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

1870 Skin. The skin is very sensitive to chronic arsenic exposure.
Dermal symptoms often are diagnostic of arsenic
exposure. Arsenic induces hyperkeratinization of the skin
(including formation of multiple corns or warts), particularly
of the palms of the hands and the soles of the feet.
It also causes areas of hyperpigmentation interspersed
with spots of hypopigmentation. These symptoms can be
observed in individuals exposed to drinking water with
arsenic concentrations of at least 100 μg/L and are typical
in those chronically exposed to much higher levels.
Hyperpigmentation can be observed after 6 months of
exposure, while hyperkeratinization takes years. Children
are more likely to develop these effects than adults. The
mechanism of arsenic-induced changes to the skin is
unknown, partly because these effects are not seen in
other animals (Mead, 2005; ATSDR, 2007a).
GI Tract. Acute or subacute exposure to high-dose arsenic
by ingestion is associated with GI symptoms ranging
from mild cramping, diarrhea, and vomiting to GI hemorrhaging
and death. GI symptoms are caused by
increased capillary permeability, leading to fluid loss. At
higher doses, fluid forms vesicles that can burst, leading
to inflammation and necrosis of the submucosa and
then rupture of the intestinal wall. GI symptoms are not
observed with chronic exposure to lower levels of arsenic.
Nervous System. Acute high-dose arsenic exposure
causes encephalopathy in rare cases, with symptoms
that can include headache, lethargy, mental confusion,
hallucination, seizures, and coma. However, the most
common neurological effect of acute or subacute
arsenic exposure is peripheral neuropathy involving
both sensory and motor neurons. This effect is characterized
by the loss of sensation in the hands and feet (a
stocking and glove distribution). This often is followed
by muscle weakness. Neuropathy occurs several days
after exposure to arsenic and can be reversible following
cessation of exposure, although recovery usually is
not complete. Arsenic exposure may cause intellectual
deficits in children. Wasserman et al. (2007) observed
a negative association between arsenic levels in drinking
water and performance on intelligence tests.
SECTION IX
SPECIAL SYSTEMS PHARMACOLOGY
Other Non-Cancer Toxicities. Acute and chronic arsenic exposures
induce anemia and leukopenia. Arsenic likely causes both direct cytotoxic
effects on blood cells and suppression of erythropoiesis through
bone marrow toxicity. Arsenic also may inhibit heme synthesis. In the
liver, arsenic causes fatty infiltrations, central necrosis, and cirrhosis
of varying severity. The action of arsenic on renal capillaries, tubules,
and glomeruli can cause severe kidney damage. Inhaled arsenic is irritating
to the lungs, and ingested arsenic may induce bronchitis progressing
to bronchopneumonia in some individuals. Chronic exposure
to arsenic is associated with an increased risk of diabetes.
Carcinogenesis. Arsenic compounds were among the first
recognized human carcinogens. At the end of the 19th
century, Hutchinson observed that patients receiving
arsenic-containing drugs had an increased occurrence
of skin tumors. Epidemiological studies performed in
regions with very high arsenic levels in drinking water
consistently observe substantially increased rates of skin
cancer (squamous cell and basal cell carcinomas), bladder
cancer, and lung cancer. There also are associations
between arsenic exposure and other cancers, including
liver, kidney, and prostate tumors. Inhalation exposure to
arsenic in occupational settings causes lung cancer.
IARC classifies arsenic as “carcinogenic to humans
(group 1).”
The developing fetus and young children may be at increased
risk of arsenic carcinogenesis, because humans exposed to arsenic in
utero and in early childhood have a greatly elevated risk of lung cancer
(Smith et al., 2006). Studies in rodents also have observed
increased cancer risks from in utero exposure and suggest that the
second trimester of pregnancy represents a critical susceptibility window
(Waalkes et al., 2007).
The mechanism of arsenic carcinogenesis is poorly understood.
Arsenic is an unusual carcinogen in that evidence for human
carcinogenesis is much stronger than for carcinogenesis in laboratory
animals. Arsenic does not directly damage DNA; rather, arsenic is
thought to work through changes in gene expression, DNA methylation,
inhibition of DNA repair, generation of oxidative stress,
and/or altered signal transduction pathways (Salnikow and
Zhitkovich, 2008; Hartwig et al., 2002). Arsenic compounds can act
as tumor promoters or co-carcinogens in rodents, particularly when
combined with ultraviolet light (Burns et al., 2004). In humans,
exposure to arsenic potentiates lung tumorigenesis from tobacco
smoke. Smokers in regions with high concentrations of arsenic in
the drinking water have a 5-fold increased risk of cancer over smokers
living in low arsenic regions (Ferreccio et al., 2000). Arsenic cocarcinogenesis
may involve inhibition of proteins involved in
nucleotide excision repair (Salnikow and Zhitkovich, 2008; Hartwig
et al., 2002). Arsenic also has endocrine-disrupting activities on several
nuclear steroid hormone receptors, enhancing hormone-dependent
transcription at very low concentrations and inhibiting it at slightly
higher levels (Bodwell et al., 2006).
Arsine Gas. Arsine gas, formed by electrolytic or metallic reduction
of arsenic, is a rare cause of industrial poisonings. Arsine induces
rapid and often fatal hemolysis, which probably results from arsine
combining with hemoglobin and reacting with oxygen. A few hours
after exposure, patients can develop headache, anorexia, vomiting,
paresthesia, abdominal pain, chills, hemoglobinuria, bilirubinemia,
and anuria. Jaundice appears after 24 hours. Arsine induces renal
toxicities that can progress to kidney failure. Approximately 25% of
cases of arsine exposure result in death.
Treatment. Following acute exposure to arsenic, stabilize the patient
and prevent further absorption of the poison. Close monitoring of fluid
levels is important because arsenic can cause fatal hypovolemic shock.
Chelation therapy is effective following short-term exposure to arsenic