Toxicology Flashcards

(42 cards)

1
Q

Toxidrome

A

signs and symptoms that are characteristic of a toxic substance ingestion

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2
Q

Anticholinergic toxidrome

A

“red as a beet, dry as a bone, blind as a bat, mad as a hatter, and hot as a hare”

Combative and delirious
Tachycardic
Dry mucus membranes and dry skin
Pupils dilated, non-reactive
Diminished bowel sounds, distended bladder
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3
Q

Anticholinergic differential diagnosis

A
Antihistamines
Tricyclic antidepressants
Phenothiazines (anti-psychotic)
Belladonna alkaloids (atropine, scopolamine)
Certain mushrooms
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4
Q

What is Clinical Toxicology?

A

Determination of the presence of toxic materials as a reason for illness or symptoms

Ordered by a physician for medical care

  • –Negative screen suggests other cause for signs/symptoms
  • —Positive screen relevant if consistent with signs/symptions
Broad coverage
drugs of abuse
prescription drugs
OTC drugs
household or industrial poisons
plants

Urine (best), blood, gastric, meconium, oral fluid (saliva-forensic, pre-employment)

Rapid result turnaround
Reduced level of proof (accuracy)

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5
Q

Which tests should be rapid (

A

Acetaminophen-Tylenol
Salicylates-Aspirin
Ethanol
Iron (ideally with U[T]IBC or transferrin)
Dig, CBZ, VPA, Phenobarb, Theo, Li, Phenytoin
COHgb and metHgb by CO-Oximeter
Methanol and ethylene glycol (2-4 hr TAT) – —-not common
Urine drugs of abuse (qualitative by immunoassay)
—-Cocaine, opiates, barbiturates
—-Amphetamines, propoxyphene, PCP, tricyclics if prevalent in area

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6
Q

What is Forensic Toxicology?

A

Determination of the presence of toxic materials as they pertain to legal matters

Post-mortem – determination of cause of death
-Blood, urine, tissue – quantitation (blood, tissue) common
Driving – EtOH and possibly others
Drugs of abuse –compliance with legal limits
-Probation
-Pre-employment (esp. Federal)
-Limited menu of drugs in urine, oral fluid, sweat
Onerous requirements and regulations common
-Chain of custody
-Testimony may be required

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7
Q

Acetaminophen

A

Active ingredient in Tylenol® and many other “non-aspirin pain relievers”
—Component of “multi-symptom” cold meds

Overdose can lead to irreversible and fatal hepatic failure

One of few drugs with specific antidote:
N-acetylcysteine (Mucomyst)
100% effective when given w/in 8 hrs of ingestion

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8
Q

How is Acetaminophen metabolized?

A

Usually via glucuronidation, and sulfation sometimes to a quinone

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9
Q

How is Acetaminophen Toxicity assessed?

A
Rumack nomogram
>200 mg/L @ 4 hr
Probable risk
>150 mg/L @ 4 hr
possible risk
T1/2 >4 hrs bad sign
Samples before 4 hrs may not reflect peak & would under-estimate risk
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10
Q

Acetaminophen Measurement?

A
Immunoassay
Enzymatic
Arylacylamidase plus o-cresol condensation (blue)
Positive interference from bilirubin
Therapeutic range: 10-20 mcg/mL

Urine spot screening can detect routine use, not just overdose situations (potential clinical false positive)
—-Not recommended – serum quantitation needed

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11
Q

Salicylates

A

Aspirin – acetylsalicylic acid (ASA)
Was once the leading cause of childhood poisoning
Rapid hydrolysis to salicylate (active metabolite)
Salicylic acid – keratolytic gels
Oil of wintergreen (methyl salicylate)
enhanced toxicity due to inc. CNS penetration
Salicylamide – not hydrolyzed to salicylate

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12
Q

Salicylate Toxicity

A

Uncouples oxidative phosphorylation
metabolic acidosis
hyperthermia

CNS stimulation
hyperventilation
respiratory alkalosis

Tinnitus – ringing ears

Done nomogram more
controversial
Beware units
mg/dL vs mcg/mL (mg/L)

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13
Q

Salicylate measurment?

A
Trinder’s reaction
Most common (cheap and stable rgt)
Fe3+ complexes with salicylate
Req. serum blank due to non-specificity
2-3 mg/dL common
Salicylamide does not react (not hydrolyzed)

Immunoassay

Enzymatic – salicylate mono-oxygenase

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14
Q

Ethanol

A

Most commonly abused drug
10 mg/dL = 0.01% (w/v)
0.08% (80 mg/dL) is legal limit in all states
Legal limit defined in terms of (whole) blood alcohol concentration (BAC), not S/P
May be lethal in naive drinkers at 400 mg/dL

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15
Q

Ethanol Distribution and Metabolism

A

Distributes in total body water
plasma/serum – 93-95% H2O
rbc – 70-75% H2O
whole blood – 85% H2O
S/P EtOH = 1.14 (1.09-1.18) x BAC
Metabolism is zero order (when >20 mg/dL)
15 (11-22) mg/dL/hr in males
18 (11-22) mg/dL/hr in females
rate increases with continued alcohol use
Medical ethanol results may be used in forensic situations, whether you like it or not

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16
Q

Ethanol Measurement

A

Enzymatic – alcohol dehydrogenase

Ethanol + NAD+   ------>  Acetaldehyde + NADH	

Linearity 10 – ~600 mg/dL (variable)
Beware evaporation in open tubes/cups (esp. calibrators or controls that sit)

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17
Q

Iron

A

Corrosive – GI hemorrhagic necrosis
Shock, acidosis  improvement  liver failure
Maximum serum levels at 4-6 hrs post ingestion
500 µg/dL – serious toxicity likely
>1000 µg/dL – may be fatal
Trf sat’n >100% indicates free iron, likely toxicity
Deferoxamine chelation – “vin rosé” urine
affects iron assays – wait 4 hrs
Stat availability required
UIBC/TIBC probably optional but desirable

18
Q

Carbon Monoxide

A
Colorless, odorless, tasteless gas
Density ≈ air (0.97 @20°C)
Formed from:
incomplete combustion
smoking
heme metabolism (↑ in in vivo hemolysis)
Binds reversibly to Hgb:O2 binding site
Hgb:CO affinity ≈ 250x Hgb:O2 affinity
Hgb:CO binding also inc. Hgb:O2 affinity
Decreased delivery to tissues
CO also binds to Mgb and cytochrome a3
CO reference ranges:
rural non-smoker :
19
Q

CO measurement

A
CO-Oximeter
multi-wavelength spectrophotometer
associated w/ blood gas instrument
hemolyzer
very short path length cuvet
matrix coefficient calculation of:
HgbO2, HHgb (deoxy), COHgb, metHgb
Results presented as % of total Hgb
Rarely (usually post-mortem) measured by GC
Decomposition affects spectrophotometric assay
Sample is stable (cf ABG, metHgb)
20
Q

CO treatment

A
Remove from source
Oxygen administration
Dissociation half-life:
5-6 hrs on room air
1.5 hrs on 100% O2
25 minutes @ 2-3 atm O2 (COHgb >25%)
Hyperbaric chamber
21
Q

Methemoglobin

A

Hemoglobin with ferric (Fe3+) iron
Does not bind O2
Oxidative environment always forming metHgb
Countered by two enzyme systems w/in rbc
Increased formation from :
Nitrites (vasodilators, inhalation)–“locker room”, “rush”
Chloroquine, Primaquine – anti-malarials
Dapsone – Pneumocystis Rx
Sulfonamide antibiotics
Lidocaine, benzocaine – local anesthetics
Congenital susceptibilities exist

22
Q

Methemoglobin treatment

A

Treatment - methylene blue

Reduces ferric metHgb to ferrous HHgb

23
Q

Methemoglobin measurement

A

CO-Oximeter
older models had interference from methylene blue
Visual – metHgb is chocolate brown
MetHgb is unstable
Collect and transport on ice (not req’d for COHgb)
Do not freeze
Measure w/in 4-8 hrs

24
Q

Volitiles

A
Methanol
Isopropanol
Acetone
Ethanol
Other solvents 
Acetonitrile – some nail polish removers
Ethyl acetate - some nail polish removers
Ether (diethyl) – automotive starting fluid
Methylene chloride – paint strippe
25
Methanol
``` Source: some antifreeze windshield washer fluid Effects: not a significant CNS depressant formaldehyde and formic acid metabolites anion-gap metabolic acidosis optic neuropathy blindness ```
26
Methanol Treatment?
``` Treatment block ADH formation of formaldehyde Administer ethanol to serum level of 100-150 mg/dL OR 4-methylpyrazole (Fomepizole) Both act as competitive inhibitors of ADH HCO3- - metabolic acidosis as needed folate – traps formate hemodialysis ```
27
Isopropanol
``` Source: rubbing alcohol is 70% isopropanol ~2-2.5x CNS depressant activity as EtOH Metabolized to acetone (T1/2 = 3.6 hr) No EtOH Rx – IPA is more toxic than acetone Supportive therapy Hemodialysis ```
28
Acetone
Source: isopropanol metabolism nail polish remover ketosis (
29
Volatiles measurement.
``` Measure by GLC Use n-propanol as internal standard Direct injection – req. periodic column replacement Headspace – column lasts “forever” sample + int. std. + NaCl in sealed vial heat (45°C) for 10-30 minutes sample the vapor (20-250 µL) and inject Uses low oven temperature (~40°C) Can also measure other solvents with higher oven temperature MeOH by enzymatic assay (non-commercial) ```
30
Ethylene glycol
``` Some CNS depression Complexes calcium (oxalic acid) CaOx xtals mechanically damage nephron Treatment EtOH to 100-150 mg/dL blocks metabolism 4-methyl pyrazole (Fomepizole) as alternative Hemodialysis if >500 mcg/mL (50 mg/dL) Correct acidosis and hypocalcemia Measurement Blood – GLC, not suitable for average lab Enzymatic assay (non-commercial) Urine – UV lamp, fluorescein in most antifreeze ```
31
Chromatography drug sceens
``` TLC – thin layer chromatography GLC – gas-liquid chromatography GC/MS – GLC/mass spectrometry LC-MS (incl. TOF) Require time, capital and experience commitment All require sample preparation steps All require skilled interpretation ```
32
Mass Spectrometer
Specific detector system for GLC or HPLC Compounds exiting chromatograph are excited and ionized by one of several energetic methods Excited compounds break at weaker bonds, yielding characteristic fragment ions as well as neutral fragments Mass filter analyzes charged fragments Increased sensitivity over FID and NPD Increased specificity (structural information)
33
TIC
Total ion chromato. Plot of abundance of all ions detected by mass spectrometer vs retention time (time since injection) Only identifying info is retention time
34
Mass spectrum
Histogram of mass:charge ratio (m/z) vs abundance at a single point in time Molecular ion – m/z representing the unfragmented molecule Not necessarily present Base peak – most abundant ion Spectrum is normalized to base peak = 100
35
SIM | MS: Selected Ion Monitoring (SIM)
Full scan (prev. slide) useful to id unknowns or from large list of potential compounds Comprehensive drug screen If targeting specific compound(s), look for (3) ions “unique” for each compound Ratio two ions to the third Enhanced sensitivity and specificity Confirmation of positive EIA drug screen Specific compound assays
36
Multiple (Selected) Reaction Monitoring
Used to quantitate known compounds: Immunosuppressants Vitamin D (25-OH D2 and D3) Steroids (e.g., testosterone in women and children)
37
Time of Flight (TOF) MS
Higher mass resolution and range Gives exact MW of compounds (nnn.nnnn) MALDI-TOF (matrix-assisted laser desorption-ionization) - useful for bacterial id
38
Toxic Metal: LEAD
Lead – no known biological function | Paint – pre-1972, up to 35%. Post
39
Lead Toxicity
``` Inhibits PBG synthase → ↑ DALA in urine Blocks Fe2+ incorp. into heme → ↑ ZPP ZPP = zinc protoporphyrin Ferrochelatase Binds to many protein sulfhydryls Deposited in bone Permanent effect on developing mental fxn ```
40
Lead Testing
``` CDC, Oct. 1991: test all children below the age of 6 yrs action limit of 10 mcg/dL (now 5 mcg/dL) CA DPH – CHDP testing req. approved lab OSHA – occupational testing req. approval Measure in whole blood only ```
41
Metals Measurement
Reinsch – urine As, Hg, Sb, Bi; but NOT Pb Obsolete Atomic absorption Graphite furnace – higher sensitivity for Al, As, Pb Cold vapor – mercury as the hydride (AA or atomic fluorescence) Single element per assay ICP-MS – inductively-coupled plasma mass spectroscopy High sensitivity and universal detector Multiple elements per assay Expensive instrument LeadCare – lead only POC disposable sensor.
42
Drugs of Abuse
``` Amphetamines Barbiturates Benzodiazepines Cannabinoids (THC, marijuana) Cocaine LSD Methadone Opiates PCP (Phencyclidine) Tricyclic antidepressants (TCAs) Measure by homogeneous immunoassay ```