Acute effects.

Alcohol has two acute effects on the brain: (1) general depression of central nervous system (CNS) function and (2) activation of the reward circuit.

How does alcohol affect CNS activity? For many years, we believed that alcohol simply dissolved into the neuronal membrane, thereby disrupting the ordered arrangement of membrane phospholipids. However, we now know that alcohol interacts with specific proteins—certain receptors, ion channels, and enzymes—that regulate neuronal excitability. Three target proteins are of particular importance, namely (1) receptors for gamma-aminobutyric acid (GABA), (2) receptors for glutamate, and (3) the 5-HT₃ subset of receptors for serotonin (5-hydroxytryptamine, 5-HT). The depressant effects of alcohol result from binding with receptors for GABA (the principal inhibitory transmitter in the CNS) and receptors for glutamate (a major excitatory transmitter in the CNS). When alcohol binds with GABA receptors, it enhances GABA-mediated inhibition, and thereby causes widespread depression of CNS activity. When alcohol binds with glutamate receptors, it blocks glutamate-mediated excitation, and thereby reduces overall CNS activity. The rewarding effects of alcohol result from binding with 5-HT₃ receptors in the brain’s reward circuit. When these receptors are activated (by serotonin), they promote release of dopamine, the major transmitter of the reward system. When alcohol binds with these receptors, it enhances serotonin-mediated release of dopamine, and thereby intensifies the reward process.

The depressant effects of alcohol are dose dependent. When dosage is low, higher brain centers (cortical areas) are primarily affected. As dosage increases, more primitive brain areas (eg, medulla) become depressed. With depression of cortical function, thought processes and learned behaviors are altered, inhibitions are released, and self-restraint is replaced by increased sociability and expansiveness. Cortical depression also impairs motor function. As CNS depression deepens, reflexes diminish greatly and consciousness becomes impaired. At very high doses, alcohol produces a state of general anesthesia. (Alcohol can’t be used for anesthesia because the doses required are close to lethal.) Table 38–1 summarizes the effects of alcohol as a function of blood alcohol level and indicates the brain areas involved.

Chronic effects.

When consumed chronically and in excess, alcohol can produce severe neurologic and psychiatric disorders. Injury to the CNS is caused by the direct actions of alcohol and by the nutritional deficiencies often seen in chronic heavy drinkers.

Two neuropsychiatric syndromes are common in alcoholics: Wernicke’s encephalopathy and Korsakoff’s psychosis. Both disorders are caused by thiamin deficiency, which results from poor diet and alcohol-induced suppression of thiamin absorption. Wernicke’s encephalopathy is characterized by confusion, nystagmus, and abnormal ocular movements. This syndrome is readily reversible with thiamin. Korsakoff’s psychosis is characterized by polyneuropathy, inability to convert short-term memory into long-term memory, and confabulation (unconscious filling of gaps in memory with fabricated facts and experiences). Korsakoff’s psychosis is not reversible.

Perhaps the most dramatic effect of long-term excessive alcohol consumption is enlargement of the cerebral ventricles, presumably in response to atrophy of the cerebrum itself. These gross anatomic changes are associated with impairment of memory and intellectual function. With cessation of drinking, ventricular enlargement and cognitive deficits partially reverse, but only in some individuals.

Impact on cognitive function.

Low to moderate drinking helps preserve cognitive function in older people and may protect against development of dementia.

Effect on sleep.

Although alcohol is commonly used as a sleep aid, it actually disrupts sleep. Drinking can alter sleep cycles, decrease total sleeping time, and reduce the quality of sleep. In addition, alcohol can intensify snoring and exacerbate obstructive sleep apnea. Having a drink with dinner won’t affect sleep—but drinking late in the evening will.

Cardiovascular system.

When alcohol is consumed acutely and in moderate doses, cardiovascular effects are minor. The most prominent effect is dilation of cutaneous blood vessels, causing increased blood flow to the skin. By doing so, alcohol imparts a sensation of warmth—but at the same time promotes loss of heat. Hence, despite images of Saint Bernards with little barrels of whiskey about their necks, alcohol may do more harm than good for the individual stranded in the snow with hypothermia.

Although the cardiovascular effects of moderate alcohol consumption are unremarkable, chronic and excessive consumption is clearly harmful. Abuse of alcohol results in direct damage to the myocardium, thereby increasing the risk of heart failure. Some investigators believe that alcohol may be the major cause of cardiomyopathy in the Western world.

In addition to damaging the heart, alcohol produces a dose-dependent elevation of blood pressure. The cause is vasoconstriction in vascular beds of skeletal muscle brought on by increased activity of the sympathetic nervous system. Estimates suggest that heavy drinking may be responsible for 10% of all cases of hypertension.

Not all of the cardiovascular effects of alcohol are deleterious: There is clear evidence that people who drink moderately (2 drinks a day or less for men, 1 drink a day or less for women) experience less ischemic stroke, coronary artery disease (CAD), myocardial infarction (MI), and heart failure than do abstainers. It is important to note, however, that heavy drinking (5 or more drinks/day) increases the risk of heart disease and stroke. How does moderate drinking protect against heart disease? Primarily by raising levels of high-density lipoprotein (HDL) cholesterol. As discussed in Chapter 50, HDL cholesterol protects against CAD, whereas low-density lipoprotein (LDL) cholesterol promotes CAD. Of all the agents that can raise HDL cholesterol, alcohol is the most effective known. In addition to raising HDL cholesterol, alcohol may confer protection through four other mechanisms: decreasing platelet aggregation, decreasing levels of fibrinogen (the precursor of fibrin, which reinforces clots), increasing levels of tissue plasminogen activator (a clot-dissolving enzyme), and suppressing the inflammatory component of atherosclerosis. The degree of cardiovascular protection is nearly equal for beer, wine, and distilled spirits. That is, protection is determined primarily by the amount of alcohol consumed—not by the particular beverage the alcohol is in. Also, the pattern of drinking matters: protection is greater for people who drink moderately 3 or 4 days a week than for people who drink just 1 or 2 days a week. Finally, cardioprotection is greatest for those with an unhealthy lifestyle: Among people who exercise, eat fruits and vegetables, and do not smoke, alcohol has little or no effect on the incidence of coronary events; conversely, among people who lack these health-promoting behaviors, moderate alcohol intake is associated with a 50% reduction in coronary risk.

Glucose metabolism.

Alcohol has several effects on glucose metabolism that may decrease the risk for type 2 diabetes. For example, alcohol raises levels of adiponectin, a compound that enhances insulin sensitivity. In addition, alcohol suppresses gluconeogenesis, blunts the postprandial rise in blood glucose, and lowers fasting levels of both glucose and insulin.

Bone health.

Alcohol increases bone mineral density. How? Probably by increasing levels of sex hormones.

Respiration.

Like all other CNS depressants, alcohol depresses respiration. Respiratory depression from moderate drinking is negligible. However, when consumed in excess, alcohol can cause death by respiratory arrest. The respiratory depressant effects of alcohol are potentiated by other CNS depressants (eg, benzodiazepines, opioids, barbiturates).

Liver.

Alcohol-induced liver damage can progress from fatty liver to hepatitis to cirrhosis, depending on the amount consumed. Acute drinking causes reversible accumulation of fat and protein in the liver. With more chronic drinking, hepatitis develops in about 90% of heavy users. In 8% to 20% of chronic alcoholics, hepatitis evolves into cirrhosis—a condition characterized by proliferation of fibrous tissue and destruction of liver parenchymal cells. Although various factors other than alcohol can cause cirrhosis, alcohol abuse is unquestionably the major cause of fatal cirrhosis.

Stomach.

Immoderate use of alcohol can cause erosive gastritis. About one-third of alcoholics have this disorder. Two mechanisms are involved. First, alcohol stimulates secretion of gastric acid. Second, when present in high concentrations, alcohol can injure the gastric mucosa directly.

Kidney.

Alcohol is a diuretic. It promotes urine formation by inhibiting the release of antidiuretic hormone (ADH) from the pituitary. Since ADH acts on the kidney to promote water reabsorption, thereby decreasing urine formation, a reduction in circulating ADH will increase urine production.

Pancreas.

Approximately 35% of cases of acute pancreatitis can be attributed to alcohol, making alcohol the second most common cause of the disorder. Flare-ups typically occur after a bout of heavy drinking. Only 5% of alcoholics develop pancreatitis, and then only after years of overindulgence.

Sexual function.

Alcohol has both psychologic and physiologic effects related to human sexual behavior. Although alcohol is not exactly an aphrodisiac, its ability to release inhibitions has been known to motivate sexual activity. Ironically, the physiologic effects of alcohol may frustrate attempts at consummating the activity that alcohol inspired: Objective measurements in males and females show that alcohol significantly decreases our physiologic capacity for sexual responsiveness. The opposing psychologic and physiologic effects of alcohol on sexual function were aptly described long ago by no less an authority than William Shakespeare. In Macbeth (Act II, Scene 1), Macduff inquires of a porter “What. . … does drink especially provoke?” To which the porter replies,

In males, long-term use of alcohol may induce feminization. Symptoms include testicular atrophy, impotence, sterility, and breast enlargement.

Cancer.

Alcohol—even in moderate amounts—is associated with an increased risk of several common cancers. Among these are cancers of the breast, liver, rectum, and aerodigestive tract, which includes the lips, tongue, mouth, nose, throat, vocal cords, and portions of the esophagus and trachea. How much cancer does alcohol cause? According to a 2011 study, alcohol causes 10% of all cancers in men and 3% of all cancers in women. The fraction attributable to alcohol is highest of aerodigestive tract cancers (44% in men and 25% in women), somewhat lower for liver cancer (33% and 18%), even lower for colorectal cancer (17% and 4%), and lowest for breast cancer in women (5%). The bottom line? Current data suggest that, regarding cancer risk, no amount of alcohol can be considered safe—although risk is lowest with moderate drinking (2 drinks or less a day for men and 1 drink or less a day for women).

Pregnancy.

Effects of alcohol on the developing fetus are dose dependent. Risk of fetal injury is greatest with heavy drinking, and much lower with light drinking. Is there some low level of drinking that is completely safe? We don’t know.

Fetal alcohol exposure can cause structural and functional abnormalities, ranging from mild neurobehavioral deficits to facial malformation and mental retardation. The term fetal alcohol spectrum disorder (FASD) is used in reference to the full range of outcomes—from mild to severe—that drinking during pregnancy can cause. In contrast, the term fetal alcohol syndrome (FAS) is reserved for the most severe cases of FASD, characterized by craniofacial malformations, growth restriction (including microcephaly), and neurodevelopmental abnormalities, manifesting during childhood as cognitive and social dysfunction. In addition to causing FASD and FAS, heavy drinking during pregnancy can result in stillbirth, spontaneous abortion, and giving birth to an alcohol-dependent infant.

Is light drinking safe during pregnancy? The data are unclear. Two studies published in 2010 suggest that light drinking may carry little risk. One study, conducted in the United Kingdom, found no clinically relevant behavioral or cognitive problems in 5-year-olds whose mothers consumed 1 to 2 drinks a week during pregnancy. The other study, conducted in Australia, found no link between low to moderate alcohol consumption during pregnancy and alcohol-related birth defects (ARBDs), although the same study did show that heavy drinking was associated with a fourfold increased risk of an ARBD. These results are consistent with other recent studies, which have failed to show a relationship between occasional or light drinking during pregnancy and abnormalities in newborns or older children. However, since all of these studies were observational, rather than randomized controlled trials, the negative results might be explained by confounding factors, especially educational level, income, or access to prenatal care. Furthermore, since the follow-up time for these studies was relatively short (only 5 years), the long-term effects of light drinking remain unknown.

What’s the bottom line? If there is some amount of alcohol that is safe during pregnancy, that amount is very low. Accordingly, despite the studies noted above, the American College of Obstetricians and Gynecologists (ACOG) continues to maintain its long-held position that no amount of alcohol can be considered safe during pregnancy. Therefore, in the interests of fetal health, all women should be advised to avoid alcohol entirely while pregnant or trying to conceive. Having said that, it is important to appreciate that a few drinks early in pregnancy are not likely to harm the fetus. Consequently, if a woman consumed a little alcohol before realizing she was pregnant, she should be reassured that the risk to her baby—if any—is extremely low.

Lactation.

The concentration of alcohol in breast milk parallels the concentration in blood. Recent data indicate that drinking while breast-feeding can adversely affect the infant’s feeding and behavior.

Absorption.

Alcohol is absorbed from the stomach and small intestine. About 20% of ingested alcohol is absorbed from the stomach. Gastric absorption is relatively slow and is delayed even further by the presence of food. Milk is especially effective at retarding absorption. Absorption from the small intestine is rapid and largely independent of food; about 80% of ingested alcohol is absorbed from this site. Because most alcohol is absorbed from the small intestine, gastric emptying time is a major determinant of individual variation in alcohol absorption.

Distribution.

Because alcohol is both nonionic and water soluble, it distributes well to all tissues and body fluids. The drug crosses the blood-brain barrier with ease, allowing alcohol in the brain to equilibrate rapidly with alcohol in the blood. Alcohol also crosses the placenta and hence can affect the developing fetus.

Distribution in body water partly explains why women are more sensitive to alcohol than men. As a rule, women have a lower percentage of body water than men. Hence, when a woman drinks, the alcohol is diluted in a smaller volume of water, causing the concentration of alcohol in tissues and fluids to be relatively high, which causes the effects of alcohol to be more intense.

Metabolism.

Alcohol is metabolized in both the liver and stomach. The liver is the primary site. The pathway for alcohol metabolism is shown in Figure 38–1. As depicted, the process begins with conversion of alcohol to acetaldehyde, a reaction catalyzed by alcohol dehydrogenase. This reaction is slow and puts a limit on the rate at which alcohol can be inactivated. Once formed, acetaldehyde undergoes rapid conversion to acetic acid. Through a series of reactions, acetic acid is then used to synthesize cholesterol, fatty acids, and other compounds.

The kinetics of alcohol metabolism differ from those of most other drugs. With most drugs, as plasma drug levels rise, the amount of drug metabolized per unit time increases too. This is not true for alcohol: As the alcohol content of blood increases, there is almost no change in the speed of alcohol breakdown. That is, alcohol is metabolized at a relatively constant rate—regardless of how much alcohol is present. The average rate at which individuals can metabolize alcohol is about 15 mL (0.5 oz) per hour.

Because alcohol is metabolized at a slow and constant rate, there is a limit to how much alcohol one can consume without having the drug accumulate. For practical purposes, that limit is about 1 drink per hour. Consumption of more than 1 drink per hour—be that drink beer, wine, straight whiskey, or a cocktail—will result in alcohol buildup.

The information in Table 38–3 helps explain why we can’t metabolize more than 1 drink’s worth of alcohol per hour. As the table indicates, beer, wine, and whiskey differ from one another with respect to alcohol concentration and usual serving size. However, despite these differences, it turns out that the average can of beer, the average glass of wine, and the average shot of whiskey all contain the same amount of alcohol—namely, 18 mL (0.6 oz). Since the liver can metabolize about 15 mL of alcohol per hour, and since the average alcoholic drink contains 18 mL of alcohol, 1 drink contains just about the amount of alcohol that the liver can comfortably process each hour. Consumption of more than 1 drink per hour will overwhelm the capacity of the liver for alcohol metabolism, and therefore alcohol will accumulate.