HEAVY METALS AND HEAVY METAL ANTAGONISTS

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HEAVY METALS AND HEAVY METAL ANTAGONISTS

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INTRODUCTION

• Metals - major fraction of Periodic Table
• generally interpreted to include those metals
  from periodic table groups IIA through VIA
• Heavy metals are natural constituents of the
  Earth's crust and are present in varying
  concentrations in all ecosystems
• Metals differ from other toxic substances in that
  they are neither created nor destroyed by humans.
  Therefore, they tend to accumulate in the soils,
  seawater, freshwater, and sediments.

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• Metals are probably the oldest toxins known to
  humans. Lead usage may have begun prior to 2000
  BC in the smelting of silver. Arsenic was
  obtained during the melting of copper and tin,
  and an early use was for decoration in Egyptian
  tombs/

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• The environmental metals of greatest concern are
  lead, mercury, arsenic, and cadmium..

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• In the past lead paint was available for use in
  homes, and lead pipes and/or lead solder. As a
  result people can be exposed to lead on a daily
  basis this exposure is a major pediatric concern

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• Mercury is a contaminant of our water ways.
  Humans are exposed to mercury in the fish they
  eat as well as in the amalgam fillings in their
  teeth.
• Arsenic is found naturally in high concentration
  in drinking water in various parts of the world.
  Cadmium has been classified as a known human
  carcinogen.

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CHEMICAL AND PHYSICAL PROPERTIES

• CHEMICAL AND PHYSICAL PROPERTIES
• 1. Physical states - solids, liquids, gases
  aerosols
• 2. Elements - indestructible
• 3. Electrophyllic cations - react with ligands
  reversible complexes molecular mimicry
• 4. Oxidation States affects toxicity
• 5. Organometallic compounds differ from inorganic
• 6. Essential versus non-essential

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• Heavy metals (HM) exert their toxic effects by
  combining with one or more reactive groups
  (ligands) essential for normal physiological
  functions.
• Heavy metal antagonists (HMA) - chelating agents
  are designed specifically to compete with these
  groups for the metals, and thereby prevent or
  reverse toxic effects and enhance excretion of
  metals.

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• Nearly all organ systems are involved in heavy
  metal toxicity however, the most commonly
  involved organ systems include the CNS, PNS, GI,
  hematopoietic, renal, and cardiovascular (CV). To
  a lesser extent, lead toxicity involves the
  musculoskeletal and reproductive systems. The
  organ systems affected and the severity of the
  toxicity vary with the particular heavy metal
  involved, the age of the individual, and the
  level of toxicity.

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chelation Treatment of Metal Poisoning

• Chelaters (Greek claw) bind directly with metal
  ions to form stable complexes that remove the
  metal from competition with the body's cells.
  Because a chelated metal is water soluble, it
  can be excreted readily by the kidney.

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• By definition, Chelation is the formation of a
  metal ion complex in which the metal ion is
  associated with a charged or uncharged electron
  donor, referred to as a ligand. A chelate is a
  cyclic complex formed between a metal and a
  compound that contains two or more ligands
  (binding sites). The most stable chelates are
  those with a five or six membered ring.

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Ideal chelating agents

• Water soluble
• Resistant to biotransformation
• Able to reach sites of metal storage
• Capable of forming nontoxic complexes with toxic
  metals
• Be excreted from the body
• Have a low affinity for essential metals

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Dimercaprol - BAL (British Antilewisite)

• BAL clinically useful for treating acute and
  chronic poisoning by organic or inorganic
  arsenals and for protecting against
  mercury-induced renal damage. Not effective in
  treating mercury-induced neurological conditions
  or CNS damage. Not useful to chelate cadmium
  because it can partially dissociate in urine and
  enhance renal damage. Also true for iron and
  selenium.

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• Must be given parentally. BAL blood concentration
  are best achieved and maintained by giving
  repeated doses within the first 4 hours after
  poisoning. Excessive large doses should be
  avoided because of possible side effects.
• Dosage of BAL is designed to assure the formation
  of a 21 complex (2 molecules of BAL 1 molecule
  of metal).

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Adverse effects

• Tachycardia, hypertension, anxiety, nausea,
  vomiting, abdominal pain, headache, agitation,
  salivation, lacrymation,
• Dental and muscle pains
• Pain at the site of injection.
• Burning sensation of the lips, mouth, throat and
  eyes, conjunctivitis,rhinorrhoea, tingling of the
  hands and other extremities, a feeling of
  constriction in the chest and throat, sweating of
  the forehead and hands.

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Calcium Disodium Edetate CaNa2 - EDTA

• will chelate any metal that has a higher binding
  affinity than Ca (lead, iron, zinc, manganese,
  beryllium and copper)
• CaNa2EDTA does not enter host cells but relies on
  excretion of lead into blood from bone. Lead
  chelates with EDTA to form a complex that is 107
  x greater than that of the Ca complex.
• Toxicity to EDTA partly restricts its usage.
  After IV administration, severe proximal nephron
  degeneration may occur. Other symptoms include
  fever, nasal congestion, and dermatitis.

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Penicillamine

• Penicillamine is formed from hydrolysis of
  penicillin. It forms tight chelates with copper,
  lead, mercury, and zinc.
• An advantage of this chelator is that it is well
  absorbed from the GI tract after oral
  administration. Penicillamine is often given for
  long-term treatment of chronic metal poisoning,
  after the patient has been removed from immediate
  danger. (i.e. CaNa2EDTA - lead BAL - mercury).
  Pen is not universally recognized as the
  first-choice antidote.

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• Added advantage of pen is that it facilitates
  removal of methyl mercury and enhances urinary
  mercury excretion after inhalation of mercury
  vapor.
• Pen may cause acute allergy-like reactions,
  particularly in individuals who are allergic to
  penicillin must be carefully given to those
  individuals.

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Succimer

• Succimer is chemically similar to dimercaprol
  (BAL) but is more water soluble, has a high
  therapeutic index, and is absorbed well from the
  GI tract. (It is given orally). It produces a
  lead diuresis comparable to that of CaNa2-EDTA
  and reverses the biochemical toxicity of lead, as
  indicated by normalization of circulatory
  delta-aminolevulinic acid dehydratase (an enzyme
  necessary for heme synthesis). The most common
  adverse effects include nausea, vomiting,
  diarrhea and anorexia.

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Deferoxamine

• Deferoxamine possesses high affinity for both
  ferrous and ferric iron. It is given
  parenterally, since less than 15 is absorbed
  from the GI tract Toxicity - includes allergy
  reactions related to histamine release. Pain at
  the site of injection, rash, itching,
  anaphylactic reactions, hypotension, tachycardia.
  

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Lead Toxicity
An estimated 1.7 million children are currently
affected by lead toxicity in United States, and
almost 900,000 of all children affected are under
the age of six. This statistic is very important
because the symptoms of lead poisoning in
children are strikingly similar to several
psychiatric "diseases" that are on the rise in
the U.S. Children with high lead levels can
exhibit lower IQ scores, learning disabilities,
hyperactivity , aggressive or disruptive
behavior, and difficulty maintaining attention. A
child exhibiting this type of behavior today
would likely be sent to a doctor's office,
diagnosed with attention deficit disorder, and
promptly started on Ritalin or other psychoactive
drugs.
Needleman HL ,1990
Lead levels and Hyperactivity
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Sources of Lead - environmental

• 1. Combustion of tetramethyl in gasoline
• 2. Persistent lead-based paint (children with
  Pica)
• 3. Improperly glazed earthenware
• 4. Lead piping (acid rain)
• 5. Solder in food containers
• 6. Moonshine whiskey
• 7. Automobile battery casing 

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Occupational

• 1. Smelters (air concentration may exceed
  1000g/m3)
• 2. Storage battery manufacture (50 total U.S.
  consumption)
• 3. Welding and cutting lead-painted structures
• 4. Automobile radiator repair
• 5. Production of lead-based paints (6 total U.S.
  consumption)
• 6. Frequent use of firearms

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LEAD Distribution
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Absorption

• Gastrointestinal Tract
• 8 absorbed (adult)
• 50 absorbed (children)
• Ca, Fe decrease absorption
• Respiratory Tract - Particle size
• Chemical form
• Skin - Does occur at high exposures 

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