Ethanol

Ethanol is one of a wide variety of structurally dissimilar agents that depress the functioning of the central nervous system (CNS). Ethanol differs from most other CNS depressants in that it is widely available to adults, and its use is legal and accepted in many societies. Associated with this widespread availability of ethanol are the enormous personal and societal costs of its abuse, with millions of individuals becoming alcohol abusers, or alcoholics. This chapter describes the pharmacological properties of ethanol in terms of its effects on a variety of organ systemsincluding the gastrointestinal, cardiovascular, and central nervous systemsand how ethanol affects disease processes. Effects of ethanol on the developing embryo and fetus are reviewed, as well as the long-term consequences of prenatal exposure to ethanol. Ethanol disturbs the fine balance that exists between excitatory and inhibitory influences in the brain, producing the disinhibition, ataxia, and sedation that follow its consumption. Tolerance to ethanol develops after chronic use, and physical dependence is demonstrated upon alcohol withdrawal. Existing and emerging pharmacotherapies for alcohol dependence are discussed, as well as recent research into the cellular and molecular mechanisms of ethanol actions in vivo, which should aid in the development of rational therapies for alcohol abuse and alcoholism.

Alcoholic beverages are so strongly associated with human society that fermentation is said to have developed in parallel with civilization. Until recently, alcoholic beverages contained relatively low concentrations of ethanol (the terms ethanol and alcohol are used interchangeably in this chapter), and there is speculation that human alcohol use is linked evolutionarily to a preference for fermenting fruit, where the presence of ethanol signals that the fruit is ripe but not yet rotten (Dudley, 2000).

The Arabs developed distillation about A.D. 800, and the word alcohol is derived from the Arabic for 'something subtle.' Alchemists of the Middle Ages were captivated by the invisible 'spirit' that was distilled from wine and thought it to be a remedy for practically all diseases. The term whiskey is derived from usquebaugh, Gaelic for 'water of life,' and alcohol became the major ingredient of widely marketed 'tonics' and 'elixirs.'

Although alcohol abuse and alcoholism are major health problems in many countries, the medical and social impacts of alcohol abuse have not always been appreciated. The economic burden to the United States economy is about $170 billion each year, and alcohol is responsible for more than 100,000 deaths annually. At least 14 million Americans meet the criteria for alcohol abuse or alcoholism, but medical diagnosis and treatment often are delayed until the disease is advanced and complicated by multiple social and health problems, making treatment difficult. Biological and genetic studies clearly place alcoholism among other diseases with both genetic and environmental influences, but persistent stigmas and attribution to moral failure have impeded recognition and treatment of alcohol problems. A major challenge for physicians and researchers is to devise diagnostic and therapeutic approaches aimed at this major health problem.

Compared with other drugs, surprisingly large amounts of alcohol are required for physiological effects, resulting in its consumption more like a food than a drug. The alcohol content of beverages ranges from 4% to 6% (volume/volume) for beer, 10% to 15% for wine, and 40% and higher for distilled spirits. The 'proof' of an alcohol-containing beverage is twice its percent alcohol (e.g., 40% alcohol is 80 proof). Remarkably, and contrary to public impressions, the serving size for alcoholic beverages is adjusted so that about 14 grams of alcohol is contained in a glass of beer or wine or a shot of spirits. Thus, alcohol is consumed in gram quantities, whereas most other drugs are taken in milligram or microgram doses. Blood alcohol levels (BALs) in human beings can be estimated readily by the measurement of alcohol levels in expired air; the partition coefficient for ethanol between blood and alveolar air is approximately 2000:1. Because of the causal relationship between excessive alcohol consumption and vehicular accidents, there has been a near universal adoption of laws attempting to limit the operation of vehicles while under the influence of alcohol. Legally allowed BALs typically are set at or below 100 mg % (100 mg of ethanol per deciliter of blood; 0.1% w/v), which is equivalent to a concentration of 22 mM ethanol in blood. A 12-ounce bottle of beer, a 5-ounce glass of wine, and a 1.5-ounce shot of 40% liquor all contain roughly 14 grams of ethanol, and the consumption of one of those beverages by a 70-kg person would produce a BAL of approximately 30 mg %. However, it is important to note that this is approximate, because the blood alcohol level is determined by a number of factors, including the rate of drinking, gender, body weight and water percentage, and the rates of metabolism and stomach emptying (see section on 'Acute Ethanol Intoxication').

Absorption, Distribution, and Metabolism

After oral administration, ethanol is rapidly absorbed into the bloodstream from the stomach and small intestine and distributes into total body water. Because absorption occurs more rapidly from the small intestine than from the stomach, delays in gastric emptying (due, for example, to the presence of food) slow ethanol absorption. After it enters the bloodstream, alcohol first travels to the liver before it quickly distributes into all body fluids. After oral consumption of alcohol, first-pass metabolism by gastric and liver alcohol dehydrogenase (ADH) enzymes leads to lower blood alcohol levels than would be obtained if the same dose were administered intravenously. Less gastric metabolism of ethanol occurs in women than in men, which may explain in part the greater susceptibility of women to ethanol (Lieber, 2000). Aspirin increases ethanol bioavailability by inhibiting gastric ADH. Although a small amount of ethanol is excreted unchanged in urine, sweat, and breath, most of it (90% to 98%) is metabolized to acetaldehyde and then to acetate, primarily in the liver. ADH, catalase, and a microsomal cytochrome P450 ethanol-oxidizing system all catalyze the oxidation of ethanol to acetaldehyde, with ADH playing the predominant role in the liver. This first step in alcohol metabolism also is the rate-limiting step in determining how quickly ethanol is cleared from the body. The oxidation of ethanol differs from that of most substances, in that it is relatively independent of concentration in blood and is constant with time (zero-order kinetics). On average, about 10 ml of ethanol are oxidized by a 70-kg person each hour (or about 120 mg/kg per hour). Acetaldehyde is rapidly metabolized to acetate by cytosolic and mitochondrial aldehyde dehydrogenase in the liver.

Although the cytochrome P450 system is not usually a major factor in the metabolism of ethanol, it can be an important site of interactions of ethanol with other drugs. The enzyme system is induced by chronic consumption of ethanol, leading to increased clearance of drugs that are substrates for it. There can be decreased clearance of the same drugs, however, after acute consumption of ethanol, as ethanol competes with them for oxidation by the enzyme system (e.g., phenytoin, warfarin).

Central Nervous System

The public often views alcoholic drinks as stimulating, but ethanol is primarily a central nervous system (CNS) depressant. Ingestion of moderate amounts of ethanol, like that of other depressants such as barbiturates and benzodiazepines, can have antianxiety actions and produce behavioral disinhibition with a wide range of doses. Individual signs of intoxication vary from expansive and vivacious affect to uncontrolled mood swings and emotional outbursts that may have violent components. With more severe intoxication, a general impairment of CNS function occurs, and a condition of general anesthesia ultimately prevails. However, there is little margin between the anesthetic actions and lethal effects (usually due to respiratory depression).

About 10% of alcohol drinkers progress to levels of consumption that are physically and socially detrimental. Chronic abuse is accompanied by tolerance, dependence, and craving for the drug (see below for a discussion of neuronal mechanisms; see also Chapter 24: Drug Addiction and Drug Abuse). Alcoholism is characterized by compulsive use despite clearly deleterious social and medical consequences. Alcoholism is a progressive illness, and brain damage from chronic alcohol abuse contributes to the deficits in cognitive functioning and judgment seen in alcoholics. Alcoholism is a leading cause of dementia in the United States (Oslin et al., 1998). Chronic alcohol abuse results in shrinkage of the brain due to loss of both white and gray matter (Kril and Halliday, 1999). The frontal lobes are particularly sensitive to damage by alcohol, and the extent of damage is determined by the amount and duration of alcohol consumption, with older alcoholics being more vulnerable than younger ones (Pfefferbaum et al., 1998). It is important to note that ethanol itself is neurotoxic and, although malnutrition or vitamin deficiencies probably play roles in complications of alcoholism such as Wernicke's encephalopathy and Korsakoff's psychosis, in western countries most of the brain damage in these disorders is due to alcohol per se. In addition to loss of brain tissue, alcohol abuse also reduces brain metabolism (as determined by positron emission tomography), and this hypometabolic state rebounds to a level of increased metabolism during detoxification. The magnitude of decrease in metabolic state is determined by the number of years of alcohol use and the age of the patients (Volkow et al., 1994; see'Mechanisms of CNS Effects of Ethanol,' below).

Cardiovascular System

Serum Lipoproteins and Cardiovascular Effects

In most countries, the risk of mortality due to coronary heart disease (CHD) is correlated with a high dietary intake of saturated fat and elevated serum cholesterol levels. France is an exception to this rule, with relatively low mortality from CHD despite the consumption of high quantities of saturated fats by the French (the 'French paradox'). Epidemiological studies suggest that widespread wine consumption by the French (20 to 30 g of ethanol per day) is one of the factors conferring a cardioprotective effect, with 1 to 3 drinks per day resulting in a 10% to 40% decreased risk of coronary heart disease, compared to abstainers. In contrast, daily consumption of greater amounts of alcohol leads to an increased incidence of noncoronary causes of cardiovascular failure, such as arrhythmias, cardiomyopathy, and hemorrhagic stroke, offsetting the beneficial effects of alcohol on coronary arteries; i.e., alcohol has a 'J-shaped' dose-mortality curve. Reduced risks for CHD are seen at intakes as low as one-half drink per day (Maclure, 1993). Young women and others at low risk for heart disease derive little benefit from light to moderate alcohol intake, while those of both sexes who are at high risk and who may have had a myocardial infarction clearly benefit. Data based on a number of prospective, cohort, cross-cultural, and case-control studies in diverse populations consistently reveal lower rates of angina pectoris, myocardial infarction, and peripheral artery disease in those consuming light (1 to 20 g/day) to moderate (21 to 40 g/day) amounts of alcohol.

One possible mechanism by which alcohol could reduce the risk of CHD is through its effects on blood lipids. Changes in plasma lipoprotein levels, particularly increases in high-density lipoprotein (HDL; see Chapter 36: Drug Therapy for Hypercholesterolemia and Dyslipidemia), have been associated with the protective effects of ethanol. HDL binds cholesterol and returns it to the liver for elimination or reprocessing, decreasing tissue cholesterol levels. Ethanol-induced increases in HDL-cholesterol could thus be expected to antagonize cholesterol buildup on arterial walls, lessening the risk of infarction. Approximately half of the risk reduction associated with ethanol consumption is explained by changes in total HDL levels (Langer et al., 1992). HDL is found as two subfractions, named HDL₂ and HDL₃. Increased levels of HDL₂ (and possibly also HDL₃) are associated with reduced risk of myocardial infarction. Levels of both subfractions are increased following alcohol consumption (Gaziano et al., 1993) and decrease when alcohol consumption ceases. Apolipoproteins A-I and A-II are constituents of HDL, with some HDL particles containing only the former, while others are composed of both. Increased levels of both apolipoproteins A-I and A-II are seen in individuals regularly consuming alcohol. In contrast, there are reports of decreased serum apolipoprotein(a) levels following periods of alcohol consumption. Elevated apolipoprotein(a) levels have been associated with an increased risk for the development of atherosclerosis.

Although the cardioprotective effects of ethanol initially were noted in wine drinkers, all forms of alcoholic beverages confer cardioprotection. A variety of alcoholic beverages increase HDL levels while decreasing the risk of myocardial infarction. The flavonoids found in red wine (and purple grape juice) may play an extra role in protecting LDL from oxidative damage. Oxidized LDL has been implicated in several steps of atherogenesis. The antiatherogenic effects of alcohol could be mediated by changes in LDL oxidation and elevated estrogen levels (Hillbom et al., 1998). Flavonoids also induce endothelium-dependent vasodilation (Stein et al., 1999). Another way in which alcohol consumption conceivably could play a cardioprotective role is by altering factors involved in blood clotting. The formation of clots is an important step in the genesis of myocardial infarctions, and a number of factors maintain a balance between bleeding and clot dissolution. Alcohol consumption elevates the levels of tissue plasminogen activator, a clot-dissolving enzyme (Ridker et al., 1994; see Chapter 55: Anticoagulant, Thrombolytic, and Antiplatelet Drugs), decreasing the likelihood of clot formation. Decreased fibrinogen concentrations seen following ethanol consumption also could have cardioprotective effects (Rimm et al., 1999), and epidemiological studies have linked the moderate consumption of ethanol to an inhibition of platelet activation (Rubin, 1999).

A question worth addressing is whether or not abstainers from alcohol should be advised to begin the consumption of moderate amounts of ethanol. The answer is no. It is important to note that there have been no randomized clinical trials to test the efficacy of daily alcohol use in reducing rates of coronary heart disease and mortality, and it is not appropriate for physicians to advocate the ingestion of alcohol solely to prevent heart disease. Many abstainers avoid alcohol because of a family history of alcoholism or for other health reasons, and it is not prudent to suggest that they begin drinking. Other lifestyle changes or medical treatments should be encouraged if patients are at risk for the development of CHD.

Hypertension

Heavy alcohol use can raise diastolic and systolic blood pressure (Klatsky, 1996). Studies indicate a positive, nonlinear association between alcohol use and hypertension, unrelated to age, education, smoking status, or the use of birth control medication. Consumption above 30 grams of alcohol per day (more than two standard drinks) is associated with a 1.5- to 2.3-mm Hg rise in diastolic and systolic blood pressure. A time effect also has been demonstrated, with diastolic and systolic blood pressure elevation being greatest for persons who consumed alcohol within 24 hours of examination (Moreira et al., 1998). Women may be at greater risk than men (Seppa et al., 1996).

A number of hypotheses have been proposed to explain the cause of alcohol-induced hypertension. One is that some hypertensive alcoholic patients abstain before a physician visit (Iwase et al., 1995). As blood alcohol levels fall, acute withdrawal causes an elevation in blood pressure that is reflected in elevated blood pressure readings in the physician's office. Another hypothesis holds that there is a direct pressor effect of alcohol caused by an unknown mechanism. Studies that have examined levels of renin, angiotensin, norepinephrine, antidiuretic hormone, cortisol, and other pressor mediators have been inconclusive. Newer hypotheses include increased intracellular Ca²⁺ levels with a subsequent increase in vascular reactivity, stimulation of the endothelium to release endothelin, and inhibition of endothelium-dependent nitric oxide production (Grogan and Kochar, 1994).

The prevalence of hypertension attributable to excess alcohol consumption is not known, but studies suggest a range of 5% to 11%. The prevalence probably is higher for men than for women because of higher alcohol consumption by men. A reduction or cessation of alcohol use in heavy drinkers may reduce the need for antihypertensive medication or reduce the blood pressure to the normal range. A safe amount of alcohol consumption for hypertensive patients who are light drinkers (one to two drinks per occasion, and less than 14 per week) has not been determined. Factors to consider are a personal history of ischemic heart disease, a history of binge drinking, or a family history of alcoholism or of cerebrovascular accident. Hypertensive patients with any of these risk factors should abstain from alcohol use.

Cardiac Arrhythmias

Alcohol has a number of pharmacological effects on cardiac conduction, including prolongation of the QT interval, prolongation of ventricular repolarization, and sympathetic stimulation (Rossinen et al., 1999; Kupari and Koskinen, 1998). Atrial arrhythmias associated with chronic alcohol use include supraventricular tachycardia, atrial fibrillation, and atrial flutter. Some 15% to 20% of idiopathic cases of atrial fibrillation may be induced by chronic ethanol use (Braunwald, 1997). Ventricular tachycardia may be responsible for the increased risk of unexplained sudden death that has been observed in persons who are alcohol-dependent (Kupari and Koskinen, 1998). During continued alcohol use, treatment of these arrhythmias may be more resistant to cardioversion, digitalis, or Ca²⁺ channelblocking agents (see Chapter 35: Antiarrhythmic Drugs). Patients with recurrent or refractory atrial arrhythmias should be questioned carefully about alcohol use.

Cardiomyopathy

Ethanol is known to have dose-related toxic effects on both skeletal and cardiac muscle (Preedy et al., 1994). Numerous studies have shown that alcohol can depress cardiac contractility and lead to cardiomyopathy (Thomas et al., 1994). Echocardiography demonstrates global hypokinesis. Fatty acid ethyl esters (formed from the enzymatic reaction of ethanol with free fatty acids) appear to play a role in the development of this disorder (Beckemeier and Bora, 1998). Approximately half of all patients with idiopathic cardiomyopathy are alcohol-dependent. Although the clinical signs and symptoms of idiopathic- and alcohol-induced cardiomyopathy are similar, alcohol-induced cardiomyopathy has a better prognosis if patients are able to stop drinking. Women are at greater risk than are men (Urbano-Marquez et al., 1995). As 40% to 50% of persons with alcohol-induced cardiomyopathy who continue to drink die within 3 to 5 years, abstinence remains the primary treatment. Some patients respond to diuretics, angiotensin converting enzyme inhibitors, and vasodilators.

Stroke

Clinical studies indicate a higher than normal incidence of hemorrhagic and ischemic stroke in persons who drink more than 40 to 60 grams of alcohol per day (Hansagi et al., 1995). Many cases of stroke follow prolonged binge drinking, especially when stroke occurs in younger patients. Proposed etiological factors include alcohol-induced (1) cardiac arrhythmias and associated thrombus formation; (2) high blood pressure and subsequent cerebral artery degeneration; (3) acute increases in systolic blood pressure and alteration in cerebral artery tone; and (4) head trauma. The effects on hemostasis, fibrinolysis, and blood clotting are variable and could prevent or precipitate acute stroke (Numminen et al., 1996). The effects of alcohol on the formation of intracranial aneurysms are controversial, but the statistical association disappears when one controls for tobacco use and gender (Qureshi et al., 1998).

Skeletal Muscle

Alcohol has a number of effects on skeletal muscle (Panzak et al., 1998). Chronic, heavy, daily alcohol consumption is associated with decreased muscle strength even when studies are controlled for other factors such as age, nicotine use, or chronic illness (Clarkson and Reichsman, 1990). Heavy doses of alcohol also cause irreversible damage to muscle, reflected by a marked increase in the activity of creatine phosphokinase in plasma. Muscle biopsies from heavy drinkers also reveal decreased levels of glycogen stores and pyruvate kinase activity (Vernet et al., 1995). Approximately 50% of chronic heavy drinkers have evidence of type II fiber atrophy. These changes correlate with reductions in muscle protein synthesis and serum carnosinase activities (Wassif et al., 1993). Most patients with chronic alcoholism show electromyographical changes, and many show evidence of a skeletal myopathy similar to alcoholic cardiomyopathy (Fernandez-Sola et al., 1994).

Body Temperature

Ingestion of ethanol causes a feeling of warmth, because alcohol enhances cutaneous and gastric blood flow. Increased sweating also may occur. Heat, therefore, is lost more rapidly and the internal temperature falls. After consumption of large amounts of ethanol, the central temperature-regulating mechanism itself becomes depressed, and the fall in body temperature may become pronounced. The action of alcohol in lowering body temperature is greater and more dangerous when the ambient environmental temperature is low. Studies of hypothermia deaths suggest that alcohol is a major risk factor in these events (Kortelainen, 1991). Patients with ischemic limbs secondary to peripheral vascular disease are particularly susceptible to cold damage (Proano and Perbeck, 1994).

Diuresis

Alcohol inhibits the release of vasopressin (antidiuretic hormone; see Chapter 30: Vasopressin and Other Agents Affecting the Renal Conservation of Water) from the posterior pituitary gland, resulting in enhanced diuresis (Leppaluoto et al., 1992). This may be complemented by ethanol-induced increases in plasma levels of atrial natriuretic peptide (Colantonio et al., 1991). Alcoholics have less urine output than do control subjects in response to a challenge dose with ethanol, suggesting that tolerance develops to the diuretic effects of ethanol (Collins et al., 1992). Alcoholics withdrawing from alcohol exhibit increased vasopressin release and a consequent retention of water, as well as dilutional hyponatremia.

Gastrointestinal System

Esophagus

Alcohol frequently is either the primary etiologic factor or one of multiple causal factors associated with esophageal dysfunction. Ethanol also is associated with the development of esophageal reflux, Barrett's esophagus, traumatic rupture of the esophagus, Mallory-Weiss tears, and esophageal cancer. When compared to nonalcoholic nonsmokers, alcohol-dependent patients who smoke have a tenfold increased risk of developing cancer of the esophagus. There is little change in esophageal function at low blood alcohol concentrations, but at higher blood alcohol concentrations, a decrease in peristalsis and decreased lower esophageal sphincter pressure occur. Patients with chronic reflux esophagitis may respond to proton pump inhibitors (see Chapter 37: Agents Used for Control of Gastric Acidity and Treatment of Peptic Ulcers and Gastroesophageal Reflux Disease).

Stomach

Heavy alcohol use can disrupt the gastric mucosal barrier and cause acute and chronic gastritis. Ethanol appears to stimulate gastric secretions by exciting sensory nerves in the buccal and gastric mucosa and promoting the release of gastrin and histamine. Beverages containing more than 40% alcohol also have a direct toxic effect on gastric mucosa. While these effects are seen most often in chronic heavy drinkers, they can occur after moderate and/or short-term alcohol use. Clinical symptoms include acute epigastric pain that is relieved with antacids or histamine H₂-receptor blockers (see Chapter 37: Agents Used for Control of Gastric Acidity and Treatment of Peptic Ulcers and Gastroesophageal Reflux Disease). The diagnosis may not be clear, because many patients have normal endoscopic examinations and upper gastrointestinal radiographs.

Alcohol is not thought to play a role in the pathogenesis of peptic ulcer disease. Unlike acute and chronic gastritis, peptic ulcer disease is not more common in alcoholics. Nevertheless, alcohol exacerbates the clinical course and severity of ulcer symptoms. It appears to act synergistically with Helicobacter pylori to delay healing (Lieber, 1997a). Acute bleeding from the gastric mucosa, while uncommon, can be a life-threatening emergency. Upper gastrointestinal bleeding more commonly is associated with esophageal varices, traumatic rupture of the esophagus, and clotting abnormalities.

Intestines

Many alcoholics have chronic diarrhea as a result of malabsorption in the small intestine (Addolorato et al., 1997). The major symptom is frequent loose stools. The rectal fissures and pruritis ani that are frequently associated with heavy drinking probably are related to chronic diarrhea. The diarrhea is caused by structural and functional changes in the small intestine (Papa et al., 1998); the intestinal mucosa has flattened villi, and digestive enzyme levels are often decreased. These changes frequently are reversible after a period of abstinence. Treatment is based on replacing essential vitamins and electrolytes, slowing transit time with an agent such as loperamide (see Chapter 39: Agents Used for Diarrhea, Constipation, and Inflammatory Bowel Disease; Agents Used for Biliary and Pancreatic Disease), and abstaining from all alcoholic beverages. Patients with severe magnesium deficiencies (serum magnesium less than 1.0 mEq/liter) or symptomatic patients (a positive Chvostek's sign or asterixis) should have replacement with 1 gram of magnesium sulfate intravenously or intramuscularly every four hours until the serum magnesium is greater than 1.0 mEq/liter (Sikkink and Fleming, 1992).

Pancreas

Heavy alcohol use is the most common cause of both acute and chronic pancreatitis in the United States. While pancreatitis has been known to occur after a single episode of heavy alcohol use, prolonged heavy drinking is common in most cases. Acute alcoholic pancreatitis is characterized by the abrupt onset of abdominal pain, nausea, vomiting, and increased levels of serum or urine pancreatic enzymes. Computed tomography is being used increasingly for diagnostic testing. While most attacks are not fatal, hemorrhagic pancreatitis can develop and lead to shock, renal failure, respiratory failure, and death. Management usually involves intravenous fluid replacementoften with nasogastric suctionand opioid pain medication. The etiology of acute pancreatitis probably is related to a direct toxic-metabolic effect of alcohol on pancreatic acinar cells. Fatty acid esters and cytokines appear to play a major role (Schenker and Montalvo, 1998).

Two-thirds of patients with recurrent alcoholic pancreatitis will develop chronic pancreatitis. Chronic pancreatitis is treated by replacing the endocrine and exocrine deficiencies that result from pancreatic insufficiency. The development of hyperglycemia often requires insulin for control of blood-sugar levels. Pancreatic enzyme capsules containing lipase, amylase, and proteases may be necessary to treat malabsorption. The average lipase dose is 4000 units to 24,000 units with each meal and snack. Many patients with chronic pancreatitis develop a chronic pain syndrome. While opioids may be helpful, nonnarcotic methods for pain relief such as antiinflammatory drugs, tricyclic antidepressants, exercise, relaxation techniques, and self-hypnosis are preferred treatments for this population, since cross-dependence to other drugs is not uncommon among alcoholics. Treatment contracts and frequent assessments for signs of addiction are important for patients receiving chronic opioid therapy for chronic pancreatitis since alcohol-dependent patients receiving chronic opioid therapy are at greater risk for narcotic addiction than are nonalcoholic patients.

Liver

Ethanol produces a constellation of dose-related deleterious effects in the liver (Fickert and Zatloukal, 2000). The primary effects are fatty infiltration of the liver, hepatitis, and cirrhosis. Because of its intrinsic toxicity, alcohol can injure the liver in the absence of dietary deficiencies (Lieber, 1994). The accumulation of fat in the liver is an early event and can occur in normal individuals after the ingestion of relatively small amounts of ethanol. This accumulation results from inhibition of both the tricarboxylic acid cycle and the oxidation of fat, in part owing to the generation of excess NADH produced by the actions of alcohol dehydrogenase and aldehyde dehydrogenase.

Fibrosis, resulting from tissue necrosis and chronic inflammation, is the underlying cause of alcoholic cirrhosis. Normal liver tissue is replaced by fibrous tissue. Alcohol can affect directly stellate cells in the liver, causing deposition of collagen around terminal hepatic venules (Worner and Lieber, 1985). Chronic alcohol use is associated with transformation of stellate cells into collagen-producing, myofibroblast-like cells (Lieber, 1998). The histologic hallmark of alcoholic cirrhosis is the formation of Mallory bodies, which are thought to be related to an altered cytokeratin intermediate cytoskeleton (Denk et al., 2000). A number of underlying molecular mechanisms have been proposed.

Phospholipids are a primary target of peroxidation and can be altered by alcohol in nonhuman primate models. Phosphatidylcholine levels are decreased in hepatic mitochondria and are associated with decreased oxidase activity and oxygen consumption (Lieber et al., 1994a,b). Cytokines, such as transforming-growth factor and tumor-necrosis factor , can increase rates of fibrinogenesis and fibrosis within the liver (McClain et al., 1993). Acetaldehyde is thought to have a number of adverse effects including depletion of glutathione (Lieber, 2000), depletion of vitamins and trace metals, and decreased transport and secretion of proteins owing to inhibition of tubulin polymerization (Lieber, 1997b). Acetaminophen-induced hepatic toxicity (see Chapter 27: Analgesic-Antipyretic and Antiinflammatory Agents and Drugs Employed in the Treatment of Gout) has been associated with alcoholic cirrhosis as a result of alcohol-induced increases in microsomal production of toxic acetaminophen metabolites (Whitcomb and Block, 1994; Seeff et al., 1986). Persons who are alcohol dependent may take large amounts of acetaminophen because of chronic pain. Alcohol also appears to increase intracellular free hydroxy-ethyl radical formation (Mantle and Preedy, 1999), and there is evidence that endotoxins may play a role in the initiation and exacerbation of alcohol-induced liver disease (Bode et al., 1987). Hepatitis C appears to be an important cofactor in the development of end-stage alcoholic liver disease (Regev and Jeffers, 1999).

Several strategies to treat alcoholic liver disease have been evaluated. Prednisolone may improve survival in patients with hepatic encephalopathy (Lieber, 1998). Nutrients such as S-adenosylmethionine and polyunsaturated lecithin have been found to have beneficial effects in nonhuman primates and are undergoing clinical trials. Other medications that have been tested include oxandrolone, propythiouracil (Orrego et al., 1987), and colchicine (Lieber, 1997b). At present, however, none of these drugs is approved by the United States Food and Drug Administration (FDA) for the treatment of alcoholic liver disease. The current primary treatment for liver failure, including alcoholic liver disease, is transplantation. Long-term outcome studies suggest that patients who are alcohol dependent have survival rates similar to those of patients with other types of liver disease. Alcoholics with hepatitis C may respond to interferon (McCullough and O'Connor, 1998).

Vitamins and Minerals

The almost complete lack of protein, vitamins, and most other nutrients in alcoholic beverages predisposes those who consume large quantities of alcohol to nutritional deficiencies. Alcoholics often present with these deficiencies due to decreased intake, decreased absorption, or impaired utilization of nutrients. The peripheral neuropathy, Korsakoff's psychosis, and Wernicke's encephalopathy seen in alcoholics probably are caused by deficiencies of the B-complex of vitamins (particularly thiamine), although direct toxicity produced by alcohol itself has not been ruled out (Harper, 1998). Liver failure secondary to cirrhosis, resulting in impaired clearance of toxins, also may result in alcohol-induced brain damage. Chronic alcohol abuse decreases the dietary intake of retinoids and carotenoids and enhances the metabolism of retinol by the induction of degradative enzymes (Leo and Lieber, 1999). Retinol and ethanol compete for metabolism by alcohol dehydrogenases; vitamin A supplementation therefore should be monitored carefully in alcoholics when they are consuming alcohol to avoid retinol-induced hepatotoxicity. The chronic consumption of alcohol inflicts an oxidative stress on the liver due to generation of free radicals, contributing to ethanol-induced liver injury. The antioxidant effects of -tocopherol (vitamin E) may ameliorate some of this ethanol-induced toxicity in the liver (Nordmann, 1994). Plasma levels of -tocopherol often are reduced in myopathic alcoholics compared to alcoholic patients without myopathy.

Chronic alcohol consumption has been implicated in osteoporosis. The reasons for this decreased bone mass remain unclear, although impaired osteoblastic activity has been implicated. Acute administration of ethanol produces an initial reduction in serum parathyroid hormone (PTH) and Ca²⁺ levels, followed by a rebound increase in PTH that does not restore Ca²⁺ levels to normal. The hypocalcemia observed after chronic alcohol intake also appears to be unrelated to effects of alcohol on PTH levels, and alcohol likely inhibits bone remodeling by a mechanism independent of Ca²⁺-regulating hormones (Sampson, 1997). Vitamin D also may play a role. Since vitamin D requires hydroxylation in the liver for activation, alcohol-induced liver damage can indirectly affect the role of vitamin D in the intestinal and renal absorption of Ca²⁺.

Alcoholics tend to have lowered serum and brain levels of magnesium, which may contribute to their predispositions to brain injuries such as stroke (Altura and Altura, 1999). Deficits in intracellular magnesium levels may disturb cytoplasmic and mitochondrial bioenergetic pathways, potentially leading to calcium overload and ischemia. Although there is general agreement that total magnesium levels are decreased in alcoholics, it is less clear that this also applies to ionized magnesium, the physiologically active form (Hristova et al., 1997). Magnesium sulfate is sometimes used in the treatment of alcohol withdrawal, but its efficacy has been questioned (Erstad and Cotugno, 1995).

Sexual Function

Despite the widespread belief that alcohol can enhance sexual activities, the opposite effect is noted more often. Many drugs of abuse, including alcohol, have disinhibiting effects that may lead initially to increased libido. With excessive, long-term use, however, alcohol often leads to a deterioration of sexual function. While alcohol cessation may reverse many sexual problems, patients with significant gonadal atrophy are less likely to respond to discontinuation of alcohol consumption (Sikkink and Fleming, 1992).

Alcohol can lead to impotence in men with both acute and chronic use. Increased blood alcohol concentrations lead to decreased sexual arousal, increased ejaculatory latency, and decreased orgasmic pleasure. The incidence of impotence may be as high as 50% in patients with chronic alcoholism. Additionally, many chronic alcoholics will develop testicular atrophy and decreased fertility. The mechanism involved in this is complex and likely involves altered hypothalamic function and a direct toxic effect of alcohol on Leydig cells. Testosterone levels may be depressed, but many men who are alcohol dependent have normal testosterone and estrogen levels. Gynecomastia is associated with alcoholic liver disease and is related to increased cellular response to estrogen and to accelerated metabolism of testosterone.

Sexual function in alcohol-dependent women is less clearly understood. Many female alcoholics complain of decreased libido, decreased vaginal lubrication, and menstrual cycle abnormalities. Their ovaries often are small and without follicular development. Some data suggest that fertility rates are lower for alcoholic women. The presence of comorbid disorders such as anorexia nervosa or bulimia is likely to aggravate the problem. The prognosis for men and women who become abstinent is favorable in the absence of significant hepatic or gonadal failure (O'Farrell et al., 1997).

Hematological and Immunological Effects

Chronic alcohol use is associated with a number of anemias. Microcytic anemia can occur because of chronic blood loss and iron deficiency. Macrocytic anemias and increases in mean corpuscular volume are common and may occur in the absence of vitamin deficiencies. Normochromic anemias also can occur due to effects of chronic illness on hematopoiesis. In the presence of severe liver disease, morphological changes can include the development of burr cells, schistocytes, and ring sideroblasts. Alcohol-induced sideroblastic anemia may respond to vitamin B₆ replacement (Wartenberg, 1998). Alcohol use also is associated with reversible thrombocytopenia. Platelet counts under 20,000 are rare. Bleeding is uncommon unless there is an alteration in vitamin K₁-dependent clotting factors. Proposed mechanisms focus on platelet trapping in the spleen and marrow.

Alcohol also affects granulocytes and lymphocytes (Schirmer et al., 2000). Effects include leukopenia, alteration of lymphocyte subsets, decreased T-cell mitogenesis, and changes in immunoglobulin production. These disorders may play a role in alcohol-related liver disease. In some patients, a depression of leukocyte migration into inflamed areas may account in part for the poor resistance of alcoholics to some types of infection (i.e., Klebsiella pneumonia, listeriosis, tuberculosis). Alcohol consumption also may alter the distribution and function of lymphoid cells by disrupting cytokine regulation, in particular that involving interleukin-2 (IL-2). Alcohol appears to play a role in the development of HIV infection. In vitro studies with human lymphocytes suggest that alcohol can suppress CD4 T-lymphocyte function and concanavalin-Astimulated IL-2 production and enhance in vitro replication of HIV. Moreover, persons who abuse alcohol have higher rates of high-risk sexual behavior.

Teratogenic Effects: Fetal Alcohol Syndrome

Although long suspected to be true, the possibility that alcohol consumption during pregnancy has deleterious consequences for the offspring has been examined rigorously only in the latter half of the twentieth century. In 1968, French researchers first noted that children born to alcoholic mothers displayed a common pattern of distinct dysmorphology that later came to be known as fetal alcohol syndrome (FAS) (Lemoine et al., 1968; Jones and Smith, 1973). The diagnosis of FAS typically is based on the observance of a triad of abnormalities in the newborn, including (1) a cluster of craniofacial abnormalities, (2) CNS dysfunction, and (3) pre- and/or postnatal stunting of growth. Hearing, language, and speech disorders also may become evident as the child ages (Church and Kaltenbach, 1997). Children who do not meet all the criteria for a diagnosis of FAS still may show physical and/or mental deficits consistent with a partial phenotype, termed fetal alcohol effects (FAEs) or alcohol-related neurodevelopmental disorders (ARNDs). The incidence of FAS is believed to be in the range of 0.5 to 1 per thousand live births in the general population, with rates as high as 2 to 3 per thousand in African-American and Native-American populations. A lower socioeconomic status of the mother, rather than racial background per se, appears to be primarily responsible for the higher incidence of FAS observed in those groups (Abel, 1995). The incidence of FAE is likely higher than that of FAS, making alcohol consumption during pregnancy a major public health problem.

Craniofacial abnormalities commonly observed in the diagnosis of FAS consist of a pattern of microcephaly, a long and smooth philtrum, shortened palpebral fissures, a flat midface, and epicanthal folds. Magnetic resonance imaging studies demonstrate decreased volumes in the basal ganglia, corpus callosum, cerebrum, and cerebellum (Mattson et al., 1992). The severity of alcohol effects can vary greatly and depends on the drinking patterns and amount of alcohol consumed by the mother. Maternal drinking in the first trimester has been associated with craniofacial abnormalities; facial dysmorphology also is seen in mice exposed to ethanol at the equivalent time in gestation.

CNS dysfunction following in utero exposure to alcohol manifests itself in the form of hyperactivity, attention deficits, mental retardation, and/or learning disabilities. FAS is the most common cause of preventable mental retardation in the western world (Abel and Sokol, 1987), with afflicted children consistently scoring lower than their peers on a variety of IQ tests. It is now clear that FAS represents the severe end of a spectrum of alcohol effects. A number of studies have documented intellectual deficits, including mental retardation, in children not displaying the craniofacial deformities or retarded growth seen in FAS. Although cognitive improvements are seen with time, decreased IQ scores of FAS children tend to persist as they mature, indicating that the deleterious prenatal effects of alcohol are irreversible. Although a correlation exists between the amount of alcohol consumed by the mother and infant scores on mental and motor performance tests, there is considerable diversity in performance on such tests among children of mothers consuming similar quantities of alcohol. It appears that the peak blood-alcohol concentration reached may be a critical factor in determining the severity of deficits seen in the offspring. Although the evidence is not conclusive, there is a suggestion that even moderate alcohol consumption (two drinks per day) in the second trimester of pregnancy is correlated with impaired academic performance of offspring at age 6 (Goldschmidt et al., 1996). Maternal age also may be a factor. Pregnant women over the age of 30 who drink alcohol create greater risks to their children than do younger women who consume similar amounts of alcohol (Jacobson et al., 1996).

Children prenatally exposed to alcohol most frequently present with attentional deficits and hyperactivity, even in the absence of intellectual deficits or craniofacial abnormalities. Furthermore, attentional problems have been observed in the absence of hyperactivity, suggesting that the two phenomena are not necessarily related. Fetal alcohol exposure also has been identified as a risk factor for alcohol abuse by adolescents (Baer et al., 1998). Apart from the risk of FAS or FAE to the child, the intake of high amounts of alcohol by a pregnant woman, particularly during the first trimester, greatly increases the chances of spontaneous abortion.

Studies with laboratory animals have demonstrated many of the consequences of in utero exposure to ethanol observed in human beings, including hyperactivity, motor dysfunction, and learning deficits. In animals, in utero exposure to ethanol alters the expression patterns of a wide variety of proteins, changes neuronal migration patterns, and results in brain regionspecific and cell typespecific alterations in neuronal numbers. Indeed, specific periods of vulnerability may exist for the various neuronal populations in the brain. Genetics also may play a role in determining vulnerability to ethanol; there are differences among strains of rats in susceptibility to the prenatal effects of ethanol. Finally, multidrug abuse, such as the concomitant administration of cocaine with ethanol, enhances fetal damage and mortality.

An increased reaction time, diminished fine motor control, impulsivity, and impaired judgment become evident when the concentration of ethanol in the blood is 20 to 30 mg/dl. More than 50% of persons are grossly intoxicated by a concentration of 150 mg/dl. In fatal cases, the average concentration is about 400 mg/dl, although alcohol-tolerant individuals often can withstand these blood alcohol levels. The definition of intoxication varies by state and country. In the United States, most states set the ethanol level defined as intoxication at 80 to 100 mg/dl. There is increasing evidence that lowering the limit to 50 to 80 mg/dl can reduce motor vehicle injuries and fatalities significantly. While alcohol can be measured in saliva, urine, sweat, and blood, measurement of levels in exhaled air remain the primary method of assessing the level of intoxication.

Many factors, such as body weight and composition and the rate of absorption from the gastrointestinal tract, determine the concentration of ethanol in the blood after ingestion of a given amount of ethanol. On average, the ingestion of three standard drinks (42 grams of alcohol) on an empty stomach results in a maximum blood concentration of 67 to 92 mg/dl in men. After a mixed meal, the maximal blood concentration from three drinks is 30 to 53 mg/dl in men. Concentrations of alcohol in blood will be higher in women than in men consuming the same amount of alcohol because, on average, women are smaller than men, have less body water per unit of weight into which ethanol can distribute, and have less gastric alcohol dehydrogenase activity than men. For individuals with normal hepatic function, ethanol is metabolized at a rate of one standard drink every 60 to 90 minutes.

The characteristic signs and symptoms of alcohol intoxication are well known. Nevertheless, an erroneous diagnosis of drunkenness may occur with patients who appear inebriated but who have not ingested ethanol. Diabetic coma, for example, may be mistaken for severe alcoholic intoxication. Drug intoxication, cardiovascular accidents, and skull fractures also may be confused with alcohol intoxication. The odor of the breath of a person who has consumed ethanol is due not to ethanol vapor but to impurities in alcoholic beverages. Breath odor in a case of suspected intoxication can be misleading, as there can be other causes of breath odor similar to that after alcohol consumption. Blood alcohol levels are necessary to confirm the presence or absence of alcohol intoxication (Schuckit, 1995).

The treatment of acute alcohol intoxication is based on the severity of respiratory and CNS depression. Acute alcohol intoxication can be a medical emergency, and a number of young people die every year from this disorder. Patients who are comatose and who exhibit evidence of respiratory depression should be intubated to protect the airway and to provide ventilatory assistance. The stomach may be lavaged, but care must be taken to prevent pulmonary aspiration of the return flow. Since ethanol is freely miscible with water, ethanol can be removed from blood by hemodialysis (Schuckit, 1995).

Acute alcohol intoxication is not always associated with coma, and careful observation is the primary treatment. Usual care involves observing the patient in the emergency room for 4 to 6 hours while the patient's tissues metabolize the ingested ethanol. Blood alcohol levels will be reduced at a rate of about 15 mg/dl per hour. During this period, some individuals may display extremely violent behavior. Sedatives and antipsychotic agents have been employed to quiet such patients. Great care must be taken, however, when using sedatives to treat patients who have ingested an excessive amount of another CNS depressant, i.e., ethanol.

Dehydrated alcohol may be injected in the close proximity of nerves or sympathetic ganglia to relieve the long-lasting pain related to trigeminal neuralgia, inoperable carcinoma, and other conditions. Epidural, subarachnoid, and lumbar paravertebral injections of ethanol also have been employed for inoperable pain. For example, lumbar paravertebral injections of ethanol may destroy sympathetic ganglia and thereby produce vasodilation, relieve pain, and promote healing of lesions in patients with vascular disease of the lower extremities.

Systemically administered ethanol is confined to the treatment of poisoning by methyl alcohol and ethylene glycol (see Chapter 68: Nonmetallic Environmental Toxicants: Air Pollutants, Solvents and Vapors, and Pesticides). The accidental or intentional consumption of methanol leads to retinal and optic nerve damage, potentially resulting in blindness. Formic acid, a metabolite of methanol, is responsible for the toxicity. Treatment consists of sodium bicarbonate to combat acidosis, hemodialysis, and the administration of ethanol, which competes with methanol for metabolism by alcohol dehydrogenase.

The use of alcohol to treat patients in alcohol withdrawal or obstetrical patients with premature contractions is no longer recommended. Some medical centers continue to use alcohol to prevent or reduce the risk of alcohol withdrawal in postoperative patients, but administering a combination of a benzodiazepine with haloperidol or clonidine may be more appropriate (Spies and Rommelspacher, 1999).

Acute Intoxication

Alcohol disturbs the fine balance that exists between excitatory and inhibitory influences in the brain, resulting in the anxiolysis, ataxia, and sedation that follow alcohol consumption. This is accomplished by either enhancing inhibitory or antagonizing excitatory neurotransmission. Although ethanol was long thought to act nonspecifically by disordering lipids in cell membranes, it is now believed that proteins constitute the primary molecular sites of action for ethanol. A number of putative sites at which ethanol may act have been identified, and ethanol likely produces its effects by simultaneously altering the functioning of a number of proteins that can affect neuronal excitability. A key issue has been to identify those proteins that determine neuronal excitability and are sensitive to ethanol at the low concentrations (5 to 20 mM) that produce behavioral effects.

Ion Channels

A number of different types of ion channels in the CNS are sensitive to ethanol, including representatives of the ligand-gated and G proteinregulated channel families and voltage-gated ion channels. The primary mediators of inhibitory neurotransmission in the brain are the ligand-gated GABA_A receptors (see Chapter 12: Neurotransmission and the Central Nervous System), whose function is markedly enhanced by a number of classes of sedative, hypnotic, and anesthetic agents including barbiturates, benzodiazepines, and volatile anesthetics (Mehta and Ticku, 1999). Substantial biochemical, electrophysiological, and behavioral data implicate the GABA_A receptor as an important target for the in vivo actions of ethanol. The GABA_A-receptor antagonist bicuculline as well as antagonists at the benzodiazepine binding site on GABA_A receptors decrease alcohol consumption in animal models (Harris et al., 1998). Furthermore, administration of the GABA_A-receptor agonist muscimol into specific regions of the limbic system in rats can substitute for ethanol in discrimination studies (Mihic, 1999). Phosphorylation, particularly by protein kinase C (PKC), appears to play a major role in determining the GABA_A receptor's sensitivity to ethanol.

Neuronal nicotinic acetylcholine receptors (see Chapter 9: Agents Acting at the Neuromuscular Junction and Autonomic Ganglia) also may be prominent molecular targets of alcohol action (Narahashi et al., 1999). Both enhancement and inhibition of nicotinic acetylcholine receptor function have been reported, depending on receptor subunit concentration and the concentrations of ethanol tested. Effects of ethanol on these receptors may be particularly important, as there is an observed association between smoking and alcohol consumption in human beings (Collins, 1990). Furthermore, several studies indicate that nicotine increases alcohol consumption in animal models (Smith et al., 1999). Another member of the cation-selective ion-channel superfamily of receptors is the serotonin 5-HT₃ receptor (see Chapter 11: 5-Hydroxytryptamine (Serotonin): Receptor Agonists and Antagonists). Electrophysiological studies demonstrate enhancement by ethanol of 5-HT₃-receptor function (Lovinger, 1999).

Excitatory ionotropic glutamate receptors are divided into the NMDA and nonNMDA receptor classes, with the latter being composed of kainate- and AMPA-receptor subtypes (see Chapter 12: Neurotransmission and the Central Nervous System). Ethanol inhibits the function of the NMDA- and kainate-receptor subtypes, whereas AMPA receptors are largely resistant to alcohol (Weiner et al., 1999). As with the GABA_A receptors, phosphorylation of the glutamate receptor can determine sensitivity to ethanol. The nonreceptor tyrosine kinase Fyn phosphorylates NMDA receptors, rendering them less sensitive to inhibition by ethanol (Anders et al., 1999) and perhaps explaining why null mutant mice lacking Fyn display significantly greater sensitivity to the hypnotic effects of ethanol. NMDA receptors play a crucial role in the development of long-term potentiation (LTP), a form of neuronal plasticity that may constitute a cellular substrate for memory. Ethanol inhibits LTP, although this does not appear to be accomplished solely through inhibition of NMDA receptors (Schummers et al., 1997).

Although considerable research effort has been expended on the ligand-gated ion channels, a number of other types of channels recently have been found to be sensitive to alcohol at concentrations routinely achieved in vivo. Ethanol enhances the activity of large conductance, calcium-activated potassium channels in neurohypophyseal terminals (Dopico et al., 1999), perhaps contributing to the reduced release of oxytocin and vasopressin after ethanol consumption. Ethanol also inhibits N- and P/Q-type Ca²⁺ channels in a manner that can be antagonized by channel phosphorylation by protein kinase A (PKA) (Solem et al., 1997). Finally, G proteincoupled, inwardly rectifying potassium channels, which regulate synaptic transmission and neuronal firing rates, exhibit enhanced function in the presence of low concentrations of ethanol (Lewohl et al., 1999; Kobayashi et al., 1999).

Kinases and Signaling Enzymes

As mentioned above, phosphorylation by a number of protein kinases can affect the functioning of many receptors. The behavioral consequences of this were illustrated in null mutant mice lacking the isoform of PKC; these mice display reduced effects of ethanol measured behaviorally and a loss of enhancement by ethanol of GABA's effects measured in vitro (Harris et al., 1995). There is some uncertainty as to whether or not ethanol directly interacts with PKC. Some investigators have reported inhibition of function, while others have seen no effect (Stubbs and Slater, 1999), perhaps due to differential sensitivity to ethanol of specific PKC isoforms. Intracellular signal transduction cascades, such as those involving MAP and tyrosine kinases and neurotrophic factor receptors, also are thought to be affected by ethanol (Valenzuela and Harris, 1997). Translocation of PKC and PKA between subcellular compartments also is sensitive to alcohol (Constantinescu et al., 1999).

Ethanol enhances the activities of some of the nine isoforms of adenylyl cyclase, with the type VII isoform being the most sensitive (Tabakoff and Hoffman, 1998). This promotes increased production of cyclic AMP and thus increased activity of PKA. Ethanol's actions appear to be mediated by activation of the stimulatory G protein G_s as well as by promotion of the interaction between the G protein and the catalytic moiety of adenylyl cyclase. Decreased adenylyl cyclase activities have been reported in alcoholics (Parsian et al., 1996) and even in nondrinkers with family histories of alcoholism, suggesting that lowered adenylyl cyclase activity may be a trait marker for alcoholism (Menninger et al., 1998).

Tolerance and Dependence

Tolerance is defined as a reduced behavioral or physiological response to the same dose of ethanol (see Chapter 24: Drug Addiction and Drug Abuse). There is a marked acute tolerance that is detectable soon after administration of ethanol. Acute tolerance can be demonstrated by measuring behavioral impairment at the same BALs on the ascending limb of the absorption phase of the BAL-time curve (minutes after ingestion of ethanol) and on the descending limb of the curve as BALs are lowered by metabolism (one or more hours after ingestion). Behavioral impairment and subjective feelings of intoxication are much greater at a given BAL on the ascending than on the descending limb. There also is a chronic tolerance that develops in the long-term heavy drinker. In contrast to acute tolerance, chronic tolerance often has a metabolic component due to induction of alcohol-metabolizing enzymes.

Physical dependence is demonstrated by the elicitation of a withdrawal syndrome when alcohol consumption is terminated. The symptoms and severity are determined by the amount and duration of alcohol consumption and include sleep disruption, autonomic nervous system (sympathetic) activation, sleeplessness, tremors, and, in severe cases, seizures. In addition, two or more days after withdrawal, some individuals experience delirium tremens, characterized by hallucinations, delirium, fever, and tachycardia. This is sometimes fatal. Another aspect of dependence is craving and drug-seeking behavior, often termed psychological dependence.

Ethanol tolerance and physical dependence are readily studied in animal models. Lines of mice with genetic differences in tolerance and dependence have been characterized, and a search for the relevant genes is under way (Crabbe et al., 1999). Neurobiological mechanisms of tolerance and dependence are not understood completely, but chronic alcohol consumption results in changes in synaptic and intracellular signaling, likely due to changes in gene expression. Most of the systems that are acutely affected by ethanol also are affected by chronic exposure, resulting in an adaptive or maladaptive response that can cause tolerance and dependence. In particular, chronic actions of ethanol likely require changes in signaling by glutamate and GABA receptors and intracellular systems such as PKC (Diamond and Gordon, 1997). There is an increase in NMDA receptor function after chronic alcohol ingestion, which may contribute to the CNS hyperexcitability and neurotoxicity seen during ethanol withdrawal (Tabakoff and Hoffman, 1996; Chandler et al., 1998). Arginine vasopressin, acting on V₁ receptors, maintains tolerance to ethanol in laboratory animals even after chronic ethanol administration has ceased (Hoffman et al., 1990).

The neurobiological basis of the switch from controlled, volitional alcohol use to compulsive and uncontrolled addiction remains obscure. Impairment of the dopaminergic reward system and the resultant increase in alcohol consumption in an attempt to regain activation of the system is a possibility. In addition, the prefrontal cortex is particularly sensitive to damage from alcohol abuse and influences decision making and emotion, processes clearly compromised in the alcoholic (Pfefferbaum et al., 1998). Thus, impairment of executive function in cortical regions by chronic alcohol consumption may be responsible for some of the lack of judgment and control that is expressed as obsessive alcohol consumption. It should be reiterated that the loss of brain volume and impairment of function seen in the chronic alcoholic is at least partially reversible by abstinence but will worsen with continued drinking (Pfefferbaum et al., 1998). Obviously, early diagnosis and treatment of alcoholism is important, as it can limit the brain damage that promotes the spiraling descent into progressively severe addiction.

Genetic Influences

The concept of alcoholism as a disease was first articulated by Jellinek in 1960; the subsequent acceptance of alcoholism and addiction as 'brain diseases' led to a search for biological causes. Studies of rats and mice carried out in Chile, Finland, and the United States showed significant heritabilities (roughly 60%) for many behavioral actions of alcohol, including sedation, ataxia, and, most notably, consumption (Crabbe and Harris, 1991). It has long been appreciated that alcoholism 'runs in families,' and definitive studies of genetics and human alcoholism appeared about 30 years ago. A series of adoption (cross-fostering) and twin studies showed that human alcohol dependence has a genetic component. It is important to note that, although the genetic contribution has varied among studies, it is generally in the range of 40% to 60%, which means that environmental variables also are critical for individual susceptibility to alcoholism (Begleiter and Kissin, 1995).

The search for the genes and alleles responsible for alcoholism is complicated by the polygenetic nature of the disease and the general difficulty in defining the multiple genes responsible for complex diseases. One area of research that has been fruitful has been the study of why some populations (mainly Asian) are protected from alcoholism. This has been found to be caused by genetic differences in alcohol- and aldehyde-metabolizing enzymes. Specifically, genetic variants of alcohol dehydrogenase that exhibit high activity and variants of aldehyde dehydrogenase that exhibit low activity protect against heavy drinking. This is because alcohol consumption by individuals who have these variants results in accumulation of acetaldehyde, which produces a variety of unpleasant effects (Li, 2000). These effects are similar to those of disulfiram therapy (see below), but the prophylactic, genetic form of inhibition of alcohol consumption is more effective than the pharmacotherapeutic approach, which is applied after alcoholism has developed.

In contrast to these protective genetic variants, there is little information about genes responsible for increased risk for alcoholism. The recent history of psychiatric genetics is that genes identified in one study are not consistently found in other populations. This also is true for alcoholism. Sequence differences in several candidate genes from alcoholics, including genes for a dopamine receptor (D₂) and for serotonin-related transporters and enzymes, are not consistently different from the sequences of those genes from nonalcoholic subjects. Several large-scale genetic studies of alcoholism currently are in progress, and these efforts, together with genetic studies in laboratory animals, should lead to identification of alcoholism susceptibility genes. It is possible that these studies also will allow genetic classification of subtypes of alcoholism and thereby resolve some of the inconsistencies among study populations. For example, antisocial alcoholism is linked with a polymorphism in a serotonin receptor (5HT_1B), but there is no association of this gene with nonantisocial alcoholism (Lappalainen et al., 1998).

Another approach to understanding the inherited biology of alcoholism is to ask what behavioral or functional differences exist between individuals with high and low genetic risks for alcoholism. This may be accomplished by studying young social drinkers with many or few alcoholic relatives [family history positive (FHP) and family history negative (FHN)]. Brain imaging by positron emission tomography has been used in this context. A family history of alcoholism is linked to lower cerebellar metabolism and a blunted effect of a benzodiazepine (lorazepam) on cerebellar metabolism (Volkow et al., 1995). Because GABA_A receptors are the molecular site of benzodiazepine action, these results suggest that a genetic predisposition to alcoholism may be reflected in abnormal function of GABA_A receptors.

Schuckit and colleagues have studied actions of alcohol in FHP college students and have followed the study subjects for almost 20 years to determine which ones will develop alcoholism or alcohol abuse. It is remarkable that a blunted behavioral and physiological response to alcohol in the original test is associated with a significantly greater risk for later development of alcohol-related problems (Schuckit, 1994). The genes that control initial sensitivity to ethanol are not known, but they may be important for risk for alcohol abuse. At present, there is little evidence that the genes important for alcoholism also are important for other addictions and diseases with the exception of tobacco use. Studies with twins indicate a common genetic vulnerability for alcohol and nicotine dependence (True et al., 1999), which is consistent with the high rate of smoking among alcoholics.

Currently, only two drugs are approved in the United States for treatment of alcoholism: disulfiram (ANTABUSE) and naltrexone (REVIA). Disulfiram has a long history of use but has fallen out of favor because of its side effects and compliance problems. Naltrexone was introduced more recently. The goal of both of these medications is to assist the patient in maintaining abstinence.

Naltrexone

Naltrexone was approved by the FDA for treatment of alcoholism in 1994. It is chemically related to the highly selective opioid-receptor antagonist naloxone (NARCAN), but it has higher oral bioavailability and a longer duration of action than does naloxone. Neither drug has appreciable opioid-receptor agonist effects. These drugs were used initially in the treatment of opioid overdose and dependence because of their ability to antagonize all of the actions of opioids (see Chapters 23: Opioid Analgesics and 24: Drug Addiction and Drug Abuse). There were suggestions from both animal research and clinical experience that naltrexone might reduce alcohol consumption and craving, and this was confirmed in clinical trials in the early 1990s (see O'Malley et al., 2000; Johnson and Ait-Daoud, 2000). There is evidence that naltrexone blocks activation by alcohol of dopaminergic pathways in the brain that are thought to be critical to reward.

Naltrexone helps to maintain abstinence by reducing the urge to drink and increasing control when a 'slip' occurs. It is not a 'cure' for alcoholism and does not prevent relapse in all patients. Naltrexone works best when used in conjunction with some form of psychosocial therapy, such as cognitive behavioral therapy (Anton et al., 1999). It is typically administered after detoxification and given at a dose of 50 mg per day for several months. Good compliance is important to ensure the therapeutic value of naltrexone and has proven to be a problem for some patients (Johnson and Ait-Daoud, 2000). The most common side effect of naltrexone is nausea, which is more common in women than in men and subsides if the patients remain abstinent (O'Malley et al., 2000). When given in excessive doses, naltrexone can cause liver damage. It is contraindicated in patients with liver failure or acute hepatitis and should be used only after careful consideration in patients with active liver disease.

Nalmefene REVEX) is another opioid antagonist that appears promising in preliminary clinical tests. It has a number of advantages over naltrexone, including greater oral bioavailability, longer duration of action, and lack of dose-dependent problems with liver toxicity.

Disulfiram

Disulfiram (tetraethylthiuram disulfide; ANTABUSE) was taken in the course of an investigation of its potential anthelminthic usefulness by two Danish physicians, who became ill at a cocktail party and were quick to realize that the compound had altered their responses to alcohol. They initiated a series of pharmacological and clinical studies that provided the basis for the use of disulfiram as an adjunct in the treatment of chronic alcoholism. Similar responses to alcohol ingestion are produced by various congeners of disulfiram, cyanamide, the fungus Coprinus atramentarius, the hypoglycemic sulfonylureas, metronidazole, certain cephalosporins, and the ingestion of animal charcoal.

Disulfiram, given alone, is a relatively nontoxic substance, but it alters the metabolism of alcohol and causes the blood acetaldehyde concentration to rise to five to ten times above the level achieved when ethanol is given to an individual not pretreated with disulfiram. Acetaldehyde, produced as a result of the oxidation of ethanol by alcohol dehydrogenase, ordinarily does not accumulate in the body, because it is further oxidized almost as soon as it is formed, primarily by aldehyde dehydrogenase. Following the administration of disulfiram, both cytosolic and mitochondrial forms of this enzyme are irreversibly inactivated to varying degrees, and the concentration of acetaldehyde rises. It is unlikely that disulfiram itself is responsible for the enzyme inactivation in vivo; several active metabolites of the drug, especially diethylthiomethylcarbamate, behave as suicide-substrate inhibitors of aldehyde dehydrogenase in vitro. These metabolites reach significant concentrations in plasma following the administration of disulfiram (Johansson, 1992).

The ingestion of alcohol by individuals previously treated with disulfiram gives rise to marked signs and symptoms. Within about 5 to 10 minutes, the face feels hot, and soon afterwards it is flushed and scarlet in appearance. As the vasodilation spreads over the whole body, intense throbbing is felt in the head and neck, and a pulsating headache may develop. Respiratory difficulties, nausea, copious vomiting, sweating, thirst, chest pain, considerable hypotension, orthostatic syncope, marked uneasiness, weakness, vertigo, blurred vision, and confusion are observed. The facial flush is replaced by pallor, and the blood pressure may fall to shock levels.

Disulfiram and/or its metabolites can inhibit many enzymes with crucial sulfhydryl groups, and it thus has a wide spectrum of biological effects. It inhibits hepatic microsomal drugmetabolizing enzymes and thereby interferes with the metabolism of phenytoin, chlordiazepoxide, barbiturates, and other drugs.

Disulfiram by itself is usually innocuous, but it may cause acneform eruptions, urticaria, lassitude, tremor, restlessness, headache, dizziness, a garlic-like or metallic taste, and mild gastrointestinal disturbances. Peripheral neuropathies, psychosis, and acetonemia also have been reported. Alarming reactions may result from the ingestion of even small amounts of alcohol in persons being treated with disulfiram. The use of disulfiram as a therapeutic agent thus is not without danger, and it should be attempted only under careful medical and nursing supervision. Patients must be warned that as long as they are taking disulfiram, the ingestion of alcohol in any form will make them sick and may endanger their lives. Patients must learn to avoid disguised forms of alcohol, as in sauces, fermented vinegar, cough syrups, and even after-shave lotions and back rubs.

The drug never should be administered until the patient has abstained from alcohol for at least 12 hours. In the initial phase of treatment, a maximal daily dose of 500 mg is given for 1 to 2 weeks. Maintenance dosage then ranges from 125 to 500 mg daily, depending on tolerance to side effects. Unless sedation is prominent, the daily dose should be taken in the morning, the time when the resolve not to drink may be strongest. Sensitization to alcohol may last as long as 14 days after the last ingestion of disulfiram because of the slow rate of restoration of aldehyde dehydrogenase (Johansson, 1992).

Acamprosate

Acamprosate (N-acetylhomotaurine, calcium salt), an analog of GABA widely used in Europe for the treatment of alcoholism, is not yet approved for use in the United States. A number of double-blind, placebo-controlled studies have demonstrated that acamprosate decreases drinking frequency and reduces relapse drinking in abstinent alcoholics. It acts in a dose-dependent manner (1.3 to 2 g/day; Paille et al., 1995) and appears to have efficacy similar to that of naltrexone. Studies in laboratory animals have shown that acamprosate decreases alcohol intake without affecting food or water consumption. Acamprosate generally is well tolerated by patients, with diarrhea being the main side effect (Garbutt et al., 1999). No abuse liability has been noted. The drug undergoes minimal metabolism in the liver, is primarily excreted by the kidneys, and has an elimination half-life of 18 hours after oral administration (Wilde and Wagstaff, 1997). Concomitant use of disulfiram appears to increase the effectiveness of acamprosate, without any adverse drug interactions being noted (Besson et al., 1998). The mechanism of action of acamprosate is obscure, although there is some evidence that it affects the function of the NMDA subtype of ionotropic glutamate receptors in brain. Whether or not this modulation of NMDA receptor function is responsible for the drug's therapeutic effects is unknown (Johnson and Ait-Daoud, 2000).

Other Agents

Ondansetron, a 5-HT₃-receptor antagonist and antiemetic drug (see Chapters 11: 5-Hydroxytryptamine (Serotonin): Receptor Agonists and Antagonists and 38: Prokinetic Agents, Antiemetics, and Agents Used in Irritable Bowel Syndrome), reduces alcohol consumption in laboratory animals and currently is being tested in alcoholic subjects. Preliminary findings suggest that ondansetron is effective in the treatment of early-onset alcoholics, who respond poorly to psychosocial treatment alone, although the drug does not appear to work well in other types of alcoholics (Johnson and Ait-Daoud, 2000). Ondansetron administration lowers the amount of alcohol consumed, particularly by drinkers who consume fewer than ten drinks per day (Sellers et al., 1994). It also decreases the subjective effects of ethanol on 6 of 10 scales measured, including the desire to drink (Johnson et al., 1993a), while at the same time not having any effect on the pharmacokinetics of ethanol (Johnson et al., 1993b).

Initial studies suggested that lithium or selective serotonin-reuptake inhibitors (SSRIs) might be useful in reducing alcohol consumption, but subsequent clinical trials have not provided evidence for beneficial effects (see Garbutt et al., 1999). There have been limited clinical tests of several dopaminergic agonists and antagonists, serotonergic agonists, and calcium channel antagonists in reducing ethanol consumption, but the results with these agents generally have not been encouraging (Johnson and Ait-Daoud, 2000). An emerging approach is treatment with a combination of two or more drugs, particularly combining drugs with different mechanisms of action (e.g., naltrexone plus ondansetron or acamprosate); this approach may be useful if a limited therapeutic response is obtained with a single agent.