Robert L.
Copeland, Jr., Ph.D.,
(c) All Rights Reserved THE DEPARTMENT OF PHARMACOLOGY
Howard University College of Medicine and
The Graduate School of Arts and Sciences
Metals differ from other toxic substances in that they are neither created nor
destroyed by humans.
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/
The environmental metals of greatest concern are lead, mercury, arsenic, and cadmium. 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.
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.
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.
Chelation Treatment of Metal Poisoning
Cheaters (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.
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.
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.
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 2:1 complex (2 molecules of BAL:
1 molecule of metal).
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.
Penicillamine
Pen 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.
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.
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.
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.