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)Penicillamine2,3-dimercatopropanol (BAL, Dimercaprol)2,3-dimercatosuccinic acid (Succimer)
Arsenic N-acetyl-penicillamine (NAP)
Antimony Ethylenediamine-tetraacetic acid (EDTA)
Iron Deferoxamine
Heavy Metal Toxicity
Metabolism after exposure to metals via skin absorption, inhalation, and ingestion
Environmental Factors That Influence Lead Toxicity
1. Pollution from air line industry- major cities like Atlanta, Chicago, New York
2. Pottery related lead toxicity – associated 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
Lead Toxicity Interferes With Heme Biosynthesis
Heme
Hemoglobin RBC function
Myoglobin Muscle function
Cytochromes Mitochondrial Respiration
MECHANISM OF LEAD TOXICITY
Heme Biosynthesis
Succinyl CoA + Glycine
δ-Aminolevulinate synthasePb
δ-Aminolevulinate
δ-Aminolevulinate dehydratasePb
Porphobilinogen
Porphobilinogen deminase
Uroporphyrinogen III cosynthase
Uroporphyrinogen III
Uroporphyrinogen decarboxylase
Coproporphyrinogen III
Coproporphyrinogen oxidase
Protoporphyrin IX
Ferrochelatase + Fe2+Pb
Pb
Increasedin plasmaand urine
Increased in plasma and
urine
Heme
Lead
Absorptiona. Skin- alkyl lead compounds (because of lipid solubility)b. Inhalation- up to 90% depending particle sizec. GI- adults 5 t0 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, moonshineb. Inhalation- metal fumesc. Skin- tetraethyl lead in gasoline
Mechanism of Toxicity:a. Inhibits heme biosynthesisb. Binds to sulfhydryl groups (-SH groups) of proteins
Diagnosis:a. History of exposureb. Whole blood lead level
1. Children: >25 μg/dl treatments2. Adults: >50 μg/dl candidates for treatment
c. Protoporphyrin levels in erythrocytes are usually elevated with lead levels> 40 μg/dl d. Urinary lead excretion >80 μg/dl e. Urinary δ aminolevulonic acid
Treatment:a. Remove from exposureb. CaNa2EDTAc. 2,3-dimercaptopropanol (Dimercaprol, BAL)d. 2,3-dimercaptosuccinic acid (Succimer)e. D-penicillamine
Liver Cell
Cd-MT
Lysosome
Renal Cell
aa
Cd
MT Cd
Cd-MTdamageCd (200 μg/g)
Cd-MT
CdMT
Cd
Cd-GSH GSH
TubularFluid
Glomerular membrane
Plasma
Cd-Alb
Cd-MT Cd-MT
Cd-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, batteriesc. Inhalation industrial, metal fumes, tobacco- 1 – 2 μg/pack
Mechanism of toxicity:a. Inhalation: lung – local irritation and inhibition of α1-antitrypsin associated with emphysema
b. Renal: Mechanism of cadmium-induced renal toxicity
Treatment:a. Remove from exposureb. CaNa2 EDTA
(2,3 dimercaptopropanol (BAL) Cadmium complex extremely
nephrotoxic and therefore is not used)
Mercury (Hg)
Source of exposure:a. environmental from electronics and plastic industryb. 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 to organic 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 membranesb. necrosis of proximal tubular epitheliumc. inhibition of sulfhydryl (-SH) group containing enzymes
Diagnosis:a. history of exposureb. blood mercury
Treatment: a. remove from exposureb. Hg and Hg salts > 4 μg/dl: 2,3 dimercaptopropanol (BAL),
penicillamine, N-acetyl-penicillamine (most effective)
Minamata disease:
Arsenic, As3+, As5+
Sources of exposure:a. GI – well 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 enzymesc. Inhibition of anaerobic and oxidative phosphorylation (substitutes for
inorganic phosphate in synthesis of high-energy phosphates)
Symptoms:a. Acute – damage to mucosa, sloughing, diarrhea (rice-water stools), hypovolemic shock, fever, etc.b. Chronic- weakness, GI irritation, hepatomegaly, melanosis, arrhythmias, peripheral neuropathy, perivascular disease (blackfoot disease)c. Carcinogenicity- epidemilogic evidence; liver angiosarcoma, skin and lung cancer
Treatment:a. Remove from exposureb. 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)
CH2CH 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
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
H3C C
CH3
SH
CH
NH2
COOH H3C C
CH3
S
CH
NH
COOH
H3C C
CH3
SH
CH
N
COOH H3C C
CH3
S
CH
N
C
Hg
CO
CH3
OHO
C CH3
OHg
Penicillamine
N-acetyl penicillamine
Penicillamine-Hg complex
N-acetyl penicillamine-Hg complex
Given orally
Uses: 1. lead, mercury, arsenic 2. copper- Wilson’s disease
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)Penicillamine2,3-dimercatopropanol (BAL, Dimercaprol)2,3-dimercatosuccinic acid (Succimer)
Arsenic N-acetyl-penicillamine (NAP)
Antimony Ethylenediamine-tetraacetic acid (EDTA)
Iron Deferoxamine
• 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 in plasma and
urine (Diagnosis); Children ingested large quantities of paint containing lead is called “Pica”• Cadmium: Inhibits 1-antitrypsin –(emphysema), nephrotoxicity• Mercury: Mercury salts precipitates proteins, necrosis, inhibits sulfhydryl (-SH) group containing 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 (Wilson’s disease)• Penicillamine; N-acetyl-penicillamine• Allergic to penicilline – Trientine (triethylenetetramine HCl)•
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