DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

NaO
O
NH 2
(CH 2 ) 5
N
O
N
R 2
O
Ca
exposure alone and, in some cases, does more harm
than good. Chelation therapy may increase the neurotoxic
effects of heavy metals and is only recommended
for acute poisonings. The structures of the most commonly
used chelators are shown in Figure 67–10.
Ethylenediaminetetraacetic Acid (EDTA)
EDTA and its various salts are effective chelators of
divalent and trivalent metals. Calcium disodium EDTA
(CaNa 2
EDTA) is the preferred EDTA salt for metal
poisoning, provided that the metal has a higher affinity
for EDTA than calcium. CaNa 2
EDTA is effective for
the treatment of acute lead poisoning, particularly in
combination with dimercaprol, but is not an effective
chelator of mercury or arsenic in vivo.
Chemistry and Mechanism of Action. The pharmacological effects of
CaNa 2
EDTA result from chelation of divalent and trivalent metals in
the body. Accessible metal ions (both exogenous and endogenous)
O
N
SH
Dimercaprol: R 1 =CH 2 OH, R 2 =H
Succimer: R 1 =R 2 =COOH
DMPS: R 1 =CH 2 SO 3 H, R 2 =H
OH
H 3 C
O
CaNa 2 EDTA
R 1
CH 3
SH
NH 2
Penicillamine
COH
O
O
ONa
Deferoxamine
Figure 67–10. Structures of chelators commonly used to treat
acute metal intoxication. CaNa 2
EDTA, calcium disodium ethylenediamine
tetraacetic acid; DMPS, sodium 2,3-dimercaptopropane
sulfonate.
O
SH
N
H
(CH 2 ) 5
N
OH
O
with a higher affinity for CaNa 2
EDTA than Ca 2+ will be chelated,
mobilized, and usually excreted. Because EDTA is charged at physiological
pH, it does not significantly penetrate cells. CaNa 2
EDTA
mobilizes several endogenous metallic cations, including those of
zinc, manganese, and iron. Additional supplementation with zinc
following chelation therapy may be beneficial. The most common
therapeutic use of CaNa 2
EDTA is for acute lead intoxication.
CaNa 2
EDTA does not provide clinical benefits for the treatment of
chronic lead poisoning. There is evidence in rats that CaNa 2
EDTA
mobilizes lead from various tissues to the brain and liver, which may
account for this observation (Sánchez-Fructuoso et al., 2002;
Andersen and Aaseth, 2002).
CaNa 2
EDTA is available as edetate calcium disodium (calcium
disodium versenate). Intramuscular administration of CaNa 2
EDTA
results in good absorption, but pain occurs at the injection site; consequently,
the chelator injection often is mixed with a local anesthetic
or administered intravenously. For intravenous use, CaNa 2
EDTA
is diluted in either 5% dextrose or 0.9% saline and is administered
slowly by intravenous drip. A dilute solution is necessary to avoid
thrombophlebitis. To minimize nephrotoxicity, adequate urine
production should be established prior to and during treatment
with CaNa 2
EDTA. However, in patients with lead encephalopathy
and increased intracranial pressure, excess fluids must be avoided.
In such cases, intramuscular administration of CaNa 2
EDTA is
recommended.
EDTA and its glycol congener, EGTA, are used in biological
research to chelate and control the concentration of Ca 2+ in biological
buffer solutions. The 2008 Nobel laureate, Roger Tsien,
and his colleagues used the EDTA/EGTA structure as a starting
point in the development of fluorescent sensors of cellular [Ca 2+ ]
(Tsien et al., 1984).
Absorption, Distribution, and Excretion. Less than 5% of
CaNa 2
EDTA is absorbed from the GI tract. After intravenous administration,
CaNa 2
EDTA has a t 1/2
of 20-60 minutes. In blood,
CaNa 2
EDTA is found only in the plasma. CaNa 2
EDTA is excreted
in the urine by glomerular filtration, so adequate renal function is
necessary for successful therapy. Altering either the pH or the rate of
urine flow has no effect on the rate of excretion. There is very little
metabolic degradation of EDTA. The drug is distributed mainly in
the extracellular fluids; very little gains access to the spinal fluid
(5% of the plasma concentration).
Toxicity. Rapid intravenous administration of Na 2
EDTA causes
hypocalcemic tetany. However, a slow infusion (<15 mg/minute)
administered to a normal individual elicits no symptoms of hypocalcemia
because of the availability of extracirculatory stores of Ca 2+ .
In contrast, CaNa 2
EDTA can be administered intravenously with no
untoward effects because the change in the concentration of Ca 2+ in
the plasma and total body is negligible.
The principal toxic effect of CaNa 2
EDTA is on the kidney.
Repeated large doses of the drug cause hydropic vacuolization of
the proximal tubule, loss of the brush border, and eventually, degeneration
of proximal tubular cells. The early renal effects usually are
reversible, and urinary abnormalities disappear rapidly with cessation
of treatment. The most likely mechanism of toxicity is chelation
of essential metals, particularly zinc, in proximal tubular cells.
Other side effects associated with CaNa 2
EDTA include
malaise, fatigue, and excessive thirst, followed by the sudden
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CHAPTER 67
ENVIRONMENTAL TOXICOLOGY: CARCINOGENS AND HEAVY METALS