Lash - Toxicology II Flashcards
What is arsenic?
Common contaminant of coal and many metal ores
Chemical forms of arsenic of toxicologic importance:
- elemental arsenic
- inorganic arsenic
- organic arsenicals (once commonly used as chemotherapeutic agents)
- arsine gas (AsH3).
What is the current medical use of arsenic?
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
What form causes the major toxicologic effects of arsenic? How does it work?
- Major toxic effects of inorganic As due to trivalent arsenic (As3+)
- As3+ acts as a sulfhydryl reagent, inhibiting SH-sensitive enzymes
What does the pentavalent form of As do?
Pentavalent arsenic (As5+): well-known uncoupler of mitochondrial oxidative phosphorylation; competes with inorganic phosphate in the formation of ATP
How does As3+ interact with PDH?
Pyruvate dehydrogenase (PDH) system very sensitive; the 2 SH-groups of lipoic acid readily react with As3+ to form a stable, 6-membered ring.
Treatment of As poisoning:
Chelation therapy with dimercaprol; may then follow with penicillamine
Environmental prevalence of cadmium:
HL:
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.
Treatment for cadmium poisoning:
What is contraindicated? What happens?
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)
Chelators:
- Number of EN- groups
- Binding accomplished by
- Excretion
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
Factors determining effectiveness of chelators
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
Properties of a Good Chelating Agent
-Don’t memorize, just review
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
Dimercaprol (BAL) properties:
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
Dimercaprol (BAL) contraindications and uses:
Contraindications:
- Presence of liver disease or severe kidney disease
- Cadmium poisoning
Use:
Arsenic, lead and mercury poisoning
Dimercaprol (BAL) Adverse effects:
What congeners are used?
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)
Dimercaprol
Adverse effects:
What congeners are used?
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)
CaNa2EDTA (Edetate Calcium Disodium): Properties
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)
CaNa2EDTA (Edetate Calcium Disodium): Contraindications:
Uses:
Renal disease (primary toxic effect of prolonged use is on the kidneys)
Mercury poisoning
Use: Lead, cadmium (zinc, chromium, copper, manganese, nickel)
Penicillamine: Properties:
Aka: cupramine
White, crystalline water-soluble product formed by degradation of penicillin
D-isomer preferred (less toxic)
N-acetylpenicllamine is its acetyl derivative
Penicillamine: use
Copper, lead and mercury poisoning
Wilson’s Disease (hepatic degeneration due to copper excess)
Deferoxamine mesylate (Desferal): Properties
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
Deferoxamine mesylate (Desferal): Contraindications and use
Contraindications: Renal insufficiency
Use:
Iron poisoning (chelator of choice)
Aluminum toxicity
Deferoxamine mesylate (Desferal): adverse reactions
diarrhea, hypertension, cataract formation
Deferoxamine mesylate (Desferal): adverse reactions
diarrhea, hypertension, cataract formation
Carbon Monoxide: Properties, sources
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
Carbon Monoxide: Mechanism and organ system affected
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)
CO toxicity is also due to:
CO toxicity not only due to interference with O2-binding of Hb, but also with
cytochromes involved in cellular respiration
Treatment of CO poisoning:
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
Correlation between COHb conc. and signs and symptoms of CO poisoning
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
Cyanide: sources
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)
Cyanide: mechanism
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
Cyanide: treatment
Endogenous detoxification
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
Cyanide: treatment
Endogenous detoxification
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
Comparison of methanol with ethanol
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)
Methanol metabolism/toxicity (3 things)
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
Methanol Treatment: (4)
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)
Methanol sources:
Used industrially in chemical syntheses, antifreeze, solvents, paint remover, as a
denaturant in denatured ethyl alcohol
Ethylene glycol: metabolism
what forms and causes kidney damage? Systemic acidosis?
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
Ethylene glycol: metabolism
what forms and causes kidney damage? Systemic acidosis?
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
Ethylene glycol: treatment (4)
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
Acetaminophen (APAP):
absorbed from:
HL:
Metabolized to:
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)
Symptoms of APAP Poisoning:
• 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
Diagnosis of APAP poisoning:
- Early diagnosis critical since APAP metabolized during first pass in liver
- Methods available for rapid determination of plasma levels of APAP
- Monitor liver functions
Metabolism of APAP: Major portion: Minor portion: What happens to the hydroxylated metabolite? Massive doses of APAP do what?
• 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
Treatment of APAP Poisoning:
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)
What is a vitamin megadose?
A dose 10 or more time the recommended daily allowance (have no demonstrated benefit)
Vitamin toxicities:
most cases due to:
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
Fat vs. water soluble vitamins
o Toxicity more commonly seen with fat-soluble vitamins (A and D; generally not seen with E and K)
