Heavy Metal Toxicity METALS AND DRUGS CHELATORS TO CONSIDER METAL Lead CHELATING AGENTS DRUGS 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 2 3 dimercatopropanol BAL Dimercaprol 2 3 dimercatosuccinic acid Succimer Arsenic N acetyl penicillamine NAP Antimony Ethylenediamine tetraacetic acid EDTA Iron Deferoxamine 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 Hemoglobin Heme RBC function Myoglobin Muscle function Cytochromes Mitochondrial Respiration MECHANISM OF LEAD TOXICITY Heme Biosynthesis Succinyl CoA Glycine Pb Increased in plasma and urine Aminolevulinate synthase Aminolevulinate Pb Aminolevulinate dehydratase Porphobilinogen Porphobilinogen deminase Uroporphyrinogen III cosynthase Uroporphyrinogen III Uroporphyrinogen decarboxylase Coproporphyrinogen III Pb Increased in plasma and urine Coproporphyrinogen oxidase Protoporphyrin IX Pb Ferrochelatase Fe2 Heme 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 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 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 1 2 g pack Mechanism of toxicity a Inhalation lung local irritation and inhibition of 1 antitrypsin associated with emphysema b Renal Mechanism of cadmium induced renal toxicity Bile Tubular Fluid Plasma Cd GSH Cd GSH Cd MT GSH Cd Alb damage Cd 200 g g Cd MT MT Cd Cd Cd Lysosome Cd MT Cd MT Cd MT Liver Cell to urine Glomerular membrane Diagnosis a History of exposure b Blood cadmium level 80 g dl Cd MT Renal Cell aa 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 a b Remove from exposure 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 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 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 membranes b necrosis of proximal tubular epithelium c inhibition of sulfhydryl SH group containing enzymes Diagnosis a history of exposure b blood mercury 4 g dl 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 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 enzymes c Inhibition of anaerobic and oxidative phosphorylation substitutes for inorganic phosphate in synthesis of high energy phosphates 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 a Remove from exposure b Acute supportive therapy fluid electrolyte replacement blood pressure support dopamine c Chronic penicillamine w o dialysis Arsine gas AsH3 acts as hemolytic
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