Transcript toxicology 3 - Calgary Emergency Medicine

TOXICOLOGY 3
Nadim J Lalani R3
Dr Mark Yarema
Special mention : Dr M. Beuhler
?
•C+C Music Factory
•dance/pop music
group
•seven #1 hits 1990's
• total 35 music awards
•Four #1 singles on
their debut album
•Their third single:
"Things That
Make You Go
Hmmm"
•Isoniazid (INH)
•a first-line agent used for
tuberculosis.
•Can be toxic ingestant
•One of the many……
things that make you go
“uuughuuughuughhh”
1. What were C + C
music factory’s 2 hits
before “Things that make
you go hmmm?
Gonna make you sweat
(everybody dance
now), and Here We Go
(Rock and Roll)
2. What talk show host
coined the phrase :
“Things that make you go
Hmmm…”?
Drug and Toxin Induced
Seizures
“the ones that make you seize”
Outline
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

Pathophysiology
DDX
ABCDEFP’s of DTS
Cases
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
Synthesis of GABA
Glutamine
Pyridoxine
NH3
Pyridoxine
Phosphokinase
Glutamate
CO2
Glutamic Acid Decarboxylase
Pyridoxal 5’-phosphate
Gamma aminobutyric acid
 GABA is broken down by GT (GABA
transaminase)  this is exploited by
the anticonvulsant Vigabatrin which
inhibits GT
 There are 3-types of GABA rec (A,B &
C with A being the main one).
 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 GABA
others
Theophylline Adeno & GABA
Carbamazepine adenosine
Cocaine Norepinephrine
MDMA & serotonin
Lithium Norepi & serotonin
INH GABA
H1/Na
Benadryl
GABA
Na-Chan
Adenosine
5-HT
Norepi
NMDA
H1
anticholn
?
 Propoxyphene
 phenobarbital
 Metoclopramide
 “the Darvon (suicide) Cocktail”
 Can sub in midaz for phenobarb
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:
 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 regoin, but 1020mg Po is great for Etoh withdrawal)
Charcoal Not good for?
“PHAILS”
Phosphates/ potassium
Hydrocarbons
Acids/alkalis
Iron
Lithium (can use kayexelate)
Solvents
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:
I
N
T
R
A
C
R
A
N
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 crime-waves in the town.
Otis would often see something genuinely
bizarre but attribute it to being drunk.
OTIS CAMPBELL
Opioids (darvon &c)
carbamazepine
Antidepressants (bupropion)
Things that make you go….
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
Bryan’s imput:
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
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
(or diazepam 5mg IV q5min up to 20mg
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 go….
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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 + 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
Bupropion: Clinical Effects
A Quote:
“THE CAROTID ARTERY, NATURE'S
EMERGENCY EXIT.”
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
& 5-HT receptors**
Diphenhydramine
 Drug of abuse for hallucinogenic
properties
 55% of fatal antihistamine OD’s are
benadryl
Pharmacology
 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
 Antimuscarinic  Anticholinergic
toxidrome
 Anti-Serotonin  Sedation
 Block Na channel  Wide QRS/QT
 Anti H1 + Anti – acH  Seizures
 High doses  K+ channel blocking
effect
Management
ABCDEFP’s
Physostigmine?* (discussed at length)
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!
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
 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
* Mark
Diphenhydramine
Effects
by Erowid
POSITIVE 
Increased awareness and appreciation of
music
NEUTRAL :/
Unusual thoughts and speech
NEGATIVE 
Difficulty differentiating hallucinations from
reality
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:
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
 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
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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
pentazocine
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Talwin
Synthetic opioid
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
A quote (on pentazocine):
“it's like codeine but qualitatively
"dreamier", more "smacky", and
stronger than an equal dose…
stuck to bed
late histamine release - 3 h?
"heavy" feeling …
it makes a buzzing sound when on”
sixthseal.com
Leading the wild into the ways of the man...
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
 Beware of stereotypes: TB doesn’t just
happen in hobos /Asians/ First Nations folk
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 t1/2 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 mg 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 intractable seizures?
 INH
 Theophylline
 Amoxapine:
(Ascendin)
Tetracyclic
antidepressant
For treatment of depression with
psychotic feats
tacchy / hypotension/ dry / aloc / Sz
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 ? “uuughuuughuugh”
Pharmacology
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50% protein-bound
Metabolized by liver Cyt P450
T1/2: 6h
V. marrow therapeutic range
Seizures related to:
1) Chronicity  chronic OD worse
2) Age  >60 do worse
3) Levels > 150mmol/L (chronic)
250mmol/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 anti-GABA effects
 P  propanolol? . Case reports of
esmolol use despite hypotension
(there was no consensus on this)
Indications for multi-dose charcoal?
“Think! Several Doses oPh Charcoal!”
 Theophylline
 Salicylates
 Dapsone
 Phenobarb
 Carbamazepine
A Quote:
“Propoxyphene…
Dosage:
2 grammes, typically 30 65mg tablets
Time:
death in an hour or so. Does not make you
unconscious
Certainty:
Suggest combine with something to make you sleep,
then use the good old bag method which turns 90%
chance into 99% chance”
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 nuxvomica.
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
** 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.
¥ Or use SMELT: salicylate methanol ethylene
glycol, Lithium theophylline. You wouldn’t
dialyze an isopropanol OD Unless high level
or hypotension, and valproate OD get better
On own usually without dialysis
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.