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Clinical Chemistry > Toxicology > Flashcards

Toxicology Flashcards

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
Q

Methanol

A 
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
Q

Methanol Treatment?

A 
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
Q

Isopropanol

A 
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
Q

Acetone

A

Source:
isopropanol metabolism
nail polish remover
ketosis (

29
Q

Volatiles measurement.

A 
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
Q

Ethylene glycol

A 
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
Q

Chromatography drug sceens

A 
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
Q

Mass Spectrometer

A

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
Q

TIC

A

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
Q

Mass spectrum

A

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
Q

SIM

MS: Selected Ion Monitoring (SIM)

A

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
Q

Multiple (Selected) Reaction Monitoring

A

Used to quantitate known compounds:
Immunosuppressants
Vitamin D (25-OH D2 and D3)
Steroids (e.g., testosterone in women and children)

37
Q

Time of Flight (TOF) MS

A

Higher mass resolution and range
Gives exact MW of compounds (nnn.nnnn)
MALDI-TOF (matrix-assisted laser desorption-ionization) - useful for bacterial id

38
Q

Toxic Metal: LEAD

A

Lead – no known biological function

Paint – pre-1972, up to 35%. Post

39
Q

Lead Toxicity

A 
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
Q

Lead Testing

A 
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
Q

Metals Measurement

A

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
Q

Drugs of Abuse

A 
Amphetamines
Barbiturates
Benzodiazepines
Cannabinoids (THC, marijuana)
Cocaine
LSD
Methadone
Opiates
PCP (Phencyclidine)
Tricyclic antidepressants (TCAs)
Measure by homogeneous immunoassay

Clinical Chemistry (9 decks)

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