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Chapter: Basic & Clinical Pharmacology : The Alcohols

Consequences of Chronic Alcohol Consumption

Chronic alcohol consumption profoundly affects the function of several vital organs—particularly the liver—and the nervous, gastro-intestinal, cardiovascular, and immune systems.

Consequences of Chronic Alcohol Consumption

Chronic alcohol consumption profoundly affects the function of several vital organs—particularly the liver—and the nervous, gastro-intestinal, cardiovascular, and immune systems. Since ethanol has low potency, it requires concentrations thousands of times higher than other misused drugs (eg, cocaine, opiates, amphetamines) to produce its intoxicating effects. As a result, ethanol is consumed in quantities that are unusually large for a pharmacologically active  drug. The tissue damage caused by chronic alcohol ingestion results from a combination of the direct effects of ethanol and acetaldehyde, and the metabolic consequences of processing a heavy load of a meta-bolically active substance. Specific mechanisms implicated in tissue damage include increased oxidative stress coupled with depletion of glutathione, damage to mitochondria, growth factor dysregulation, and potentiation of cytokine-induced injury.

Chronic consumption of large amounts of alcohol is associated with an increased risk of death. Deaths linked to alcohol con-sumption are caused by liver disease, cancer, accidents, and suicide.

A. Liver and Gastrointestinal Tract

Liver disease is the most common medical complication of alco-hol abuse; an estimated 15–30% of chronic heavy drinkers even-tually develop severe liver disease. Alcoholic fatty liver, a reversible condition, may progress to alcoholic hepatitis and finally to cir-rhosis and liver failure. In the United States, chronic alcohol abuse is the leading cause of liver cirrhosis and of the need for liver transplantation. The risk of developing liver disease is related both to the average amount of daily consumption and to the duration

of alcohol abuse. Women appear to be more susceptible to alcohol hepatotoxicity than men. Concurrent infection ith hepatitis B or C virus increases the risk of severe liver disease.

The pathogenesis of alcoholic liver disease is a multifactorial process involving metabolic repercussions of ethanol oxidation in the liver, dysregulation of fatty acid oxidation and synthesis, and activation of the innate immune system by a combination of direct effects of ethanol and its metabolites and by bacterial endo-toxins that access the liver as a result of ethanol-induced changes in the intestinal tract. Tumor necrosis factor-α, a proinflammatory cytokine that is consistently elevated in animal models of alcoholic liver disease and in patients with alcoholic liver disease, appears to play a pivotal role in the progression of alcoholic liver disease and may be a fruitful therapeutic target.

Other portions of the gastrointestinal tract can also be injured. Chronic alcohol ingestion is by far the most common cause of chronic pancreatitis in the Western world. In addition to its direct toxic effect on pancreatic acinar cells, alcohol alters pancreatic epithelial permeability and promotes the formation of protein plugs and calcium carbonate-containing stones.

Individuals with chronic alcoholism are prone to gastritis and have increased susceptibility to blood and plasma protein loss during drinking, which may contribute to anemia and protein malnutri-tion. Alcohol also injures the small intestine, leading to diarrhea, weight loss, and multiple vitamin deficiencies.

Malnutrition from dietary deficiency and vitamin deficiencies due to malabsorption are common in alcoholism. Malabsorption of water-soluble vitamins is especially severe.

B. Nervous System

1. Tolerance and dependence—The consumption of alcoholin high doses over a long period results in tolerance and in physical and psychological dependence. Tolerance to the intoxicating effects of alcohol is a complex process involving poorly understood changes in the nervous system as well as the metabolic changes described earlier. As with other sedative-hypnotic drugs, there is a limit to tolerance, so that only a relatively small increase in the lethal dose occurs with increasing alcohol use. 

Chronic alcohol drinkers, when forced to reduce or discon-tinue alcohol, experience a withdrawal syndrome, which indicates the existence of physical dependence. Alcohol withdrawal symptoms classically consist of hyperexcitability in mild cases and seizures, toxic psychosis, and delirium tremens in severe ones. The dose, rate, and duration of alcohol consumption determine the intensity of the withdrawal syndrome. When consumption has been very high, merely reducing the rate of consumption may lead to signs of withdrawal.

Psychological dependence on alcohol is characterized by a com-pulsive desire to experience the rewarding effects of alcohol and, for current drinkers, a desire to avoid the negative consequences of withdrawal. People who have recovered from alcoholism and become abstinent still experience periods of intense craving for alcohol that can be triggered by environmental cues associated in the past with drinking, such as familiar places, groups of people, or events.

The molecular basis of alcohol tolerance and dependence is not known with certainty, nor is it known whether the two phenom-ena reflect opposing effects on a shared molecular pathway. Tolerance may result from ethanol-induced up-regulation of a pathway in response to the continuous presence of ethanol. Dependence may result from overactivity of that same pathway after the ethanol effect dissipates and before the system has time to return to a normal ethanol-free state.

Chronic exposure of animals or cultured cells to alcohol elicits a multitude of adaptive responses involving neurotransmitters and their receptors, ion channels, and enzymes that participate in signal transduction pathways. Up-regulation of the NMDA subtype of glutamate receptors and voltage-sensitive Ca2+ channels may underlie the seizures that accompany the alcohol withdrawal syn-drome. Based on the ability of sedative-hypnotic drugs that enhance GABAergic neurotransmission to substitute for alcohol during alcohol withdrawal and evidence of down-regulation of GABAA-mediated responses with chronic alcohol exposure, changes in GABA neurotransmission are believed to play a central role in tolerance and withdrawal.

Like other drugs of abuse, ethanol modulates neural activity in the brain’s mesolimbic dopamine reward circuit and increasesdopamine release in the nucleus accumbens . Alcohol affects local concentrations of serotonin, opioids, and dopamine—neurotransmitters involved in the brain reward system— and has complex effects on the expression of receptors for these neurotransmitters and their signaling pathways. The discovery that naltrexone, a nonselective opioid receptor antagonist, helps patients who are recovering from alcoholism abstain from drink-ing supports the idea that a common neurochemical reward system is shared by very different drugs associated with physical and psy-chological dependence. There is also convincing evidence from animal models that ethanol intake and seeking behavior are reduced by antagonists of another important regulator of the brain reward system, the cannabinoid CB1 receptor, which is the molecular target of active ingredients in marijuana. Two other important neuroendocrine systems that appear to play key roles in modulating ethanol-seeking activity in experimental animals are the appetite-regulating system—which uses peptides such as leptin, ghrelin, and neuropeptide Y—and the stress response system, which is controlled by corticotropin-releasing factor.

2. Neurotoxicity—Consumption of large amounts of alcoholover extended periods (usually years) often leads to neurologic deficits. The most common neurologic abnormality in chronic alcoholism is generalized symmetric peripheral nerve injury, which begins with distal paresthesias of the hands and feet. Degenerative changes can also result in gait disturbances and ataxia. Other neu-rologic disturbances associated with alcoholism include dementia and, rarely, demyelinating disease.


Wernicke-Korsakoff syndrome is a relatively uncommon butimportant entity characterized by paralysis of the external eye muscles, ataxia, and a confused state that can progress to coma and death. It is associated with thiamine deficiency but is rarely seen in the absence of alcoholism. Because of the importance of thiamine in this pathologic condition and the absence of toxicity associated with thiamine administration, all patients suspected of having Wernicke-Korsakoff syndrome (including virtually all patients who present to the emergency department with altered consciousness, seizures, or both) should receive thiamine therapy. Often, the ocular signs, ataxia, and confusion improve promptly upon administra-tion of thiamine. However, most patients are left with a chronic disabling memory disorder known as Korsakoff ’s psychosis.

Alcohol may also impair visual acuity, with painless blurring that occurs over several weeks of heavy alcohol consumption. Changes are usually bilateral and symmetric and may be followed by optic nerve degeneration. Ingestion of ethanol substitutes such as methanol (see Pharmacology of Other Alcohols) causes severe visual disturbances.

C. Cardiovascular System

·        Cardiomyopathy and heart failure—Alcohol has complexeffects on the cardiovascular system. Heavy alcohol consumption of long duration is associated with a dilated cardiomyopathy with ventricular hypertrophy and fibrosis. In animals and humans, alcohol induces a number of changes in heart cells that may con-tribute to cardiomyopathy. They include membrane disruption, depressed function of mitochondria and sarcoplasmic reticulum,intracellular accumulation of phospholipids and fatty acids, and up-regulation of voltage-gated calcium channels. There is evidence that patients with alcohol-induced dilated cardiomyopathy do significantly worse than patients with idiopathic dilated cardio-myopathy, even though cessation of drinking is associated with a reduction in cardiac size and improved function. The poorer prog-nosis for patients who continue to drink appears to be due in part to interference by ethanol with the beneficial effects of β blockers and angiotensin-converting enzyme (ACE) inhibitors.

·        Arrhythmias—Heavy drinking—and especially “binge”drinking—are associated with both atrial and ventricular arrhyth-mias. Patients undergoing alcohol withdrawal syndrome can develop severe arrhythmias that may reflect abnormalities of potassium or magnesium metabolism as well as enhanced release of catecholamines. Seizures, syncope, and sudden death during alcohol withdrawal may be due to these arrhythmias.


·        Hypertension—A link between heavier alcohol consump-tion (more than three drinks per day) and hypertension has been firmly established in epidemiologic studies. Alcohol is estimated to be responsible for approximately 5% of cases of hypertension, making it one of the most common causes of reversible hyperten-sion. This association is independent of obesity, salt intake, coffee drinking, and cigarette smoking. A reduction in alcohol intake appears to be effective in lowering blood pressure in hypertensives who are also heavy drinkers; the hypertension seen in this popula-tion is also responsive to standard blood pressure medications.


·        Coronary heart disease— Although the deleterious effectsof excessive alcohol use on the cardiovascular system are well estab-lished, there is strong epidemiologic evidence that moderate alcohol consumption actually prevents coronary heart disease (CHD), ischemic stroke, and peripheral arterial disease. This type of rela-tionship between mortality and the dose of a drug is called a “J-shaped” relationship. Results of these clinical studies are sup-ported by ethanol’s ability to raise serum levels of high-density lipoprotein (HDL) cholesterol (the form of cholesterol that appears to protect against atherosclerosis;), by its ability to inhibit some of the inflammatory processes that underlie athero-sclerosis while also increasing production of the endogenous anti-coagulant tissue plasminogen activator (t-PA,), and by the presence in alcoholic beverages (especially red wine) of anti-oxidants and other substances that may protect against atheroscle-rosis. These observational studies are intriguing, but randomized clinical trials examining the possible benefit of moderate alcohol consumption in prevention of CHD have not been carried out.

D. Blood

Alcohol indirectly affects hematopoiesis through metabolic and nutritional effects and may also directly inhibit the proliferation of all cellular elements in bone marrow. The most common hemato-logic disorder seen in chronic drinkers is mild anemia resulting from alcohol-related folic acid deficiency. Iron deficiency anemia may result from gastrointestinal bleeding. Alcohol has also beenimplicated as a cause of several hemolytic syndromes, some of which are associated with hyperlipidemia and severe liver disease.

E. Endocrine System and Electrolyte Balance

Chronic alcohol use has important effects on the endocrine system and on fluid and electrolyte balance. Clinical reports of gyneco-mastia and testicular atrophy in alcoholics with or without cirrhosis suggest a derangement in steroid hormone balance.

Individuals with chronic liver disease may have disorders of fluid and electrolyte balance, including ascites, edema, and effusions. Alterations of whole body potassium induced by vomiting and diar-rhea, as well as severe secondary aldosteronism, may contribute to muscle weakness and can be worsened by diuretic therapy. The metabolic derangements caused by metabolism of large amounts of ethanol can result in hypoglycemia, as a result of impaired hepatic gluconeogenesis, and in ketosis, caused by excessive lipolytic factors, especially increased cortisol and growth hormone.

F. Fetal Alcohol Syndrome

Chronic maternal alcohol abuse during pregnancy is associated with teratogenic effects, and alcohol is a leading cause of mental retardation and congenital malformation. The abnormalities that have been characterized as fetal alcohol syndrome include (1) intrauterine growth retardation, (2) microcephaly, (3) poor coor-dination, (4) underdevelopment of midfacial region (appearing as a flattened face), and (5) minor joint anomalies. More severe cases may include congenital heart defects and mental retardation. Although the level of alcohol intake required to cause serious neu-rologic deficits appears quite high, the threshold for more subtle neurologic deficits is uncertain.

The mechanisms that underlie ethanol’s teratogenic effects are unknown. Ethanol rapidly crosses the placenta and reaches concentra-tions in the fetus that are similar to those in maternal blood. The fetal liver has little or no alcohol dehydrogenase activity, so the fetus must rely on maternal and placental enzymes for elimination of alcohol

The neuropathologic abnormalities seen in humans and in ani-mal models of fetal alcohol syndrome indicate that ethanol triggers apoptotic neurodegeneration and also causes aberrant neuronal and glial migration in the developing nervous system. In tissue culture systems, ethanol causes a striking reduction in neurite outgrowth.

G. Immune System

The effects of alcohol on the immune system are complex; immune function in some tissues is inhibited (eg, the lung), whereas pathologic, hyperactive immune function in other tissues is triggered (eg, liver, pancreas). In addition, acute and chronic exposure to alcohol have widely different effects on immune func-tion. The types of immunologic changes reported for the lung include suppression of the function of alveolar macrophages, inhi-bition of chemotaxis of granulocytes, and reduced number and function of T cells. In the liver, there is enhanced function of key cells of the innate immune system (eg, Kupffer cells, hepatic stellate cells) and increased cytokine production. In addition to the inflammatory damage that chronic heavy alcohol use precipitates in the liver and pancreas, it predisposes to infections, especially of the lung, and worsens the morbidity and increases the mortality risk of patients with pneumonia.

H. Increased Risk of Cancer

Chronic alcohol use increases the risk for cancer of the mouth, pharynx, larynx, esophagus, and liver. Evidence also points to a small increase in the risk of breast cancer in women. Much more information is required before a threshold level for alcohol con-sumption as it relates to cancer can be established. Alcohol itself does not appear to be a carcinogen in most test systems. However, its primary metabolite, acetaldehyde, can damage DNA, as can the reactive oxygen species produced by increased cytochrome P450 activity. Other factors implicated in the link between alcohol and cancer include changes in folate metabolism and the growth-promoting effects of chronic inflammation.

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