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Pharm Exam 1 > Lash - Toxicology II > Flashcards

Lash - Toxicology II Flashcards

1
Q

What is arsenic?

A

Common contaminant of coal and many metal ores

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2
Q

Chemical forms of arsenic of toxicologic importance:

A
  • elemental arsenic
  • inorganic arsenic
  • organic arsenicals (once commonly used as chemotherapeutic agents)
  • arsine gas (AsH3).
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3
Q

What is the current medical use of arsenic?

A

Current medical uses of arsenicals:
• treatment of certain tropical diseases
• FDA approved combination use of arsenic trioxide (ATO) and all-trans retinoic acid in
treatment of certain leukemias unresponsive to first-line agents
• Most common non-medical uses: herbicides, insecticides, fungicides, algicides, and wood
preservatives

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4
Q

What form causes the major toxicologic effects of arsenic? How does it work?

A
  • Major toxic effects of inorganic As due to trivalent arsenic (As3+)
  • As3+ acts as a sulfhydryl reagent, inhibiting SH-sensitive enzymes
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5
Q

What does the pentavalent form of As do?

A

Pentavalent arsenic (As5+): well-known uncoupler of mitochondrial oxidative phosphorylation; competes with inorganic phosphate in the formation of ATP

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6
Q

How does As3+ interact with PDH?

A 
Pyruvate dehydrogenase (PDH) system very sensitive; the 2 SH-groups of lipoic acid
readily react with As3+ to form a stable, 6-membered ring.
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7
Q

Treatment of As poisoning:

A

Chelation therapy with dimercaprol; may then follow with penicillamine

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8
Q

Environmental prevalence of cadmium:

HL:

A

Cadmium is an environmental poison that is very prone to accumulation
o Less than 5% is recycled, so environmental pollution is a problem
o Sources include Ni-Cd batteries and cigarette smoke

The t1/2 of cadmium in the body is 10 to 30 years.

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9
Q

Treatment for cadmium poisoning:

What is contraindicated? What happens?

A

Treatment: no effective treatment has been developed yet

Patient stabilization and prevention of further absorption of cadmium
Chelation therapy with CaNa2EDTA recommended (but has questionable utility)

Dimercaprol CONTRAINDICATED (mobilizes cadmium and causes it to concentrate within the kidneys, increasing nephrotoxicity)

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10
Q

Chelators:

  • Number of EN- groups
  • Binding accomplished by
  • Excretion
A

Flexible molecules with TWO OR MORE electronegative groups (can form stable coordinate-covalent bonds with cationic metal atom)

Binding accomplished by sharing a pair of electrons between metal ion and ligand (both e- usually supplied by ligand- most common donor atoms are N, S and O)

Chelation complexes are then excreted from the body

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11
Q

Factors determining effectiveness of chelators

A

o Affinity of the chelator for the heavy metal vs. its affinity for essential metals in the body (Mg, Ca, Zn)

o Distribution of the chelator in the body vs. distribution of the metal

o Ability of the chelator, once it has bound to the metal, to mobilize it from the body

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12
Q

Properties of a Good Chelating Agent

-Don’t memorize, just review

A

o Good water solubility
o Resistance to metabolism in vivo
o Ability to get to the site where metal ions have been sequestered
o Ready excretion of the chelate
o Ability to chelate the toxic agent at the pH of body fluids
o Complexes formed with metals should be less toxic than the free metal ions
o Greater affinity of the chelating agent for the mental than that possessed by endogenous ligands (ie. low affinity for Ca++, Zn++)
o Minimal inherent toxicity
o Absorbed via oral administration

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13
Q

Dimercaprol (BAL) properties:

A

Colorless, oily, foul smelling liquid

Administered IM (in solution of peanut oil due to instability and easy oxidation of solutions)

Water soluble

Readily absorbed, metabolized, and excreted by kidneys within 4 hours if IM administration

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14
Q

Dimercaprol (BAL) contraindications and uses:

A

Contraindications:

  • Presence of liver disease or severe kidney disease
  • Cadmium poisoning

Use:
Arsenic, lead and mercury poisoning

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15
Q

Dimercaprol (BAL) Adverse effects:

What congeners are used?

A

Adverse Effects: lots!

Resulted in the production of various congeners that are more water soluble and confined to extracellular space (less side effects)
o	DMSA (2,3-dimercaptosuccinate)
o	DMPS (2,3-dimercaptopropane-1-sulfonate)
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16
Q

Dimercaprol

Adverse effects:
What congeners are used?

A

Adverse Effects: lots!

Resulted in the production of various congeners that are more water soluble and confined to extracellular space (less side effects)
o	DMSA (2,3-dimercaptosuccinate)
o	DMPS (2,3-dimercaptopropane-1-sulfonate)
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17
Q

CaNa2EDTA (Edetate Calcium Disodium): Properties

A

 Good chelator of many trivalent and divalent metals
o Chelates essential Ca++ in vivo, limiting clinical usage (addition of calcium disodium salt to EDTA attempts to correct this)
 Penetrates cell membranes poorly (extracellular chelatory)

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18
Q

CaNa2EDTA (Edetate Calcium Disodium): Contraindications:

Uses:

A

Renal disease (primary toxic effect of prolonged use is on the kidneys)

Mercury poisoning

Use: Lead, cadmium (zinc, chromium, copper, manganese, nickel)

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19
Q

Penicillamine: Properties:

A

Aka: cupramine

White, crystalline water-soluble product formed by degradation of penicillin

D-isomer preferred (less toxic)

N-acetylpenicllamine is its acetyl derivative

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20
Q

Penicillamine: use

A

Copper, lead and mercury poisoning

Wilson’s Disease (hepatic degeneration due to copper excess)

21
Q

Deferoxamine mesylate (Desferal): Properties

A

Binds tightly to iron with a little affinity for trace metals or Ca++

Will remove iron from cellular proteins but NOT from Hb or cytochromes

Excreted in the urine

Toxic and should only be used when severity of poisoning justifies it

22
Q

Deferoxamine mesylate (Desferal): Contraindications and use

A

Contraindications: Renal insufficiency

Use:
Iron poisoning (chelator of choice)
Aluminum toxicity

23
Q

Deferoxamine mesylate (Desferal): adverse reactions

A

diarrhea, hypertension, cataract formation

24
Q

Deferoxamine mesylate (Desferal): adverse reactions

A

diarrhea, hypertension, cataract formation

25
Q

Carbon Monoxide: Properties, sources

A

Properties: colorless, tasteless, odorless, non-irritating gas

Sources: by product of incomplete combustion
o	Automobile exhaust
o	Charcoal fires
o	Improperly adjusted gas furnaces
o	Methylene chloride
26
Q

Carbon Monoxide: Mechanism and organ system affected

A

Mechanism:
CO combines REVERSIBLY with Hb at O2-binding sites –> carboxyHb (unable to transport O2)

o Affinity of Hb for CO >100 times that for O2 (therefore, dangerous even at low levels)
o CO also interferes with cytochromes involved in cellular respiration

Organ Systems Affected:
o Brain and heart most affected (high blood flow and O2 requirement)

27
Q

CO toxicity is also due to:

A

CO toxicity not only due to interference with O2-binding of Hb, but also with
cytochromes involved in cellular respiration

28
Q

Treatment of CO poisoning:

A

o remove individual from source of exposure
o make sure that respiration is maintained or reinstituted if it has failed
o CO is readily dissociated from COHb, so CO will be exhaled through lungs if
exposure ceases
o pure oxygen, in either a hyperbaric chamber or through a face mask, administered
in severe cases

29
Q

Correlation between COHb conc. and signs and symptoms of CO poisoning

A

0 - 10
No symptoms

10 - 20
Tightness across forehead; possibly slight headache; dilatation of
cutaneous blood vessels

20 - 30
Headache; throbbing in temples

30 - 40
Severe headache; weakness; dizziness; dimness of vision; nausea
and vomiting; collapse

40 - 50
Same as previous group with greater possibility of collapse or
syncope; increased respiration and pulse

50 - 60
Syncope; increased respiration and pulse; coma with intermittent
convulsions; Cheyne-Stokes respiration

60 - 70
Coma with intermittent convulsions; depressed cardiac function
and respiration; possible death

70 - 80 Weak pulse and slowed respiration; respiratory failure and death

30
Q

Cyanide: sources

A

o Fumigants
o Metal cleaners
o In production of synthetic rubber and chemical syntheses
o Fires involving nitrogen containing plastics
o In the home (silver polish, insecticides, rodenticides, fruit seeds- apricot pits)

31
Q

Cyanide: mechanism

A

o Result of CN- (cyanide ion), which has a high affinity for iron in the ferric state (Fe3+)
o Binds oxidized iron in cytochromes oxidase of mitochondria to form a complex that halts cellular respiration (results in cytotoxic hypoxia)

Fatal does of CN: 50-200 mg

32
Q

Cyanide: treatment

Endogenous detoxification

A

Treatment aimed at preventing/reversing binding by providing a large pool of Fe(III) ions to compete for the CN

Amyl nitrite or sodium nitrite (react with Hb to form metHb with Fe3+)

  • Speed of administration is important
  • Give amyl nitrite by inhalation and sodium nitrite by IV

Endogenous detoxification also occurs via enzymatic conversion in mitochondria by thiosulfate sulfurtransferase enzyme (rhodanese)

  • Conversion of CN- –> SCN- (thiocyanate)
  • Thiocyanate non-toxic and excreted in the urine
33
Q

Cyanide: treatment

Endogenous detoxification

A

Treatment aimed at preventing/reversing binding by providing a large pool of Fe(III) ions to compete for the CN

Amyl nitrite or sodium nitrite (react with Hb to form metHb with Fe3+)

  • Speed of administration is important
  • Give amyl nitrite by inhalation and sodium nitrite by IV

Endogenous detoxification also occurs via enzymatic conversion by thiosulfate sulfurtransferase enzyme (rhodanese)

  • Conversion of CN- –> SCN- (thiocyanate)
  • Thiocyanate non-toxic and excreted in the urine
34
Q

Comparison of methanol with ethanol

A

Oxidized more slowly in the body than ethanol

Metabolized by the same enzymes (but enzymes have a higher affinity for ethanol)

Symptoms of toxicity similar to those seen with ethanol (GI cramps, vomiting)

35
Q

Methanol metabolism/toxicity (3 things)

A

MeOH metabolized to formaldehyde and formic acid (toxic)

MeOH –> formaldehyde (alcohol dehydrogenase) –> formic acid (aldehyde dehydrogenase)

Formaldehyde causes blindness by damaging retinal cells

Formic acid is cardiotoxic and causes systemic acidosis

36
Q

Methanol Treatment: (4)

A

Keep patient warm and protect eyes from any light

Correct acidosis with sodium bicarbonate (key to survival)

Continuously monitor blood pH and blood gases

Give ethanol (metabolized by the same enzymes, which have a much higher affinity for ethanol)

37
Q

Methanol sources:

A

Used industrially in chemical syntheses, antifreeze, solvents, paint remover, as a
denaturant in denatured ethyl alcohol

38
Q

Ethylene glycol: metabolism

what forms and causes kidney damage? Systemic acidosis?

A

o Ethylene glycol –> Glyceraldehyde –> Glycolic Acid –> Glyoxylic Acid –> Formic Acid + Oxalate
o Overall, metabolized by alcohol dehydrogenase –> Oxalate + Formic Acid

Oxalate crystallizes, causing oxalate crystalluria (causes severe renal injury and failure)

Formic acid causes systemic acidosis

39
Q

Ethylene glycol: metabolism

what forms and causes kidney damage? Systemic acidosis?

A

o Ethylene glycol –> Glyceraldehyde –> Glycolic Acid –> Glyoxylic Acid –> Formic Acid + Oxalate
o Overall, metabolized by alcohol dehydrogenase –> Oxalate + Formic Acid

Oxalate crystallizes, causing oxalate crystalluria (causes severe renal injury and failure)

Formic acid causes systemic acidosis

40
Q

Ethylene glycol: treatment (4)

A

o Gastric lavage to remove poison
o Correct acidosis with sodium bicarbonate
o Give ethanol (slows metabolism for same reasons as seen with methanol)
o Hemodialysis in extreme cases to prevent kidney damage

41
Q

Acetaminophen (APAP):
absorbed from:
HL:
Metabolized to:

A

Readily absorbed from GI tract

Half life is 1-3 hours

Metabolized to:

  • Glucouronide (most common)
  • Sulfate conjugate (less common)
  • Reactive electrophile (hydroxylated metabolite; small amount)
42
Q

Symptoms of APAP Poisoning:

A

• During first 24 to 48 hr: pallor, nausea and vomiting, but no really abnormal physical
signs
• Within 2 to 4 days after ingestion of toxic doses: clinical indications of hepatic damage
observed; possibly also renal damage

43
Q

Diagnosis of APAP poisoning:

A
  • Early diagnosis critical since APAP metabolized during first pass in liver
  • Methods available for rapid determination of plasma levels of APAP
  • Monitor liver functions
44
Q 
Metabolism of APAP:
Major portion:
Minor portion:
What happens to the hydroxylated metabolite?
Massive doses of APAP do what?
A

• Major portion is glucuronidated
• A small amount is hydroxylated by cytochrome P450
• The hydroxylated metabolite is then normally conjugated with GSH and excreted in urine
as a mercapturate
• Massive doses of APAP deplete supply of GSH, which allows the hydroxylated
metabolite to bind to tissue components, producing cellular necrosis

45
Q

Treatment of APAP Poisoning:

A

Want to administer sulfhydryl compounds to act as alternative targets for hydroxylated metabolite OR that act to maintain hepatic GSH concentrations

o N-Acetylcystein (Mucomist): sulfur amino acid source that supports GSH synthesis (given orally in cola, fruit juice or water)

46
Q

What is a vitamin megadose?

A

A dose 10 or more time the recommended daily allowance (have no demonstrated benefit)

47
Q

Vitamin toxicities:

most cases due to:

A

o Acute toxicities are rare (most due to chronic use of vitamins over many years)
o Symptoms appear gradually and are readily recognized
o Most cases due to multivitamin therapy and many are due to iron

48
Q

Fat vs. water soluble vitamins

A

o Toxicity more commonly seen with fat-soluble vitamins (A and D; generally not seen with E and K)

Pharm Exam 1 (23 decks)

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