line and 2nd line AEDs
management failed (>60 min)
Guidelines for management of Epilepsy in India- GEMIND, IES
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DEFINITIONS
Medically Intractable Epilepsy: 2 AEDs used
in optimal dosage, or continued epilepsy after > 2
yrs of appropriate treatment(adults),
Or – Children with epileptic encephalopathy,
infantile spasm, seizure >1/month, catastrophic
onset epilepsy, disabling epilepsy
Guidelines for management of Epilepsy in India- GEMIND, IES
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NEURONAL ACTION POTENTIAL
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MECHANISM OF SEIZURE GENERATION
Deregulation of balance
Excitation (too much)Œ
Ionic‐inward Na+, Ca++ currents (EPSPs)
Neurotransmitters : glutamate, aspartate
Inhibition (too little)
Ionic‐inward CI‐, outward K+ currents(IPSPs)
Neurotransmitter: GABA
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NEUROTRANSMITTERS
GLUTAMATE
Brain’s major excitatory neurotransmitter™
Two groups of receptors
Inotropic ‐fast synaptic transmission
• NMDA, AMPA, kainate
• Gated Ca++ and gated Na+ channels
Metabotropic ‐slow synaptic transmission
• Regulation of second messengers (cAMP and
Inositol)
• Modulation of synaptic activity
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NEUROTRANSMITTERS
GABA
Major inhibitory neurotransmitter in the CNS
Œ
Two types of receptors
GABA-A
• Post‐synaptic
• Specific recognition sites
• Linked to CI‐ channel
GABA-B
• Pre‐synaptic reduction in calcium influx
• Mediated by K+ currents
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CLASSIFICATION (DECKERS’ ET AL )
Group 1- Blockade of voltage-dependent Na+ or Ca
channels(generalised and partial seizures)
Group 2 – enhance inhibitory events mediated by GABA
(absence, generalised, partial seizures)
Group 3 – blocks T-type calcium channels (absence seizures).
Group X- reduce events mediated by excitatory amino acids-
glutamate
Some drugs like leviracetam, Hormonal agents, MgSO4
unaccounted.
Most of the AEDs act by more than 1 mechanism
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CLASSIFICATION
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PHARMACOKINETICS
Absorption
Essentially complete for all AEDs (except
gabapentin- dose dependent,)
Timing varies widely by drug, formulation,
patient characteristics
Generally slowed by food in stomach (CBZ may
be exception, lamotrigine not slowed by food)
Therapeutic levels- Usually takes several hours
(importance for interpreting blood levels)
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PHARMACOKINETICS
Elimination
Metabolism/biotransformation — generally
hepatic (usually rate‐limiting step)
Excretion — mostly renal
Active and inactive metabolites
Changes in metabolism over time
(Auto‐induction with carbamazepine, with
polytherapy enzyme induction or inhibition)
Differences in metabolism by age, systemic
disease
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AED INTERACTION
Metabolism inducer Metabolism Inhibitor
Carbamazepine Valproate
Phenytoin Felbamate
Phenobarbital Topiramate
Primidone
Neither inducer/inhibitor Protein Bound
oGabapentin oValproate
oLamotrigine oPhenytoin
oPregabalin oTiagabine
oTiagabine oCarbamazepine
oLevetiracetam oOxcarbazepine
oZonisamide oTopiramate
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AED INTERACTIONS- COMORBIDITIES
Effects Older AED Newer AED
Metabolic disorder may increase risk VPA –
of hepatotoxicity
Increased risk of hyponatremia CBZ OXC
Measurable increase in free fraction PHT, VPA –
with hypoalbuminemia
Metabolism affected by renal disease PB GBP, LEV,
TPM
Metabolism affected by liver disease CBZ, PHT, LTG, ZNS,
VPA OXC, TGB
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ADVERSE EFFECTS
Acute (dose related – reversible)
Adverse effects AED
Dizziness, Fatigue, Ataxia, all AEDs
Diplopia
Irritability/behaviour change Levetiracetam, Gabapentin
Weight loss/anorexia Topiramate, zonisamide,
felbamate
Weight gain Valproate (associated with PCOS
in women), Carbamazepine,
Gabapentin, Pregabalin
Tics and Insomnia Lamotrigine
Metabolic acidosis Topiramate
Language dysfunction Topiramate
Photosensitivity Zonisamide
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ADVERSE EFFECTS
Idiosyncratic (uncommon, serious)
Adverse effects Drugs
Renal stones Topiramate, zonisamide
Anhydrosis, heat stroke Topiramate, zonisamide
Acute closed‐angle glaucoma Topiramate
Hyponatremia Carbamazepine, oxcarbazepine
(used in DI)
Aplastic anemia Valproate, Carbamazepine,
Felbamate, Zonisamide,
Hepatic Failure Valproate, Felbamate,
Lamotrigine, Phenobarbital
Peripheral vision loss Vigabatrin
Stupor- spike wave Zonisamide
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ADVERSE EFFECTS
Idiosyncratic (uncommon, serious)
Rash – Phenytoin, Lamotrigine, Zonisamide,
Carbamazepine
– Risk of “dangerous or even fatal skin reactions” such as
Steven‐Johnson Syndrome and Toxic epidermal necrolysis is
increased in patients with HLA‐B*1502 allele
– Estimated absolute risk for those with the allele: 5%
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ADVERSE EFFECTS
Long term (vary in severity and reversibility)
Endocrine/Metabolic AEDs
Osteomalacia, osteoporosis Carbamazepine, Phenobarbital,
Phenytoin, Oxcarbazepine
(ADOPT trial- RCT on
bisphosphonates v/s Ca/Vitamin
D supplementation- ongoing)
Folate deficiency (anaemia, Phenobarbital, Phenytoin,
teratogenesis) Carbamazepine, Valproate
Altered connective tissue Phenytoin, Phenobarbital
metabolism or growth
(facial coarsening, gum
hyperplasia, hirsutism)
o Neuropathy, Cerebellar Syndrome : Phenytoin
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AED SERUM LEVEL
Optimizing AED therapy
ŒAssessing compliance
ŒTo monitor pharmacodynamic and pharmacokinetic
interactions.
Most often individual patients define their own “
therapeutic range” for AEDs.
New AEDs there is no clearly defined “therapeutic
range”.
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AEDS- BEFORE STARTING
Discuss:
Adverse effects- dose dependent and serious
Likelihood of success
Recording/reporting- seizures, adverse effects,
potential precipitants
American Epilepsy Society 2010
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AEDS- CHOICE
Limited Placebo controlled trials available- especially
newer AEDs
Several drugs are commonly used for indications other
than those for which they are officially
approved/recommended
Partial epilepsy- choice depends on drug side‐effect
profile & patient’s preference/concerns
Generalized epilepsy- choice depends on predominant
seizure type(s) , drug side‐effect & patient’s
preference/concerns
ILAE Summary Guidelines and Summary of AAN evidence‐based guidelines
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AEDS- CHOICE
Seizure type GTCS Partial Absence Myoclonic
BEST Valproate Carbamazepine Ethosuximide Valproate
EVIDENCE Topiramate Oxcarbazepine Valproate Levetiracetam
Phenytoin Clonazepam
Topiramate
Alternatives Phenytoin Lamotrigine Lamotrigine Zonisamide
Carbamazepine Gabapentine Levetiracetam Topiramate
Levetiracetam Gabapentine Levetiracetam
Lamotrigine Levetiracetam Clonazepam
Valproate Topiramate
Phenobarbitol Felbamate
Pregabilin
Zonisamide
American Epilepsy Society 2010
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AED- HOW TO START
Monotherapy preferred- simplifies Rx, fewer adverse
effects and drug interactions
~70-80% seizures are controlled on monotherapy
alone
Monotherapy with different drug should be tried
together before starting polytherapy
Conversion to single drug from multiple drugs
• Eliminate sedative drugs first
(barbiturate/benzodiazepine)
• Withdraw AEDs slowly over several months
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AEDS- WHEN TO STOP
Seizure freedom for ≥2 years implies overall >60%
chance of success
Favourable factors
• Control achieved easily on one drug at low dose
• No previous unsuccessful attempts at withdrawal
• Normal neurologic exam and EEG
• Primary generalized seizures except JME
– Consider relative risks/benefits (e.g., driving,
pregnancy)
Practice parameter. Neurology. 1996;47:600–602.
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NEUROSURGERY AND AEDS
Perioperative seizures are relatively rare, and all available drugs
do not have 100% efficacy in preventing them.
Great degree of heterogeneity among neurosurgical patients
Incidence of epilepsy differs between patients with trauma,
intracerebral hemorrhage and tumors – and even tumor type and
localization
AEDs interfere with adjuvant treatments for brain tumors:
severe skin reaction ns (Stevens–Johnson syndrome) in patients
under-going radiotherapy while taking phenytoin, phenobarbital
or carbamazepine are reported.
AEDs decrease efficacy of chemotherapy due to liver enzyme
induction by carbamazepine , phenobarbital and phenytoin
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NEUROSURGERY AND AEDS (TRAUMATIC
BRAIN INJURY)
Prophylactic use of phenytoin or valproate is not
recommended for preventing late PTS- level II
recommendation
AEDs are indicated to decrease the incidence of early
PTS (within 7 days of injury)- level II
recommendation
Risk factors for late PTS-
(1) Glasgow Coma Scale (G CS) Score less than 10 .
(2) Cortical contusion.
(3) Depressed skull fracture.
(4) Subdural /epidural/ intracerebral hematoma .
(5) Penetrating head wound.
Bratton SL, Chestnut RM, Ghajar J, et al. Guidelines for the management of
severe traumatic brain injury. XIII: Antiseizure prophylaxis. J Neurotrauma
2007; 24 (Suppl 1):S83 –S86.
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NEUROSURGERY AND AEDS
(SUBARACHNOID HEMMORHAGE)
Rosengart AJ, Huo D, Tolentino J. Outcome in patients with subarachnoid
hemorrhage treated with antiepileptic drugs. J Neurosurg 2007; 107:253 –
260. – META ANALYSIS
Significantly increased risk of neurologic
complications in patients after subarachnoid
hemorrhage, who were treated with AEDs.
Patients at risk of seizures not yet defined
Incidence of seizures is also uncertain (??<10%)
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NEUROSURGERY AND AEDS
(PROPHYLAXIS IN BRAIN TUMORS)
Tremont-Lukats IW, Ratilal BO, Armstrong T, Gilbert MR.
Antiepileptic drugs for preventing seizures in people with brain
tumors. Cochrane Database Syst Rev 2008:CD004424.
No difference between the intervention and control groups in
preventing a first seizure in patients with brain tumors
Patients treated with antiepileptic agents had a higher risk of
adverse effect than those untreated
Glantz MJ, Cole BF, Forsyth PA, et al. Practice parameter: anticonvulsant
prophylaxis in patients with newly diagnosed brain tumors – report of the
Quality Standards subcommittee of the American Academy of Neurology.
Neurology 2000; 54:1886 –1893.
Discourages the prophylactic use of AEDs
Duration of prophylactic therapy in patients without preoperative
seizures should be restricted to the first postoperative week
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NEUROSURGERY AND AEDS
(THERAPEUTIC USE IN BRAIN TUMORS)
In patients with preoperative seizures- AEDs
should be given
Factors for post operative seizures-
1. the amount of resection,
2. parietal tumor localization
3. seizure complexity
4. pre-operative seizure duration
Van Breemen MSM, Wilms EB, Vecht CJ. Epilepsy in patients with brain
tumours: epidemiology, mechanisms and management. Lancet Neurol 2007;
6:421–430.
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NEUROSURGERY AND AEDS
(EPILEPTOGENESIS)
Latent period of epileptogenesis following acute
brain insult
Newer therapies directed at cellular level under
investigation-
Tetrodotoxin and BDNF(brain derived
neurotrophic factor)- promising in vitro results
Prince DA, Parada I, Scalise K, et al. Epilepsy following cortical
injury: cellular and molecular mechanisms as targets for potential
prophylaxis. Epilepsia 2009; 50 (Suppl 2):S30 –S40.
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PROPHYLAXIS – PHENYTOIN V/S LEVETIRACETAM
Lim DA, Tarapore P, Chang E, et al. Safety and feasibility of switching from
phenytoin to levetiracetam monotherapy for glioma-related seizure control
following craniotomy: a randomized phase II pilot study. J Neurooncol 2009;
93:349 –354.
No difference in efficacy could be detected
Levetiracetam showed fewer adverse effects.
Good tolerability with Levetiracetam
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AEDS & PREGNANCY
EPTOIN : Fetal Hydantoin Syndrome
Consensus
• Monotherapy with
VALPROATE : Neural tube defects lowest dose CBZ
• Periconceptional Folate
OTHER CONGENITAL Supplementation 5 mg
MALFORMATIONS • Vit K at 34th and 36th wk
• Cardiac defects (GEMIND)
• Genitourinary defects • MSAFP at 16 wk, and
• supplementation in all USG at 18 wk (GEMIND)
• Oral clefts
• Risk with AED monotherapy 4.5% (OR
2.6)
• Risk with Polytherapy 8.6% (OR 5.1)
Holmes et al. N Engl J Med. 2001;344:1132–1138.
[PubMed]
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AEDS AND LACTATION
Breastfeeding should be encouraged unless clear risk posed
Probably safe:
• Carbamazepine
• Phenytoin
• Valproate
• Lamotrigine
“Use with caution” in lactating women:
• Primidone
• Phenobarbital
• Ethosuximide
Pennell et al. Epilepsy and Behavior. 2007. 11: 263‐9
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STATUS EPILEPTICUS
Out of Hospital Setting (first 5 min):
Diazepam(rectal) 0.5 mg/kg oral OR Midazolam (buccal)
0.2-0.3 mg/kg OR Lorazepam 2 mg/Diazepam 5-10 mg iv
First Stage(5-20 min)
Lorazepam 0.1 mg/kg(max 4 mg) iv OR
Diazepam 0.5 mg/kg (max 10 mg) iv
Wait for 5 min and repeat if no response (give
pyridoxine 100 mg iv <2 yrs old)
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Second stage(20-60 min)- Established GCSE
Phenytoin 15-20 mg/kg loading iv (@ 50mg/min max)
Fosphenytoin 20-25 mg/kg loading (@150 mg/min max)
↓(seizure persists 10 min after loading)
Consider
Phenytoin 5-10 mg/kg iv Or Fosphenytoin 5mg/kg iv
Alternatives
Valproate 25-35 mg/kg iv loading(max @ 6mg/kg/min)
Phenobarbitone 20 mg/kg iv loading( max @ 60mg/min)- needs
ventilator backup
Investigate: ABG- glucose, LFT, RFT, BUN, electrolytes,
Ca, LP(if suspected), CT head
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Refractory Status Epilepticus(>60 min)
Mechanical Ventilation-
Drug Loading/Bolus(iv) Maintenance(infusi
on)
Midazolam 0.1mg/kg(max 10 mg) 0.2-0.4 mg/kg/h
Propofol 2-5 mg/kg 5-10 mg/kg/h
Thiopentone 10-20 mg/kg 0.5-1 mg/kg/h
Weaning Off: Seizure free 12 hrs(EEG burst
suppression) reduce infusion every 3 hrs, if seizure recur,
reinstitute coma with same drug
NCSE- consider using Propofol/midazolam
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AED Dose/ dosing Remarks Theraupt Adverse effects
frequency ic level
(Mcg/mL)
Phenytoin 300–400 mg/d Cardiac monitoring 10 ‐20 Gum hyperplasia,
(3–6 mg/kg, check BP Lymphadenopathy,
adult; 4–8 mg/kg, Hirsutism, Osteomalacia;
child); od‐bid Hyperglycemia
Loading dose: 20 Dizziness, Diplopia, Ataxia
mg/kg @ <50 mg/min Incoordination
infusion
Valproate 750–2000 mg/d Start 15 mg/kg/day 50 – 100 Hepatotoxicity
(20–60 mg/kg); Increment wkly Thrombocytopenia
bid‐qid 5‐10mg/kg/day Hyperammonemia
Pancreatitis
Carbamazepi 600–1800 mg/d Start low and 6-12 Leukopenia, Aplastic
ne (15–35 mg/kg, increase anemia, Hyponatremia,
child); bid qid slowly
Oral form only
Leveracetam 1000–3000 Sedation
mg/d; bid Fatigue
Incoordination
Psychosis
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AED Dose/ dosing Remarks Therauptic Adverse effects
frequency level
(Micrmol/L)
Gabapentin Start 300 mg OD, 70 – 120 Weight gain, peripheral
increase – 900 to edema
1,800 mg divided behavioral changes
TDS/QID
Lamotrigine Start 50 mg OD(25 Risk of 10 – 60 Rash(Steven johnson
mg with VPA), rash/SJS/TEN syndrome), arthritis, tics,
increase to 300-500 increased with insomnia
mg – divided concomitant
BD(max 150 mg valproate use,
OD withVPA) reduced with
slow titration
Felbamate Start 1200 mg 125 – 250 Anorexia, vomiting,
daily divided insomnia, somnolence,
TDS/QID aplastic anemia,
or 15 -45 mg/kg/day hepatotoxicity
divided 6 to 8
hours
Topiramate Begin with 50 mg 15 – 60 Dizziness, somnolence,
daily; increase to ataxia, confusion, fatigue,
50 – 400 mg daily paresthesias, speech
divided 12 hrly difficulities, diplopia,
impaired concentration
and nausea,
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AED Dose/ dosing Remarks Theraup Adverse effects
frequency tic level
(Micrmo
l/L)
Oxcarbazepin 150 mg BD increase CBZ can be 50 – 140 Hyponatremia (more
150 mg each week , directly switched common in elderly), rash
Max dose 600 mg BD to Oxcarbazepine
Tiagabine Start 4mg OD, BD 50 – Stupor or spike wave
next week, then 250(nmol/ stupor, Weakness
TDS,in 4th week 4 mg L)
QID, Max- dose – 56
mg/day
Zonisamide Start 25 mg OD, add 45 – 180 Rash, renal calculi,
25 mg every week , hypohidrosis, Irritability,
max – 300 mg BD photosensitivity,
weight loss
Vigabatrin Start 500 mg BD, Regular vision 6-78 30% patients permanently
increase to 1500 mg testing required, loss of peripheral vision,
BD over 1 month
Clobazam 10 mg HS, max 30 mg rebound seizures – Somnolence, Ataxia,
OD upon abrupt or Dysarthria, Diplopia,
over-rapid Gelastic seizures, urticaria,
discontinuation of rashes
therapy(BZD
withdrawal
syndrome)
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THANK YOU
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