Download ANTI_EPILEPTIC_DRUGS

ANTI EPILEPTIC DRUGS
 EPILEPSY: A chronic disorder characterized by
recurrent seizure
 SEIZURE: Is a violent involuntary spasmodic
contraction of skeletal muscle
 EPIDEMIOLOGY: 1% worlds population & 57/1000
AETIOLOGY
• in children-idiopathic
•
in young- hypoxia, birth asphyxia, intracranial trauma during birth,
metabolic disturbances, infection
• In adult- head injury, alcohol abuse, cerebrovascular disease
• DIAGNOSIS: EEG( electroencephalo gram)
MRI(magnetic resonance imaging)
CT scan
brain mapping
ACTIVATION OF
EXCITATORY
NEURO
TRANSMITTOR
TISSUE DAMAGE
PATHOPHYSIOLOGY
IDIOPATHIC &
HERIDITORY
INHIBITION OF
INHIBITORY
NEURO
TRANSMITTOR
SEIZURE CLASSIFICATION
MECHANISM OF ANCTIONS
• a) enhancement of GABAnergic transmission
• b) diminution of excitatory transmission
• c) modification of ionic conductance
1ST LINE TREATMENT
2ND LINE TREATMENT
SIMPLE PARTIAL SEIZURE
CARBAMAZEPINE
VIGABATRIN ,ZONISAMIDE
COMPLEX PARTIAL SEIZURE
PHENYTOIN
CLOBAZAM
TONIC CLONIC
VALPROATE
VIGABATRIN
TONIC
CARBAMAZEPINE
CLOBAZAM
CLONIC
PHENYTOIN, LAMOTRIGINE
PHENOBARBITAL
ABSENCE
ETHOSUXIMIDE ,VALPROATE
CLONAZEPAM, LAMOTRIGINE
ACETAZOLAMIDE
ATONIC
CLONAZEPAM ,CLOBAZEPAM
LAMOTRIGINE ,CARBAMAZEPINE
PHENYTOIN ,ACETAZOLAMIDE
MYOCLONIC
VALPROATE, CLONAZEPAM
PHENOBARBITAL, ACETAZOLAMIDE
TOPIRAMATE
SEIZURE TYPE
PARTIAL SEIZURE
GENERALISEDSEIZURES
Cyclic ureides: Phenytoin, fosphenytoin
MECHANISM OF ACTION
• Blocks high-frequency firing of neurons through action on voltage-gated (VG)
Na+channels, decreases synaptic release of glutamate
PHARMACO KINETICS
• Absorption is formulation dependent,highly bound to plasma proteins
• no active metabolites ,Dose dependent elimination, ,t1/2 12-36h
• fosphenytoin is for IV, IM routes
Toxicity: Diplopia, ataxia,, hirsutism, neuropathy
Interactions: isoniazid, felbamate, oxcarbazepine, topiramate, fluoxetine,
fluconazole, digoxin, quinidine, cyclosporine, steroids, oral contraceptives,.
Phenobarbital
• Mechanism of action:
• Enhances phasic GABAa receptor responses ,Reduces excitatory
synaptic responses
• Pharmaco kinetics:
• Nearly complete absorption,
not significantly bound to plasma
Proteins,peak concentrations in 4 h, no active metabolites,t1/2 varies
from 75 to 125h
•
Toxicity: Sedation, cognitive issues, ataxia, hyperactivity
•
Interactions:Valproate,carbamazepine,felbamate,phenytoin,cyclosporine,
felodipine,,nifedipine, nimodipine, steroids,theophylline, verapamil,
Ethosuximide
• Mechanism of action: Reduces low threshold Ca2+ currents (Ttype)
• Pharmacokinetics: Well absorbed orally, with peak levels in 3-7 h, not proteinbound completely metabolized to inactive compounds ,t1/2 typically 40 h
• Toxicity: Nausea, headache, dizziness,hyperactivity
• Interactions: Valproate,phenobarbital, phenytoin, carbamazepine,rifampicin
Tricyclics: Carbamazepine
• Mechanism of action: Blocks high- frequencyfiring of neurons through
action on VG Na+ channels decreases synaptic release of glutamate
• pharmacokinetics: Well absorbed orally, with peak levels in 6 to 8 h
•
no significant protein binding
• metabolized in part to active 10-11-epoxide
•
t1/2 of parent ranges from 8to 12 h in treated patients to 36 h in normal subjects
• Toxicity: Nausea,, headache
• Interactions: valproate, fluoxetine, verapamil, macrolide antibiotics, isoniazid.
Benzodiazepines : Diazepam &LORAZEPAM
• MECHANISM OF ACTION: Potentiates GABAA responses
• PHARMACO KINETICS:
• Well absorbed orally
•
rectal administration gives peakconcentration in ~1 h with 90% bioavailability
• IV for status epilepticus,highly protein-bound
• extensively metabolized to several active metabolites, t1/2 ~2 d
• Toxicity: Sedation
Clonazepam
• MECHANISM OF ACTION: As for diazepam
• PHARMACO KINETICS:
• >80% bioavailability
• Extensively metabolized but no active metabolites
• t1/2 20-50 h
• Toxicity: Similar to diazepam
GABA derivatives :Gabapentin
• MECHANISM OF ACTION: Decreases excitatory transmission by acting on VG
Ca2+ channels presynaptically
• PHARMACO KINETICS:
• Bioavailability 50%, decreasing with increasing doses ,not bound to plasma proteins
•
not metabolized,t1/2 6-8 h
• Toxicity: Somnolence, dizziness, ataxia
Pregabalin
• MECHANISM OF ACTION: As for gabapentin
• PHARMACO KINETICS:
•
Well absorbed orally ,not bound to plasma proteins
•
not metabolized,t1/2 6-7 h
• Toxicity: Somnolence, dizziness, ataxia
Vigabatrin
• MECHANISM OF ACTION:
• Irreversibly inhibits GABA-trans aminase
• PHARMACO KINETICS:
• 70% bioavailable ,not bound to plasma proteins
• not metabolized,t1/2 5-7 h
• Toxicity: Drowsiness, dizziness, psychosis visual field loss
Miscellaneous: Valproate
• MECHANISM OF ACTION: Blocks high-frequency firing of
neurons, modifies amino acid metabolism
• PHARMACO KINETICS:
• Well absorbed from several formulations
• highly bound to plasma proteins
• Extensively metabolized, t1/2 9-16 h
• Toxicity: Nausea, tremor, weight gain, hair loss, teratogenic,
hepatotoxic
• Interactions: felbamate, rifampin, ethosuximide, primidone
Lamotrigine
• MECHANISM OF ACTION: Prolongs inactivation of VG-Na+ channels,acts
presynaptically on VG-Ca2+ channels,decreasing glutamate release
• PHARMACO KINETICS:
• Well absorbed orally
•
no significant protein binding
•
extensively metabolized, but no active metabolites
•
t1/2 25-35 h
• Toxicity: Dizziness, headache, diplopia, rash
• Interactions: Valproate, oxcarbazepine, primidone, succinimides, topiramate
Levetiracetam
• MECHANISM OF ACTION: Action on synaptic protein SV2A
• PHARMACO KINETICS:
• Well absorbed orally
• not bound to plasma proteins
•
metabolized to 3 inactive metabolites
•
t1/2 6-11 h
• Toxicity: Nervousness, dizziness, depression,
•
Interactions:,primidone
Tiagabine
• MECHANISM OF ACTION: Blocks GABA reuptake in forebrain
by selective blockade of GAT-1
• PHARMACO KINETICS:
• Well absorbed
• highly bound to plasma proteins
•
extensively metabolized, but no active metabolites
• t1/2 4-8 h
• Toxicity: Nervousness, dizziness, depression, seizures
•
Interactions: Phenobarbital, phenytoin, carbamazepine, primidone
Topiramate
MECHANISM OF ACTION: Multiple actions onsynaptic function, probably
via actions on phosphorylation
PHARMACO KINETICS:
Well absorbed, not bound to plasma proteins
extensively metabolized, but 40% excreted unchanged in the urine
no active metabolites
t1/2 20 h, but decreases with concomitant drugs
Toxicity: confusion
Interactions: Phenytoin, carbamazepine, oral contraceptives,, lithium
Zonisamide
• MECHANISM OF ACTION: Blocks high-frequency firing via action on
VG Na+ channels
• PHARMACO KINETICS:
• Approximately 70% bioavailable orally
• minimally bound to plasma proteins
• >50% metabolized, t1/2 50-70 h
• Toxicity: Drowsiness,, confusion.
Lacosamide
• MECHANISM OF ACTION:
• Enhances slow inactivation of Na+ channels
• Blocks effect of neurotrophins (via CRMP-2)
• PHARMACO KINETICS:
• Well absorbed ,minimal protein binding
• one major nonactive metabolite ,t1/2 12-14 h
• Toxicity: Dizziness, headache, nausea small increase in PR interval
RETIGABINE
• MECHANISM OF ACTION: Enhances k+ channel opening
• PHARMACOKINETICS: Readily absorbed,Requires 3-times daily dosing
• TOXICITY : dizziness, confusion, blurred vision
RUFINAMIDE
• MECHANISM OF ACTION: Prolongs inactivation of VG Na+ channels
• PHARMACOKINETICS:
• Well absorbed orally,Peak concentration in 4-6h
•
t1/2 6-10h,Minimal plasma protein binding
• No active metabolites ,Excreted in urine
• TOXICITY: vomiting ,diarrhea
• INTERACTIONS: not metabolized by CYP 450 Enzymes
REFERENCES
• Basic and clinical pharmacology- katzung, RogerJ.Porter,MD ,& Brain S.
Meldrum,MB, PhD 11th edition
• RANG & DALE’S Pharmacology 7th edition
• CLINICAL PHARMACOLOGY BY Rooger & Walker
• Conceptual pharmacology by D. jagadeesh Prasad
•
Goodman & Gilman