Goodman and Gilman Manual of Pharmacology and Therapeutics

Section II

chapter 23
Ethanol and Methanol

The 2-carbon alcohol ethanol (CH3CH2OH), or beverage alcohol, is one of the most versatile drugs known to man, with multiple direct effects on a diverse range of neurochemical systems. Produced in nature, rewarding in its effects, and easy to manufacture, it has been taken by humans since the beginning of recorded history, is consumed by a large majority of people in the Western world, and is likely to contribute to more morbidity, mortality, and public health costs than all of the illicit drugs combined.

ETHANOL CONSUMPTION. Compared with other drugs, surprisingly large amounts of alcohol are required for physiological effects, resulting in its consumption more as a food than a drug. The alcohol content of beverages typically ranges from 4-6% (volume/volume) for beer, 10-15% for wine, and 40% and higher for distilled spirits (the “proof” of an alcoholic beverage is twice its percentage of alcohol; e.g., 40% alcohol is 80 proof). A glass of beer or wine, a mixed drink, or a shot of spirits contains ~14 g alcohol, or ~0.3 mol ethanol. Thus, alcohol is consumed in gram quantities, whereas most other drugs are taken in milligram or microgram doses.

Because the ratio of ethanol in end-expiratory alveolar air and ethanol in the blood is relatively consistent, blood ethanol concentrations (BECs) in humans can be estimated readily by the measurement of alcohol levels in expired air; the partition coefficient for ethanol between blood and alveolar air is approximately 2000:1. Because of the causal relationship between excessive alcohol consumption and vehicular accidents, there has been a near-universal adoption of laws attempting to limit the operation of vehicles while under the influence of alcohol. Legally allowed BECs in the U.S. typically are set at or below 80 mg% (80 mg ethanol per 100 mL blood; 0.08% w/v), which is equivalent to a concentration of 17 mM ethanol in blood. A 12-oz bottle of beer, a 5-oz glass of wine, and a 1.5-oz “shot” of 40% liquor each contains approximately 14 g ethanol, and the consumption of 1 of these beverages by a 70-kg person would produce a BEC of ~30 mg%. However, it is important to note that this is approximate because the BEC is determined by a number of factors, including the rate of drinking, gender, body weight and water percentage, and the rates of metabolism and stomach emptying (see “Acute Ethanol Intoxication” later in the chapter).



ABSORPTION. After oral administration, ethanol is absorbed rapidly into the bloodstream from the stomach and small intestine and distributes into total-body water (0.5-0.7 L/kg). Peak blood levels occur about 30 min after ingestion of ethanol when the stomach is empty. Because absorption occurs more rapidly from the small intestine than from the stomach, delays in gastric emptying (owing, e.g., to the presence of food) slow ethanol absorption. Because of first-pass metabolism by gastric and liver alcohol dehydrogenase (ADH), oral ingestion of ethanol leads to lower BECs than would be obtained if the same quantity were administered intravenously. Gastric metabolism of ethanol is lower in women than in men, which may contribute to the greater susceptibility of women to ethanol. Aspirin increases ethanol bioavailability by inhibiting gastric ADH.

METABOLISM. Ethanol is metabolized largely (90-98%) by sequential hepatic oxidation, first to acetaldehyde by ADH and then to acetic acid by aldehyde dehydrogenase (ALDH) (Figure 23–1). Each metabolic step requires NAD+; this greatly exceeds the supply of NAD+ in the liver and NAD+ availability limits ethanol metabolism to ~8 g or 10 mL (~170 mmol) per hour in a 70-kg adult, or ~120 mg/kg/h. Thus, hepatic ethanol metabolism functionally saturates at relatively low blood levels compared with the high BECs achieved, and ethanol metabolism is a zero-order process (constant amount per unit time). Small amounts of ethanol are excreted in urine, sweat, and breath.


Figure 23–1 Metabolism of ethanol and methanol.

CYP2E1 also can contribute, especially at higher ethanol concentrations. CYP2E1 is induced by chronic consumption of ethanol, increasing the clearance of its substrates and the activation of certain toxins such as CCl4. There can be decreased clearance of the same drugs, however, after acute consumption of ethanol because ethanol competes with them for oxidation by the enzyme system (e.g., phenytoin and warfarin).

The large increase in the hepatic NADH:NAD+ ratio during ethanol oxidation has profound consequences in addition to limiting the rate of ethanol metabolism. Enzymes requiring NAD+ are inhibited; thus, lactate accumulates, activity of the tricarboxylic acid cycle is reduced, and acetyl coenzyme A (acetyl CoA) accumulates (and it is produced in quantity from ethanol-derived acetic acid; see Figure 23–1). The combination of increased NADH and elevated–acetyl CoA supports fatty acid synthesis and the storage and accumulation of triacylglycerides; ketone bodies accrue, exacerbating lactic acidosis. Ethanol metabolism by the CYP2E1 pathway produces elevated NADP+, limiting the availability of NADPH for the regeneration of reduced glutathione (GSH), thereby enhancing oxidative stress.

Genetic Variation in Ethanol Metabolism. The enzymes involved in ethanol metabolism are mainly ADH and ALDH, and secondarily, catalase and CYP2E1. CYPs 1A2 and 3A4 may also participate. 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 3 relevant forms are ADH1A, 1B, and 1C. These class I ADHs have Km<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). These ADH forms are the rate-limiting step in ethanol metabolism, reducing the BECs by ~4-5 mM (0.015-0.020 g/dL) per hour, the approximate levels of alcohol resulting from the consumption of 1 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 Vmax 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. 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 Vmax. ADHlB*3 is seen in about 30% of Africans and also is associated with lower risk of heavy drinking and ethanol problems.

Acetaldehyde is produced from the breakdown of ethanol at the rate of approximately 1 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 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. 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 1 drink or less. 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. A number of these polymorphisms affect risk for alcohol use disorder (Table 23–1).

Table 23–1

Genes for Intermediate Phenotypes Affecting Risk for Alcohol Use Disorder



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; methanol is added to industrial-use ethanol to mark it unsafe for human consumption.

Absorption and Metabolism. Methanol is rapidly absorbed via the oral route, inhalation, and through the skin, with the latter 2 routes most relevant to industrial settings. Methanol is metabolized by ADH and ALDH. 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.

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 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.


William Shakespeare described the acute pharmacological effects of imbibing ethanol in the Porter scene (act 2, scene 3) of Macbeth. The Porter, awakened from an alcohol-induced sleep by Macduff, explains three effects of alcohol and then wrestles with a fourth effect that combines the contradictory aspects of soaring overconfidence with physical impairment:

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.

More recent research has added details to Shakespeare’s enumeration—see the bracketed additions to the Porter’s words in the preceding paragraph and the section on organ systems later in the chapter—but the most noticeable consequences of the recreational use of ethanol still are well summarized by the gregarious and garrulous Porter, whose delighted and devilish demeanor demonstrates frequently observed influences of modest concentrations of ethanol on the CNS.


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

Chronic alcohol abuse is accompanied by tolerance, dependence, and craving for the drug. 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. Chronic alcohol abuse results in shrinkage of the brain owing to loss of both white and gray matter. In addition to loss of brain tissue, alcohol abuse also reduces brain metabolism, 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.

Actions of Ethanol on Neurochemical Pathways and Signaling. Ethanol affects almost all brain systems. The changes across neural 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. Alcohol perturbs the balance between excitatory and inhibitory influences in the brain, resulting in anxiolysis, ataxia, and sedation. This is accomplished by either enhancing inhibitory or antagonizing excitatory neurotransmission. The 12th edition of the parent text summarizes research supporting effects of ethanol on a number of ion channels and neurotransmitter signal transducing systems that alter neuronal excitability within the CNS.

Ethanol Consumption and CNS Function. 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. 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. The transient CNS effects of heavy ethanol consumption that produce a hangover—the “next morning” syndrome of headache, thirst, nausea, and cognitive impairment—may reflect mechanisms similar to mild alcohol withdrawal, dehydration, and/or mild acidosis.

Chronic heavy drinking reportedly increases the probability of developing alcoholic dementia. 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. The thiamine depletion that can accompany heavy ethanol consumption contributes to Wernicke-Korsakoff syndromes. 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.


Ethanol intake greater than 3 standard drinks per day elevates the risk for heart attacks and bleeding-related strokes. The risk includes a 6-fold increased risk for coronary artery disease, a heightened risk for cardiac arrhythmias, and an elevated rate of congestive heart failure. The causes are complex and observations are complicated by certain positive effects of small amounts of ethanol.

Serum Lipoproteins and Cardiovascular Effects. In France, the risk of mortality due to coronary heart disease (CHD) is relatively low despite the consumption of high quantities of saturated fats (the “French paradox”). Epidemiological studies suggest that widespread wine consumption (20-30 g ethanol per day) is 1 of the factors conferring a cardioprotective effect, resulting in a 10-40% decreased risk of coronary heart disease compared with abstainers. In contrast, daily consumption of greater amounts of alcohol leads to an increased incidence of non-coronary causes of cardiovascular failure, such as arrhythmias, cardiomyopathy, and hemorrhagic stroke, offsetting the beneficial effects of alcohol on coronary arteries.

One possible mechanism by which alcohol could reduce the risk of CHD is through its effects on blood lipids. Changes in plasma lipoprotein levels, particularly increases in high-density lipoprotein (HDL;see Chapter 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. HDL is found as 2 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. The flavonoids found in red wine (and purple grape juice) may have an additional anti-atherogenic role by protecting low-density lipoprotein (LDL) from oxidative damage. Alcohol consumption also is linked to elevated levels of tissue plasminogen activator (a clot-dissolving enzyme), decreased fibrinogen concentrations, and inhibition of platelet activation.

Hypertension. Heavy alcohol use can raise diastolic and systolic blood pressure. Consumption >30 g alcohol per day (>2 standard drinks) is associated with a 1.5-2.3 mm Hg rise in diastolic and systolic blood pressure.

Cardiac Arrhythmias. Alcohol prolongs the QT interval, prolongs ventricular repolarization, and enhances sympathetic stimulation. Atrial arrhythmias associated with chronic alcohol use include supraventricular tachycardia, atrial fibrillation, and atrial flutter. Some 15-20% of idiopathic cases of atrial fibrillation may be induced by chronic ethanol use.

Cardiomyopathy. Alcohol can depress cardiac contractility and lead to cardiomyopathy. Echocardiography demonstrates global hypokinesis. Approximately half of all patients with idiopathic cardiomyopathy are alcohol-dependent. Alcohol-induced cardiomyopathy has a better prognosis if patients are able to stop drinking. Women are at greater risk of alcohol-induced cardiomyopathy than are men.

Stroke. Clinical studies indicate an increased incidence of hemorrhagic and ischemic stroke in persons who drink >40-60 g alcohol per day. Proposed etiological factors include:

• Alcohol-induced cardiac arrhythmias and associated thrombus formation

• High blood pressure from chronic alcohol consumption and subsequent cerebral artery degeneration

• Acute increases in systolic blood pressure and alterations in cerebral artery tone

• Head trauma


Chronic, heavy, daily alcohol consumption is associated with decreased muscle strength, even when adjusted for other factors such as age, nicotine use, and chronic illness. Heavy doses of alcohol also can cause irreversible damage to muscle, reflected by a marked increase in the activity of creatine kinase in plasma. Muscle biopsies from heavy drinkers also reveal decreased glycogen stores and reduced pyruvate kinase activity. Approximately 50% of chronic heavy drinkers have evidence of type II fiber atrophy. Most patients with chronic alcoholism show evidence of a skeletal myopathy similar to alcoholic cardiomyopathy.


Ingestion of ethanol causes a feeling of warmth because alcohol enhances cutaneous and gastric blood flow. Increased sweating also may occur. Heat, therefore, is lost more rapidly, and the internal body temperature falls. After consumption of large amounts of ethanol, the central temperature-regulating mechanism becomes depressed, and the fall in body temperature may become pronounced. The action of alcohol in lowering body temperature is greater and more dangerous when the ambient environmental temperature is low. Studies of deaths from hypothermia suggest that alcohol is a major risk factor in these events.


Alcohol inhibits the release of vasopressin (antidiuretic hormone) from the posterior pituitary gland, resulting in enhanced diuresis. Alcoholics withdrawing from alcohol exhibit increased vasopressin release and a consequent retention of water, as well as dilutional hyponatremia.


Esophagus. Alcohol is 1 of multiple factors associated with esophageal dysfunction. Ethanol also is associated with the development of esophageal reflux, Barrett esophagus, traumatic rupture of the esophagus, Mallory-Weiss tears, and esophageal cancer. 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.

Stomach. Heavy alcohol use can disrupt the gastric mucosal barrier and cause acute and chronic gastritis. Ethanol appears to stimulate gastric secretions by exciting sensory nerves in the buccal and gastric mucosa and promoting the release of gastrin and histamine. Beverages containing more than 40% alcohol also have a direct toxic effect on gastric mucosa. Clinical symptoms include acute epigastric pain that is relieved with antacids or histamine H2 receptor antagonists. Alcohol exacerbates the clinical course and severity of ulcer symptoms. It appears to act synergistically with Helicobacter pylori to delay healing.

Intestines. Many alcoholics have chronic diarrhea as a result of malabsorption in the small intestine. The rectal fissures and pruritus ani that frequently are associated with heavy drinking probably are related to chronic diarrhea. The diarrhea is caused by structural and functional changes in the small intestine; the intestinal mucosa has flattened villi, and digestive enzyme levels often are decreased. These changes frequently are reversible after a period of abstinence.

Pancreas. Heavy alcohol use is the most common cause of both acute and chronic pancreatitis in the U.S. Acute alcoholic pancreatitis is characterized by the abrupt onset of abdominal pain, nausea, vomiting, and increased levels of serum or urine pancreatic enzymes. Management usually involves intravenous fluid replacement—often with nasogastric suction—and opioid pain medication. The etiology of acute pancreatitis probably is related to a direct toxic metabolic effect of alcohol on pancreatic acinar cells. 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 (see Chapter 43). Pancreatic enzyme capsules containing lipase, amylase, and proteases may be necessary to treat malabsorption (see Chapter 46).

Liver. Ethanol produces dose-related deleterious effects in the liver that include fatty infiltration of the liver, hepatitis, and cirrhosis. The accumulation of fat in the liver is an early event and can occur in normal individuals after the ingestion of relatively small amounts of ethanol. This accumulation results from inhibition of both the tricarboxylic acid cycle and the oxidation of fat, in part owing to the generation of excess NADH produced by the actions of ADH and ALDH (see Figure 23–1). Fibrosis, resulting from tissue necrosis and chronic inflammation, is the underlying cause of alcoholic cirrhosis. Alcohol can affect stellate cells in the liver directly; chronic alcohol use is associated with transformation of stellate cells into collagen-producing, myofibroblast-like cells, resulting in deposition of collagen around terminal hepatic venules. The histological hallmark of alcoholic cirrhosis is the formation of Mallory bodies, which are thought to be related to an altered intermediate cytoskeleton. Acetaminophen-induced hepatic toxicity (see Chapters 46, and 34) has been associated with alcoholic cirrhosis as a result of alcohol-induced increases in microsomal production of toxic acetaminophen metabolites.


Alcoholics often present with nutritional deficiencies owing to decreased intake, decreased absorption, or impaired utilization of nutrients. The peripheral neuropathy, Korsakoff psychosis, and Wernicke encephalopathy seen in alcoholics probably are caused by deficiencies of the B complex of vitamins (particularly thiamine). 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. Chronic alcohol consumption has been implicated in osteoporosis. 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.


Despite the widespread belief that alcohol can enhance sexual activities, the opposite effect is generally noted. Many drugs of abuse, including alcohol, have disinhibiting effects that may lead initially to increased libido. Both acute and chronic alcohol use can lead to impotence in men. Increased blood ethanol 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. Gynecomastia is associated with alcoholic liver disease and is related to increased cellular response to estrogen and to accelerated metabolism of testosterone. 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.


Chronic alcohol use is associated with a number of anemias including microcytic anemias, macrocytic anemias, normochromic anemias, and alcohol-induced sideroblastic anemia. Alcohol-induced sideroblastic anemia may respond to vitamin B6 replacement. Alcohol use also is associated with reversible thrombocytopenia, although platelet counts <20,000/mm3 are rare. Alcohol also affects granulocytes and lymphocytes. Effects include leukopenia, alteration of lymphocyte subsets, decreased T-cell mitogenesis, and changes in immunoglobulin production. 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). In vitro studies with human lymphocytes suggest that alcohol can suppress CD4 T-lymphocyte function.


Signs of intoxication typical of CNS depression are seen in most people following 2-3 drinks, with the most prominent effect seen at the times of peak BEC, ~30-60 min following consumption on an empty stomach. These symptoms include an initial feeling of stimulation (perhaps due to inhibition of CNS inhibitory systems), giddiness, muscle relaxation, and impaired judgment. Higher blood levels (~80 mg/dL or ~17 mM) are associated with slurred speech, incoordination, unsteady gait, and potential impairments of attention; levels between 80 and 200 mg/dL (~17-43 mM) are associated with more intense mood lability, and greater cognitive deficits, potentially accompanied by aggressiveness, and anterograde amnesia (an alcoholic blackout). Blood ethanol levels >200 mg/dL can produce nystagmus and unwanted falling asleep; levels of 300 mg/dL (~65 mM) and higher can produce failing vital signs, coma, and death. All of these symptoms are likely to be exacerbated and occur at a lower BEC when ethanol is taken along with other CNS depressants (e.g., diazepam or similar benzodiazepines), or with any drug or medication for which sleepiness and uncoordination are likely.

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 3 drinks is 30-53 mg/dL in men. For individuals with normal hepatic function, ethanol is metabolized at a rate of 1 standard drink every 60-90 min. In women with smaller body size and a lower leaner body mass (lower volume of distribution for ethanol), the equivalent consumption could produce levels about 30-50% higher, on average.

Diabetic coma, drug intoxication, cardiovascular accidents, and skull fractures may be confused with alcohol intoxication. 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.

The treatment of acute alcohol intoxication is based on the severity of respiratory and CNS depression. Patients with evidence of respiratory depression should be intubated to protect the airway and to provide ventilatory assistance. The stomach may be lavaged. Because ethanol is freely miscible with water, ethanol can be removed from blood by hemodialysis. 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 h while the patient metabolizes the ingested ethanol. Blood ethanol levels will be reduced by 15 mg/dL/h. 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.


Systemically administered ethanol is confined to the treatment of poisoning by methyl alcohol and ethylene glycol. Methanol ingestion results in formation of methanol’s metabolites, formaldehyde and formic acid (see 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.

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.


Tolerance is defined as a reduced behavioral or physiological response to the same dose of ethanol (see Chapter 24). There is a marked acute tolerance that is detectable soon after administration of ethanol. Acute tolerance can be demonstrated by measuring behavioral impairment at the same BECs on the ascending limb of the absorption phase of the BEC–time curve (minutes after ingestion of alcohol) and on the descending limb of the curve as BECs are lowered by metabolism (1 or more hours after ingestion). Behavioral impairment and subjective feelings of intoxication are much greater at a given BEC on the ascending than on the descending limb. There also is a chronic tolerance that develops in the long-term heavy drinker. In contrast to acute tolerance, chronic tolerance often has a metabolic component owing to induction of alcohol-metabolizing enzymes.

Physical dependence is demonstrated by the elicitation of a withdrawal syndrome when alcohol consumption is terminated. The symptoms and severity are determined by the amount and duration of alcohol consumption and include sleep disruption, autonomic nervous system (sympathetic) activation, tremors, and in severe cases, seizures. In addition, 2 or more days after withdrawal, some individuals experience delirium tremens, characterized by hallucinations, delirium, fever, and tachycardia. Another aspect of dependence is craving and drug-seeking behavior, often termed psychological dependence.


Environmental and cultural factors that contribute to alcohol use include stress, drinking patterns within one’s culture and peer group, availability of alcohol, and attitudes toward drunkenness. These nonbiological forces contribute to perhaps 70-80% of the initial decision to drink and at least 40% of the transition from drinking to alcohol-related problems and alcohol use disorders. Correspondingly, ~60% of the susceptibility to alcohol use disorders results from heritable factors (see Table 23–1).

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. 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. The identified polymorphisms include 2 variations of the GABAA receptors, a variation in ADH4 hypothesized to be related to personality characteristics, and a muscarinic cholinergic receptor gene, CHRM2.

Another phenotype is associated with a low level of response to ethanol. Genetic contributions to the level of response have been tentatively identified for 2 GABAA subunits, a polymorphism in the promoter region of the 5HT transporter that is associated with lower levels of 5HT in the synaptic space, a polymorphism of the p subunit of K+ channel KCNMA1, and a variant nicotinic ACh receptor that is also related to an increased risk for heavy smoking and related consequences. Antisocial alcoholism has been linked with polymorphisms of several 5HT receptors.


Children born to alcoholic mothers display a common pattern of distinct dysmorphology known as fetal alcohol syndrome (FAS). The diagnosis of FAS typically is based on the observance of a triad of abnormalities in the newborn, including:

• A cluster of craniofacial abnormalities

• CNS dysfunction

• Pre- and/or postnatal stunting of growth

Hearing, language, and speech disorders also may become evident as the child ages. Children who do not meet all the criteria for a diagnosis of FAS still may show physical and mental deficits consistent with a partial phenotype, termed fetal alcohol effects (FAEs) or alcohol-related neurodevelopmental disorders. FAS is seen in offspring born to ~5% of heavy-drinking females. The incidence of FAS is believed to be in the range of 0.5-1 per 1000 live births in the general U.S. population, with rates as high as 2-3 per 1000 in African American and Native American populations.

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. Maternal drinking in the first trimester has been associated with craniofacial abnormalities. 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, with afflicted children consistently scoring lower than their peers on a variety of IQ tests. Although the evidence is not conclusive, there is a suggestion that even moderate alcohol consumption (2 drinks per day) in the second trimester of pregnancy is correlated with impaired academic performance of offspring at age 6. 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. 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.


Currently, 3 drugs are approved in the U.S. for treatment of alcoholism: disulfiram (ANTABUSE), naltrexone (REVIA), and acamprosate (Table 23–2). Disulfiram has a long history of use but has fallen into disfavor because of its side effects and problems with patient adherence to therapy. Naltrexone and acamprosate were introduced more recently. The goal of these medications is to assist the patient in maintaining abstinence.

Table 23–2

Oral Medications for Treating Alcohol Abuse



Naltrexone, a N-opioid receptor antagonist, is chemically related to the highly selective opioid-receptor antagonist naloxone (NARCAN) but has higher oral bioavailability and a longer duration of action. These drugs were used initially in the treatment of opioid overdose and dependence because of their ability to antagonize all the actions of opioids (see Chapters 18 and 24). There is evidence that naltrexone blocks activation by alcohol of dopaminergic pathways in the brain that are thought to be critical to reward.

Naltrexone helps to maintain abstinence by reducing the urge to drink and increasing control when a “slip” occurs. It is not a “cure” for alcoholism and does not prevent relapse in all patients. Naltrexone works best when used in conjunction with some form of psychosocial therapy, such as cognitive behavioral therapy. 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 has a number of advantages over naltrexone, including greater oral bioavailability, longer duration of action, and lack of dose-dependent liver toxicity.


(N-acetylhomotaurine; CAMPRAL) is an analogue of GABA.


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. Acamprosate generally is well tolerated by patients, with diarrhea being the main side effect. The drug undergoes minimal metabolism in the liver, is excreted primarily by the kidneys, and has an elimination t1/2 of 18 h after oral administration. Concomitant use of disulfiram appears to increase the effectiveness of acamprosate, without any adverse drug interactions being noted.


Disulfiram (tetraethylthiuram disulfide; ANTABUSE), 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.


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.

The ingestion of alcohol by individuals previously treated with disulfiram gives rise to marked signs and symptoms of acetaldehyde poisoning. Within 5-10 min, 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; 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 learn to avoid disguised forms of alcohol, as in sauces, fermented vinegar, cough syrups, and even aftershave lotions and back rub lotions.

Disulfiram never should be administered until the patient has abstained from alcohol for at least 12 h. 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.

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 acne-form 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.


Ondansetron, a 5HT3-receptor antagonist and antiemetic drug (see 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 s10 drinks per day. It also decreases the subjective effects of ethanol on 6 of 10 scales measured, including the desire to drink, while at the same time not having any effect on the pharmacokinetics of ethanol.

Topiramate, a drug used for treating seizure disorders (see 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. 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.