6.2: Heavy Metals And Chelators Flashcards by Margaux Amaro

Heavy Metals

• Lead
• Arsenic
• Mercury

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What are the 9 Chelator/Chelating Agent?

Dimercaprol
Succimer
Edetate Calcium Disodium
Unithiol
Penicillamine
Deferoxamine
Deferasirox and Deferiprone
Prussian Blue

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• Storage batteries, ammunition,
• metal alloys, solder, glass,
• plastics, pigments and
• ceramics
• No useful purpose in the human body

Lead

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Absorbed slowly but consistently via respiratory and gastrointestinal tract

Pharmacokinetics

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Identify the heavy metal based on its pharmacokinetics:

Low dietary calcium, iron deficiency and ingestion on an empty stomach increases absorption

Lead

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Identify the heavy metal based on its pharmacokinetics:

Poor absorption in the skin

Lead

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Up to what % absorbed in children in lead

50%

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Up to what % in adults is absorbed in lead?

10-15%

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Lead (pharmacokinetics):

What exposure is seen in respiratory tract?

industrial exposure

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Lead (pharmacokinetics):

What exposure is seen in intestinal tract?

nonindustrial exposure

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Lead [pharmacokinetics]

What % bound to RBCs, what % free in plasma

99% : 1%

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Identify the heavy metal based on its pharmacokinetics:

Distributed to bone marrow, brain, kidney, liver, muscle and gonads; then bones

Lead

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Identify the heavy metal based on its pharmacokinetics:

Crosses the placenta

Lead

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What is the half-life of Lead?

1-2 mos

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What is the half-life of Lead in bones?

years to decades

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Lead [pharmacokinetics]

What % excreted in the urine

70%

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Identify the heavy metal based on its pharmacodynamics:

Multiple mechanisms of action
Inhibition of enzymatic function
Interference with action of essential cations (calcium, zinc, iron)
Oxidative stress generation
Gene expression changes
Cell signaling alteration
Disruption of membrane integrity

Lead

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Major Forms of Lead Intoxication

Inorganic Lead Poisoning
Organolead Poisoning

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What is the treatment for Lead?

Immediate termination of exposure, supportive care and rational use of chelation therapy

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Identify the heavy metal based on its treatment:

Retained lead objects require gastrointestinal decontamination

Lead

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Lead [Treatment]

Intravenous edetate calcium disodium (CaNa2EDTA) at a dosage of ___ mg/kg/d by continuous infusion for up to __ days only

30-50 mg/kg/d : 5

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Treatment for Lead:

Oral Succimer (DMSA) after __ days

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Identify this heavy metal:

Semiconductors, wood preservatives, nonferrous alloys, glass and turf herbicide monosodium methane arsonate (MSMA)

Arsenic

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Groundwater may contain high amounts of arsenic

Arsenic

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# Identify this **heavy metal:** Historically, used as a pharmaceutical agent but now limited in use

Arsenic

# Identify the **heavy metal** based on its pharmacokinetics: Well-absorbed via respiratory and GI tract

Arsenic

# True or False: In the pharmacokinetics of Arsenic, **percutaneous absorption** is limited.

True

In the pharmacokinetic of Arsenic, it is metabolized by the liver via?

methylation reactions

Arsenic [Pharmacokinetics] is excreted in the?

Urine (major), sweat and feces

# Identify the **heavy metal** based on its **pharmacodynamics:** Multiple mechanism of actions: * Inhibition of enzyme functions * Oxidative stress generation * Gene expression changes * Cell signaling alteration

Arsenic

# Identify this **heavy metal:** * **Hyperpigmentation** and **hyperkeratosis** involving **hands and feet** * Chronic inorganic arsenic poisoning

Raindrop pattern

• Immediate termination of exposure, supportive care and chelation therapy • Gut decontamination if appropriate

Arsenic [Treatment]

Arsenic [Treatment] Acute Poisoning: Chelation with Unithiol __mg/kg every __ hours or Dimercaprol every __ hours

3-5mg/kg : 4-6 hours

Quicksilver or liquid metal

Mercury

Mined predominantly as HgS in cinnabar ores

Mercury

Electrolytic production of chlorine and caustic soda; electrical equipment, thermometer, instruments, fluorescent lamps; dental amalgams; artisanal gold production

Mercury

# True or False: **Thimerosal**, an organomercurial preservative, are **kept in almost all vaccines** in mercury.

False | They are removed from almost all vaccines.

Environmental release of mercury from burning of fossil fuels contributes to bioaccumulation in fishes

Mercury

Absorption varies depending on chemical form

Mercury [Pharmacokinetics]

Mercury [Pharmacokinetics] Absorbed from the??

Lungs, GI tract, and percutaneous route

In the pharmacokinetics of Mercury, it is **well-distributed into tissues** and most concentrated in __?

Kidneys

Mercury [Pharmacokinetics] Excreted via?

urine and feces

immediate removal from source, supportive care and chelation therapy

Mercury [Treatment]

Mercury [Treatment] Acute

Unithiol, dimercaprol or succimer

# True or False. Dimecaprol should never be used for elemental or organic mercury intoxication.

True

Pharmacology of Chelators

Metallic ion + chelating agent —> metallic chelate

Drugs used to prevent or reverse the toxic effects of heavy metals on an enzyme or other cellular target, or to accelerate the elimination of metal from the body

Chelators or Chelating Agents

The metal-mobilizing effects of a therapeutic chelating agent may also redistribute some of the metal to vital organs

Chelators or Chelating Agents

They may also enhance excretion of essential cations (Zinc, Copper)

Chelators or Chelating Agents

# True or False: The longer the half-life of a metal in a particular organ, the **more effectively** they can be removed by chelation.

False | It will be less effective.

What are the chelators or chelating agents?

* Dimercaprol * Succimer * Edetate Calcium Disodium (EDTA) * Unithiol * Penicillamine * Deferoxamine * Deferasirox * Deferiprone * Prussian Blue

What is the antidote to a warfare agent of Dimercaprol?

Lewesite

Adverse effects: hypertension, tachycardia, nausea, vomiting, lacrimation, salivation, fever, pain at injection site, thrombocytopenia, increase Prothrombin time

Dimercaprol [ 2,3-Dimercaptopropanolol, BAL]

Dimercaprol [ 2,3-Dimercaptopropanolol, BAL] As single-agent: arsenic and inorganic mercury

acute poisoning

Dimercaprol [ 2,3-Dimercaptopropanolol, BAL] As conjunction with EDTA

severe lead poisoning

[ T or F ] Dimercaprol [ 2,3-Dimercaptopropanolol, BAL] It prevents and reverses metal-induced inhibition ofsulfhydryl-containing enzyme

True

Dimercaprol [ 2,3-Dimercaptopropanolol, BAL] Increases rate of excretion of ?

arsenic and lead

Dimercaprol [ 2,3-Dimercaptopropanolol, BAL] Is given via __, excreted via __

IM : kidneys

Redistributes arsenic and mercury to CNS

Dimercaprol [ 2,3-Dimercaptopropanolol, BAL]

# Identify this **chelating agent:** **Water-soluble analog** of dimercaprol

Succimer | Dimercaptosuccinic Acid, DMSA

It prevents and reverses metal-induced inhibition of sulfhydryl-containing enzyme

Succimer [Dimercaptosuccinic Acid, DMSA]

Succimer [Dimercaptosuccinic Acid, DMSA] Treatment of children with blood lead concentration of?

>45mcg/dL

# Identify this chelating agent: * Increase rate of excretion of lead * It decreases mercury content in kidney

Succimer | Dimercaptosuccinic Acid, DMSA

# Identify this chelating agent: Has protective effect against arsenic as well

Succimer | Dimercaptosuccinic Acid, DMSA

Succimer (Dimercaptosuccinic Acid, DMSA) is given in what route?

Oral, IV

Succimer [Dimercaptosuccinic Acid, DMSA] Adverse effects

GI disturbances are the most common

Succimer [Dimercaptosuccinic Acid, DMSA] Associated with increase in?

ALT, AST, mild neutropenia

Calcium disodium salt form of EDTA

Edetate Calcium Disodium [Ethylenediaminetetraacetic Acid, EDTA]

Indicated mainly for chelation of lead

Edetate Calcium Disodium [Ethylenediaminetetraacetic Acid, EDTA]

# Identify this **chelating agent:** Chelator of **zinc**, **manganese** and certain heavy **radionucleotide poisoning**

Edetate Calcium Disodium | Ethylenediaminetetraacetic Acid, EDTA

# Identify the **chelating agents**: Chelates **extracellular metals ions** much more effectively compared to intracellular metal ions

Edetate Calcium Disodium | Ethylenediaminetetraacetic Acid, EDTA

[T or F ] Edetate Calcium Disodium [Ethylenediaminetetraacetic Acid, EDTA] Limited oral absorption

True

Edetate Calcium Disodium [Ethylenediaminetetraacetic Acid, EDTA] Given __; Excreted via the __

IV infusion : kidney

Water-soluble analog of dimercaprol

Unithiol [Dimercaptopropanesulfonic Acid, DMPS]

# Identify this **chelating agent:** Protective effects against mercury and arsenic

Unithiol | Dimercaptopropanesulfonic Acid, DMPS

# [ T or F ] Unithiol has **FDA approved indications.**

FALSE | Wala!!!!

# True or False: In Unithiol, it **decreases urinary excretion** of mercury, arsenic and lead.

False | Increases.

# True or False: Unithiol [Dimercaptopropanesulfonic Acid, DMPS] * Given **Orally** and **IV** (slow infusion) * Excreted via **kidneys**

True

What are the adverse effects of Unithiol?

* Dermatologic reactions * Urticaria * Exanthems; isolated cases of SJS * Erythema multiforme

# Identify this **chelating agent:** White, crystalline, derivative of Penicillin

Penicillamine | D-Dimethylcysteine

# Identify this **chelating agent:** Also used in **Severe Rheumatoid Arthritis**

Penicillamine | D-Dimethylcysteine

# Identify the **chelating agent:** Used primarily to treat or prevent **Copper poisoning** (i.e. **Wilson’s Disease**)

Penicillamine | D-Dimethylcysteine

[ T or F ] Penicillamine [D-Dimethylcysteine] L-isomer form is less toxic than the D-Penicillamine

False. Should be D-Penicillamine is less toxic than the L-isomer form

Penicillamine [D-Dimethylcysteine] Adverse effects:

Hypersensitivity, nephrotoxicity with proteinuria, pancytopenia, pyridoxine insufficiency

[ T or F ] Penicillamine [D-Dimethylcysteine] Absorbed via oral route

True

Isolated from Streptomyces pilosus

Deferoxamine

# Identify what **chelating agent:** The **parenteral chelator** of choice for **iron poisoning.**

Deferoxamine

# Identify this **chelating agent:** This chelating agent is useful in **treatment of aluminum toxicity** with **hemodialysis.**

Deferoxamine

What is the **adverse effects** of **Deferoxamine**?

* Hypotension * Flushing * Abdominal discomfort * Rashes * Pulmonary complications

[Deferoxamine] Excreted in the __

Urine

The given route of Deferoxamine is through:

IM or IV

# Identify this **chelating agent:** Indicated for treatment of **contamination with radioactive Cesium** and intoxication with **thallium salts**

Prussian Blue | Ferric Hexacyanoferrate

# Identify this **chelating agent:** Ion exchange and mechanical trapping or adsorption

Prussian Blue | Ferric Hexacyanoferrate

Prussian Blue [Ferric Hexacyanoferrate] Adverse effects:

Constipation

[ T or F ] Prussian Blue [Ferric Hexacyanoferrate] Given orally, minimal GI absorption (<2%), excreted via feces

False. (<1%)