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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
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
Idiopathic Epilepsy vs
Drug Induced Seizures?
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
Most Acute Idiopathic Seizures Are Treated With:
BenzodiazepinesPhenytoinBarbituratesPropofol
• Should drug-induced seizures be treated in the same way?
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
Adenosine Antagonism
Theophylline
Caffeine
Theobromine
Adenosine
K+
A
A
G
G GA
Excitation, Seizures, Cell death
+vasodilator
Exp Neurol. 1989 Feb;103(2):179-85.
Adenosine Antagonist Induced Seizures
• Implications– Poor prognosis– Adenosine antagonism allows for:
• Progression to status epilepticus
• Rapid metabolic failure
• Subsequent neurological injury
Blake and Massey
Ann Emerg Med. 1988 Oct;17(10):1024-8
Sodium Channel Blockade
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
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
Toxicol Appl Pharmacol. 1976 Oct;38(1):1-6
GABAA Antagonism
GABA
Cl-
Cl-Cl-
GABA
Cl-
Cl-Cl-Cl-
Cl-
Cl-
Cl-
Cl-
BZ
Pyridoxine (B6) and GABA
Glutamine
Glutamic Acid(brain)
GABA
NH2
COOH GAD Pyridoxal Pyridoxine 5’Phosphate
INH
X
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
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
Decreasing Alcohol Level
Alcoholic TremulousnessHypertensionTachycardia
HyperthermiaTremor
Diaphoresis
Delirium Tremens
Alcohol Withdrawal Alcoholic Hallucinosis Seizure
NMDA Receptor Complex
Mg++
MK-801
Ca++
Gly Glu, NMDAEthanol
Tsai G: Am J Psych 1995;152:332
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
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
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
Chlordiazepoxide
Blum: J Toxicol 1976;3:427
Haloperidol
Blum: J Toxicol 1976;3:427
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
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
Synergy (BZ + PB)
Twyman: Ann Neurol 1989;25:213
Summary
• Try to define the etiology
• Always start with a benzodiazepine
• Avoid phenytoin
• Think about antidotes
• Add barbiturates for synergy– Think about anesthetic barbiturates