Page 414 - Basic _ Clinical Pharmacology ( PDFDrive )

400 SECTION V Drugs That Act in the Central Nervous System

The pathogenesis of alcoholic liver disease is a multifactorial after the ethanol effect dissipates and before the system has time
process involving metabolic repercussions of ethanol oxidation to return to a normal ethanol-free state.
in the liver, dysregulation of fatty acid oxidation and synthesis, Chronic exposure of animals or cultured cells to alcohol elicits
and activation of the innate immune system by a combination of a multitude of adaptive responses involving neurotransmitters and
direct effects of ethanol and its metabolites and by bacterial endo- their receptors, ion channels, and enzymes that participate in sig-
toxins that access the liver as a result of ethanol-induced changes nal transduction pathways. Up-regulation of the NMDA subtype
2+
in the intestinal tract. Tumor necrosis factor-α appears to play a of glutamate receptors and voltage-sensitive Ca channels may
pivotal role in the progression of alcoholic liver disease and may underlie the seizures that accompany the alcohol withdrawal syn-
be a fruitful therapeutic target. drome. GABA neurotransmission is believed to play a significant
Other portions of the gastrointestinal tract can also be injured. role in tolerance and withdrawal because (1) sedative-hypnotic
Chronic alcohol ingestion is by far the most common cause of drugs that enhance GABAergic neurotransmission are able to
chronic pancreatitis in the Western world. In addition to its direct substitute for alcohol during alcohol withdrawal, and (2) there is
toxic effect on pancreatic acinar cells, alcohol alters pancreatic epi- evidence of down-regulation of GABA -mediated responses with
A
thelial permeability and promotes the formation of protein plugs chronic alcohol exposure.
and calcium carbonate-containing stones. Like other drugs of abuse, ethanol modulates neural activity
Individuals with chronic alcoholism are prone to gastritis and in the brain’s mesolimbic dopamine reward circuit and increases
have increased susceptibility to blood and plasma protein loss dopamine release in the nucleus accumbens (see Chapter 32).
during drinking, which may contribute to anemia and protein Alcohol affects local concentrations of serotonin, opioids, and
malnutrition. Alcohol also injures the small intestine, leading to dopamine—neurotransmitters involved in the brain reward
diarrhea, weight loss, and multiple vitamin deficiencies. system. The discovery that naltrexone, a nonselective opioid
Malnutrition from dietary deficiency and vitamin deficiencies receptor antagonist, helps patients who are recovering from
due to malabsorption are common in alcoholism. Malabsorption alcoholism abstain from drinking supports the idea that a com-
of water-soluble vitamins is especially severe. mon neurochemical reward system is shared by very different
drugs associated with physical and psychological dependence.
B. Nervous System There is also convincing evidence from animal models that
1. Tolerance and dependence—The consumption of alcohol ethanol intake and seeking behavior are reduced by antagonists
in high doses over a long period results in tolerance and in physi- of another important regulator of the brain reward system, the
cal and psychological dependence. Tolerance to the intoxicating cannabinoid CB receptor. Two other important neuroendocrine
1
effects of alcohol is a complex process involving poorly understood systems that appear to play key roles in modulating ethanol-
changes in the nervous system as well as the pharmacokinetic seeking activity in experimental animals are the appetite-reg-
changes described earlier. As with other sedative-hypnotic drugs, ulating system—which uses peptides such as leptin, ghrelin,
there is a limit to tolerance, so that only a relatively small increase and neuropeptide Y—and the stress response system, which is
in the lethal dose occurs with increasing alcohol use. controlled by corticotropin-releasing factor.
Chronic alcohol drinkers, when forced to reduce or discon-
tinue alcohol, experience a withdrawal syndrome, which indicates 2. Neurotoxicity—Consumption of large amounts of alcohol
the existence of physical dependence. Alcohol withdrawal symp- over extended periods (usually years) often leads to neurologic
toms usually consist of hyperexcitability in mild cases and seizures, deficits. The most common neurologic abnormality in chronic
toxic psychosis, and delirium tremens in severe ones. The dose, alcoholism is generalized symmetric peripheral nerve injury, which
rate, and duration of alcohol consumption determine the intensity begins with distal paresthesias of the hands and feet. Degenerative
of the withdrawal syndrome. When consumption has been very changes can also result in gait disturbances and ataxia. Other neu-
high, merely reducing the rate of consumption may lead to signs rologic disturbances associated with alcoholism include dementia
of withdrawal. and, rarely, demyelinating disease.
Psychological dependence on alcohol is characterized by a com- Wernicke-Korsakoff syndrome is a relatively uncommon but
pulsive desire to experience the rewarding effects of alcohol and, important entity characterized by paralysis of the external eye
for current drinkers, a desire to avoid the negative consequences muscles, ataxia, and a confused state that can progress to coma
of withdrawal. People who have recovered from alcoholism and and death. It is associated with thiamine deficiency but is rarely
become abstinent still experience periods of intense craving for seen in the absence of alcoholism. Because of the importance of
alcohol that can be triggered by environmental cues associated in thiamine in this pathologic condition and the absence of toxicity
the past with drinking, such as familiar places, groups of people, associated with thiamine administration, all patients suspected
or events. of having Wernicke-Korsakoff syndrome (including virtually all
The molecular basis of alcohol tolerance and dependence patients who present to the emergency department with altered
is not known with certainty, nor is it known whether the two consciousness, seizures, or both) should receive thiamine therapy.
phenomena reflect opposing effects on a shared molecular path- Often, the ocular signs, ataxia, and confusion improve promptly
way. Tolerance may result from ethanol-induced up-regulation upon administration of thiamine. However, most patients are left
of a pathway in response to the continuous presence of ethanol. with a chronic disabling memory disorder known as Korsakoff’s
Dependence may result from overactivity of that same pathway psychosis.