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

638 pancreatitis has been known to occur after a single
episode of heavy alcohol use, prolonged heavy drinking
is common in most cases. Acute alcoholic pancreatitis
is characterized by the abrupt onset of abdominal pain,
nausea, vomiting, and increased levels of serum or
urine pancreatic enzymes. Computed tomography is
being used increasingly for diagnostic testing. While
most attacks are not fatal, hemorrhagic pancreatitis can
develop and lead to shock, renal failure, respiratory failure,
and death. Management usually involves intravenous
fluid replacement—often with nasogastric
suction—and opioid pain medication. The etiology of
acute pancreatitis probably is related to a direct toxic
metabolic effect of alcohol on pancreatic acinar cells.
SECTION II
NEUROPHARMACOLOGY
Two-thirds of patients with recurrent alcoholic pancreatitis
will develop chronic pancreatitis. Chronic pancreatitis is treated by
replacing the endocrine and exocrine deficiencies that result from
pancreatic insufficiency. The development of hyperglycemia often
requires insulin for control of blood-sugar levels (Chapter 43).
Pancreatic enzyme capsules containing lipase, amylase, and proteases
may be necessary to treat malabsorption (Chapter 46).
Liver. Ethanol produces a constellation of dose-related
deleterious effects in the liver (Fickert and Zatloukal,
2000). The primary effects are fatty infiltration of the
liver, hepatitis, and cirrhosis. Because of its intrinsic toxicity,
alcohol can injure the liver in the absence of dietary
deficiencies (Lieber, 2000). The accumulation of fat in
the liver is an early event and can occur in normal individuals
after the ingestion of relatively small amounts of
ethanol. This accumulation results from inhibition of both
the tricarboxylic acid cycle and the oxidation of fat, in
part owing to the generation of excess NADH produced
by the actions of ADH and ALDH (Figure 23–1).
Fibrosis, resulting from tissue necrosis and
chronic inflammation, is the underlying cause of alcoholic
cirrhosis. Normal liver tissue is replaced by
fibrous tissue. Alcohol can affect stellate cells in the
liver directly; chronic alcohol use is associated with
transformation of stellate cells into collagen-producing,
myofibroblast-like cells, resulting in deposition of collagen
around terminal hepatic venules (Lieber, 2000).
The histological hallmark of alcoholic cirrhosis is the
formation of Mallory bodies, which are thought to be
related to an altered intermediate cytoskeleton (Denk
et al., 2000).
A number of molecular mechanisms for alcoholic cirrhosis
have been proposed. In nonhuman primate models, alcohol alters
phospholipid peroxidation. Ethanol decreases phosphatidylcholine
levels in hepatic mitochondria, a change associated with decreased
oxidase activity and O 2
consumption. Cytokines, such as transforming
growth factor and tumor necrosis factor , can increase rates of
fibrinogenesis and fibrosis in the liver. Acetaldehyde is thought to
have a number of adverse effects, including depletion of glutathione
(Lieber, 2000), depletion of vitamins and trace metals, and decreased
transport and secretion of proteins owing to inhibition of tubulin polymerization.
Acetaminophen-induced hepatic toxicity (Chapters 4, 6,
and 34) has been associated with alcoholic cirrhosis as a result of
alcohol-induced increases in microsomal production of toxic acetaminophen
metabolites (Whitcomb and Block, 1994). Liver failure
secondary to cirrhosis and resulting in impaired clearance of toxins
such as ammonia also may contribute to alcohol-induced hepatic
encephalopathy. Ethanol also appears to increase intracellular free
hydroxy-ethyl radical formation.
Vitamins and Minerals
The almost complete lack of protein, vitamins, and most other nutrients
in alcoholic beverages predisposes those who consume large
quantities of alcohol to nutritional deficiencies. Alcoholics often
present with these deficiencies owing to decreased intake, decreased
absorption, or impaired utilization of nutrients. The peripheral neuropathy,
Korsakoff’s psychosis, and Wernicke’s encephalopathy seen
in alcoholics probably are caused by deficiencies of the B complex
of vitamins (particularly thiamine), although direct toxicity produced
by alcohol itself has not been ruled out (Harper, 1998). Chronic alcohol
abuse decreases the dietary intake of retinoids and carotenoids
and enhances the metabolism of retinol by the induction of degradative
enzymes (Lieber, 2000). Retinol and ethanol compete for metabolism
by ADH; vitamin A supplementation therefore should be
monitored carefully in alcoholics when they are consuming alcohol
to avoid retinol-induced hepatotoxicity. The chronic consumption of
alcohol inflicts an oxidative stress on the liver owing to the generation
of free radicals, contributing to ethanol-induced liver injury. The
antioxidant effects of -tocopherol (vitamin E) may ameliorate
some of this ethanol-induced toxicity in the liver. Plasma levels of
-tocopherol often are reduced in myopathic alcoholics compared
with alcoholic patients without myopathy.
Chronic alcohol consumption has been implicated in osteoporosis
(Chapter 44). The reasons for this decreased bone mass
remain unclear, although impaired osteoblastic activity has been
implicated. Acute administration of ethanol produces an initial
reduction in serum parathyroid hormone (PTH) and Ca 2+ levels, followed
by a rebound increase in PTH that does not restore Ca 2+ levels
to normal. Alcohol-induced osteopenia improves with abstinence
(Alvisa-Negrin J, et al., 2009). Since vitamin D requires hydroxylation
in the liver for activation, alcohol-induced liver damage can indirectly
affect the role of vitamin D in the intestinal and renal
absorption of Ca 2+ .
Sexual Function
Despite the widespread belief that alcohol can enhance
sexual activities, the opposite effect is generally noted.
Many drugs of abuse, including alcohol, have disinhibiting
effects that may lead initially to increased libido.
Both acute and chronic alcohol use can lead to impotence in
men. Increased blood alcohol concentrations lead to decreased sexual
arousal, increased ejaculatory latency, and decreased orgasmic
pleasure. The incidence of impotence may be as high as 50% in