American College of Medical Toxicology 2012 www.acmt.net

ACMT Medical Toxicology Board Review Course

ARE YOU PREPARED? Astor Crowne Plaza Hotel New Orleans, LA September 8-10, 2012 SYLLABUS

Day Three - 3 slides per page

Sponsored by the University of Alabama School of Medicine Division of Continuing Medical Education American College of Medical Toxicology Medical Toxicology Board Review Course September 8-10, 2012 - New Orleans, LA

Day 1 - Saturday, September 8, 2012 7:00-7:50am Breakfast & Stimulus Room 7:50-8:20am Welcome & Introductions 8:20-9:10am Pharmacokinetics/Toxicokinetics Howard A. Greller, MD, FACMT 9:10-10:00am Molecular Mechanisms William P. “Russ” Kerns II, MD, FACMT 10:00-10:20am Break 10:20-11:10am Analytical/Forensics Evan S. Schwarz, MD 11:10-12:00pm Autonomics/Neurotransmitters G. Patrick Daubert, MD 12:00-1:30pm Lunch –n-Learn: Mushrooms & Fish-borne Howard A. Greller, MD, FACMT 1:30-2:20pm Psychotropics G. Patrick Daubert, MD 2:30-3:20pm Cardiovascular Toxins Trevonne M. Thompson, MD 3:20-3:40pm Break 3:40-4:05pm Hydrocarbons Trevonne M. Thompson, MD 4:05-4:30pm Pharmaceutical Additives G. Patrick Daubert, MD 4:30-4:55pm Endocrine Trevonne M. Thompson, MD 6:00-7:30pm Welcome Reception - Napoleon House, 500 Chartres Street in the French Quarter

Day 2 - Sunday, September 9, 2012 7:00-8:00AM Breakfast & Stimulus Room 8:00-8:50am Pesticides J. Dave Barry, MD, FACMT 8:50-9:15am Terrorism Hazmat J. Dave Barry, MD, FACMT 9:15-9:40am Antimicrobials Michael Policastro, MD 9:40-10:00am Break 10:00-10:50am GI/Heme Michael Policastro, MD 10:50-11:15am Chemotherapeutics Michael Policastro, MD 11:15-12:05pm Plants Thomas C. Arnold, MD, FACMT 12:05-1:30pm Lunch-n-Learn: Historical Outbreaks Stephen W. Munday, MD, MPH FACMT 1:30-2:20pm Envenomations Thomas C. Arnold, MD, FACMT 2:20-3:10pm Carcinogens Stephen W. Munday, MD, MPH, FACMT 3:10-3:30pm Break 3:30-4:20pm Misc Toxins 1 Brandon K. Wills, DO, FACMT 4:20-4:45pm Misc Toxins 2 Brandon K. Wills, DO, FACMT

Day 3 - Monday, September 10, 2012 7:00-8:00am Breakfast & Stimulus Room 8:00-8:50am Anesthetics; Drugs of Abuse & Withdrawal Kurt C. Kleinschmidt, MD, FACMT 8:50-9:15am Herbal/Supplemental Tox Kurt C. Kleinschmidt, MD, FACMT 9:15-10:05am Industrial Poisons Jefrey Brent, MD, PhD, FACMT 10:05-10:25am Break 10:25-11:15am Assessment/Population Health/Risk Jefrey Brent, MD, PhD, FACMT 11:15-12:05pm Metals/Metalloids 1 Cyrus Rangan, MD 12:05-12:30pm Metals/Metalloids 2 Cyrus Rangan, MD John G. Benitez, MD, MPH, FACMT 12:30-3:00pm Stimulus Room Russ Kerns, MD, FACMT Anesthetics; Drugs of Abuse & Withdrawal

Anesthecs; Drugs of Abuse & Withdrawal

Kurt Kleinschmidt, MD, FACEP, FACMT Professor of Emergency Medicine Secon Chief and Program Director Medical Toxicology UT Southwestern Medical Center 1

Much Thanks To…

Sean M. Bryant, MD

Associate Professor Cook County Hospital (Stroger) Department of Emergency Medicine

Assistant Fellowship Director: Toxikon Consorum

Associate Medical Director Illinois Poison Center

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Overview

Anesthecs – Local – Inhalaonal – NM Blockers & Malignant Hyperthermia

Drugs of Abuse (Pearls)

Withdrawal

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History

1904-Procaine (short Duraon of Acon) 1925 (dibucaine) & 1928 (tetracaine) → potent, long acng 1943-lidocaine 1956-mepivacaine, 1959-prilocaine 1963-bupivacaine, 1971-edocaine, 1996-ropivacaine 4

Lipophilic Intermediate Amine Substituents Group Esters Structure

2 Disnct Groups 1) Amino Esters

Amides 2) Amino Amides

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Local Anesthecs Toxic Reacons • Few & iatrogenic • Blood vessel administraon or toxic dose

AMIDES have largely replaced ESTERS • Increased stability • Relave absence of hypersensivity reacons – ESTER hydrolysis = PABA (cross sensivity) – AMIDES = Muldose preps → methylparabens » Chemically related to PABA with rare allergic reacons

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Local Anesthecs Mode of Acon

• Reversible & Predictable Binding • Within membrane-bound sodium channels of conducng ssue (cytoplasmic side of membrane) → Failure to form/propagate acon potenals (Small-diam. fibers carrying pain/ temp sensaon)

• Sodium Channel (3 States) – Closed (resng or hyperpolarized) – Open – Inacvated BLOCKADE

Pain fibers - higher firing rate & longer AP → ↑ susceptible to local 7 anesthetics

ONSET OF ACTION HIGHER POTENCY ↓ pKa (uncharged) Higher lipophilicity Intermediate chain length

Higher protein binding 3-7 carbon equiv’s 8

Local Anesthecs Pharmacokinecs • Local vs. Systemic disposions • Lipophilic = crosses membranes! (BBB, placenta) • Distribuon depends on ssue perfusion • Lungs = uptake; buffers systemic toxicity? – Saturable kinecs (lung uptake is exceeded → Toxicity) • Peripheral vasodilaon (except cocaine)

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Local Anesthecs Pharmacokinecs Metabolism AMINO ESTERS PABA

Plasma Cholinesterase AMINO AMIDES Metabolites unrelated to PABA

Slower via Liver Factors that may ↑ Tox ↓ plasma cholinesterase ↓ Liver blood flow (CHF) 10

Local Anesthecs Clinical manifestaons

Direct cytotoxicity (nerve cells) • Excessive concentraons or Bad formulaons • Uncommon

Transient neurologic symptoms • Spinal anesthesia with lidocaine (intrathecal or infusion) • Mech = Unknown (NOT Na channel blockade)

Skeletal muscle changes • IM injecons (highly potent, longer acng agents) • Reversible (2 weeks)

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Local Anesthecs Systemic Toxicity

– Allergic reacons (Amino Esters -- PABA) - Rare – Methemoglobinemia • Reported with lidocaine, tetracaine, prilocaine • Topical/oropharyngeal benzocaine

OXIDIZING aniline

AGENTS phenylhydroxylamine & nitrobenzene

Vasovagal Reactions Reported 12

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Local Anesthecs Systemic Toxicity • Correlates with [plasma] – Dose, Rate, Site – Vasoconstrictor? – Potency – Metabolism (rate)

Brain & Heart - #1 Targets • Rich perfusion • Moderate ssue-blood paron coefficients • Lack of diffusion limitaons • Cells that rely on voltage-gated Na channels

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Local Anesthecs Systemic Toxicity CNS Excitation: Bupivacaine: block inhibitory Large IV bolus = pathways in May only see brady, amygdala → CNS depression ↑ excitatory & respiratory arrest! activity. Both Inhibitory & Excitatory neurons blocked as concentration ↑ → CNS ↓

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Local Anesthecs Systemic Toxicity CNS Effects Determinants – Potency & Dose – Rate of injecon – Drug interacons – Acid-base status • Acidemia → ↓ protein binding → ↑ free drug • Hypercarbia

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Local Anesthecs Systemic Toxicity Bupivacaine significantly more Cardiotoxic

CC/CNS ([Cardio collapse/CNS Tox]) – Lidocaine = 7 (CNS tox more evident) – Bupivacaine = 3.7

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Local Anesthecs Systemic Toxicity • Lidocaine – Na channel blockade greater if pt is tachycardic – Quickly dissociates at diastolic potenals • Rapid recovery Non Na+- • Bupivacaine channel Issues – Rapid binding & Slow dissociaon – S is less cardiotoxic vs. R – Uncouples & inhibits Complex I of respiratory chain – Inhibits carnine-acylcarnine translocase – Blocks GABAergic neurons – May ↓ Ca++ release from SR →↓ Contraclity

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Local Anesthecs Management CNS • DC administraon • Supporve care (CV monitoring) • Benzos, Barbs (Thiopental, Propofol) • NM blocking agents (EEG monitoring) • HD not effecve (HP for lidocaine?)

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Local Anesthecs Management

CV • Recognize! (CNS effects may preoccupy) • Correct physiologic derangements – Hypoxemia, acidemia, hyperkalemia • Maximize Oxygenaon • Support Venlaon/Circulaon • Hypotension (adrenergic agonists) • Bradycardia (atropine)

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Local Anesthecs Management

CV • Dysrhythmias – Oen refractory to standard care • Pacing, Bypass • Lidocaine for bupivacaine? (relavely less toxic) • Prolonged CPR/Resuscitaon efforts • Na Bicarbonate? (To prevent acidosis) • Insulin? (same magical reasons as elsewhere) LIPIDS 20

http://lipidrescue.squarespace.com/welcome/

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Pretreatment or Resuscitation with a Lipid Infusion Shifts the Dose-Response to Bupivacaine-induced Asystole in Rats Weinberg, Guy L. MD; VadeBoncouer, Timothy MD; Ramaraju, Gopal A. MD; Garcia-Amaro, Marcelo F. MD; Cwik, Michael J. PhD Issue:Volume 88(4), April 1998, pp 1071-1075 Began as a chance observation in the lab. This was a “confirmation” study

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Inhalaonal Anesthecs

• Ether – Paracelsus – put hens “to sleep” – The 1st descripon – 1735 used for “headaches & fits” – 1864 Mass Gen. Hospital dental procedure - Public Demo – Oliver Wendell Holmes (anesthesia = without feeling) • Nitrous Oxide • Chloroform – Replaced ether as choice for OB (1840s) • Volale Anesthecs (Fluroxene, Halothane, Methoxyflurane) – 1840’s – 1940’s = combusbility and direct organ toxicity

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Inhalaonal Anesthecs

Improved Clinical Properes

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Inhalaonal Anesthecs Pathophysiology

Unique Receptor = Improbable (Because there are so many agents → anesthesia)

• Funcon modulated from within cells • Interact with many ion channels (target?) • Side effects = effects in nonneural ssue (cardiac)

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Inhalaonal Anesthecs Pathophysiology

Goal = Reversible changes in neuro funcon • Loss of percepon and reacon to pain • Unawareness of immediate events • Loss of memory of events

Mechanism = Uncertain • Physical-chemical behavior within hydrophobic regions of biological membrane lipids & proteins

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Inhalaonal Anesthecs Pharmacokinecs Potency – Physiochemical Properes • Meyer-Overton lipid solubility theory – Potency correlates directly with relave lipid solubility

• Volume expansion theory – High pressures (100-200 atm) reverse anesth. effects – Suggests that drugs cause anesthesia by ↑ membrane volume at normal atm pressure

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Inhalaonal Anesthecs Pharmacokinecs Factors that influence absorpon & distribuon • Solubility in blood • Solubility in ssue • Blood flow through lungs • Blood flow distribuon to various organs • Mass of the ssue

GOAL: Develop & Maintain satisfactory partial pressure

in the Brain!

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Inhalaonal Anesthecs Pharmacokinecs

• Linked to pharmacodynamics • Strive to achieve & maintain desired [alveolar]

Minimum alveolar concentraon (MAC) • Potency • The [alveolar] at 1 atm that prevents movement in 50% of subjects in response to a painful smulus

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Inhalaonal Anesthecs

NITROUS OXIDE Advantages • Mild odor • Absence of airway irritaon • Rapid inducon & emergence • Potent • Minimal respiratory & circulatory effects • Safe 32

Inhalaonal Anesthecs

NITROUS OXIDE • Abuse Potenal • Asphyxia - Death/Brain damage from asphyxia (2°) • Impuries – Nitric oxide, nitrogen dioxide • Barotrauma – 35x more soluble in blood than Nitrogen – Pressure in air-containing spaces (bowel, ears, chest)

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Inhalaonal Anesthecs

NO → oxidizes cobalt in B12 → Inactive form

Methionine & THF both required for DNA & myelin36 synthesis!!!

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Inhalaonal Anesthecs NITROUS OXIDE Hematologic Effects • BONE MARROW SUPPRESSION • Occurs in all paents • Recovery generally occurs (4 days) • PERNICIOUS ANEMIA-Like – This has ↓ B12 Absorpon due to absence of Intrinsic Factor (vs NO – acve B12 can’t be made by the body)

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Inhalaonal Anesthecs

NITROUS OXIDE Neurologic Effects • Only aer chronic exposure • Is a disabling polyneuropathy • Subacute Combined Degeneraon of Spinal Cord • Sensorimotor polyneuropathy • Posterior & Lateral cord involvement • Numbness & paresthesias in extremees • Weakness & truncal ataxia 38

Inhalaonal Anesthecs NITROUS OXIDE Management • Removal of source • B12 – Helps best if brief exposure – Won’t help chronically exposed paents? • Folinic acid 30 mg IV – May reverse BM abnormalies • Methionine Supplementaon – Experimentally (Primates) reduced

demyelinaon 39

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Inhalaonal Anesthecs HALOTHANE HALOTHANE HEPATITIS

(1) Mild Dysfuncon – 20% of exposed paents – Asymptomac – Modestly ↑ transaminases within days – Complete recovery

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Inhalaonal Anesthecs HALOTHANE (2) Life-Threatening Hepas – 1 in 10,000 paents – Fatal hepac necrosis in 1 of 35,000 paents – A diagnosis of exclusion – Increased risk » Mulple exposures » Obesity (fat reservoir, prolonged release) » Female » Age (middle age) » Ethnicity (Mexican) 41

Inhalaonal Anesthecs HALOTHANE HALOTHANE HEPATITIS 20% oxidative metabolism via CYP – trifluoroacetic acid

Volatile Metabolites: Free Radicals or Haptens

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Inhalaonal Anesthecs

• Enflurane – weakly associated • Immune form of hepas (all but sevoflurane)

Isoflurane, Desflurane Low Hepatotoxic Potenal

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Inhalaonal Anesthecs HALOTHANE ABUSE Ingeson • AGE, depressed CNS, low BP, shallow breathing, bradycardia & extrasystoles, & Acute Lung Injury • Coma resolves in 72 hours • Sweet fruity odor of breath

Intravenous • Coma, hypotension, Acute Lung Injury

Inhalaon • Most reported cases = hospital personnel 44

Inhalaonal Anesthecs

NEPHROTOXICITY Methoxyflurane (intro 1962) • Vasopressin-resistant polyuric renal insufficiency • Nephrogenic DI • Polyuria = negave fluid balance • High Na, Osmolality, BUN • Lasted 10-20 days (up to > 1year) • Tox = Inorganic Fluoride (F) released during biotransformaon of methoxyflurane – F inhibits adenylate cyclase (ADH interference)?

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Inhalaonal Anesthecs

Currently Used Anesthecs • Halothane, Isoflurane, Enflurane, Desflurane, Sevo. • Enflurane & Sevoflurane biotransform by deF – 5% of sevoflurane is metabolized – Transient decrease in urine-concentrang ability – Rarely clinically relevant • Pre-exisng RI = risk of renal dysfuncon?

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Inhalaonal Anesthecs Anesthec-Related CO Poisoning Desflurane, Enflurane, Isoflurane • Contain a difluoromethoxy moiety – Can be degraded to Carbon Monoxide

• CO producon

– Inversely propor. to H2O content of CO2 absorbents – Soda lime and Baralyme = CO2 absorbents – May dry with high gas-inflow rates – Worst = first case Mon. aer weekend of drying

• COHb up to 36% (no M&M reported)

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Anesthesia Is GOOD!!!

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Neuromuscular Blockers History Curare: Sir Walter Raleigh (Guyana 1595) – 1898: King’s American Dispensatory • “Curare is a frighully poisonous extract, prepared by the savages of South America” – Curare pivotal in mech. of NM transmission • Claude Bernard frog studies – “curare must act on the terminal plates of motor nerves” – 1878: Curare 1st clinical use (tetanus & Sz) – Malicious use of NM Blockers! (Swango...)

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Neuromuscular Blockers Purpose Reversibly inhibits transmission at the skeletal NMJ – All = 1 +charged quaternary ammonium moiety → binds to the postsynapc niconic (nAch) receptor at the NMJ → ↓ acvaon by Ach

nAch receptor Ligand-gated ion channel 4 different protein subunits Pentameric structure with central channel

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Goldfrank’s 8th ed, page 1026

Excitation-Contraction coupling in skeletal muscle

Calcium Release Unit the intimate association of DHPR, RYR-1, & SR

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Neuromuscular Blockers Modulaon of postsynapc Ach receptor Depolarizing (phase I block) • Succinylcholine (the only one clinically) • 2 molecules bind to each α site of nAch receptor • Prolonged open state of ion channel! • Fasciculaons!!

• Succ not hydrolyzed efficiently by true AchE • Voltage-gated Na channel in peri-junconal region – Prolonged inacve state → desensizaon block → Muscle= temporarily refractory to presyn Ach release (phase I block)

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Neuromuscular Blockers Modulaon of postsynapc Ach receptor Nondepolarizing (phase II block) • Compevely inhibit effects of Ach • Prevent muscle depolarizaon! • One molecule of NDNMB binds to α site – Compevely inhibits normal channel acvaon

• DO NOT block voltage-gated Na channels on mus mem – So…Direct electrical smulaon of muscle contracon = possible • Also block nAch receptors on prejunconal nerves – Inhibits Ach-smulated Ach producon & release

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Neuromuscular Blockers Pharmacokinecs

Highly water soluble (won’t cross BBB) Speed of onset - 1/ molar potency (The > affinity for receptor, the fewer molecules/Kg ssue required)

In general: small, fast contracng muscles • Most suscepble (e.g. extraocular vs. large slow) • Respiratory Sparing Effect Recovery fastest for diaphragm and IC muscles

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Neuromuscular Blockers Complicaons

Paent Awareness • NMBs do not affect consciousness • Pupillary light reflex preserved in healthy paents Histamine Release • Nonimmunologic dose- and rate-related release • Tubocuarine>atracurium & mivacurium>Succ • NO release w/ pan, roc, vec Anaphylaxis • 60% anaphylactoid rxns during anestheisa – NMBs • Of the NMBs, Rocuronium 43%, Succ 23% (Pancuronium=least) 56

Neuromuscular Blockers Complicaons

Control of Respiraon Subparalyzing doses – Blunt hypoxic venlatory response (HVR) – But not the venlatory response to hypercapnia Autonomic Side Effects Tubocurarine – Blocks nAch rec at PNS ganglia → Tachycardia

– At SNS ganglia → ↓ sympathec response – Histamine release HYPOTENSION! 57

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Neuromuscular Blockers Complicaons

Autonomic Side Effects • Muscarinic receptors mostly unaffected • Pancuronium – Blocks PNS transmission at Cardiac M Recs (Atropine-like effect) – Block of presynapc M receptors at SNS terminals – ? Indirect NE-releasing effect at postgang fibers

→ Dose- and injecon rate-related increase in Heart Rate, BP, CO, and Sympathec Tone 58

Neuromuscular Blockers Complicaons

Autonomic Side Effects Succinylcholine – Rarely: Dysrhythmias -bradycardia, junct & vent rhythms – Due to Smulaon of Cardiac M Receptors – May be prevented with atropine (15-20 mcg/kg IV)

Bradycardia » May be severe in children with large/repeated doses

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Neuromuscular Blockers Interacons

Potenate duraon or effect of NDNMB • Respiratory acidosis, hypoK, hypoCa, hyperMg, hypoP, hypothermia, shock, liver or kidney failure

Resistance (mild) to effect of NDNMB • Acute sepsis & inflammatory states

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Neuromuscular Blockers Succinylcholine TOX 1) Prolonged Effect – Decreased plasma cholinesterase (or abnormal acvity) – OP or Carbamate Poisoning – Hepac Dz, Malnutrion, Pregnancy – Phase II block (large doses over short period – 8mg/kg)

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Neuromuscular Blockers “Normal or RI Patients” 1 mg/kg raises [K] approximately 0.5 mEq/ L Succinylcholine TOX 2) Hyperkalemia Exaggerated with myopathy or proliferaon of extrajunconal Ach rec Suscepbility aer neuro injury begins in 4-7 days! Denervaon Assume Head or SC injury, CVA, neuropathy cardiac arrest Muscle pathology after Sucks is Trauma, compartment syndrome, musc dystrophy due to Crical illness hyperkalemia Hem shock, neuropathy, myopathy, ICU > 1 wk Thermal burn or cold injury Sepsis (x several days)

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Neuromuscular Blockers

Succinylcholine TOX 3) Rhabdomyolysis – Especially at risk = underlying myopathy – Ex; Kids with Duchenne musculary dystrophy

– Life-threatening hyper K? » Mortality is highest with rhabdomyolysis (30%)

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Neuromuscular Blockers

Succinylcholine TOX 4) Muscle Spasms – Masseter Muscle Rigidity (MMR) » Pediatric Paents: 0.3-1% (Succ + Halothane)

– Trismus, myoclonus, chest wall rigidity » Can’t be aborted by NDNMB (indep of neural acvity)

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Neuromuscular Blockers

Succinylcholine TOX Also Volatile Anesthetics! 5) Malignant Hyperthermia » Inherited hypermetabolic condion » 1:20,000 children, 1:50,000 adults » Duchenne MD, central core Dz, King-Denborough syndrome, osteogenesis imperfecta, myotonia

MH-triggering agents (within 12 hours) » Interact with an abnormal RYR-1 channel (mostly) » Prolonged open state » Rapid efflux of calcium from SR (accelerated) » Hypermetabolic – pCO2, temp, tone, lactate (all ↑)

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Malignant Hyperthermia

Signs and Symptoms of MH (First 30 Min)

Tachycardia 90% Hypercarbia 80% Rigidity 80% Hypertension 75% Hyperthermia 70%

May be a late sign

Earliest signs = EARLY & RAPID INCREASED CO2 production and artrerial,venous end tidal CO2 66

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Malignant Hyperthermia Management • Aggressive Supporve Care volume, cooling, hyper K…

DANTROLENE » Prior Mortality Rate = 70% (now < 5%!!!) » Parally blocks Calcium release from SR » Dose = 2-3 mg/Kg » Maintence dosing for any reoccurance (25%) IV q 4-6 hrs for 24-48 hours

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Neuromuscular Blockers

NDNMBs TOX • Persistent Weakness – Administraon longer than 48 hours – Crical illness associated (mulfactorial) • 2.5-3.5 – fold increase in ICU mortality & ICU stay

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Neuromuscular Blockers

Unique Toxicity • Metocurine – connes iodine, hypersensivity and shellfish allergy • Rapacuronium – fatal bronchospasm, withdrawn.

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Drugs of Abuse/Withdrawal

Tolerance • Physiologic process: increasing drug concentraons required • Shi in dose-response curve to the right • Receptor modulaon (opioids), metab (barbs), or both (EtOH) • “Cross Tolerance” Key to treang W/D

Dependence • Implies that cessaon leads to withdrawal

Withdrawal • Physiologic (autonomic instability, N/V/D, hyperacvity, AMS) • Psychological (emoonal symptoms & craving)

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Hallucinogens • Lysergamides • Tetrahydrocannabinoids – LSD – Marijuana – Ergine – Hashish • Indolalkylamines / Typtamine • Belladonna Alkaloids – Psilocin & Psilocybin – Jimsonweed – Dimethyltryptamine (DMT) – Deadly nightshade – 5-Methoxy-DMT • Miscellaneous – Bufotenine – Salvia divinorum • Phenylethylamines – Ketamine – Mescaline – Phencyclidine (PCP) – MDMA (Ecstasy) – Methcathinone (Khat, Jeff) – Methamphetamine 72

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Hallucinogens • Many flavors • Common acon - CNS serotonin receptors (5-HT) • Affects many psychological & physiologic processes (Mood, personality, affect, appete, motor funcon, sexual acvity, temperature regulaon, pain percepon) • > 14 known 5-HT receptor subtypes; Each with different effects & degrees of effect by different structures • Other neurotransmiers also contribute to effects

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Drugs of Abuse/Withdrawal Amphetamines

Now = Serotonergic Methyl additions = ↑ CNS & duration

Primary mechanism of Tox  release of catecholamines (DA, NE) from presynaptic terminals & block reuptake by competitive inhibition 74

Dopamine Release due to Amphetamines

• Low Dose – Released from cyto by exchange diffusion at dopa uptake transporter site in membrane • Moderate Dose – Amphetamines diffuse into presyn terminal → affect NT transporter on vesicular membrane → releasing dopa into cyto → Dopa undergoes reverse transport at Dopa Uptake Receptor → Dopa in synapse • High Dose – amphetamines diffuse into the vesicle → alkalinizes vesicles → Dopa release from vesicles → Membrane Reverse Transport → Dopa in Synapse

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Drugs of Abuse/Withdrawal

Amphetamines Methamphetamine • CNS effect more substanal (chemistry!) • Prolonged half-life (19-34 hours)

• Primary ingredient = ephedrine – Hydrogenated to Methamphetamine • Meth Lab Tox Lead, HCl acid, HCl gas, anhydrous ammonia, red phosphorus, iodine

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Drugs of Abuse/Withdrawal

Amphetamines 3,4-Methylenedioxymethamphetamine (MDMA) • Entactogen (means touching within) – Euphoria, expands consciousness, Inner peace – Desire to socialize, heightened sexuality • One-tenth the CNS smulant effect

• Serotonergic (5-HT chemistry!) • Hyponatremia – Hypovolemic (dancing/sweang), Euvolemic (SIADH), Hypervolemic (water drinking)

• Long-term neuropsychiatric effects 77

Other Phenylethylamines Mescaline

Goldfranks Substuon at the para Toxicology posion of the phenyl ring → ↑ hallucinogenic or 2006 2CB, Nexus, 5HT effects. Bromo

Myristicin is also phenylethylamine based

2CT-7, Blue Mystic 78

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Peyote & Mescaline • A spineless cactus • Lophophora williamsii • Disk-shaped buons are cut from the roots, on the top of the cactus and dried • Peyote buons - round, fleshy tops of the cactus that have been sliced off and dried.

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Peyote & Mescaline • Bier-tasng buons – Eaten whole – Dried → crushed into a powder → Τea • 6-12 buons (270-540 mg of mescaline) typical • Equivalent to roughly 5 grams of dried peyote • Legal use in the US - Nave American Church → religious ceremonies & treatment of physical and psychological ailments. • Used for centuries for the psychedelic effects experienced when it is ingested

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Peyote Mescaline

• Contains a large spectrum of phenethylamines …the principal of which is mescaline • Clinical – Visual hallucinaons and radically altered states of consciousness – Usually pleasurable and illuminang – Occasional - Anxiety or revulsion – Not physically addicve – N/V & Diaphoresis oen precede hallucinaons – Effects lasng for up to 12 hours 81

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Indolalkylamines (Tryptamines)

Bufotenine

www.nida.nih.gov 82

Lysergamides

• LSD is the synthec one • Natural lysergamides – Morning glory (Rivea corymbosa, Ipomoea violacea) • These seeds have many alkaloids • 200-300 seeds - hallucinogenic – Hawaiian baby wood rose (Argyreia nervosa)

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• A dried grain spike of rye grass infected with ergot (Claviceps purpurea). Some of the grains have been replaced by a dark, compact, fungal mass called a sclerotium (superficially resemble rat droppings). • The sclerotia contain • vasoconstricting ergotamine alkaloids • lysergic acid alkaloids which are the precursor for LSD 25.

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Is an Lysergic acid Indole diethylamide

LSD Lysergic Acid The morning glory seeds contain a lysergic acid alkaloid called ergine (d-lysergic acid amide, the "natural" LSD). The more potent synthetic LSD is d-lysergic acid diethylamide 85

Psilocybin • Found in Psilocybe, Panaelous, and Concocybe genera • Grow in Pacific Northwest and southern US; oen in pastures • In the GI tract, is metabolized to Psilocin (acve hallucinogen) • Effects same as LSD but duraon is shorter; ~ 4 hours

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Toads and Hallucinaons

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The Bufo genus

• All species have parod glands on their backs that → various xenobiocs (dopamine, epinephrine, serotonin) • Many species → bufotenine • Only B. alvarius → 5-MeO-DMT

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N Other Hallucinogen Flavors • PCP • Ketamine

Piperidine 89

PCP • Developed in 1950s • Dissociave anesthec • Never approved for human use (Delirium & Bad agitaon as awoke from anesthesia) • Brain Effects – Disrupts NMDA receptor for glutamate – Glutamate receptors… • Percepon of pain • Cognion - including learning and memory • Emoon – Dopamine acon altered • Neurotransmier • Euphoria and "rush" due to many abused drugs. 90

30 Anesthetics; Drugs of Abuse & Withdrawal

Ketamine • Dissociave anesthec • Made in 1963 to replace PCP • Current Use - Anesthesia and veterinary medicine. • “Street” K mostly diverted from veterinarians' offices. • Manufactured → Liquid. • Illicit ketamine – Evaporizaon → powder → Snorted or compressed into pills. • Versus PCP - Much ↓ potency & ↓ Duraon.

91

92

Cocaine Derivaon and Types Mechanical Hydrocarbon Cocaine Alkaloid Leaf (benzoylmethylecgonine)

Dissolve in HCl Extracted into Aqueous Phase white powder Cocaine HCl Evaporated Salt in Solution (cocaine hydrochloride)

Dissolve in water • Decomposes if heated Hydrocarbon Solvent Add a strong base • Insufflated (Ether) extracts cocaine base • Applied to other Free-Base Evaporated w/ Heating Crack mucous membrane Liquid • Dissolved in water tobacco or marijuana cigarette is dipped… dried… Smoked Injected or Ingested93

31 Anesthetics; Drugs of Abuse & Withdrawal

Cocaine Metabolism

N-Demethylation Non-Enzymatic Hydrolysis

Cholinesterase

Norcocaine Benzoylecgonine

Goldfranks Toxicology 2006 Robert Hoffman Cocaine Chapter Ecgonine Methyl Ester 94

Mechanism Cocaine blocks the Pre-Synaptic reuptake of biogenic amines

Serotonin Dopamine Neuronal Adrenal Norepinephrine epinephrine

Addiction Locomotor Hypertension Tachycardia Reward Effects Seizures Cocaine → ↑ Cerebral Excitatory amino acids Psychomotor agitation Hyperthermia Sedation → ↓ CNS & peripheral Seizures effects of biogenic amines95

An important consideraon for Treatment

96

32 Anesthetics; Drugs of Abuse & Withdrawal

Drugs of Abuse/Withdrawal

Cocaine Withdrawal – Emoonal component = YES • Intense craving

– Physical component = DEBATABLE • Washed-Out Syndrome – Catecholamine Depleon – Lethargy & Adynamic

97

98

U.S. : 100 Proof = 50% EtOH by volume

99

33 Anesthetics; Drugs of Abuse & Withdrawal

No specific Receptor

100

é NADH/NAD!!

Gluconeogenesis is Inhibited Pyruvate is reduced to lactate Oxaloacetate is reduced to malate

PREVENTS… flow of metabolites in the direction of gluconeogenesis

101

Ethanol EtOH induced hypoglycemia due to high redox ratio!

Malnourished & Children Highest Risk!

102

34 Anesthetics; Drugs of Abuse & Withdrawal

Ethanol

Also cofactor for α-KGD (Krebs) & transketolase (PPP) & important for neuronal conduction

103

Ethanol

104

Disulfiram Reacons

Cyto ALDH 1 & (Mito ALDH 2 = KEY)

Accumulation of Acetaldehyde = histamine release?.... symptomatology Also inhibits DA beta-hydroxylase (NE synthesis), via chelation of Cu 50% inhib of CYP 2E1, induces 2B1 & 2A1

105

35 Anesthetics; Drugs of Abuse & Withdrawal

- GABA Withdrawal - Cl GABA Cl Pathophysiology Barb Benzo Ethanol

Cl- GABA Receptor Cl- Chloride Channel

Inside Cell → ↑ Negative (Hyperpolarized) Cell Firing ↓

Action Potential Acute 0 EtOH Effects

-30 Threshold Potential mV Resting -70 Potential

Membrane Potential Potential Membrane -90 New Resting 1 2 3 4 Potential Time (ms)

107

Chronic Suddenly Disinhibited Action Remove Potential EtOH EtOH → New ↓ In-Cell0 Cl- Effects Resting Potential

-30 Threshold Potential mV Original -70 Resting Tolerance!

Potential (Cell Δ) Membrane Potential Potential Membrane -90 Resting Potential 1 2 3 4

Time (ms) 108

36 Anesthetics; Drugs of Abuse & Withdrawal

Ethanol/Sedave Hypnoc Withdrawal MILD Alcoholic Hallucinos. Tremor Visual or auditory Tachycardia Persecutory HTN Within a few hours Diaphoresis Independently? Anxiety Clear Mentation Disturbing Delirium Tremens 24 hrs after Lasts 3-5 days Altered sensorium May=hallucinate (visual or tactile), Seizures “rum fits” Sz’s, psycomotor 6-48 hours after agitation. Single, Generalized, Brief, short postictal Autonom Instable 109

Drugs of Abuse/Withdrawal

Gamma-Hydroxybutyric Acid

110

111

37 Anesthetics; Drugs of Abuse & Withdrawal

Drugs of Abuse/Withdrawal

GHB Withdrawal – Potenally severe & life-threatening – Rapid development (within hours of use) – Agitaon, disorientaon, hallucinaons, HTN, tachycardia, hyperthermia, tremor, Sz – Consistent with sedave-hypnoc W/D • Treatment the same

112

Drugs of Abuse/Withdrawal Inhalants

113

Drugs of Abuse/Withdrawal

Inhalants

114

38 Anesthetics; Drugs of Abuse & Withdrawal

Slip em a Mickey!

115

Drugs of Abuse/Withdrawal

Metabolites may be Cannabinoids detected in the urine of chronic W/D? users Tremor for several weeks Sweaty Fever Nausea Irritable Restless Sleepless Nervous

116

Drugs of Abuse/Withdrawal Nicone – Terary amine, colorless, bier, H2O soluble – Weakly alkaline (pKa=8.0-8.5) – Solanaceae family of plants • Nicoana tabacum • N. rusca (higher concentraon, Turkish tobacco) – Lobeline • Lobelia inflata (Indian tobacco) – Cyssine (mescal beans) – Coniine • Lethal alkaloid in poison hemlock

117

39 Anesthetics; Drugs of Abuse & Withdrawal

Drugs of Abuse/Withdrawal

• Oen biphasic; with niconic smulaon early ; followed by “loss of smulaon” due to receptor fague • Note can have both sympathec and parasympathec signs and symptoms • Voming is #1 most common; occurs early. • Death due to CV collapse and respiratory depression 118

Drugs of Abuse/Withdrawal Nicone Withdrawal

119

Opioids

120

40 Anesthetics; Drugs of Abuse & Withdrawal

Drugs of Abuse/Withdrawal Opioids • 2D6 polymorphisms affect clinical effects • Heroin – beer BBB penetraon bc of more hydrocarbon groups →the “Rush” • 6-MAM – Not natural; confirms heroin presence – More potent than morphine

121

Drugs of Abuse/Withdrawal

Opioids Heroin (3,6-diacetylmorphine) Hydrochloride salt – White or beige powder (insufflaon) – H2O soluble = IV administraon Heroin base – More prevalent form – Brown or black – Relavely insoluble in H2O – Insufflaon – Chasing the dragon

» Spongiform leukoencephalopathy 122

Dextromethorphan • D-isomer of codeine analog levorphanol • No analgesic, respiratory, or CNS effects at therapeuc doses • Dextrophan is acve metabolite → ↑ serotonin release → Affects NMDA receptor at PCP site (→ Hallucinaons) → Sigma receptor effects • Toxicity: Hyperexcitable, lethargy, ataxia, diaphoresis, HTN, nystagmus, dystonia, seizures; occasionally opioid-like

Does Narcan work? Variable 123

41 Anesthetics; Drugs of Abuse & Withdrawal

Meperidine • Meperidine → Nor-meperidine T½ 3-4 hrs 15-30 hrs • Serotonin ↑ due to ↓ reuptake of the NT & ↑ release • Toxicity: twitches, tremors, myoclonus; seizures

MAOIs potentiated: The unique drug reaction Agitation Irritability compared to other opioids? Hyperpyrexia Tachycardia

Hypertension 124

Tramadol • Analog of codeine • Analgesia: – Mu-agonism is 10% of codeine – NE and serotonin reuptake ↓ → pain modulaon

Toxicity - lethargy, tachycardia, agitation, seizures, hypertension. • Narcan reverses sedaon and some ot the analgesia; but…its use has → seizures • Physical dependence has occurred

125

Drugs of Abuse/Withdrawal

Opioids Averse Effects • Acute lung injury • Seizures (tramadol, propoxyphene, meperidine) • Na channel blockade (propoxyphene) • Decreased BP (histamine release) • Rigid Chest (fentanyl) • Myoclonus (fentanyl, meperidine)

126

42 Anesthetics; Drugs of Abuse & Withdrawal

Drugs of Abuse/Withdrawal

Opioid Withdrawal – Uncomfortable – Generally not life-threatening Physiologic – Heroin W/D = 4 – 8 hours Tachycardia – Methadone W/D = 36 – 72 hours Tachypnea – Psychological Diaphoresis • Craving Tearing Not • Dysphoria Yawning Delirium • Anxiety Rhinorrhea Seizures Myalgias • Insomnia CV collapse Piloerection Hyperpyrexia Abdominal pain

N/V/D 127

Drugs of Abuse/Withdrawal

Critical Care Toxicology 128

You are geng

sleepy… 129

43 Herbals & Supplements

Herbals and Supplements

Kurt C. Kleinschmidt, MD Professor Of Emergency Medicine Section Chief and Program Director Medical Toxicology UT Southwestern Medical Center

1

Topics

• History and Regulations • Name the top selling herbs • State what reasons people use Complimentary & Alternative Medicine (CAM) • The most dangerous herbs • The most important drug interactions

2

The Concept

3

1 Herbals & Supplements

Coca Leaves and Cocaine Castor Bean (Ricin)

Brown Centruroides exilicauda Recluse4

Foxglove (Digitalis purpurea)

Red Barracuda Tide Dinoflagellates Ciguatoxin

Poppy

Poison Amanita Ivy phalloides 5

Did you know…? http://www.herbalhealer.com/allopaths.html Allopaths Naturopaths • Do double blind studies on • Never do testing on animals pts…means 50% of the sick or people. Always strive…heal get sugar pills, with no each person. regard for helping them if the medicine works! • Very expensive. Emphasis • Economical. Natural foods & on licenses, professional herbs can not be patented nor personnel, special monopolized. Much can be government regulated do-it-yourself. No expensive facilities, controlled prices, facilities. Most cases… expensive patents, making Naturopaths desire to heal is much money. Drugs come much greater than the desire from labs. for money.

6

2 Herbals & Supplements

The Other Trend on Herbal Sites…

7

Herbal & Dietary Supplements • Dietary Supplements – Botanicals (plants/herbs), vitamins, amino acids, food additives (or any combination of) – Supplements diet – 20,000-30,000 on the market • Herb – Certain leafy plants without woody stems – Preparations often include “nonherb” plant materials (and even animal and mineral products) – “Supplement” - reflects their classification as “nutrients” with nondrug status

8

Herbal & Dietary Supplements

• Commonly used – WHO estimates up to 80% of world population – Series: Used ≥ 1 during the preceding week (14%) and the past 12-months (19%) • Factors for the upswing – Lower cost – Ease of purchase – Consumer empowerment – Dissatisfaction with conventional therapies – Perception that herbals are better and safer

9

3 Herbals & Supplements

Herbal & Dietary Supplements Top Sellers • Kava kava • Ginkgo biloba • Saw palmetto (for BPH) • St. John’s wort • Evening primrose • Ginseng • Goldenseal • Garlic • Cranberrry • Echinacea • Valerian • Glucosamine/Chondroitin • Grape seed extract

10

NCCAM 2007

11

Herbal & Dietary Supplements • DSHEA (Dietary Supplement Health and Education Act of 1994) – Manufacturers can do “claims” “Stimulates CV health”, “Enhances sex drive” – NOT “Cures atherosclerosis”, “Cures impotence” • FDA → dietary supplement (include vitamins, minerals, herbals, amino acids, and any product that had been sold as a "supplement" before October 15, 1994) • Any new supplement ingredient, after Oct 1994, → must notify the FDA 75 days before marketing – FDA must review - expected to be safe? – Most supplement ingredients were in use prior to 1994

12

4 Herbals & Supplements

Herbal & Dietary Supplements

• After marketing, if agent is felt to be unsafe, the FDA – can warn the public – suggest changes to make it safer – urge the manufacturer to recall the product Chances of – Recall or ban the product • To “ban” a supplement Success – the FDA must prove that the product is unsafe FDA – April 2004 - "banned" all sales For the ephedra (the 1st ban of any supplement since 1994) • Food products - Quality control & Production are set by the Current Good Manufacturing Practices regulations – Ensures - supplements are made sanitary conditions – Do NOT guarantee the purity, safety, or efficacy

13

Types of Toxicity All substances are poisons; there is none which is not a poison. The right dose differentiates a poison…." Paracelsus (1493-1541)

Minimal problem Low concentration Inherent toxicity Misuse Heavy-metal poisonings Misidentification from lead, cadmium, Misrepresentation mercury, copper, zinc, and Contamination arsenic Drug interaction Use precludes some from seeking allopathic /osteopathic care

14

Alkaloids • Heterogenous group of organic(carbons) & nitrogenous compounds • CNS stimulation/depression, hepatotoxicity • Groundel (Senecio longilobus), comfrey (Symphytum officinale): hepatic veno- occlusive disease • Aconitum (Aconitum napellus), Goldenseal (Hydrastis canadensis), Jimson weed (Datura stramonium)

15

5 Herbals & Supplements

Glycosides Glycoside is any molecule in which • Esters that contain a sugar (glycol) and non-sugar (aglycone) which yields one or more sugars with hydrolysis • Examples • Anthroquinones (senna and aloe) • Saponins (licorice [Glycyrrhiza ledpidata] • Ginseng [Panax ginseng] • Lactone glycosides

16

Glycoside Example - Digoxin

Non-Sugar Glycone Aglycone Genin Anomeric Carbon Is a steroid (Bound to two oxygens) for “Digoxin” (The stereocenter) 17

Essential Oils • A concentrated hydrophobic liquid containing volatile aroma compounds from plants. • Also known as volatile oils, ethereal oils or aetherolea, or simply as the "oil of" the plant from which they were extracted, such as oil of clove. Sweet orange • An oil is "essential" in the sense that it Cedarwood carries a distinctive scent, or essence, Peppermint of the plant. Cedarwood • Essential oils do not form a distinctive Lemon category for any medical, pharmacological, Eucalyptus globulus or culinary purpose. Clove (leaf) Spearmint Pennyroyal Oil

18

6 Herbals & Supplements

Time for Common Flavors

19

• Maidenhair tree Common Flavors • Ginkgolides • Uses – Antioxidant (?) Ginkgo biloba – PVD • Platelet aggregation ↓ • Circulation ↑ Major study – Alzheimer disease (JAMA 2002;288:835) • Adverse Effects – Bleeding ↑ (?) in pts on antiplatelet agentsNo help in cognition in or anticoagulants – GI distress healthy elderly subjects – HA – Allergic reactions without cognitive impairment.

20

Common Flavors St John’s Wort (Hypericum perforatum) • Uses: Depression Anxiety, gastritis, insomnia, AIDS • Components – Hyperfoin Hypericin – Flavonoids Tannins • Adverse Events – MAOI-A and B inhibition (? Mild) – ? Agonism GABA / adenosine – ? ↓ Reuptake (DA, NE, GABA)

Major study Ineffective in treating depression.

JAMA 2002;287:1807-1814 21

7 Herbals & Supplements

Common Flavors St John’s Wort Toxicity

• Photosensitization • Serotonin Syndrome • Drug interactions (CYP 3A4) – Indinavir – Oral contraceptives – Cycloserine

22

23

Common Flavors ” Ginseng (Panax ginseng) “ALL HEALING • P. ginseng is from Far East. P. quinquefolius in North America • Uses - Respiratory illnesses, GI disorders, impotence, fatigue, and stress ("adaptogenic effect") • Complex - many ginsenosides • Metabolic - Glucose ↓, Cholesterol ↓, Erythropoiesis ↑, BP & HR ↑, GI motility ↑; and CNS stimulation • Side Effect - may ↓ warfarin's anticoagulant effect

24

8 Herbals & Supplements

Common Flavors Ginseng • Long-term use – Ginseng Abuse Syndrome • HTN • Nervousness • Sleeplessness • AM diarrhea

25

Common Flavors Garlic

• Uses – Antibacterial and antioxidant activity – Infections, hypertension, colic, and cancer prevention. • Intact cells - odorless, sulfur-containing amino acid derivative alliin. • Crushed, alliin → allicin • Adverse Effects – Contact dermatitis, gastroenteritis, & N/V – Antiplatelet effects (? → ↑ Bleeding)

26

Common Flavors Echinacea

• Uses – Immunostimulant - for cold and flu symptoms. • Adverse Events – Rare allergic reactions

27

9 Herbals & Supplements

Valerian Root

• Uses: Sedation and anxiolysis

28

Dangerous Flavors

29

Aristolochic Acid (Aristolochia clematis)

• Birthwort, heartwort, fangii • Ingredient (±) in Chinese herbal products labeled fang ji, mu tong, ma dou ling, and mu xiang • Unlabeled substitute for other herbs • Use: Uterine stimulant • Aristolochic acid – Nephrotoxicity (renal fibrosis) • 12-24 months • Failure, Hemodialysis, Transplantation need – Carcinogen (urothelial cancer) • FDA warning April 2001. Banned in 7 European countries and Egypt, Japan, and Venezuela.

30

10 Herbals & Supplements

Pyrrolizidine Alkaloids

Comfrey (Symphytum officinale) Heliotrope (Crotalaria specatabulis) Gordolobo (Gnaphalium spp.)

• Likely converted to pyrroles in liver (alkylating agents) • Liver Venoocclusive disease (Sinusoidal hypertrophy & venous occlusion) – Liver function ↓, Irreversible ±; Deaths – Cirrhosis ? • ? Association with hepatic CA • Treatment: supportive, transplant

31

Gordolobo Heliotrope

Comfrey 32

Dangerous Flavors Chaparral (Larrea divaricata) • Creosote bush, Hediondilla, jarilla, larreastat • Liver - Abnormal function, often irreversible; deaths • FDA warning to consumers in Dec 1992.

33

11 Herbals & Supplements

Dangerous Flavors Germander (Teucrium chamaedrys)

• Liver - Abnormal function, often irreversible; deaths • Banned in France and Germany.

34

Dangerous Flavors Kava (Piper methysticum) • Kavalactones - ??? Weak • GABA-agonism, NE/serotonin reuptake blockade, Na channel blockade, MAOI-B inhibition Uses: Sleeping aid Stress reliever Muscle relaxant Arthralgias HA Asthma Dysuria 35

Dangerous Flavors Kava • Adverse Events – CNS depression – Kava dermopathy or Kavaism • Chronic, high-dose • Flaky, dry, and yellowing of the skin, hair loss • Ataxia, Hearing ↓, Appetite ↓, and body weight reduction • Reversible. – Hepatotoxicity • 2002 - 70 cases hepatotoxicity, including 4 deaths • Sales restricted in many countires. • FDA issued a consumer advisory in March 2002.

36

12 Herbals & Supplements

Dangerous Flavors Lobelia (Lobelia inflata)

• Indian tobacco • Uses: Antispasmodic, respiratory stimulant, relaxant • Component = Pyridine-derived alkaloids (Lobeline) • Nicotinic

37

Lobelia & Its Nicotinic Friends • Betel Nut (Areca catechu) – Chewed for euphoria (Stimulant) – Arecholine - Direct acting Nicotinic agonist • Bronchoconstrictor – Methacholine • Bronchospasm in asthmatic – Leaf = a phenolic volatile oil and an alkaloid • Sympathomimetic reactions – Long-term use = leukoplakia, SC CA of oral mucosa

38

Lobelia & Its Nicotinic Friends

• Blue cohosh (Caulophyllum thalictroides) – Traditionally = Abortifacient, menstrual d/o’s, antispasmodic – Methylcytisine (1/40 as potent as nicotine)

Blue Cohosh 39

13 Herbals & Supplements

Dangerous Flavors Ephedra

• Genus Ephedra = erect evergreens (small shrubs) • Ma-huang, “Herbal Ecstasy” Mormon tea, desert tea • Uses - Stimulant, Rx Bronchospasm • Alkaloids – Ephedrine & Pseudoephedrine • Adverse Events – Dizzy, palpitations, flushing, anxiety, mania – Seizures, CVA, MI, Death – NV, HA

40

Dangerous Flavors Yohimbe (Pausinystalia yohimbe)

• Uses - Bodybuilding, hallucinogen, aphrodisiac • Alkaloid – Yohimbine (alkaloid) from bark • Alpha-2 agonists • Adverse Events – Hypotension – Weakness/paralysis – Abdominal pain

41

Dangerous Flavors Pennyroyal Oil (Mentha pulegium)

• Volatile oil from leaves • Uses - Abortifacient, regulate menstruation – Irritation and contraction of uterus • Strong tea or oil ingested • Hepatic failure (15 mL) (Direct) – Pulegone (depletes hepatic glutathione stores) • N-acetylcysteine for treatment? • Can also … neurotoxicity, ARF

42

14 Herbals & Supplements

Hallucinogens

• Absinthe • Nutmeg • Khat

43

Dangerous Flavors Wormwood (Artemisia absinthium) (Absinthe) • Wormwood extract – Main ingredient in toxic liquor • Volatile oil (mixture) – Thujone (α-, & β-) – Common receptor binding as THC • Chronic use – Psychosis, hallucinations, Sz, Intellectual decline – Vincent Van Gogh?

44

Absinthe & Wormwood

45

15 Herbals & Supplements

Nutmeg Myristica fragrans

The brown seed is the Nutmeg The red aril has the (Contains the myristicin) spice, Mace 46

Nutmeg Myristica fragrans • Uses: Oh so many • Effects – Nausea – Skin flushing – Altered speedh – Altered motor functions – Hallucinations

47

Khat (Catha edulis)

A small bag cost ~ $10 US per day and will provide a few hours of effects Sold in small bundles of leaves Leaves / stems are usually chewed; infrequently made into a tea. Khat is bundled in banana leaves to maintain moisture 48

16 Herbals & Supplements

Primary active ingredient The basis for the “Bath Salts” • Dried Leaves – Cathine (norpseudoephedrine). This has 1/10 potency of D-amphetamine. • Fresh leaves – Cathinone (benzylketoamphetamine). Is more potent pscychoactive. • As leaves age, cathinone degrades to cathine • Khat leaves must be used within days to have optimal potency.

49

The Super Herbal…

DRUG

INTERACTIONS 50

St Johns Wort

• With Indinavir a protease inhibitor • Concomitant administration of St. John’s wort and indinavir → big ↓ indinavir plasma concentrations • ? Due to induction of the cytochrome P450 metabolic pathway.

Center fro Drug Evaluation and Research (Feb 10, 2000) http://www.fda.gov/cder/drug/advisory/stjwort.htm 51

17 Herbals & Supplements

Do ya’ know you are getting’?

52

What’s inside that stuff

• Herbal products PC SPES and SPES capsules • Undeclared prescription drug ingredients – PC SPES contains warfarin – SPES contains alprazolam "Prostate health" Surprise!!! “Strengthening the immune system”

Sep 20, 2002 FDA Medalert http://www.fda.gov/medwatch/ safety/2002/safety02.htm#spes 53

What’s inside that stuff • FDA alert about Chinese weight-loss products – Deaths have occurred – Products of this type are often sold in small urban markets as alternatives to Western medicine. – Contained fenfluramine - removed from the market in 1997 after being associated with valvulopathy • "Treasure of the East" – In 2001, FDA - nationwide alert on the recall – Aristolochic acid (Kidney damage)

August 13, 2002 Medalert http://www.fda.gov/bbs/topics/NEWS/2002/NEW00826.html 54

18 Herbals & Supplements

You’re Done…

55

19 Industrial Chemicals

ACMT MEDICAL TOXIOLOGY SUB-BOARD REVIEW COURSE: INDUSTRIAL TOXINS- DUSTS AND GASES Jeffrey Brent, M.D., Ph.D. Toxicology Associates University of Colorado School of Medicine

1

Occupational Exposure levels • OSHA PEL = an 8 hr TWA STEL/Ceil = 15 minute max • ACGIH TLV = TWAs– also 8 hr STEL

2

Pneumoconiosis

• The accumulation of dusts in the lung and reactions, if any, to them • Radiographically evaluated by B- readers using ILO classification • CT more sensitive

3

1 Industrial Chemicals

Which Pneumoconioses Are Fibrogenic? Fibrogenic dusts Non-fibrogenic dusts Silica (crystalline) Tin (stannosis) Mica Barium (baritosis) Graphite Iron (siderosis) Beryllium Coal dust Asbestos Talc Not all patients with pneumoconiosis from the above develop fibrosis

4

What is this?

5

Coal workers’ Pneumoconiosis “Black Lung” • Caused by iron in coal dust Types Simple coal workers pneumoconiosis CWP complicated by fibrosis Silicosis COPD • Pathognomonic lesion is the coal dust macule = coal dust filled macrophages • Smoking not a risk factor • Not an accepted risk factor for lung ca • Exposure limits based on amount of silica exposure

6

2 Industrial Chemicals

What do you see in this slide?

7

Asbestos

• Natural hydrated magnesium silicate fibers • OSHA expresses the asbestos PEL as fibers/mm3 in air • All disease caused only by inhalation exposure • It is not systemically absorbed by any route but inhaled fibers can migrate

8

Types of Asbestos Fibers

2 types 1. Serpentine (“white asbestos”) = chrysotile Fibers tend to be degraded after inhalation Curly fibers 2. Amphiboles (“brown asbestos”) 5 sub-types (most disease assoc. with crocidolite) Fibers resist degradation Tendency to migrate Straight fibers This is the form that causes mesothelioma

9

3 Industrial Chemicals

Asbestos – Related Diseases

• Only clearly established target organ is lung and surrounding tissues • All have long latencies 1. Asbestosis 2. Malignancies A. Bronchogenic carcinoma B. Mesothelioma C. Larynx D. Ovary 3. Non-malignant pleural disease • Does not cause: 10 COPD

Asbestosis

• A fibrogenic pneumoconiosis • ↑ Risk c smoking • Due to persistent inflammation of non- degradable fiber • CXR may be read by B-reader • HRCT is better

11

2 Pulmonary Asbestos-Related Malignancies Established

Bronchogenic Ca • Risk ↑ > 10 X for smokers Mesothelioma • Only non-asbestos cause = eronite (a naturally occurring fiber found in Turkey) • No ↑ risk with smoking

12

4 Industrial Chemicals

Asbestos-Related Pleural Disease • Effusions • Plaques – The most specific sign of asbestos exposure • Pleural thickening • Rounded atelectasis

13

Diagnosis of Asbestos-Related Diseases • Asbestos bodies are only a marker of exposure, not dose or disease • Fiber counts – Obtained PM, or by bx (not BAL) – Correlate with dose, hence risk • CXR Useful but can be of low sensitivity • CT (partic high resolution) 14

ORGANIC TOXIC DUST SYNDROME • Occurs after inhaling dust containing large amounts of mold spores • May be due to spores or substances produced by them • Immunological reaction

15

5 Industrial Chemicals

Man Made Mineral Fibers

• Fiber Glass • Mineral wool • Refractory Ceramic fibers

Documented Health Effects 1. Skin irritation 2. Upper respiratory tract irritation

16

CO

• Sources: – Incomplete combustion – Metabolism of methylene chloride

• 200 – 250 X the affinity of O2 for Hb • Approx. 15% of an inhaled dose is distributed into tissues

• Elimination T1/2s (of COHb) – Room air: 4-5 hrs

– 100% O2: 1-2 hrs

– HBO: 20 – 30 min 17

Methylene Chloride

• CH2Cl2 (aka dichloromethane) • Good dermal and pulmonary absorption • Used for paint-stripping, bath tub refinishing • Metabolized to CO • Peak may be many hrs post-exposure • Ongoing production gives an apparent

T1/2 of approx. 13 hrs 18

6 Industrial Chemicals

Pathophysiology of CO Poisoning • Binds heme groups • Ischemia reperfusion type injury • Ultimately neuronal necrosis or apoptosis • Structures affected: – Basal ganglia – hippocampus – Cortex – Cerebellum

– Substantia nigra 19

CO

NO release from platelets Glutamate Inhibition of Cytochrome Peroxynitrite Oxidase Endothelial Damage NMDA Receptor Agonism

WBC Adherence

Tissue Hypoxia

Proteases Xanthine DH Xanthine Free Ca++ release/lipid Oxidase radials peroxidation

Neuronal Injury

Necrosis/Delayed Apoptosis

20

Diagnosis of CO Poisoning

• Generally from COHb level – CO endogenously formed from catabolism of protoporphyrin to bilirubin – Refrigerated samples stable for weeks – Should be measured c a co-oximeter – Bedside reagent based tests unreliable • Pulse oximeters read COHb as oxyHb • Plasma CO can be measured but interpretation not validated • Back extrapolations unreliable

21

7 Industrial Chemicals

HBO Therapy of CO Poisoning • Indications controversial – Neuro impairment • Cerebellar dysfxn • > 36 yrs old – CV dysfunction – Pregnancy – CO Hb Levels?

• Supplies enough dissolved O2 in the plasma to meet metabolic needs • Inhibits lipid peroxidation • Speed regeneration of cytochrome oxidase • Reduces leukocyte adherence to endothelium • Prevents learning/memory deficits in CO poisoned rodents • Meta-analysis (Buckley et al, Toxicological Reviews, 2006: RR for neuro sequelae 0.77 ( 0.51 – 1.14) 22

CO Poisoning in Pregnancy

• Primates - CO exposure preferentially affects fetus: – Intrauterine hypoxia – Fetal brain injury – Fetal demise • Effects can occur with clinically normal mothers • HBO standard of care? • Indications controversial – hopefully not a board question

23

24

8 Industrial Chemicals

Cyanide

• HCN causes the acute toxicity

• pKa = 9.5 • So, HCN formed if pH < 10-11 Ex. NaCN + HCl → ↑ HCN + NaCl

• This can even happen with H2O such as when cyanide salts are used in fumigation or rodent burrows

25

Cyanide detoxification

• Naturally occurs by combination with sulfane sulfur to form thiocyanate • Rapidly taken up into RBCs • Has high affinity for Fe3+ • Has high affinity for Co2+

26

Glucose glycolysis

Pyruvate

FAD NAD Krebs cycle

FADH NADH

FAD FADH NADH NAD Electron Transport Chain (cytochrome aa3) 27 ATP ADP

9 Industrial Chemicals

Glucose glycolysis

Pyruvate Lactate

FAD NAD Krebs cycle

FADH NADH

CN- FAD FADH NADH NAD Electron Transport Chain (cytochrome aa3) 28 ATP ADP

Cyanide Poisoning

ACUTE • > 10 PPM: toxic effects > 100 PPM: potentially lethal • Metabolic acidosis • Lactic acidosis • Distribution into brain and myocardium • Carotid body stimulation → hyperventilation • Inhibits glutamate decarboxylase → ↓GABA • Persistent neuro deficits possible – One of the basal ganglia toxins Chronic • SCN- competes with iodine for uptake into thyroid → goiter & hypothyroidism

29

Diagnose CN- poisoning by serum (or plasma) levels

• These best correlate with tissue levels • Whole blood levels may be artificially elevated during the analysis

30

10 Industrial Chemicals

Methemoglobin as a cyanide antidote • Effective because: – Affinity of CN- for Fe+3 – Concentration of CN- in RBCs • Sodium nitrite: – Dose: 300 mg (adult) = 10 cc of 3% – Generates MetHg fraction in the teens – MetHb fraction ↑ with anemia or children so ↓ dose – Pediatric dose (nl HCT) 10 mg/kg = 0.33 cc of 3%/kg – May also work as a vasodilator • 4-Dimethylaminophenol – Also a MetHb former – Used primarily in Germany

31

MetHb CN- Cytochrome aa3

32

Sodium Thiosulfate

• Source of sulfane sulfur • Synergistic with nitrites (or hydroxycobalamin) • Adult dose 12.5 grams (50 cc of 25%) • Pediatric dose: – 410 mg/kg (1.65 cc of 25%/kg)

33

11 Industrial Chemicals

The antidotal treatment of cyanide poisoning has completely changed • The old – cyanide treatment kit 1. Amyl nitrite pearls – good for getting high, doesn’t’ do much for cyanide toxicity 2. Sodium nitrite 1. MetHb former 2. Vasodilator 3. Sodium thiosulfate – complexes with CN- • The new – hydroxocobalamin

34

Hydroxocobalamin

What it is – “Vit B12” (cobalamins) = a group of compounds that can be interconverted – Hydroxocobalamin (HC) is one – The most common is cyanocobalamin – The active form is methylcobalamin – HC + CN-→ cyanocobalamin (irreversible)

Methylcobalamin Urine 35

Geraci 2011

Doses of hydroxocobalamin to know • Adults: – 5 g IV over >15 min • Peds: – 70 mg/kg over > 15 min • Adverse effects: – Flushing – Turns skin red – Interferes with colorimetric tests –  BP 36

12 Industrial Chemicals

NITROGEN OXIDES

• NOX = – Nitric oxide (NO)

– Nitrogen dioxide (NO2) – Nitrogen tetroxide (N2O4) • NO2 has low water solubility – Penetrates deep into resp tract – Causes oxidative injury – Excreted after oxidation as nitrate – Chronic low level exposure can cause ↑ airway reactivity and respiratory illnesses • NO has low water solubility – Penetrates deep and is absorbed as NO – Very high affinity for Hb → metHB – Excreted as urinary nitrate

37

Sources of NOX to know

• Major environmental source is the burning of fossil fuels • Contact of nitrogen acids with organic material • Ice skating rinks (from Zambonis) • Welding • Gas stoves • Silos (Silo Filler’s disease)

38

Acute inhalation of NOX may have a multiphasic course 1. Acute pulmonary sxs at time of exposure • CXR may be normal at this time • Initial sxs can be mild • Can see bronchospasm • ? Use minimal oxygen supplementation 2. May have asymptomatic period of hours (up to 12) 3. May then develop ALI (can see methemoglobinemia in this stage) 4. Apparent recovery 5. May develop BO up to a month after exposure • Initially prevents as acute febrile illness • May occur even in absence of stage 3 6. Some patients may develop chronic bronchitis with obstructive or restrictive patterns on PFTs

39

13 Industrial Chemicals

Sulfur Oxides

SO2 is the principal one – Highly irritating – Water soluble → affects upper resp tract and mucus membranes and bronchoconstriction – Massive exposures can cause deep pulmonary injury – Pungent odor

40

What causes the effects of SO2 exposure? Effects may be due to:

1. SO2

2. H2SO4 3. Bisulfite (strong bronchoconstrictor in asthmatics) • Asthmatics and atopics have ↑ susceptibility 4. Hydrogen bisulfite

41

H2S

• Irritant • Rotten egg odor • Combines with Fe+3 • Sources: Decomposition of organic matter Oil wells/petroleum refineries Kraft Paper mills Smelters Tanning processes Natural springs Waste water treatment • Can be released when sulfur containing molecules are acidified

42

14 Industrial Chemicals

H2S Poisoning

• “Gas eye”: Keratoconjunctivitis • Mucus membrane and pulmonary irritant – Impairs ciliary action → pneumonia • Pulmonary edema/ARDS • Respiratory depression at approx 1,000 PPM • CNS depression • AA3 poison • Non-specific enzyme inhibitor • Forms sulfHb, but levels not clinically predictive • Darkens coins • Does not bioaccumulate

43

Treatment of H2S Poisoning

• Supportive care/O2 • Rescuers beware: – Knock down potential at approx. 1,000 PPM – Olfactory fatigue at approx. 100 PPM – Rescuers have been poisoned by mouth- to-mouth resuscitation • ? metHb induction with sodium nitrite – No role for thiosulfate

• HBO - anecdotal 44

RADON

• Naturally occurring • Formed from decay of U238 in rocks & soil • Radon & its daughters emit α particles Radon also emits beta particles • Can concentrate in houses due to negative pressure created by air rising from lower levels

45

15 Industrial Chemicals

U 238

Radium 226

T 1600 yrs. 1/2 α particles

Radon 222

T 3.8 days 1/2 α & β particles

Multiple steps – Radon Daughters α particles

Pb 46

Radon Levels If it is not in green forget it for the test • Measured in picocuries/L or becquerels/M3 • Typical levels are: – Outdoor 0.2 pc/L – Indoor 1.2 pc/L • One “Working level” (WL) = 1.3 X 105 MeV of α energy/L • 1 pc approximates 0.0005 WL • One WLMonth = exposure to 1 WL X 170 hours • Level for home remediation = 2 WLM • ¾ of US homes have levels < 4 pc/L • It is generally recommended that remediation take

place at 11 pc/L 47

Radon- Health Effects

• Lung cancer from breathing in α particles – Based on studies done on uranium miners • Synergistic effect with smoking

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16 Industrial Chemicals

That’s it. Good Luck on the boards!!

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17

Pearls and Last minute things to remember regarding Industrial Chemicals

1. CO has 200 – 250 X the affinity of O2 for hemoglobin

2. Know T1/2s of COHB under conditions of room air, 100% O2, and HBO

3. CN- has high affinity for ferric iron (Fe3+)

4. Cn- is potentially toxic at >10 PPM and potentially lethal at >100 PPM.

5. Cn- concentrations should be determined on plasma or serum, not whole blood.

6. Know doses of sodium nitrite and sodium thiosulfate in the cyanide antidote kit. Also, know the

doses of hydroxocobalamin.

7. Remember that NOxs are relatively non-irritating, of relatively low solubility, and can penetrate

deeply into the lungs. This is in distinct contrast to SO2 which is highly irritating and water

soluble and therefore primarily affects the upper respiratory tract.

3+ 8. H2S has a high affinity for Fe this can treat toxicity by methemoglobin formation with sodium

nitrite from the Cyanide Antidote Kit. It smells like rotten eggs and can cause severe

keratoconjunctivitis “gas eye”. It Inhibits cytochrome oxidase (cyt AA3), as does CO. Major

knockdown potential (more rescuers affected than victims). Darken coins in pockets of victims. Assessment/Population Health/Risk

ACMT Board Review Course Population Health and Assessments

Jeffrey Brent, M.D., Ph.D. Toxicology Associates University of Colorado Health Sciences Center

Topics for this Lecture 1. Exposure monitoring and sampling 2. PPE 3. Study designs and measures of association 4. Statistical concepts 5. Bias and confounding 6. The Hill “criteria” 7. Sensitivity, specificity, predictive values

2

Exposure monitoring and sampling Exposure monitoring  Environmental sampling:  Wipe sampling  Water sampling  Air sampling  Breathing zone measurements are best for inhalational exposures  Biological monitoring e.g.:  Blood Pb

 Urine mercury 3

1 Assessment/Population Health/Risk

Personal protective equipment

 Respiratory  Chemically protective clothing

4

5

Respiratory protection

 Classification by size  Quarter face  Half face  Full face  Classification by function  Air-purifying  Uses chemical specific cartridges  Supplied air

 Scba 6

2 Assessment/Population Health/Risk

Protection Factor  The factor by which exposure is reduced by use of a respirator  Ambient/protection factor = exposure  For example:  Ambient of 100 PPM  Protection factor of 10  Exposure = 100/10 = 10 PPM  Protection factors range form 5 – 10,000  The goal is to get exposure to below safe limits 7

8

Chemically protective clothing  Simple protection  Ex. Aprons, boots, gloves  Nonencpasulating suits  1 or 2 pieces, for example:  1 piece hooded coveralls  Hooded jacket + chem protective pants  Encapsulating suit  Highest level of protection

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3 Assessment/Population Health/Risk

Chemically protective clothing is usually designated by the EPA rating system  Level A = Max protection  Encapsulating suit  SCBA  Level B  Supplied air respirator (or SCBA)  Non-encapsulating garment  Level C  Air purifying respirator  Non-encapsulating garment  Level D = standard work clothes 10

NEXT

STUDY DESIGN AND MEASURES OF ASSOCIATION STATISTICAL CONCEPTS

11

Types of human data

 Anecdotal  Case-reports and series  Controlled observational  Controlled epidemiological studies  Controlled interventional  Trials

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4 Assessment/Population Health/Risk

Controlled observational studies  Cohort  Cross-sectional  Mortality  Case-control  Ecologic For all epi studies:  Groups should be matched for relevant variables (e.g.)  Age  Sex

 Anything else that can affect results 13

Cohort studies  Compares exposed group to an unexposed group  Can be retrospective or prospective  Can assess incidence rates  Incidence = Rate of new cases (e.g. Cases/100,00/yr)  Prevalence = Number of cases in the population (e.g. cases/100,000)  Results expressed as Relative Risk (aka risk

ratio or rate ratio) 14

Cross-sectional studies

 Compares exposed group to an unexposed group at one snapshot in time  Provides prevalence data  Example: Prevalence of drug abuse in medial toxicologists taking the boards in November v those that are not  Results expressed as Relative Risk (aka risk ratio or rate ratio)

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5 Assessment/Population Health/Risk

Mortality Studies  Typically a variation of a cohort study  Assesses diagnoses at time of death  Results expressed as mortality rates corrected for relevant factors (“Standardized mortality rates”)  Usually expressed as a percentage (Mortality rate of exposed/rate in unexposed) X 100 = SMR)  Thus an SMR of 100 = no difference btw exposed and unexposed 16

Case-control studies

 Compares individuals with a specific condition with individuals that do not have that condition and compares exposures (or other risk factors)  For example: Comparing medical toxicologists with drug abuse (the cases) with those w/o this dx (controls) to see if there is a higher likelihood of being alcoholic if preparing to take the boards.  Thus assesses risk factors (e.g. exposures) related to specific conditions  Recall bias major problem  Results expressed as Odds Ratios 17

Ecologic Studies  Assesses population numbers, not individuals  Example: Rate of admission for asthma exacerbations in a city with high airborne

PM10 compared to a city with low PM10  Results expressed as Relative Risk (aka risk ratio or rate ratio)  Ex: Snow’s study of cholera rates in London districts

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6 Assessment/Population Health/Risk

Assessment of results of epi studies  By convention a result is statistically significant if the likelihood that it is chance result is < 5% or approx 2SDs from the mean

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Interpretation of EPI Data  You can never assess the degree of association based only on the magnitude of the RR, OR or SMR  These values have an inherent uncertainty that is determined by the nature of the data  In modern epi this uncertainty is expressed as Confidence Intervals

20

The 95% Convention  In science the uncertainty in a result is expressed as that range of data in which there is a 95% likelihood that the real value exists  CIs express this range  Ex: RR 1.6 (CI 0.7 – 2.4)

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7 Assessment/Population Health/Risk

The importance of confidence intervals

 If RR 1.6 (0.7 – 2.4) Than there is a 95% likelihood that the real value lies between 0.7 – 2.4  If the real RR is:  >1= association  1= Non-association  <1 = negative association (protective effect)  The 95% rule defines “statistical significance”  Thus, in order to be a statistically significant result the CI must not include 1 22

What about “p values”?

 p Values are an older way of describing statistical significance  P < 0.05 means a result is statistically significant  OR 1.6 (0.7 – 2.4) = OR 1.6 p > 0.05  OR 1.6 (1.1 – 2.1) = OR 1.6 p < 0.05

23

Now the Bad News A statistical relationship never a priori means a causal relationship

Does epi data show a statistically significant relationship?

No Yes

Does the statistical No established association association mean a causal relationship? 24

8 Assessment/Population Health/Risk

It is not the falling of the leaves that causes winter to come

There are many more statistical associations in toxicology than there are causal relationships

25

How to get from association to causation

 Requires specific rigorous methodology  Stems from Doll and Hills’ observation of an association between smoking and lung cancer

26

Hill’s Viewpoints  To be applied if a statistical association is shown to exist  Does not account for quality of studies showing such an association 27

9 Assessment/Population Health/Risk

Hill’s “Viewpoints”  Strength of association  Consistency  Specificity  Biological gradient  Temporal precedence  Coherence  Plausibility  Experimental support  Analogy

Also must consider the quality of the study

28

Bias and confounding  Bias = systematic error  Ex: You are doing a study on childhood bl Pb concentrations and behavior. However, your lab technique inflates blood lead values by 20% = a bias.  Confounding = uncontrolled for factor affecting results.  Ex: You are doing a retrospective cohort study on chronic exposures to phosgene in laboratory workers and the incidence of lung cancer but you do not control for smoking.

Smoking is a confounder 29

A LITTLE TIP -KNOW HOW TO CALCULATE SENSITIVITY, SPECIFICITY, AND PREDICTIVE VALUES

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10 Assessment/Population Health/Risk

Sensitivity  The likelihood of a test being positive if the condition is present  Ex: Being under 16 yrs old has 100% sensitivity for the detection of childhood Pb poisoning.  Good for screening (few false negatives (FN))

Sensitivity = True positives (TP)/(TP + FN) Sensitivity is often expressed as a %

In example above if screen 100 individuals and 10 had Pb poisoning: Sens = 10/(10+0) = 10/10 = 1 (or 100%)

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Another example To determine the sensitivity of a terminal R in lead AVR for the detecting of Na+ channel antagonist toxicity in all OD patients.  Screen 1,000 EKGs of OD patients, 100 had OD’d on Na+ channel blockers and 80 had a terminal R wave (TPs). 50 had a terminal R wave but did not OD on these agents.  TP = 80  FN = 20  Sens = TP/(TP + FN) = 80/(80 + 20) = 80/100 = 0.8 (80%) 32

Specificity  The likelihood of the unaffected individuals correctly having a negative test  Test: using criteria of being under 16 for dx of childhood Pb poisoning.  N = 100  10 with Pb poisoning - the other 90 are false positives (FP) Specificity = True neg (TN)/(TN + FP)= 0/0+90 = 0

33

11 Assessment/Population Health/Risk

The second experiment  Screen 1,000 EKGs of OD patients, 100 had OD’d on Na+ channel blockers and 80 had a terminal R wave. 50 others had a terminal R wave but did not OD on these agents (FPs).  TN= 850  FP = 50 Sp = TN/(TN+FP) = 850/(850+50) = 850/900 =0.94 (94%) 34

Comparison btw Sensitivity and specificity

 Both= True/(True + False)  Sens = TP/(TP+FN)  Specificity is the mirror image Spec = TN/(TN+FP)  For both the “trues” in the numerator and denominator terms are the same.  The other denominator term is the

complete opposite 35

Positive predicative value

 PPV = likelihood that the test will correctly Dx the condition  Test: using criteria of being under 16 for dx of childhood Pb poisoning.  N = 100  10 with Pb poisoning (TP) - the other 90 are false positives (FP) PPV = TP/(TP+FP) = 10/(10 + 90) = 0.1 So 10% PPV 36

12 Assessment/Population Health/Risk

PPV – the second experiment

 Screen 1,000 EKGs of OD patients, 100 had OD’d on Na+ channel blockers and 80 had a terminal R wave (TP). 50 others had a terminal R wave but did not OD on these agents (FPs).  TP = 80  FP = 50 PPV = TP/(TP + FP) = 80/(80+50)= 80/130 = 0.6 37

Negative predicative value

 The likelihood that the disease is not present if the test is negative  Test: using criteria of being under 16 for dx of childhood Pb poisoning.  N = 100  0 are TN  0 are FN NPV = TN/(TN+FN) = 0/(0+0) = 1 (100%)

38

NPV – a more rational study  Screen 1,000 EKGs of OD patients, 100 had OD’d on Na+ channel blockers and 80 had a terminal R wave. 50 others had a terminal R wave but did not OD on these agents (FPs). NPV = TN/(TN + FN) TN = 850 FN = 20 NPV = 850/(850+20) = 850/870 = 0.97

39

13 Assessment/Population Health/Risk

Predicative values - summary

 PPV uses only positive terms  PPV = TP/(TP+FP)  NPV uses only negative terms and is exactly opposite of the PPV  NPV = TN/(TN+FN)

40

If, when you are studying, this you have any questions call me (24/7) @ 303-765-3800 or e-mail me at [email protected]

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14

Pearls and Last Minute Study Facts from the POPULATION HEALTH LECTURE

1. To determine the exposure of an individual wearing PPE the correct equation to use is: Ambient concentration of toxicant/Protection factor of PPE = exposure

2. Maximum protection comes from an encapsulating suit + SCBA. This is referred to as EPA Level A protection

3. A cohort study is observational and compares an exposed and unexposed group and determines incidence rates. The results are generally expressed as Relative Risks (aka Risk Ratio or Rate Ratio)

4. A cross-sectional study is observational and compares the prevalence rates at an instant in time. They too most commonly express the results as Relative Risks (aka Risk Ratio or Rate ratio)

5. Mortality studies most commonly express the results as Standardized Mortality Ratios

SMR = mortality rate of exposed/Rate in unexposed X 100

6. Uncertainty in epi studies is best expressed as confidence intervals. If the confidence interval for a result does not include 1 it is statistically significant.

7. If a study shows a significant association between and exposure and an effect, that association should be evaluated by the Hill viewpoints to determine if the association represents a true causal relationship to the effect.

8. Know the Hill viewpoints

9. Know how to calculate sensitivity, specificity, negative and positive predication values. Metals/Metalloids

Metals and Metalloids

Cyrus Rangan MD, FAAP, ACMT Los Angeles County Department of Public Health California Poison Control System Childrens Hospital Los Angeles

1

Treatment of Metal Poisoning Old School Approaches “The treatment of acute [insert metal here]-poisoning consists in the evacuation of the stomach, if necessary, the exhibition of the sulphate of sodium or of magnesium, and the meeting of the indications as they arise. The Epsom and Glauber’s salts act as chemical antidotes, by precipitating the insoluble sulphate of [insert metal here], and also, if in excess, empty the bowel of the compound formed. To allay gastrointestinal irritation, albuminous drinks should be given and opium freely exhibited…”

Wood, HC: Therapeutics Materia Medica and Toxicology, 1879

2

Treatment of Metal Poisoning Old School Approaches “If possible, the rapid administration of 2 oz. (6-7 heaping teaspoonfuls) of Magnesium sulfate (Epsom Salts) or Sodium sulfate (Glauber’s Salt) in plenty of water. Alum (aluminum potassium sulfate) will also be useful in 4 gm (60 gr.) doses (dissolved) repeated. Very dilute Sulfuric acid may be employed (30 cc of a 10 % solution diluted to 1 quart). All soluble sulfates precipitate [metal] as an insoluble sulfate…”

Lucas, GW: The Symptoms and Treatment of Acute Poisoning; 1953

3

1 Metals/Metalloids

Overview of Metals

• Iron • Lead • Arsenic • Mercury • … a whole bunch of other ones

4

What’s a Metal? What’s a Metalloid?

5

Iron Poisoning Introduction • Essential for normal tissue and organ function

• In toxic doses, iron salts (ferrous sulfate, fumarate or gluconate) cause corrosive gastrointestinal effects followed by hypotension, metabolic acidosis, and multisystem failure.

6

2 Metals/Metalloids

Iron Poisoning Historical Data • From 1999-2001 – 10852 cases of iron poisoning were reported to the AAPCC – 60% occurred in children under 6 years – 30% of all pediatric pharmaceutical-related deaths reported to the AAPCC during that time period were a result of iron ingestion • In 1997, the FDA mandated child-proof “strip packaging” & warning labels to be placed on all iron-containing products

7

Iron Poisoning Elemental Iron Content Ferrous Gluconate 11.6% Ferrous Lactate 19% Ferrous Sulfate 20% Ferrous Chloride 28% Ferrous Fumarate 33% Iron dextran 50mg Fe/mL

8

Iron Sources

9

3 Metals/Metalloids

* Daily Value not established. Supplement Facts For 2-3 yrs old For Adults and Children 4 Years of Age and Older 1/2 Tablet 1 Tablet Serving Size: Servings Per Container: % Daily Value for 2-3 yrs old % Daily Value for Adults and Children 4 Years of Age and Older Amount per Serving

Vitamin A 5000 IU 100% 100% Vitamin C 60 mg 75% 100% Vitamin D 400 IU 50% 100% Vitamin E 30 IU 150% 100% Thiamin (B1) 1.5 mg 107% 100% Riboflavin (B2) 1.7 mg 106% 100% Niacin (B3) 20 mg 111% 100% Vitamin B6 2 mg 143% 100% Folate,Folic Acid,Folacin 400 mcg 100% 100% Vitamin B12 6 mcg 100% 100% Biotin 40 mcg 13% 13% Pantothenic acid 10 mg 100% 100% Calcium 100 mg 6% 10% Iron (elemental) 18 mg 90% 100% Phosphorus 100 mg 6% 10% Iodine 150 mcg 107% 100% Magnesium 20 mg 5% 5% Zinc 15 mg 94% 100% Copper 2 mg 100% 100% 10

Iron Other Sources

11

Iron Poisoning Range of Toxicity • Minimum toxic dose: 20-60 mg/kg

• Fatal poisonings rare <60 mg/kg

• A 10-kg toddler can ingest 10 tablets of a 325mg preparation containing ferrous sulfate… Result: ingestion of 65 mg/kg of Fe

12

4 Metals/Metalloids

Iron Poisoning Pathophysiology – GI Effects • Direct corrosive effects on the GI mucosa. – Emesis and stools may or may not be bloody – VS changes from volume losses, as well as vasodilation due to absorbed iron

• Mild metabolic acidosis may ensue, secondary to lactate production from dehydration.

13

Iron Poisoning Pathophysiology – Liver Failure • Portal vein transports iron to the liver

• Iron travels the portal triad and comes into immediate contact with hepatocytes  resulting in hemorrhagic periportal injury and necrosis (direct hepatotoxin)

• This process takes several hours!

14

15

5 Metals/Metalloids

Iron Poisoning Pathophysiology – Metabolic Acidosis

M U D P I – Iron L E S

16

Sidenote: Metabolic Acidosis after Tox Fellowship… BEJRWFGKJLVDNRSVJLNWRJKLGJRW VBLJNJNJNLSRVJNSWBRJNDEVGKJS NDLGJVNWSDLJVNWLEJRNFGWDNV KJUDNFRKUMUDPILESKFKHUJGWOS UHVLKENRILHSLIFGNEIRUSDVWIRH NBVINSWRIGCL…HOLY@#$%ALOTOF THINGSCAUSEMETABOLICACIDOSIS…J GRLUINBDFKGHJEJBDIVKUBELVAJV

17

Iron Poisoning Pathophysiology – Metabolic Acidosis • Excess Fe in the blood is converted from the ferrous (Fe2+) to the ferric (Fe3+) form

• Fe3+ builds up in mitochondria and attracts electrons from the electron transport chain, disrupting oxidative phosphorylation

• Process takes several hours!

18

6 Metals/Metalloids

19

Iron Poisoning Pathophysiology – Metabolic Acidosis • Pool of hydrogen ions (H+) earmarked for the conversion of ADP to ATP is liberated, exacerbating metabolic acidosis

• Multisystem failure: cell death and necrosis from to injury to the GI mucosa, the liver and the lung. Elevated tissue levels of iron also be found in the kidneys and brain

20

Iron Poisoning Clinical Presentation – “The 5 Stages” • Stage I – vomiting, diarrhea, and abdominal pain resulting from the direct effects of iron on the GI mucosa in the first 6 hours of toxicity

• Stage II – “latent” period during which patients can experience an apparent recovery that may last 6-18 hours

21

7 Metals/Metalloids

Iron Poisoning Clinical Presentation – “The 5 Stages” • Stage III – shock from volume losses, decreased tissue perfusion, and metabolic acidosis in 24 h. MS changes, abnormal respirations, seizures

• Stage IV – severe hepatic injury, apparent clinically and biochemically 2-3d after exposure

• Stage V – gastrointestinal strictures and scars that manifest weeks after exposure

22

Iron Poisoning Clinical Presentation – “The 5 Stages” • Patients may go directly from Stage I (GI) to Stage III (shock/acidosis) if they do not receive appropriate therapy – can occur well before the described time frames

• Stage IV (hepatic injury) can be concurrent with Stage III (shock/acidosis)

23

Iron Poisoning Diagnostics • Serum iron level – Initial levels may not accurately predict the severity of toxicity – May rise during treatment if a significant amount of iron remains in the GI tract – Best for following progression • Patients with serum iron levels lower than 300 mcg/dL are rarely symptomatic

24

8 Metals/Metalloids

Iron Poisoning Diagnostics • May see evidence of radio-opaque pills or pill fragments in the GI tract (negative KUB is an unreliable indicator)

• Elixir preparations are not visible on X-Ray

• Chewable tablets appear on 5% of KUB’s

25

Iron Poisoning Diagnostic Pearls • Consider Fe poisoning in any patient with: – GI symptoms – Mental status changes – Unexplained anion-gap metabolic acidosis

• Anemia, bloody emesis/stools may be absent or unreported

• Unreliable: WBC>15.0, glucose>150 to predict Fe>300

• Useless: TIBC

26

Iron Poisoning Treatment - Decontamination • Syrup of Ipecac – NO (vomiting confounds)

• Gastric Lavage – NO (pills usually too big)

• Activated Charcoal – NO (does not bind)

• Whole Bowel Irrigation – possible benefit

27

9 Metals/Metalloids

Iron Poisoning Treatment • Symptomatic and general supportive treatment with close monitoring of vital signs and aggressive IVF, NaHCO3

• Initial labs CBC, lytes, and serum Fe level

• ABG, transaminases, and PT may be useful in patients who continue to be symptomatic

28

Iron Poisoning Treatment • Asymptomatic – observe for at least 4 hours – start workup with onset of any GI symptoms

• Symptomatic – start workup immediately – watch for several hours after fluid resuscitation

29

Iron Poisoning Treatment – Deferoxamine Chelation • DFO + Fe3+  ferrioxamine

• Turns urine red-brown: “vin rose”

• Consider in patients with metabolic acidosis, mental status changes, or shock (base on symptoms, not levels)

• 100 mg DFO chelates only 8.5 mg Fe

30

10 Metals/Metalloids

Iron Poisoning Treatment – Deferoxamine Chelation • Start infusion at 15 mg/kg/h • May need to increase to 30-45 mg/kg/h • Rate limit: histamine-mediated hypotension • Little effect from H1-blocker premedication • Treatment duration until symptoms resolve – Don’t base on color reversion – Don’t use non-validated published time limits

31

Iron Poisoning Extra Credit

What infectious side effect is most commonly documented with deferoxamine infusion?

32

Iron Poisoning Extra Credit

Yersinia septicemia

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11 Metals/Metalloids

Iron Poisoning Take-Home Points! • Must think of diagnosis early – Ask about recent pregnancies and presence of household iron for EVERY PATIENT WITH GI SYMPTOMS! – Always suspect Fe (and get a level!) in any patient with GI symptoms, MS changes, and unexplained metabolic acidosis • Don’t rely on KUB/WBC/Glucose/TIBC • Symptomatic treatment is most important

34

Lead Poisoning Sources • Children – History of pica (FE deficiency often concurrent) – Paint chips, dirt, folk remedies (“Azarcon”), candy, pottery, makeup • Adults – Inadvertent occupational exposure – Pottery, folk remedies (“Litargirio”)

35

Lead Poisoning Clinical Effects • Can affect almost every organ system. – Central and peripheral nervous systems – Cardiovascular – Gastrointestinal – Renal – Endocrine – Hematologic systems • Teratogenicity

36

12 Metals/Metalloids

Lead Poisoning Acute Toxicity • Young children: history of pica • Adults: inadvertent occupational exposure • Reversible renal injury – mild-to-moderate exposure • Acute Lead Encephalopathy: – Most often from rapidly absorbed lead salts – Hepatic injury, hemolysis, anorexia, vomiting, malaise, and seizures due to increased intracranial pressure; chronic exposure effects may also be present

37

Lead Poisoning Chronic Toxicity • Diagnosis much more vague • Children – Weight loss, weakness, abdominal complaints, anemia – Abnormal cognitive development: first signs in children may be subtle neurobehavioral deficits adversely affecting classroom behavior and social interaction; • Adults – Vague gastrointestinal and CNS complaints – Hypertension – Wrist-drop/foot-drop and colic quite rare

38

Lead Poisoning Pathophysiology • Anemia – Heme synthesis – several enzymes inhibited via binding to sulfhydryl groups – Build-up of delta-aminolevulinic acid, coproporphyrin and zinc protoporphyrin – Microcytic, hypochromic; Fe deficiency • Neuronal effects – Inhibition of dendritic arborization, especially in developing brains

39

13 Metals/Metalloids

Lead Poisoning Treatment • Removal from source of exposure

• Whole bowel irrigation for retained metal

• Chelation if indicated (BAL, EDTA, DMSA)… BAL for encephalopathy (well documented). Role for others is still not fully determined.

40

Mercury Poisoning Sources • Elemental: – Thermometers, paints, ceramics, batteries, amalgams – Inhaled Hg vapor • Inorganic: – Industry (photography, explosives, inking, cosmetics) • Organic: – Bactericides/Fungicides – Fish – Farming – Embalming preparations 41

Mercury Poisoning Clinical Effects • Can affect almost every organ system. – Central and peripheral nervous systems – Cardiovascular – Gastrointestinal – Renal – Hematologic systems • Teratogenicity

42

14 Metals/Metalloids

Mercury Poisoning Clinical Effects • Elemental: – Acute pneumonitis, corrosive bronchitis, embolism – May be preceded by stomatitis, colitis, lethergy, confusion, fever/chills, dyspnea, metallic taste

– Chronic Triad: tremor, gingivitis, erethism (insomnia, shyness, memory loss, emotional lability, nervousness, anorexia – Other findings • Corneoscleral junction, lens damage • Peripheral neuropathy

43

Mercury Poisoning Clinical Effects • Inorganic: – Acute corrosion – patient may die within hours – Shock, electrolyte imbalances, protein loss

– Chronic effects similar to elemental mercury • Long-term behavioral impairment • Subclinical psychomotor and neuromuscular changes • Renal effects may resemble chronic renal failure

44

Mercury Poisoning Clinical Effects • Organic: (may take weeks) – Fatigue, ataxia, dyscoordination, tremor, spasticity, weakness (hands, face, legs) – Numbness: mouth, stocking-glove – Deafness, tunnel vision, visual field constriction, scanning speech, dysphagia – poor concentration/memory, emotional lability, depression

45

15 Metals/Metalloids

Mercury Poisoning Pathophysiology • Binding to enzymatic sulfhydryl groups – Enzymes of cellular function – Impaired metabolism of carbohydrates at pyruvic acid level

• Binding to carboxyl, amide, amine, phosphoryl groups

46

Mercury Poisoning Pathophysiology • Elemental mercury – Lung is primary target for mercury vapor • Poor GI absorption • Moderate absorption via alveoli (remains in elemental form

– Some systemic absorption • Oxidized by RBC’s and tissues to Hg2+ • Some elemental Hg passes through blood-brain-barrier • Accumulation in kidney – renal dysfunction RARE

47

Mercury Poisoning Pathophysiology • Inorganic mercury: – 10-15% absorbed from GI tract • Much remains bound to mucosa

– Remains in ionized form post absorption • Very little passes into CNS • High renal accumulation (terminal portion of proximal tubule), leading to ATN (anuria within 24h in 50% of cases) • Some liver/spleen accumulation (mild)

48

16 Metals/Metalloids

Mercury Poisoning Pathophysiology • Organic mercury: – 90% absorption from GI tract – Distribution: liver, kidney, RBC, brain, hair, epidermis – Rapid crossing over blood-brain barrier likely after conjugation to glutathione: depostion in cerebellum, occipital lobe, precentral gyrus; – Binds to typical enzyme moieties • Also inhibits choline acetyltransferase, may lead to some anticholinergic signs and symptoms, muscular weakness

49

Mercury Poisoning Treatment • Removal from source of exposure

• Whole bowel irrigation for retained metal (need to perform early)

• Supportive care for fluid/electrolyte disturbances, renal failure, and pulmonary injury

• Chelation if indicated (BAL, EDTA)

50

Arsenic Poisoning Sources • Food and water contamination – Pesticides (seafood, well water) – Production of arsenicals • Microelectronic manufacturing • Smelting, fossil fuel combustion • Wood preservatives manufacturing • Opium inhalation

51

17 Metals/Metalloids

Arsenic Poisoning Clinical Effects • Can affect almost every organ system. – Central and peripheral nervous systems – Cardiovascular – Gastrointestinal – Renal – Hematologic systems – Skin • Teratogenicity

52

Arsenic Poisoning Acute Toxicity • Inhaled: – Cough, dyspnea, chest pain, resp. failure • Ingestion: – Hemolysis and increased vascular permeability – Dehydration, intense thirst, vomiting, diarrhea, electrolyte imbalance – Burning/dry mucous membranes – Confusion, delirium, encephalopathy, seizures – Ventricular tachydysrhythmias – Delayed peripheral neuropathy

53

Arsenic Poisoning Chronic Toxicity • Hematologic changes – Leukopenia, anemia, pancytopenia – Basal and squamous cell cancer, lung cancer • Eczematous skin lesions, hyperkeratosis, warts, Mee’s lines • Renal failure • Sensorimotor peripheral neuropathy – 1-3 weeks after exposure – Distal-to-proximal progression (days to weeks)

54

18 Metals/Metalloids

Arsenic Poisoning Pathophysiology • Airborne As2O3 – deposited mostly in upper airways (most is ingested); AsH3 (arsine gas) easily inhaled • 90% of ingested doses are absorbed • Dilation of small blood vessels in splanchnic circulation causes vesiculation with or without rupture • Mechanism of tissue injury not well-described • Organic forms not very toxic (fund mostly in seafood)

55

Arsenic Poisoning Treatment • Removal from source of exposure

• Whole bowel irrigation for retained metal (need to perform early)

• Supportive care for fluid/electrolyte disturbances, hypotension, dysrhythmias, renal failure, and pulmonary injury

• Chelation if indicated (BAL, EDTA)

56

Thallium

• Sources: Rat poison (Russia, China), homicidal poison, semiconductors, jewelry manufacturing • Mechanism: likes to go where potassium goes, disrupts Na-K ATP transport enzymes – likely explanation for neuropathy (functional, not structural damage) • Dose: 15 mg/kg. Salt forms more toxic. May absorb through skin.

57

19 Metals/Metalloids

Thallium

• Clinical: GI distress (12-24h), THEN painful neuropathy (24-72h), THEN alopecia (2-4 weeks later) • Lab: urine >20mcg/L • Treatment: Charcoal (MDAC?) & Dialysis for acute exposures, Prussian Blue; BAL may help, but little evidence

58

Cadmium

• Sources: Mining, smelting, electroplating, soldering, batteries, water contamination • Mechanism: corrosive; binds to metallothionein, deposits in kidney • Dose: oral (>5gm); inhaled cadmium is worse-case (>5mg/m3)

59

Cadmium

• Clinical: cough/wheezing, NCPE (inhaled); GI distress, renal failure (ingested); “itai- itai” (chronic) • Lab: whole blood (>1 mcg/mL); minimal urinary excretion • Treatment: supportive; chelators don’t work

60

20 Metals/Metalloids

Chromium

• Sources: Electroplating, chrome yellow paint, • Mechanism: hexavalent form is corrosive and an oxidizer • Dose: inhaled (0.05mg/m3); ingested form mostly turns into trivalent form – rarely toxic unless acute ingestion >500mg

61

Chromium

• Clinical: airway irritation, nose/throat/lung cancer; GI corrosion, renal failure, hemolysis in massive ingestion • Lab: urine >> 1mcg/L • Treatment: supportive; ascorbic acid may accelerate hexavalent  trivalent in GI tract; light evidence for N-Ac in animal models

62

Antimony (Stibine)

• Sources: alloy, rubber manufacturing; flame retardant, • Mechanism: corrosive; poorly understood cellular mechanisms – may bind to sulfhydryl groups; hemolysis from stibine • Dose: antimony 100mg/kg; stibine 0.1ppm

63

21 Metals/Metalloids

Antimony (Stibine)

• Clinical: antimony – GI distress, hepato- renal insufficiency; stibine – hemolysis, jaundice, renal failure • Lab: urine >> 2mcg/L • Treatment: supportive

64

Barium

• Sources: depilatories, fireworks, glass- making • Mechanism: shifts K+ into cells and prevents efflux • Dose: 200mg of non-sulfate salts

65

Barium

• Clinical: hypokalemia with weakness/ flaccid paralysis, dysrhythmias, GI distress; pneumoconiosis from inhalation • Lab: blood >1 mg/L • Treatment: potassium replacement; sodium/ magnesium sulfate to ppt insoluble salt

66

22 Metals/Metalloids

Boron

• Sources: Boric acid – pesticide, fungicide • Mechanism: irritant; cellular mechanisms poorly understood • Dose: >2gm in children; >10gm in adults

67

Boron

• Clinical: GI distress with blue-green emesis and renal failure (immediate); agitation/ seizures (1 day); lobster rash (5 days) with alopecia • Lab: levels obtainable, but correlate poorly • Treatment: supportive

68

Copper

• Sources: pennies, plumbing, pesticides, • Mechanism: irritant; cellular mechanisms poorly understood • Dose: >200mg ingestion; 100mg/m3 inhalation

69

23 Metals/Metalloids

Copper

• Clinical: GI distress with blue-green emesis and renal failure; centrilobular hepatic necrosis; hemolysis • Lab: serum >4mg/L • Treatment: supportive; BAL and d- penicillamine

70

Manganese

• Sources: welding, mining, smelting • Mechanism: unknown • Dose: highly variable – 10,000ppm IDLH

71

Manganese

• Clinical: pneumonitis acutely; atypical psychosis/schizophrenia (“manganese madness”) followed by parkinsonism • Lab: serum or urine >2mcg/L • Treatment: supportive; poor response to chelators and anti-parkinson drugs

72

24 Metals/Metalloids

Selenium

• Sources: “Gun Blue”, copper refining, supplements • Mechanism: poorly understood • Dose: “one swallow” in children (gun-blue) may be fatal; about 5mg/kg is toxic in most cases

73

Selenium

• Clinical: onion/garlic odor; GI corrosion; coma, hypotension, cardiac depression with T-wave inversion, seizures • Lab: whole blood >> 1mg/L • Treatment: supportive; minimal animal evidence for N-Ac; ascorbic acid may turn salts into elemental selenium (poor proof)

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25 Accreditation Statement The University of Alabama School of Medicine is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

The University of Alabama School of Medicine designates this educational activity for a maximum of 22.5 AMA PRA Category 1 credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

The University of Alabama School of Medicine is an equal opportunity/affirmative action institution.

Program Objectives: • Present study content specifically designed for the medical toxicology subspecialty exam offered jointly by ABEM,ABP, and ABPM • Present a comprehensive review of medical toxicology • Allow attendees to gain new insight into current clinical issues

Target Audience: Physicians preparing for the biennial certification and recertification examination in Medical Toxicology, and others with an interest in medical toxicology.

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