Transcript toxicology 3 - Calgary Emergency Medicine

TOXICOLOGY 3
Nadim J Lalani MD
Special mention : Dr M. Beuhler
Dr Mark Yarema
Dr Vicas
Name the General. Epilepsy or no?
Sun Tzu ? 722–481 BC
• heroic general of the King of
Wu [544—496 BC]
• Author of “The Art of War”
– Huge Influence on China
– Adopted by Japanese Samurai
– Studied by Napoleon
• ?Existence of Sun Tzu
– Based on anachronisms in
text
• Did not have seizures
Julius Caesar 100–44 BC
• Was a priest at age 17
• Inspired by Alexander
• Invented the 365 day
calendar
• Killed on March 15 44
BC “the Ides”
• Never said “et tu
Brutus”
• four documented
episodes of ? complex
partial seizures
Drug and Toxin Induced Seizures
“The Generalised Version”
Outline
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Pathophysiology
DDX
ABCDEFP’s of DTS
Cases
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Bupropion
Diphenhydramine
Opioids
INH
Theophylline
• Short snappers at any moment
Pathophysiology
• Sz activity results from chaotic electrical
discharge in the CNS
• Disruption of normal structure
– Congenital
– acquired [mass/trauma]
• Disruption of local metabolic milieu
• Drugs/Toxins
– metab/drugs/toxins/withdrawal result in changes
in neurochemical pathways that “kindle” up a Sz
Neurochemical pathways
• Balance exists between inhibitory and
excitatory pathways
• Main inhibitory neurotransmitters consist of
– GABA
– Glycine
• Main excitatory neurotransmitter is glutamate
Neurochemical p-ways : Inhibitors
Gamma-aminobutyric acid (GABA)
• main inhibitory neurotransmitter of the CNS.
• Stimulated GABA receptors  chloride ion
flux inhibit membrane depolarization
• GABA antagonists/depletn of GABA  incr
membrane depolarization  seizures
GABA Channel
http://edpharmacologystuff.blogspot.com
Synthesis of GABA
Glutamine
Pyridoxine
NH3
Pyridoxine
Phosphokinase
Glutamate
CO2
Glutamic Acid Decarboxylase
Pyridoxal 5’-phosphate
Gamma aminobutyric acid
• GABA is broken down by GABA transaminase
 this is exploited by the anticonvulsant
Vigabatrin which inhibits GT
• 3-types of GABA rec (A [main one], B & C).
• GABA B rec affected by GHB (drug of abuse)
and Baclofen (antispasmodic)
– in someone with Sz and a Baclofen pump think
pump failure)
• Anitbiotix that cause Sz do so through GABA
antagonism
How Do Benzos Work?
Barbituates?
Mechanism of Action
• Benzodiazepines
– At least two different binding sites
– Increase GABA affinity for receptor
– Increase frequency of channel opening
– Inhibit adenosine uptake
– Therefore Inhibits neuronal activity
Mechanism of Action
• Barbiturates
– Increase duration of channel opening
– At high concentrations, open Cl- channel directly
– Will not require GABA presence to open channel
– NB! Propofol also works by opening the Cl
channel
Inhibitors
ADENOSINE
• Adenosine binds (A1) receptors inhibit
glutamate release anticonvulsant effect
• A1 antagonists increase seizure activity
HISTAMINE
• anticonvulsive properties via central H1
receptor
• Animal models  Toxic doses of
antihistaminesSz
Excitors
GLUTAMATE
• excitatory amino acid
• binds one of four glutamate receptors
NMDA/AMPA/kainate/metabotropic
• Influx of Na and Ca  depolarization.
• Excess stimulation by glutamate receptors Sz.
• Mg blocks glutamate in eclampsia Sz.
• Glutamate channels potentiate other CNS injuries
(stroke/trauma)
NOREPINEPHRINE
• Autonomic over stimulation can lead to Sz.
• [e.g. ++ sympathetic outflow in Etoh
withdrawal]
ACETYLCHOLINE
• ACh overstim can result in Sz [e.g. carbamates
and organophosphates]
Others:
GLYCINE
• excitatory neurotransmitter in CNS
• Binds to NMDA receptorsNa influx
• However, Postsynaptic receptors chloride
influxinhibitory
• Postsynaptic antagonists, [e.g.strychnine]
cause seizure-like myoclonic activity.
Others
SODIUM CHANNELS
• Na channel blockers slow nerve transmission
and hence should inhibit Sz.
• However, in overdose, Lidocaine known to
produce Sz by an unknown mechanism.
• Same goes for other Na channel blockers e.g.
carbamazepine (CMZ also antagonises
adenosineSz)
Match the following drug with the mechanism
TCA
Theophylline
Carbamazepine
Cocaine
MDMA
Lithium
INH
Benadryl
GABA
Na-Chan
5-HT
Norepi
NMDA
H1
Anticholinergic
Adenosine
Name the General. Sz or no?
Genghis Khan 1162–1227
• Born Temüjin “iron”
• Came to power in
1190
• Mongol Empire
– Largest empire in hx.
• Ruthless when
crossed
• Buried in secret grave
• Did not have epilepsy
CASE
• 40 yo M brought to ED with GTC Sz . Now
comatose (may have ingested)
• Approach?
ABCDEFP’S of D&T Sz
A: Airway
B: Breathing
C: Circulation & Chemstrip
D: Decontamination
E: Elimination
F: Find a cure
P’s:
Penes (benzodiaza…)
Phenobarb (NO PHENYTOIN)
Propofol
Pyridoxine
More on treatment:
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No trials  best anticonvulsant
Penes followed by Phenobarb 1st and 2nd line
Ativan preferred (but can use midaz)
Phenytoin not good for:
– TCA / Etoh withdrawal
– Worsens theophylline, LA’s and Lindane
• Therefore not recommended
More on Benzo’s: (know pharmacology of benzo’s for exams)
Longest t1/2 ?  ativan (can also cause toxicity from its diluent propylene
glycol)
Active metabolites?  Diazepam (can’t give IV in our region, but 10-20mg
Po is great for Etoh withdrawal)
Charcoal Not good for?
“PHAILS”
Phosphates/ potassium
Hydrocarbons
Acids/alkalis
Iron
Lithium (can use kayexelate)
Solvents/ “syanide”
Dialyzable overdoses?
SMELT
Salycilates
Methanol
Ethlene Glycol
Lithium
Theophylline
HX & P/E pointers
• Always suspect intoxication
– Foraging / Food ingestions
– Psych hx
• Use all potential historians
• Look for toxidromes:
– Sympath cocaine/amphet/withdrawal
• Beware mimickers
• Note other injuries (head) rhabdo
• Know DDx for Sz in general
–?
Secondary Seizures:
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N
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R
A
C
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A
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I
A
L
“IS IT MEATh?”
• Iintracranial Hemorrhage
[Sub/epidural, arachnoid, parenchymal]
• Sstructural AbN
[Vascular, mass, congenital, degenerative]
• Iinfection
[mening,enceph,abscess]
• Ttrauma
E
X
T
R
A
C
R
A
N
I
A
L
• Mmetabolic
[hypo/hyper Glycemia, hypo/hyper Na, hyperosm,
uremia, hepatic,, hypoCa++, HypoMg++]
• Eeclampsia
• Aanoxia/ischemia
[cardiac arrest, severe hypox]
• Ttoxins/Drugs
– [Cocaine, lidocaine, antiD, w/drawal,
theophylline]
• hhtn encephalopathy
?
OTIS CAMPBELL
The "town drunk" in The Andy Griffith Show in
the 60’s
known to go on regular binges, then lock himself
in the town jail until he sobered up. (He had a key
to the jail )
When sober enough, Otis would occasionally be
deputized, when needed to fight minor crimewaves in the town.
Otis would often see something genuinely
bizarre but attribute it to being drunk.
OTIS CAMPBELL
Opioids (darvon &c)
carbamazepine
Antidepressants (bupropion)
Envenomations, ephedra
CASE
• Teenager found agitated/combative and
tremulous at home
• Last seen 3 hours earlier  was well. EMS found
an empty pill bottle which they lost
• En route sinus tach, but developed N/V then a
GTC seizure
• o/e: Still seizing (now 10mins)
• Approach?
Chest Volume 126 • Number 2 • August 2004
NEED EEG
Seizing people are actually easier to get IV’s in
Ativan: don’t have to give the whole 0.1 mg/kg right off the bat. Give 0.05mg/kg for paeds
and in adults do 2mg at a time.
INGRID  GO TO MIDAZ QUICK [even before Phenobarb]
Airway
IV, O2, Monitor, BW, glu
Dextrose 25-50g IV
Consider Thiamine 100mg IV, Mg 1-2gIV
Lorazepam 2mg/min IV up to 0.1mg/kg
Can Load with 4mg IV or Diazepam]
Phenobarb 20mg/kg at 5-75mg/min IV
Propofol
Pyridoxine 5g
Others (propofol/pentobarb)
Adapted from: Lowenstein DH Status Epilepticus NEJM 338(14):
970 1998
EKG:
Ddx for (toxin) Seizure and Prolonged QRS?
Ddx Seizure with  QRS
Which antidepressants make you seize?
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TCA’s
Venlafaxine (Effexor)
Bupropion (Wellbutrin, Zyban)
Lithium
Citalopram
BUPROPION (Wellbutrin)
• Wellbutrin, Wellbutrin SR, Zyban
• Monocyclic antidepressant structurally
similar to amphetamines
• Inhibits uptake of norepi and dopamine
• QRS effects because of cardiac sodium
channel blockade
Journal of Toxicology: Clinical Toxicology v36.n6 (Oct 1998): pp 595 (4).
Pharmacokinetics
• Metabolized in liver 3 active metabolites:
– Hydroxybupropion,threohydrobupropion
– & erythrohydrobupropion.
• half-life:
– Bupropion & hydroxybupropion  20 h
– Other metabs  35 h.
• Seizure dose: 30 g or more
• False + urine amphetamines screen
Bupropion
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15% OD end up with Sz
1% present in Status
Can get idiopathic Sz with N dose
Exposed Teens 46% get effects
Inc QRS (but not wide QT) responsive to Bicarb
Death rare : resp/cardiac arrest
Treatment: symptomatic. Admit / follow
QRS/QT  BICARB BICARB  LIPIDS
Bupropion: Clinical Effects
Name the General. Sz or no?
Hannibal 247–183 BC
• Born in Carthage
• 218 BC crossed the
Pyrenes  attacked
Rome.
• Genius of strategy
– Romans copied
– “Snake Bombs”
• No record of epilepsy
CASE
• 34 y F lawyer had fight with hubbie
took pills 
• Became disoriented
• c/o blurred vision then had a seizure
• O/E: Hr 130, Bp 140/85, RR 22, 380
E4, V3, M6, Pupils 8mm, wide QRS
• Doctor?
Diphenhydramine
• Benadryl, Dimedrol
• OTC antihistamine/
sleep aids
• First generation
• So not selective H1 rec:
• potent muscarinic aCH receptorantagonists (anticholinergic)
• Also have action at α-adrenergic & 5HT receptors**
Diphenhydramine
• Drug of abuse for hallucinogenic properties
• 55% of fatal antihistamine OD’s are benadryl
Pharmacology
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Half life 2.5 hours
90% protein-bound
Cleared by Cyt P450
Readily crosses bbb where anti-aCH affect visual and auditory
cortex
• Renally excreted
• Asian descent “fast acetylators”  less effects
• Autoinduction of metabolism  chronic use enhances it’s
own clearance
clinical
• CNS: limbic system & hippocampus  confusion
& temporary amnesia.
• Autonomic NS:
– NMJ  ataxia & EPS
– sympathetic post-ganglionic junctions
–
urinary retention / ileus
–
pupil dilation
–
tachycardia
–
dry skin and mucous membranes.
• “Mad as a hatter, dry as a bone, blind as a bat,
red as a beet, hot as a hare…”
Clinical Summary
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Antimuscarinic  Anticholinergic toxidrome
Anti-Serotonin  Sedation
Block Na channel  Wide QRS/QT
Anti H1 + Anti – acH  Seizures
High doses  K+ channel blocking effect
Management
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ABCDEFP’s
Physostigmine?
The only indication: KNOWN ingestion
Give one dose  can clear up delerium long enough to get a better hx from
the pt.
Problem physostigmine usually clears quicker than toxin so pts revert back to
toxidromic state
Multi-dose associated with bradyrhythmias  have atropine by the bedside!
• If you don’t know for SURE  don’t use
– Used to be given as cocktail and that’s when people ran into problems
– Can precipitate Sz / cholinergic symptoms.
– Asystole with cyclic antidepressant poisoning.
• Does Bicarb work for QRS?
– Yes – use it. Helps with Na channel blockade and rhabdo
Case
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16 yo rushed into ED by step-dad.
Found her in room
Breathing slow, blue in face
Had been surfing net …something about a
“cocktail”
O/E: HR 50, SBP 70, RR6, Wide QRS
Pinpoint pupils GCS E1, V1, M4
Cyanotic
Starts to seize …
DOCTOR?
OPIOIDS
• Evidence of opium use as early as 1500 BCE
• Opium is extract from poppy plant Papaver somniferum
• Extracts (alkaloids) from opium are called opiates 
morphine, codeine & papaverine
• Semi synthetic “opioids”  heroin, naloxone &
oxycodone
• Synthetics  Methadone & fentanyl
• Morphine purified in 1804
• 1898 Bayer created a semi synthetic morphine as
antiptussive. Anyone?
– Heroin!
Opioid pharmacology
• Readily absorbed [any method]
• Bind 3 types of G-protein receptors:
– μ (mu), κ (kappa), and δ (delta)
• mu  widespread in CNS. Controls
resp / pain / euphoria / GI motility
• kappa & delta  mostly spinal cord
Opioids
• Bound recs  inhibit presynaptic NT release.
• Cleared by liver (glucoronidation)
• Toxidrome:
ALOC, Resp depression, hypotension and miosis
(constricted pupils)
• However certain ones can infact cause seizures:
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Propoxyphene
Meperidine
Tramodol
pentazocine
Propoxyphene
• Darvon = Propoxyphene (racemic mix)
• Dextropropoxyphene: r-isomer usually found
in combinations Darvocet (with APAP)
Darvon Compound-65
(with ASA & caffeine)
• Both drugs have narrow therapeutic index
pharmacology
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Peak levels 2h
Propoxyphene  t1/2 of 6 - 12 h
Metabolite norpropoxyphene  30 - 36 h
Max dose is 360mg/day
Potent anti- Na channel effects
prolonged QRS
Seizures
clinical
• Behave like TCA’s
– Hypotension
– Cardiac effects
– ALOC
– Seizures in 10% of OD
• Management:
– ABCEFP’s
– Bicarb
Tramadol
• Ultram® Ultracet®.
• Weak Mu opiod activity
• Inhibits:
norepi reuptake
Seratonin reuptake
• Also modulates GABA
pharmacology
• Hepatic metab via the cyt P450 isozyme
CYP2D6  5 metabolites.
• M1 metabolite more active at mu rec
• t1/2  6 h
• 8% of OD will have seizure
Meperidine
• Acts at mu receptor
• Anticholinergic
• Na – channels
• Some serotonin effects
• Postulated less spasmodic activity
NB! Don’t ever signover a patient on demerol
without noting how much they’ve had or
placing a maximum dose 300mg!!!
pharmacology
• v. lipid soluble so fast onset
• 70% protein bound
• t1/2: 4h
• Metabolized by liver  normeperidine
• Normeperidine toxic
• Build up leads to agitation, myoclonus, seizures
Risk factors:
• IV (instead of PO)
• > 300 mg/d
• Renal failure
What else should you know about before giving
Meperidine?
pentazocine
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Talwin
Synthetic opioid
2004 Mcgill Study  Red heads require less!
T1/2: 2.5 h
Cleared by liver
Also a proconvulsant
Why don’t you use Narcan for known OD of
Tramadol and Demerol?
• Known to precipitate Sz with Tramadol and
Meperidine
General? Seizures or no?
Alexander the Great 356–323 BC
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Mentored by Aristotle
Became King at 20
Huge empire
Didn’t have seizures
Death at 33
Septic + using
Hellebore:
– Veratrine  Na
channel poison
CASE
• 26 yo M found in NE Calgary (Rundle to be exact)
seizing
• Brought in by EMS:
• o/e GTC sz
• Doctor?
• Further Hx: being treated for depression and TB
Isoniazid INH
• Used for treatment of tuberculosis
• Prodrug activated by bacterial
catalase.
• Active form inhibits the synthesis of
mycolic acid╪ in the mycobacterial
cell wall.
• Metabolized by acetylation and
hydrolysis
• Variability in metabolic rate
depending on genetics of patient
Isoniazid
• N half-life is 3h
• Fast acetylators have half-life of 1 hour
• More toxic effects with slow acetylators
Effect of INH on
GABA synthesis
Glutamine
Pyridoxine
NH3
Pyridoxine
Phosphokinase
Glutamic Acid
CO2
Glutamic Acid Decarboxylase
Pyridoxal 5’-phosphate
Gamma aminobutyric acid
Effect of INH on
GABA synthesis
Glutamine
Increased
urinary
excretion
NH3
Pyridoxine
Inhibits
Glutamic Acid
CO2
Glutamic Acid Decarboxylase
Pyridoxal 5’-phosphate
Gamma aminobutyric acid
Pyridoxine
Phosphokinase
Effect of INH on
GABA synthesis
Glutamine
Pyridoxine
NH3
Pyridoxine
Phosphokinase
Glutamic Acid
CO2
Glutamic Acid Decarboxylase
Pyridoxal 5’-phosphate
Gamma aminobutyric acid
Levels Fall
Isoniazid Overdose
Clinically:
• Nausea/Vomiting/ataxia/mydraisis
• Triad of
Severe Metabolic Acidosis
Coma
Seizures
Why severe lactic acidosis?
• INH inhibits NAD  Lactate buildup
Isoniazid Management
• ABCD (charcoal) EF
• “Penes” or phenobarb?
– Need GABA for “penes” to work
• P Pyridoxine
• If don’t know amount of INH:
Give 5 grams IV
• Otherwise 1g for each g INH
(may get transient base deficit w/ >5g)
Problem hospital often don’t have enough … so go
to local supplement store and buy vit b6 and put
down NG!!!
Ddx Status Epilepticus?
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Hypoglycemia
INH
TCA
CO
Theophylline
Gyrometra
Wellbutrin
Other process  bleed/tumor
CASE
• 68 yo M via EMS. Got cough and so was
taking old asthma medication
• c/o profound N/V
• EMS: HR 150, BP 90 systolic, began to seize
• Doctor?
• Additional hx – was taking theophylline
Theophylline
• Is a methylxanthine
– Caffeine in same group
• Extracted from tea leaves
• Used for treatment of COPD and asthma b/c
relaxes sm. muscle
• Inhibits phosphodiesterase enzymes 
increase in intracellular cAMP;
Mechanism of Action
• Theophylline (& caffeine): adenosine A1 &
A2 receptor antagonists
• Peripherally  release of catecholamines
• Catecholamine responses made worse by
blocking of A1 receptors
• Cause vasoconstriction of the cerebral
vasculature by A2 antagonism
result ? SEIZure
Pharmacology
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50% protein-bound
Metabolized by liver Cyt P450
T1/2: 6h
V. narrow therapeutic range
Seizures related to:
1) Chronicity  chronic OD worse
2) Age  >60 do worse
3) Levels > 250mmol/L (chronic)
550mmol/L (acute)
Theophylline
• In overdose is very dangerous
– Causes seizures (27%)
– Tachydysrhythmias (75%)
– Hypotension
– Hypokalemia (25%)
Theophylline management:
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ABC
D: Multi dose charcoal effective
E  don’t forget dialysis
Other therapies?
P  Pyridoxine as theophylline has some antiGABA effects
• P  propanolol? . Case reports of esmolol use
despite hypotension
Indications for multi-dose charcoal?
“Think! Several Doses oPh Charcoal!”
• Theophylline
• Salicylates
• Dapsone
• Phenobarb
• Carbamazepine
Seizures or no?
Napoleon I 1769–1821
• Coup in 1799
• Studied “Art of War”
• Brilliant military strategist
– Semaphore system
– Espionage
– Moving artillery
• Purported to have had
seizures
• Drop attacks vs syncope
4 indications for pyridoxine?
•INH
•Theophylline
•Ethylene Glycol
•Gyromitra
Name the poison
+
Strychnine Poisoning:
WHAT:
bitter, white, powder alkaloid derived from the
seeds of the tree Strychnos nux-vomica.
introduced in the 16th century as a rodenticide,
until recently it was used as a respiratory,
circulatory and digestive stimulant
no longer used in any pharmaceutical products,
but is still used as a rodenticide.
Strychnine is also found as an adulterant in street
drugs such as amphetamines, heroin and
cocaine
PATHOPHYS:
• Lethal dose 50mg [15mg paeds]
• T1/2 10-15h
• Readily absorbed from MM’s/intact skin
• Antagonises post-synaptic glycine
receptors muscles over stimulated
• rhabdo,
• lactic acidosis
• Eventually die of resp compromise
CLINICALLY:
• features occur from 15 to 30 minutes after
ingestion
• muscular spasms and twitches can
progress to painful generalized
convulsions (patients remain awake as
CNS NMDA-glycine receptors not affected)
• Risus sardonicus?
• hypersensitivity to stimuli.
• HTN, Tacchy, cyanosis
Mgmt:
ABC’s – may have to intubate/paralyse
IV, O2, Monitor
Decontaminate with charcoal [if ingested]
Benzos
Avoid stimulation
Treat hyperkalemia/rhabdo/hyperthermia
The End
SEIZURES Dr Vicas
Is this a toxin-induced seizure?
Or
Is this toxin known to cause seizures ?
And
If seizures occur, what is the outcome ?
TOXIN-INDUCED SEIZURES
OUTCOME
• Catastrophic event
– cyclic antidepressants
– theophylline
• Expected short-lived
effect
– diphenhydramine
• Refractory to
conventional therapy
– INH
• Mistaken for seizures
– myoclonic jerks
– dystonic reactions
– strychnine
** knowledge of this led to discovery of SSRI’s notably
prozac
╪ Mycolic acids  in cell walls Mycobacterium
tuberculosis  increased resistance to chemical
damage & antibiotics allow bacterium to grow
inside macrophages.
¥
REFERENCES
Patti A. Paris. ECG conduction delays associated with massive bupropion overdose.
Journal of Toxicology: Clinical Toxicology v36.n6 (Oct 1998): pp 595 (4).
David J McCann. Toxicity, Antihistamine
http://www.emedicine.com/emerg/topic38.htm
Greg Hymel. Toxicity, Theophylline
http://www.emedicine.com/EMERG/topic577.htm
Michael Seneff et al , Acute theophylline toxicity and the use of esmolol to
reverse cardiovascular instability. Annals of Emergency Medicine Volume 19,
Issue 6 , June 1990, Pages 671-673
Kempf J. Rusterholtz T. Ber C. Gayol S. Jaeger A. Haemodynamic study as guideline
for the use of beta blockers in acute theophylline poisoning.Intensive Care
Medicine. 22(6):585-7, 1996 Jun.