toxicology 3 nadim j lalani r3 dr mark yarema special mention : dr m. beuhler
TRANSCRIPT
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TOXICOLOGY 3TOXICOLOGY 3Nadim J Lalani R3
Dr Mark YaremaSpecial mention : Dr M. Beuhler
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?
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•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 "Things That Make You Go Make You Go Hmmm"Hmmm"
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•Isoniazid (INH)
•a first-line agent used for tuberculosis.
•Can be toxic ingestant
•One of the many……
things that make you go things that make you go “uuughuuughuughhh”“uuughuuughuughhh”
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1. What were C + C music factory’s 2 hits before “Things that make you go hmmm?
2. What talk show host coined the phrase : “Things that make you goHmmm…”?
Gonna make you sweat (everybody dancenow), and Here We Go (Rock and Roll)
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“the ones that make you seize”
Drug and Toxin Induced Drug and Toxin Induced SeizuresSeizures
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Outline Pathophysiology DDX ABCDEFP’s of DTS Cases
Bupropion
Diphenhydramine
Opioids
INH
Theophylline
Short snappers at any moment
NO LITHIUM
NO TCA
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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
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Neurochemical pathways Balance exists between inhibitory
and excitatory pathways
Main inhibitory neurotransmitters consist of– GABA– Glycine
Main excitatory neurotransmitter is glutamate
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Neurochemical p-ways : InhibitorsGamma-aminobutyric acid (GABA)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
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Glutamine
Glutamate
NH3
Gamma aminobutyric acid
Pyridoxal 5’-phosphate
Glutamic Acid DecarboxylaseCO2
Pyridoxine Phosphokinase
Pyridoxine
Synthesis of GABASynthesis of GABA
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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
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How Do Benzos Work?
Barbituates?
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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
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Mechanism of Action
BarbituratesIncrease 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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InhibitorsADENOSINEADENOSINE Adenosine binds (A1) receptors
inhibit glutamate release anticonvulsant effect
A1 antagonists increase seizure activity
HISTAMINEHISTAMINE anticonvulsive properties via central
H1 receptor Animal models Toxic doses of
antihistaminesSz
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ExcitorsGLUTAMATEGLUTAMATE 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)
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NOREPINEPHRINENOREPINEPHRINE Autonomic over stimulation can lead
to Sz. [e.g. ++ sympathetic outflow in Etoh
withdrawal]
ACETYLCHOLINEACETYLCHOLINE ACh overstim can result in Sz [e.g.
carbamates and organophosphates]
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Others:GLYCINEGLYCINE excitatory neurotransmitter in CNS Binds to NMDA receptorsNa influx However, Postsynaptic receptors
chloride influxinhibitory Postsynaptic antagonists,
[e.g.strychnine] cause seizure-like myoclonic activity.
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OthersSODIUM CHANNELSSODIUM 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 adenosineSz)
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Match the following drug with the mechanism
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TCA
Theophylline GABAGABA
Carbamazepine Na-ChanNa-Chan
CocaineAdenosineAdenosine
MDMA 5-HT5-HT
NorepiNorepi
Lithium NMDANMDA
INH H1H1
Benadryl anticholnanticholn
GABA & others
Adeno & GABA
Norepinephrine
& serotonin
Norepi & serotonin
GABA
H1/Na
adenosine
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? Propoxyphene
phenobarbital
Metoclopramide
“the Darvon (suicide) Cocktail” Can sub in midaz for phenobarb
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CASE 40 yo M brought to ED with GTC Sz .
Now comatose (may have ingested)
Approach?
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ABCDEFP’S of D&T SzA: Airway
B: Breathing
C: Circulation & Chemstrip
D: Decontamination
E: Elimination
F: Find a cure
P’s:
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, LA’s and Lindane
Therefore not recommended
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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 10-20mg Po is great for Etoh withdrawal)
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Charcoal Not good for?
““PHAILS”PHAILS”Phosphates/ potassiumHydrocarbonsAcids/alkalisIronLithium (can use kayexelate)Solvents
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Dialyzable overdoses?
““SMELT”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:
““IS IT MEATh?”IS IT MEATh?” Iintracranial
Hemorrhage [Sub/epidural, arachnoid, parenchymal]
Sstructural AbN[Vascular, mass, congenital, degenerative]
Iinfection [mening,enceph,abscess]
Ttrauma
II
NN
TT
RR
AA
CC
RR
AA
NN
II
AA
LL
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Mmetabolic[hypo/hyper Glycemia, hypo/hyper Na, hyperosm, uremia, hepatic,, hypoCa++, HypoMg++]
Eeclampsia Aanoxia/ischemia
[cardiac arrest, severe hypox]
Ttoxins/Drugs[Cocaine, lidocaine, antiD, w/drawal,
theophylline]
hhtn encephalopathy
EE
XX
TT
RR
AA
CC
RR
AA
NN
II
AA
LL
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?
OTIS CAMPBELL
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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.
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OTIS CAMPBELL
Antidepressants (bupropion)
Opioids (darvon &c)
carbamazepine
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Things that make you go….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
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
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AirwayIV, O2, Monitor, BW, glu
Dextrose 25-50g IVConsider 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
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EKG:
Ddx for (toxin) Seizure and Prolonged QRS?
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Ddx Seizure with QRS
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Which antidepressants make you go….
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TCA’s 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
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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
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Bupropion: Clinical Effects
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A Quote:
“THE CAROTID ARTERY, NATURE'S EMERGENCY EXIT.”
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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?
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Diphenhydramine
Benadryl, Dimedrol OTC antihistamine/
sleep aids First generation So not selective H1 rec:
potent muscarinic aCH receptor-antagonists (anticholinergic)(anticholinergic)
Also have action at α-adrenergic & 5-HT receptors**
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Diphenhydramine Drug of abuse for hallucinogenic
properties 55% of fatal antihistamine OD’s are
benadryl
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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
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clinical CNS: limbic system & hippocampus
confusion & temporary amnesia. Autonomic NS:
NMJ ataxia & EPSsympathetic post-ganglionic junctions
urinary retention / ileuspupil dilationtachycardiadry 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 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! 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
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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!Heroin!
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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
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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:PropoxypheneMeperidineTramodolpentazocine
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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
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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
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clinical Behave like TCA’s
Hypotension
Cardiac effects
ALOC
Seizures in 10% of OD
Management:ABCEFP’s
Bicarb
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Tramadol Ultram® Ultracet®. Weak Mu opiod activity Inhibits:
norepi reuptake
Seratonin reuptake Also modulates GABA
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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
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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!!!
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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, seizuresRisk factors: IV (instead of PO) > 300 mg/d Renal failure
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pentazocine Talwin Synthetic opioid Red heads require less! T1/2: 2.5 h Cleared by liver Also a proconvulsant
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Why don’t you use Narcan for known OD of Tramadol and Demerol?
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Known to precipitate Sz with Tramadol and Meperidine
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A quote (on pentazocine):
“it's like codeine but qualitatively "dreamier", more "smacky", and stronger than an equal dose…
stuck to bedlate histamine release - 3 h?
"heavy" feeling …it makes a buzzing sound when on”
sixthseal.comLeading the wild into the ways of the man...
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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
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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
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Isoniazid
N t1/2 is 3h Fast acetylators have half-life of 1
hour More toxic effects with slow
acetylators
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Glutamine
Glutamic Acid
NH3
Gamma aminobutyric acid
Pyridoxal 5’-phosphate
Glutamic Acid DecarboxylaseCO2
Pyridoxine Phosphokinase
Pyridoxine
Effect of INH on GABA Effect of INH on GABA synthesis synthesis
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Glutamine
Glutamic Acid
NH3
Gamma aminobutyric acid
Pyridoxal 5’-phosphate
Glutamic Acid DecarboxylaseCO2
Pyridoxine Phosphokinase
Pyridoxine
Increased urinary
excretion
Effect of INH on Effect of INH on GABA synthesis GABA synthesis
Inhibits
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Glutamine
Glutamic Acid
NH3
Gamma aminobutyric acid
Pyridoxal 5’-phosphate
Glutamic Acid DecarboxylaseCO2
Pyridoxine Phosphokinase
Pyridoxine
Effect of INH on Effect of INH on GABA synthesisGABA synthesis
Levels Fall
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Isoniazid Overdose
Clinically: Nausea/Vomiting/ataxia/mydraisis Triad of
Severe Metabolic Acidosis
Coma
Seizures
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Why severe lactic acidosis?
INH inhibits NAD Lactate buildup
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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!!!
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Ddx intractable seizures?
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INH Theophylline Amoxapine:
(Ascendin) Tetracyclic antidepressant
For treatment of depression with psychotic feats
tacchy / hypotension/ dry / aloc / Sz
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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
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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;
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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”
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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 >60 do worse
3) Levels > 150mmol/L (chronic)
250mmol/L (acute)
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Theophylline In overdose is very dangerous
Causes seizures (27%)
Tachydysrhythmias (75%)
Hypotension
Hypokalemia (25%)
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Theophylline management: 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)
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Indications for multi-dose charcoal?
““TThink!hink! S Severaleveral D Dosesoses ooPh CPh Charcoal!harcoal!”” Theophylline Salicylates Dapsone Phenobarb Carbamazepine
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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”
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4 indications for pyridoxine?
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INHTheophyllineEthylene GlycolGyromitra
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Name the poison
+
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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
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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
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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
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Mgmt:ABC’s – may have to
intubate/paralyseIV, O2, MonitorDecontaminate with charcoal [if
ingested]BenzosAvoid stimulationTreat
hyperkalemia/rhabdo/hyperthermia
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The EndThe End
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** 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
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REFERENCES
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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, Antihistaminehttp://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.