Epilepsy
is a disorder of cerebral cortex characterized by recurrent (periodic and unpredictable) seizures, with more than 24 hours interval and is unprovoked (unknown cause)
Seizures
Seizures are sudden, transitory, and uncontrolled episodes of brain dysfunction, resulting from abnormal electrical discharge in cerebral neuronal cells, associated with prolonged depolarisation of cerebral neurons result in motor, sensory or behavioral changes.
ILAE Classification
Unclassified (3%) Myoclonic (3%) Other Generalized Absence (6%) (8%) Partial Unknown (7%)
Hauser WA. Epilepsia. 1992;33(suppl 4):S10.
Management of Epilepsy
The goal of the therapy is to improve the patients quality of life through:
1.Classification of seizures. 2.Patients age & health state 3.Data on efficacy, tolerability, safety and
pharmacokinetics
Classification of Anticonvulsants
Classical Newer
Felbatol (felbamate) Neurontin (gabapentin) 1993 1994
Lamictal (lamotrigine)
Topamax (topiramate) Gabitril (tiagabine) Keppra (levetiracetam) Zonegran (zonisamide) Lyrica (pregabalin)
1995
1996 1998 1999 2000 2005
Ezogabine
Rufinamide, Lacosamide, other
When to Start?
How to Start?
3rd AED is added if 1st and 2nd AED are already titrated to max dose and fail
2.
Classification of Anticonvulsants
Ion Channels#
Na+: Phenytoin, Carbamazepine, Lamotrigine Topiramate Valproic acid # For general tonic-clonic and partial seizures Ca++ #: Ethosuximide Valproic acid Zonisamide # For Absence seizures
Enhance Inhibitory aa #
Benzodiazepines Felbamate (diazepam, clonazepam) Barbiturates (phenobarbital) Topiramate Valproic acid Gabapentin Vigabatrin Topiramate Felbamate # Most effective in myoclonic but also in tonic-clonic and partial Clonazepam: for Absence
Inhibit Excitatory aa
ILAE GUIDELINES Based on the best evidence available, what is the optimal initial monotherapy for patients with newly diagnosed or untreated epilepsy?
A total of 33 randomized clinical trials (RCTs) and 5 meta-analyses examined initial monotherapy of adults with partial-onset seizures Level A: CBZ, PHT Level B: VPA Level C: GBP, LTG, OXC, PB, TPM, VGB Level D: CZP, PRM Level E: Others
Level F: None
A total of 25 RCTs and 1 meta-analysis examined initial monotherapy of children with partial-onset seizures Level A: OXC
Level B: None
Level C: CBZ, PB, PHT,TPM, VPA Level D: LTG,VGB
Level E: Others
Level F: None
A total of 30 RCTS with elderly participants included which examined initial monotherapy for partial-onset seizures Level A: GBP, LTG Level B: None
Level C: CBZ
Level D: TPM, VPA
Level E: Others
Level F: None
A total of 23 RCTs and 5 meta-analyses examined initial monotherapy of adults with generalized-onset tonic clonic seizures Level A: None
Level B: None
Level C: CBZ,LTG,OXC, PB, PHT,TPM,VPA Level D: GBP,VGB Level E: Others Level F: None
A total of 20 RCTs examined initial monotherapy of children with generalized onset tonic clonic seizures Level A: None Level B: None
AED Dosages
AED CBZ PHT VPA PB INITIAL (mg/day) 400-600 200-300 500-1000 50-100 MAINTAIN (mg/day) 400-1600 200-400 500-2500 50-200 DIVIDED DOSE 2-3x 1-2x 2-3x 1x TITRATION 200-300 mg/day per 1-4 weeks 100mg/day per 3-7 days. 500mg/day per 7 days. 30-50mg/day per 10-15 days.
OXC
LVT
600-900
1000-2000
600-3000
1000-3000
2-3x
2x
AED Dosages
AED INITIAL (mg/day) MAINTAIN (mg/day) DIVIDED DOSE TITRATION
TPM
GBP LTG ZOS PGB
100
900-1800 50-100 100-200 50-75
100-400
900-3600 50-200 100-400 50-600
2x
2-3x 1-2x 1-2x 2-3x
PHENYTOIN
Adverse Effects: Ataxia and nystagmus. Cognitive impairment. Hirsutism Gingival hyperplasia, Coarsening of facial features. folate dependent megaloblastic anaemia, Osteomalacia, Inhibition of ADH, inhibition of insulin secretionhyperglycemia and glycosuria Hypoprothrominemiacoagulopathy Exacerbates absence seizures.
PHENYTOIN
CARBAMAZEPINE
Adverse Effects : Stupor, coma, respiratory depression, drowsiness, dizziness, vertigo, ataxia, blurred vision, diplopia, bradycardia, skin rashes, GI upsets. Hyponatremia in elderly
SODIUM VALPROATE
Adverse Effects : Elevated liver enzymes Tremor, hair loss, changes in hair growth
FELBAMATE
GABAPENTIN
Adverse Effects :
VIGABATRIN
Adverse Effects :
LAMOTRIGINE
Presently use as add-on therapy with valproic acid.
Almost completely absorbed T1/2 = 24 hrs Low plasma protein binding Blocks sodium channels, & high voltage Ca+2 channel Adverse effects:
thus its effective in partial, generalized, myoclonic, absence seizures & LennoxGastaut syndrome (LGS).
Approved for use in bipolar disorder
Dizziness
Headache
Diplopia Nausea
Somnolence
Rash
LEVETIRACETAM
Adjunct Rx of refractory Partial Seizure
Unknown mechanism of action but binds to presynaptic vesicle protein
ADVERSE EFFECT Dizziness, sleep disturbances, headache, and asthenia (LACK OF ENERGY)
TIAGABINE
100% bioavailable, highly protein bound. Adverse effects: Dizziness Nervousness Tremor Difficulty concentrating Depression Asthenia Emotional Psychosis Skin rash
T1/2 = 5 -8 hrs
Effective against partial and generalized tonic-clonic seizures.
TOPIRAMATE
Broad spectrum antiseizure activity, also used in migraine
Adverse effects: Somnolence Rapidly absorbed, bioav. is > 80%, has no active metabolites, excreted in urine.T1/2 = 20- Fatigue 30 hrs Dizziness blocking of voltage-dependent sodium Cognitive channels slowing Additionally the frequency of Cl- channel Paresthesias opening by binding to GABA receptor. Nervousness High-voltage calcium currents (L-type) are Confusion reduced Urolithiasis Depresses excitatory action of kainate on Weight loss
AMPA receptors. Carbonic anhydrase inhibiter effect Teratogenic in animal models.
ZONISAMIDE
Sulfonamide derivative Orally active half-life 50-60 hrs
Mechanism of action
Adverse effects:
Ataxia,
hyperthermia (children) Kidney stone
Drugs are secreted in small quantities into breast milk but not usually sufficient to prevent breast feeding (phenobarbitone significantly)
isoniazid
oral contraceptives salicylates theophyline
toxicity of phenytoin
antiepileptics metabolism. displaces phenytoin and v.a. carb and phenytoin may effect.
It is an alternative for patients whose conditions have been refractory to multiple drugs and in those who are sensitive to the many adverse effects of antiseizure drugs and those who have difficulty adhering to medication schedules. However, VNS is a costly and invasive procedure.