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Drug-Induced Seizures (in 15 minutes or Less)

Drug-Induced Seizures (in 15 minutes or Less). 800-222-1222. Robert S. Hoffman, MD Director, NYC Poison Center Associate Professor Emergency Medicine and Medicine NYU School of Medicine. Why Do People Seize?. Impaired inhibition GABA A antagonism GABA B agonism Adenosine antagonism

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Drug-Induced Seizures (in 15 minutes or Less)

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  1. Drug-Induced Seizures(in 15 minutes or Less) 800-222-1222 Robert S. Hoffman, MD Director, NYC Poison Center Associate Professor Emergency Medicine and Medicine NYU School of Medicine

  2. Why Do People Seize? • Impaired inhibition • GABAA antagonism • GABAB agonism • Adenosine antagonism • Enhanced excitation • NMDA and other excitatory amino acids • Disordered conduction • Sodium channel blockade • Metabolic failure • Oxygen, glucose, sodium, etc

  3. Idiopathic Epilepsy vsDrug Induced Seizures?

  4. Mortality and Status Epilepticus Towne AR, et al. Epilepsia 1994;35:27-34

  5. Most Acute Idiopathic Seizures Are Treated With: Benzodiazepines Phenytoin Barbiturates Propofol • Should drug-induced seizures be treated in the same way?

  6. Adenosine Antagonism Theophylline Caffeine Theobromine

  7. Adenosine GA G A A G +vasodilator K+ Excitation, Seizures, Cell death

  8. Exp Neurol. 1989 Feb;103(2):179-85.

  9. Adenosine Antagonist Induced Seizures • Implications • Poor prognosis • Adenosine antagonism allows for: • Progression to status epilepticus • Rapid metabolic failure • Subsequent neurological injury

  10. Blake and Massey Ann Emerg Med. 1988 Oct;17(10):1024-8

  11. Sodium Channel Blockade

  12. Tricyclics • Complex drugs • Block the re-uptake of biogenic amines • Block alpha adrenergic receptors • Block muscarinic receptors • Block fast sodium channels • Bind to the picrotoxin receptor • GABA antagonism

  13. Phenytoin and TCAs • Once thought to be the drug of choice • In theory • Narrows QRS • Narrows QTc • Terminates seizures • In reality • Exacerbates V-tach (Callaham) • Doesn’t treat seizures

  14. Toxicol Appl Pharmacol. 1976 Oct;38(1):1-6

  15. GABAA Antagonism

  16. GABA Cl- Cl- Cl-

  17. GABA Cl- Cl- Cl- Cl- Cl- Cl- Cl- Cl- BZ

  18. X INH Pyridoxine (B6) and GABA Glutamine Glutamic Acid (brain) GABA NH2 GAD Pyridoxal Pyridoxine 5’Phosphate COOH

  19. Isoniazid • Most GABA agonists require GABA • Try a benzodiazepine • No role for phenytoin (doesn’t work; Saad) • No role for phenobarbital (takes too long) • Give pyridoxine • Chin L: Toxicol Appl Pharmacol 1978;45:713-22

  20. INH Induced Status Epilepticus • Use intubating barbiturates • Open Cl- channel without GABA • Consider NMBs to prevent hyperthermia and metabolic complications • EEG monitoring • Consider hemodialysis • Give pyridoxine for prolonged coma • Brent: Arch Intern Med 1990;150:1751-3

  21. Decreasing Alcohol Level Alcoholic Tremulousness Hypertension Tachycardia Hyperthermia Tremor Diaphoresis Delirium Tremens Alcohol Withdrawal Alcoholic Hallucinosis Seizure

  22. NMDA Receptor Complex Ethanol Gly Glu, NMDA MK-801 Mg++ Ca++ Tsai G: Am J Psych 1995;152:332

  23. Onset of Seizures Number Hours from last drink Victor: Epilepsia 1967

  24. Number of Seizures # of patients # of seizures

  25. Time From First to Last Seizure # of patients Time in hours n=77

  26. Chlordiazepoxide Blum: J Toxicol 1976;3:427

  27. Haloperidol Blum: J Toxicol 1976;3:427

  28. Phenytoin for Withdrawal Seizures • 90 patients with alcohol related seizures • Random assignment to phenytoin (1gm) or placebo • End points • Seizure recurrence • 12 hour seizure free period • No benefit demonstrated with strong power analysis (14%) Alldredge: Am J Med 1989;87:645

  29. Benzodiazepine Failures • Failure of cross tolerance • Large doses in short periods of time • Large doses with no clinical effect • > 200 mg of diazepam + • Imperfect cross tolerance • Demonstrated in SS vs LS mice

  30. Synergy (BZ + PB) Twyman: Ann Neurol 1989;25:213

  31. Summary • Try to define the etiology • Always start with a benzodiazepine • Avoid phenytoin • Think about antidotes • Add barbiturates for synergy • Think about anesthetic barbiturates

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