Chemistry Reference
In-Depth Information
that may be dialyzable are arsenic, copper, iron, lead,
lithium, magnesium, mercury, potassium, sodium,
strontium, and zinc. The procedure is indicated when
a potentially fatal dose has been absorbed, when the
clinical condition is deteriorating despite adequate
treatment by other means, and when a complication
exists, such as aspiration pneumonia or renal insuffi -
ciency. Severe poisoning with lithium salts should be
treated with prolonged hemodialysis. Peritoneal dialy-
sis may be used where hemodialysis is not available.
In severe acute inorganic mercury poisoning, dial-
ysis may be performed after giving dimercaprol to
remove the mercury complex.
particular in Wilson's disease, in blood transfusion iron
overload as in the thalassemias and in hemochromato-
sis, and to aid the elimination of metallic radionuclides
from the body. The pharmacology and therapeutic
applications of chelating agents were reviewed by
Catsch and Harmuth-Hoene (1976) and updated by
Andersen (1999), Andersen and Aaseth (2002), and
Andersen (2004). The basic principle underlying che-
lation is that the therapeutic agent should possess
electron donor groups showing a high affi nity for the
metal to be removed, thus releasing it from complexes
with proteins or other endogenous ligands in a form
in which it can be readily excreted. The effectiveness
of ligand exchange depends on the relative stability
constants for the metal-endogenous ligand and the
metal-therapeutic ligand complexes, on the rate of
ligand exchange, on the effective concentration of the
agent in the region of the metal-endogenous ligand
complex, and on the stability of the newly formed
chelate. The chelating agent should form complexes
with the toxic metal that have much greater stability
than those formed with physiologically essential met-
als such as iron, calcium, zinc, or copper. Treatment
is most effective if the chelating agent is given while
the metal is still in the circulation or in the extracellu-
lar fl uid compartment, because once intracellular, the
metal is less accessible. Many chelating agents are in
an ionized form and, therefore, have limited ability to
penetrate cell membranes.
Effective chelation forming a less toxic species that
may be effectively excreted depends on physical and
chemical characteristics of metals and chelators, such
as ionic diameter, ring size and deformability, hard-
ness/softness of electron donors and acceptors, admin-
istration route, bioavailability, metabolism, organ and
intra/extra cellular compartmentalization, and excre-
tion. Account has to be taken that the metal selectivity
of chelators may result in depletion of essential metals
or to the redistribution of toxic metals to other tissues
(e.g., the brain) (Andersen 2004; Andersen and Aaseth
2002).
3.3.4 Exchange Transfusion
When there are no facilities for hemodialysis or when
the toxic material is poorly dialyzable, exchange trans-
fusion may be lifesaving in severe poisoning by agents
that remain in the blood in appreciable concentrations.
3.4 Inactivation of the Absorbed Poison
A limited number of therapeutic agents may be
administered to counteract the effects of an absorbed
toxic metal. Such a specifi c antidote may act in differ-
ent ways. It may combine with the toxic agent to form
a less toxic or a nontoxic compound, which may be
excreted more effectively in the urine; it may compete
with the toxic agent and displace it from its receptor
site; or it may displace the poison into a tissue where it
cannot exert its toxic effects. The intravenous adminis-
tration of calcium gluconate will displace lead from its
site of action and will temporarily relieve the intense
pain of lead colic. An infusion of potassium has been
shown to correct the potassium-displacing capacity of
absorbed soluble barium salts (Berning, 1975).
Certain antidotes have been designed specifi cally
to compete, for toxic metals, with ligands essential for
normal physiological function. These toxic metal antag-
onists, or chelating agents, form a stable complex with
the metal in the form of a heterocyclic ring (Klaassen,
1980). The antagonists and the chelates produced are
not themselves without toxic effects, and they should
not, therefore, be administered therapeutically in those
mild cases of poisoning where removal from further
exposure is suffi cient to promote recovery. Chelation
therapy, because of its value in metal poisoning, is con-
sidered in greater detail below.
3.5.1 Dimercaprol
2,3-Dimercaptopropanol (dimercaprol, British anti-
lewisite, BAL), now a classic chelator, was synthe-
sized as a specifi c antagonist to the vesicant arsenical
war gases. It is a dithiol compound that successfully
competes with protein sulfhydryl groups for arsenic
compounds and for other heavy metals by forming
a stable chelate with them. The other metals for which
dimercaprol has been shown to be effective are mer-
cury in inorganic form, antimony, bismuth, and gold.
In cases with acute lead encephalopathy and increased
3.5 Chelation Therapy
Chelation is indicated in the treatment of metal poi-
soning, in the treatment of metal-storage diseases, in
