Heavy metals Chelators Flashcards
Toxicology
study of adverse effects of a chemical, physical, or biological agent
Toxicity
the ability of a material to damage a biological system, cause injury, or impair function
What effects degree of toxicity
dose, route of exposure, and chemical species, as well as the age, gender, genetics, and nutritional status of exposed individuals
Hazard
ability of an agent to cause toxicity
Risk
the expected frequency of exposure to a hazardous agent
Route of exposure
Route of entry into body
inhalation, transdermal, oral mucosal
Duration of Exposure
may effect selection of treatment
acute vs. chronic
ADME
the Adsorption, Distribution, Metabolism, and Excretion of toxic substances and their metabolites
Clearance
measure of plasma cleared per unit time
sum of both renal and hepatic contributions
1st order clearance
normal conditions
eliminations of drugs/chemicals is proportional to their plasma concentration
Zero order kinetics
when plasma levels become very high, protein binding and normal metabolism can both become saturated, rate of elimination can become fixed
More drug will be delivered into circulation in unbound fraction
Volume of distribution
apparent volume into which a substance is distributed
Which volume of distribution is more difficult to remove (like with hemodialysis)
Large volume of distribution is more difficult to remove than small volume of distribution
Bioaccumulation
Biomagnification
- accumulation of a toxic agent when the uptake exceeds the organism’s ability to metabolize/excrete
- Biomagnification: increases in the relative amount of contaminant in a biological system as it passes up the food chain
Why, at very high blood concentrations, do normal kinetic properties of drugs or toxins change
Larger, unbound free fractions
prolonged half life and increase toxicity
What defines metals as heavy
high atomic weight and having a density at least five times greater than that of water (specific density of more than 5g/cm3)
Top 3 most toxic substances
- Lead
- Mercury
- Arsenic
- Cadmium
How do heavy metals interfere with normal biological processes
by competing with normal substrates
Chelators and half life
the shorter the half life, the more effective it is to use chelators to remove heavy metals
Primary exposure sources of lead
Building materials/construction Batteries Lead pipes paint soil, dust, water industry fold remedies
Why is lead exposure particularly detrimental to young children
Their bodies absorb b/c Pb competes with Ca and growing bodies require more Ca.
children absorb more than 50% consumed
adults - about 10-15%
Kids suck on stuff
Half life of lead
1-2 months
Symptoms of lead poisoning
Headaches
neurocognitive deficits
kidney damage
Main repository in body for lead burden
Substitutes for Ca in bone
What are Burtonian lines
Lead lines causing a darkening of the gingiva
Mechanism of leads toxicity
Interferes with Ca us
Causes anemia
Causes immunosuppression
treatment regimen for lead toxicity - recommended chelators
Remove exposure
Chelators - EDTA, removes Pb from bone slowly and requires multiple chelating treatments
Mercury primarily used in what form
methyl/Hg form
Primary exposure sources of mercury
Fish
Amalgam (CDC says it’s not a problem)
Thermometers
Mechanism of mercury toxicity
Reacts with selenium (necessary for reducing oxidized vitamin C and E)
Can cause gingivostomatitis
Symptoms of mercury poisoning
Mad hatter disease
Neurological
Psychiatric problems
Gingivostomatitis
CDC’s conclusions regarding mercury exposure in thimerosal in flu vaccines
and dental amalgam
other than redness and swelling at injection site
neither have evidence of causing harm
Treatment regimen for mercury toxicity - including chelators
Chelators - Dimercaprol and Succimer
Why is dimercaprol contraindicated in chronic mercury intoxication
Chronic use of dimercaprol can cause serious renal toxicity
Exposure sources of Arsenic
Industry
Groundwater
Arsenite - used in chemotherapeutics for leukemia
Toxicokinetics of Arsenic - route of intake
absorbed through respiratory mucosa and GI tract
poor skin absorption
Symptoms/effects of arsenic
Fatigue, anemia, renal failure, hyperpigmentation
Carcinogenic in lungs, skin, and bladder
hemolytic on RBCs
Mechanism of arsenic toxicity
interferes with enzyme function increases ROS and oxidative stress interferes with signal transduction hemolytic effects on RBCs Carcinogenic
Treatment for acute arsenic intoxication
Decontamination and supportive care
Chelators: Unithiol or Dimercaprol
Emperic chelation if exposure is suspected
Treatment for chronic arsenic intoxication
Supportive care
Dietary supplementation with folate
No chelators since chronic arsenosis leads to irreversible damage to several vital organs, carcinogenic
Treatment for acute arsine gas intoxication
Blood exchange hemodialysis and transfusions
aggressive hydration
No chelators - no benefit
How do chelators work on heavy metals
They render heavy metal ions unavailable for covalent interactions
How does the half-life of the heavy metal effect the ability of a chelator to remove it from a target organ
The longer the half life, the less effective the chelator action
Is it better to treat with chelators quickly or to wait
Most effective if administered ASAP after exposure
Dimercaprol: Approved for which heavy metal poisonings as a monotherapy
Arsenic (acute) and Mercury
Combo with Edetate calcium disodium for severe lead poisoning
Dimercaprol monotherapy contraindicated for what
Chronic exposure to lead
b/c it redistributes larger doses of lead to CNS
Dimercaprol Combo with what for chronic poisoning of what
Combo with CaNa2-EDTA (edetate calcium disodium) for severe lead exposure
Is Dimercaprol water soluble
no (cannot give orally)
Only route of administration for dimercaprol
Intramuscular (i.m.)
Therapeutic index of dimercaprol compared to succimer or unithiol
It can be very toxic, especially on kidneys
Succimer has replaced dimercaprol for the most part
Succimer
Water-soluble form of dimercaprol
For oral use only
Succimer approved for which heavy metal poisonings
Lead
Arsenic
Mercury
Succimer’s main mechanism for removing heavy metals
Binds to cysteine to form mixed disulfides which are excreted by the kidney
Half life of Succimer
2-4 hours
Adverse effects of Succimer
only diarrhea/GI upset, maybe mild rashes
much better than dimercaprol
Edetate Calcium Disodium (CaNa2-EDTA) approved for which heavy metal poisonings
Lead
Edetate Calcium disodium targets intra or extra-cellular lead
Extra cellular
Edetate calcium only route of administration
Intravenous
Half life of edetate calcium disodium
excretion
1 hour
excreted 100% by kidney
Edetate calcium disodium contraindicated for what population
Anuric patients
excreted by kidneys
Unithiol
another form of what
routes of administration
Another water-soluble form of dimercaprol
Orally or IV
Half life of Unithiol
20 hours
Unithiol effective against which heavy metals
FDA approved for which
Mercury
Arsenic
Lead
FDA approved for none
Biocompatibility
ability of a material to elicit an appropriate biological response in a given application in the body
4 biocompatibility criteria for the ideal dental material
Should not be harmful to pulp or soft tissues
Should not contain toxic diffusable substances that may be released and absorbed into the circulatory system to cause systemic toxicity
Should be free of potentially sensitizing agents that may cause allergic reactions
Should have NO carcinogenic potential
Most common allergic reactions observed in dental practices
How to avoid them
Allergic contact dermatitis: distal fingers and tips after repeated exposure to monomers of bond - wear gloves wash hands
Latex Allergies - use non-latex
Allergies to denture base materials - soak in water 24 hours before first-time use
What step releases mercury the most
Polishing amalgam
How to avoid pulpitis from unpolymerized monomers in resin composite deep fillings
Use twice the recommended time of exposure
Cure in increments
Zinc phosphate cement
Glass ionomer
How to avoid lesions caused by zinc phosphate cement
Use proper mix or alternatively use a resin-modified glass ionomer cement
Make sure it isn’t too thin
How to reduce cytotoxicity of acrylate bonding agents
rinse with tap water between applications of subsequent reagents
Importance of ventilation in lab with metals
Beryllium dust
Nickel dust
Beryllium vapors
Mechanism of cyanide poisoning
not a heavy metal, but very common
prevents cells of body from getting oxygen and ATP, causing cell death
Antidote for Cyanide
hydroxycobalamin - reacts with cyanide to form cyanocobalamin which is excreted by kidneys
