Page 416 - Basic _ Clinical Pharmacology ( PDFDrive )

402 SECTION V Drugs That Act in the Central Nervous System

G. Immune System Pharmacodynamic interactions are also of great clinical
The effects of alcohol on the immune system are complex; significance. The additive CNS depression that occurs when
immune function in some tissues is inhibited (eg, the lung), alcohol is combined with other CNS depressants, particularly
whereas pathologic, hyperactive immune function in other tissues sedative-hypnotics, is most important. Alcohol also potentiates
is triggered (eg, liver, pancreas). In addition, acute and chronic the pharmacologic effects of many nonsedative drugs, including
exposure to alcohol have widely different effects on immune func- vasodilators and oral hypoglycemic agents.
tion. The types of immunologic changes reported for the lung
include suppression of the function of alveolar macrophages, inhi-
bition of chemotaxis of granulocytes, and reduced number and ■ CLINICAL PHARMACOLOGY OF
function of T cells. In the liver, there is enhanced function of key ETHANOL
cells of the innate immune system (eg, Kupffer cells, hepatic stel-
late cells) and increased cytokine production. In addition to the Alcohol is the cause of more preventable morbidity and mortal-
inflammatory damage that chronic heavy alcohol use precipitates ity than all other drugs combined with the exception of tobacco.
in the liver and pancreas, it predisposes to infections, especially of Epidemiologic studies indicate that for men under 65, risk is
the lung, and worsens the morbidity and increases the mortality increased by consumption of more than four drinks on any single
risk of patients with pneumonia. day or more than 14 drinks per average week; for women and
for men over 65, risk is increased by consumption of more than
H. Increased Risk of Cancer three drinks on a single day or seven drinks per week. The search
Chronic alcohol use increases the risk for cancer of the mouth, for specific etiologic factors or the identification of significant
pharynx, larynx, esophagus, and liver. Evidence also points to a predisposing variables for alcohol abuse has led to disappointing
small increase in the risk of breast cancer in women. A threshold results. Personality type, severe life stresses, psychiatric disorders,
level for alcohol consumption as it relates to cancer has not been and parental role models are not reliable predictors of alcohol
determined. Alcohol itself does not appear to be a carcinogen in abuse. Although environmental factors clearly play a role, evi-
most test systems. However, its primary metabolite, acetaldehyde, dence suggests that there is a large genetic contribution to the
can damage DNA, as can the reactive oxygen species produced development of alcoholism. Not surprisingly, polymorphisms in
by increased cytochrome P450 activity. Other factors impli- alcohol dehydrogenase and aldehyde dehydrogenase that lead to
cated in the link between alcohol and cancer include changes in increased aldehyde accumulation and its associated facial flushing,
folate metabolism and the growth-promoting effects of chronic nausea, and hypotension appear to protect against alcoholism.
inflammation. Much attention in genetic mapping experiments has focused on
membrane-signaling proteins known to be affected by ethanol and
Alcohol-Drug Interactions on protein constituents of reward pathways in the brain. Poly-
morphisms associated with a relative insensitivity to alcohol and
Interactions between ethanol and other drugs can have important presumably thereby a greater risk of alcohol abuse have been iden-
clinical effects resulting from alterations in the pharmacokinetics tified in genes encoding an α subunit of the GABA receptor, an
A
or pharmacodynamics of the second drug. M muscarinic receptor, a serotonin transporter, adenylyl cyclase,
2
The most common pharmacokinetic alcohol-drug interac- and a potassium channel. The link between a polymorphism in an
tions stem from alcohol-induced increases of drug-metabolizing opioid receptor gene and a blunted response to naltrexone raises
enzymes, as described in Chapter 4. Thus, prolonged intake of the possibility of genotype-guided pharmacotherapy for alcohol
alcohol without damage to the liver can enhance the metabolic dependence.
biotransformation of other drugs. Ethanol-mediated induction
of hepatic cytochrome P450 enzymes is particularly important
with regard to acetaminophen. Chronic consumption of three MANAGEMENT OF ACUTE ALCOHOL
or more drinks per day increases the risk of hepatotoxicity due INTOXICATION
to toxic or even high therapeutic levels of acetaminophen as a
result of increased P450-mediated conversion of acetaminophen Nontolerant individuals who consume alcohol in large quantities
to reactive hepatotoxic metabolites (see Figure 4–5). Current develop typical effects of acute sedative-hypnotic drug overdose
US Food and Drug Administration (FDA) regulations require along with the cardiovascular effects previously described (vasodi-
that over-the-counter products containing acetaminophen carry lation, tachycardia) and gastrointestinal irritation. Since tolerance
a warning about the relation between ethanol consumption and is not absolute, even individuals with chronic alcohol dependence
acetaminophen-induced hepatotoxicity. may become severely intoxicated if sufficient alcohol is consumed.
In contrast, acute alcohol use can inhibit metabolism of other The most important goals in the treatment of acute alcohol
drugs because of decreased enzyme activity or decreased liver intoxication are to prevent severe respiratory depression and aspira-
blood flow. Phenothiazines, tricyclic antidepressants, and sedative- tion of vomitus. Even with very high blood ethanol levels, survival
hypnotic drugs are the most important drugs that interact with is probable as long as the respiratory and cardiovascular systems
alcohol by this pharmacokinetic mechanism. can be supported. The average blood alcohol concentration in