Transcript drug induced Seizures hoffman

800-222-1222
Drug-Induced Seizures
(in 15 minutes or Less)
Robert S. Hoffman, MD
Director, NYC Poison Center
Associate Professor Emergency Medicine and
Medicine
NYU School of Medicine
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
% Mortality
45
40
35
30
25
20
15
10
5
0
0:300:59
1:001:59
2:004:00
5:00- 11:0010:00 23:00
Seizure Duration (hours)
Towne AR, et al. Epilepsia 1994;35:27-34
24+
Most Acute Idiopathic Seizures
Are Treated With:
Benzodiazepines
Phenytoin
Barbiturates
Propofol
• Should drug-induced seizures be
treated in the same way?
Drug Induced Seizures
Status
Epilepticus
Amphetamines
Anticholinergics
Camphor
Lidocaine
Lithium
Hypoglycemics
CO
Bupropion
Hypoglycemics
Carbamazepine
Organophosphates Isoniazid
CO
Cocaine
Phenytoin
TCAs and others
Cyanide
Insulin
Isoniazid
Theophylline
Withdrawal
XTC
Theophylline
Adenosine Antagonism
Theophylline
Caffeine
Theobromine
Adenosine
A G
GA
A
G
+vasodilator
Excitation, Seizures,
Cell death
K+
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
ClCl- Cl-
GABA
Cl-
Cl-
Cl- Cl-
Cl- ClClCl-
Pyridoxine (B6) and GABA
Glutamine
NH2
Glutamic Acid
(brain)
COOH
GAD
Pyridoxal
5’Phosphate
GABA
X
INH
Pyridoxine
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
Alcohol Withdrawal
Seizure
Alcoholic Hallucinosis
Alcoholic Tremulousness
Hypertension
Tachycardia
Hyperthermia
Tremor
Diaphoresis
Delirium Tremens
NMDA Receptor Complex
Ethanol
Gly
Glu, NMDA
MK-801
Mg++
Ca++
Tsai G: Am J Psych 1995;152:332
Onset of Seizures
40
35
30
Number 25
20
15
10
5
0
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
Victor: Epilepsia 1967
Number of Seizures
100
90
80
# of
patients
70
60
50
40
30
20
10
0
1
2
3
4
5
# of seizures
6
7-12
Status
Time From First to Last Seizure
70
60
50
# of
patients 40
30
20
10
0
<6
8
9
10
12
Time in hours
20
96
120
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