drug-induced seizures (in 15 minutes or less) robert s. hoffman, md director, nyc poison center...
TRANSCRIPT
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Drug-Induced Seizures(in 15 minutes or Less)
Robert S. Hoffman, MDDirector, NYC Poison Center
Associate Professor Emergency Medicine and Medicine
NYU School of Medicine
800-222-1222
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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
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Idiopathic Epilepsy vs
Drug Induced Seizures?
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Mortality and Status Epilepticus
05
1015202530354045
% Mortality
0:30-0:59
1:00-1:59
2:00-4:00
5:00-10:00
11:00-23:00
24+
Seizure Duration (hours)Towne AR, et al. Epilepsia 1994;35:27-34
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Most Acute Idiopathic Seizures Are Treated With:
BenzodiazepinesPhenytoinBarbituratesPropofol
• Should drug-induced seizures be treated in the same way?
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Drug Induced Seizures Status Epilepticus
Amphetamines Lidocaine CO
Anticholinergics Lithium Bupropion
Camphor Hypoglycemics Hypoglycemics
Carbamazepine Organophosphates Isoniazid
CO Phenytoin Theophylline
Cocaine TCAs and others
Cyanide Theophylline
Insulin Withdrawal
Isoniazid XTC
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Adenosine Antagonism
Theophylline
Caffeine
Theobromine
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Adenosine
K+
A
A
G
G GA
Excitation, Seizures, Cell death
+vasodilator
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Exp Neurol. 1989 Feb;103(2):179-85.
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Adenosine Antagonist Induced Seizures
• Implications– Poor prognosis– Adenosine antagonism allows for:
• Progression to status epilepticus
• Rapid metabolic failure
• Subsequent neurological injury
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Blake and Massey
Ann Emerg Med. 1988 Oct;17(10):1024-8
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Sodium Channel Blockade
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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
• GABA antagonism
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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)
• Doesn’t treat seizures
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Toxicol Appl Pharmacol. 1976 Oct;38(1):1-6
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GABAA Antagonism
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GABA
Cl-
Cl-Cl-
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GABA
Cl-
Cl-Cl-Cl-
Cl-
Cl-
Cl-
Cl-
BZ
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Pyridoxine (B6) and GABA
Glutamine
Glutamic Acid(brain)
GABA
NH2
COOH GAD Pyridoxal Pyridoxine 5’Phosphate
INH
X
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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
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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: Arch Intern Med 1990;150:1751-3
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Decreasing Alcohol Level
Alcoholic TremulousnessHypertensionTachycardia
HyperthermiaTremor
Diaphoresis
Delirium Tremens
Alcohol Withdrawal Alcoholic Hallucinosis Seizure
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NMDA Receptor Complex
Mg++
MK-801
Ca++
Gly Glu, NMDAEthanol
Tsai G: Am J Psych 1995;152:332
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Onset of Seizures
0
5
10
15
20
25
30
35
40
0-6 7-12 13-18 19-24 25-30 31-36 37-42 43-48 49-54 55-60 61-65 >65
Hours from last drink
Number
Victor: Epilepsia 1967
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Number of Seizures
0
10
20
30
40
50
60
70
80
90
100
1 2 3 4 5 6 7-12 Status
# ofpatients
# of seizures
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Time From First to Last Seizure
0
10
20
30
40
50
60
70
<6 8 9 10 12 20 96 120
# ofpatients
Time in hours n=77
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Chlordiazepoxide
Blum: J Toxicol 1976;3:427
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Haloperidol
Blum: J Toxicol 1976;3:427
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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 1989;87:645
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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
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Synergy (BZ + PB)
Twyman: Ann Neurol 1989;25:213
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Summary
• Try to define the etiology
• Always start with a benzodiazepine
• Avoid phenytoin
• Think about antidotes
• Add barbiturates for synergy– Think about anesthetic barbiturates