Brody's Human Pharmacology: With STUDENT CONSULT

Chapter 32 Ethanol, Other Alcohols, and Drugs for Alcohol Dependence



Drugs for Alcohol Dependence

Aldehyde dehydrogenase inhibitor

Glutamate receptor antagonist

Opioid receptor antagonist

Therapeutic Overview

Ethanol belongs to a class of compounds known as the central nervous system (CNS) depressants that includes the barbiturate and non-barbiturate sedative/hypnotics and the benzodiazepines. Although these latter compounds are used for their sedative and anxiolytic properties, ethanol is not prescribed for these purposes. Rather, ethanol is used primarily as a social drug, with only limited application as a therapeutic agent. It has been used by injection to produce irreversible nerve block or tumor destruction and is effective for the treatment of methanol and ethylene glycol poisonings, because it can inhibit competitively the metabolism of these alcohols to toxic intermediates.

In cultures in which ethanol use is accepted, the substance is misused and abused by a fraction of the population and is associated with social, medical, and economic problems, including life-threatening damage to most major organ systems and psychological and physical dependence in people who use it excessively. It is estimated that in the United States, 65% to 70% of the population uses ethanol, and more than 10 million individuals are alcohol-dependent. An additional 10 million people are subject to negative consequences of alcohol abuse such as arrests, automobile accidents, violence, occupational injuries, and deleterious effects on job performance and health. Approximately 50% of all traffic deaths are estimated to involve alcohol, and the annual cost of alcohol-related problems in the United States is more than $180 billion. In 2000, there were more than 20,000 alcohol-related deaths in the United States, and alcohol dependence in the United States ranks third as a preventable cause of morbidity and mortality.

In the primary care setting, approximately 15% of patients exhibit an “at risk” pattern of alcohol use or an alcohol-related health problem. A medical history designed to elicit information on alcohol use is an essential feature of a modern medical workup. Clearly, alcohol dependence is a chronic and relapsing disorder much like diabetes and hypertension and can be treated with



Alcohol dehydrogenase


Aldehyde dehydrogenase


Blood alcohol concentration


Central nervous system


γ-Aminobutyric acid






Nicotinamide adenine dinucleotide


Nicotinamide adenine dinucleotide, reduced


Nicotinamide adenine dinucleotide phosphate


Nicotinamide adenine dinucleotide phosphate, reduced






Tumor necrosis factor


Ventral tegmental area

pharmacological agents to enhance the efficacy of psychosocial/behavioral therapy.

This chapter covers the behavioral and toxicological problems associated with the use of ethanol and reviews the deleterious effects of other alcohols. In addition, the pharmacology of the three currently approved treatments for alcohol dependence are discussed including the aldehyde dehydrogenase inhibitor disulfiram, the glutamate receptor antagonist acamprosate, and the opioid receptorantagonist naltrexone.

The uses of ethanol and treatment of ethanol dependence are summarized in the Therapeutic Overview Box.

Therapeutic Overview

Ethanol is used:

Topically to reduce body temperature and as an antiseptic

By injection to produce irreversible nerve block by protein denaturation

By inhalation to reduce foaming in pulmonary edema

In treatment of methanol and ethylene glycol poisoning

Ethanol dependence may be treated with psychosocial/behavioral therapy and an:

Aldehyde dehydrogenase inhibitor (Disulfiram)

Glutamate receptor antagonist (Acamprosate)

Opioid receptor antagonist (Naltrexone)

Mechanisms of Action


Before the advent of ether, ethanol was used as an “anesthetic” agent for surgical procedures, and for many years, ethanol and the general anesthetic agents were assumed to share a common mechanism of action to “fluidize” or “disorder” the physical structure of cell membranes, particularly those low in cholesterol. Although ethanol may interfere with the packing of molecules in the phospholipid bilayer of the cell membrane, increasing membrane fluidity, this bulk fluidizing effect is small and not primarily responsible for the depressant effects of ethanol on the CNS. This action, however, may play a role in disrupting membranes surrounding neurotransmitter receptors or ion channels, proteins thought to mediate the actions of ethanol.

Studies suggest that the effects of ethanol may be attributed to its direct binding to lipophilic areas either near or in ion channels and receptors. The ion channels influenced by ethanol are listed in Table 32-1. Ethanol may have either inhibitory or facilitatory effects, depending on the channel, but its resultant action is CNS depression. Because the barbiturates and benzodiazepines exhibit cross-tolerance to ethanol, and their CNS depressant effects are additive with those of ethanol, they may share a common mechanism, perhaps through the γ-aminobutyric acid (GABA) type A receptor (see Chapter 31). Ethanol may also exert some of its effects by actions at glutamate N-methyl-D-aspartate (NMDA) receptors or serotonin (5-HT) receptors.

TABLE 32–1 Ion Channels Affected by Ethanol



Ethanol Concentration (mM)

Na+ (voltage-gated)


100 and higher*

K+ (voltage-gated)



Ca++ (voltage-gated)


50 and higher

Ca++ (glutamate receptor-activated)



Cl (GABAA receptor-gated)



Cl (glycine receptor-gated)



Na+/K+ (5HT3 receptor-gated)



* 100 mM ethanol is 460 mg/dL.

The reinforcing actions of ethanol are complex but are mediated in part through its ability to stimulate the dopaminergic reward pathway in the brain (see Fig. 27-8). Evidence has indicated that ethanol increases the synthesis and release of the endogenous opioid β-endorphin in both the ventral tegmental area (VTA) and the nucleus accumbens. Increased β-endorphin release in the VTA dampens the inhibitory influence of GABA on the tonic firing of VTA dopaminergic neurons, whereas increased β-endorphin release in the nucleus accumbens stimulates dopaminergic nerve terminals to release neurotransmitter. Both of these actions to increase dopamine release may be involved in the rewarding effects of ethanol.

Other Alcohols

Methanol, ethylene glycol, and isopropanol are commonly encountered alcohols. Methanol and ethylene glycol have applications in industry and are fairly toxic to humans, whereas isopropyl alcohol, like ethanol, is bacteriocidal and used as a disinfectant.

Drugs for Alcohol Dependence

Aldehyde Dehydrogenase Inhibitor

Disulfiram, used for the treatment of alcoholism since the 1940s, is an inhibitor of the enzyme aldehyde dehydrogenase (ALDH), a major enzyme involved in the metabolism of ethanol (Fig. 32-1). Inhibiting the catabolism of acetaldehyde produced by the oxidation of ethanol, leads to the accumulation of acetaldehyde in the plasma, resulting in aversive effects.


FIGURE 32–1 Metabolism of ethanol by ADH, ALDH, and cytochrome P450. ETS, Electron transport system; LDH, lactate dehydrogenase.

Glutamate Receptor Antagonist

Acamprosate is a synthetic taurine derivative resembling GABA and is the first glutamate receptor antagonist approved by the United States Food and Drug Administration in 2004 for the treatment of alcoholism. Acamprosate is an antagonist at glutamate NMDA receptors and modulates the ability of glutamate to activate the metabotropic type 5 glutamate receptor. Both of these effects decrease the excitatory actions of glutamate in the CNS. Based on studies indicating that ethanol disrupts the balance between excitatory and inhibitory neurotransmission in the CNS, acamprosate is thought to restore this balance by inhibiting the excitatory component. Imaging studies in human volunteers have supported the ability of acamprosate to inhibit glutamatergic activity in the brain.

Opioid Receptor Antagonist

Naltrexone is an opioid receptor antagonist at both κ and μ opioid receptors (see Chapter 36). Its ability to inhibit alcohol consumption has been attributed to blockade of μ receptors in both the VTA and nucleus accumbens, thereby decreasing the ethanol-induced activation of the dopamine reward pathway.



Alcohol taken orally is absorbed throughout the gastrointestinal (GI) tract. Absorption depends on passive diffusion and is governed by the concentration gradient and the mucosal surface area. Food in the stomach will dilute the alcohol and delay gastric emptying time, thereby retarding absorption from the small intestine (where absorption is favored because of the large surface area). High ethanol concentrations in the GI tract cause a greater concentration gradient and therefore hasten absorption. Absorption continues until the alcohol concentration in the blood and GI tract are at equilibrium. Because ethanol is rapidly metabolized and removed from the blood, eventually all the alcohol is absorbed.

Once ethanol reaches the systemic circulation, it is distributed to all body compartments at a rate proportional to blood flow to that area; its distribution approximates that of total body H2O. Because the brain receives a high blood flow, high concentrations of ethanol occur rapidly in the brain.

Ethanol undergoes significant first-pass metabolism. Most (>90%) of the ethanol ingested is metabolized in the liver, with the remainder excreted through the lungs and in urine. Alcohol dehydrogenase (ADH) catalyzes the oxidation of ethanol to acetaldehyde, which is oxidized further by ALDH to acetate (see Fig. 32-1). Acetate is oxidized primarily in peripheral tissues to CO2 and H2O. Both ADH and ALDH require the reduction of nicotinamide adenine dinucleotide (NAD+), with 1 mol of ethanol producing 2 mol of reduced NAD+ (NADH). The NADH is reoxidized to NAD+ by conversion of pyruvate to lactate by lactate dehydrogenase (LDH) and the mitochondrial electron transport system (ETS). During ethanol oxidation the concentration of NADH can rise substantially, and NADH product inhibition can become rate-limiting. Similarly, with large amounts of ethanol, NAD+ may become depleted, limiting further oxidation through this pathway. At typical blood alcohol concentrations (BACs), the metabolism of ethanol exhibits zero-order kinetics; that is, it is independent of concentration and occurs at a relatively constant rate (Fig. 32-2). Fasting decreases liver ADH activity, decreasing ethanol metabolism.


FIGURE 32–2 Disappearance of ethanol after oral ingestion follows zero-order kinetics.

Ethanol may also be metabolized to acetaldehyde in the liver by cytochrome P450, a reaction that requires 1 mol of reduced nicotinamide adenine dinucleotide phosphate (NADPH) for every ethanol molecule (see Fig. 32-1). Although P450-mediated oxidation does not normally play a significant role, it is important with high concentrations of ethanol (≥100 mg/dL), which saturate ADH and deplete NAD+. Because this enzyme system also metabolizes other compounds, ethanol may alter the metabolism of many other drugs. In addition, this system may be inhibited or induced (Chapter 2), and induction by ethanol may contribute to the oxidative stress of chronic alcohol consumption by releasing reactive O2 species during metabolism.

A third system capable of metabolizing ethanol is a peroxidative reaction mediated by catalase, a system limited by the amount of hydrogen peroxide available, which is normally low. Small amounts of ethanol are also metabolized by formation of phosphatidylethanol and ethyl esters of fatty acids. The significance of these pathways is unknown.

Significant genetic differences exist for both ADH and ALDH that affect the rate of ethanol metabolism. Several forms of ADH exist in human liver, with differing affinities for ethanol. Whites, Asians, and African-Americans express different relative percentages of the genes and their respective alleles that encode subunits of ADH, contributing to ethnic differences in the rate of ethanol metabolism. Similarly, there are genetic differences in ALDH. Approximately 50% of Asians have an inactive ALDH, caused by a single base change in the gene that renders them incapable of oxidizing acetaldehyde efficiently, especially if they are homozygous. When these individuals consume ethanol, high concentrations of acetaldehyde are achieved, leading to flushing and other unpleasant effects. People with this condition rarely become alcoholic. As discussed, the unpleasant effects of acetaldehyde accumulation form the basis for the aversive treatment of chronic alcoholism with disulfiram. The pharmacokinetics of ethanol are summarized in Table 32-2.

TABLE 32–2 Pharmacokinetic Considerations of Ethanol

Pharmacokinetic Parameter


Route of administration

Topically, orally, inhalation, by injection into nerve trunks, or intravenously for poison management


Slight topically

Complete from stomach and intestine by passive diffusion

Rapid via lungs


Total body H2O; volume of distribution is 68% of body weight in men and 55% in women; varies widely


>90% to CO2 and H2O by liver and other tissues

Follows zero-order kinetics

Rate is approximately 100 mg/kg/hr of total body burden; higher or lower with hepatic enzyme induction or disease


Excreted in expired air, urine, milk, sweat

Other Alcohols

Methanol, which may be accidentally or intentionally ingested, is metabolized by ADH and ALDH in a manner similar to ethanol, but at a much slower rate, forming formaldehyde and formic acid. Because ethanol can compete with methanol for ADH and saturate the enzyme, ethanol can be used successfully for methanol intoxication.

Ethylene glycol and isopropyl alcohol are also metabolized by ADH; thus ethanol can be used as a competitive antagonist for these compounds.

Drugs for Alcohol Dependence

Disulfiram is rapidly absorbed from the GI tract. It is highly lipid soluble, accumulates in fat stores, and is slowly eliminated. Disulfiram is metabolized by the liver and inhibits the metabolism of several drugs including phenytoin and oral anticoagulants.

Acamprosate is administered orally with a bioavailability of approximately 11%. It exhibits negligible plasma protein binding, is not metabolized, and has a terminal elimination half-life of 20 to 33 hours. Acamprosate is excreted unchanged by the kidneys.

Naltrexone is available both orally and as depot injections for the treatment of alcohol dependence. The pharmacokinetics of oral naltrexone are discussed in Chapter 36. The depot microsphere preparations are administered intramuscularly once per month and release naltrexone steadily to maintain constant plasma levels.

Relationship of Mechanisms of Action to Clinical Response


Like general anesthetics and most CNS depressants, ethanol decreases the function of inhibitory centers in the brain, releasing normal mechanisms controlling social functioning and behavior, leading to an initial excitation. Thus ethanol is described as a disinhibitor or euphoriant. The higher integrative areas are affected first, with thought processes, fine discrimination, judgment, and motor function impaired sequentially. These effects may be observed with BACs of 0.05% or lower. Specific behavioral changes are difficult to predict and depend to a large extent on the environment and the personality of the individual. As BACs increase to 100 mg/dL, errors in judgment are frequent, motor systems are impaired, and responses to complex auditory and visual stimuli are altered. Patterns of involuntary motor action are also affected. Ataxia is noticeable, with walking becoming difficult and staggering common as the BAC approaches 0.15% to 0.2%. Reaction times are increased, and the person may become extremely loud, incoherent, and emotionally unstable. Violent behavior may occur. These effects are the result of depression of excitatory areas of the brain. At BACs of 0.2% to 0.3%, intoxicated people may experience periods of amnesia or “blackout” and fail to recall events occurring at that time.

Anesthesia occurs when BAC increases to 0.25% to 0.30%. Ethanol shares many properties with general anesthetics but is less safe because of its low therapeutic index (see Chapter 3). It is also a poor analgesic. Coma in humans occurs with BAC above 0.3%, and the lethal range for ethanol, in the absence of other CNS depressants, is 0.4% to 0.5%, though people with much higher concentrations have survived. Death from acute ethanol overdose is relatively rare compared with the frequency of death resulting from combinations of alcohol with other CNS depressants, such as barbiturates and benzodiazepines. Death is due to a depressant effect on the medulla, resulting in respiratory failure.

Physiological and behavioral changes as a function of BAC are summarized in Table 32-3Measures of BAC are important for providing adequate medical care to intoxicated individuals. BAC is calculated based on the amount of ethanol ingested, the percentage of alcohol in the beverage (usually volume/volume, with 100-proof equivalent to 50% ethanol by volume), and the density of 0.8 g/mL of ethanol. BACs are expressed in a variety of ways. The legal limit for operating a motor vehicle in most states is 80 mg/dL, or 0.08%. An example of a typical calculation for a 70 kg person ingesting 1 oz, or 30 mL, of 80-proof distilled spirits is as follows:

TABLE 32–3 Physiological and Behavioral States as a Function of Blood Ethanol Concentrations

Blood Ethanol Concentrations






Loss of inhibitions, excitement, incoordination, impaired judgment, slurred speech, body sway



Impaired reaction time, further impaired judgment, impaired driving ability, ataxia



Staggering gait, inability to operate a motor vehicle



Respiratory depression, danger of death in presence of other CNS depressants, blackouts



Unconsciousness, severe respiratory and cardiovascular depression, death



Highest known blood concentration with survival in a chronic alcoholic


If absorbed immediately and distributed in total body H2O (assuming blood is 80% H2O and body H2O content averages 55% of body weight in women and 68% in men):


The average rate at which ethanol is metabolized in nontolerant individuals is 100 mg/kg body weight/hr, or 7 g/hr in a 70-kg person. Chronic alcoholics metabolize ethanol faster because of hepatic enzyme induction. In the calculation above, a male with a body burden of 9.6 g of ethanol would metabolize the alcohol totally in less than 2 hours.

Figure 32-3 shows approximate maximum BACs in men of various body weights ingesting one to five drinks in 1 hour. Rapid absorption is assumed. This figure emphasizes how little consumption is required to impair motor skills and render a person unable to drive safely.


FIGURE 32–3 Approximate percentages of ethanol in blood (BAC) in male subjects of different body weights, calculated as percentage, weight/volume (w/v), after indicated number of drinks. One drink is 12 oz of beer, 5 oz of wine, or 1 oz of 80-proof distilled spirits. People with BACs of 0.08% (80 mg/dL) or higher are considered intoxicated in most states; those with BACs of 0.05% to 0.079% (50 to 79 mg/dL) are considered impaired. Light rust-colored area, impaired; dark rust-colored area, legally intoxicated. BAC can be 20% to 30% higher in female subjects. Notice the small number of drinks that can result in a state of intoxication.

The BAC varies with hematocrit; that is, people living at higher altitudes have a higher hematocrit and a lower H2O content in blood. It is therefore essential to know whether the BAC was determined by using whole blood, serum, or plasma. Urine, cerebrospinal fluid, and vitreous concentrations of ethanol have also been used in estimating BAC.

Because expired air contains ethanol in proportion to its vapor pressure at body temperature, the ratio of ethanol concentrations between exhaled air and blood alcohol (1/2100) forms the basis for thebreathalyzer test, in which BAC is extrapolated from the alcohol content of the expired air.

BACs can also be calculated from the weight and sex of the person if the amount of ethanol consumed orally is known. However, this estimate is somewhat higher than actual concentrations because of rapid first-pass metabolism after oral administration. BACs are higher in women than in men after consumption of comparable amounts of ethanol, even after correcting for differences in body weight. This can be attributed to both the volume of distribution and first-pass metabolism of ethanol in women. Women have a smaller volume of distribution than men because, on average, they have a greater percentage of adipose tissue that does not contain as much H2O as do other tissues. In addition, the first-pass metabolism of ethanol, which occurs primarily in gastric tissue, is less in women than men because ADH activity in the female gastric mucosa is less than that in the male. Thus with low doses of ethanol, first-pass metabolism is lower in women, leading to higher BACs; at higher doses, the percentage of ethanol that undergoes first-pass metabolism is relatively small. Women are also more susceptible to alcoholic liver disease for this reason as well as a consequence of interactions with estrogen. This applies to both nonalcoholic and alcoholic women and partially explains the increased vulnerability of women to the deleterious effects of acute and chronic alcoholism. It was once assumed that higher BACs in women were entirely the result of differences in apparent volumes of distribution between men and women; however, they do not account entirely for this difference.

Drugs for Alcohol Dependence

Aldehyde Dehydrogenase Inhibitor

Disulfiram has been the most widely used drug for alcoholism for many years. All of the effects of disulfiram are attributed to its adverse effects that are evident upon ethanol ingestion. Although disulfiram does not have any effect on alcohol craving, it may help prevent relapse in compliant individuals. For disulfiram to be effective, individuals must be highly motivated and compliant.

Glutamate Receptor Antagonist

Acamprosate is modestly effective in maintaining abstinence after alcohol withdrawal. The approval of acamprosate for the treatment of alcoholism in the United States was based largely on results from clinical trials conducted in Europe. Acamprosate appears to have a small therapeutic effect but may be of greater benefit in alcoholics who exhibit increased anxiety rather than the entire population of alcohol-dependent individuals.

Opioid Receptor Antagonist

Short-term, double-blind, placebo-controlled trials have shown that naltrexone decreased the craving for alcohol, the number of drinking days, the number of drinks per occasion, and the relapse rate. Naltrexone appears to have the greatest benefits in individuals with a family history of alcohol dependence and high craving, decreasing the rewarding efficacy of ethanol.

The depot forms of naltrexone may be of benefit because they produce greater compliance than the oral formulation.

Pharmacovigilance: Side Effects, Clinical Problems, and Toxicity


Ethanol has detrimental effects on many organs and tissues, and knowledge of these actions is important for understanding its hazards. Deleterious effects of ethanol on the liver and other organs resulting from chronic alcoholism are listed in the Clinical Problems Box.

Gastrointestinal Tract

The oral mucosa, esophagus, stomach, and small intestine are exposed to higher concentrations of ethanol than other tissues of the body and are susceptible to direct toxic effects. Acute gastritis resulting in nausea and vomiting results from ethanol abuse; bleeding ulcers and cancer of the upper GI tract are possible consequences.


Ethanol metabolism by the liver causes a large increase in the NADH/NAD+ ratio, which disrupts liver metabolism. The cell attempts to maintain NAD+ concentrations in the cytosol by reducing pyruvate to lactate, leading to increased lactic acid in liver and blood. Lactate is excreted by the kidney and competes with urate for elimination, which can increase blood urate concentrations. Excretion of lactate also apparently leads to a deficiency of zinc and Mg++. A more direct effect of increased NADH concentrations in the liver is increased fatty acid synthesis, because NADH is a necessary cofactor. Because NADH participates in the citric acid cycle, the oxidation of lipids is depressed, further contributing to fat accumulation in liver cells.

The increase in NADH/NAD+ ratio and the inability to regenerate NAD+ may cause hypoglycemia and ketoacidosis. The former occurs in the noneating user of alcohol when hepatic glycogen stores are exhausted (72 hours), and gluconeogenesis is inhibited as a result of the increased NADH/NAD+ ratio. The metabolic acidosis observed in nondiabetic alcoholics is an anion gap acidosis, with an increase in the plasma concentration of β-hydroxybutyrate and lactate.

Acetaldehyde may also play a prominent role in liver damage. If there is an initial insult to the liver, the concentration of ALDH decreases, and acetaldehyde is not removed efficiently and can react with many cell constituents. For example, acetaldehyde blocks transcriptional activation by peroxisome proliferator-activated receptor-α (PPAR-α). Normally, fatty acids activate this receptor, and this action of acetaldehyde may contribute to fatty acid accumulation in liver. Acetaldehyde also increases collagen in the liver.

During ethanol ingestion the intestine releases increased amounts of lipopolysaccharide (endotoxin), which are taken up from the portal blood by the Kupffer cells of the liver. In response to this, these cells release tumor necrosis factor-α (TNF-α) and a host of other proinflammatory cytokines. In the face of depleted glutathione and S-adenosylmethionine, liver cells die. This process of secondary liver injury occurs over and above the primary liver injury caused directly by ethanol. In spite of this, there are many heavy drinkers who never develop severe liver damage, indicating a substantial genetic effect in producing alcoholic hepatic damage.

The use of acetaminophen by alcoholics may result in hepatic necrosis. This reaction can occur with acetaminophen doses that are less than the maximum recommended (4 g/24 hours). Ethanol has this effect because it induces the cytochrome P450 responsible for formation of a hepatotoxic acetaminophen metabolite, which cannot be detoxified when glutathione stores are depleted by ethanol or starvation. This condition is characterized by greatly elevated serum aminotransferase concentrations. N-Acetylcysteine is given orally to provide the required glutathione substrate in such patients.


Ethanol use is a known cause of acute pancreatitis, and repeated use can lead to chronic pancreatitis, with decreased enzyme secretion and diabetes mellitus as possible consequences.

Endocrine System

Large amounts of ethanol decrease testosterone concentrations in males and cause a loss of secondary sex characteristics and feminization. Ovarian function may be disrupted in premenopausal females who abuse alcohol, and this may be manifest as oligomenorrhea, hypomenorrhea, or amenorrhea. Ethanol also stimulates release of adrenocortical hormones by increasing secretion of adrenocorticotropic hormone.

Cardiovascular System

Alcoholic cardiomyopathy is a consequence of chronic ethanol consumption. Other cardiovascular effects include mild increases in blood pressure and heart rate and cardiac dysrhythmias. Cardiovascular complications also result from hepatic cirrhosis and accompanying changes in the venous circulation that predispose to upper GI bleeding. Coagulopathy, caused by hepatic dysfunction and bone marrow depression, increases the risk of bleeding.

Epidemiological studies have demonstrated an association between alcohol use and a reduced risk of cardiovascular disease, including nonfatal myocardial infarction and fatal coronary heart disease. Alcohol increases the levels of high-density lipoprotein cholesterol. However, the biological foundations of the observed cardioprotective effects of alcohol have not been established. Ethanol relaxes blood vessels, and in severe intoxication, hypothermia resulting from heat loss as a consequence of vasodilatation may occur.


Ethanol has a diuretic effect unrelated to fluid intake that results from inhibition of antidiuretic hormone secretion, which decreases renal reabsorption of H2O.

Immune System

Alcoholics are frequently immunologically compromised and are subject to infectious diseases. The mortality resulting from cancers of the upper GI tract and liver is also excessively high in alcoholics. Although the mechanism of this latter effect is unknown, alcohol consumption is a known risk factor for cancer, and this may be related to vitamin A metabolism.

Nervous System

There are several well-documented neurological conditions resulting from excessive ethanol intake and concomitant nutritional deficiencies. These include Wernicke-Korsakoff syndrome, cerebellar atrophy, central pontine myelinosis, demyelination of the corpus callosum, and mamillary body destruction.

Fetal Alcohol Syndrome

Although fetal alcohol syndrome has been recognized from early times, it was rediscovered in the 1970s, and the general public is well aware of the deleterious effects of drinking on the health of the fetus. Consequences of maternal ingestion of alcohol can include miscarriage, stillbirth, low birth weight, slow postnatal growth, microcephaly, mental retardation, and many other organic and structural abnormalities. The incidence of fetal alcohol syndrome in some parts of the United States is estimated to be as high as 1 in 300 births. It is the most common cause of birth defects that is entirely preventable.


Both acute tolerance and chronic tolerance occur in response to ethanol use. Acute tolerance can occur in a matter of minutes and rapidly dissipates when ethanol is applied directly to nerve cells. Chronic tolerance occurs in people who ingest alcohol daily for weeks to months, with very high tolerances developing in some individuals. BACs must be approximately double to produce effects in tolerant as opposed to nontolerant people. This is much less, however, than that observed in those who use opiate drugs, in whom a tolerance of 10- to 30-fold can be demonstrated. The development of tolerance to alcohol has greater implications than that to other agents, because organ systems are exposed to much higher concentrations of ethanol, with deleterious consequences, particularly to the liver. Because the liver becomes injured as a function of the dose and duration of ethanol exposure, metabolism of ethanol may be impaired in late-stage alcoholism with serious liver damage.


It is often difficult to diagnose alcohol dependence. Success depends on obtaining a reliable history from the patient or from a member of the patient’s family. Even if a diagnosis can be made, it is frequently difficult to manage the problem, because treatment is often initiated when the disorder is already well advanced.

Over the past 10 to 15 years, the role of genetic factors in the development of chronic alcoholism has been identified with the hope that early intervention may be more successful. Results of studies involving family members of alcoholics and twins support a predisposition and an increased risk among close relatives. This conclusion that primary alcoholism is genetically influenced is based on several interesting findings.

Studies indicate a threefold to fourfold higher risk of alcoholism primarily in sons but also in some daughters of alcoholic parents. Comparisons in identical twins versus fraternal twins should reveal whether alcoholism is related to childhood environment. Because both types of twins have similar backgrounds, if alcoholism is related to childhood environment, its incidence should be the same in identical and fraternal twins. Most studies show that there is a twofold higher concordance for alcoholism in identical twins than in fraternal twins. In another study alcoholic risk was assessed in male children of alcoholics raised by adoptive parents who were nonalcoholic. A threefold to fourfold higher risk of alcoholism was found in these males. Being raised by alcoholic adoptive parents did not increase the risk for alcoholism. In some studies, in fact, there was a protective effect.

Other studies have categorized alcoholics into several subgroups. One is the alcoholism most frequently seen in males and is associated with criminality; the second is a subtype observed in both sexes and influenced by the environment. Genetic predisposition, however, is merely one of several factors leading to alcoholism. Studies are attempting to reveal biological markers with which to identify potential alcoholics (e.g., differences in blood proteins, enzymes involved in ethanol degradation, and enzymes concerned with brain neurotransmitters and signaling components, including G proteins) to encourage such people to seek assistance sooner.

Effective management of chronic alcoholism includes social, environmental, and medical approaches and involves the family of the person undergoing treatment. Several types of treatment are available, including group psychotherapy (e.g., Alcoholics Anonymous) that may be rendered in private and public clinics outside of a hospital setting. Hypnotherapy and psychoanalysis have been used. Studies have shown that pharmacological therapy is of benefit when added to psychosocial/behavioral therapy.

Both psychological and physical dependence are characteristic of chronic alcohol use. The clinical manifestations of ethanol withdrawal are divided into early and late stages. Early symptoms occur between a few hours and up to 48 hours after relative or absolute abstinence. Peak effects occur around 24 to 36 hours. Tremor, agitation, anxiety, anorexia, confusion, and signs of autonomic hyperactivity occur individually or in combinations. Seizures occurring in the early phase of withdrawal may reflect decreased neurotransmission at GABAA receptors and increased neurotransmission at NMDA receptors. Late withdrawal symptoms (delirium tremens) occur 1 to 5 days after abstinence, and while relatively rare, can be life-threatening if untreated. Signs of sympathetic hyperactivity, agitation, and tremulousness characterize the onset of the syndrome. There are sensory disturbances including auditory or visual hallucinations, confusion, and delirium. Death may occur, even in treated patients. Complicating factors in alcohol withdrawal include trauma from falls or accidents, bacterial infections, and concomitant medical problems such as heart and liver failure. The alcohol withdrawal syndrome is more likely to be life-threatening than that associated with opioids.

Management of withdrawal is directed toward protecting and calming the person while identifying and treating underlying medical problems. Clinical data have demonstrated that the longer acting benzodiazepines (chlordiazepoxide, diazepam, or lorazepam) have a favorable effect on clinically important outcomes, including the severity of the withdrawal syndrome, risk of delirium and seizures, and incidence of adverse responses to the drugs used. The benzodiazepines are the treatment of choice. The phenothiazine antipsychotics and haloperidol are less effective in preventing seizures or delirium. Phenobarbital is problematic because its long half-life makes dose adjustment difficult, and in high doses it may cause respiratory depression. Adrenergic β receptor blockers and centrally acting α2adrenergic receptor agonists are useful as adjuvants to limit autonomic manifestations. Neither class of drugs reduces the risk of seizures or delirium tremens.

Treatment of Intoxication

Emergency treatment of acute alcohol intoxication includes maintenance of an adequate airway and support of ventilation and blood pressure. In addition to depressant actions on the CNS, other organs, including the heart, may be affected. It is also important to assess the level of consciousness relative to the BAC, because other drugs may influence the apparent degree of intoxication. Acetaminophen concentration should also be determined. A short-acting opioid receptor antagonist is generally administered as a precaution. Glucose may need to be administered in the event of hypoglycemia, ketoacidosis, or dehydration. Loss of body fluids may necessitate intravenous infusion of fluids containing K+, Mg++, and PO4−3. Thiamine and other vitamins, such as folate and pyridoxine, are usually administered with intravenous glucose to prevent neurological deficits. Extreme caution is needed when one is modifying Na+ concentrations in such patients, however, because overcorrection has been associated with central pontine myelinolysis.

Although the only proven cure for advanced liver damage is transplantation, other drugs are being tried. These include prednisolone, vitamin E, S-adenosylmethionine, precursors of glutathione, propylthiouracil, polyunsaturated lecithin, and colchicine. In general, management regimens have had variable success rates, with many being effective over the long term in no more than 10% to 15% of participants.

Other Alcohols

Methanol has a toxicological profile quite different from that of ethanol. The metabolic products of methanol, formaldehyde and formic acid, are responsible for causing optic nerve damage, which can lead to blindness and severe acidosis. Maintenance of the airways and ventilation are required with methanol intoxication. Management also includes attempts to remove residual methanol, treatment of the acidosis, and administration of intravenous ethanol to reduce formation of toxic metabolic products and provide the time necessary to remove methanol by dialysis, which is the treatment of choice.

Ingestion of ethylene glycol may cause severe CNS depression and renal damage. In addition, the glycolic acid produced from metabolism by ADH can cause metabolic acidosis, whereas the oxalate formed is responsible for renal toxicity. Management of intoxication in this context is similar to that for methanol.

Isopropanol is a CNS depressant that is more toxic to the CNS than ethanol. Signs and symptoms of intoxication are similar to those of ethanol intoxication, but toxicity is limited because isopropanol produces severe gastritis with accompanying pain, nausea, and vomiting. In severe intoxication, hemodialysis is used to remove isopropanol from the body.

Drugs for Alcohol Dependence

Aldehyde Dehydrogenase Inhibitor

Disulfiram causes a rise in blood acetaldehyde concentrations, producing flushing, headache, nausea and vomiting, sweating, and hypotension. Disulfiram also inhibits dopamine β-hydroxylase, the enzyme that converts dopamine to norepinephrine (NE) in sympathetic neurons (see


Effects of Ethanol on the Liver


NADH/NAD+ ratio, acetaldehyde concentration, lipid content, protein accumulation, collagen deposition, cytochrome P450 content, O2 uptake, production of free radicals and lipoperoxidation products


Protein export, production of coagulation factors, gluconeogenesis

Centrilobular hypoxia, proliferation of endoplasmic reticulum

Altered drug metabolism

Hepatitis, scarring, cirrhosis with portal hypertension, hepatocellular death

Effects of Ethanol on Other Organs

Gastritis and GI tract bleeding

Peptic ulcer disease


Cardiomyopathy and cardiac dysrhythmias

Myopathy and peripheral neuropathy

Cancers of upper GI tract

Fetal alcohol syndrome

Wernicke-Korsakoff syndrome

Chapter 9). Thus, in an alcoholic taking disulfiram, there is an altered ability to synthesize NE, possibly contributing to the hypotension when alcohol is taken in conjunction with disulfiram.

Glutamate Receptor Antagonist

Acamprosate is relatively free from adverse events, with diarrhea the most common, dose-related side effect. Other reported effects include nervousness, fatigue, nausea, depression, and anxiety. Acamprosate has been shown to be teratogenic in animals.

Opioid Receptor Antagonist

The most common adverse effects noted by alcohol-dependent individuals taking naltrexone included nausea, headache, dizziness, nervousness, and fatigue. A small percentage of individuals experienced withdrawal-like symptoms consisting of abdominal cramps, bone or joint pain, and myalgia. Depot injections lead to injection site reactions and eosinophilia. At high doses naltrexone can produce hepatic injury, and a black-box warning noting this effect is included in its labeling.


(In addition to generic and fixed-combination preparations, the following trade-named materials are some of the important compounds available in the United States.)

Acamprosate (Campral)

Disulfiram (Antabuse)

Naltrexone (Revia, Naltrel, Vivitrex, Vivitrol, Depotrex)

New Horizons

Although alcohol dependence has been viewed as a social problem for many years, it is finally beginning to be accepted as a medical problem much like other chronic illnesses such as asthma, type 2 diabetes, and hypertension. To this end, drugs are being investigated for both the treatment of alcohol craving and the prevention of relapse. Several nonapproved medications being studied include other NMDA receptor antagonists such as memantine (see Chapter 28), the anticonvulsant topiramate (see Chapter 34), the GABAB receptor agonist baclofen (see Chapter 12), and the dopamine receptor antagonists such as aripiprazole and quetiapine (see Chapter 29). In addition, based on data from animal studies and limited clinical trials, agents affecting 5-HT transmission are being studied including 5-HT reuptake inhibitors, 5-HT1 receptor partial agonists, and 5-HT2/3 receptor antagonists.

Much effort is also being expended in identifying genes associated with both a risk for alcohol dependence and prediction of the success of drug therapy. In particular, studies have postulated that the ability of naltrexone to alter alcohol craving and consumption may be related to variants in the μ opioid receptor gene OPRM1. Data from both human and animal studies are revealing new avenues for development of tools for early detection of risk.


Johnson BA. Update on neuropharmacological treatments for alcoholism: Scientific basis and clinical findings. Biochem Pharmacol. 2008;751:34-56.

McLellan AT, Lewis DC, O’Brien CP, Kleber HD. Drug dependence, a chronic medical illness. JAMA. 2000;284:1689-1695.

Mukamal KJ, Conigrave KM, Mittleman MA, et al. Roles of drinking pattern and type of alcohol consumed in coronary heart disease in men. N Engl J Med. 2003;348:109-118.

Spanagel R, Kiefer F. Drugs for relapse prevention of alcoholism: Ten years of progress. Trends Pharmacol Sci. 2008;29:109-115.

For further information on alcohol, see:



1. An adequate medical history from a patient should include information concerning alcohol usage because alcohol may be implicated in:

A. Cardiovascular disease.

B. Liver malfunction.

C. Cancer of the larynx and pharynx.

D. Mental retardation of children.

E. All of the above.

2. Ascites resulting from chronic excessive alcohol intake is most likely caused by:

A. Obstructed hepatic venous return.

B. Increased osmolality of the blood.

C. Increased blood uric acid concentrations.

D. Increased Mg++ excretion.

E. Increased blood lactate concentrations.

3. Current evidence indicates that genetic risk for developing alcoholism is:

A. Mediated by a single gene.

B. Greater in men than women.

C. Caused by inheritance of altered genes encoding liver ADH.

D. Caused by high concentrations of acetaldehyde.

E. Caused by inheritance of genes coding for increased dopamine concentrations in the reward pathways of the brain.

4. Women’s risk for alcohol-induced disorders is greater than that in men in which organ?

A. Pancreas

B. Stomach

C. Larynx

D. Liver

E. Heart

5. Flushing reactions in response to ethanol in Asians resemble the response to ethanol in people who have taken:

A. Benzodiazepines

B. Barbiturates

C. Antihistamines

D. Disulfiram

E. Chloral hydrate

6. Which of the following may occur as a consequence of the metabolism of ethanol by the cytochrome P450 system and also its induction by ethanol?

A. Increased rate of metabolism of other drugs

B. When ethanol is present, a decreased rate of metabolism of some drugs

C. Increased production of carcinogenic compounds from procarcinogens

D. Increased clearance of ethanol

E. All of the above