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Drug-Induced Seizures

Drug-Induced Seizures. Dr Ian TF Cheung AED Prince of Wales Hospital. 9th March 2005. Definitions. Seizure Abnormal electrical activity of the brain Leads to loss of neurologic function Abnormal motor, sensory, cognitive, or emotional activity Leads to abnormal behaviors

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Drug-Induced Seizures

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  1. Drug-Induced Seizures Dr Ian TF Cheung AED Prince of Wales Hospital 9th March 2005

  2. Definitions • Seizure • Abnormal electrical activity of the brain • Leads to loss of neurologic function • Abnormal motor, sensory, cognitive, or emotional activity • Leads to abnormal behaviors • The term convulsion is used to describe a seizure that results in motor activity. • Focal vs generalized

  3. Differential Diagnosis • Idiopathic epilepsy • Idiopathic epilepsy with sub-therapeutic drug levels • Trauma • Electrolyte and metabolic abnormalities • Glucose, sodium, oxygen • Drug induced

  4. Primary event • direct reduction of seizure threshold • Secondary event • - cellular hypoxia caused by e.g. CO

  5. Virtually any drug can cause seizure as a terminal event.

  6. Small-molecules Neurotransmitters and Neuropeptides

  7. Mechanisms • Impaired inhibition • Enhanced excitation • Disordered conduction • Metabolic failure

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

  9. GABAA Antagonism

  10. GABAA Antagonism

  11. Synergy (BDZ + Barb)

  12. GABA Antagonism • Prevents GABA binding • Picrotoxin (TCA) • Penicillin • Reduces GABA • Isoniazid • Monomethylhydrazine

  13. GABA Agonism GABA Antagonism

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

  15. Isoniazid • Mechanism of action • Enhances pyridoxine elimination • Prevents activation of pyridoxine • Blocks activated pyridoxine

  16. Isoniazid • Toxidrome • Nausea and vomiting • Usually within 30 minutes to 2 hours • Seizures • Rapid onset (near the time of vomiting) • Progression to status epilepticus • Delayed hepatotoxicity

  17. 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

  18. Pyridoxine Dosing • Empiric • 70 mg/kg up to 5 grams • Known ingestion • Gram for gram • First dose not to exceed 70 mg/kg • IV preferred, oral acceptable • Follow with benzodiazepines

  19. 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)

  20. Adenosine • at least four subtypes of the adenosine receptor ¾ A1, A2A, A2B and A3 receptors. • A1 receptors are highly expressed in the brain, especially in the hippocampus, thalamus, cerebellum and cortex. • A3 receptors are moderately expressed in the brain • A2 receptors limited distribution in CNS, mostly concentrated on cerebral vasculature.

  21. Adenosine ATP GT ATP catabolism ADP AMP AK ADA Inosine Adenosine G A Na+ ATP ADP AMP Glut Excitation, Seizures, Cell death

  22. Adenosine • Net result: • Prevents pre-synaptic excitatory neurotransmitter release • Reduces post-synaptic effects of excitatory neurotransmitter • Supplies critical cells with glucose, oxygen • Vasodilates • Removes toxic metabolic byproducts

  23. Theophylline • Complex mechanisms of action • Increase in catecholamines • Adenosine antagonism • Phosphodiesterase inhibition • Fluid and electrolyte abnormalities

  24. Theophylline • Toxidrome • Nausea • Vomiting • Tachycardia • Hypotension • Cardiac dysrhythmias • Seizures

  25. Theophylline Induced Seizures • Implications • Poor associated prognosis • Adenosine antagonism allows for: • Progression to status epilepticus • Rapid metabolic failure • Neurological injury

  26. Theophylline Induced Seizures • Treatment • A, B, C and D (check glucose) • Aggressive seizure control • Diazepam or lorazepam • Barbiturate • Most effective in prevent and eliminate methylxanthine-induced seizure • Etomidate?, Propofol? • Avoid phenytoin, not only ineffective but actually increases likelihood of seizure and mortality.

  27. Strategy • One or two doses of benzodiazepines • Secure airway and terminate seizures • Intubating barbiturate, propofol, etomidate • Try to get EEG monitoring • Correct hemodynamics and electrolytes • Multiple dose activated charcoal +/- WBI • Hemodialysis / Hemoperfusion

  28. Indication for charcoal Hemoperfusion/Hemodialysis • All Patients • Level >40ug/ml and any of the following: • Seizure • Hypotension unresponsive to fluids • Ventricular dysrhythmias • Protracted vomiting despite antiemetic (cannot receive activated charcoal)

  29. Indication for charcoal Hemoperfusion/Hemodialysis • Acute • Level >90ug/ml • Acute on Chronic • Level >70ug/ml, 4 hours after ingestion of SR • Chronic • Controversial; • Consider when level >60ug/ml or level 40-60ug/ml if age >60

  30. 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

  31. Tricyclics • Toxidrome • Rapid onset of sedation • Anticholinergic effects • Seizures • Hypotension • Widened QRS complex on ECG

  32. 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

  33. GABAA

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

  35. Onset of Seizures Number Hours from last drink

  36. Number of Seizures # of patients # of seizures

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

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

  39. Benzodiazepine Dosing • Choice of benzodiazepines • Intravenous vs oral • Active metabolites vs. inactive metabolites • Rapidity of onset • PRN vs. standing orders • All decisions favor intravenous diazepam

  40. Role of Magnesium in Withdrawal • Randomized double-blind study in 100 alcoholics • 4 IM injections of 2g of MgSO4 q6h or NS • All got benzodiazepines as needed • 3 observers rated withdrawal scores • No difference between groups with regard to • withdrawal score • total benzodiazepine dose Wilson:Alcoholism 1984;8:542

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