Valentovic - Heavy Metals Flashcards by Ellen Petryna

Name 5 Heavy Metals that come in to play in the medical field.

Pb, Hg, As, Cd and Cu

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It’s not that you are exposed to metals, its the accumulation of these metals in your body that result in symptoms and conditions.

t_1/2 > 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

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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

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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)

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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)

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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))

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What Chelator MUST BE AVOIDED in patients with allergies to peanuts?

Dimercaprol (BAL)

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What type of drug administration?

When asymptomatic or light symptoms?
With more severe toxicities?

Asymptomatic: Oral

Severe: IM

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What Chelator is contraindicated in Liver DIsease?

Dimercaprol (BAL) bc the metal-BAL complex is excreted in urine and bile.

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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

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Drug of Choice in Wilson’s Disease? ******

Penicillamine d/t accumulation of Copper

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What is the major serious adverse effect of Penicillamine?

What is it contradindicated for?

Agranulocytosis

Renal Disease

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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! (t_1/2 > 10 years)

Lead Toxicity

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**** 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 ******

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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! (t_1/2 > 10 years)

Liver, Kidney, RBC

Calcium

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When do you have to use a chelating agent with Lead toxicity?

When it first distributes to the Liver, Kidney and RBC.

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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**)

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Lead Poisoning

What toxicity has the MOST SERIOUS CONDITION OF ENCEPHALOPATHY?

-convulsions, cerebral edema, death

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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

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Lead

What is the most sensitive indicator of Lead Toxicity?

*earliest sign of toxicity, not the earliest target

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Lead levels in whole blood (inhibits heme synthesis)

********Lead inhibits 2 Sulfhydryl-dependent enzymes in the Heme Pathway?

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*******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.

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Delta-Aminolevulinate Acid and Coporphryin III

Chelation Therapy for Lead Toxicity?

Low Levels, Asymptomatic: ____________ and ____________

Aggressive Therapy: ________________ and ____________

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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

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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. 3. Arsine Gas?

1. Penicillamine 2. Dimercaprol (bc Arsenic likes to bind sulfhydrl groups) 3. 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 c**auses 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)

Valentovic - Heavy Metals Flashcards

(42 cards)