Page 1040 - Basic _ Clinical Pharmacology ( PDFDrive )

1026 SECTION IX Toxicology

substitution for phosphate. Inorganic arsenic or its metabolites may followed by cardiac dysfunction, pancytopenia, and peripheral
induce oxidative stress, alter gene expression, and interfere with cell neuropathy. The diagnosis may be confirmed by demonstration
signal transduction. Although on a molar basis, inorganic trivalent of elevated amounts of inorganic arsenic and its metabolites in
3+
arsenic (As , arsenite) is generally two to ten times more acutely the urine (typically in the range of several thousand micrograms
5+
toxic than inorganic pentavalent arsenic (As , arsenate), in vivo in the first 2–3 days after acute symptomatic poisoning). Arsenic
interconversion is known to occur, and the full spectrum of arsenic disappears rapidly from the blood, and except in anuric patients,
toxicity has occurred after sufficient exposure to either form. Recent blood arsenic levels should not be used for diagnostic purposes.
studies suggest that the trivalent form of the methylated metabolites Treatment is based on appropriate gut decontamination, intensive
III
(eg, monomethylarsonous acid [MMA ]) may be more toxic than supportive care, and prompt chelation with unithiol, 3–5 mg/kg
the inorganic parent compounds. Reduced efficiency in the meth- intravenously every 4–6 hours, or dimercaprol, 3–5 mg/kg intra-
ylation of MMA to dimethylarsonous acid (DMA), resulting in an muscularly every 4–6 hours. In animal studies, the efficacy of
elevated percentage of MMA in the urine, has been associated with chelation has been highest when it is administered within minutes
an increased risk of chronic adverse effects. Arsenic methylation to hours after arsenic exposure; therefore, if diagnostic suspicion
requires S-adenosylmethionine, a universal methyl donor in the is high, treatment should not be withheld for the several days to
body, and arsenic-associated perturbations in one-carbon metabo- weeks often required to obtain laboratory confirmation.
lism may underlie some arsenic-induced epigenetic effects such as Succimer has also been effective in animal models and has a
altered gene expression. higher therapeutic index than dimercaprol. However, because it
Arsine gas is oxidized in vivo and exerts a potent hemolytic effect is available in the United States only for oral administration, its
associated with alteration of ion flux across the erythrocyte mem- use may not be advisable in the initial treatment of acute arsenic
brane; it also disrupts cellular respiration in other tissues. Arsenic is poisoning, when severe gastroenteritis and splanchnic edema may
a recognized human carcinogen and has been associated with cancer limit absorption by this route.
of the lung, skin, and bladder. Marine organisms may contain large
amounts of a well-absorbed trimethylated organoarsenic, arseno- B. Chronic Inorganic Arsenic Poisoning
betaine, as well as a variety of arsenosugars and arsenolipids. Arseno- Chronic inorganic arsenic poisoning also results in multisys-
betaine exerts no known toxic effects when ingested by mammals temic signs and symptoms. Overt noncarcinogenic effects may
and is excreted in the urine unchanged; arsenosugars are partially be evident after chronic absorption of more than 0.01 mg/kg/d
metabolized to dimethylarsinic acid. Thioarsenite compounds that (~500–1000 mcg/d in adults). The time to appearance of symp-
occur as minor metabolites of inorganic arsenic and methylated toms varies with dose and interindividual tolerance. Constitutional
arsenic compounds in vivo may contribute to toxicity. symptoms of fatigue, weight loss, and weakness may be present,
along with anemia, nonspecific gastrointestinal complaints, and a
Major Forms of Arsenic Intoxication sensorimotor peripheral neuropathy, particularly featuring a stock-
ing glove pattern of dysesthesia. Skin changes—among the most
A. Acute Inorganic Arsenic Poisoning characteristic effects—typically develop after years of exposure and
Within minutes to hours after exposure to high doses (tens to include a “raindrop” pattern of hyperpigmentation, and hyperkera-
hundreds of milligrams) of soluble inorganic arsenic compounds, toses involving the hands and feet (Figure 57–1). Peripheral vas-
many systems are affected. Initial gastrointestinal signs and symp- cular disease and noncirrhotic portal hypertension may also occur.
toms include nausea, vomiting, diarrhea, and abdominal pain. Epidemiologic studies suggest a possible link to hypertension, car-
Diffuse capillary leak, combined with gastrointestinal fluid loss, diovascular disease mortality, diabetes, chronic nonmalignant respi-
may result in hypotension, shock, and death. Cardiopulmonary ratory disease, and adverse reproductive outcomes. Cancer of the
toxicity, including congestive cardiomyopathy, cardiogenic or lung, skin, bladder, and possibly other sites, including the kidney
noncardiogenic pulmonary edema, and ventricular arrhythmias and liver, may appear years after exposure to doses of arsenic that are
(particularly in association with QT c prolongation on the electro- not high enough to elicit other acute or chronic effects. Some stud-
cardiogram) may occur promptly or after a delay of several days. ies suggest that tobacco smoking may interact synergistically with
Pancytopenia usually develops within 1 week, and basophilic stip- arsenic in increasing the risk of certain adverse health outcomes.
pling of erythrocytes may be present soon after. Central nervous Administration of arsenite in cancer chemotherapy regimens,
system effects, including delirium, encephalopathy, and coma, often at a daily dose of 10–20 mg for weeks to a few months,
may occur within the first few days of intoxication. An ascending has been associated with prolongation of the QT interval on the
sensorimotor peripheral neuropathy may begin to develop after a electrocardiogram and occasionally has resulted in malignant ven-
delay of 2–6 weeks. This neuropathy may ultimately involve the tricular arrhythmias such as torsades de pointes.
proximal musculature and result in neuromuscular respiratory The diagnosis of chronic arsenic poisoning involves integra-
failure. Months after an acute poisoning, transverse white striae tion of the clinical findings with confirmation of exposure. The
(Aldrich-Mees lines) may be visible in the nails. urine concentration of the sum of inorganic arsenic and its pri-
Acute inorganic arsenic poisoning should be considered in mary metabolites MMA and DMA is <20 mcg/L in the general
an individual presenting with abrupt onset of gastroenteritis in population. High urine levels associated with overt adverse effects
combination with hypotension and metabolic acidosis. Suspicion may return to normal within days to weeks after exposure ceases.
should be further heightened when these initial findings are Because it may contain large amounts of nontoxic organoarsenic