Anti epileptic drugs
Transcript of Anti epileptic drugs
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Anti-epileptic Drugs
• Classification of Seizures– Partial: simple or complex
– Generalized: absence, tonic, clonic, tonic-clonic, myoclonic, febrile
• Animal Models of Seizures– Chemical-induced: pentylenetetrazole, kainic acid,
– Maximal electrochock
– Kindling
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Pathophysiology of Seizures
• The Interictal Spike (paroxysmal depolarization shift)
• Increased excitability – Membrane depolarization, potassium buildup– Increased excitatory (EAA, glutamate) input– Decreased inhibitory (GABA) input
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Evidence for the Pathophysiology of Seizures
Increased EAA• Increased Excitatory
Amino Acid Transmission• Increased sensitivity to
EAA• Progressive increase in
glutamate release during kindling
• Increased glutamate and aspartate at start of seizure
• Upregulation of NMDA receptors in kindled rats
Decreased GABA• Decreased binding of
GABA and benzodiazepines
• Decreased Cl- currents in response to GABA
• Decreased glutamate decarboxylase activity (synthesizes GABA)
• Interfere with GABA causes seizures
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Strategies in Treatment
• Stabilize membrane and prevent depolarization by action on ion channels
• Increase GABAergic transmission
• Decrease EAA transmission
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Classification of AnticonvulsantsAction on Ion
ChannelsEnhance GABA
Transmission
Inhibit EAA
TransmissionNa+:
Phenytoin, Carbamazepine, Lamotrigine
Topiramate
Valproic acid
Ca++:
Ethosuximide
Valproic acid
Benzodiazepines
(diazepam, clonazepam) Barbiturates (phenobarbital)
Valproic acid
Gabapentin
Vigabatrin
Topiramate
Felbamate
Felbamate
Topiramate
Na+:
For general tonic-clonic and partial seizures
Ca++:
For Absence seizures
Most effective in myoclonic but also in tonic-clonic and partial
Clonazepam: for Absence
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Classification of Anticonvulsants
Classical• Phenytoin
• Phenobarbital
• Primidone
• Carbamazepine
• Ethosuximide
• Valproic Acid
• Trimethadione
Newer• Lamotrigine• Felbamate• Topiramate• Gabapentin• Tiagabine• Vigabatrin• Oxycarbazepine• Levetiracetam• Fosphenytoin• Others
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Phenytoin
Phenobarbital Carbamazepine
Ethosuximide Trimethadione
Valproic Acid
R1
R2
R3
X
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Phenytoin or Diphenylhydantoin
• Limited water solubility – not given i.m.• Slow, incomplete and variable absorption.• Extensive binding to plasma protein.• Metabolized by hepatic ER by hydroxylation.
Chance for drug interactions.• Therapeutic plasma concentration: 10-20 µg/ml• Shift from first to zero order elimination within
therapeutic concentration range.
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Dose (mg/day)
Pla
sma
Con
cen
trat
ion
(m
g/L
)Relationship between Phenytoin Daily Dose and
Plasma Concentration In 5 Patients
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Phenytoin – Toxicity and Adverse Events
Acute Toxicity
• High i.v. rate: cardiac arrhythmias ± hypotension; CNS depression.
• Acute oral overdose: cerebellar and vestibular symptoms and signs:
nystagmus, ataxia, diplopia vertigo.
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Chronic Toxicity• Dose related vestibular/cerebellar effects• Behavioral changes• Gingival Hyperplasia • GI Disturbances• Sexual-Endocrine Effects:
– Osteomalacia– Hirsutism– Hyperglycemia
Phenytoin – Toxicity
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Chronic Toxicity• Folate Deficiency - megaloblastic anemia• Hypoprothrombinemia and hemorrhage in newborns• Hypersenstivity Reactions – could be severe. SLE,
fatal hepatic necrosis, Stevens-Johnson syndrome.• Pseudolymphoma syndrome• Teratogenic• Drug Interactions: decrease (cimetidine, isoniazid) or
increase (phenobarbital, other AED’s) rate of metabolism; competition for protein binding sites.
Phenytoin – Toxicity and Adverse Events
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Fosphenytoin
• A Prodrug. Given i.v. or i.m. and rapidly converted to phenytoin in the body.
• Avoids local complications associated with phenytoin: vein irritation, tissue damage, pain and burning at site, muscle necrosis with i.m. injection, need for large fluid volumes.
• Otherwise similar toxicities to phenytoin.
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Other Na Channel Blockers
• Carbamazepine: may have adrenergic mechanism as well. Serious hematological toxicity: aplastic anemia. Antidiuretic effect (anti ADH).
• Also for trigeminal neuralgia• Lamotrigine: possible other mechanisms.
Effective in Absence seizures and has antidepressant effects in bipolar depression. No chronic associated effects.
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Inhibitors of Calcium ChannelsEthosuximide
• Drug of choice for Absence. Blocks Ca++ currents (T-currents) in the thalamus.
• Not effective in other seizure types• GI complaints most common• CNS effects: drowsiness lethargy).• Has dopamine antagonist activity (? In seizure
control) but causes Parkinsonian like symptoms.• Potentially fatal bone marrow toxicity and skin
reactions (both rare)
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Enhancers of GABA Transmission
Phenobarbital• The only barbiturate with selective anticonvulsant effect.• Bind at allosteric site on GABA receptor and ↑ duration of
opening of Cl channel.• ↓ Ca-dependent release of neurotransmitters at high doses.• Inducer of microsomal enzymes – drug interactions.• Toxic effects: sedation (early; tolerance develops);
nystagmus & ataxia at higher dose; osteomalacia, folate deficiency and vit. K deficiency.
• In children: paradoxical irritability, hyperactivity and behavioral changes.
• Deoxybarbiturates: primidone: active but also converted to phenobarbital. Some serious additional ADR’s: leukopenia, SLE-like.
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Benzodiazepines• Sedative - hypnotic- anxiolytic drugs.• Bind to another site on GABA receptor. Other mechanisms
may contribute. ↑ frequency of opening of Cl channel.• Clonazepam and clorazepate for long term treatment of
some epilepsies. • Diazepam and lorazepam: for control of status epilepticus.
Disadvantage: short acting.• Toxicities: chronic: lethargy drowsiness.
in status epilepticus: iv administration: respiratory and cardiovascular depression. Phenytoin and PB also used.
Enhancers of GABA Transmission
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GABA-A ReceptorBinding Sites
Cl-
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• Gabapentin: Developed as GABA analogue. Mechanism: Increases release of GABA by unknown mechanism.
• Vigabatrin: Irreversible inhibitor of GABA transaminase. Potential to cause psychiatric disorders (depression and psychosis).
• Tiagabine: decreases GABA uptake by neuronal and extraneuronal tissues.
Enhancers of GABA Transmission
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VigabatrinGABA
Tiagabine Gabapentin
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TGB
VGBBZD
TPM
VGB
GBP
GABA-T
GABA-T
Modulators of GABA Transmission
TGB
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Valproic Acid
• Effective in multiple seizure types.• Blocks Na and Ca channels. Inhibits GABA
transaminase. Increases GABA synthesis. • Toxicity: most serious: fulminant hepatitis. More
common if antiepileptic polytherapy in children < 2 years old. (?) Toxic metabolites involved.
• Drug interactions: inhibits phenobarbital and phenytoin metabolism.
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Other Drugs
• Topiramate; multiple mechanisms of action (Na channel, GABA enhancement like BZD, antagonist at AMPA subtype of glutamate receptors (not NMDA).
• Felbamate: multiple mechanisms: Na channel block; modulates glutamate transmission interacts with glycine site. Serious hematological and hepatic toxicities.
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Treatment of Epilepsy
• Start with a single agent. Raise to maximum tolerated dose before shifting to another.
• If therapy fails may use combination of drugs.
• Frequent physician visits early on and therapeutic drug monitoring.
• Importance of compliance.• Aim and duration of therapy.
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