Postgraduate Medicine
ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: http://www.tandfonline.com/loi/ipgm20
The pharmacology of alcohol Sidney Cohen To cite this article: Sidney Cohen (1978) The pharmacology of alcohol, Postgraduate Medicine, 64:6, 97-102, DOI: 10.1080/00325481.1978.11715002 To link to this article: http://dx.doi.org/10.1080/00325481.1978.11715002
Published online: 07 Jul 2016.
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Date: 04 August 2017, At: 20:09
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Third of seven symposium articles in this issue
The pharmacology of alcohol Consider What factors determine the blood alcohol concentration produced by a given dose of alcohol? How does continuous drinking affect alcohol tolerance? What are the main effects of alcohol on the CNS?
Sidney Cohen, MD
The sustained, immoderate drinking of spirits in any form can lead to a series of biochemical and physiologic deviations which can, in turn, result in a variety of disorders of the CNS, liver, gastrointestinal tract, endocrine system, and skin. This article, highlighting major aspects of the metabolism and excretion of alcohol, 1-6 complements Dr Becker's article,* which deals more fully with alcohol-related disease. Absorption, excretion, and metabolism Alcohol is readily absorbed from the empty gastrointestinal tract, particularly from the small intestine, and evenly distributed throughout the body according to the water content of the tissues. Distribution includes absorption across the placenta and into the fetal circulation. More than 90% of ingested ethanol is broken down (oxidized), and the remainder is excreted unchanged through the lungs, kidneys, and skin. The metabolic breakdown, largely confined to the liver, is rate limited and specific for each person; about 10 to 15 ml of ethanol (about one drink) is oxidized each hour. The metabolism of ethanol requires nicotinamide adenine dinucleotide (NAD) as a cofactor and alcohol dehydrogenase (ADH), a zinccontaining enzyme, to produce acetaldehyde, as shown by the formula: CH3 CH2 0H+NAD A_Q.H CH3 CHO+H+NADH The acetaldehyde is then converted by an aldehyde dehydrogenase in the presence of N AD to acetyl coenzyme A, which enters the Krebs cycle, where it can be converted to fatty acids and cholesterol and eventually to carbon dioxide and water. Other enzyme systems, particularly the microsomal ethanolcontinued *See page 88.
VOL 64/NO 6/DECEMBER 1978/POSTGRADUATE MEDICINE
97
Downloaded by [Australian Catholic University] at 20:09 04 August 2017
More than 90% of ingested alcohol is metabolized, and th~e remaining 1 0% is excreted u11changed through the lungs, kidneys, and skin. Oxidation talc.es place at the rate of about ontt drink per hour.
trations of blood alcohol than can occasional drinkers. Also, a rising concentration of blood alcohol produces more impairment at any given level than does a falling concentration.
Illustration: Alan E. Cober
oxidizing system and catalase, are lesser pathways of ethanol metabolism in the liver.
Blood alcohol concentration Many factors determine blood alcohol concentration. A given dose of alcohol produces higher blood levels if the beverage is drunk rapidly, the percentage of alcohol is high, there is no food in the stomach, body weight is low, and the person is not tolerant to ethanol. A concentration as high as 0.05% (also called 50 mg% or 50 mg of alcohol/ 100 m1 of blood) is not assumed to indicate a state of severe intoxication but does result in some impaired motor performance. Such a level is achieved when a 150-lb person consumes two average-sized drinks. Concentrations of 0.05% to 0.08% produce slight to moder.:tte psychomotor impairment, while the common legal level of intoxication, 0.1 %, is reached after about four to six drinks. Concentrations of 0.4% to 0.5% can be fatal. Because of tolerance and learned behavior, chronic drinkers can function with higher concen-
98
Tolerance and cross-tolerance Tolerance-Daily intake of more than one or two mixed drinks or the equivalent in wine or beer leads to the development of increasing tolerance to a fixed amount or to the ability to tolerate higher and higher amounts. This physiologic tolerance is never as complete as that seen with opiates, and it is lost after two or more weeks of abstinence. Because physiologic tolerance to potentially lethal doses of alcohol increases at a slower rate than does tolerance to the psychologic effects, death from respiratory arrest could take place in a psychologically tolerant person after a moderate increase above the usual level of consumption. A sort of "reverse tolerance" can occur in some drinkers who find that they are unable to drink as much as previously, eg, where a single drink might intoxicate and unleash aggressive activities. This sometimes follows a head injury in which the ability to compensate for the intoxicated state is lost and behavioral controls are extinguished, but it can also be seen in end-stage liver disease when the organ is unable to detoxify even small amounts of ethanol. Cross-tolerance-Cross-tolerance occurs between alcohol and almost all other CNS depressants, a phenomenon which helps to account for the heavy drinker's resistance to the effects of other drugs during detoxification. However, exactly the opposite effect can be observed when an actively drinking person consumes another CNS depressant, eg, a barbiturate. Even though a certain degree of enzyme induction may have occurred, the joint offering of large amounts of ethanol and barbiturates may overwhelm the metabolizing capability of the organism, with the result that the two drugs continue to recirculate and exert their depressant activity. In this manner,
VOL 84/NO &/DECEMBER 1978/POSTGRADUATE MEDICINE
Downloaded by [Australian Catholic University] at 20:09 04 August 2017
Because of tolerance and learned behavior, chronic drinkers can function with higher concen· trations of blood alcohol than can occasional drinkers.
normally sublethal amounts of alcohol and of a hypnotic can induce an unexpected degree of intoxication or even death. Withdrawal-Chronic exposure to high doses of alcohol results in a state of physical dependence, with a resulting abstinence or withdrawal syndrome when ethanol ingestion is stopped abruptly. This topic is discussed by Drs Robertson and Sellers.* Pharmacologic effects of alcohol on body systems Sustained, immoderate consumption of alcohol can cause biochemical and physiologic deviations which may result in a variety of disorders (table 1). The following discussion emphasizes the metabolic alterations which occur with acute and chronic alcohol ingestion. The information presented complements Dr Becker's articlet on medical consequences, and the two should be read together. Central nervous system-Like other anesthetics, alcohol produces an initial period of CNS stimulation, which is ordinarily seen at blood levels of less than 0.1%. The excitatory effects on mood and behavior are probably due to depression of inhibitory pathways of the brain. These tracts are the first to be affected, and a release of cortical activity is evoked. The disinhibition is manifested by garrulousness, expansiveness, emotional }ability, and a loosening of behavioral controls. As drinking continues, the various stages of anesthesia emerge. Performance is invariably impaired except when preexisting anxiety has already caused a reduction in thinking ability or in performance skills. Under such conditions a small to moderate amount of alcohol might improve functioning by its anxietyreducing property. However, large amounts have been shown to increase, rather than decrease, anxiety levels. *See page 133. tSee page 88.
VOL 64/NO 6/DECEMBER 1978/POSTGRADUATE MEDICINE
Table 1. Alcohol-related disorders and their causes Disorder
Cause
Hypoglycemia
Inhibition of gluconeogenesis, depletion of glycogen stores, low-carbohydrate diet
Hyperlipidemia
Increased lipoprotein production, increased lipoprotein clear ance. mobilization of nonhepatic fat stores
Hyperuricemia
Decreased renal clearance of uric acid
Esophagitis
Direct toxic effect, vomiting
Gastritis
Increased secretin and histamine production, direct toxic effect
Duodenal ulceration
Increased secretin and histamine production
Steatorrhea and malabsorption
Pancreatic insufficiency, thiamine deficiency, hyperperistalsis
Fatty liver
Triglyceride accumulation in hepatocytes
Alcoholic hepatitis
Inflammation and necrosis in hepatocytes
Cirrhosis
Scarification of liver parenchyma
Pancreatitis
Increased secretin production, malnutrition
Various anemias
Direct toxic effect, malabsorption, malnutrition, decreased transferrin synthesis
Beriberi heart disease
Thiamine deficiency
Cardiomyopathy
Direct toxic effect, malnutrition
Skeletal myopathies
Direct toxic effect
Other effects of alcohol on the CNS should be briefly mentioned: 1. Alcohol lowers the convulsive threshold during the withdrawal period. 2. Sleep patterns are disrupted. Severe decreases in periods of rapid eye movement (REM) and increases in periods of stage IV sleep have continued 99
Downloaded by [Australian Catholic University] at 20:09 04 August 2017
Alcohol's effects on the CNS include initial stimul11tion followed by various stages of a1nesthesia. Performance is invariiably impaired except when anxiety prior to drinking has a. I ready caused impairment.
been recorded during intoxi~.tion. During withdrawal a REM rebound occurs thatcanaccountfor nightmarish dreams and disrupted sleep. 3. Sexual aggressiveness may be increased, but sexual performance is impaired. 4. Alcohol intoxication releases all types of violent behavior. 5. A common form of alcohol-related memory impairment occurs at high blood alcohol levelsan alcoholic amnesia (blackout). liver-The central role of the liver in the metabolism of alcohol has been established, and liver insufficiency results in impaired alcohol breakdown. The oxidation of alcohol to acetaldehyde and hydrogen ions by hepatic alcohol dehydrogenase contributes to many of the untoward effects of heavy alcohol intake, including a direct toxic effect of acetaldehyde on the liver, inhibiting protein synthesis. Other effects are discuss•:!d in the following paragraphs. Pyruvate ordinarily forms glucose via the Krebs Sidney Cohen Dr Cohen is at the University of Califonia School of Medicine, Los Angeles, where he is clinical profess•>r of psychiatry, Neuropsychiatric Institute. He is editor of the Drug Abuse and Alcoholism Ne ~·sletter and was formerly director of the division of narcotic addict: on and drug abuse, Natiom.l Institute of Mental Health, Bethesda.
100
cycle, but in the presence of hydrogen ions, pyruvate is converted to lactate. This conversion, along with the low-carbohydrate diet of chronic drinkers and the depletion of liver glycogen stores, can result in hypoglycemic episodes. The lactic acidosis from excessive lactate formation impairs the kidney's ability to excrete uric acid. This leads to hyperuricemia and, in predisposed persons, to attacks of gout. The excess of hydrogen ions in the liver is handled by converting fatty acids to triglycerides, thereby contributing lipid for fat deposition in the liver. In addition, ethanol mobilizes fat from nonhepatic stores. The liver is unable to deal with the additional load, and some spills over into the plasma. The resulting hyperlipidemia can contribute to the development of arteriosclerotic disorders. Substantial amounts of alcohol induce the liver to increase the production of microsomal enzymes; the resulting level of metabolizing enzymes interferes with the therapeutic action of many classes of drugs. This interaction is biphasic, with acute alcohol intoxication causing certain drugs to have an increased effect because of competition for the insufficient amount of available enzymes. Chronic intoxication, on the other hand, results in a decreased therapeutic effect of such drugs as meprobamate, certain anticoagulants, phenothiazines, phenytoin, and the tricyclic antidepressants. With high doses of alcohol, liver cells become unable to deal with the bilirubin load, the manufacture of plasma proteins is impaired, and prothrombin and fibrinogen formation is diminished. This results in jaundice, hypoalbuminemia, and bleeding tendencies. Iron-deficiency anemia is, in part, caused by reduced synthesis of transferrin, the iron-binding protein. Decreased complement manufacture impairs the immune response and reduces resistance to infections. Production of testosterone may be reduced and its destruction accelerated, inducing gynecomastia, continued VOL 64/NO 6/0ECEMBER 1978/POSTGRAOUATE MEDICINE
Downloaded by [Australian Catholic University] at 20:09 04 August 2017
The liver plays a central role in the metabolism of alcohol. Oxidation of alcohol to acetaldehyde, which has a direct toxic effe«:t on the liver, contributes to many o1f the untoward effects of heavy alcoh1e»l intake.
loss of chest hair, "liver" palms, and spider angiomas. If liver insults from alcohol
ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: http://www.tandfonline.com/loi/ipgm20
The pharmacology of alcohol Sidney Cohen To cite this article: Sidney Cohen (1978) The pharmacology of alcohol, Postgraduate Medicine, 64:6, 97-102, DOI: 10.1080/00325481.1978.11715002 To link to this article: http://dx.doi.org/10.1080/00325481.1978.11715002
Published online: 07 Jul 2016.
Submit your article to this journal
Article views: 2
View related articles
Citing articles: 2 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ipgm20 Download by: [Australian Catholic University]
Date: 04 August 2017, At: 20:09
Downloaded by [Australian Catholic University] at 20:09 04 August 2017
Third of seven symposium articles in this issue
The pharmacology of alcohol Consider What factors determine the blood alcohol concentration produced by a given dose of alcohol? How does continuous drinking affect alcohol tolerance? What are the main effects of alcohol on the CNS?
Sidney Cohen, MD
The sustained, immoderate drinking of spirits in any form can lead to a series of biochemical and physiologic deviations which can, in turn, result in a variety of disorders of the CNS, liver, gastrointestinal tract, endocrine system, and skin. This article, highlighting major aspects of the metabolism and excretion of alcohol, 1-6 complements Dr Becker's article,* which deals more fully with alcohol-related disease. Absorption, excretion, and metabolism Alcohol is readily absorbed from the empty gastrointestinal tract, particularly from the small intestine, and evenly distributed throughout the body according to the water content of the tissues. Distribution includes absorption across the placenta and into the fetal circulation. More than 90% of ingested ethanol is broken down (oxidized), and the remainder is excreted unchanged through the lungs, kidneys, and skin. The metabolic breakdown, largely confined to the liver, is rate limited and specific for each person; about 10 to 15 ml of ethanol (about one drink) is oxidized each hour. The metabolism of ethanol requires nicotinamide adenine dinucleotide (NAD) as a cofactor and alcohol dehydrogenase (ADH), a zinccontaining enzyme, to produce acetaldehyde, as shown by the formula: CH3 CH2 0H+NAD A_Q.H CH3 CHO+H+NADH The acetaldehyde is then converted by an aldehyde dehydrogenase in the presence of N AD to acetyl coenzyme A, which enters the Krebs cycle, where it can be converted to fatty acids and cholesterol and eventually to carbon dioxide and water. Other enzyme systems, particularly the microsomal ethanolcontinued *See page 88.
VOL 64/NO 6/DECEMBER 1978/POSTGRADUATE MEDICINE
97
Downloaded by [Australian Catholic University] at 20:09 04 August 2017
More than 90% of ingested alcohol is metabolized, and th~e remaining 1 0% is excreted u11changed through the lungs, kidneys, and skin. Oxidation talc.es place at the rate of about ontt drink per hour.
trations of blood alcohol than can occasional drinkers. Also, a rising concentration of blood alcohol produces more impairment at any given level than does a falling concentration.
Illustration: Alan E. Cober
oxidizing system and catalase, are lesser pathways of ethanol metabolism in the liver.
Blood alcohol concentration Many factors determine blood alcohol concentration. A given dose of alcohol produces higher blood levels if the beverage is drunk rapidly, the percentage of alcohol is high, there is no food in the stomach, body weight is low, and the person is not tolerant to ethanol. A concentration as high as 0.05% (also called 50 mg% or 50 mg of alcohol/ 100 m1 of blood) is not assumed to indicate a state of severe intoxication but does result in some impaired motor performance. Such a level is achieved when a 150-lb person consumes two average-sized drinks. Concentrations of 0.05% to 0.08% produce slight to moder.:tte psychomotor impairment, while the common legal level of intoxication, 0.1 %, is reached after about four to six drinks. Concentrations of 0.4% to 0.5% can be fatal. Because of tolerance and learned behavior, chronic drinkers can function with higher concen-
98
Tolerance and cross-tolerance Tolerance-Daily intake of more than one or two mixed drinks or the equivalent in wine or beer leads to the development of increasing tolerance to a fixed amount or to the ability to tolerate higher and higher amounts. This physiologic tolerance is never as complete as that seen with opiates, and it is lost after two or more weeks of abstinence. Because physiologic tolerance to potentially lethal doses of alcohol increases at a slower rate than does tolerance to the psychologic effects, death from respiratory arrest could take place in a psychologically tolerant person after a moderate increase above the usual level of consumption. A sort of "reverse tolerance" can occur in some drinkers who find that they are unable to drink as much as previously, eg, where a single drink might intoxicate and unleash aggressive activities. This sometimes follows a head injury in which the ability to compensate for the intoxicated state is lost and behavioral controls are extinguished, but it can also be seen in end-stage liver disease when the organ is unable to detoxify even small amounts of ethanol. Cross-tolerance-Cross-tolerance occurs between alcohol and almost all other CNS depressants, a phenomenon which helps to account for the heavy drinker's resistance to the effects of other drugs during detoxification. However, exactly the opposite effect can be observed when an actively drinking person consumes another CNS depressant, eg, a barbiturate. Even though a certain degree of enzyme induction may have occurred, the joint offering of large amounts of ethanol and barbiturates may overwhelm the metabolizing capability of the organism, with the result that the two drugs continue to recirculate and exert their depressant activity. In this manner,
VOL 84/NO &/DECEMBER 1978/POSTGRADUATE MEDICINE
Downloaded by [Australian Catholic University] at 20:09 04 August 2017
Because of tolerance and learned behavior, chronic drinkers can function with higher concen· trations of blood alcohol than can occasional drinkers.
normally sublethal amounts of alcohol and of a hypnotic can induce an unexpected degree of intoxication or even death. Withdrawal-Chronic exposure to high doses of alcohol results in a state of physical dependence, with a resulting abstinence or withdrawal syndrome when ethanol ingestion is stopped abruptly. This topic is discussed by Drs Robertson and Sellers.* Pharmacologic effects of alcohol on body systems Sustained, immoderate consumption of alcohol can cause biochemical and physiologic deviations which may result in a variety of disorders (table 1). The following discussion emphasizes the metabolic alterations which occur with acute and chronic alcohol ingestion. The information presented complements Dr Becker's articlet on medical consequences, and the two should be read together. Central nervous system-Like other anesthetics, alcohol produces an initial period of CNS stimulation, which is ordinarily seen at blood levels of less than 0.1%. The excitatory effects on mood and behavior are probably due to depression of inhibitory pathways of the brain. These tracts are the first to be affected, and a release of cortical activity is evoked. The disinhibition is manifested by garrulousness, expansiveness, emotional }ability, and a loosening of behavioral controls. As drinking continues, the various stages of anesthesia emerge. Performance is invariably impaired except when preexisting anxiety has already caused a reduction in thinking ability or in performance skills. Under such conditions a small to moderate amount of alcohol might improve functioning by its anxietyreducing property. However, large amounts have been shown to increase, rather than decrease, anxiety levels. *See page 133. tSee page 88.
VOL 64/NO 6/DECEMBER 1978/POSTGRADUATE MEDICINE
Table 1. Alcohol-related disorders and their causes Disorder
Cause
Hypoglycemia
Inhibition of gluconeogenesis, depletion of glycogen stores, low-carbohydrate diet
Hyperlipidemia
Increased lipoprotein production, increased lipoprotein clear ance. mobilization of nonhepatic fat stores
Hyperuricemia
Decreased renal clearance of uric acid
Esophagitis
Direct toxic effect, vomiting
Gastritis
Increased secretin and histamine production, direct toxic effect
Duodenal ulceration
Increased secretin and histamine production
Steatorrhea and malabsorption
Pancreatic insufficiency, thiamine deficiency, hyperperistalsis
Fatty liver
Triglyceride accumulation in hepatocytes
Alcoholic hepatitis
Inflammation and necrosis in hepatocytes
Cirrhosis
Scarification of liver parenchyma
Pancreatitis
Increased secretin production, malnutrition
Various anemias
Direct toxic effect, malabsorption, malnutrition, decreased transferrin synthesis
Beriberi heart disease
Thiamine deficiency
Cardiomyopathy
Direct toxic effect, malnutrition
Skeletal myopathies
Direct toxic effect
Other effects of alcohol on the CNS should be briefly mentioned: 1. Alcohol lowers the convulsive threshold during the withdrawal period. 2. Sleep patterns are disrupted. Severe decreases in periods of rapid eye movement (REM) and increases in periods of stage IV sleep have continued 99
Downloaded by [Australian Catholic University] at 20:09 04 August 2017
Alcohol's effects on the CNS include initial stimul11tion followed by various stages of a1nesthesia. Performance is invariiably impaired except when anxiety prior to drinking has a. I ready caused impairment.
been recorded during intoxi~.tion. During withdrawal a REM rebound occurs thatcanaccountfor nightmarish dreams and disrupted sleep. 3. Sexual aggressiveness may be increased, but sexual performance is impaired. 4. Alcohol intoxication releases all types of violent behavior. 5. A common form of alcohol-related memory impairment occurs at high blood alcohol levelsan alcoholic amnesia (blackout). liver-The central role of the liver in the metabolism of alcohol has been established, and liver insufficiency results in impaired alcohol breakdown. The oxidation of alcohol to acetaldehyde and hydrogen ions by hepatic alcohol dehydrogenase contributes to many of the untoward effects of heavy alcohol intake, including a direct toxic effect of acetaldehyde on the liver, inhibiting protein synthesis. Other effects are discuss•:!d in the following paragraphs. Pyruvate ordinarily forms glucose via the Krebs Sidney Cohen Dr Cohen is at the University of Califonia School of Medicine, Los Angeles, where he is clinical profess•>r of psychiatry, Neuropsychiatric Institute. He is editor of the Drug Abuse and Alcoholism Ne ~·sletter and was formerly director of the division of narcotic addict: on and drug abuse, Natiom.l Institute of Mental Health, Bethesda.
100
cycle, but in the presence of hydrogen ions, pyruvate is converted to lactate. This conversion, along with the low-carbohydrate diet of chronic drinkers and the depletion of liver glycogen stores, can result in hypoglycemic episodes. The lactic acidosis from excessive lactate formation impairs the kidney's ability to excrete uric acid. This leads to hyperuricemia and, in predisposed persons, to attacks of gout. The excess of hydrogen ions in the liver is handled by converting fatty acids to triglycerides, thereby contributing lipid for fat deposition in the liver. In addition, ethanol mobilizes fat from nonhepatic stores. The liver is unable to deal with the additional load, and some spills over into the plasma. The resulting hyperlipidemia can contribute to the development of arteriosclerotic disorders. Substantial amounts of alcohol induce the liver to increase the production of microsomal enzymes; the resulting level of metabolizing enzymes interferes with the therapeutic action of many classes of drugs. This interaction is biphasic, with acute alcohol intoxication causing certain drugs to have an increased effect because of competition for the insufficient amount of available enzymes. Chronic intoxication, on the other hand, results in a decreased therapeutic effect of such drugs as meprobamate, certain anticoagulants, phenothiazines, phenytoin, and the tricyclic antidepressants. With high doses of alcohol, liver cells become unable to deal with the bilirubin load, the manufacture of plasma proteins is impaired, and prothrombin and fibrinogen formation is diminished. This results in jaundice, hypoalbuminemia, and bleeding tendencies. Iron-deficiency anemia is, in part, caused by reduced synthesis of transferrin, the iron-binding protein. Decreased complement manufacture impairs the immune response and reduces resistance to infections. Production of testosterone may be reduced and its destruction accelerated, inducing gynecomastia, continued VOL 64/NO 6/0ECEMBER 1978/POSTGRAOUATE MEDICINE
Downloaded by [Australian Catholic University] at 20:09 04 August 2017
The liver plays a central role in the metabolism of alcohol. Oxidation of alcohol to acetaldehyde, which has a direct toxic effe«:t on the liver, contributes to many o1f the untoward effects of heavy alcoh1e»l intake.
loss of chest hair, "liver" palms, and spider angiomas. If liver insults from alcohol
