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