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Toxicology Flashcards

1
Q

drug steady state

A
  • amount of drug leaving body = amount of drug entering body
  • reached after 5 halflives (i.e., after 5 doses given at intervals of 1 halflife)
  • in steady state drug concentration is lowest right before a dose (trough) and highest shortly after (peak)
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2
Q

Free versus bound drug

A
  • free drug is therapeutically active component
  • small molecules compete for binding spots and a 2nd drug may displace the first leading to inceased free drug concentrations
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3
Q

Volume of distribution

A
  • drug size and solubility influence how widely the drug is distributed
  • Hydrophilic drugs remain confined within vascular space
  • Others distribute into extravascular and intravascular spaces (aqueous)
  • Hydrophobic drugs go into adipose
  • Volume of distribution (Vd) defined as theoretical volume in which drug is distributed
    • Hydrophilic drugs have low Vd, while hydrophobic drugs have high Vd
    • Vd expressed in L/kg
    • D is the administered IV dose and C is the plasma concentration:
      • Vd = (D/C) / (body weight in kg)
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4
Q

Drugs of abuse screening (forensic toxicology)

  • places of testing
  • specimen type
  • assay type
  • specificity
  • additional testing
  • adulterant characteristics
A
  • refers to testing in workplace, in a drug treatment program, or in legal settings
  • urine is usual specimen
  • screening drug tests are usually based on immunoassay
  • specificty is low
  • crossreacting substances cause false positives
  • positive tests often require confirmation (gas chromatography/mass spectrometry)
  • witnessed collection required to ensure that urine sample has not been altered
  • specimen divided into 2 aliquots so that retesting can be performed if positive result is obtained
  • check for adulterants:
    • color
    • odor
    • temperature (suspicious if cool)
    • pH (suspicious if <4.5 or >8)
    • specific gravity (suspicious if < 1.005)
    • creatinine (suscpicious if < 20 mg/dl)
    • nitrite (suspicious if > 500 ug/mL)
  • chain of custody precautions needed for a test that may have implications in criminal case
  • duration that agent may be detected depends on range of variables including
    • dose
    • methodology
    • sample type
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5
Q

Window of detection

A
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6
Q

Ethanol

  • metabolism
  • specimen
  • legal limits
  • markers of alcohol consumption
A
  • metabolized by hepatic alcohol dehydrogenase to acetaldehyde, which is converted by acetaldehyde dehydrogenase to acetic acid
  • specimen
    • overdose evaluation, usually serum or plasma is measured
    • in forensic testing whole blood or breath alcohol measured (ratio of blood: breath alcohol is 2100:1)
  • Legal limit for operation of a car: 80-100 mg/dL (0.08%-0.1%) in whole blood
  • whole blood ethanol tends to run lower than serum or plasma ethanol concentration
  • legal definitions usually in terms of whole blood
  • Markers of alcohol consumption
    • gamma glutamyl transferase (GGT) is increased in heavy consumers; 4 weeks of abstinence required for normalization of GGT
    • carbohydrate deficient transferrin (CDT) is at least as sensitive and more specific than GGT
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7
Q

Clinical effects of blood alcohol

A
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8
Q
A
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9
Q

These signs and symptoms are associated with what toxic agents?

A
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10
Q

The National Academy of Clinical Biochemistry (NACB) guidelines advises ____

A

Tier 1 testing for all labs that support an ED

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11
Q

Laboratory evaluation of apparently intoxicated patient

A
  • Urine toxicology screening
  • serum/plasma toxicology tests
  • assessment of anion gap, osmolar gap, and oxygen gap
  • abnormally high venous oxygen content (arterialization of venous blood) is seen in cyanide and hydrogen sulfide poisoning
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12
Q

Significance of anion gap in tox screening

A
  • anion gap > 20 mEq/L is significant (note: hypoalbuminemia may falsely lower the gap)
  • toxins that cause anion gap metabolic acidoses include (SAFE CHEAPEN)
    • acetaminophen
    • salicylates
    • ascorbate
    • hydrogen sulfide
    • ethylene glycol
    • methanol
    • ethanol
    • formaldehyde
    • carbon monoxide
    • nitroprusside
    • epinephrine
    • paraldehyde
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13
Q

signficance of osmolal gap in toxicology and calculation

A
  • osmolal gap > 10 mOsm is significant
  • osmolal gap is the difference between the calculated osmolarity by the following formula:
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14
Q

significance of oxygen saturation gap in toxicology

A
  • O2 sat gap is the difference between saturation given by cooximetry and the saturation given by the pulse oximeter
  • normally the difference is < 5%
  • causes of increased gap:
    • CO poisoning
    • methemoglobin
    • hydrogen sulfide poisoning (sulfmethemoglobin)
    • cyanide poisoning
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15
Q

Toxic alcohol poisoning

  • substances
  • gaps they cause
  • metabolism
  • treatment
A
  • Substances
    • ethylene glycol (antifreeze)
    • methanol (windshield washer fluid, paint removers, wood alcohol)
    • isopropyl alcohol (rubbing alcohol)
  • Ingestion suspected if osmolal gap > 10
  • Gaps caused by these agents
    • ethanol is often present in conjunction with toxic alcohol ingestion and can itself widen the osmolal gap
    • ethylene glycol and methanol cause
      • increased anion gap
      • increased osmolal gap
    • isopropyl alcohol does not cause acidosis, like ethanol, but does cause osmolal gap
  • Metabolism of these agents
    • ethylene glycol is metabolized to oxalate; oxalate crystals can be found in urine where they appear envelope shaped, translucent, and birefringent
    • methanol is metabolized to formaldehyde and then to formic acid
    • isopropyl alcohol is metabolized to acetone
  • treatment of methanol or ethylene glycol poisoning c/o inhibiting activity of alcohol dehydrogenase since the metabolites are toxic
    • used to give ethanol to do this
    • now give fomepizole
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16
Q

Calculated osmolality in presence of ethanol with toxic alcohol ingestion

18
Q

Lead poisoning

  • sources
  • how does it enter body
  • toxicity derives from
A
  • Sources
    • lead paint
    • lead pipes
    • lead gasoline
    • contaminated soil
    • manufacture of lead batteries
    • lead smelters
  • Enters body through inhalation and ingestion; distributed into RBCs, bone, kidney
  • Toxicity:
    • nonspecifically binds to and inhibits enzymes having sulfydryl groups; inhibits:
      • heme synthesis
      • delta-ALA-dehydratase and ferrochelatase
        • leads to accumulation of protoporphyrin (free erythrocyte protoporphyrin, FEP) which binds to zinc (FEP and zinc-protoporphyrin increased in lead toxicity and iron deficiency)
      • sodium channel ATPases leading to increased osmotic fragility and shortened red cell survival
      • directly toxic to mitochondria
  • basophilic stippling results from inhibition of 5’ nucleotidase, an enzyme that breaks down RNA
19
Q

Effect of coexistent iron deficiency on toxic effects of lead

A

enhanced toxicity

20
Q

Manifestations of lead toxicity

A
  • microcytic hypochromic anemia with basophilic stippling
  • neurologic impairment: central and peripheral (bilateral wrist drop)
  • renal insufficiency
    • especially aminoaciduria, glycosuria, and phosphaturia (similar to Fanconi anemia)
  • Abdominal pain
21
Q

Laboratory testing for lead poisoning

A
  • nonspecific
    • Hb
    • Hct
    • FEP
    • ZPP (zinc protoporphyrin)
    • urinalysis (proteinuria and glycosuria)
    • iron studies
  • Specific
    • venous blood lead level by atomic absorption spectrophotometry; > 10 ug/dL is elevated
22
Q

Carbon monoxide poisoning

  • sources
  • lab testing
  • treatment
  • clinical effects
A
  • Sources:
    • incomplete combustion of fossil fuels
    • produced endogenously from breakdown of heme resulting in normal Hb-CO <= 1%
  • CO bind with great affinity to Hb forming Hb-CO; has even greater avidity for fetal Hb
  • CO directly toxic to intracellular oxidative mechanisms
  • Lab testing
    • Nonspecific:
      • lactate
      • anion gap
      • cardiac markers
      • cyanide levels
    • Specific:
      • cooximetry with levels correlating with clinical effect
      • pulse oximetry may give falsely reassuring O2 sat
  • Treatment: 100% O2
23
Q

Acetaminophen poisoning

  • clinical manifestations
  • Prognosis determined by
  • toxic dose
  • metabolism
  • Treatment
A
  • manifestations are polyphasic
    • Phase I: mild nausea and abdominal discomfort; abates within hours
    • Phase II: usually after 24 hours, progressive liver injury
    • Phase III: fulminant hepatic failure
    • Phase IV: resolution in the form of recovery, liver transplant, or death
  • Rumack-Matthew nomogram
    • majority of poisonings do not result in significant hepatic necrosis
    • Rumack-Matthew nomogram may be used to predict risk
    • approximate time of ingestion must be known; initial blood sample is drawn >= 4 hours following ingestion
    • stratifies patients into probable hepatic toxicity, possible hepatic toxicity, and no hepatic toxicity
  • potentially toxic dose is > 150 mg/kg in healthy people
  • Most acetaminophen is conjugated with glucuronide or sulfate to form nontoxic metabolites; some is metabolized by p450 system into toxic N-acetyl-P-benzoquinone imine (NAPQI) which induces centrilobular necrosis
  • Treatment: N-acetylcysteine (Mucomyst)
24
Q

Cyanide poisoning

  • sources
  • inhibits
  • skin appearance
  • odor
  • tests
  • treatment
A
  • Sources
    • inhalation of smoke from fire (burning insulation)
    • exposure to pesticides and other industrial materials
    • accidental or intentional ingestion
  • Inhibits cytochrome a3 thus uncoupling the electron transport chain resulting in diminished oxygen dependent metabolism and severe anion gap metabolic (lactic) acidosis
  • oxygen accumulates in the blood giving rise to the bright cherry red skin color
  • HCN gas imparts a bitter almond odor (only ~50% of people can smell it)
  • Lab testing
    • nonspecific tests:
      • lactate (normal lactate excludes diagnosis)
      • blood gases
      • anion gap
      • elevated glucose
      • decreased arterial venous oxygen gap
    • specific tests:
      • not usually available
      • cyanide is rapidly metabolized to thiocyanate, which is a better analyte if testing is available
  • Treatment:
    • sodium nitrite and amyl nitrite (formation of methemoglobin, which binds available cyanide)
    • sodium thiosulfate (enhances conversion of cyanide to thiocyanate)
25
Q

Salicylate poisoning

  • effects on acid base balance
  • mortality correlates wtih
A
  • Effects on acid base balance
    • directly stimulates respiratory center within medulla leading to respiratory alkalosis (3-8 hours post ingestion)
    • physiologic compensation with metabolic acidosis
    • uncouples oxidative phosphorylation and inhibits the Krebs cycle leading to anaerobic metabolism with development of a metabolic acidosis
    • CNS depression may result in respiratory acidosis
  • Mortality is best correlated with 6 hour plasma salicylate concentration with values >130 mg/dL having a high fatality rate
26
Q

Arsenic poisoning

  • sources
  • excretion
  • inhibits __
  • clinical manifestations
  • samples used for diagnosis of chronic disease
A
  • Sources
    • intentional
    • pesticides
    • wood preservatives
    • leather tanning
    • contaminated water
    • arsine gas
  • Excreted in urine with some distribution into skin, nails, hair
  • Inhibits oxidative production of ATP
  • Clinical:
    • manifested in dividing tissue such as GI mucosa with N/V/bloody diarrhea, and abdominal pain
    • marrow is affected - cytopenias with RBC basophilic stipling like lead poisoning
    • chronic toxicity:
      • peripheral neuropathy
      • nephropathy
      • skin hyperpigmentation
      • hyperkeratosis (palms and soles)
      • transverse Mees lines in the nails
  • Samples for diagnosis of chronic disease:
    • fingernails
    • hair
    • urine (most reliable test is 24 hour urine)
    • blood arsenic level is highly unreliable
27
Q

TCAs

A
  • anticholinergic effects (dry mouth, constipation, urinary retention, pupillary dilation, hyperthermia, confusion)
  • QRS prolonged
  • ventricular arrhythmias
28
Q

organophosphate and carbamate poisoning

A
  • Source: insecticide
  • Inhibit acetylcholinesterase leading to cholinergic effects (miosis, diaphoresis, excess salivation, lacrimation, GI hypermotility, bradycardia, and bronchospasm)
  • Lab test: increase RBC or plasma cholinesterase activity
29
Q

Mercury poisoning

  • source
  • clinical manifestations
  • lab tests
A
  • Source: occupational (“mad hatter’s disease”), mainly from inhalation of vapor
  • Acute toxicity manifests as respiratory distress and renal failure
  • Chronic toxicity takes the form of acrodynea or erethism
    • Acrodynea (Feer syndrome): autonomic manifestations (sweating, hemodynamic instability) and desquamative erythematous rash on palms and soles
    • Erethism: personality changes, irritability, fine motor disturbances
  • Lab testing: 24 hour urine collection for elemental mercury; whole blood or hair analysis for organic
30
Q

Digoxin drug monitoring

  • indicated for
  • when should sample be drawn
  • factors that increase digoxin toxicity
  • endogenous substances that cross react with digoxin
A
  • Monitoring indicated for:
    • dose adjustments
    • changes in renal function
    • change in concomitantly administered medications
  • halflife ~36 hours; samples should be drawn 8-12 hours after last dose
  • factors that increase digoxin toxicity
    1. hypoK
    2. hyperCa
    3. hypoMg
    4. hypoxia
    5. hypothyroidism
    6. quinidine
    7. calcium channel blockers
  • Endogenous substances that cross react with digoxin (termed digoxin like immunoreactive substances, DLIS)
    • found in blood of some people not taking digoxin:
      • neonates
      • pregnant women
      • liver failure
      • renal failure
31
Q

Procainamide monitoring

A
  • Cleared predominantly by the liver
  • metabolized to N-acetylprocainamide (NAPA), which is pharmacologically active and renally cleared
  • rate of conversion to NAPA depends upon concentration of hepatic acetyltransferase, which is genetically determined
  • rate of clearance of NAPA depends upon renal function
32
Q

aminoglycoside monitoring

  • cleared by ___
  • toxic to which organs
  • efficacy versus toxicity
A
  • Cleared by kidneys
  • monitoring advisable to ensure efficacy and to prevent toxicity
  • nephrotoxicity and ototoxicity
  • peaks are considered most useful for assessing efficacy, while troughs reflect likelihood of toxicity
33
Q

vancomycin monitoring

A

only troughs are measured

34
Q

Lithium monitoring

A
  • margin between therapeutic effect and toxicity is narrow (0.4-1.2 mmol/L)
  • adverse effects high when >1.5
  • Monitor patients who are stable on therapy
    • q1-3 months
    • sample should be measured 12 hours following last dose
  • halflife varies from 8-40 hours, depending on age and renal function
  • following intitiation of lithium or a change in dose steady state conditions would be expected in 2-8 days
  • checking levels after 3 days to 1 week is a good idea

Compendium Chemistry (13 decks)

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