Drug-Induced Seizures

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Drug-Induced Seizures

• Dr Ian TF Cheung
• AED Prince of Wales Hospital

9th March 2005
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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

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Differential Diagnosis

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

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

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Virtually any drug can cause seizure as a
terminal event.
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Types of neurotransmitters  Site of Synthesis
Three amines Three amines
epinephrine                   adrenal medulla, some CNS cells
dopamine CNS
serotonin  CNS, chromaffin cells of the gut,enteric cells
Four amino acids Four amino acids
glutamate () CNS
aspartate () CNS
Gama aminobutyric acid (GABA) (-)             CNS
glycine  (-) Spinal cord
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Types of neurotransmitters  Site of Synthesis
Small molecules Small molecules
acetylcholine  CNS, parasympathetic nerves
norepinephrine CNS, sympathetic nerves
histamine   hyppthalamus
ATP sympathetic, sensory and enteric nerves
adenosine CNS, periperal nerves
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Small-molecules Neurotransmitters and
Neuropeptides
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Mechanisms

• Impaired inhibition
• Enhanced excitation
• Disordered conduction
• Metabolic failure

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Mortality and Status Epilepticus
Towne AR, et al. Epilepsia 19943527-34
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Drug Induced Seizures Drug Induced Seizures Status Epilepticus
Amphetamines Isoniazid Carbon monoxide
Anticholinergics Lidocaine Bupropion
Camphor Hypoglycemics Hypoglycemics
Carbamazepine Organophosphates Isoniazid
Carbon monoxide Phenytoin Theophylline
Cocaine Theophylline Tetramine (424)
Cyanide Tricyclic antidepressants Withdrawal ETOH
Insulin Withdrawal
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GABAA Antagonism
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GABAA Antagonism
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Synergy (BDZ Barb)
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GABA Antagonism

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

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GABA Agonism
GABA Antagonism
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Pyridoxine (B6) and GABA
Glutamine Glutamic Acid (brain) GABA
NH2
Pyridoxine kinase
GAD Pyridoxal
Pyridoxine 5Phosphate (PLP)
COOH
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Isoniazid

• Mechanism of action
• Enhances pyridoxine elimination
• Prevents activation of pyridoxine
• Blocks activated pyridoxine

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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

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Isoniazid

• Most GABA agonists require GABA
• Try a benzodiazepine
• No role for phenytoin (doesnt work Saad)
• No role for phenobarbital (takes too long)
• Give pyridoxine

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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

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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)

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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.

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

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Theophylline

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

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Theophylline

• Toxidrome
• Nausea
• Vomiting
• Tachycardia
• Hypotension
• Cardiac dysrhythmias
• Seizures

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Theophylline Induced Seizures

• Implications
• Poor associated prognosis
• Adenosine antagonism allows for
• Progression to status epilepticus
• Rapid metabolic failure
• Neurological injury

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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.

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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

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Indication for charcoal Hemoperfusion/Hemodialysis

• All Patients
• Level gt40ug/ml and any of the following
• Seizure
• Hypotension unresponsive to fluids
• Ventricular dysrhythmias
• Protracted vomiting despite antiemetic (cannot
  receive activated charcoal)

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Indication for charcoal Hemoperfusion/Hemodialysis

• Acute
• Level gt90ug/ml
• Acute on Chronic
• Level gt70ug/ml, 4 hours after ingestion of SR
• Chronic
• Controversial
• Consider when level gt60ug/ml or level 40-60ug/ml
  if age gt60

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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

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Tricyclics

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

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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)
• Doesnt treat seizures

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GABAA
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Decreasing Alcohol Level Alcoholic
Tremulousness Hypertension Tachycardia Hyperthermi
a Tremor Diaphoresis Delirium Tremens
Alcohol Withdrawal
Alcoholic Hallucinosis Seizure
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Onset of Seizures
Number
Hours from last drink
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Number of Seizures
of patients
of seizures
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Time From First to Last Seizure
of patients
Time in hours
n77
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Chlordiazepoxide
Blum J Toxicol 19763427
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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

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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

WilsonAlcoholism 19848542
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Haloperidol
Blum J Toxicol 19763427
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Benzodiazepine Failures

• Failure due to cross tolerance
• Large doses in short periods of time
• Large doses with no clinical effect
• gt 200 mg of diazepam

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Benzodiazepine Failures

• Midazolam rapid onset iv
• Lorazepam no active metabolites, may be used in
  severe liver dx patient.
• Phenobarbital slow onset iv, narrow therapeutic
  index.
• Propofol rapid onset iv, easy to titrate, rapid
  offset.

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Propofol

• GABA agonist
• NMDA antagonist
• Rapidly acting
• Highly lipophilic, large Vd (600-800L)
• Ease to titrate
• Supported by case reports
• McCowan Crit Care Med 2000281781-1784
• Coomes Ann Emerg Med 199730825-828
• Olmedo J Toxicol Clin Toxicol 200038537

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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 198987645
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Problem Seizures

• Definition
• Seizures that respond to anticonvulsants but
  patient is at risk even after the seizure if
  etiology not defined
• Considerations
• Hypoglycemia (various)
• Hyponatremia (XTC)
• Carbon monoxide

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???
??? (smell to death) is also
called ???,??????????????????????????????????????
?????????????????????????????????????,????????????
??????????????????????????????????????????????????
????
Tetramethylene Disulfotetramine or
Tetramine ????????(???) C4-H8-N4-O4-S2
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• sodium dimercaptopropanesulfonateate DMPS
  succimer also useful for non-metalic pesticide
  -Tetramine

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• Bring home message
• Think 3x before using phenytoin in treating all
  these drug-induced seizure
• Correct metabolic and electrolytes disturbances
• Decontamination

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Thank you

• -END-

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