Susan B. Masters, PhD, & Anthony J. Trevor, PhD
An 18-year-old college freshman began drinking alcohol at 8:30 PM during a hazing event at his new fraternity. Between 8:30 and approximately midnight, he and several other pledges consumed beer and a bottle of whiskey, and then he consumed most of a bottle of rum at the urging of upperclassmen. The young man complained of feeling nauseated, lay down on a couch, and began to lose consciousness. Two upperclassmen carried him to his bedroom, placed him on his stomach, and positioned a trash can nearby. Approximately 10 minutes later, the freshman was found unconscious and covered with vomit. There was a delay in treatment because the upperclassmen called the college police instead of calling 911. After the call was transferred to 911, emergency medical technicians responded quickly and discovered that the young man was not breathing and that he had choked on his vomit. He was rushed to the hospital, where he remained in a coma for 2 days before ultimately being pronounced dead. The patient’s blood alcohol concentration shortly after arriving at the hospital was 510 mg/dL. What was the cause of this patient’s death? If he had received medical care sooner, what treatment might have prevented his death?
Alcohol, primarily in the form of ethyl alcohol (ethanol), has occupied an important place in the history of humankind for at least 8000 years. In Western society, beer and wine were a main staple of daily life until the 19th century. These relatively dilute alcoholic beverages were preferred over water, which was known—long before the discovery of microbes—to be associated with acute and chronic illness. Partially sterilized by the fermentation process and the alcohol content, alcoholic beverages provided important calories and nutrients and served as a main source of daily liquid intake. As systems for improved sanitation and water purification were introduced in the 1800s, beer and wine became less important components of the human diet, and the consumption of alcoholic beverages, including distilled preparations with higher concentrations of alcohol, shifted toward their present-day role, in many societies, as a socially acceptable form of recreation.
Today, alcohol is widely consumed. Like other sedative-hypnotic drugs, alcohol in low to moderate amounts relieves anxiety and fosters a feeling of well-being or even euphoria. However, alcohol is also the most commonly abused drug in the world, and the cause of vast medical and societal costs. In the United States, approximately 75% of the adult population drinks alcohol regularly. The majority of this drinking population is able to enjoy the pleasurable effects of alcohol without allowing alcohol consumption to become a health risk. However, about 8% of the general population in the United States has an alcohol-use disorder. Individuals who use alcohol in dangerous situations (eg, drinking and driving or combining alcohol with other medications) or continue to drink alcohol in spite of adverse consequences related directly to their alcohol consumption suffer from alcohol abuse (see also Chapter 32). Individuals with alcohol dependence have characteristics of alcohol abuse and additionally exhibit physical dependence on alcohol (tolerance to alcohol and signs and symptoms upon withdrawal). They also demonstrate an inability to control their drinking and devote much time to getting and using alcohol, or recovering from its effects. The alcohol-use disorders are complex, with genetic as well as environmental determinants.
The societal and medical costs of alcohol abuse are staggering. It is estimated that about 30% of all people admitted to hospitals have coexisting alcohol problems. Once in the hospital, people with chronic alcoholism generally have poorer outcomes. In addition, each year tens of thousands of children are born with morphologic and functional defects resulting from prenatal exposure to ethanol. Despite the investment of many resources and much basic research, alcoholism remains a common chronic disease that is difficult to treat.
Ethanol and many other alcohols with potentially toxic effects are used as fuels and in industry—some in enormous quantities. In addition to ethanol, methanol and ethylene glycol toxicity occurs with sufficient frequency to warrant discussion in this chapter.
BASIC PHARMACOLOGY OF ETHANOL
Ethanol is a small water-soluble molecule that is absorbed rapidly from the gastrointestinal tract. After ingestion of alcohol in the fasting state, peak blood alcohol concentrations are reached within 30 minutes. The presence of food in the stomach delays absorption by slowing gastric emptying. Distribution is rapid, with tissue levels approximating the concentration in blood. The volume of distribution for ethanol approximates total body water (0.5–0.7 L/kg). After an equivalent oral dose of alcohol, women have a higher peak concentration than men, in part because women have a lower total body water content and in part because of differences in first-pass metabolism. In the central nervous system (CNS), the concentration of ethanol rises quickly, since the brain receives a large proportion of total blood flow and ethanol readily crosses biologic membranes.
Over 90% of alcohol consumed is oxidized in the liver; much of the remainder is excreted through the lungs and in the urine. The excretion of a small but consistent proportion of alcohol by the lungs can be quantified with breath alcohol tests that serve as a basis for a legal definition of “driving under the influence (DUI)” in many countries. At levels of ethanol usually achieved in blood, the rate of oxidation follows zero-order kinetics; that is, it is independent of time and concentration of the drug. The typical adult can metabolize 7–10 g (150–220 mmol) of alcohol per hour, the equivalent of approximately one “drink” [10 oz (300 mL) beer, 3.5 oz (105 mL) wine, or 1 oz (30 mL) distilled 80-proof spirits].
Two major pathways of alcohol metabolism to acetaldehyde have been identified (Figure 23–1). Acetaldehyde is then oxidized to acetate by a third metabolic process.
FIGURE 23–1 Metabolism of ethanol by alcohol dehydrogenase and the microsomal ethanol-oxidizing system (MEOS). Alcohol dehydrogenase and aldehyde dehydrogenase are inhibited by fomepizole and disulfiram, respectively. NAD+, nicotinamide adenine dinucleotide; NADPH, nicotinamide adenine dinucleotide phosphate.
A. Alcohol Dehydrogenase Pathway
The primary pathway for alcohol metabolism involves alcohol dehydrogenase (ADH), a family of cytosolic enzymes that catalyze the conversion of alcohol to acetaldehyde (Figure 23–1, left). These enzymes are located mainly in the liver, but small amounts are found in other organs such as the brain and stomach. There is considerable genetic variation in ADH enzymes, affecting the rate of ethanol metabolism and also appearing to alter vulnerability to alcohol-abuse disorders. For example, one ADH allele (the ADH1B*2 allele), which is associated with rapid conversion of ethanol to acetaldehyde, has been found to be protective against alcohol dependence in several ethnic populations and especially East Asians.
Some metabolism of ethanol by ADH occurs in the stomach in men, but a smaller amount occurs in women, who appear to have lower levels of the gastric enzyme. This difference in gastric metabolism of alcohol in women probably contributes to the sex-related differences in blood alcohol concentrations noted above.
During conversion of ethanol by ADH to acetaldehyde, hydrogen ion is transferred from ethanol to the cofactor nicotinamide adenine dinucleotide (NAD+) to form NADH. As a net result, alcohol oxidation generates an excess of reducing equivalents in the liver, chiefly as NADH. The excess NADH production appears to contribute to the metabolic disorders that accompany chronic alcoholism and to both the lactic acidosis and hypoglycemia that frequently accompany acute alcohol poisoning.
B. Microsomal Ethanol-Oxidizing System (MEOS)
This enzyme system, also known as the mixed function oxidase system, uses NADPH as a cofactor in the metabolism of ethanol (Figure 23–1, right) and consists primarily of cytochrome P450 2E1, 1A2, and 3A4 (see Chapter 4).
During chronic alcohol consumption, MEOS activity is induced. As a result, chronic alcohol consumption results in significant increases not only in ethanol metabolism but also in the clearance of other drugs eliminated by the cytochrome P450s that constitute the MEOS system, and in the generation of the toxic byproducts of cytochrome P450 reactions (toxins, free radicals, H2O2).
C. Acetaldehyde Metabolism
Much of the acetaldehyde formed from alcohol is oxidized in the liver in a reaction catalyzed by mitochondrial NAD-dependent aldehyde dehydrogenase (ALDH). The product of this reaction is acetate (Figure 23–1), which can be further metabolized to CO2 and water, or used to form acetyl-CoA.
Oxidation of acetaldehyde is inhibited by disulfiram, a drug that has been used to deter drinking by patients with alcohol dependence. When ethanol is consumed in the presence of disulfiram, acetaldehyde accumulates and causes an unpleasant reaction of facial flushing, nausea, vomiting, dizziness, and headache. Several other drugs (eg, metronidazole, cefotetan, trimethoprim) inhibit ALDH and can cause a disulfiram-like reaction if combined with ethanol.
Some people, primarily of East Asian descent, have genetic deficiency in the activity of the mitochondrial form of ALDH, which is encoded by the ALDH2 gene. When these individuals drink alcohol, they develop high blood acetaldehyde concentrations and experience a noxious reaction similar to that seen with the combination of disulfiram and ethanol. This form of reduced-activity ALDH is strongly protective against alcohol-use disorders.
Pharmacodynamics of Acute Ethanol Consumption
A. Central Nervous System
The CNS is markedly affected by acute alcohol consumption. Alcohol causes sedation, relief of anxiety and, at higher concentrations, slurred speech, ataxia, impaired judgment, and disinhibited behavior, a condition usually called intoxication or drunkenness (Table 23–1). These CNS effects are most marked as the blood level is rising, because acute tolerance to the effects of alcohol occurs after a few hours of drinking. For chronic drinkers who are tolerant to the effects of alcohol, higher concentrations are needed to elicit these CNS effects. For example, an individual with chronic alcoholism may appear sober or only slightly intoxicated with a blood alcohol concentration of 300–400 mg/dL, whereas this level is associated with marked intoxication or even coma in a nontolerant individual. The propensity of moderate doses of alcohol to inhibit the attention and information-processing skills as well as the motor skills required for operation of motor vehicles has profound effects. Approximately 30–40% of all traffic accidents resulting in a fatality in the United States involve at least one person with blood alcohol near or above the legal level of intoxication, and drunken driving is a leading cause of death in young adults.
TABLE 23–1 Blood alcohol concentration (BAC) and clinical effects in nontolerant individuals.
Like other sedative-hypnotic drugs, alcohol is a CNS depressant. At high blood concentrations, it induces coma, respiratory depression, and death.
Ethanol affects a large number of membrane proteins that participate in signaling pathways, including neurotransmitter receptors for amines, amino acids, opioids, and neuropeptides; enzymes such as Na+/K+-ATPase, adenylyl cyclase, phosphoinositide-specific phospholipase C; a nucleoside transporter; and ion channels. Much attention has focused on alcohol’s effects on neurotransmission by glutamate and γ-aminobutyric acid (GABA), the main excitatory and inhibitory neurotransmitters in the CNS. Acute ethanol exposure enhances the action of GABA at GABAA receptors, which is consistent with the ability of GABA-mimetics to intensify many of the acute effects of alcohol and of GABAA antagonists to attenuate some of the actions of ethanol. Ethanol inhibits the ability of glutamate to open the cation channel associated with the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors. The NMDA receptor is implicated in many aspects of cognitive function, including learning and memory. “Blackouts”—periods of memory loss that occur with high levels of alcohol—may result from inhibition of NMDA receptor activation. Experiments that use modern genetic approaches eventually will yield a more precise definition of ethanol’s direct and indirect targets. In recent years, experiments with mutant strains of mice, worms, and flies have reinforced the importance of previously identified targets and helped identify new candidates, including a calcium-regulated and voltage-gated potassium channel that may be one of ethanol’s direct targets (see Box: What Can Drunken Worms, Flies, and Mice Tell Us about Alcohol?).
Significant depression of myocardial contractility has been observed in individuals who acutely consume moderate amounts of alcohol, ie, at a blood concentration above 100 mg/dL.
C. Smooth Muscle
Ethanol is a vasodilator, probably as a result of both CNS effects (depression of the vasomotor center) and direct smooth muscle relaxation caused by its metabolite, acetaldehyde. In cases of severe overdose, hypothermia—caused by vasodilation—may be marked in cold environments. Ethanol also relaxes the uterus and—before the introduction of more effective and safer uterine relaxants (eg, calcium channel antagonists)—was used intravenously for the suppression of premature labor.
Consequences of Chronic Alcohol Consumption
Chronic alcohol consumption profoundly affects the function of several vital organs—particularly the liver—and the nervous, gastrointestinal, cardiovascular, and immune systems. Since ethanol has low potency, it requires concentrations thousands of times higher than other misused drugs (eg, cocaine, opiates, amphetamines) to produce its intoxicating effects. As a result, ethanol is consumed in quantities that are unusually large for a pharmacologically active drug. The tissue damage caused by chronic alcohol ingestion results from a combination of the direct effects of ethanol and acetaldehyde, and the metabolic consequences of processing a heavy load of a metabolically active substance. Specific mechanisms implicated in tissue damage include increased oxidative stress coupled with depletion of glutathione, damage to mitochondria, growth factor dysregulation, and potentiation of cytokine-induced injury.
What Can Drunken Worms, Flies, and Mice Tell Us about Alcohol?
For a drug like ethanol, which exhibits low potency and specificity, and modifies complex behaviors, the precise roles of its many direct and indirect targets are difficult to define. Increasingly, ethanol researchers are employing genetic approaches to complement standard neurobiologic experimentation. Three experimental animal systems for which powerful genetic techniques exist—mice, flies, and worms—have yielded intriguing results.
Strains of mice with abnormal sensitivity to ethanol were identified many years ago by breeding and selection programs. Using sophisticated genetic mapping and sequencing techniques, researchers have made progress in identifying the genes that confer these traits. A more targeted approach is the use of transgenic mice to test hypotheses about specific genes. For example, after earlier experiments suggested a link between brain neuropeptide Y (NPY) and ethanol, researchers used two transgenic mouse models to further investigate the link. They found that a strain of mice that lacks the gene for NPY—NPY knockout mice—consume more ethanol than control mice and are less sensitive to ethanol’s sedative effects. As would be expected if increased concentrations of NPY in the brain make mice more sensitive to ethanol, a strain of mice that overexpresses NPY drinks less alcohol than the controls even though their total consumption of food and liquid is normal. Work with other transgenic knockout mice supports the central role in ethanol responses of signaling systems that have long been believed to be involved (eg, GABAA, glutamate, dopamine, opioid, and serotonin receptors) and has helped build the case for newer candidates such as NPY and corticotropin-releasing hormone, cannabinoid receptors, ion channels, and protein kinase C.
It is easy to imagine mice having measurable behavioral responses to alcohol, but drunken worms and fruit flies are harder to imagine. Actually, both invertebrates respond to ethanol in ways that parallel mammalian responses. Drosophila melanogaster fruit flies exposed to ethanol vapor show increased locomotion at low concentrations but at higher concentrations, become poorly coordinated, sedated, and finally immobile. These behaviors can be monitored by sophisticated laser or video tracking methods or with an ingenious “chromatography” column of air that separates relatively insensitive flies, from inebriated flies, which drop to the bottom of the column. The worm Caenorhabditis elegans similarly exhibits increased locomotion at low ethanol concentrations and, at higher concentrations, reduced locomotion, sedation, and—something that can be turned into an effective screen for mutant worms that are resistant to ethanol—impaired egg laying. The advantage of using flies and worms as genetic models for ethanol research is their relatively simple neuroanatomy, well-established techniques for genetic manipulation, an extensive library of well-characterized mutants, and completely or nearly completely solved genetic codes. Already, much information has accumulated about candidate proteins involved with the effects of ethanol in flies. In an elegant study on C elegans, researchers found evidence that a calcium-activated, voltage-gated BK potassium channel is a direct target of ethanol. This channel, which is activated by ethanol, has close homologs in flies and vertebrates, and evidence is accumulating that ethanol has similar effects in these homologs. Genetic experiments in these model systems should provide information that will help narrow and focus research into the complex and important effects of ethanol in humans.
Chronic consumption of large amounts of alcohol is associated with an increased risk of death. Deaths linked to alcohol consumption are caused by liver disease, cancer, accidents, and suicide.
A. Liver and Gastrointestinal Tract
Liver disease is the most common medical complication of alcohol abuse; an estimated 15–30% of chronic heavy drinkers eventually develop severe liver disease. Alcoholic fatty liver, a reversible condition, may progress to alcoholic hepatitis and finally to cirrhosis and liver failure. In the United States, chronic alcohol abuse is the leading cause of liver cirrhosis and of the need for liver transplantation. The risk of developing liver disease is related both to the average amount of daily consumption and to the duration of alcohol abuse. Women appear to be more susceptible to alcohol hepatotoxicity than men. Concurrent infection with hepatitis B or C virus increases the risk of severe liver disease.
The pathogenesis of alcoholic liver disease is a multifactorial process involving metabolic repercussions of ethanol oxidation in the liver, dysregulation of fatty acid oxidation and synthesis, and activation of the innate immune system by a combination of direct effects of ethanol and its metabolites and by bacterial endotoxins that access the liver as a result of ethanol-induced changes in the intestinal tract. Tumor necrosis factor-α, a proinflammatory cytokine that is consistently elevated in animal models of alcoholic liver disease and in patients with alcoholic liver disease, appears to play a pivotal role in the progression of alcoholic liver disease and may be a fruitful therapeutic target.
Other portions of the gastrointestinal tract can also be injured. Chronic alcohol ingestion is by far the most common cause of chronic pancreatitis in the Western world. In addition to its direct toxic effect on pancreatic acinar cells, alcohol alters pancreatic epithelial permeability and promotes the formation of protein plugs and calcium carbonate-containing stones.
Individuals with chronic alcoholism are prone to gastritis and have increased susceptibility to blood and plasma protein loss during drinking, which may contribute to anemia and protein malnutrition. Alcohol also injures the small intestine, leading to diarrhea, weight loss, and multiple vitamin deficiencies.
Malnutrition from dietary deficiency and vitamin deficiencies due to malabsorption are common in alcoholism. Malabsorption of water-soluble vitamins is especially severe.
B. Nervous System
1. Tolerance and dependence—The consumption of alcohol in high doses over a long period results in tolerance and in physical and psychological dependence. Tolerance to the intoxicating effects of alcohol is a complex process involving poorly understood changes in the nervous system as well as the metabolic changes described earlier. As with other sedative-hypnotic drugs, there is a limit to tolerance, so that only a relatively small increase in the lethaldose occurs with increasing alcohol use.
Chronic alcohol drinkers, when forced to reduce or discontinue alcohol, experience a withdrawal syndrome, which indicates the existence of physical dependence. Alcohol withdrawal symptoms usually consist of hyperexcitability in mild cases and seizures, toxic psychosis, and delirium tremens in severe ones. The dose, rate, and duration of alcohol consumption determine the intensity of the withdrawal syndrome. When consumption has been very high, merely reducing the rate of consumption may lead to signs of withdrawal.
Psychological dependence on alcohol is characterized by a compulsive desire to experience the rewarding effects of alcohol and, for current drinkers, a desire to avoid the negative consequences of withdrawal. People who have recovered from alcoholism and become abstinent still experience periods of intense craving for alcohol that can be triggered by environmental cues associated in the past with drinking, such as familiar places, groups of people, or events.
The molecular basis of alcohol tolerance and dependence is not known with certainty, nor is it known whether the two phenomena reflect opposing effects on a shared molecular pathway. Tolerance may result from ethanol-induced up-regulation of a pathway in response to the continuous presence of ethanol. Dependence may result from overactivity of that same pathway after the ethanol effect dissipates and before the system has time to return to a normal ethanol-free state.
Chronic exposure of animals or cultured cells to alcohol elicits a multitude of adaptive responses involving neurotransmitters and their receptors, ion channels, and enzymes that participate in signal transduction pathways. Up-regulation of the NMDA subtype of glutamate receptors and voltage-sensitive Ca2+ channels may underlie the seizures that accompany the alcohol withdrawal syndrome. Based on the ability of sedative-hypnotic drugs that enhance GABAergic neurotransmission to substitute for alcohol during alcohol withdrawal and evidence of down-regulation of GABAA-mediated responses with chronic alcohol exposure, changes in GABA neurotransmission are believed to play a central role in tolerance and withdrawal.
Like other drugs of abuse, ethanol modulates neural activity in the brain’s mesolimbic dopamine reward circuit and increases dopamine release in the nucleus accumbens (see Chapter 32). Alcohol affects local concentrations of serotonin, opioids, and dopamine—neurotransmitters involved in the brain reward system—and has complex effects on the expression of receptors for these neurotransmitters and their signaling pathways. The discovery that naltrexone, a nonselective opioid receptor antagonist, helps patients who are recovering from alcoholism abstain from drinking supports the idea that a common neurochemical reward system is shared by very different drugs associated with physical and psychological dependence. There is also convincing evidence from animal models that ethanol intake and seeking behavior are reduced by antagonists of another important regulator of the brain reward system, the cannabinoid CB1 receptor, which is the molecular target of active ingredients in marijuana. Two other important neuroendocrine systems that appear to play key roles in modulating ethanol-seeking activity in experimental animals are the appetite-regulating system—which uses peptides such as leptin, ghrelin, and neuropeptide Y—and the stress response system, which is controlled by corticotropin-releasing factor.
2. Neurotoxicity—Consumption of large amounts of alcohol over extended periods (usually years) often leads to neurologic deficits. The most common neurologic abnormality in chronic alcoholism is generalized symmetric peripheral nerve injury, which begins with distal paresthesias of the hands and feet. Degenerative changes can also result in gait disturbances and ataxia. Other neurologic disturbances associated with alcoholism include dementia and, rarely, demyelinating disease.
Wernicke-Korsakoff syndrome is a relatively uncommon but important entity characterized by paralysis of the external eye muscles, ataxia, and a confused state that can progress to coma and death. It is associated with thiamine deficiency but is rarely seen in the absence of alcoholism. Because of the importance of thiamine in this pathologic condition and the absence of toxicity associated with thiamine administration, all patients suspected of having Wernicke-Korsakoff syndrome (including virtually all patients who present to the emergency department with altered consciousness, seizures, or both) should receive thiamine therapy. Often, the ocular signs, ataxia, and confusion improve promptly upon administration of thiamine. However, most patients are left with a chronic disabling memory disorder known as Korsakoff’s psychosis.
Alcohol may also impair visual acuity, with painless blurring that occurs over several weeks of heavy alcohol consumption. Changes are usually bilateral and symmetric and may be followed by optic nerve degeneration. Ingestion of ethanol substitutes such as methanol (see Pharmacology of Other Alcohols) causes severe visual disturbances.
C. Cardiovascular System
1. Cardiomyopathy and heart failure—Alcohol has complex effects on the cardiovascular system. Heavy alcohol consumption of long duration is associated with a dilated cardiomyopathy with ventricular hypertrophy and fibrosis. In animals and humans, alcohol induces a number of changes in heart cells that may contribute to cardiomyopathy. They include membrane disruption, depressed function of mitochondria and sarcoplasmic reticulum, intracellular accumulation of phospholipids and fatty acids, and up-regulation of voltage-gated calcium channels. There is evidence that patients with alcohol-induced dilated cardiomyopathy do significantly worse than patients with idiopathic dilated cardiomyopathy, even though cessation of drinking is associated with a reduction in cardiac size and improved function. The poorer prognosis for patients who continue to drink appears to be due in part to interference by ethanol with the beneficial effects of β blockers and angiotensin-converting enzyme (ACE) inhibitors.
2. Arrhythmias—Heavy drinking—and especially “binge” drinking—are associated with both atrial and ventricular arrhythmias. Patients undergoing alcohol withdrawal syndrome can develop severe arrhythmias that may reflect abnormalities of potassium or magnesium metabolism as well as enhanced release of catecholamines. Seizures, syncope, and sudden death during alcohol withdrawal may be due to these arrhythmias.
3. Hypertension—A link between heavier alcohol consumption (more than three drinks per day) and hypertension has been firmly established in epidemiologic studies. Alcohol is estimated to be responsible for approximately 5% of cases of hypertension, making it one of the most common causes of reversible hypertension. This association is independent of obesity, salt intake, coffee drinking, and cigarette smoking. A reduction in alcohol intake appears to be effective in lowering blood pressure in hypertensive individuals who are also heavy drinkers; the hypertension seen in this population is also responsive to standard blood pressure medications.
4. Coronary heart disease—Although the deleterious effects of excessive alcohol use on the cardiovascular system are well established, there is strong epidemiologic evidence that moderate alcohol consumption actually preventscoronary heart disease (CHD), ischemic stroke, and peripheral arterial disease. This type of relationship between mortality and the dose of a drug is called a “J-shaped” relationship. Results of these clinical studies are supported by ethanol’s ability to raise serum levels of high-density lipoprotein (HDL) cholesterol (the form of cholesterol that appears to protect against atherosclerosis; see Chapter 35), by its ability to inhibit some of the inflammatory processes that underlie atherosclerosis while also increasing production of the endogenous anticoagulant tissue plasminogen activator (t-PA, see Chapter 34), and by the presence in alcoholic beverages (especially red wine) of antioxidants and other substances that may protect against atherosclerosis. These observational studies are intriguing, but randomized clinical trials examining the possible benefit of moderate alcohol consumption in prevention of CHD have not been carried out.
Alcohol indirectly affects hematopoiesis through metabolic and nutritional effects and may also directly inhibit the proliferation of all cellular elements in bone marrow. The most common hematologic disorder seen in chronic drinkers is mild anemia resulting from alcohol-related folic acid deficiency. Iron deficiency anemia may result from gastrointestinal bleeding. Alcohol has also been implicated as a cause of several hemolytic syndromes, some of which are associated with hyperlipidemia and severe liver disease.
E. Endocrine System and Electrolyte Balance
Chronic alcohol use has important effects on the endocrine system and on fluid and electrolyte balance. Clinical reports of gynecomastia and testicular atrophy in alcoholics with or without cirrhosis suggest a derangement in steroid hormone balance.
Individuals with chronic liver disease may have disorders of fluid and electrolyte balance, including ascites, edema, and effusions. Alterations of whole body potassium induced by vomiting and diarrhea, as well as severe secondary aldosteronism, may contribute to muscle weakness and can be worsened by diuretic therapy. The metabolic derangements caused by metabolism of large amounts of ethanol can result in hypoglycemia, as a result of impaired hepatic gluconeogenesis, and in ketosis, caused by excessive lipolytic factors, especially increased cortisol and growth hormone.
F. Fetal Alcohol Syndrome
Chronic maternal alcohol abuse during pregnancy is associated with teratogenic effects, and alcohol is a leading cause of mental retardation and congenital malformation. The abnormalities that have been characterized as fetal alcohol syndrome include (1) intrauterine growth retardation, (2) microcephaly, (3) poor coordination, (4) underdevelopment of midfacial region (appearing as a flattened face), and (5) minor joint anomalies. More severe cases may include congenital heart defects and mental retardation. Although the level of alcohol intake required to cause serious neurologic deficits appears quite high, the threshold for more subtle neurologic deficits is uncertain.
The mechanisms that underlie ethanol’s teratogenic effects are unknown. Ethanol rapidly crosses the placenta and reaches concentrations in the fetus that are similar to those in maternal blood. The fetal liver has little or no alcohol dehydrogenase activity, so the fetus must rely on maternal and placental enzymes for elimination of alcohol.
The neuropathologic abnormalities seen in humans and in animal models of fetal alcohol syndrome indicate that ethanol triggers apoptotic neurodegeneration and also causes aberrant neuronal and glial migration in the developing nervous system. In tissue culture systems, ethanol causes a striking reduction in neurite outgrowth.
G. Immune System
The effects of alcohol on the immune system are complex; immune function in some tissues is inhibited (eg, the lung), whereas pathologic, hyperactive immune function in other tissues is triggered (eg, liver, pancreas). In addition, acute and chronic exposure to alcohol have widely different effects on immune function. The types of immunologic changes reported for the lung include suppression of the function of alveolar macrophages, inhibition of chemotaxis of granulocytes, and reduced number and function of T cells. In the liver, there is enhanced function of key cells of the innate immune system (eg, Kupffer cells, hepatic stellate cells) and increased cytokine production. In addition to the inflammatory damage that chronic heavy alcohol use precipitates in the liver and pancreas, it predisposes to infections, especially of the lung, and worsens the morbidity and increases the mortality risk of patients with pneumonia.
H. Increased Risk of Cancer
Chronic alcohol use increases the risk for cancer of the mouth, pharynx, larynx, esophagus, and liver. Evidence also points to a small increase in the risk of breast cancer in women. Much more information is required before a threshold level for alcohol consumption as it relates to cancer can be established. Alcohol itself does not appear to be a carcinogen in most test systems. However, its primary metabolite, acetaldehyde, can damage DNA, as can the reactive oxygen species produced by increased cytochrome P450 activity. Other factors implicated in the link between alcohol and cancer include changes in folate metabolism and the growth-promoting effects of chronic inflammation.
Interactions between ethanol and other drugs can have important clinical effects resulting from alterations in the pharmacokinetics or pharmacodynamics of the second drug.
The most common pharmacokinetic alcohol-drug interactions stem from alcohol-induced increases of drug-metabolizing enzymes, as described in Chapter 4. Thus, prolonged intake of alcohol without damage to the liver can enhance the metabolic biotransformation of other drugs. Ethanol-mediated induction of hepatic cytochrome P450 enzymes is particularly important with regard to acetaminophen. Chronic consumption of three or more drinks per day increases the risk of hepatotoxicity due to toxic or even high therapeutic levels of acetaminophen as a result of increased P450-mediated conversion of acetaminophen to reactive hepatotoxic metabolites (see Figure 4–5). Current FDA regulations require that over-the-counter products containing acetaminophen carry a warning about the relation between ethanol consumption and acetaminophen-induced hepatotoxicity.
In contrast, acute alcohol use can inhibit metabolism of other drugs because of decreased enzyme activity or decreased liver blood flow. Phenothiazines, tricyclic antidepressants, and sedative-hypnotic drugs are the most important drugs that interact with alcohol by this pharmacokinetic mechanism.
Pharmacodynamic interactions are also of great clinical significance. The additive CNS depression that occurs when alcohol is combined with other CNS depressants, particularly sedative-hypnotics, is most important. Alcohol also potentiates the pharmacologic effects of many nonsedative drugs, including vasodilators and oral hypoglycemic agents.
CLINICAL PHARMACOLOGY OF ETHANOL
Alcohol is the cause of more preventable morbidity and mortality than all other drugs combined with the exception of tobacco. The search for specific etiologic factors or the identification of significant predisposing variables for alcohol abuse has led to disappointing results. Personality type, severe life stresses, psychiatric disorders, and parental role models are not reliable predictors of alcohol abuse. Although environmental factors clearly play a role, evidence suggests that there is a large genetic contribution to the development of alcoholism. Not surprisingly, polymorphisms in alcohol dehydrogenase and aldehyde dehydrogenase that lead to increased aldehyde accumulation and its associated facial flushing, nausea, and hypotension appear to protect against alcoholism. Much attention in genetic mapping experiments has focused on membrane-signaling proteins known to be affected by ethanol and on protein constituents of reward pathways in the brain. Polymorphisms associated with a relative insensitivity to alcohol and presumably thereby a greater risk of alcohol abuse have been identified in genes encoding an α subunit of the GABAA receptor, an M2 muscarinic receptor, a serotonin transporter, adenylyl cyclase, and a potassium channel. The link between a polymorphism in an opioid receptor gene and a blunted response to naltrexone raises the possibility of genotype-guided pharmacotherapy for alcohol dependence.
MANAGEMENT OF ACUTE ALCOHOL INTOXICATION
Nontolerant individuals who consume alcohol in large quantities develop typical effects of acute sedative-hypnotic drug overdose along with the cardiovascular effects previously described (vasodilation, tachycardia) and gastrointestinal irritation. Since tolerance is not absolute, even individuals with chronic alcohol dependence may become severely intoxicated if sufficient alcohol is consumed.
The most important goals in the treatment of acute alcohol intoxication are to prevent severe respiratory depression and aspiration of vomitus. Even with very high blood ethanol levels, survival is probable as long as the respiratory and cardiovascular systems can be supported. The average blood alcohol concentration in fatal cases is above 400 mg/dL; however, the lethal dose of alcohol varies because of varying degrees of tolerance.
Electrolyte imbalances often need to be corrected and metabolic alterations may require treatment of hypoglycemia and ketoacidosis by administration of glucose. Thiamine is given to protect against Wernicke-Korsakoff syndrome. Patients who are dehydrated and vomiting should also receive electrolyte solutions. If vomiting is severe, large amounts of potassium may be required as long as renal function is normal.
MANAGEMENT OF ALCOHOL WITHDRAWAL SYNDROME
Abrupt alcohol discontinuation in an individual with alcohol dependence leads to a characteristic syndrome of motor agitation, anxiety, insomnia, and reduction of seizure threshold. The severity of the syndrome is usually proportionate to the degree and duration of alcohol abuse. However, this can be greatly modified by the use of other sedatives as well as by associated factors (eg, diabetes, injury). In its mildest form, the alcohol withdrawal syndrome of increased pulse and blood pressure, tremor, anxiety, and insomnia occurs 6–8 hours after alcohol consumption is stopped (Figure 23–2). These effects usually lessen in 1–2 days, although some, such as anxiety and sleep disturbances, can be seen at decreasing levels for several months. In some patients, more severe acute reactions occur, with patients at risk of withdrawal seizures or alcoholic hallucinations during the first 1–5 days of withdrawal. Alcohol withdrawal is one of the most common causes of seizures in adults. Several days later, individuals can develop the syndrome of delirium tremens, which is characterized by delirium, agitation, autonomic nervous system instability, low-grade fever, and diaphoresis.
FIGURE 23–2 Time course of events during the alcohol withdrawal syndrome. The signs and symptoms that manifest earliest are anxiety, insomnia, tremor, palpitations, nausea, and anorexia as well as (in severe syndromes) hallucinations and seizures. Delirium tremens typically develops 48–72 hours after alcohol discontinuation. The earliest symptoms (anxiety, insomnia, etc) can persist, in a milder form, for several months after alcohol discontinuation.
The major objective of drug therapy in the alcohol withdrawal period is prevention of seizures, delirium, and arrhythmias. Potassium, magnesium, and phosphate balance should be restored as rapidly as is consistent with renal function. Thiamine therapy is initiated in all cases. Individuals in mild alcohol withdrawal do not need any other pharmacologic assistance.
Specific drug treatment for detoxification in more severe cases involves two basic principles: substituting a long-acting sedative-hypnotic drug for alcohol and then gradually reducing (“tapering”) the dose of the long-acting drug. Because of their wide margin of safety, benzodiazepines are preferred. The choice of a specific agent in this class is generally based on pharmacokinetic or economic considerations. Long-acting benzodiazepines, including chlordiazepoxide and diazepam, have the advantage of requiring less frequent dosing. Since their pharmacologically active metabolites are eliminated slowly, the long-acting drugs provide a built-in tapering effect. A disadvantage of the long-acting drugs is that they and their active metabolites may accumulate, especially in patients with compromised liver function. Short-acting drugs such as lorazepam and oxazepam are rapidly converted to inactive water-soluble metabolites that will not accumulate, and for this reason the short-acting drugs are especially useful in alcoholic patients with liver disease. Benzodiazepines can be administered orally in mild or moderate cases, or parenterally for patients with more severe withdrawal reactions.
After the alcohol withdrawal syndrome has been treated acutely, sedative-hypnotic medications must be tapered slowly over several weeks. Complete detoxification is not achieved with just a few days of alcohol abstinence. Several months may be required for restoration of normal nervous system function, especially sleep.
TREATMENT OF ALCOHOLISM
After detoxification, psychosocial therapy either in intensive inpatient or in outpatient rehabilitation programs serves as the primary treatment for alcohol dependence. Other psychiatric problems, most commonly depressive or anxiety disorders, often coexist with alcoholism and, if untreated, can contribute to the tendency of detoxified alcoholics to relapse. Treatment for these associated disorders with counseling and drugs can help decrease the rate of relapse for alcoholic patients.
Three drugs—disulfiram, naltrexone, and acamprosate—have FDA approval for adjunctive treatment of alcohol dependence.
Naltrexone, a relatively long-acting opioid antagonist, blocks the effects at μ-opioid receptors (see Chapter 31). Studies in experimental animals first suggested a link between alcohol consumption and opioids. Injection of small amounts of opioids was followed by an increase in alcohol drinking, whereas administration of opioid antagonists inhibited self-administration of alcohol.
Naltrexone, both alone and in combination with behavioral counseling, has been shown in a number of short-term (12- to 16-week) placebo-controlled trials to reduce the rate of relapse to either drinking or alcohol dependence and to reduce craving for alcohol, especially in patients with high rates of naltrexone adherence. Naltrexone is approved by the FDA for treatment of alcohol dependence.
Naltrexone is generally taken once a day in an oral dose of 50 mg for treatment of alcoholism. An extended-release formulation administered as an IM injection once every 4 weeks is also effective. The drug can cause dose-dependent hepatotoxicity and should be used with caution in patients with evidence of abnormalities in serum aminotransferase activity. The combination of naltrexone plus disulfiram should be avoided, since both drugs are potential hepatotoxins. Administration of naltrexone to patients who are physically dependent on opioids precipitates an acute withdrawal syndrome, so patients must be opioid-free before initiating naltrexone therapy. Naltrexone also blocks the therapeutic analgesic effects of usual doses of opioids.
Acamprosate has been used in Europe for a number of years to treat alcohol dependence and is approved for this use by the FDA. Like ethanol, acamprosate has many molecular effects including actions on GABA, glutamate, serotonergic, noradrenergic, and dopaminergic receptors. Probably its best-characterized actions are as a weak NMDA-receptor antagonist and a GABAA-receptor activator. In European clinical trials, acamprosate reduced short-term and long-term (more than 6 months) relapse rates when combined with psychotherapy. However, in a large American trial that compared acamprosate with naltrexone and with combined acamprosate and naltrexone therapy (the COMBINE study), acamprosate did not show a statistically significant effect alone or in combination with naltrexone.
Acamprosate is administered as one or two enteric-coated 333 mg tablets three times daily. It is poorly absorbed, and food reduces its absorption even further. Acamprosate is widely distributed and is eliminated renally. It does not appear to participate in drug-drug interactions. The most common adverse effects are gastrointestinal (nausea, vomiting, diarrhea) and rash. It should not be used in patients with severe renal impairment.
Disulfiram causes extreme discomfort in patients who drink alcoholic beverages. Disulfiram alone has little effect; however, flushing, throbbing headache, nausea, vomiting, sweating, hypotension, and confusion occur within a few minutes after an individual taking disulfiram drinks alcohol. The effects may last 30 minutes in mild cases or several hours in severe ones. Disulfiram acts by inhibiting aldehyde dehydrogenase. Thus, alcohol is metabolized as usual, but acetaldehyde accumulates.
Disulfiram is rapidly and completely absorbed from the gastrointestinal tract; however, a period of 12 hours is required for its full action. Its elimination rate is slow, so that its action may persist for several days after the last dose. The drug inhibits the metabolism of many other therapeutic agents, including phenytoin, oral anticoagulants, and isoniazid. It should not be administered with medications that contain alcohol, including nonprescription medications such as those listed in Table 63–3. Disulfiram can cause small increases in hepatic transaminases. Its safety in pregnancy has not been demonstrated.
Because adherence to disulfiram therapy is low and because the evidence from clinical trials for its effectiveness is weak, disulfiram is no longer commonly used.
Several other drugs have shown efficacy in maintaining abstinence and reducing craving in chronic alcoholism, although none has FDA approval yet for this use. Such drugs include ondansetron, a serotonin 5-HT3-receptor antagonist (see Chapters 16, 62); topiramate, a drug used for partial and generalized tonic-clonic seizures (see Chapter 24); and baclofen, a GABA receptor antagonist used as a spasmolytic (see Chapter 27). Based on evidence from model systems, efforts are underway to explore agents that modulate cannabinoid CB1 receptors, corticotropin-releasing factor receptors, and GABA receptor systems, as well as several other possible targets. Rimonabant, a CB1receptor antagonist, has been shown to suppress alcohol-related behaviors in animal models and is being tested in clinical trials of alcoholism.
PHARMACOLOGY OF OTHER ALCOHOLS
Other alcohols related to ethanol have wide applications as industrial solvents and occasionally cause severe poisoning. Of these, methanol and ethylene glycol are two of the most common causes of intoxication. Isopropyl alcohol(isopropanol, rubbing alcohol) is another alcohol that is sometimes ingested when ethanol is not available. It produces coma and gastrointestinal irritation, nausea, and vomiting, but is not usually associated with retinal or renal injury.
Methanol (methyl alcohol, wood alcohol) is widely used in the industrial production of synthetic organic compounds and as a constituent of many commercial solvents. In the home, methanol is most frequently found in the form of “canned heat” or in windshield-washing products. Poisonings occur from accidental ingestion of methanol-containing products or when it is misguidedly ingested as an ethanol substitute.
Methanol can be absorbed through the skin or from the respiratory or gastrointestinal tract and is then distributed in body water. The primary mechanism of elimination of methanol in humans is by oxidation to formaldehyde, formic acid, and CO2 (Figure 23–3).
FIGURE 23–3 Methanol is converted to the toxic metabolites formaldehyde and formate by alcohol dehydrogenase and aldehyde dehydrogenase. By inhibiting alcohol dehydrogenase, fomepizole and ethanol reduce the formation of toxic metabolites.
Animal species show great variability in mean lethal doses of methanol. The special susceptibility of humans to methanol toxicity is due to metabolism to formate and formaldehyde, not to methanol itself. Since the conversion of methanol to its toxic metabolites is relatively slow, there is often a delay of 6–30 hours before the appearance of severe toxicity.
Physical findings in early methanol poisoning are generally nonspecific, such as inebriation and gastritis, and possibly an elevated osmolar gap (see Chapter 58). In severe cases, the odor of formaldehyde may be present on the breath or in the urine. After a delay, the most characteristic symptom in methanol poisoning—visual disturbance—occurs along with anion gap metabolic acidosis. The visual disturbance is frequently described as “like being in a snowstorm” and can progress to blindness. Changes in the retina may sometimes be detected on examination, but these are usually late. The development of bradycardia, prolonged coma, seizures, and resistant acidosis all imply a poor prognosis. The cause of death in fatal cases is sudden cessation of respiration. A serum methanol concentration higher than 20 mg/dL warrants treatment, and a concentration higher than 50 mg/dL is considered serious enough to require hemodialysis. Serum formate levels are a better indication of clinical pathology but are not widely available.
The first treatment for methanol poisoning, as in all critical poisoning situations, is support of respiration. There are three specific modalities of treatment for severe methanol poisoning: suppression of metabolism by alcohol dehydrogenase to toxic products, hemodialysis to enhance removal of methanol and its toxic products, and alkalinization to counteract metabolic acidosis.
The enzyme chiefly responsible for methanol oxidation in the liver is alcohol dehydrogenase (Figure 23–3). Fomepizole, an alcohol dehydrogenase inhibitor, is approved for the treatment of methanol and ethylene glycol poisoning. It is administered intravenously in a loading dose of 15 mg/kg followed by 10 mg/kg every 12 hours for 48 hours and then 15 mg/kg every 12 hours thereafter until the serum methanol level falls below 20–30 mg/dL. The dosage increase after 48 hours is based on evidence that fomepizole rapidly induces its own metabolism by the cytochrome P450 system. Patients undergoing hemodialysis are given fomepizole more frequently (6 hours after the loading dose and every 4 hours thereafter). Fomepizole appears to be safe during the short time it is administered for treatment of methanol or ethylene glycol poisoning. The most common adverse effects are burning at the infusion site, headache, nausea, and dizziness. Intravenous ethanol is an alternative to fomepizole. It has a higher affinity than methanol for alcohol dehydrogenase; thus, saturation of the enzyme with ethanol reduces formate production. Ethanol is used intravenously as treatment for methanol and ethylene glycol poisoning. The dose-dependent characteristics of ethanol metabolism and the variability of ethanol metabolism require frequent monitoring of blood ethanol levels to ensure appropriate alcohol concentration.
In cases of severe poisoning, hemodialysis (discussed in Chapter 58) can be used to eliminate both methanol and formate from the blood. Two other measures are commonly taken. Because of profound metabolic acidosis in methanol poisoning, treatment with bicarbonate often is necessary. Since folate-dependent systems are responsible for the oxidation of formic acid to CO2 in humans (Figure 23–3), folinic and folic acid are often administered to patients poisoned with methanol, although this has never been fully tested in clinical studies.
Polyhydric alcohols such as ethylene glycol (CH2OHCH2OH) are used as heat exchangers, in antifreeze formulations, and as industrial solvents. Young children and animals are sometimes attracted by the sweet taste of ethylene glycol and, rarely, it is ingested intentionally as an ethanol substitute or in attempted suicide. Although ethylene glycol itself is relatively harmless and eliminated by the kidney, it is metabolized to toxic aldehydes and oxalate.
Three stages of ethylene glycol overdose occur. Within the first few hours after ingestion, there is transient excitation followed by CNS depression. After a delay of 4–12 hours, severe metabolic acidosis develops from accumulation of acid metabolites and lactate. Finally, deposition of oxalate crystals in renal tubules occurs, followed by delayed renal insufficiency. The key to the diagnosis of ethylene glycol poisoning is recognition of anion gap acidosis, osmolar gap, and oxalate crystals in the urine in a patient without visual symptoms.
As with methanol poisoning, early fomepizole is the standard treatment for ethylene glycol poisoning. Intravenous treatment with fomepizole is initiated immediately, as described above for methanol poisoning, and continued until the patient’s serum ethylene glycol concentration drops below a toxic threshold (20–30 mg/dL). Intravenous ethanol is an alternative to fomepizole in ethylene glycol poisoning. Hemodialysis effectively removes ethylene glycol and its toxic metabolites and is recommended for patients with a serum ethylene glycol concentration above 50 mg/dL, significant metabolic acidosis, and significant renal impairment. Fomepizole has reduced the need for hemodialysis, especially in patients with less severe acidosis and intact renal function.
SUMMARY The Alcohols and Associated Drugs
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CASE STUDY ANSWER
This young man exhibits classic signs and symptoms of acute alcohol poisoning, which is confirmed by the blood alcohol concentration. We do not know from the case whether the patient was tolerant to the effects of alcohol but note that his blood alcohol concentration was in the lethal range for a nontolerant individual. Death most likely resulted from respiratory and cardiovascular collapse prior to medical treatment, complicated by a chemical pneumonitis secondary to aspiration of vomitus. The treatment of acute alcohol poisoning includes standard supportive care of airway, breathing, and circulation (“ABCs,” see Chapter 58). Intravenous access would be obtained and used to administer dextrose and thiamine, as well as other electrolytes and vitamins. If a young, previously healthy individual receives medical care in time, supportive care will most likely be highly effective. As the patient recovers, it is important to be vigilant for signs and symptoms of the alcohol withdrawal syndrome.