Metal Toxicity M2 2011

7/31/2019 Metal Toxicity M2 2011

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Heavy Metal Toxicity

METALS AND DRUGS (CHELATORS) TO CONSIDER

METAL CHELATING AGENTS (DRUGS)

Lead Ethylenediamine-tetraacetic acid (EDTA)

2,3-dimercatosuccinic acid (Succimer)

2,3-dimercatopropanol (BAL, Dimercaprol)

Penicillamine

Cadmium Ethylenediamine-tetraacetic acid (EDTA)

Mercury N-acetyl-penicillamine (NAP)

Penicillamine



Arsenic N-acetyl-penicillamine (NAP)

Antimony Ethylenediamine-tetraacetic acid (EDTA)

Iron Deferoxamine


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Metabolism after exposure to metals via skin absorption, inhalation, and ingestion


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Environmental Factors That Influence Lead Toxicity

1. Pollution from air line industry- major cities like Atlanta,

Chicago, New York

2. Pottery related lead toxicityassociated with travelling

3. School Children Projects-associated with handling clay

4. Consumption of illicitly distilled liquor

5. Old lead pipes corrode and contaminate drinking water

6. Lead contamination associated with painting

7. Gasoline tank cleaning associated organic lead toxicity

8. Recent recalls on toys (Made in China) due to excessive lead

contamination


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Lead Toxicity Interferes With Heme Biosynthesis

Heme

Hemoglobin RBC function

Myoglobin Muscle function

Cytochromes Mitochondrial Respiration


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MECHANISM OF LEAD TOXICITY

Heme Biosynthesis

Succinyl CoA + Glycine

-Aminolevulinate synthasePb

-Aminolevulinate

-Aminolevulinate dehydratasePb

Porphobilinogen

Porphobilinogen deminase

Uroporphyrinogen III cosynthase

Uroporphyrinogen III

Uroporphyrinogen decarboxylase

Coproporphyrinogen III

Coproporphyrinogen oxidase

Protoporphyrin IX

Ferrochelatase + Fe2+Pb

Pb

Increased

in plasma

and urine

Increasedin plasma and

urine

Heme


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Lead

Absorption

a. Skin- alkyl lead compounds (because of lipid solubility)

b. Inhalation- up to 90% depending particle size

c. GI- adults 5 to 10%, children 40%

Distribution: Initially carried in RBC and distributed to soft tissues

(kidney and liver); redistributed to bone, teeth, and hair

Source of exposure:

a. GI- paint, pottery, moonshine

b. Inhalation- metal fumes

c. Skin- tetraethyl lead in gasoline

Mechanism of Toxicity:

a. Inhibits heme biosynthesis

b. Binds to sulfhydryl groups (-SH groups) of proteins

Diagnosis:

a. History of exposure

b. Whole blood lead level

1. Children: >25 g/dl treatments

2. Adults: >50 g/dl candidates for treatment

c. Protoporphyrin levels in erythrocytes are usually elevated

with lead levels> 40 g/dl

d. Urinary lead excretion >80 g/dl

e. Urinary aminolevulonic acid


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Clinical Symptoms

Acute: nausea, vomiting, thirst, diarrhea/constipation, abdominal pain

hemoglobinuria, oliguria leading to hypovolemic shock

Chronic: GI- lead colic (nausea, vomiting, abdominal pain)

NMJ- lead palsy (weakness, fatigue, wrist-drop)

CNS- lead encephalopathy (headache, vertigo, irritation, insomnia

CNS edema)

Treatment

a. Remove from exposure

b. CaNa2EDTA

c. 2,3-dimercaptopropanol (Dimercaprol, BAL)

d. 2,3-dimercaptosuccinic acid (Succimer)

e. D-penicillamine


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Liver Cell

Cd-MT

Lysosome

Renal Cell

aa

Cd

MT Cd

Cd-MTdamageCd (200 g/g)

Cd-MT

CdMT

Cd

Cd-GSH GSH

Tubular

Fluid

Glomerular

membrane

Plasma

Cd-Alb

Cd-MT Cd-MT

-GSH

Bile

to urine

Cadmium (Cd++)Absorption:

a. Inhalation 10 to 40%

b. GI 1.5 to 5%Source of Exposure:

a. GI-pigments, polishes, antique toys

Environmental- electroplating, galvanization, plastics, batteries

c. Inhalation industrial, metal fumes, tobacco- 12 g/pack

Mechanism of toxicity:

a. Inhalation: lunglocal irritation and inhibition of1-antitrypsin

associated with emphysema

b. Renal:

Mechanism of cadmium-induced renal toxicity

Diagnosis:

a, History of exposure

b, Blood cadmium level >80 g/dl


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Clinical Symptoms

Acute: Oral- vomiting, diarrhea, abdominal cramps

Inhalation- chest pains, nausea, dizziness, diarrhea, pulmonary edema

Chronic: Oral- nephrotoxicity

Inhalation- emphysema-like syndrome and nephrotoxicity

Treatment


b. CaNa2 EDTA

(2,3 dimercaptopropanol (BAL) Cadmium complex extremely

nephrotoxic and therefore is not used)


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Mercury (Hg)

Source of exposure:

a. environmental from electronics and plastic industry

b. seed fungicide treatment, dentistry (dental amalgam fillings), wood

preservatives, herbicides and insecticides, thermometers, batteries, and other

products

Absorption:

a. GI- inorganic salts are variably absorbed (10%) but may be converted toorganic mercury (methyl and ethyl in the gut by bacteria); organic

compounds are well absorbed >90%

b. Inhalation- elemental Hg completely absorbed

Mechanisms of toxicity:

a. dissociation of salts precipitates proteins and destroys mucosal

membranes

b. necrosis of proximal tubular epitheliumc. inhibition of sulfhydryl (-SH) group containing enzymes

Diagnosis:

a. history of exposure

b. blood mercury >4 g/dl


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Clinical Symptoms

Acute:

1, (inorganic salts) degradation of mucosa- GI pain, vomiting, diuresis,

anemia, hypovolemic shock, renal toxicity.

2, (organic) CNS involvement- vision, depression, irritability, blushing,

intention tremors, insomnia, fatigue, diuresis

Chronic: CNS symptoms similar to acute organic poisoning with gingivitis,

tachycardia, goiter, increased urinary Hg

Treatment

a. remove from exposure

b. Hg and Hg salts > 4 g/dl: 2,3 dimercaptopropanol (BAL), penicillamine,

N-acetyl-penicillamine (most effective)

c. Methyl Hg- supportive treatment (non absorbable thiol resins can be given

orally to reduce Hg level in the gut)

Minamata disease:


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Arsenic, As3+, As5+

Sources of exposure:

a. GIwell water, food

b. Inhalation- fumes and dust from smelting

Environmental: byproducts of smelting ore, AsGa in semiconductors,

herbicides and pesticides

Absorption:

a. GI-inorganic: trivalent (arsenites) and pentavalent (arsenates) salts >90%

organic: also bound as tri and pentavalent >90%

Distribution: accumulates in lung, heart, kidney, liver, muscle and neural tissue.

Concentrates in skin, nails and hair. Half life is 7 to 10 hours

Mechanism of toxicity:

a. Membranes: protein damage of capillary endothelium increased vascular

permeability leading to vasodilation and vascular collapse

b. Inhibition of sulfhydryl group containing enzymes

c. Inhibition of anaerobic and oxidative phosphorylation (substitutes for

inorganic phosphate in synthesis of high-energy phosphates)


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Clinical Symptoms

Acute: damage to mucosa, sloughing, diarrhea (rice-water stools),

hypovolemic shock, fever, GI discomport/pain, anorexia.

Chronic: weakness, GI irritation, hepatomegaly, melanosis, arrhythmias,

peripheral neuropathy, perivascular disease (blackfoot disease)

Carcinogenicity: epidemilogic evidence; liver angiosarcoma, skin and lung cancer

Treatment


b. Acute: supportive therapy- fluid, electrolyte replacement, blood pressure

support (dopamine)

c. Chronic: penicillamine w/o dialysis

Arsine gas (AsH3) acts as hemolytic agent with secondary to

renal failure. Supportive therapy: transfusion (chelators have not

been shown to be beneficial)


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CH2 CH CH2

OHSH SH

CH2 CH CH2

OHS S

Hg

CH2 CH CH2

OHS S

Hg

S S

CH2 CH CH2

OH

Chelators

2, 3-dimercaptopropanol (dimercaprol) or BAL

Structure Complex with Hg

IM-administration in peanut oil

Use-arsenic, mercury, antimony, lead


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Ethylene diamine-tetraacetic acid (EDTA)

EDTA disodium salt

EDTA calcium disodium salt

Pb-EDTA complex

Given IV as calcium disodium salt.

EDTA is not cell permeable


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H3C C

CH3

SH

CH

NH2

COOH H3C C

CH3

S

CH

NH

COOH

H3C C

CH3

SH

CH

N

COOH H3CC

CH3

S

CH

N

C

Hg

C

O

CH3

OH

O

C CH3OHg

Penicillamine

N-acetyl penicillamine

Penicillamine-Hg complex

N-acetyl penicillamine-Hg complex

Given orally

Uses: 1. lead, mercury, arsenic

2. copper- Wilsons disease


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METALS AND DRUGS (CHELATORS) TO CONSIDER

METAL CHELATING AGENTS (DRUGS)

Lead Ethylenediamine-tetraacetic acid (EDTA)



Penicillamine

Cadmium Ethylenediamine-tetraacetic acid (EDTA)

Mercury N-acetyl-penicillamine (NAP)

Penicillamine



Arsenic N-acetyl-penicillamine (NAP)

Antimony Ethylenediamine-tetraacetic acid (EDTA)

Iron Deferoxamine


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Study Aid For Heavy Metal Toxicity

Know specific chelating agents for each metals and route of administration.

Lead: Calcium disodium EDTA (IV)

2, 3-dimercaptosuccinic acid (Succimer) (Oral)

2, 3-dimercaptoproponol (BAL, Dimercaprol) (IM)

Penicillamine (Oral)

Cadmium: Calcium disodium EDTA (IV)

Mercury: 2, 3-dimercaptosuccinic acid (Succimer) (Oral)

2, 3-dimercaptoproponol (BAL, Dimercaprol) (IM)

Penicillamine (Oral) N-acetyl-penicillamine (Oral)

Arsenic: N-acetyl-penicillamine (Oral)

Penicillamine (Oral)

Arsine gas (AsH3) (hemolytic agent): transfusion

Iron: Defroxamine (IM, slow IV, Oral-under rare circumstance)

Know the mechanism of absorption.

Skin, Inhalation, GI

Know the mechanisms of toxicity

Lead: Inhibits Heme Biosynthesis- -aminolevulonic acid and Protoporphyrin IX increases inplasma and urine (Diagnosis); Children ingested large quantities of paint containing lead iscalled Pica

Cadmium: Inhibits 1-antitrypsin(emphysema), nephrotoxicity

Mercury: Mercury salts precipitates proteins, necrosis, inhibits sulfhydryl (-SH) groupcontaining enzymes; plastic industry-Minamata disease

Arsenic: Increases vascular permeability, Inhibits anaerobic and oxidative phosphorylation;(semiconductors, herbicides, pesticides, water contamination)

Know why EDTA given IV.

EDTA cannot cross the cell membrane.

Know why EDTA given as Calcium disodium salt. To balance the calcium level

Know how to treat copper poison (Wilsons disease)

Penicillamine; N-acetyl-penicillamine

Allergic to penicillineTrientine (triethylenetetramine HCl)


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Documents

Metal Toxicity M2 2011