TOXICOLOGY 3 Nadim J Lalani R 3 Dr

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

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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 Make You Go Hmmm"

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

1. What were C + C music factory’s 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…”?

Drug and Toxin Induced Seizures “the ones that make you seize”

Outline § § Pathophysiology DDX ABCDEFP’s of DTS NO Cases NO LIT Bupropion Diphenhydramine Opioids INH Theophylline 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

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 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 § 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 GABA & others Theophylline Adeno & GABA Carbamazepine adenosine Cocaine Norepinephrine MDMA & serotonin Lithium Norepi & serotonin INH GABA H 1/Na Benadryl GABA Na-Chan Adenosine 5 -HT Norepi NMDA H 1 anticholn

? § 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 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 regoin, but 1020 mg Po is great for Etoh withdrawal)

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

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 crime-waves in the town. §Otis would often see something genuinely bizarre but attribute it to being drunk.

OTIS CAMPBELL Opioids (darvon &c) carbamazepine Antidepressants (bupropion)

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 10 mins) § 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. 05 mg/kg for paeds and in adults do 2 mg at a time

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 (or diazepam 5 mg IV q 5 min up to 20 mg 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 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 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 + 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 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? * (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

Diphenhydramine Effects by 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, 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

pentazocine § § § Talwin Synthetic opioid 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

A quote (on pentazocine): “it's like codeine but qualitatively "dreamier", more "smacky", and stronger than an equal dose… stuck to bed late histamine release - 3 h? "heavy" feeling … it makes a buzzing sound when on” sixthseal. com Leading 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 t 1/2 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 mg 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 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 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 ? “uuughuugh”

Pharmacology § § § 50% protein-bound Metabolized by liver Cyt P 450 T 1/2: 6 h V. marrow therapeutic range Seizures related to: 1) Chronicity chronic OD worse 2) Age >60 do worse 3) Levels > 150 mmol/L (chronic) 250 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 (there was no consensus on this)

Indications for multi-dose charcoal? “Think! Several Doses o. Ph Charcoal!” § Theophylline § Salicylates § Dapsone § Phenobarb § Carbamazepine

A Quote: “Propoxyphene… Dosage: 2 grammes, typically 30 65 mg 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?

§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 NMDA-glycine 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

** 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 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.