TOXICOLOGY 3

1
TOXICOLOGY 3

• Nadim J Lalani R3
• Dr Mark Yarema
• Special mention Dr M. Beuhler

2

?
3

• CC 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"

4

• Isoniazid (INH)
• a first-line agent used for tuberculosis.
• Can be toxic ingestant
• One of the many
• things that make you go uuughuuughuughhh
  

5

• 1. What were C C music factorys 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?
6
Drug and Toxin Induced Seizures

• the ones that make you seize

7
Outline

• Pathophysiology
• DDX
• ABCDEFPs of DTS
• Cases
• Bupropion
• Diphenhydramine
• Opioids
• INH
• Theophylline
• Short snappers at any moment

NO LITHIUM NO TCA
8
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

9
Neurochemical pathways

• Balance exists between inhibitory and excitatory
  pathways
• Main inhibitory neurotransmitters consist of
• GABA
• Glycine
• Main excitatory neurotransmitter is glutamate

10
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

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GABA Channel
12
Synthesis of GABA
Glutamine
Pyridoxine
NH3
Pyridoxine Phosphokinase
Glutamate
Glutamic Acid Decarboxylase
CO2
Pyridoxal 5-phosphate
Gamma aminobutyric acid
13

• 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

14

• How Do Benzos Work?
• Barbituates?

15
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

16
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

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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

18
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)

19

• 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

20
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.

21
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)

22

• Match the following drug with the mechanism

23

• TCA
• Theophylline GABA
• Carbamazepine Na-Chan
• Cocaine Adenosine
• MDMA 5-HT
• Norepi
• Lithium NMDA
• INH H1
• Benadryl anticholn

GABA others
Adeno GABA
adenosine
Norepinephrine serotonin
Norepi serotonin
GABA
H1/Na
24
?

• Propoxyphene
• phenobarbital
• Metoclopramide
• the Darvon (suicide) Cocktail
• Can sub in midaz for phenobarb

25
CASE

• 40 yo M brought to ED with GTC Sz . Now comatose
  (may have ingested)
• Approach?

26
ABCDEFPS of DT Sz

• A Airway
• B Breathing
• C Circulation Chemstrip
• D Decontamination
• E Elimination
• F Find a cure
• Ps
• Penes (benzodiaza)
• Phenobarb (NO PHENYTOIN)
• Propofol
• Pyridoxine

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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, LAs and Lindane
• Therefore not recommended

28
More on Benzos (know pharmacology of benzos
for exams) Longest t1/2 ? ? ativan (can also
cause toxicity from its diluent propylene
glycol) Active metabolites? ? Diazepam (cant
give IV in our regoin, but 10-20mg Po is great
for Etoh withdrawal)
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Charcoal Not good for?

• PHAILS
• Phosphates/ potassium
• Hydrocarbons
• Acids/alkalis
• Iron
• Lithium (can use kayexelate)
• Solvents

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Dialyzable overdoses?

• SMELT
• Salycilates
• Methanol
• Ethlene Glycol
• Lithium
• Theophylline

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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
• ?

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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

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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

34
?
OTIS CAMPBELL
35

• The "town drunk" in The Andy Griffith Show in the
  60s
• 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.

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OTIS CAMPBELL
Opioids (darvon c)
carbamazepine
Antidepressants (bupropion)
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Things that make you go.
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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?

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Chest Volume 126 Number 2
August 2004
Bryans imput Seizing people are actually easier
to get IVs in Ativan dont 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
40

• 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

Intubate?
Adapted from Lowenstein DH Status Epilepticus
NEJM 338(14) 970 1998
41
EKG
Ddx for (toxin) Seizure and Prolonged QRS?
42
Ddx Seizure with ? QRS
43

• Which antidepressants make you go.

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• TCAs
• Venlafaxine (Effexor)
• Bupropion (Wellbutrin, Zyban)
• Lithium
• Citalopram

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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).
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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

47
Bupropion

• 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

48
Bupropion Clinical Effects
49
A Quote

• THE CAROTID ARTERY, NATURE'S EMERGENCY EXIT.

50
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?

51
Diphenhydramine

• Benadryl, Dimedrol
• OTC antihistamine/
• sleep aids
• First generation
• So not selective H1 rec
• potent muscarinic aCH receptor-antagonists
  (anticholinergic)
• Also have action at a-adrenergic 5-HT
  receptors

52
Diphenhydramine

• Drug of abuse for hallucinogenic properties
• 55 of fatal antihistamine ODs are benadryl

53
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 its own clearance

54
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

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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

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Management

• ABCDEFPs
• 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!
• If you dont know for SURE ? dont use
• Used to be given as cocktail and thats 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

57
DiphenhydramineEffectsby Erowid

• POSITIVE ?
• Increased awareness and appreciation of music
• NEUTRAL /
• Unusual thoughts and speech
• NEGATIVE ?
• Difficulty differentiating hallucinations from
  reality

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Case

• 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?

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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!

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Opioid pharmacology

• Readily absorbed any method
• Bind 3 types of G-protein receptors
• µ (mu), ? (kappa), and d (delta)
• mu ? widespread in CNS. Controls
• resp / pain / euphoria / GI motility
• kappa delta ? mostly spinal cord

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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

62
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

63
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

64
clinical

• Behave like TCAs
• Hypotension
• Cardiac effects
• ALOC
• Seizures in 10 of OD
• Management
• ABCEFPs
• Bicarb

65
Tramadol

• Ultram Ultracet.
• Weak Mu opiod activity
• Inhibits
• norepi reuptake
• Seratonin reuptake
• Also modulates GABA

66
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

67
Meperidine

• Acts at mu receptor
• Anticholinergic
• Na channels
• Some serotonin effects
• Postulated less spasmodic activity
• NB! Dont ever signover a patient on demerol
  without noting how much theyve had or placing a
  maximum dose 300mg!!!

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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)
• gt 300 mg/d
• Renal failure

69
pentazocine

• Talwin
• Synthetic opioid
• Red heads require less!
• T1/2 2.5 h
• Cleared by liver
• Also a proconvulsant

70

• Why dont you use Narcan for known OD of Tramadol
  and Demerol?

71

• Known to precipitate Sz with Tramadol and
  Meperidine

72
A quote (on pentazocine)

• it's like codeine but qualitatively "dreamier",
  more "smacky", and stronger than an equal
  dosestuck to bedlate histamine release - 3
  h?"heavy" feeling it makes a buzzing sound
  when on

sixthseal.com Leading the wild into the ways of
the man...
73
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 doesnt just happen in
  hobos /Asians/ First Nations folk

74
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

75
Isoniazid

• N t1/2 is 3h
• Fast acetylators have half-life of 1 hour
• More toxic effects with slow acetylators

76
Effect of INH on GABA synthesis
Glutamine
Pyridoxine
NH3
Pyridoxine Phosphokinase
Glutamic Acid
Glutamic Acid Decarboxylase
CO2
Pyridoxal 5-phosphate
Gamma aminobutyric acid
77
Effect of INH on GABA synthesis
Glutamine
Increased urinary excretion
Pyridoxine
NH3
Pyridoxine Phosphokinase
Inhibits
Glutamic Acid
Glutamic Acid Decarboxylase
CO2
Pyridoxal 5-phosphate
Gamma aminobutyric acid
78
Effect of INH on GABA synthesis
Glutamine
Pyridoxine
NH3
Pyridoxine Phosphokinase
Glutamic Acid
Glutamic Acid Decarboxylase
CO2
Pyridoxal 5-phosphate
Levels Fall
Gamma aminobutyric acid
79
Isoniazid Overdose

• Clinically
• Nausea/Vomiting/ataxia/mydraisis
• Triad of
• Severe Metabolic Acidosis
• Coma
• Seizures

80

• Why severe lactic acidosis?
• INH inhibits NAD ? Lactate buildup

81
Isoniazid Management

• ABCD (charcoal) EF
• Penes or phenobarb?
• Need GABA for penes to work
• P ?Pyridoxine
• If dont know amount of INH
• Give 5 grams IV
• Otherwise 1g for each mg INH
• (may get transient base deficit w/ gt5g)
• Problem? hospital often dont have enough so go
  to local supplement store and buy vit b6 and put
  down NG!!!

82

• Ddx intractable seizures?

83

• INH
• Theophylline
• Amoxapine
• ?(Ascendin) Tetracyclic antidepressant
• ?For treatment of depression with psychotic
  feats
• ?tacchy / hypotension/ dry / aloc / Sz

84
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

85
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

86
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

87
Pharmacology

• 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 ? gt60 do worse
• 3) Levels gt 150mmol/L (chronic)
• 250mmol/L (acute)

88
Theophylline

• In overdose is very dangerous
• Causes seizures (27)
• Tachydysrhythmias (75)
• Hypotension
• Hypokalemia (25)

89
Theophylline management

• ABC
• D Multi dose charcoal effective
• E ? dont 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)

90
Indications for multi-dose charcoal?

• Think! Several Doses oPh Charcoal!
• Theophylline
• Salicylates
• Dapsone
• Phenobarb
• Carbamazepine

91
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

92

• 4 indications for pyridoxine?

93

• INH
• Theophylline
• Ethylene Glycol
• Gyromitra

94
Name the poison

95
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

96

• PATHOPHYS
• Lethal dose 50mg 15mg paeds
• T1/2 10-15h
• Readily absorbed from MMs/intact skin
• Antagonises post-synaptic glycine receptors?
  muscles over stimulated
• rhabdo,
• lactic acidosis
• Eventually die of resp compromise

97

• 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

98

• Mgmt
• ABCs may have to intubate/paralyse
• IV, O2, Monitor
• Decontaminate with charcoal if ingested
• Benzos
• Avoid stimulation
• Treat hyperkalemia/rhabdo/hyperthermia

99
The End
100

• knowledge of this led to discovery of SSRIs
  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 wouldnt
  dialyze an isopropanol OD Unless high level or
  hypotension, and valproate OD get better On own
  usually without dialysis

101
REFERENCES
102
(No Transcript)
103

• 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//ww
w.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.