Ethanol is a small water-soluble molecule that is absorbed rapidly from the gastrointestinal tract. After ingestion of alcohol in the fasting state, peak blood alcohol concentrations are reached within 30 minutes. The presence of food in the stomach delays absorption by slowing gastric emptying. Distribution is rapid, with tissue levels approximating the concentration in blood. The volume of distribution for ethanol approximates total body water (0.5–0.7 L/kg). After an equivalent oral dose of alcohol, women have a higher peak concentration than men, in part because women have a lower total body water content and in part because of differences in first-pass metabolism. In the central nervous system (CNS), the concentration of ethanol rises quickly, since the brain receives a large proportion of total blood flow and ethanol readily crosses biologic membranes.
Over 90% of alcohol consumed is oxidized in the liver; much of the remainder is excreted through the lungs and in the urine. The excretion of a small but consistent proportion of alcohol by the lungs can be quantified with breath alcohol tests that serve as a basis for a legal definition of “driving under the influence” (DUI) in many countries. In most states in the USA, the alcohol level for driving under the influence is set at 80 mg/dL (0.08%). At levels of ethanol usually achieved in blood, the rate of oxidation follows zero-order kinetics; that is, it is independent of time and concentration of the drug. The typical adult can metabolize 7–10 g (150–220 mmol) of alcohol per hour, the equivalent of approximately one “drink” [10 oz (300 mL) beer, 3.5 oz (105 mL) wine, or 1 oz (30 mL) distilled 80-proof spirits]. A commercial product (“Palcohol”), approved in the USA in 2015, consists of a powder to be mixed to form a drink containing 10% ethanol (approximately equivalent to wine).
Two major pathways of alcohol metabolism to acetaldehyde have been identified (Figure 23–1). Acetaldehyde is then oxidized to acetate by a third metabolic process.
Metabolism of ethanol by alcohol dehydrogenase and the microsomal ethanol-oxidizing system (MEOS). Alcohol dehydrogenase and aldehyde dehydrogenase are inhibited by fomepizole and disulfiram, respectively. NAD+, nicotinamide adenine dinucleotide; NADPH, nicotinamide adenine dinucleotide phosphate.
A. Alcohol Dehydrogenase Pathway
The primary pathway for alcohol metabolism involves alcohol dehydrogenase (ADH), a family of cytosolic enzymes that catalyze the conversion of alcohol to acetaldehyde (Figure 23–1, left). These enzymes are located mainly in the liver, but small amounts are found in other organs such as the brain and stomach. There is considerable genetic variation in ADH enzymes, affecting the rate of ethanol metabolism and also appearing to alter vulnerability to alcohol-abuse disorders. For example, one ADH allele (the ADH1B*2 allele), which is associated with rapid conversion of ethanol to acetaldehyde, has been found to be protective against alcohol dependence in several ethnic populations, especially East Asians.
Some metabolism of ethanol by ADH occurs in the stomach in men, but a smaller amount occurs in women, who appear to have lower levels of the gastric enzyme. This difference in gastric metabolism of alcohol in women probably contributes to the sex-related differences in blood alcohol concentrations noted above.
During conversion of ethanol by ADH to acetaldehyde, hydrogen ion is transferred from ethanol to the cofactor nicotinamide adenine dinucleotide (NAD+) to form NADH. As a net result, alcohol oxidation generates an excess of reducing equivalents in the liver, chiefly as NADH. The excess NADH production appears to contribute to the metabolic disorders that accompany chronic alcoholism and to both the lactic acidosis and hypoglycemia that frequently accompany acute alcohol poisoning.
B. Microsomal Ethanol-Oxidizing System (MEOS)
This enzyme system, also known as the mixed function oxidase system, uses NADPH as a cofactor in the metabolism of ethanol (Figure 23–1, right) and consists primarily of cytochrome P450 2E1, 1A2, and 3A4 (see Chapter 4).
During chronic alcohol consumption, MEOS activity is induced. As a result, chronic alcohol consumption results in significant increases not only in ethanol metabolism but also in the clearance of other drugs eliminated by the cytochrome P450s that constitute the MEOS system, and in the generation of the toxic byproducts of cytochrome P450 reactions (toxins, free radicals, H2O2).
C. Acetaldehyde Metabolism
Much of the acetaldehyde formed from alcohol is oxidized in the liver in a reaction catalyzed by mitochondrial NAD-dependent aldehyde dehydrogenase (ALDH). The product of this reaction is acetate (Figure 23–1), which can be further metabolized to CO2 and water, or used to form acetyl-CoA.
Oxidation of acetaldehyde is inhibited by disulfiram, a drug that has been used to deter drinking by patients with alcohol dependence. When ethanol is consumed in the presence of disulfiram, acetaldehyde accumulates and causes an unpleasant reaction of facial flushing, nausea, vomiting, dizziness, and headache. Several other drugs (eg, metronidazole, cefotetan, trimethoprim) inhibit ALDH and have been claimed to cause a disulfiram-like reaction if combined with ethanol.
Some people, primarily of East Asian descent, have genetic deficiency in the activity of the mitochondrial form of ALDH, which is encoded by the ALDH2 gene. When these individuals drink alcohol, they develop high blood acetaldehyde concentrations and experience a noxious reaction similar to that seen with the combination of disulfiram and ethanol. This form of reduced-activity ALDH is strongly protective against alcohol-use disorders.
Pharmacodynamics of Acute Ethanol Consumption
A. Central Nervous System
The CNS is markedly affected by acute alcohol consumption. Alcohol causes sedation, relief of anxiety and, at higher concentrations, slurred speech, ataxia, impaired judgment, and disinhibited behavior, a condition usually called intoxication or drunkenness (Table 23–1). These CNS effects are most marked as the blood level is rising, because acute tolerance to the effects of alcohol occurs after a few hours of drinking. For chronic drinkers who are tolerant to the effects of alcohol, higher concentrations are needed to elicit these CNS effects. For example, an individual with chronic alcoholism may appear sober or only slightly intoxicated with a blood alcohol concentration of 300–400 mg/dL (0.30-0.40%), whereas this level is associated with marked intoxication or even coma in a nontolerant individual. The propensity of moderate doses of alcohol to inhibit the attention and information-processing skills as well as the motor skills required for operation of motor vehicles has profound effects. Approximately 30–40% of all traffic accidents resulting in a fatality in the United States involve at least one person with blood alcohol near or above the legal level of intoxication, and drunken driving is a leading cause of death in young adults.
TABLE 23–1Blood alcohol concentration (BAC) and clinical effects in nontolerant individuals. ||Download (.pdf) TABLE 23–1 Blood alcohol concentration (BAC) and clinical effects in nontolerant individuals.
|BAC (mg/dL)1 ||Clinical Effect |
| 50–100 ||Sedation, subjective “high,” slower reaction times |
|100–200 ||Impaired motor function, slurred speech, ataxia |
|200–300 ||Emesis, stupor |
|300–400 ||Coma |
|>400 ||Respiratory depression, death |
Like other sedative-hypnotic drugs, alcohol is a CNS depressant. At high blood concentrations, it induces coma, respiratory depression, and death.
Ethanol affects a large number of membrane proteins that participate in signaling pathways, including neurotransmitter receptors for amines, amino acids, opioids, and neuropeptides; enzymes such as Na+/K+-ATPase, adenylyl cyclase, phosphoinositide-specific phospholipase C; a nucleoside transporter; and ion channels. Much attention has focused on alcohol’s effects on neurotransmission by glutamate and γ-aminobutyric acid (GABA), the main excitatory and inhibitory neurotransmitters in the CNS. Acute ethanol exposure enhances the action of GABA at GABAA receptors, which is consistent with the ability of GABA-mimetics to intensify many of the acute effects of alcohol and of GABAA antagonists to attenuate some of the actions of ethanol. Ethanol inhibits the ability of glutamate to open the cation channel associated with the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors. The NMDA receptor is implicated in many aspects of cognitive function, including learning and memory. “Blackouts”—periods of memory loss that occur with high levels of alcohol—may result from inhibition of NMDA receptor activation. Experiments that use modern genetic approaches eventually will yield a more precise definition of ethanol’s direct and indirect targets. In recent years, experiments with mutant strains of mice, worms, and flies have reinforced the importance of previously identified targets and helped identify new candidates, including a calcium-regulated and voltage-gated potassium channel that may be one of ethanol’s direct targets (see Box: What Can Drunken Worms, Flies, and Mice Tell Us about Alcohol?).
What Can Drunken Worms, Flies, and Mice Tell Us about Alcohol?
For a drug like ethanol, which exhibits low potency and specificity and modifies complex behaviors, the precise roles of its many direct and indirect targets are difficult to define. Increasingly, ethanol researchers are employing genetic approaches to complement standard neurobiologic experimentation. Three experimental animal systems for which powerful genetic techniques exist—mice, flies, and worms—have yielded intriguing results.
Strains of mice with abnormal sensitivity to ethanol were identified many years ago by breeding and selection programs. Using sophisticated genetic mapping and sequencing techniques, researchers have made progress in identifying the genes that confer ethanol susceptibility or resistance traits. A more targeted approach is the use of transgenic mice to test hypotheses about specific genes. For example, after earlier experiments suggested a link between brain neuropeptide Y (NPY) and ethanol, researchers used two transgenic mouse models to further investigate the link. They found that a strain of mice that lacks the gene for NPY—NPY knockout mice—consume more ethanol than control mice and are less sensitive to ethanol’s sedative effects. As would be expected if increased concentrations of NPY in the brain make mice more sensitive to ethanol, a strain of mice that overexpresses NPY drinks less alcohol than the controls even though their total consumption of food and liquid is normal. Work with other transgenic knockout mice supports the central role in ethanol responses of signaling systems that have long been believed to be involved (eg, GABAA, glutamate, dopamine, opioid, and serotonin receptors) and has helped build the case for newer candidates such as NPY and corticotropin-releasing hormone, cannabinoid receptors, ion channels, and protein kinase C.
It is easy to imagine mice having measurable behavioral responses to alcohol, but drunken worms and fruit flies are harder to imagine. Actually, both invertebrates respond to ethanol in ways that parallel mammalian responses. Drosophila melanogaster fruit flies exposed to ethanol vapor show increased locomotion at low concentrations but at higher concentrations, become poorly coordinated, sedated, and finally immobile. These behaviors can be monitored by sophisticated laser or video tracking methods or with an ingenious “chromatography” column of air that separates relatively insensitive flies from inebriated flies, which drop to the bottom of the column. The worm Caenorhabditis elegans similarly exhibits increased locomotion at low ethanol concentrations and, at higher concentrations, reduced locomotion, sedation, and—something that can be turned into an effective screen for mutant worms that are resistant to ethanol—impaired egg laying. The advantage of using flies and worms as genetic models for ethanol research is their relatively simple neuroanatomy, well-established techniques for genetic manipulation, extensive libraries of well-characterized mutants, and completely or nearly completely solved genetic codes. Already, much information has accumulated about candidate proteins involved with the effects of ethanol in flies. In an elegant study on C elegans, researchers found evidence that a calcium-activated, voltage-gated BK potassium channel is a direct target of ethanol. This channel, which is activated by ethanol, has close homologs in flies and vertebrates, and evidence is accumulating that ethanol has similar effects in these homologs. Genetic experiments in these model systems should provide information that will help narrow and focus research into the complex and important effects of ethanol in humans.
Significant depression of myocardial contractility has been observed in individuals who acutely consume moderate amounts of alcohol, ie, at a blood concentration above 100 mg/dL.
Ethanol is a vasodilator, probably as a result of both CNS effects (depression of the vasomotor center) and direct smooth muscle relaxation caused by its metabolite, acetaldehyde. In cases of severe overdose, hypothermia—caused by vasodilation—may be marked in cold environments. Preliminary evidence indicates that flibanserin augments the hypotensive effects of ethanol and may cause severe orthostatic hypotension and syncope (see Chapter 16). Ethanol also relaxes the uterus and—before the introduction of more effective and safer uterine relaxants (eg, calcium channel antagonists)—was used intravenously for the suppression of premature labor.
Consequences of Chronic Alcohol Consumption
Chronic alcohol consumption profoundly affects the function of several vital organs—particularly the liver—and the nervous, gastrointestinal, cardiovascular, and immune systems. Since ethanol has low potency, it requires concentrations thousands of times higher than other misused drugs (eg, cocaine, opiates, amphetamines) to produce its intoxicating effects. As a result, ethanol is consumed in quantities that are unusually large for a pharmacologically active drug. The tissue damage caused by chronic alcohol ingestion results from a combination of the direct effects of ethanol and acetaldehyde, and the metabolic consequences of processing a heavy load of a metabolically active substance. Specific mechanisms implicated in tissue damage include increased oxidative stress coupled with depletion of glutathione, damage to mitochondria, growth factor dysregulation, and potentiation of cytokine-induced injury.
Chronic consumption of large amounts of alcohol is associated with an increased risk of death. Deaths linked to alcohol consumption are caused by liver disease, cancer, accidents, and suicide.
A. Liver and Gastrointestinal Tract
Liver disease is the most common medical complication of alcohol abuse; an estimated 15–30% of chronic heavy drinkers eventually develop severe liver disease. Alcoholic fatty liver, a reversible condition, may progress to alcoholic hepatitis and finally to cirrhosis and liver failure. In the United States, chronic alcohol abuse is the leading cause of liver cirrhosis and of the need for liver transplantation. The risk of developing liver disease is related both to the average amount of daily consumption and to the duration of alcohol abuse. Women appear to be more susceptible to alcohol hepatotoxicity than men. Concurrent infection with hepatitis B or C virus increases the risk of severe liver disease. Cirrhosis contributes to elevated portal blood pressure and esophageal and gastric venous varices. These varices may rupture and result in massive bleeding.
The pathogenesis of alcoholic liver disease is a multifactorial process involving metabolic repercussions of ethanol oxidation in the liver, dysregulation of fatty acid oxidation and synthesis, and activation of the innate immune system by a combination of direct effects of ethanol and its metabolites and by bacterial endotoxins that access the liver as a result of ethanol-induced changes in the intestinal tract. Tumor necrosis factor-α appears to play a pivotal role in the progression of alcoholic liver disease and may be a fruitful therapeutic target.
Other portions of the gastrointestinal tract can also be injured. Chronic alcohol ingestion is by far the most common cause of chronic pancreatitis in the Western world. In addition to its direct toxic effect on pancreatic acinar cells, alcohol alters pancreatic epithelial permeability and promotes the formation of protein plugs and calcium carbonate-containing stones.
Individuals with chronic alcoholism are prone to gastritis and have increased susceptibility to blood and plasma protein loss during drinking, which may contribute to anemia and protein malnutrition. Alcohol also injures the small intestine, leading to diarrhea, weight loss, and multiple vitamin deficiencies.
Malnutrition from dietary deficiency and vitamin deficiencies due to malabsorption are common in alcoholism. Malabsorption of water-soluble vitamins is especially severe.
1. Tolerance and dependence—The consumption of alcohol in high doses over a long period results in tolerance and in physical and psychological dependence. Tolerance to the intoxicating effects of alcohol is a complex process involving poorly understood changes in the nervous system as well as the pharmacokinetic changes described earlier. As with other sedative-hypnotic drugs, there is a limit to tolerance, so that only a relatively small increase in the lethal dose occurs with increasing alcohol use.
Chronic alcohol drinkers, when forced to reduce or discontinue alcohol, experience a withdrawal syndrome, which indicates the existence of physical dependence. Alcohol withdrawal symptoms usually consist of hyperexcitability in mild cases and seizures, toxic psychosis, and delirium tremens in severe ones. The dose, rate, and duration of alcohol consumption determine the intensity of the withdrawal syndrome. When consumption has been very high, merely reducing the rate of consumption may lead to signs of withdrawal.
Psychological dependence on alcohol is characterized by a compulsive desire to experience the rewarding effects of alcohol and, for current drinkers, a desire to avoid the negative consequences of withdrawal. People who have recovered from alcoholism and become abstinent still experience periods of intense craving for alcohol that can be triggered by environmental cues associated in the past with drinking, such as familiar places, groups of people, or events.
The molecular basis of alcohol tolerance and dependence is not known with certainty, nor is it known whether the two phenomena reflect opposing effects on a shared molecular pathway. Tolerance may result from ethanol-induced up-regulation of a pathway in response to the continuous presence of ethanol. Dependence may result from overactivity of that same pathway after the ethanol effect dissipates and before the system has time to return to a normal ethanol-free state.
Chronic exposure of animals or cultured cells to alcohol elicits a multitude of adaptive responses involving neurotransmitters and their receptors, ion channels, and enzymes that participate in signal transduction pathways. Up-regulation of the NMDA subtype of glutamate receptors and voltage-sensitive Ca2+ channels may underlie the seizures that accompany the alcohol withdrawal syndrome. GABA neurotransmission is believed to play a significant role in tolerance and withdrawal because (1) sedative-hypnotic drugs that enhance GABAergic neurotransmission are able to substitute for alcohol during alcohol withdrawal, and (2) there is evidence of down-regulation of GABAA-mediated responses with chronic alcohol exposure.
Like other drugs of abuse, ethanol modulates neural activity in the brain’s mesolimbic dopamine reward circuit and increases dopamine release in the nucleus accumbens (see Chapter 32). Alcohol affects local concentrations of serotonin, opioids, and dopamine—neurotransmitters involved in the brain reward system. The discovery that naltrexone, a nonselective opioid receptor antagonist, helps patients who are recovering from alcoholism abstain from drinking supports the idea that a common neurochemical reward system is shared by very different drugs associated with physical and psychological dependence. There is also convincing evidence from animal models that ethanol intake and seeking behavior are reduced by antagonists of another important regulator of the brain reward system, the cannabinoid CB1 receptor. Two other important neuroendocrine systems that appear to play key roles in modulating ethanol-seeking activity in experimental animals are the appetite-regulating system—which uses peptides such as leptin, ghrelin, and neuropeptide Y—and the stress response system, which is controlled by corticotropin-releasing factor.
2. Neurotoxicity—Consumption of large amounts of alcohol over extended periods (usually years) often leads to neurologic deficits. The most common neurologic abnormality in chronic alcoholism is generalized symmetric peripheral nerve injury, which begins with distal paresthesias of the hands and feet. Degenerative changes can also result in gait disturbances and ataxia. Other neurologic disturbances associated with alcoholism include dementia and, rarely, demyelinating disease.
Wernicke-Korsakoff syndrome is a relatively uncommon but important entity characterized by paralysis of the external eye muscles, ataxia, and a confused state that can progress to coma and death. It is associated with thiamine deficiency but is rarely seen in the absence of alcoholism. Because of the importance of thiamine in this pathologic condition and the absence of toxicity associated with thiamine administration, all patients suspected of having Wernicke-Korsakoff syndrome (including virtually all patients who present to the emergency department with altered consciousness, seizures, or both) should receive thiamine therapy. Often, the ocular signs, ataxia, and confusion improve promptly upon administration of thiamine. However, most patients are left with a chronic disabling memory disorder known as Korsakoff’s psychosis.
Alcohol may also impair visual acuity, with painless blurring that occurs over several weeks of heavy alcohol consumption. Changes are usually bilateral and symmetric and may be followed by optic nerve degeneration. Ingestion of ethanol substitutes such as methanol (see Pharmacology of Other Alcohols) causes severe visual disturbances.
1. Cardiomyopathy and heart failure—Alcohol has complex effects on the cardiovascular system. Heavy alcohol consumption of long duration is associated with a dilated cardiomyopathy with ventricular hypertrophy and fibrosis. In animals and humans, alcohol causes cardiac membrane disruption, depressed function of mitochondria and sarcoplasmic reticulum, intracellular accumulation of phospholipids and fatty acids, and up-regulation of voltage-gated calcium channels. There is evidence that patients with alcohol-induced dilated cardiomyopathy do significantly worse than patients with idiopathic dilated cardiomyopathy, even though cessation of drinking is associated with a reduction in cardiac size and improved function. The poorer prognosis for patients who continue to drink appears to be due in part to interference by ethanol with the beneficial effects of β blockers and angiotensin-converting enzyme (ACE) inhibitors.
2. Arrhythmias—Heavy drinking—and especially “binge” drinking—are associated with both atrial and ventricular arrhythmias. Patients undergoing alcohol withdrawal syndrome can develop severe arrhythmias that may reflect abnormalities of potassium or magnesium metabolism as well as enhanced release of catecholamines. Seizures, syncope, and sudden death during alcohol withdrawal may be due to these arrhythmias.
3. Hypertension—A link between heavier alcohol consumption (more than three drinks per day) and hypertension has been firmly established in epidemiologic studies. Alcohol is estimated to be responsible for approximately 5% of cases of hypertension, independent of obesity, salt intake, coffee drinking, and cigarette smoking. A reduction in alcohol intake appears to be effective in lowering blood pressure in hypertensive individuals who are also heavy drinkers; the hypertension seen in this population is also responsive to standard blood pressure medications.
4. Coronary heart disease—Although the deleterious effects of excessive alcohol use on the cardiovascular system are well established, there is strong epidemiologic evidence that moderate alcohol consumption actually prevents coronary heart disease (CHD), ischemic stroke, and peripheral arterial disease. This type of relationship between mortality and the dose of a drug is called a “J-shaped” relationship. Results of these clinical studies are supported by ethanol’s ability to raise serum levels of high-density lipoprotein (HDL) cholesterol (the form of cholesterol that appears to protect against atherosclerosis; see Chapter 35), by its ability to inhibit some of the inflammatory processes that underlie atherosclerosis while also increasing production of the endogenous anticoagulant tissue plasminogen activator (t-PA, see Chapter 34), and by the presence in alcoholic beverages (especially red wine) of antioxidants and other substances that may protect against atherosclerosis. These observational studies are intriguing, but randomized clinical trials examining the possible benefit of moderate alcohol consumption in prevention of CHD have not been carried out.
Alcohol indirectly affects hematopoiesis through metabolic and nutritional effects and may also directly inhibit the proliferation of all cellular elements in bone marrow. The most common hematologic disorder seen in chronic drinkers is mild anemia resulting from alcohol-related folic acid deficiency. Iron deficiency anemia may result from gastrointestinal bleeding. Alcohol has also been implicated as a cause of several hemolytic syndromes, some of which are associated with hyperlipidemia and severe liver disease.
E. Endocrine System and Electrolyte Balance
Chronic alcohol use has important effects on the endocrine system and on fluid and electrolyte balance. Clinical reports of gynecomastia and testicular atrophy in alcoholics with or without cirrhosis suggest a derangement in steroid hormone balance.
Individuals with chronic liver disease may have disorders of fluid and electrolyte balance, including ascites, edema, and effusions. Alterations of whole body potassium induced by vomiting and diarrhea, as well as severe secondary aldosteronism, may contribute to muscle weakness and can be worsened by diuretic therapy. The metabolic derangements caused by metabolism of large amounts of ethanol can result in hypoglycemia, as a result of impaired hepatic gluconeogenesis, and in ketosis, caused by excessive lipolytic factors, especially increased cortisol and growth hormone.
F. Fetal Alcohol Syndrome
Chronic maternal alcohol abuse during pregnancy is associated with teratogenic effects, and alcohol is a leading cause of mental retardation and congenital malformation. The abnormalities that have been characterized as fetal alcohol syndrome include (1) intrauterine growth retardation, (2) microcephaly, (3) poor coordination, (4) underdevelopment of midfacial region (appearing as a flattened face), and (5) minor joint anomalies. More severe cases may include congenital heart defects and mental retardation. Although the level of alcohol intake required to cause serious neurologic deficits appears quite high, the threshold for more subtle neurologic deficits is uncertain.
The mechanisms that underlie ethanol’s teratogenic effects are unknown. Ethanol rapidly crosses the placenta and reaches concentrations in the fetus that are similar to those in maternal blood. The fetal liver has little or no alcohol dehydrogenase activity, so the fetus must rely on maternal and placental enzymes for elimination of alcohol.
The neuropathologic abnormalities seen in humans and in animal models of fetal alcohol syndrome indicate that ethanol triggers apoptotic neurodegeneration and also causes aberrant neuronal and glial migration in the developing nervous system. In tissue culture systems, ethanol causes a striking reduction in neurite outgrowth.
The effects of alcohol on the immune system are complex; immune function in some tissues is inhibited (eg, the lung), whereas pathologic, hyperactive immune function in other tissues is triggered (eg, liver, pancreas). In addition, acute and chronic exposure to alcohol have widely different effects on immune function. The types of immunologic changes reported for the lung include suppression of the function of alveolar macrophages, inhibition of chemotaxis of granulocytes, and reduced number and function of T cells. In the liver, there is enhanced function of key cells of the innate immune system (eg, Kupffer cells, hepatic stellate cells) and increased cytokine production. In addition to the inflammatory damage that chronic heavy alcohol use precipitates in the liver and pancreas, it predisposes to infections, especially of the lung, and worsens the morbidity and increases the mortality risk of patients with pneumonia.
H. Increased Risk of Cancer
Chronic alcohol use increases the risk for cancer of the mouth, pharynx, larynx, esophagus, and liver. Evidence also points to a small increase in the risk of breast cancer in women. A threshold level for alcohol consumption as it relates to cancer has not been determined. Alcohol itself does not appear to be a carcinogen in most test systems. However, its primary metabolite, acetaldehyde, can damage DNA, as can the reactive oxygen species produced by increased cytochrome P450 activity. Other factors implicated in the link between alcohol and cancer include changes in folate metabolism and the growth-promoting effects of chronic inflammation.
Interactions between ethanol and other drugs can have important clinical effects resulting from alterations in the pharmacokinetics or pharmacodynamics of the second drug.
The most common pharmacokinetic alcohol-drug interactions stem from alcohol-induced increases of drug-metabolizing enzymes, as described in Chapter 4. Thus, prolonged intake of alcohol without damage to the liver can enhance the metabolic biotransformation of other drugs. Ethanol-mediated induction of hepatic cytochrome P450 enzymes is particularly important with regard to acetaminophen. Chronic consumption of three or more drinks per day increases the risk of hepatotoxicity due to toxic or even high therapeutic levels of acetaminophen as a result of increased P450-mediated conversion of acetaminophen to reactive hepatotoxic metabolites (see Figure 4–5). Current US Food and Drug Administration (FDA) regulations require that over-the-counter products containing acetaminophen carry a warning about the relation between ethanol consumption and acetaminophen-induced hepatotoxicity.
In contrast, acute alcohol use can inhibit metabolism of other drugs because of decreased enzyme activity or decreased liver blood flow. Phenothiazines, tricyclic antidepressants, and sedative-hypnotic drugs are the most important drugs that interact with alcohol by this pharmacokinetic mechanism.
Pharmacodynamic interactions are also of great clinical significance. The additive CNS depression that occurs when alcohol is combined with other CNS depressants, particularly sedative-hypnotics, is most important. Alcohol also potentiates the pharmacologic effects of many nonsedative drugs, including vasodilators and oral hypoglycemic agents.