Download Drug-Induced Seizures

Drug-Induced Seizures
Dr Ian TF Cheung
AED Prince of Wales Hospital
9th March 2005
Definitions
• Seizure
– Abnormal electrical activity of the brain
• Leads to loss of neurologic function
– Abnormal motor, sensory, cognitive, or
emotional activity
• Leads to abnormal behaviors
– The term convulsion is used to describe a
seizure that results in motor activity.
– Focal vs generalized
Differential Diagnosis
• Idiopathic epilepsy
• Idiopathic epilepsy with sub-therapeutic
drug levels
• Trauma
• Electrolyte and metabolic abnormalities
– Glucose, sodium, oxygen
• Drug induced
Primary event
-direct reduction of seizure threshold
Secondary event
- cellular hypoxia caused by e.g. CO
Virtually any drug can cause
seizure as a terminal event.
Types of
neurotransmitters
Site of Synthesis
Three amines
epinephrine
dopamine
serotonin
adrenal medulla, some CNS cells
CNS
CNS, chromaffin cells of the
gut,enteric cells
Four amino acids
glutamate (+)
Gama aminobutyric acid (GABA) (-)
CNS
CNS
CNS
glycine (-)
Spinal cord
aspartate (+)
Types of
neurotransmitters
Site of Synthesis
Small molecules
acetylcholine
CNS, parasympathetic nerves
norepinephrine
CNS, sympathetic nerves
histamine
hyppthalamus
ATP
sympathetic, sensory and enteric
nerves
adenosine
CNS, periperal nerves
Small-molecules Neurotransmitters and Neuropeptides
Mechanisms
•
•
•
•
Impaired inhibition
Enhanced excitation
Disordered conduction
Metabolic failure
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
24+
Seizure Duration (hours)
Towne AR, et al. Epilepsia 1994;35:27-34
Drug Induced Seizures
Status
Epilepticus
Amphetamines
Isoniazid
Anticholinergics
Camphor
Lidocaine
Hypoglycemics
Carbon
monoxide
Bupropion
Hypoglycemics
Carbamazepine
Organophosphates Isoniazid
Carbon
monoxide
Phenytoin
Theophylline
Cocaine
Cyanide
Theophylline
Tricyclic
antidepressants
Tetramine (424)
Withdrawal
ETOH
Insulin
Withdrawal
GABAA Antagonism
GABAA Antagonism
Synergy (BDZ + Barb)
GABA Antagonism
• Prevents GABA binding
– Picrotoxin (TCA)
– Penicillin
• Reduces GABA
– Isoniazid
– Monomethylhydrazine
GABA Agonism
GABA Antagonism
Pyridoxine (B6) and GABA
Glutamine
NH2
Glutamic Acid
(brain)
COOH
GAD
Pyridoxine
kinase
X
5’Phosphate (PLP)
+Pyridoxal
GABA
INH
Pyridoxine
Isoniazid
• Mechanism of action
– Enhances pyridoxine elimination
– Prevents activation of pyridoxine
– Blocks activated pyridoxine
Isoniazid
• Toxidrome
– Nausea and vomiting
• Usually within 30 minutes to 2 hours
– Seizures
• Rapid onset (near the time of vomiting)
• Progression to status epilepticus
– Delayed hepatotoxicity
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
Pyridoxine Dosing
• Empiric
– 70 mg/kg up to 5 grams
• Known ingestion
– Gram for gram
– First dose not to exceed 70 mg/kg
• IV preferred, oral acceptable
• Follow with benzodiazepines
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)
Adenosine
• at least four subtypes of the adenosine receptor ¾
A1, A2A, A2B and A3 receptors.
• A1 receptors are highly expressed in the brain,
especially in the hippocampus, thalamus,
cerebellum and cortex.
• A3 receptors are moderately expressed in the brain
• A2 receptors limited distribution in CNS, mostly
concentrated on cerebral vasculature.
Adenosine
ATP
GT
ATP
catabolism
ADP
AMP
AK ADA
A
Adenosine
G
Na+
ATP
Glut
Excitation,
Seizures,
Cell death
ADP
AMP
Inosine
Adenosine
• Net result:
– Prevents pre-synaptic excitatory
neurotransmitter release
– Reduces post-synaptic effects of excitatory
neurotransmitter
– Supplies critical cells with glucose, oxygen
– Vasodilates
• Removes toxic metabolic byproducts
Theophylline
• Complex mechanisms of action
–
–
–
–
Increase in catecholamines
Adenosine antagonism
Phosphodiesterase inhibition
Fluid and electrolyte abnormalities
Theophylline
• Toxidrome
–
–
–
–
–
–
Nausea
Vomiting
Tachycardia
Hypotension
Cardiac dysrhythmias
Seizures
Theophylline Induced Seizures
• Implications
– Poor associated prognosis
– Adenosine antagonism allows for:
• Progression to status epilepticus
• Rapid metabolic failure
• Neurological injury
Theophylline Induced Seizures
• Treatment
– A, B, C and D (check glucose)
– Aggressive seizure control
• Diazepam or lorazepam
• Barbiturate
– Most effective in prevent and eliminate methylxanthineinduced seizure
• Etomidate?, Propofol?
• Avoid phenytoin, not only ineffective but actually
increases likelihood of seizure and mortality.
Strategy
• One or two doses of benzodiazepines
• Secure airway and terminate seizures
– Intubating barbiturate, propofol, etomidate
•
•
•
•
Try to get EEG monitoring
Correct hemodynamics and electrolytes
Multiple dose activated charcoal +/- WBI
Hemodialysis / Hemoperfusion
Indication for charcoal
Hemoperfusion/Hemodialysis
•
All Patients
–
Level >40ug/ml and any of the following:
1.
2.
3.
4.
Seizure
Hypotension unresponsive to fluids
Ventricular dysrhythmias
Protracted vomiting despite antiemetic (cannot
receive activated charcoal)
Indication for charcoal
Hemoperfusion/Hemodialysis
•
Acute
–
•
Acute on Chronic
–
•
Level >90ug/ml
Level >70ug/ml, 4 hours after ingestion of SR
Chronic
–
–
Controversial;
Consider when level >60ug/ml or level 4060ug/ml if age >60
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
Tricyclics
• Toxidrome
–
–
–
–
–
Rapid onset of sedation
Anticholinergic effects
Seizures
Hypotension
Widened QRS complex on ECG
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
GABAA
Decreasing Alcohol Level
Alcohol Withdrawal
Seizure
Alcoholic Hallucinosis
Alcoholic Tremulousness
Hypertension
Tachycardia
Hyperthermia
Tremor
Diaphoresis
Delirium Tremens
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
Hours from last drink
61-65
>65
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
Benzodiazepine Dosing
• Choice of benzodiazepines
–
–
–
–
Intravenous vs oral
Active metabolites vs. inactive metabolites
Rapidity of onset
PRN vs. standing orders
– All decisions favor intravenous diazepam
Role of Magnesium in
Withdrawal
•
•
•
•
Randomized double-blind study in 100 alcoholics
4 IM injections of 2g of MgSO4 q6h or NS
All got benzodiazepines as needed
3 observers rated withdrawal scores
»
• No difference between groups with regard to
– withdrawal score
– total benzodiazepine dose
Wilson:Alcoholism 1984;8:542
Haloperidol
Blum: J Toxicol
1976;3:427
Benzodiazepine Failures
• Failure due to cross tolerance
– Large doses in short periods of time
– Large doses with no clinical effect
– > 200 mg of diazepam +
Benzodiazepine Failures
• Midazolam – rapid onset iv
• Lorazepam –no active metabolites, may be
used in severe liver dx patient.
• Phenobarbital – slow onset iv, narrow
therapeutic index.
• Propofol – rapid onset iv, easy to titrate,
rapid offset.
Propofol
•
•
•
•
•
•
GABA agonist
NMDA antagonist
Rapidly acting
Highly lipophilic, large Vd (600-800L)
Ease to titrate
Supported by case reports
– McCowan: Crit Care Med 2000;28:1781-1784
– Coomes: Ann Emerg Med 1997;30:825-828
– Olmedo: J Toxicol Clin Toxicol 2000;38:537
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
Problem Seizures
• Definition:
– Seizures that respond to anticonvulsants but
patient is at risk even after the seizure if
etiology not defined
• Considerations:
– Hypoglycemia (various)
– Hyponatremia (XTC)
– Carbon monoxide
聞到死
“聞到死” (smell to death) is also called:
毒鼠強，聞氣即死小霸王、氣體麻醉殺鼠靈、快殺靈
、特效氣體滅鼠膏、超級氣體、氣體超級膏王、聞到
即死、超霸鼠藥、威力誘殺迷鼠精、滅鼠神、誘鼠穿
心丸、三步倒、三步跳，沒命鼠、滅鼠一掃光、死光
光、三秒得、鼠必死、最後晚餐、滴滴香、王中王、
特效滅鼠藥、超級膏王、神奇快殺靈、四二四、四亞
甲基二硫四氨等。
Tetramethylene Disulfotetramine or Tetramine
四亞甲基二硫四氨(四二四) C4-H8-N4-O4-S2
sodium
dimercaptopropanesulfonateate
DMPS & succimer also useful for nonmetalic pesticide -Tetramine
Bring home message:
Think 3x before using phenytoin in
treating all these drug-induced seizure
 Correct metabolic and electrolytes
disturbances
 Decontamination

Thank you
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