TOXICOLOGY 3 Nadim J Lalani MD Special mention

TOXICOLOGY 3 Nadim J Lalani MD Special mention : Dr M. Beuhler Dr Mark Yarema Dr 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

Drug and Toxin Induced Seizures “The Generalised Version”

Outline • • Pathophysiology DDX ABCDEFP’s of DTS Cases – Bupropion – Diphenhydramine – Opioids – INH – Theophylline NO NO LIT TC HIU M A • 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 http: //edpharmacologystuff. blogspot. com

Synthesis of GABA Glutamine Pyridoxine NH 3 Pyridoxine Phosphokinase Glutamate CO 2 Glutamic Acid Decarboxylase Pyridoxal 5’-phosphate Gamma aminobutyric acid

• 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 ADENOSINE • Adenosine binds (A 1) receptors inhibit glutamate release anticonvulsant effect • A 1 antagonists increase seizure activity HISTAMINE • anticonvulsive properties via central H 1 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 Theophylline Carbamazepine Cocaine MDMA Lithium INH Benadryl GABA Na-Chan 5 -HT Norepi NMDA H 1 Anticholinergic 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 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 1 st and 2 nd 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 t 1/2 ? ativan (can also cause toxicity from its diluent propylene glycol) Active metabolites? Diazepam (can’t give IV in our region, but 10 -20 mg Po is great for Etoh withdrawal)

Charcoal Not good for? “PHAILS” Phosphates/ potassium Hydrocarbons Acids/alkalis Iron Lithium (can use kayexelate) Solvents/ “syanide”

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 Ab. N [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, , hypo. Ca++, Hypo. Mg++] • E eclampsia • A anoxia/ischemia [cardiac arrest, severe hypox] • T toxins/Drugs – [Cocaine, lidocaine, anti. D, 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 crimewaves in the town. §Otis would often see something genuinely bizarre but attribute it to being drunk.

OTIS CAMPBELL Opioids (darvon &c) carbamazepine Antidepressants (bupropion) 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 10 mins) • Approach?

Chest Volume 126 • Number 2 • August 2004 NEED EEG 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. 05 mg/kg for paeds and in adults do 2 mg at a time. INGRID GO TO MIDAZ QUICK [even before Phenobarb]

Airway IV, O 2, Monitor, BW, glu Dextrose 25 -50 g IV Consider Thiamine 100 mg IV, Mg 1 -2 g. IV Lorazepam 2 mg/min IV up to 0. 1 mg/kg Can Load with 4 mg IV or Diazepam] Phenobarb 20 mg/kg at 5 -75 mg/min IV Propofol Pyridoxine 5 g 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 v 36. n 6 (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 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 E 4, V 3, M 6, Pupils 8 mm, wide QRS • Doctor?

Diphenhydramine • Benadryl, Dimedrol • OTC antihistamine/ sleep aids • First generation • So not selective H 1 rec: • potent muscarinic a. CH 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 P 450 Readily crosses bbb where anti-a. CH 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 H 1 + Anti – ac. H 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, RR 6, Wide QRS Pinpoint pupils GCS E 1, V 1, M 4 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 2 h Propoxyphene t 1/2 of 6 - 12 h Metabolite norpropoxyphene 30 - 36 h Max dose is 360 mg/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 P 450 isozyme CYP 2 D 6 5 metabolites. • M 1 metabolite more active at mu rec • t 1/2 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 300 mg!!!

pharmacology • v. lipid soluble so fast onset • 70% protein bound • t 1/2: 4 h • Metabolized by liver normeperidine • Normeperidine toxic • Build up leads to agitation, myoclonus, seizures Risk factors: • IV (instead of PO) • > 300 mg/d • Renal failure What else should you know about before giving Meperidine?

pentazocine • • • Talwin Synthetic opioid 2004 Mcgill Study Red heads require less! T 1/2: 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 3 h • Fast acetylators have half-life of 1 hour • More toxic effects with slow acetylators

Effect of INH on GABA synthesis Glutamine Pyridoxine NH 3 Pyridoxine Phosphokinase Glutamic Acid CO 2 Glutamic Acid Decarboxylase Pyridoxal 5’-phosphate Gamma aminobutyric acid

Effect of INH on GABA synthesis Glutamine Increased urinary excretion NH 3 Pyridoxine Inhibits Glutamic Acid CO 2 Glutamic Acid Decarboxylase Pyridoxal 5’-phosphate Gamma aminobutyric acid Pyridoxine Phosphokinase

Effect of INH on GABA synthesis Glutamine Pyridoxine NH 3 Pyridoxine Phosphokinase Glutamic Acid CO 2 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 1 g for each g INH (may get transient base deficit w/ >5 g) Problem hospital often don’t have enough … so go to local supplement store and buy vit b 6 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 c. AMP;

Mechanism of Action • Theophylline (& caffeine): adenosine A 1 & A 2 receptor antagonists • Peripherally release of catecholamines • Catecholamine responses made worse by blocking of A 1 receptors • Cause vasoconstriction of the cerebral vasculature by A 2 antagonism result ? SEIZure

Pharmacology • • • 50% protein-bound Metabolized by liver Cyt P 450 T 1/2: 6 h V. narrow therapeutic range Seizures related to: 1) Chronicity chronic OD worse 2) Age >60 do worse 3) Levels > 250 mmol/L (chronic) 550 mmol/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 Otherapies? P Pyridoxine as theophylline has some anti. GABA effects • P propanolol? . Case reports of esmolol use despite hypotension • • •

Indications for multi-dose charcoal? “Think! Several Doses o. Ph Charcoal!” • 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 16 th 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 50 mg [15 mg paeds] • T 1/2 10 -15 h • 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 NMDAglycine receptors not affected) • Risus sardonicus? • hypersensitivity to stimuli. • HTN, Tacchy, cyanosis

Mgmt: ABC’s – may have to intubate/paralyse IV, O 2, Monitor Decontaminate with charcoal [if ingested] Benzos Avoid stimulation Treat hyperkalemia/rhabdo/hyperthermia

The 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 v 36. n 6 (Oct 1998): pp 595 (4). David J Mc. Cann. Toxicity, Antihistamine http: //www. emedicine. com/emerg/topic 38. htm Greg Hymel. Toxicity, Theophylline http: //www. emedicine. com/EMERG/topic 577. 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.