Valentovic - Heavy Metals Flashcards
Name 5 Heavy Metals that come in to play in the medical field.
Pb, Hg, As, Cd and Cu
It’s not that you are exposed to metals, its the accumulation of these metals in your body that result in symptoms and conditions.
- t1/2 > 10 yr (so over 40 years to get rid of)
- Metals are not metabolized
- Metals are water-soluble and don’t accumulate in fat
- Metals bind to target proteins, enzymes via ____, _____, _____ functional groups
What are used for detoxification: _______________?
S, O, N functional groups
Chelators
An ideal Chelating Agent….
- should bind the heavy metal complex and is _____ (less/more) toxic than the individual metal
- enhances excretion of metal faster
-must work at what pH level?
-not readily metabolized (biotransformed so it holds on to the metal)
-hydrophilic, distribution similar to the heavy metals
-_________ (greater/less) affinity for metals than calcium or iron in body
less toxic complex
physiological pH = 7.4
greater
Name the chelator.
-metal displaces Ca++ in center of molecule
- administration by IV and IM injection
- ->IM: used for lead encephalopathy tx over 5+ days
-used for Lead and Cadmium
- metal-chelator complex excreted in urine
- ***CONTRAINDICATED** in renal disease
Calcium Disodium EDTA
*DON’T GET CONFUSED WITH DISODIUM EDTA, used for hypercalcemia (has no Calcium so seeks it out in the body)
Name the Chelator.
- administered ORALLY
- Sulfhydryl groups bind to metal
- Excreted in Urine
-Lead Toxicity
-Low compliance d/t nausea and bad taste (rotten egg)
Succimer (Meso-2,3-dimercaptosuccininc acid, DMSA)
Name the Chelator.
- SH groups bind to metal
- Lead, Arsenic & *INORGANIC Mercury
- Administered IM (in peanut oil)
*DON’T USE IN PATIENT ALLERGIC TO PEANUT
-Complex excreted in urine and bile
(If urine acidified, complex will dissociate)
Dimercaprol (2,3-Dimercaptopropanol, British Anti Lewisite (BAL))
What Chelator MUST BE AVOIDED in patients with allergies to peanuts?
Dimercaprol (BAL)
What type of drug administration?
- When asymptomatic or light symptoms?
- With more severe toxicities?
Asymptomatic: Oral
Severe: IM
What Chelator is contraindicated in Liver DIsease?
Dimercaprol (BAL) bc the metal-BAL complex is excreted in urine and bile.
Name the Chelator.
- administered orally
- sulfhydryl containing agent
- Metal-Chelator complex excreted in Urine
-Lead, Arsenic and Copper
*Drug of Choice in Wilson’s Disease
Penicillamine
Drug of Choice in Wilson’s Disease? ******
Penicillamine d/t accumulation of Copper
What is the major serious adverse effect of Penicillamine?
What is it contradindicated for?
Agranulocytosis
Renal Disease
Name the Heavy Metal.
- exposure by ingestion or inhalation
- in water, soil, paint chips (old houses), home brew distilled in radiators, pottery made outside the US
Kids absorb >5x higher than adults.
-distributes 1st to Liver, Kidney, RBC then redistributes to the bone replacing Calcium in the brain and bone, where it stays and cannot be chelated! (t1/2 > 10 years)
Lead Toxicity
**** REMEMBER, for LEAD you take a WHOLE BLOOD SAMPLE, not a Plasma sample bc >95% of the lead is bound to Hb in the RBC ******
Lead distributes 1st to _______, _______, _______ then redistributes to the bone replacing __________ in the brain and bone forming tertiary lead phosphate, where it stays and cannot be chelated! (t1/2 > 10 years)
Liver, Kidney, RBC
Calcium
When do you have to use a chelating agent with Lead toxicity?
When it first distributes to the Liver, Kidney and RBC.
What kind of poisoning?
Blood: microcytic anemia, basophilic stipling and hemolysis (Acute)
GI: colic (chronic)
Nerve: muscle weakness, memory loss, palsy - perpetual loss of muscle stregnth (chronic/irreversible)
MOST SERIOUS CONDITION: ENCEPHALOPATHY (convulsions, cerebral edema, death**)
Lead Poisoning
What toxicity has the MOST SERIOUS CONDITION OF ENCEPHALOPATHY?
-convulsions, cerebral edema, death
Lead Poisoning - essentially takes over the role of Calcium in the brain.
Target Tissues for ___________ (what heavy metal)
- *Neurological:**
- peripheral, axon degeneration
- Brain, interferes with Ca++ dependent reactions
- *Hematologic**
- Most sensitive indicator of toxicity**
- *-inhibits Heme synthesis**
- basophilic stipling d/t ppt of RNA
- Anemia d/t dec RBC life span and dec Heme synthesis
Lead
What is the most sensitive indicator of Lead Toxicity?
*earliest sign of toxicity, not the earliest target
Lead levels in whole blood (inhibits heme synthesis)
********Lead inhibits 2 Sulfhydryl-dependent enzymes in the Heme Pathway?
*******delta-aminolevulinate dehydratase (cytosolic)
*******ferrochelatase (mitochondrial) gets in bc looks like Calcium
Lead Toxicity causes increased urinary levels of _______________ and _______________ due to inhibitition of enzymes in the Heme pathway.
Delta-Aminolevulinate Acid and Coporphryin III
Chelation Therapy for Lead Toxicity?
Low Levels, Asymptomatic: ____________ and ____________
Aggressive Therapy: ________________ and ____________
Low Levels: Succimer (oral) and Penicillamine (Oral), not FDA approved
Aggressive Therapy: Calcium Disodium EDTA (IV) and Dimercaprol (IM)
What Heavy Metal?
- exists in 3 Chemical Forms (Elemental, Inorganic, Organomercurial)
- Cellular Mechanism: binds to sulfhydryl groups and inactivates proteins and enzymes
Mercury
Fact: Mercury exists in 3 Chemical Forms
(1) ELEMENTAL (Hg0) toxic through inhalation
(2) INORGANIC (Hg+2) toxic by oral or inhalation
(3) ORGANOMERCURIAL (C-Hg) most toxic, any route
What Chemical form of Mercury?
- inhalation (respiratory & neurological damage)
- Oral, not toxic bc not absorbed
- uncharged (Hg0) crossing BBB
- converted from valence of 0 –> +2 by catalase in RBCs (it becomes trapped and accumulates in brain)
Symptoms: tremor, irritability, erethism (irritability, depressio, delirium d/t Hg vapor excess)
Elemental Mercury (Hg0)
What Chemical Form of Mercury?
- oral exposure
- binds to SH-proteins in mouth and esophagus causing a gray color
- GI, vomiting, hematochezia (bloody diarrhea)
- Renal toxicity (proximal tubules and chronic tubular and glomerular damage)
- Photophobia and Acrodynia (reddening of face & chest) occurs with chronic exposure
Inorganic Mercury
What Chemical Form of Mercury?
*Most toxic form (Carbon-Hg Bond -> neutral molecules can cross BBB rapidly)
-Methyl Mercury or DiMethyl Mercury
**2 Drops of Dimethyl Mercury (dermal) –> LETHAL!
Targets: nervous system (rapidly crosses BBB)
Symptoms: muscle tremor, visual field constriction, ataxia
Organomercurials
What disease?
- toxic substance found in humans was methylmercury
- permanent weakness, visual field constrction, ataxia/balance issues & numbness
- release occured for 30 yrs
- inorganic mercury released into environment taken up by algae & converted to methylmercury
-methylmercury then entered food chain as algae eaten by fish
Minamata Disease (Environmental disaster)
Treatment of Mercury Toxicity
Hg measured for inorganic and elemental Mercury
Elemental and Inorganic mercury use _________ (low) & __________ (severe).
Difficult to measure methyl mercury, rapidly taken up in to brain
____________ (moderate success)
____________ CONTRAINDICATED increases brain levels!
Penicillamine (low)
Dimercaprol (severe)
Penicillamine
Dimercaprol (CONTRAINDICATED bc inc. lipophilicity and inc. brain levels)
What Heavy Metal?
- *Forms:**
- inorganic (As+3, As+5)
- Organoarsenical
- Arsine gas (AsH3) can happen in semiconductor industry (computer chips)
- *Mechanism of Toxicity**
- As+3 binds to sulfhydryl groups
- As+5 replaces Phosphorus in ATP production causing uncoupling of oxidative phosphorylation
- *-AsH3** causes spontaneous, rapid hemolysis
Arsenic
What toxicity?
Vascular: vasodilator, increases capillary permeability (leakiness), arrhythmia
GI: inc. blood flow, loss of albumin into Small Intestine coagulates giving gelatinous diarrhea termed “rice water diarrhea” bc losing protein
Skin: cancer and hyperkaratosis (thickening of palms and soles)
**Arsine Gas: hemolysis
Kidney: proximal tubular and glomerular
Arsenic toxicity
Facts: Chronic Arsenic Toxicity
- Muscle weakness
- Hyperkeratosis
- Arrhythmia
- Enlarged liver
- Garlic odor to breath & sweat (arsenic binds to sulfhydrl groups in mucosa)
- Mee’s lines on fingernails (horizontal) - binds to proteins in fingernails
Treatment for Arsenic Toxicity?
1.
2.
- Arsine Gas?
- Penicillamine
- Dimercaprol (bc Arsenic likes to bind sulfhydrl groups)
- Chelation Therapy ineffective –> Treat Symptoms
Name the Heavy Metal.
-Ingestion (contaminated water, oysters)
*target is Kidney (damage to proximal tubules)
-Inhalation (industry)
*target: kidney and lung
*Kidney: proximal tubular necrosis
*Lung: pulmonary edema, irritation and chronic exposure causes emphysema
Cadmium
Cadmium Toxicity
_______________ is an inducible zinc finger protein.
- induced by Cadmium, Mercury & Arsenic exposure
- endogenous chellating agent in the body
- high cysteine content, metal-SH binding
Metallothionein
Cadmium accumulates in Liver & Kidney bound to ____________.
This complex taken up by liver/kidney. Cadium can be cleaved giving high levels in the tissues. Part of the reason you get Renal Toxicity.
Metallothionein
Treatment for Cadium.
Chelation Therapy: ___________
What is CONTRAINDICATED? _____________, increases renal toxicity
Calcium Disodium EDTA
Dimercaprol (BAL)
What biomarker is utilized to monitor Cadmium toxicity?
- occupational exposure
- protein excretion increased following renal damage
- excellent correlation of cadmium exposure and urinary excretion
urinary B2 microglobulin
What Disease?
- environmental accident
- accidental ingestion of Cadmium in H2O and food
- chronic exposure combined with low Ca+2 diet
- caused renal damage, osteoporosis and bone pain
- replacement of Ca+2 by Cd
Itai Itai Disease (‘ouch, ouch’ disease)
Name the Disease.
-inappropriately high Copper Levels
- defect in ATP7B protein -> problem in transporter protein
- impacts biliary copper excretion in to the bile
- diminished copper incorpation within the ceruloplasmin in the plasma
Wilson’s Disease
What is the 1st line of therapy for Wilson’s Disease?
If not tolerated, what is the alternate choice chelator?
Chelator Therapy: Penicillamine - must monitor Agranulocytosis!
Trientine (oral)
