TOXICOLOGY 3TOXICOLOGY 3Nadim J Lalani R3

Dr Mark YaremaSpecial 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 "Things That Make You Go Make You Go Hmmm"Hmmm"

•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”

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)

“the ones that make you seize”

Drug and Toxin Induced Drug and Toxin Induced SeizuresSeizures

Outline Pathophysiology DDX ABCDEFP’s of DTS Cases

Bupropion

Diphenhydramine

Opioids

INH

Theophylline

Short snappers at any moment

NO LITHIUM

NO TCA

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 : 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

GABA Channel

Glutamine

Glutamate

NH3

Gamma aminobutyric acid

Pyridoxal 5’-phosphate

Glutamic Acid DecarboxylaseCO2

Pyridoxine Phosphokinase

Pyridoxine

Synthesis of GABASynthesis of GABA

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

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

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

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)

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]

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.

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)

Match the following drug with the mechanism

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

? 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 SzA: 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 10-20mg Po is great for Etoh withdrawal)

Charcoal Not good for?

““PHAILS”PHAILS”Phosphates/ potassiumHydrocarbonsAcids/alkalisIronLithium (can use kayexelate)Solvents

Dialyzable overdoses?

““SMELT”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:

““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

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

?

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

Antidepressants (bupropion)

Opioids (darvon &c)

carbamazepine

Things that make you go….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

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

EKG:

Ddx for (toxin) Seizure and Prolonged QRS?

Ddx Seizure with QRS

Which antidepressants make you go….

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 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 receptor-antagonists (anticholinergic)(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 & 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…”

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! 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

DiphenhydramineEffectsby Erowid

POSITIVE Increased awareness and appreciation of

music

NEUTRAL :/Unusual thoughts and speech

NEGATIVE Difficulty differentiating hallucinations from

reality

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?

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!

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:PropoxypheneMeperidineTramodolpentazocine

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 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

pentazocine 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 bedlate histamine release - 3 h?

"heavy" feeling …it makes a buzzing sound when on”

sixthseal.comLeading 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

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

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

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

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 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: 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?

““TThink!hink! S Severaleveral D Dosesoses ooPh CPh Charcoal!harcoal!”” 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?

INHTheophyllineEthylene GlycolGyromitra

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/paralyseIV, O2, MonitorDecontaminate with charcoal [if

ingested]BenzosAvoid stimulationTreat

hyperkalemia/rhabdo/hyperthermia

The EndThe 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, 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.