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

the FDA but is approved for use in Germany. DMPS is
available from compounding pharmacies and is used by
some doctors in the U.S.
Chemistry and Mode of Action. DMPS is a clinically effective chelator
of lead, arsenic, and especially mercury. It is orally available and
is rapidly excreted, primarily through the kidneys. It is negatively
charged and exhibits distribution properties similar to those of succimer.
DMPS is less toxic than dimercaprol but mobilizes zinc and
copper and thus is more toxic than succimer. In a small clinical trial,
DMPS exhibited some clinical benefit for the treatment of chronic
arsenic poisoning. Similar benefits were not observed with either
dimercaprol or succimer, suggesting that DMPS might be effective
for treatment of chronic heavy metal poisonings (Kalia and Flora,
2005). However, more thorough clinical studies are needed.
Penicillamine; Trientine
Penicillamine was first isolated in 1953 from the urine
of patients with liver disease who were receiving penicillin.
Discovery of its chelating properties led to its use
in patients with Wilson’s disease (excess body burden
of copper due to diminished excetion) and heavy-metal
intoxications. Penicillamine is more toxic and is less
potent and selective for chelation of heavy metals relative
to other available chelation drugs. It is therefore not
a first-line treatment for acute intoxication with lead,
mercury, or arsenic. However, because it is inexpensive
and orally bioavailable, it often is given at fairly low
doses following treatment with CaNa 2
EDTA and/or
dimercaprol to ensure that the concentration of metal
in the blood stays low following the patient’s release
from the hospital.
Penicillamine is an effective chelator of copper,
mercury, zinc, and lead and promotes the excretion of
these metals in the urine.
Absorption, Distribution, Biotransformation, and Excretion.
Penicillamine (CUPRIMINE, DEPEN) is available for oral administration.
For chelation therapy, the usual adult dose is 1-1.5 g/day in four
divided doses. The drug should be given on an empty stomach to
avoid interference by metals in food. In addition to its use as a chelating
agent for the treatment of copper, mercury, and lead poisoning,
penicillamine is used in Wilson’s disease (hepatolenticular degeneration
owing to an excess of copper), cystinuria, and rheumatoid
arthritis (rarely). For the treatment of Wilson’s disease, 1-2 g/day
usually is administered in four doses. The urinary excretion of copper
should be monitored to determine whether the dosage of penicillamine
is adequate.
Penicillamine is well absorbed (40-70%) from the GI tract.
Food, antacids, and iron reduce its absorption. Peak concentrations
in blood are obtained between 1 and 3 hours after administration.
Penicillamine is relatively stable in vivo compared to its unmethylated
parent compound cysteine. Hepatic biotransformation primarily
is responsible for degradation of penicillamine, and very little
drug is excreted unchanged. Metabolites are found in both urine and
feces. N-Acetylpenicillamine is more effective than penicillamine in
protecting against the toxic effects of mercury, presumably because
it is more resistant to metabolism.
Toxicity. With long-term use, penicillamine induces several cutaneous
lesions, including urticaria, macular or papular reactions, pemphigoid
lesions, lupus erythematosus, dermatomyositis, adverse
effects on collagen, and other less serious reactions, such as dryness
and scaling. Cross-reactivity with penicillin may be responsible for
some episodes of urticarial or maculopapular reactions with generalized
edema, pruritus, and fever that occur in as many as one-third
of patients taking penicillamine. The hematological system also may
be affected severely; reactions include leukopenia, aplastic anemia,
and agranulocytosis. These may occur at any time during therapy
and may be fatal, so patients should be monitored carefully.
Renal toxicity induced by penicillamine usually is manifested
as reversible proteinuria and hematuria, but it may progress to
nephrotic syndrome with membranous glomerulopathy. More rarely,
fatalities have been reported from Goodpasture’s syndrome. Toxicity
to the pulmonary system is uncommon, but severe dyspnea has been
reported from penicillamine-induced bronchoalveolitis. Myasthenia
gravis also has been induced by long-term therapy with penicillamine.
Penicillamine is a teratogen in laboratory animals, but for
pregnant women with Wilson’s disease, the benefits appear to outweigh
the risks. Less serious side effects include nausea, vomiting,
diarrhea, dyspepsia, anorexia, and a transient loss of taste for sweet
and salt, which is relieved by supplementation of the diet with copper.
Contraindications to penicillamine therapy include pregnancy,
renal insufficiency, or a previous history of penicillamine-induced
agranulocytosis or aplastic anemia.
Trientine. Penicillamine is the drug of choice for treatment
of Wilson’s disease. However, the drug produces
undesirable effects, as discussed in “Toxicity,” and
some patients become intolerant. For these individuals,
trientine (triethylenetetramine dihydrochloride, SYPRINE)
is an acceptable alternative. Trientine is an effective
cupriuretic agent in patients with Wilson’s disease,
although it may be less potent than penicillamine. The
drug is effective orally. Maximal daily doses of 2 g for
adults or 1.5 g for children are taken in two to four
divided portions on an empty stomach. Trientine may
cause iron deficiency; this can be overcome with
short courses of iron therapy, but iron and trientine
should not be ingested within 2 hours of each other.
Deferoxamine; Deferasirox
Deferoxamine is isolated as the iron chelate from
Streptomyces pilosus and is treated chemically to obtain
the metal-free ligand. Deferoxamine has the desirable
properties of a remarkably high affinity for ferric iron
(K a
= 1031) coupled with a very low affinity for calcium
(K a
= 102). In vitro, it removes iron from hemosiderin
and ferritin and, to a lesser extent, from transferrin.
Iron in hemoglobin or cytochromes is not removed by
deferoxamine.
1875
CHAPTER 67
ENVIRONMENTAL TOXICOLOGY: CARCINOGENS AND HEAVY METALS