Chapter 23: Ethanol and Methanol

Human Consumption of Ethanol: A Brief History. The use of alcoholic beverages has been documented since at least 10,000 BC (Hanson, 1995). By about 3000 BC, the Greeks, Romans, and inhabitants of Babylon continued to incorporate ethanol into religious festivals, while also using these beverages for pleasure, to facilitate socialization, as a source of nutrition, and as part of medicinal practices. The role of ethanol in society continued through biblical times, with beverage alcohol incorporated into most religions, and occupying a central role in daily life. Over the last 2000 years, alcoholic beverages have been identified in most cultures, including pre-Columbian America in ~200 AD, and the Islamic world in the 700s.

Whiskey was invented in ~1400 in Ireland and rapidly increased in popularity; champagne was developed in France in 1670. In 1690, the English government enacted a law encouraging the consumption of distilled spirits, and the production of gin subsequently increased from about 0.5 million gallons in 1685 to 5 million by 1727 and 18 million gallons by the early 1800s.

The dangers of heavy consumption of beverage alcohol have been recognized by almost all cultures, with most stressing the importance of moderation. Despite these warnings, problems with ethanol are as ancient as the pattern of use of this beverage itself, and were noted early on in India, Greece, and Rome. The increase in use of ethanol in the 1800s, along with industrialization and need for a more dependable work force, contributed to the development of more widespread organized efforts to discourage drunkenness. The subsequent temperance movements set the stage for the prohibition against drinking instituted in the U.S. in 1920. In 1933, the long tradition of the use of alcohol, as well as the large minority of the population who favored the availability of alcoholic beverages, resulted in the repeal of the constitutional amendment enacting prohibition.

Beverage alcohol has widespread use in today's society, with an average age of first use of ~15 years in most Western countries. Almost two-thirds of women and as many as 80% of men in these countries have consumed alcoholic beverages, with one-half to two-thirds reporting alcohol consumption within the past year (Faden, 2006). The highest quantities and frequencies of drinking are usually observed in the late teens to early 20s, and in the U.S., the average adult consumes alcoholic beverages containing the equivalent of 2.2 gallons (8.3 L) of absolute alcohol per year. Among drinkers, as many as half have had a temporary alcohol-related problem such as missing school or work, alcohol-related amnesia (blackouts), or operating a motor vehicle after consuming alcohol. More severe repetitive problems with alcohol (known as abuse and dependence) have a lifetime risk in men of almost 20% and in women of 10-15% (Hasin et al., 2007). The annual costs associated with heavy drinking and associated problems have been estimated to be $185 billion in the U.S. in recent years, and this drug contributes to 100,000 deaths per year in the U.S. alone, including as many as 20,000 alcohol-related fatal car accidents annually (Harwood et al., 1999; Rehm et al., 2007). Thus, the delivery of optimal medical care in modern times is greatly affected by the use of beverage alcohol, with this drug adversely affecting many body systems, interacting with medications and other drugs, and responsible for a great deal of the healthcare dollar.

Methanol. One carbon alcohol, methanol (CH₃OH), is also known as methyl and wood alcohol. It is an important industrial reagent and solvent found in products such as paint removers, shellac, and antifreeze (Lushine et al., 2003); methanol is added to industrial-use ethanol to mark it unsafe for human consumption.

Methanol is rapidly absorbed via the oral route, inhalation, and through the skin, with the latter two routes most relevant to industrial settings. Methanol also is metabolized by ADH and ALDH, with damaging consequences (described later in the chapter). Competition between methanol and ethanol for ADH forms the basis of the use of ethanol in methanol poisoning. Several drugs inhibit alcohol metabolism, including fomepizole (4-methylpyrazole) an ADH inhibitor useful in ethylene glycol poisoning, and disulfiram, an ALDH inhibitor used in treating alcoholism (described later in the chapter). Ethanol also can competitively inhibit the metabolism of other substrates of ADH and CYP2E1, such as methanol and ethylene glycol, and therefore is an effective antidote.

Feelings of intoxication from methanol, while similar in many ways to those with ethanol, are less intense, and often delayed by 8 or more hours from ingestion, progressing even more slowly if methanol is taken along with ethanol. As little as 15 mL of methanol can produce toxicity, including blindness, with doses in excess of 70 mL capable of producing death. Methanol poisoning consists of headache, GI distress, and pain (partially related to pancreatic injury), difficulty breathing, restlessness, and blurred vision associated with hyperemic optic disks. Severe metabolic acidosis can develop due to the accumulation of formic acid, and the respiratory depression can be severe, especially in the context of coma. The visual disturbances associated with methanol intoxication are a prominent part of the picture, and occur as a consequence of injury to ganglion cells of the retina by the metabolite, formic acid, with subsequent inflammation, atrophy, and potential bilateral blindness. The clinical picture can also include necrosis of the pancreas.

Genetic Variation in Ethanol Metabolism. The enzymes involved in ethanol metabolism (Figure 23–1) are mainly ADH and ALDH, and secondarily, catalase and CYP2E1. Several of these enzymes have genetic variants that alter alcohol metabolism and susceptibility to its effects.

The genetics of the ADH isoforms are important for understanding risk factors for severe repetitive ethanol problems. The three relevant forms are ADH1A, 1B, and 1C (genes on chromosome 4 q22). These class I ADHs have K_m<34 mmol (0.15 g/dL) and are responsible for 70% of the ethanol metabolizing capacity at BECs of 22 mM (i.e., ~0.10 g/dL) (Edenberg et al., 2006). These ADH forms are the rate-limiting step in ethanol metabolism, reducing the blood ethanol concentrations by ~4-5 mM (0.015-0.020 g/dL) per hour, the approximate levels of alcohol resulting from the consumption of one standard drink.

The ADH1A gene has no polymorphisms known to significantly affect the rate of alcohol metabolism. The ADH1B gene has a polymorphism, ADH1B*2, with arginine 47 replaced by histidine to produce a variant form of ADH with a 40-fold higher V_max than ADH1B. This polymorphism is seen in 30-45% of Chinese, Japanese, and Koreans, less than 10% of most Europeans, but in 50-90% of Russians and Jews (Edenberg et al., 2006). The potential faster metabolism of ethanol may result in a transient slightly higher blood level of acetaldehyde and is reported to be associated with a lower risk for heavy drinking and ethanol-related problems. A second polymorphism for ADH1B, ADH1B*3 (arginine 269 replaced by cysteine), has a 30-fold higher V_max. ADHlB*3 is seen in about 30% of Africans and also is associated with lower risk of heavy drinking and ethanol problems.

A third ADH gene found in the chromosome 4q22 cluster, ADH1C, exhibits two polymorphisms in high linkage disequilibrium, the γ1 and γ2 forms. The V_max of γ1 is twice that of γ2, and this ADH1C*1 allele is hypothesized to be associated with a slightly faster metabolism of ethanol and/or a higher level of acetaldehyde. The independent effects of ADH1C*1 and ADH1B*2 alleles are difficult to determine. The ADH cluster on chromosome 4 also contains class II ADHs with K_m = 34 mM (~0.15 g/dL). The class II forms contribute about 30% of the ethanol metabolizing capacity noted above. There are polymorphisms hypothesized to be associated with the alcoholism risk, but less information is known about these forms (Luo et al., 2007).

Other systems also contribute to the metabolism of ethanol to acetaldehyde including via catalase (Kuo et al., 2008). In addition, at higher BELs, the microsomal ethanol metabolizing system (MEOS) is important, especially CYP2E1, but also CYPs1A2 and 3A4. Variations of the CYP2E1 gene located on chromosome 10 have been hypothesized to relate to the level of sensitivity or reaction to the ethanol observed in the brain.

Acetaldehyde is produced from the breakdown of ethanol at the rate of approximately one standard drink per hour. As shown in Figure 23–1, the acetaldehyde is then rapidly broken down through the actions of ALDH2, primarily in the mitochondria of liver cells. The actions of ALDH2, a phase 2 enzyme (Chapter 6), are important because low levels of acetaldehyde may be perceived as rewarding and stimulating, while high blood levels of this substance produce severe adverse reactions that can include vomiting, diarrhea, and unstable blood pressure (Husemoen et al., 2008). There is a mutation in the ALDH2 gene (12q24), ALDH2*2 (resulting from a substitution of glycine 487 with lysine). Homozygotes with a nonfunctional ALDH2*2 occur in 5-10% of Japanese, Chinese, and Korean individuals, for whom severe adverse reactions occur after consumption of one drink or less. Consequently, their risk for severe repetitive heavy drinking is close to zero. This reaction operates through the same mechanism that occurs with drinking after taking the ALDH2 inhibitor, disulfiram. Heterozygotes for this polymorphism (ALDH2*2, 2*1) make up 30-40% of Asian individuals who, after consuming ethanol experience a facial flush and an enhanced sensitivity to beverage alcohol, but who do not necessarily report an overall adverse response to the drug (Wall and Ehlers, 1995). The heterozygotes tend to drink lower quantities of ethanol than the general population, although repeated intake may relate to an enhanced risk for adverse ethanol-related organ damage (including esophageal cancer and, perhaps, pancreatitis), possibly associated with higher acetaldehyde levels. While additional ALDH mutations occur, less is known about potential associations between these polymorphisms and the risk from alcohol.

• Porter: . . and drink, sir, is a great provoker of three things.

• Macduff: What three things does drink especially provoke?

• Porter: Marry, sir, nose-painting [cutaneous vasodilation], sleep [CNS depression], and urine [a consequence of the inhibition of antidiuretic hormone (vasopressin) secretion, exacerbated by volume loading]. Lechery, sir, it provokes and unprovokes: it provokes the desire but it takes away the performance. Therefore much drink may be said to be an equivocator with lechery: it makes him and it mars him; it sets him on and it takes him off; it persuades him and disheartens him, makes him stand to and not stand to [the imagination desires what the corpus cavernosum cannot deliver]; in conclusion, equivocates him in a sleep, and, giving him the lie, leaves him.

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

Actions of Ethanol on Neurochemical Pathways and Signaling. Ethanol affects almost all brain systems. The changes across neurochemical pathways occur simultaneously and the alterations often interact. An additional complication in describing CNS effects is the rapid adaptation to ethanol observed in the brain, with the result that the acute effects of the first dose of ethanol are often the opposite of the neurochemical consequences from repeated administration and those observed during falling blood ethanol levels and withdrawal syndromes (Schuckit, 2006b).

Ion Channels. The primary mediators of inhibitory neurotransmission in the brain are the ligand-gated γ-aminobutyric acid A (GABA_A) receptors, whose function is markedly enhanced by a number of classes of sedative, hypnotic, and anesthetic agents, including barbiturates, benzodiazepines, and volatile anesthetics (Chapter 14). Substantial data implicate the GABA_A receptor as an important target for the in vivo actions of ethanol. Stimulation of this multi-subunit, ligand-gated Cl⁻ channel system contributes to feelings of sleepiness, muscle relaxation, and the acute anticonvulsant properties associated with all GABA-boosting drugs (Krystal et al., 2006). Acutely, ethanol results in GABA release; chronic heavy use alters the pattern of expression of genes impacting on GABA_A subunits. Intoxication with ethanol can be viewed as a GABA-rich state, and withdrawal phenomena are related in part to GABA_A activity deficiencies. Several GABA_A receptor gene polymorphisms correlate with a predisposition toward heavy drinking and alcohol use disorders (Dick et al., 2006a,b).

The nicotinic ACh receptor is also sensitive to the effects of ethanol. Drinking acutely increases ACh in the ventral tegmental area, with a subsequent increase in DA in the nucleus accumbens (Joslyn et al., 2008). Varenicline, a partial agonist at the α₄β₂ subtype of the nicotininc ACh receptor (Chapter 11), decreases ethanol-seeking behavior and ethanol consumption in a rodent model, similar to its actions to effects on nicotine dependence (Steensland et al., 2007). Effects of ethanol on these receptors may be particularly important because there is an association between nicotine exposure (smoking) and alcohol consumption in humans. Furthermore, several studies indicate that nicotine increases alcohol consumption in animal models (Smith et al., 1999).

Excitatory ionotropic glutamate receptors are divided into the N-methyl-D-aspartate (NMDA) and non-NMDA receptor classes, with the latter consisting of kainate- and AMPA-receptor subtypes (see Chapter 14). Ethanol inhibits the function of the NMDA- and kainate-receptor subtypes; AMPA receptors are largely resistant to alcohol (Carta et al., 2003). As with the GABA_A receptors, phosphorylation of the glutamate receptor can modulate sensitivity to ethanol.

A number of other types of channels are sensitive to alcohol at concentrations routinely achieved in vivo. Ethanol enhances the activity of large conductance, Ca²⁺-activated K⁺ channels in neurohypophyseal terminals (Dopico et al., 1999), perhaps contributing to the reduced release of oxytocin and vasopressin after ethanol consumption. Ethanol inhibits N- and P/Q-type Ca²⁺ channels in a manner that can be antagonized by channel phosphorylation by PKA (Solem et al., 1997). BK (Maxi-K, slo1) channels also are a target for alcohol action (Davies et al., 2003). G protein-gated inwardly rectifying K⁺ channels (GIRK or Kir channels) can be activated by the βγ subunits of the G_i/G_o family, by PIP₂, and, via a different mechanism, by alcohols. Small alcohols bind to a hydrophobic binding pocket on GIRKs, leading to channel activation via stabilization of the open conformation (Aryal et al., 2009).

Other Neurotransmitter Systems. Dopamine-related systems have central importance regarding the feelings of reward and craving associated with all intoxicating substances (Koob and Kreek, 2007). Of special importance are alterations in DA activity in the ventral tegmental and related areas, especially the nucleus accumbens, which are likely to play a major role in feelings of euphoria and reward. Acute alcohol results in an increase in synaptic DA; repeated administration is associated with changes in both D₂ and D₄ receptors that may be important in the perpetuation of alcohol use as well as in relapse (Voronin et al., 2008).

The impact of ethanol on dopaminergic pathways is closely linked to changes in stress-related systems. These changes are hypothesized to relate to reinforcement from beverage alcohol and other drugs of abuse, as well as withdrawal symptoms and negative moods related to problems with regulation of the DA-rich brain reward systems. Dopaminergic activity in the nucleus accumbens is affected by multiple types of opioid receptors, and acute ethanol causes the release of β endorphins (Job et al., 2007). These actions subsequently activate μ opioid receptors in the ventral tegmentum and nucleus accumbens, with associated release of DA. Thus, many of the effects of alcohol on reward systems, and changes in how the CNS reacts to ethanol (including sensitization), may relate to alterations in opioid systems (Pastor and Aragon, 2006).

The acute administration of ethanol is associated with a significant increase in 5-HT in the synaptic space; continued use of ethanol produces an up-regulation of 5-HT receptors. Lower levels of 5-HT in the synapse, perhaps related to a more rapid reuptake by the 5-HT transporter, is associated with higher levels of alcohol intake and, potentially, lower levels of intensity of reaction to beverage alcohol (Barr et al., 2005). Changes in DA systems are likely to relate to alterations in 5-HT as well.

Cannabinoid receptors, especially CB₁ encoded by the gene CNR1, are also affected by ethanol (Hutchinson et al., 2008; Perra et al., 2008). CB₁ is a GPCR that is densely represented in the ventral tegmentum, nucleus accumbens, and prefrontal cortex. Activation of CB₁ occurs with acute ethanol administration and affects the release of DA, GABA, and glutamate, and reward circuits of the brain. Antagonists of CB₁ receptors, such as rimonabant, may block the effect of ethanol on dopaminergic systems.

Protein Kinases and Signaling Enzymes. Knockout mice lacking the γ isoform of PKC display reduced effects of ethanol measured behaviorally and a loss of enhancement by ethanol of GABA's effects measured in vitro (Harris et al., 1995). Intracellular signal-transduction cascades, such as MAPK, tyrosine kinases, and neurotrophic factor receptors, also are thought to be affected by ethanol (Valenzuela and Harris, 1997). Translocation of PKC and PKA between subcellular compartments also is sensitive to alcohol (Constantinescu et al., 1999).

Ethanol enhances the activities of several isoforms of adenylyl cyclase, with AC7 being the most sensitive (Tabakoff and Hoffman, 1998). This promotes increased production of cyclic AMP and thus increased activity of PKA. Ethanol's actions appear to be mediated by activation of G_s and promotion of the interaction between G_s and adenylyl cyclase.

Ethanol Consumption and CNS Function. There are a series of relatively common and temporary effects of ethanol with relatively high prevalence rates reflecting changes in the GABA system that are generally caused by CNS depressants. Large doses of ethanol can interfere with encoding of memories, producing anterograde amnesias, commonly referred to as alcoholic blackouts; affected individuals are unable to recall all or part of experiences during the period of heavy intake. At even 2-3 drinks, ethanol consumption can produce disturbances in sleep architecture, with frequent awakenings and restless sleep; high doses are associated with vivid and disturbing dreams late as a consequence of earlier suppression of night rapid eye movement dream state at higher blood ethanol levels. Perhaps reflecting the effect of ethanol on respirations as well as the muscle-relaxant effects of this drug, heavier drinking can be associated with sleep apnea, especially in older alcohol-dependent subjects (Sakurai et al., 2007). The transient CNS effects of heavy ethanol consumption that produce a hangover—the "next morning" syndrome of headache, thirst, nausea, and cognitive impairment—contribute to much time lost from work and school, and may reflect mechanisms similar to mild alcohol withdrawal, dehydration, and/or mild acidosis (Stephens et al., 2008).

Chronic heavy drinking reportedly increases the probability of developing a more permanent cognitive deficit often referred to as alcoholic dementia. However, the signs of cognitive deficits and brain atrophy observed soon after a heavy drinking period often reverse over the subsequent several weeks to months following abstinence (Bartsch et al., 2007). The thiamine depletion that can accompany heavy ethanol consumption contributes to Wernicke-Korsakoff syndromes; however, the ataxia and ophalmoparesis of Wernicke's, and the severe anterograde and retrograde amnesias of Korsakoff's, are seen in <<1% of chronic alcohol-dependent individuals. Additional severe neurological syndromes associated with chronic heavy use of alcohol include cerebellar degeneration with associated atrophy of the cerebellar vermis (seen in ~1% of alcoholics), and a peripheral neuropathy (observed in ~10% of alcoholics) (Alexander-Kaufman et al., 2007; Peters et al., 2006). The specific mechanisms associated with damage to the cerebellum and peripheral nerves have not been definitively identified.

Heavy doses of ethanol over multiple days or weeks are also associated with several temporary but disturbing "alcohol-induced" psychiatric syndromes (Schuckit, 2006a). As many as 40% of alcohol-dependent humans develop severe alcohol-related depressive symptoms that can include temporary suicidal thoughts and behaviors. Similarly, a range of anxiety conditions, including those characterized by panic attacks and generalized anxiety, are likely in a large minority of alcohol-dependent individuals during the withdrawal syndrome. Perhaps 3% of alcohol-dependent men and women report experiencing temporary auditory hallucinations and paranoid delusions that resemble schizophrenia beginning during periods of heavy intoxication; all of these psychiatric syndromes are likely to markedly improve within several days to a month of abstinence, with residual mild symptoms continuing to diminish thereafter. While no definitive data on the mechanisms for these alcohol-induced psychiatric conditions are available, it is logical to assume that alcohol-related changes in CNS pathways (NE and 5-HT levels, the balance between GABA_A and NMDA receptor activity, dopaminergic activity) may operate here in a manner similar to those seen in depression, anxiety, and schizophrenic disorders.

One possible mechanism by which alcohol could reduce the risk of CHD is through its effects on blood lipids. Changes in plasma lipoprotein levels, particularly increases in high-density lipoprotein (HDL; Chapter 31), have been associated with the protective effects of ethanol. HDL binds cholesterol and returns it to the liver for elimination or reprocessing, decreasing tissue cholesterol levels. Ethanol-induced increases in HDL-cholesterol thus could antagonize cholesterol accumulation in arterial walls, lessening the risk of infarction. Approximately half the risk reduction associated with ethanol consumption is explained by changes in total HDL levels (Langer et al., 1992). HDL is found as two subfractions, named HDL₂ and HDL₃. Increased levels of HDL₂ (and possibly also HDL₃) are associated with reduced risk of myocardial infarction. Levels of both subfractions are increased following alcohol consumption and decrease when alcohol consumption ceases. Apolipoproteins A-I and A-II are constituents of HDL. Increased levels of both apolipoproteins A-I and A-II are associated with individuals who are daily heavy drinkers. In contrast, there are reports of decreased serum apolipoprotein(a) levels following acute alcohol consumption. Elevated apolipoprotein(a) levels have been associated with an increased risk for the development of atherosclerosis.

All forms of alcoholic beverages confer cardio-protection. A variety of alcoholic beverages increase HDL levels while decreasing the risk of myocardial infarction. The flavonoids found in red wine (and purple grape juice) may have an additional antiatherogenic role by protecting low-density lipoprotein (LDL) from oxidative damage. Oxidized LDL has been implicated in several steps of atherogenesis (Chapter 31). Another way in which alcohol consumption conceivably could play a cardioprotective role is by altering factors involved in blood clotting. Alcohol consumption elevates the levels of tissue plasminogen activator, a clot-dissolving enzyme (Chapter 30), decreasing the likelihood of clot formation. Decreased fibrinogen concentrations seen following ethanol consumption also could be cardioprotective (Rimm et al., 1999), and epidemiological studies have linked the moderate consumption of ethanol to an inhibition of platelet activation (Rubin, 1999).

The prevalence of hypertension attributable to excess alcohol consumption is not known, but studies suggest a range of 5-11%. The prevalence probably is higher for men than for women because of higher alcohol consumption by men. A reduction in or cessation of alcohol use in heavy drinkers may reduce the need for antihypertensive medication or reduce the blood pressure to the normal range. A safe amount of alcohol consumption for hypertensive patients who are light drinkers (1-2 drinks per occasion and less than 14 drinks per week) has not been determined. Factors to consider are a personal history of ischemic heart disease, a history of binge drinking, or a family history of alcoholism or of cerebrovascular accident. Hypertensive patients with any of these risk factors should abstain from alcohol use.

Muscle biopsies from heavy drinkers also reveal decreased glycogen stores and reduced pyruvate kinase activity (Vernet et al., 1995). Approximately 50% of chronic heavy drinkers have evidence of type II fiber atrophy. These changes correlate with reductions in muscle protein synthesis and serum carnosinase activities (Wassif et al., 1993). Most patients with chronic alcoholism show electromyographical changes, and many show evidence of a skeletal myopathy similar to alcoholic cardiomyopathy.

Alcoholics have less urine output than do control subjects in response to a challenge dose with ethanol, suggesting that tolerance develops to the diuretic effects of ethanol (Collins et al., 1992). Alcoholics withdrawing from alcohol exhibit increased vasopressin release and a consequent retention of water, as well as dilutional hyponatremia.

When compared with nonalcoholic nonsmokers, alcohol-dependent patients who smoke have a 10-fold increased risk of developing cancer of the esophagus. There is little change in esophageal function at low blood alcohol concentrations, but at higher blood alcohol concentrations, a decrease in peristalsis and decreased lower esophageal sphincter pressure occur. Patients with chronic reflux esophagitis may respond to proton pump inhibitors and abstinence from alcohol.

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

Two-thirds of patients with recurrent alcoholic pancreatitis will develop chronic pancreatitis. Chronic pancreatitis is treated by replacing the endocrine and exocrine deficiencies that result from pancreatic insufficiency. The development of hyperglycemia often requires insulin for control of blood-sugar levels (Chapter 43). Pancreatic enzyme capsules containing lipase, amylase, and proteases may be necessary to treat malabsorption (Chapter 46).

A number of molecular mechanisms for alcoholic cirrhosis have been proposed. In nonhuman primate models, alcohol alters phospholipid peroxidation. Ethanol decreases phosphatidylcholine levels in hepatic mitochondria, a change associated with decreased oxidase activity and O₂ consumption. Cytokines, such as transforming growth factor β and tumor necrosis factor α, can increase rates of fibrinogenesis and fibrosis in the liver. Acetaldehyde is thought to have a number of adverse effects, including depletion of glutathione (Lieber, 2000), depletion of vitamins and trace metals, and decreased transport and secretion of proteins owing to inhibition of tubulin polymerization. Acetaminophen-induced hepatic toxicity (Chapters 4, 6, and 34) has been associated with alcoholic cirrhosis as a result of alcohol-induced increases in microsomal production of toxic acetaminophen metabolites (Whitcomb and Block, 1994). Liver failure secondary to cirrhosis and resulting in impaired clearance of toxins such as ammonia also may contribute to alcohol-induced hepatic encephalopathy. Ethanol also appears to increase intracellular free hydroxy-ethyl radical formation.

Vitamins and Minerals.

The almost complete lack of protein, vitamins, and most other nutrients in alcoholic beverages predisposes those who consume large quantities of alcohol to nutritional deficiencies. Alcoholics often present with these deficiencies owing to decreased intake, decreased absorption, or impaired utilization of nutrients. The peripheral neuropathy, Korsakoff's psychosis, and Wernicke's encephalopathy seen in alcoholics probably are caused by deficiencies of the B complex of vitamins (particularly thiamine), although direct toxicity produced by alcohol itself has not been ruled out (Harper, 1998). Chronic alcohol abuse decreases the dietary intake of retinoids and carotenoids and enhances the metabolism of retinol by the induction of degradative enzymes (Lieber, 2000). Retinol and ethanol compete for metabolism by ADH; vitamin A supplementation therefore should be monitored carefully in alcoholics when they are consuming alcohol to avoid retinol-induced hepatotoxicity. The chronic consumption of alcohol inflicts an oxidative stress on the liver owing to the generation of free radicals, contributing to ethanol-induced liver injury. The antioxidant effects of α-tocopherol (vitamin E) may ameliorate some of this ethanol-induced toxicity in the liver. Plasma levels of α-tocopherol often are reduced in myopathic alcoholics compared with alcoholic patients without myopathy.

Chronic alcohol consumption has been implicated in osteoporosis (Chapter 44). The reasons for this decreased bone mass remain unclear, although impaired osteoblastic activity has been implicated. Acute administration of ethanol produces an initial reduction in serum parathyroid hormone (PTH) and Ca²⁺ levels, followed by a rebound increase in PTH that does not restore Ca²⁺ levels to normal. Alcohol-induced osteopenia improves with abstinence (Alvisa-Negrin J, et al., 2009). Since vitamin D requires hydroxylation in the liver for activation, alcohol-induced liver damage can indirectly affect the role of vitamin D in the intestinal and renal absorption of Ca²⁺.

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

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

Alcohol also affects granulocytes and lymphocytes (Schirmer et al., 2000). Effects include leukopenia, alteration of lymphocyte subsets, decreased T-cell mitogenesis, and changes in immunoglobulin production. These disorders may play a role in alcohol-related liver disease. In some patients, depressed leukocyte migration into inflamed areas may account in part for the poor resistance of alcoholics to some types of infection (e.g., Klebsiella pneumonia, listeriosis, and tuberculosis). Alcohol consumption also may alter the distribution and function of lymphoid cells by disrupting cytokine regulation, in particular that involving interleukin 2 (IL-2). Alcohol appears to play a role in the development of infection with the human immunodeficiency virus-1 (HIV). In vitro studies with human lymphocytes suggest that alcohol can suppress CD4 T-lymphocyte function and concanavalin A–stimulated IL-2 production and enhance in vitro replication of HIV. Moreover, persons who abuse alcohol have higher rates of high-risk sexual behavior.

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

Many factors, such as body weight and composition and the rate of absorption from the GI tract, determine the concentration of ethanol in the blood after ingestion of a given amount of ethanol. On average, the ingestion of 3 standard drinks (42 g ethanol) on an empty stomach results in a maximum blood concentration of 67-92 mg/dL in men. After a mixed meal, the maximal blood concentration from three drinks is 30-53 mg/dL in men. Concentrations of alcohol in blood will be higher in women than in men consuming the same amount of alcohol because, on average, women are smaller than men, have less body water per unit of weight into which ethanol can distribute, and have less gastric ADH activity than men. For individuals with normal hepatic function, ethanol is metabolized at a rate of one standard drink every 60-90 minutes.

The characteristic signs and symptoms of alcohol intoxication are well known. Nevertheless, an erroneous diagnosis of drunkenness may occur with patients who appear inebriated but who have not ingested ethanol. Diabetic coma, e.g., may be mistaken for severe alcoholic intoxication. Drug intoxication, cardiovascular accidents, and skull fractures also may be confused with alcohol intoxication. The odor of the breath of a person who has consumed ethanol is due not to ethanol vapor but to impurities in alcoholic beverages. Breath odor in a case of suspected intoxication can be misleading because there can be other causes of breath odor similar to that after alcohol consumption. Blood alcohol levels are necessary to confirm the presence or absence of alcohol intoxication (Schuckit, 2006b).

The treatment of acute alcohol intoxication is based on the severity of respiratory and CNS depression. Acute alcohol intoxication can be a medical emergency, and a number of young people die every year from this disorder. Patients who are comatose and who exhibit evidence of respiratory depression should be intubated to protect the airway and to provide ventilatory assistance (see Chapter 4). The stomach may be lavaged, but care must be taken to prevent pulmonary aspiration of the return flow. Since ethanol is freely miscible with water, ethanol can be removed from blood by hemodialysis (Schuckit, 2006b).

Acute alcohol intoxication is not always associated with coma, and careful observation is the primary treatment. Usual care involves observing the patient in the emergency room for 4-6 hours while the patient metabolizes the ingested ethanol. Blood alcohol levels will be reduced by ~15 mg/dL per hour. During this period, some individuals may display extremely violent behavior. Sedatives and antipsychotic agents have been employed to quiet such patients. Great care must be taken, however, when using sedatives to treat patients who have ingested an excessive amount of another CNS depressant, such as, ethanol, because of synergistic effects.

CLINICAL USES OF ETHANOL

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

Systemically administered ethanol is confined to the treatment of poisoning by methyl alcohol and ethylene glycol. The ingestion results in formation of methanol's metabolites, formaldehyde and formic acid (Figure 23–1). Formic acid causes nerve damage; its effects on the retina and optic nerve can cause blindness. Treatment consists of sodium bicarbonate to combat acidosis, hemodialysis, and the administration of ethanol, which slows formate production by competing with methanol for metabolism by alcohol dehydrogenase.

The use of alcohol to treat patients in alcohol withdrawal or obstetrical patients with premature contractions is no longer recommended (Chapter 24).

Ethanol tolerance and physical dependence are studied readily in animal models. Strains of mice with genetic differences in tolerance and dependence have been characterized, and a search for the relevant genes and ethanol-sensitive microRNAs is under way (Miranda et al., 2010). Neurobiological mechanisms of tolerance and dependence are not understood completely, but chronic alcohol consumption results in changes in synaptic and intracellular signaling likely owing to changes in gene expression. Most of the systems that are acutely affected by ethanol also are affected by chronic exposure, resulting in an adaptive or maladaptive response that can cause tolerance and dependence (see Table 23–1). In particular, chronic actions of ethanol likely require changes in signaling by glutamate and GABA receptors and down-stream signaling pathways. The increase in NMDA-receptor function after chronic alcohol ingestion could contribute to the CNS hyperexcit-ability and neurotoxicity seen during ethanol withdrawal. Arginine vasopressin, acting on V₁ receptors, maintains tolerance to ethanol in laboratory animals even after chronic ethanol administration has ceased (Hoffman et al., 1990).

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

The search for the genes and alleles responsible for alcoholism is complicated by the polygenetic nature of the disease and the general difficulty in defining multiple genes responsible for complex diseases. As noted earlier in the chapter, polymorphisms in the enzymes of ethanol metabolism seem to explain why some populations (mainly Asian) are protected from alcoholism. This has been attributed to genetic differences in alcohol- and aldehyde-metabolizing enzymes. Specifically, genetic variants of ADH that exhibit high activity and variants of ALDH that exhibit low activity protect against heavy drinking, probably because alcohol consumption by individuals who have these variants results in accumulation of acetaldehyde, which produces a variety of unpleasant effects (Li, 2000).

In contrast to these protective genetic variants, there are few consistent data about genes responsible for increased risk for alcoholism. A genetic mechanism associated with an enhanced risk for both alcohol and other drug use disorders operates through the intermediate characteristic (or phenotype) of impulsivity and disinhibition (King et al., 2004). The identified polymorphisms include two variations of the GABA_A receptors (Dick et al., 2006a,b), a variation in ADH4 hypothesized to be related to personality characteristics (Edenberg et al., 2006), and a muscarinic cholinergic receptor gene, CHRM2 (Jones et al., 2006).

Another phenotype related to an enhanced risk for alcohol use disorders (but not other drug use disorders) is associated with a low level of response (perhaps reflecting low sensitivity) to ethanol (Schuckit, 2009b). The need for higher amounts of ethanol to achieve the desired effects may contribute to the decision to drink more per occasion, which in turn leads to altered expectations of the effects of beverage alcohol, an enhanced probability of selecting heavier-drinking peers, as well as problematic approaches to dealing with stress (Schuckit et al., 2008). To date, genetic contributions to the level of response have been tentatively identified for two GABA_A subunits (Dick et al., 2006a,b), a polymorphism in the promoter region of the 5-HT transporter that is associated with lower levels of 5-HT in the synaptic space (Barr et al., 2005), a polymorphism of the K⁺ channel-related KCNMA1 (Schuckit et al., 2005), and a variant nicotinic Ach receptor that is also related to an increased risk for heavy smoking and related consequences (Joslyn et al., 2008). Antisocial alcoholism has been linked with polymorphisms of several 5-HT receptors (Ducci et al, 2009). Polymorphisms in dopaminergic and opioid systems and in genes that correlate with a predisposition to bipolar disorder, schizophrenia, and several anxiety disorders may also contribute to a general vulnerability to a range of substance abuse disorders.

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

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

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

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

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

Nalmefene (revex) is another opioid antagonist that appears promising in preliminary clinical tests (Mason et al., 1999). It has a number of advantages over naltrexone, including greater oral bio-availability, longer duration of action, and lack of dose-dependent liver toxicity.

A number of double-blind, placebo-controlled studies have demonstrated that acamprosate (1.3-2 g/day) decreases drinking frequency and reduces relapse drinking in abstinent alcoholics and appears to have efficacy similar to that of naltrexone. Studies in laboratory animals have shown that acamprosate decreases alcohol intake without affecting food or water consumption. Acamprosate generally is well tolerated by patients, with diarrhea being the main side effect (Garbutt et al., 1999). No abuse liability has been noted. The drug undergoes minimal metabolism in the liver, is excreted primarily by the kidneys, and has an elimination t_1/2 of 18 hours after oral administration. Concomitant use of disulfiram appears to increase the effectiveness of acamprosate, without any adverse drug interactions being noted (Besson et al., 1998).

Disulfiram, given alone, is a relatively nontoxic substance, but it inhibits ALDH activity and causes the blood acetaldehyde concentration to rise to 5-10 times above the level achieved when ethanol is given to an individual not pretreated with disulfiram. Acetaldehyde, produced as a result of the oxidation of ethanol by ADH, ordinarily does not accumulate in the body because it is further oxidized almost as soon as it is formed. Following the administration of disulfiram, both cytosolic and mitochondrial forms of ALDH are irreversibly inactivated to varying degrees, and the concentration of acetaldehyde rises. It is unlikely that disulfiram itself is responsible for the enzyme inactivation in vivo; several active metabolites of the drug, especially diethylthiomethylcarbamate, behave as suicide-substrate inhibitors of ALDH in vitro. These metabolites reach significant concentrations in plasma following the administration of disulfiram (Johansson, 1992).

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

Alarming reactions may result from the ingestion of even small amounts of alcohol in persons being treated with disulfiram. The use of disulfiram as a therapeutic agent thus is not without danger, and it should be attempted only under careful medical and nursing supervision. Patients must be warned that as long as they are taking disulfiram, the ingestion of alcohol in any form will make them sick and may endanger their lives. Patients must learn to avoid disguised forms of alcohol, as in sauces, fermented vinegar, cough syrups, and even after-shave lotions and back rubs.

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

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

Disulfiram by itself usually is innocuous, but it may cause acneform eruptions, urticaria, lassitude, tremor, restlessness, headache, dizziness, a garlic-like or metallic taste, and mild GI disturbances. Peripheral neuropathies, psychosis, and ketosis also have been reported.

Other Agents

Ondansetron, a 5-HT₃-receptor antagonist and antiemetic drug (Chapters 13 and 46), reduces alcohol consumption in laboratory animals and currently is being tested in humans. Preliminary findings suggest that ondansetron is effective in the treatment of early-onset alcoholics, who respond poorly to psychosocial treatment alone, although the drug does not appear to work well in other types of alcoholics. Ondansetron administration lowers the amount of alcohol consumed, particularly by drinkers who consume fewer than 10 drinks per day (Sellers et al., 1994). It also decreases the subjective effects of ethanol on 6 of 10 scales measured, including the desire to drink (Johnson et al., 1993), while at the same time not having any effect on the pharmacokinetics of ethanol.

Topiramate, a drug used for treating seizure disorders (Chapter 21), appears useful for treating alcohol dependence. Compared with the placebo group, patients taking topiramate achieved more abstinent days and a lower craving for alcohol (Johnson et al., 2003). The mechanism of action of topiramate is not well understood but is distinct from that of other drugs used for the treatment of dependence (e.g., opioid antagonists), suggesting that it may provide a new and unique approach to pharmacotherapy of alcoholism.