Lec 14 & 15 (Toxicology & Poisoning) Flashcards Preview

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Flashcards in Lec 14 & 15 (Toxicology & Poisoning) Deck (52):
1

Therapuetic Index Equation

LD50/ED50
higher = safer

2

Standardized Safety Margin Equation

100x(LD1-ED99/ED99)
How close are LD1 and ED99?
more (+) = safer
more (-) = more toxic

3

Acute Toxicity

effects after a single, short term exposure, typically within 24 hours

4

Chronic Toxicity

-delayed poisonous effect from exposure
-measure in experimental conditions after 3 months of continuous or occasional exposure
(i.e. pesticides over time)

5

FDA (4)

Food & Drug Administration
-drugs
-food additives
-cosmetics
-medical devices

6

EPA (4)

Environmental Protection Agency
-pesticides
-industrial chemicals
-hazardous waste
-pollutants (in air, water, soil)

7

OSHA (1)

Occupational Health and Safety Administration
-chemicals in the workplace

8

TLV

Threshold Limit Value
-estimates of max exposure levels during work hours on a long term basis
-levels that won’t cause effects
-guideline for use

9

PEL

Permissible Exposure Value
-OSHA regulation
-protect workers during normal work duration

10

RFD

Reference Dose
-EPA regulation
-max oral dose for no human effect over lifetime
-based on animal studies of NOEL (no observable effect level)

11

Extrapolation Challenge

-extrapolate from animals to humans
-LOEL: lowest observed effect dose

12

Difficulties in Carcinogenic Risk Assessment in Humans (4)

-uncertainty of extrapolation of dose-response data from studies in animals to low doses
-species differences in carcinogenicity of chemicals
-lack of in-vivo with humans, monkeys
-expense of conducting lifetime exposure studies in rate (but the best way to study carcinogenic risk)
-uncertainty about role of minor metabolites in causing cancer

13

Protein Interaction (mechanism of toxicity)

binding to receptors or enzymes
(i.e. AChE inhibitor or irreversible agonist)

14

DNA (mechanism of toxicity)

interaction or binding

15

Oxidative Stress (mechanism of toxicity)

-leads to GSH (glutathione) depletion (prevents cell damage)
-formation of O2 radicals & lipid peroxidation

16

Increased Intracellular Ca2+ (mechanism of toxicity)

can over-activate pathways that lead to membrane and nuclear damage, decrease levels of ATP

17

Genotoxic vs. Epigenetic (mechanism of toxicity)

-paths to cell transformation
-Genotoxic: chemical agents that alter DNA causing activation of a proto-oncogene and/or inhibition of a tumor suppressor gene
-Epigenetic (non-genotoxic): increased DNA replication & clonal expansion of transformed cell, decreased cell death

18

Apoptosis (mechanism of toxicity)

-programmed cell death, signal transduction pathway
-apoptotic bodies are phagocytosed, no inflammation, intact cell membrane
-cell shrinkage and convolution
-pyknosis
-karyorrhexis

19

Necrosis (mechanism of toxicity)

-path to cell death that leads to swelling, membrane lysis and inflammation
-cytoplasm is released
-karyolysis
-pyknosis
-karyorrhesis

19

Karyorrhexis

nuclear fragmentation (following pyknosis)

20

Karyolysis

cell membrane disruption

22

Pyknosis

chromatin condensation

22

Ames Test

-His- salmonella strain requires His in media in in order to replicate
-if plated on media without His, colony growth only in bacteria that revert to WT His+ strain
-asses ability of a compound/chemical to cause mutations

23

Acetaminophen Toxicity
(agents to increase elimination of toxic metabolite)

-CYP450 enzyme converts acetaminophen to a toxic metabolite that can lead to hepatic necrosis
-typically, glutathione binds (via a transferase), converting the toxic metabolite to non-toxic
-with overdose, have build up of toxic metabolite with depletion of glutathione

-treat with N-acetylcysteine (NAC)
-acts to increase glutathione levels, which can bind to toxic metabolite
(critical window)

24

Organochlorides (DDT) Toxicity
(insecticide/pesticide)

-Na+ channel activation, hypopolarize
-environmental persistence, toxic to avian and aquatic species
-long half-life in humans

25

AChE Inhibitor Toxicity
(agents that restore function of an inactivated enzyme)

-inhibitor leads to no AChE action, high levels of ACh and over-activation of nicotinic (CNS effects) and muscarinic (SLUD effects) receptors

-atropine: acts as a muscarinic antagonist, blocking ACh binding

-pralidoxime: reactivates AChE by binding at a different site on the enzyme, kicking off the inhibitor
(poisoning with organophosphate AChE inhibitors)

26

Organophosphate (AChE inhibitor) Toxicity
(insecticide/pesticide)

-nicotinic + muscarinic effects, delayed nueropathy
-potentiate ACh synaptic transcription
-need muscarinic antagonist to increase AChE levels, decrease ACh levels
-muscarinic toxicity: lacrimation, sweating, salvation, muscle twitch

27

Herbicide Toxicity (Roundup)

-glyphosphate (active ingredient)
-inhibits enzyme required for synthesis of amino acids that are required for growth
-weed resistance increases use
-may be human carcinogen

28

Herbicide Toxicity (Agent Orange)

-Dioxin TCDD (primary contaminant), environmentally persistent
-increases gene transcription with cystolic aryl hydrocarbon receptor (CYP1A1)
-carcinogenic in some animal species, though marked variation of LD50
-chloracne (dermatologic abnormality) in humans

29

Benzene Toxicity (aromatic hydrocarbon)

leads to leukemia
-oxidation by CYP450's and epoxide hydrolase to toxic metabolites

30

Benzopyrene Toxicity (aromatic hydrocarbon)

leads to lung cancer
-oxidation by CYP450's and epoxide hydrolase to toxic metabolites
-activation of proto-oncogenes with polycyclic aromatic hydrocarbons in cigarette smoke

31

Lead Toxicity

long half-life, neurotoxic effects
(affects IQ, hearing, neuropathy, GI, anemia, encephalopathy, death)
most damaging in children

32

Warfarin

-warfarin is an anticoagulant, depletes clotting factors by inhibiting vitamin K epoxide reductase (VKER)
-vitamin K is a cofactor for hepatic synthesis of clotting factors

-in overdose (or vit k deficiency), treatment with vitamin K directly bypasses need for VKER
-delayed onset, but complete in 24 hours

33

Mercury Toxicity

pre and/or post-natal exposure increases risk of neurotoxic effects
(neuropsych, tremors, ataxia, deafness, CNS)

34

Flumazenil

binds to GABA-A receptor
used for benzodiazepine overdose

35

Carbon Monoxide Poisoning

use 100% O2, unless severe - use hyperbaric chamber

36

Chelating Agents (bind metals in blood or tissue)

-work to redistribute metals out of the tissue and into blood, increasing clearance
-metal intoxication

37

Naloxone

binds to Mu receptor, kicking off opioid (inhibitor)
used for opioid overdose

opioids: CNS depressant
naloxone: CNS stimulant

39

Atropine

binds to muscarinic receptor
used for muscarinic agonist poisoning

40

Methanol Toxicity
(agents to slow formation of toxic metabolites)

pyrazoles to inhibit alcohol dehydrogenase, which converts methanol (or ethylene glycol) to toxic metabolites
-agents inhibit enzymatic conversion + slow formation of toxic metabolite
-fomepizole (for methanol) inhibits alcohol dehydrogenase conversion to formaldehyde/formic acid (toxic)

42

Cyanide Toxicity

1. hydroxocobalamin (Vit B12) binds CN in blood
2. amyl nitrite inhalation and sodium nitrate via IV
-oxidize Fe2+ to Fe3+ in hemoglobin (methemoglobin)
-decreases O2 carrying capacity, but allows CN to bind, redistributing out of mitochondria (where it interferes with aerobic respiration, leading to lactic acidemia)
3. sodium thiosulfate via IV to form thiocyanate (SCN)
-increases clearance
-catalyzed by a mitochondrial enzyme

43

TESS of the AAPCC

toxic exposure surveillance system
American association of poison control centers
-frequency of various types of exposure
-relative frequency of call location type
-case reports on fatal drugs
-frequency of use of various types of antidotal management of poisons to PCCs

44

Source of Exposure

93% of exposures at site of residence
primary source of calls regarding pediatrics

45

Means of Increased Renal Clearance

-diuretics
-alteration of renal pH (acidify for base, alkalize for acid)
-agents that bind poison in blood or tissue (chelators, metal)
-agents that bind (trap) poison in blood (cyanide)
-dialysis (non renal, artificially clean blood)

46

Source of Treatment

67% treated at site of exposure
23% at a health care facility

47

Age

children <6 ~50% of total calls
adults 35%, older adults
-cases are most clinically serious in adolescents

48

Source of Poison

56% of calls involve drugs and medications
44% involve non-pharmaceuticals (i.e. household and personal products, plants, bites/stings, CO, pesticides)

49

Substance Number + Related Fatalities

-majority of calls involve only one substance
-increased risk with more than one substance, 12% of all calls
-of the 12% with > 1 substance, account for 58% of fatalities

49

Class of Poison
(overall + by age group)

all groups: analgesics (opioids)
-children < 6: (14%) cosmetics, personal care products (11%) household cleaning products
-teens 13-19: (20%) analgesics (10%) antidepressants
-adults > 19: (20%) analgesics

49

Route of Poison + Related Fatality

79% ingestion (oral)
-accounts for 73% of fatalities

50

Reason (intention)

78% unintentional
18% intentional
(overall intentional poisoning accounts for ~50% of adult fatalities)

51

Gender

-exposures < 12 years, mostly males
-larger number of female fatalities in teens and adults
-more females of those with repeated exposures