TOXICOLOGY 3TOXICOLOGY 3

Nadim J Lalani MDSpecial mention : Dr M. Beuhler

Dr Mark YaremaDr 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

“The Generalised Version”

Drug and Toxin Induced SeizuresDrug and Toxin Induced Seizures

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 : Inhibitors

Gamma-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

http://edpharmacologystuff.blogspot.com

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 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

ADENOSINEADENOSINE • 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

Excitors

GLUTAMATEGLUTAMATE • 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.

Others

SODIUM 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

TCATheophyllineCarbamazepineCocaineMDMALithiumINHBenadryl

GABANa-Chan

5-HTNorepiNMDA

H1Anticholinergic

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 SzA: AirwayB: BreathingC: Circulation & ChemstripD: DecontaminationE: EliminationF: 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 region, but 10-20mg Po is great for Etoh withdrawal)

Charcoal Not good for?

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

Dialyzable overdoses?

SMELTSMELTSalycilatesMethanol

Ethlene GlycolLithium

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

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

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]

NEED EEG

AirwayIV, O2, Monitor, BW, glu

Dextrose 25-50g IVConsider Thiamine 100mg IV, Mg 1-2gIV

Lorazepam 2mg/min IV up to 0.1mg/kgCan 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?

• 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

• 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 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 & 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?• 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• 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. Controlsresp / 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 QRSSeizures

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 reuptakeSeratonin 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 failureWhat else should you know about before giving

Meperidine?

pentazocine

• 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

• 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

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 AcidosisComaSeizures

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?

• 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• 50% protein-bound• Metabolized by liver Cyt P450• T1/2: 6h• V. narrow therapeutic range• Seizures related to:

1) Chronicity chronic OD worse2) Age >60 do worse3) Levels > 250mmol/L (chronic)

550mmol/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

Indications for multi-dose charcoal?

““TThink! hink! SSeveral everal DDoses ooses oPhPh CCharcoal!”harcoal!”• 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/paralyseIV, O2, MonitorDecontaminate with charcoal [if

ingested]BenzosAvoid stimulationTreat

hyperkalemia/rhabdo/hyperthermia

The EndThe 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, 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.