Anti-Epileptic Drugs

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Anti-Seizure Drugs

Transcript of Anti-Epileptic Drugs

  • 2. ANTI-EPILEPTIC DRUG (AED) A drug which decreases the frequency and/or severity of seizures in people with epilepsy Treats the symptom of seizures, not the underlying epileptic condition Goal: maximize quality of life by minimizing seizures and adverse drug effects Currently no anti-epileptogenic drugs available
  • 3. Current Pharmacotherapy Just under 60% of all people with epilepsy can become seizure free with drug therapy In another 20%, the seizures can be drastically reduced In ~ 20% of epileptic patients, seizures are refractory to currently available AEDs
  • 4. Choosing the right AED Seizure type Epilepsy syndrome Pharmacokinetic profile Interactions/other medical conditions Efficacy Expected adverse effects Cost
  • 5. Classification of AEDs Classical Phenytoin Phenobarbital Primidone Carbamazepine Ethosuximide Valproate (valproic acid) Trimethadione (not currently in use) Newer Lamotrigine Felbamate Topiramate Gabapentin/Preg abalin Tiagabine Vigabatrin Oxycarbazepine Levetiracetam Fosphenytoin
  • 6. General Facts About AEDs Good oral absorption and bioavailability Most metabolized in liver but some excreted unchanged in kidneys Classic AEDs generally have more severe CNS sedation than newer drugs (except ethosuximide) Because of overlapping mechanisms of action, best drug can be chosen based on minimizing side effects in addition to efficacy
  • 7. Targets for AEDs Increase inhibitory neurotransmitter system GABA Decrease excitatory neurotransmitter system glutamate Block voltage-gated inward positive currents Na+ or Ca++ Increase outward positive currentK+ Many AEDs pleiotropicact via multiple mechanisms
  • 8. AEDs: Mechanisms of Action Voltage-gated sodium channel Open Inactivated Na+ Na+ X I Na+ Carbamazepine Phenytoin A = activation gate I = inactivation gate McNamara JO. Goodman & Gilmans. 9th ed. 1996:461-486. I Na+ Lamotrigine Valproate
  • 9. AEDs: Mechanisms of Action Calcium channel blockade
  • 10. AEDs: Mechanisms of Action GABA
  • 11. Side effect issues Sedation - especially with barbiturates Cosmetic - phenytoin Weight gain valproic acid, gabapentin Weight loss - topiramate Reproductive function valproic acid Cognitive - topiramate Behavioral felbamate, leviteracetam Allergic - many
  • 12. END OF INTRO
  • 13. GABA GABA Barbiturates Benzodiazepines Gabapentin Levetiracetam Tiagabine Topiramate Valproate Vigabatrin Na+ Na+ Carbamazepine Lamotrigine Oxcarbazepine Phenytoin Topiramate Valproate Ca2+ Ca2+ Ethosuximide Levetiracetam Pregabalin Valproate
  • 14. CLINICAL USES Generalized Tonic-Clonic Seizures Partial Seizures Absence Seizures Myoclonic & Atypical Absence Syndromes Status Epilepticus Other Clinical Uses
  • 15. GENERALIZE D TONICCLONIC SEIZURES PARTIAL SEIZURES ABSENCE SEIZURES MYOCLONI STATUS C& EPILEPTICUS ATYPICAL SYNDROMES Drugs of Choice Valproic Acid Carbamazepine Phenytoin Carbamazepine Lamotrigine Phenytoin Ethosuximide Valproic Valproic Acid Clonazepam Diazepam Lorazepam Alternativ e Agents Phenobarbital Felbamate Phenobarbital Topiramate Valproic Acid Clonazepam Levetiracetam Topiramate Zonisamide Phenytoin Phenobarbital Adjunctive Drugs Lamotrigine Topiramate Gabapentin Pregabalin Lamotrigine Levetiracetam Zonisamide Lamotrigine Felbamate
  • 16. Other Clinical Uses Valproic acid mania Carbamazepine, Lamotrigine bipolar disorder Carbamazepine trigeminal neuralgia Gabapentin pain of neuropathic origin Topiramate migraine Pregabalin neuropathic pain
  • 18. TOXICITY Teratogenicity Overdosage Toxicity Life-Threatening Toxicity
  • 19. Teratogenicity Valproic acid neural tube defects Carbamazepine craniofacial anomalies, spina bifida Phenytoin fetal hydantoin syndrome
  • 20. Overdosage Toxicity Respiratory depression Management: supportive Airway management Mechanical ventilation
  • 21. Life-Threatening Toxicity Valproic acid fatal hepatoxicity Lamotrigine Stevens-Johnson syndrome Zonisamide severe skin reactions Felbamate aplastic anemia, acute hepatic failure
  • 23. Drug Name Indication Mechanism Pharmacoki Therapeutic Drug of Action netics Levels and Interaction Dosage Carbamazepine Indicated It blocks for complex sodium partial channels at seizures, therapeutic generalized concentrations tonic-clonic and inhibits seizures, high frequency mixed repetitive firing seizure in neurons patterns or other Acts partial or presynaptically generalized to decrease seizures. synaptic Not transmission indicated for Absence seizures. Absorptionvaries widely among patients Maintenance dose range: 800-1200 mg/day PO in divided doses Interactions are related to the drugs enzymeinducing properties Side effects/ ContraAdverse indications Reactions Common: Diplopia and ataxia (most common), gastrointestinal Peak levels: disturbances; 6-8 hours after Therapeutic Propoxyphene, sedation at high administration range: 4-12 troleandomycin, doses mg/L (16.9valproic acid Distribution50.8 inhibit Occasional: slow micromoles/L) carbamazepine Retention of Volume clearance and water and distribution: Maximum dose increase hyponatremia; 1L/kg of 1600 steady-state rash, agitation mg/day carbamazepine in children Systemic recommended blood levels clearance(rarely, some Rare: 1L/kg/d patients have Phenytoin, Idiosyncratic required 1.6- phenobarbital blood 70% bound to 2.4 g/day) decrease dyscrasias and plasma steady state severe rashes proteins concentration of carbamazepine Half-life 36hrs Hypersensitivity Kidney disease Cardiovascular disease Seizure disorder, myasthenia gravis Dehydration hypothyroidism
  • 24. Drug Name Indication Mechanis Pharmacokinet Therapeutic m of ics Levels and Action Dosage Phenytoin Control of Blocks grand mal & sodium complex channels partial seizure, Prevents prevention nerve & treatment conduction of seizure during or following neurosurger y, migraine, trigeminal neuralgia, certain psychoses, cardiac arrhythmias, digitalis intoxication, post-event treatment of MI. Absorption after oral ingestion may be slow, variable and occasionally incomplete Adult Initially 100 mg tid. Maintenance: 300-400 mg daily in equally divided doses. Childn 6 yr T1/2 = 20-30 hrs Initially 100 mg tid, subsequent Rapidly dosage should distributed to all be adjusted tissues according to therapeutic Metabolized response. primarily by liver Pedia Initially 5 P450 mg/kg/day in 2-3 Highly