Drug-Induced Seizures (in 15 minutes or Less)

1
Drug-Induced Seizures(in 15 minutes or Less)
800-222-1222

• Robert S. Hoffman, MD
• Director, NYC Poison Center
• Associate Professor Emergency Medicine and
  Medicine
• NYU School of Medicine

2
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

3
Idiopathic Epilepsy vsDrug Induced Seizures?
4
(No Transcript)
5
Mortality and Status Epilepticus
Towne AR, et al. Epilepsia 19943527-34
6
Most Acute Idiopathic Seizures Are Treated With

• Benzodiazepines
• Phenytoin
• Barbiturates
• Propofol
• Should drug-induced seizures be treated in the
  same way?

7
Drug Induced Seizures 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
8
Adenosine Antagonism

• Theophylline
• Caffeine
• Theobromine

9
Adenosine
GA
G
A
A
G
vasodilator
K
Excitation, Seizures, Cell death
10
(No Transcript)
11
Exp Neurol. 1989 Feb103(2)179-85.
12
Adenosine Antagonist Induced Seizures

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

13
Blake and Massey
Ann Emerg Med. 1988 Oct17(10)1024-8
14
(No Transcript)
15
Sodium Channel Blockade
16
(No Transcript)
17
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

18
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

19
Toxicol Appl Pharmacol. 1976 Oct38(1)1-6
20
(No Transcript)
21
GABAA Antagonism
22
Cl-
Cl-
Cl-
23
Cl-
Cl-
Cl-
Cl-
Cl-
Cl-
Cl-
Cl-
BZ
24
Pyridoxine (B6) and GABA
Glutamine Glutamic Acid (brain) GABA
NH2
GAD Pyridoxal
Pyridoxine 5Phosphate
COOH
25
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
• Chin L Toxicol Appl Pharmacol 197845713-22

26
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 19901501751-3

27
(No Transcript)
28
Decreasing Alcohol Level Alcoholic
Tremulousness Hypertension Tachycardia Hyperthermi
a Tremor Diaphoresis Delirium Tremens
Alcohol Withdrawal
Alcoholic Hallucinosis Seizure
29
(No Transcript)
30
NMDA Receptor Complex
Ethanol
Gly
Glu, NMDA
MK-801
Mg
Ca
Tsai G Am J Psych 1995152332
31
Onset of Seizures
Number
Hours from last drink
Victor Epilepsia 1967
32
Number of Seizures
of patients
of seizures
33
Time From First to Last Seizure
of patients
Time in hours
n77
34
Chlordiazepoxide
Blum J Toxicol 19763427
35
Haloperidol
Blum J Toxicol 19763427
36
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
37
Benzodiazepine Failures

• Failure of cross tolerance
• Large doses in short periods of time
• Large doses with no clinical effect
• gt 200 mg of diazepam
• Imperfect cross tolerance
• Demonstrated in SS vs LS mice

38
Synergy (BZ PB)
Twyman Ann Neurol 198925213
39
Summary

• Try to define the etiology
• Always start with a benzodiazepine
• Avoid phenytoin
• Think about antidotes
• Add barbiturates for synergy
• Think about anesthetic barbiturates