Page 413 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 23 The Alcohols 399

antagonists)—was used intravenously for the suppression of pre- Chronic consumption of large amounts of alcohol is associ-
mature labor. ated with an increased risk of death. Deaths linked to alcohol
consumption are caused by liver disease, cancer, accidents, and
Consequences of Chronic Alcohol suicide.
Consumption
A. Liver and Gastrointestinal Tract
Chronic alcohol consumption profoundly affects the function of
several vital organs—particularly the liver—and the nervous, gas- Liver disease is the most common medical complication of alcohol
trointestinal, cardiovascular, and immune systems. Since ethanol abuse; an estimated 15–30% of chronic heavy drinkers eventually
has low potency, it requires concentrations thousands of times develop severe liver disease. Alcoholic fatty liver, a reversible con-
higher than other misused drugs (eg, cocaine, opiates, amphet- dition, may progress to alcoholic hepatitis and finally to cirrhosis
amines) to produce its intoxicating effects. As a result, ethanol and liver failure. In the United States, chronic alcohol abuse is
is consumed in quantities that are unusually large for a phar- the leading cause of liver cirrhosis and of the need for liver trans-
macologically active drug. The tissue damage caused by chronic plantation. The risk of developing liver disease is related both to
alcohol ingestion results from a combination of the direct effects the average amount of daily consumption and to the duration of
of ethanol and acetaldehyde, and the metabolic consequences of alcohol abuse. Women appear to be more susceptible to alcohol
processing a heavy load of a metabolically active substance. Spe- hepatotoxicity than men. Concurrent infection with hepatitis
cific mechanisms implicated in tissue damage include increased B or C virus increases the risk of severe liver disease. Cirrhosis
oxidative stress coupled with depletion of glutathione, damage to contributes to elevated portal blood pressure and esophageal and
mitochondria, growth factor dysregulation, and potentiation of gastric venous varices. These varices may rupture and result in
cytokine-induced injury. massive bleeding.

What Can Drunken Worms, Flies, and Mice Tell Us about Alcohol?

For a drug like ethanol, which exhibits low potency and specific- It is easy to imagine mice having measurable behavioral
ity and modifies complex behaviors, the precise roles of its many responses to alcohol, but drunken worms and fruit flies are harder
direct and indirect targets are difficult to define. Increasingly, to imagine. Actually, both invertebrates respond to ethanol in
ethanol researchers are employing genetic approaches to com- ways that parallel mammalian responses. Drosophila melanogaster
plement standard neurobiologic experimentation. Three experi- fruit flies exposed to ethanol vapor show increased locomotion at
mental animal systems for which powerful genetic techniques low concentrations but at higher concentrations, become poorly
exist—mice, flies, and worms—have yielded intriguing results. coordinated, sedated, and finally immobile. These behaviors can
Strains of mice with abnormal sensitivity to ethanol were be monitored by sophisticated laser or video tracking methods or
identified many years ago by breeding and selection programs. with an ingenious “chromatography” column of air that separates
Using sophisticated genetic mapping and sequencing tech- relatively insensitive flies from inebriated flies, which drop to the
niques, researchers have made progress in identifying the genes bottom of the column. The worm Caenorhabditis elegans similarly
that confer ethanol susceptibility or resistance traits. A more exhibits increased locomotion at low ethanol concentrations and,
targeted approach is the use of transgenic mice to test hypoth- at higher concentrations, reduced locomotion, sedation, and—
eses about specific genes. For example, after earlier experiments something that can be turned into an effective screen for mutant
suggested a link between brain neuropeptide Y (NPY) and etha- worms that are resistant to ethanol—impaired egg laying. The
nol, researchers used two transgenic mouse models to further advantage of using flies and worms as genetic models for ethanol
investigate the link. They found that a strain of mice that lacks research is their relatively simple neuroanatomy, well-established
the gene for NPY—NPY knockout mice—consume more ethanol techniques for genetic manipulation, extensive libraries of well-
than control mice and are less sensitive to ethanol’s sedative characterized mutants, and completely or nearly completely
effects. As would be expected if increased concentrations of NPY solved genetic codes. Already, much information has accumu-
in the brain make mice more sensitive to ethanol, a strain of mice lated about candidate proteins involved with the effects of etha-
that overexpresses NPY drinks less alcohol than the controls even nol in flies. In an elegant study on C elegans, researchers found
though their total consumption of food and liquid is normal. Work evidence that a calcium-activated, voltage-gated BK potassium
with other transgenic knockout mice supports the central role channel is a direct target of ethanol. This channel, which is acti-
in ethanol responses of signaling systems that have long been vated by ethanol, has close homologs in flies and vertebrates, and
believed to be involved (eg, GABA A, glutamate, dopamine, opioid, evidence is accumulating that ethanol has similar effects in these
and serotonin receptors) and has helped build the case for newer homologs. Genetic experiments in these model systems should
candidates such as NPY and corticotropin-releasing hormone, provide information that will help narrow and focus research into
cannabinoid receptors, ion channels, and protein kinase C. the complex and important effects of ethanol in humans.