John J. Woodward, BS, MS, PhD
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DEFINITION
Alcohols are a group of related chemical compounds that contain a hydroxyl group (−OH) bound to a carbon atom. The form of alcohol most often consumed by humans is ethyl alcohol or ethanol and consists of two carbons and a single hydroxyl group (written as C2H5OH or C2H6O). Unless otherwise noted, the term alcohol will be used throughout this chapter to mean ethanol.
SUBSTANCES INCLUDED IN THIS CLASS
All commercially available alcoholic beverages contain ethyl alcohol with concentrations depending upon the type of beverage. Beverages made by fermentation of sugar-containing fruits and grains include beer (3% to 8% ethanol by volume) and wines (11% to 13% ethanol by volume). Spirits are produced after distillation and generally contain at least 30% ethanol. Ethanol can be concentrated by simple distillation up to approximately 95%, while pure ethanol requires addition of benzene or related substances or desiccation using glycerol. Denatured alcohol contains additives or toxins to prevent human consumption. Rubbing alcohol is prepared from denatured alcohol or isopropyl alcohol and is used for topical purposes.
FORMULATIONS AND METHODS OF USE
In the United States, a standard alcoholic drink is defined as one that contains 0.6 fluid ounces of alcohol, the amount of alcohol typically contained in 12 oz of beer, 5 oz of wine, or 1.5 oz of distilled spirits (40% ethanol by volume). Although most alcohol is consumed orally, there are isolated cases of individuals injecting ethanol intravenously. Ethanol vapor can also be inhaled, and machines called AWOL (alcohol without liquid; www.awolusa.com) have been introduced into the United States as a novel means of self-administering alcohol. A number of US states have since banned the sale or use of these devices.
CLINICAL USES
In addition to its use as a topical antiseptic, alcohol has several clinical indications including treatment of accidental or voluntary ingestion of methanol or ethylene glycol. Ethanol has a higher affinity for alcohol dehydrogenase than methanol and thus reduces the formation of methanol metabolites formaldehyde and formic acid. For both indications, hemodialysis is the recommended first line of treatment.
BRIEF HISTORICAL FEATURES
Alcohol is one of the oldest used psychoactive substances. Consumption of alcohol containing beverages predate recorded human history while written records of its use are found in Chinese and Middle Eastern texts as far back as 9,000 years ago. In modern times, alcohol is second only to caffeine in incidence of use, and its manufacture, distribution, and sale are of major economic importance across the world.
EPIDEMIOLOGY
The lifetime exposure to alcohol is high with nearly 88% of the US population reporting using alcohol at least once in their lifetime. In 2011, current alcohol use (defined as use in the past 30 days) ranged from 3.9% among 12- to 13-year-olds to nearly 70% of 21- to 25-year-olds. Prevalence decreased among older groups, although it was nearly 50% among 60- to 64-year-olds. Results from clinical studies of alcohol abuse and alcoholism suggest that there are several types of alcohol use disorders, based on the appearance and severity of certain alcohol-related problems. Two particularly well-known classification schemes are the type I and II forms proposed by Cloninger and colleagues and the types A and B forms proposed by Babor. Cloninger’s type I and Babor’s type A share several similarities including:
1. Later onset of alcohol-related problems (>25 years old)
2. Fewer childhood behavior problems
3. Relatively mild alcohol-related issues with fewer hospitalizations
4. Lower degree of novelty seeking coupled with a preference toward harm avoidance
5. Less tendency to run in families
PHARMACOKINETICS
Alcohol is a small, water-soluble molecule that is rapidly and efficiently absorbed into the bloodstream from the stomach, small intestine, and colon. The rate of absorption depends on the gastric emptying time and can be delayed by the presence of food in the small intestine. Alcohol is rapidly distributed throughout the body and gains access to all tissues, including the fetus in pregnant women. As women show less gastric metabolism of alcohol than men, when body weights are equivalent, women show a 20% to 25% higher blood alcohol level than men following ingestion of the same amount of alcohol.
In the liver, alcohol is broken down by alcohol dehydrogenase (ADH) and mixed function oxidases such as P450IIE1 (CYP2E1). Levels of CYP2E1 may be increased in chronic drinkers. ADH converts alcohol to acetaldehyde, which subsequently can be converted to acetate by the actions of acetaldehyde dehydrogenase (ALDH). The rate of alcohol metabolism by ADH is relatively constant, as the enzyme is saturated at low blood alcohol levels and thus exhibits zero-order kinetics (constant amount oxidized per unit of time). Alcohol metabolism is proportional to body weight (and probably liver weight) and averages approximately 1 oz of pure alcohol per 3 hours in adults.
PHARMACODYNAMICS
Central Nervous System
Acutely, alcohol acts as a central nervous system (CNS) depressant. During the initial phase when blood alcohol levels are rising, a period of disinhibition often occurs and signs of behavioral arousal are common. At higher blood levels, alcohol acts as a sedative and hypnotic, although the quality of sleep often is reduced after alcohol intake.
Other Organ Systems
Acute alcohol ingestion produces a feeling of warmth as cutaneous blood flow is increased, and this is accompanied by a reduction in core body temperature. Gastric secretions are usually increased, although the concentration of alcohol ingested affects this response, with high concentrations (>20%) inhibiting secretions. Long-term ingestion of high concentrations of alcohol produces deleterious effects on the gastrointestinal tract (GI) including esophageal varices and bleeding, erosive gastritis, and diarrhea and malabsorption of nutrients and vitamins. Heavy alcohol consumption increases the risk of developing tumors in the GI system as well as in other tissues including lung and breast. Acute and chronic ingestion of alcohol generally decreases sexual performance in both men and women. Alcohol causes changes in contractility and function of cardiovascular system, and chronic alcohol increases fat accumulation in the liver that can progress to severe liver damage and cirrhosis. Low-to-moderate alcohol use is associated with a reduced risk of coronary disease.
DRUG–DRUG INTERACTIONS
Alcohol depressant actions on the CNS are additive with those produced by barbiturates, benzodiazepines, general anesthetics and solvents, and anticonvulsants. Alcohol enhances the sedative effects of antihistamines. Combining these medications with alcohol can result in significant CNS depression and reduced ability to safely carry out normal functions such as automobile driving. Alcohol enhances the hepatotoxic effects of acetaminophen (Tylenol) and the gastric irritating effects of NSAIDs and increases the risk of gastritis and upper GI bleeding.
NEUROBIOLOGY (MECHANISMS OF ADDICTION)
All drugs of abuse including alcohol produce reward by enhancing the release of dopamine (DA) within limbic and cortical circuits that regulate motivated behavior. The DA neurons that provide these projections are located in the midbrain ventral tegmental area (VTA), and their rate of firing is enhanced by alcohol. Chronic intake of alcohol leads to alterations in the excitability of these neurons that can persist for significant periods of time. Genetic differences in the responsiveness of these neurons and their connections may contribute to the motivational factors that drive greater alcohol-seeking behavior in certain individuals.
Psychostimulants such as cocaine and amphetamine or opiates like heroin and morphine produce their effect by binding to specific protein receptors expressed on brain neurons. In contrast, alcohol interacts with a wide variety of targets including both lipids and proteins. While initial observations suggested that alcohol’s acute actions arose from its effects on membrane lipids, the current consensus is that alcohol’s behavioral actions result from interactions with a diverse set of ligand-gated and voltage-gated ion channels that regulate neuronal excitability.
Distinct families of subunits make up GABAA and glycine receptors, and different combinations of these give rise to ion channels with variable sensitivity to pharmacologic agents, including alcohol. In general, alcohol enhances GABAA and glycine receptor function, although in some cases, these effects may occur via increased release of GABA rather than direct effects of the ion channel itself.
Glutamate is the major excitatory neurotransmitter in the brain and activates three major subtypes of ion channels called AMPA, kainate, and NMDA receptors. These channels cause depolarization of the neuronal membrane and are implicated in processes that underlie cognition, learning, and memory. NMDA receptors are readily antagonized by alcohol at concentrations associated with intoxication and sedation, while most non-NMDA receptors are unaffected by ethanol. Alcohol blockade of excitatory NMDA signaling may underlie its rewarding effects since more selective NMDA antagonists also increase levels of dopamine in reward areas of the brain. Chronic exposure to alcohol increases the density and clustering of NMDA receptors leading to increased neuronal excitability and enhanced susceptibility to seizures that can develop during withdrawal from alcohol.
Other Ion Channel Subtypes
5-HT3 receptors are ligand-gated ion channels activated by serotonin. Alcohol potentiates currents carried by 5-HT3 receptor, and 5-HT3 receptor antagonists block the discriminative stimulus properties of ethanol in animals. Human studies with the 5-HT3 antagonist ondansetron (Zofran) report that the drug reduces drinking in certain individuals.
Alcohol has been shown to potentiate or inhibit acetylcholine receptors, and this seems to be related to which subtypes of nicotinic receptors are expressed. It is not clear how these effects on the nicotinic receptor are manifested at the behavioral level. However, the α4β2 nicotinic receptor partial agonist varenicline, which is used in smoking cessation, reduces alcohol seeking and consumption in animal models.
Adenosine triphosphate (ATP) activates a variety of ion channels, some of which are sensitive to ethanol. Like nicotinic receptors, the behavioral implication of these effects is not yet fully known but positive modulator of some ATP-gated channels can reduce drinking in rodent models.
Potassium channels that are regulated by calcium (SK and BK channels) and those gated by G protein (GirK) channels serve as a brake on excitatory glutamatergic transmission by hyperpolarizing the membrane. The activity of some of these channels is enhanced by ethanol, and this may contribute to the inhibition of vasopressin release from neurohypophysial terminals and the resulting diuresis that accompanies alcohol ingestion. Changes in the expression and location of certain potassium channels following chronic alcohol exposure contribute to the hyperexcitability that is often observed during ethanol withdrawal. Alcohol inhibits certain subtypes of voltage-gated calcium channels, and this may contribute to disruptions in sleep that are commonly observed in alcohol-dependent individuals.
Pharmacologic Studies Implicating Other Neurotransmitter Systems
In addition to its effects on ion channels, alcohol also has important actions on various neurotransmitters.
Adenosine is present in high concentrations in the brain and may serve as an endogenous antiepileptic because of its ability to inhibit neuronal function. Alcohol increases extracellular adenosine levels by inhibiting a nucleoside transporter.
Alcohol increases the firing of VTA dopamine neurons leading to enhanced dopamine release in the nucleus accumbens, prefrontal cortex, and other areas although the mechanism underlying this effect is not precisely known.
Alcohol increases the release of opioid peptides, and selective opioid antagonists (naloxone, naltrexone) can reduce alcohol consumption in both animals and man. Mice genetically modified to lack the μ opiate receptor do not voluntarily drink alcohol and do not respond to the rewarding effects of opiates, nicotine, or cannabinoids. While opioid antagonists are a mainstream treatment of alcohol addiction, their clinical efficacy is modest suggesting that other factors may be important.
5-HT and 5-HT–metabolite levels are reduced in the cerebrospinal fluid of many alcohol abusers, suggesting that reduced 5-HT levels or a reduction in 5-HT–mediated neurotransmission may predispose certain people to uncontrollable drinking behavior. However, agents that enhance levels of serotonin (such as fluoxetine [Prozac] and sertraline [Zoloft]) appear to have limited efficacy in the treatment of alcohol use disorders.
The endogenous cannabinoid system has been shown to be an important mediator of ethanol drinking. CB1 antagonists reduce ethanol preference in wild-type mice, and animals genetically lacking CB1 receptors show reduced alcohol preference.
ADDICTION LIABILITY
Lifetime prevalence of alcohol dependence is approximately 13%, and the risk of developing alcohol dependence shows a strong inverse correlation with the age at which heavy drinking begins. Chronic use of alcohol produces several neuroadaptive changes that may be important in the development of alcohol addiction.
Sensitization is the increase in the pharmacologic and physiologic response to a drug after repeated exposures. Another form of sensitization is characterized by an increase in the severity and intensity of withdrawal signs after multiple episodes of alcohol intoxication and withdrawal. This form of sensitization is similar to the kindling phenomena observed after repeated brain seizures and may involve some of the same mechanisms.
Tolerance is manifested as a reduced sensitivity to alcohol. In human alcoholics, tolerance to the sedative and even lethal effects of alcohol can be profound. For example, while the lethal dose 50% (LD50) in nontolerant humans is approximately 400 to 500 mg%, blood levels far exceeding those values are often reported in individuals arrested for drunk driving. Dependence is defined by the occurrence of symptoms that appear during withdrawal from alcohol. These symptoms include both physical (tremors, convulsions) and psychological (negative emotions, craving) components. Although reward mechanisms are undoubtedly important in the initiation of heavy alcohol use, processes and brain areas involved in dependence may be critical for maintaining continued drinking through negative reinforcement (anxiety, stress) generated during withdrawal. Changes in these systems may also underlie the phenomena of craving that can persist long after the symptoms of alcohol withdrawal have long subsided.
Alcohol is metabolized under zero-order kinetics (constant amount oxidized per unit time), and blood alcohol levels fall at a rate of about 20 mg/dL/h. Alcohol produces a well-studied progression of behavioral symptoms that are highly correlated with blood alcohol levels. In nontolerant individuals,
- Low levels (10 to 50 mg%)—decreased anxiety, feelings of well-being, and increased sociability.
- Moderate levels (80 to 100 mg%)—impaired judgment and motor function.
- Higher levels (150 to 200 mg%)—marked ataxia, reduced reaction time, and blackout.
- Anesthetic levels (300 to 400 mg%)—severe motor impairment, vomiting, and loss of consciousness.
- Lethal level (400 to 500 mg% and above)—as mentioned previously, lethal doses of alcohol in nontolerant individuals are on the order of 400 to 500 mg%, although this can vary widely.
Alcohol affects nearly all tissue and organ systems studied, and heavy drinkers show skeletal fragility and damage to tissues such as brain, liver, and heart, as well as increased susceptibility to some cancers. Human alcoholics have increases in cortical cerebrospinal fluid in both gray and white matter and diminished volume of frontal lobes and cerebellar gray matter, anterior hippocampus, and reduced area of the corpus callosum. Untreated alcoholics show reduced brain glucose metabolism as compared with control subjects, and brief episodes of heavy drinking, or binges, cause neuron loss in animal models of alcoholism. Despite these negative effects, light-to-moderate levels of drinking (1 drink per day for women, 2 drinks for men) are associated with reduced risk of cardiovascular disease.
ACKNOWLEDGMENTS
Development of this chapter was supported by grant R37-AA009986 from the National Institute on Alcohol Abuse and Alcoholism.
KEY POINTS
1. Alcohol is among the most widely used substances in the world, and its manufacturing, distribution, and sales are of great economic importance.
2. Nearly 90% of the US population report some use of alcohol over their lifetime, and annual costs associated with alcohol-related injury, health care, and lost productivity exceed $220 billion.
3. Alcohol has actions on all organ systems, and excessive consumption is associated with enhanced risk of GI pathologies, cardiovascular incidents, certain cancers, and liver and brain dysfunction.
4. Ethanol targets a variety of excitatory and inhibitory ion channels that regulate neuronal excitability, and perturbation of these channels underlies many of the behavioral effects of alcohol.
5. Acutely, alcohol engages brain reward systems and enhances the activity of midbrain dopamine neurons. Chronic use of alcohol induces changes in reward and stress circuits, and continued drinking may result from an attempt to minimize the negative aspects associated with withdrawal from alcohol.
REVIEW QUESTIONS
1. True or False: Women typically have higher blood alcohol levels than men of similar weights when drinking similar amounts. Explain the concept of zero-order metabolism of alcohol and why women typically experience higher blood alcohol levels than men of similar weight when drinking similar amounts.
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