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

1874 appearance of chills and fever and subsequent myalgia, frontal
headache, anorexia, occasional nausea and vomiting, and rarely,
increased urinary frequency and urgency. CaNa 2
EDTA is teratogenic
in laboratory animals, probably as a result of zinc depletion; it should
be used in pregnant women only under conditions in which the benefits
clearly outweigh the risks (Kalia and Flora, 2005). Other possible
undesirable effects include sneezing, nasal congestion, and
lacrimation; glycosuria; anemia; dermatitis with lesions strikingly
similar to those of vitamin B 6
deficiency; transitory lowering of systolic
and diastolic blood pressures; prolonged prothrombin time; and
T-wave inversion on the electrocardiogram.
SECTION IX
SPECIAL SYSTEMS PHARMACOLOGY
Dimercaprol
Dimercaprol was developed during World War II as an
antidote to lewisite, a vesicant arsenical war gas; hence
its alternative name, British anti-lewisite (BAL).
Arsenicals form a stable and relatively nontoxic chelate
ring with dimercaprol. Pharmacological investigations
revealed that dimercaprol protects against other heavy
metals as well.
Chemistry and Mechanism of Action. The pharmacological actions of
dimercaprol result from formation of chelation complexes between
its sulfhydryl groups and metals. Dissociation of dimercaprol–metal
complexes and oxidation of dimercaprol occurs in vivo. Furthermore,
the sulfur–metal bond may be labile in the acidic tubular urine, which
may increase the delivery of metal to renal tissue and increase toxicity.
The dosage regimen should maintain a concentration of dimercaprol
in plasma adequate to favor the continuous formation of the more stable
2:1 (BAL–metal) complex. However, because of pronounced and
dose-related side effects, excessive plasma concentrations must be
avoided. The concentration in plasma therefore must be maintained
by repeated dosage until the metal is excreted.
Dimercaprol is most beneficial when given very soon after
exposure to the metal because it is more effective in preventing inhibition
of sulfhydryl enzymes than in reactivating them. Dimercaprol
limits toxicity from arsenic, gold, and mercury, which form mercaptides
with essential cellular sulfhydryl groups. It also is used in combination
with CaNa 2
EDTA to treat lead poisoning.
Dimercaprol is contraindicated for use following chronic
exposures to heavy metals because it does not prevent neurotoxic
effects. There is evidence in laboratory animals that dimercaprol
mobilizes lead and mercury from various tissues to the brain
(Andersen and Aaseth, 2002). This effect may be due to the
lipophilic nature of dimercaprol and is not observed with its more
hydrophilic analogs described later (see “Succimer” and “Sodium
2,3-Dimercaptopropane Sulfonate [DMPS]”).
Absorption, Distribution, and Excretion. Dimercaprol cannot be administered
orally; it is given by deep intramuscular injection as a 100 mg/mL
solution in peanut oil and should not be used in patients who are allergic
to peanuts or peanut products. Peak concentrations in blood are
attained in 30-60 minutes. The t 1/2
is short, and metabolic degradation
and excretion essentially are complete within 4 hours. Dimercaprol
and its chelates are excreted in both urine and bile.
Toxicity. The administration of dimercaprol produces a number of
side effects, which occur in ~50% of subjects receiving 5 mg/kg
intramuscularly. One of the most consistent responses to dimercaprol
is a rise in systolic and diastolic arterial pressures, accompanied by
tachycardia. The rise in pressure may be as great as 50 mm Hg in
response to the second of two doses (5 mg/kg) given 2 hours apart.
The pressure rises immediately but returns to normal within 2 hours.
Dimercaprol also can cause anxiety and unrest, nausea and
vomiting, headache, a burning sensation in the mouth and throat, a
feeling of constriction or pain in the throat and chest, conjunctivitis,
blepharospasm, lacrimation, rhinorrhea, salivation, tingling of the
hands, a burning sensation in the penis, sweating, abdominal pain,
and the occasional appearance of painful sterile abscesses at the injection
site. The dimercaprol–metal complex breaks down easily in an
acidic medium; production of an alkaline urine protects the kidney
during therapy. Children react similarly to adults, although ~30% also
may experience a fever that disappears on drug withdrawal.
Dimercaprol is contraindicated in patients with hepatic insufficiency,
except when this condition is a result of arsenic poisoning.
Succimer
Succimer (2,3-dimercaptosuccinic acid [DMSA],
CHEMET) is an orally effective chelator that is chemically
similar to dimercaprol but contains two carboxylic
acids that modify the spectrum of absorption, distribution,
and chelation of the drug. It has an improved toxicity
profile over dimercaprol.
Absorption, Distribution, and Excretion. After its absorption in
humans, succimer is biotransformed to a mixed disulfide with cysteine
(Aposhian and Aposhian, 2006). Succimer lowers blood lead
levels and attenuates lead toxicity. The succimer–lead chelate is
eliminated in both urine and bile. The fraction eliminated in bile can
undergo enterohepatic circulation.
Succimer has several desirable features over other chelators.
It is orally bioavailable, and because of its hydrophilic nature, it does
not mobilize metals to the brain or enter cells. It also does not significantly
chelate essential metals such as zinc, copper, or iron. As a result
of these properties, succimer exhibits a much better toxicity profile
relative to other chelators. Animal studies suggest that succimer also
is effective as a chelator of arsenic, cadmium, mercury, and other toxic
metals (Andersen and Aaseth, 2002; Kalia and Flora, 2005).
Toxicity. Succimer is much less toxic than dimercaprol. Transient
elevations in hepatic transaminases have been observed with succimer
treatment. The most commonly reported adverse effects are
nausea, vomiting, diarrhea, and loss of appetite. In a few patients,
rashes necessitate discontinuation of therapy.
Succimer has been approved in the U.S. for treatment of children
with blood lead levels >45 μg/dL. Because of its oral availability,
improved toxicity profile, and selective chelation of heavy metals,
succimer also is used off label for the treatment of adults with lead
poisoning and for the treatment of arsenic and mercury intoxication,
although no large clinical trials have been undertaken for these
indications.
Sodium 2,3-Dimercaptopropane
Sulfonate (DMPS)
DMPS is another dimercapto compound used for the
chelation of heavy metals. DMPS is not approved by