Chapter 27 - Ethanol PDF

27Chapter Ethanol Jody Mayfield and S. John Mihic HUMAN CONSUMPTION OF ETHANOL: A BRIEF HISTORY AND CURRENT PERSPECTIVE Hematolog...

27Chapter Ethanol Jody Mayfield and S. John Mihic HUMAN CONSUMPTION OF ETHANOL: A BRIEF HISTORY AND CURRENT PERSPECTIVE Hematological Effects Immune System Neuroimmune System BLOOD ETHANOL CONCENTRATION Cancers METABOLISM OF ETHANOL TERATOGENIC EFFECTS: FETAL ALCOHOL SPECTRUM Absorption and Gastric Metabolism DISORDERS Liver Metabolism CLINICAL USES OF ETHANOL METHANOL DRUG INTERACTIONS EFFECTS OF ETHANOL ON PHYSIOLOGICAL SYSTEMS COMORBIDITY OF ALCOHOL USE DISORDER WITH OTHER The Wisdom of Shakespeare Central Nervous System PSYCHIATRIC DISORDERS Endocrine System Sexual and Reproductive Function ALCOHOL USE DISORDER AND GENETICS Bone Body Temperature PHARMACOTHERAPIES FOR ALCOHOL USE DISORDER Kidneys Disulfiram Cardiovascular System Naltrexone Lungs Acamprosate Skeletal Muscle Other Drugs With Repurposing Potential Digestive System Treatment Outlook Ethanol (CH3CH2OH), or beverage alcohol, is a two-carbon alcohol pleasure and in medicinal practice. Over the last 2000 years, alcoholic that is rapidly distributed in the body and brain. Ethanol alters many beverages have been identified in most cultures, including pre-Columbian neurochemical systems and has rewarding and addictive properties. It America about ad 200 and the Islamic world in the 8th century. is the oldest recreational drug and likely contributes to more morbidity, The dangers of heavy consumption of alcohol have long been recog- mortality, and public health costs than all illicit drugs combined. The nized by almost all cultures. The increase in ethanol consumption in the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders 1800s, along with industrialization and the need for a dependable work- (DSM-5) integrates alcohol abuse and alcohol dependence into a sin- force, contributed to widespread organized efforts to discourage drunk- gle disorder called alcohol use disorder (AUD), with mild, moderate, enness, including a constitutional ban on the sale of alcoholic beverages and severe subclassifications (American Psychiatric Association, 2013). in the U.S. from 1920 to 1933. In the DSM-5, all types of substance abuse and dependence have been Today, AUD is one of the most prevalent psychiatric disorders world- combined into a single substance use disorder (SUD) on a continuum wide. In the U.S., among adults 18 years and older, AUD is highly comor- from mild to severe. A diagnosis of AUD requires that at least two of bid with other substance use and psychiatric disorders. In 2019, about the 11 DSM-5 behaviors be present within a 12-month period (mild 14.5 million people in the U.S. had AUD (Substance Abuse and Men- AUD: 2–3 criteria; moderate AUD: 4–5 criteria; severe AUD: 6–11 crite- tal Health Services Administration, 2019). Roughly one-third of men ria). The four main behavioral effects of AUD are impaired control over (36%) and one-quarter of women (23%) will meet the criteria for a mild, drinking, negative social consequences, risky use, and altered physio- moderate, or severe AUD in their lifetimes (Grant et al., 2015). Among logical effects (tolerance, withdrawal). This chapter presents an over- ethnic groups, Native Americans have the highest prevalence of AUD. view of the prevalence and harmful consequences of AUD in the U.S., According to the Centers for Disease Control and Prevention (CDC), the systemic nature of the disease, neurocircuitry and stages of AUD, alcohol-related deaths are the third leading preventable cause of death comorbidities, fetal alcohol spectrum disorders, genetic risk factors, and in the U.S. (the first is tobacco and the second is poor diet and physical pharmacotherapies for AUD. inactivity). Alcohol-impaired driving accounts for almost one-third of the overall driving fatalities. The cost of excessive drinking in the U.S. reached about $249 billion in 2010 (Sacks et al., 2015). Human Consumption of Ethanol: A Brief History Binge drinking to a blood ethanol concentration (BEC) of 0.08% or above is the most common, costly, and deadly pattern of excessive drink- and Current Perspective ing. This pattern of intake is defined as four or more drinks on the same The use of alcoholic beverages is documented as far back as 10,000 bc. occasion (within ~2 h) for females and five or more drinks for males By about 3000 bc, the Greeks, Romans, and inhabitants of Babylon were and accounts for 77% of the total cost of excessive alcohol use in the U.S. incorporating ethanol into religious festivals, while also using it for (Sacks et al., 2015). In the past, AUD was more prevalent in men than https://ebooksmedicine.net/  520 Abbreviations Metabolism of Ethanol ADH: alcohol dehydrogenase Absorption and Gastric Metabolism ALDH: aldehyde dehydrogenase After oral administration, ethanol is absorbed rapidly into the blood- AMPA: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic stream from the stomach and small intestine and distributes into total acid body water (~0.65 L/kg body weight). Due to high surface area, absorp- APA: American Psychiatric Association tion occurs more rapidly from the small intestine than from the stomach; ARBD: alcohol-related birth defect delays in gastric emptying (e.g., due to the presence of food) slow ethanol ARDS: acute respiratory distress syndrome absorption. Peak blood levels occur about 30 min after ingestion of eth- ARND: alcohol-related neurodevelopmental disorder anol if the stomach is empty. Because of first-pass metabolism by gastric and liver alcohol dehydrogenase (ADH), oral ingestion of ethanol leads AUD: alcohol use disorder to lower blood ethanol concentrations (BECs) than would be obtained if CHAPTER 27 ETHANOL BEC: blood ethanol concentration the same dose were administered intravenously. Compared with males, CDC: U.S. Centers for Disease Control and Prevention females have very little gastric ADH and consequently absorb more CYP: cytochrome P450 alcohol into their bloodstreams. In addition, the activities of liver ADH DSM-5: Diagnostic and Statistical Manual of Mental Disorders isozymes are lower in females. Thus, females generally metabolize eth- (5th edition) anol more slowly than males. In addition, women are generally smaller FAS: fetal alcohol syndrome and have lower body water percentages than men; this results in females GABA: γ-aminobutyric acid reaching higher BECs than men after consuming the same amounts of GHB: γ-hydroxybutyric acid alcohol. GI: gastrointestinal 5HT: 5-hydroxytryptamine, serotonin Liver Metabolism LPS: lipopolysaccharide Only small amounts of ethanol are excreted in urine, sweat, and NMDA: N-methyl-d-aspartate breath. The main enzymes involved in ethanol metabolism are ADH, PTSD: posttraumatic stress disorder catalase, and CYP2E1. CYPs 1A2 and 3A4 may also participate. Eth- SSRI: selective serotonin reuptake inhibitor anol is metabolized primarily by sequential hepatic oxidation, first to SUD: substance use disorder acetaldehyde by ADH and then to acetic acid by aldehyde dehydroge- nase (ALDH) (Figure 27–1). Each metabolic step requires NAD+; thus, oxidation of 1 mol ethanol (46 g) to 1 mol acetic acid requires 2 mol NAD+ (~1.3 kg). This greatly exceeds the supply of NAD+ in the liver; thus, the bioavailability of NAD+ limits ethanol metabolism to about 8 g/h (10 mL/h, 170 mmol/h) in a 70-kg adult. Ethanol metabolism women, but in the last decade, the difference between the sexes has nar- proceeds via zero-order kinetics at BECs greater than 10 mg% and by rowed for both AUD and binge drinking. In the 2019 National Survey first-order kinetics at BECs less than 10 mg%. Genetic variants of ADH on Drug Use and Health, more adults ages 18 and older reported binge and ALDH influence risk for developing AUD and are discussed later drinking (~26%) in the past month than reported heavy alcohol use in the section on genetics. (~6%). Despite the high prevalence, morbidity, mortality, and socioeco- In addition to limiting the rate of ethanol metabolism, the large nomic costs, AUD often goes undiagnosed and untreated. increase in the hepatic NADH:NAD+ ratio resulting from ethanol oxida- tion has other profound consequences. The function of NAD+-requiring enzymes is impaired, resulting in accumulation of lactate, reduced activity of the tricarboxylic acid cycle, and accumulation of acetyl-CoA (which is produced from ethanol-derived acetic acid; Figure 27–1). The Blood Ethanol Concentration combination of increased NADH and elevated acetyl-CoA supports Compared with other drugs, surprisingly large amounts of ethanol are fatty acid synthesis and the storage and accumulation of triacylglycer- required for physiological effects. Ethanol is consumed in gram quanti- ides; ketone bodies then accrue, exacerbating lactic acidosis. ties. In contrast, most other drugs with affinities for specific proteins are Although ADH is responsible for the majority of ethanol metabo- taken in milligram or microgram doses. The alcohol content of beverages lism, CYP2E1 accounts for about 10%. This constituent of the microso- typically ranges from 4% to 6% (volume/volume) for beer, 10% to 15% for mal ethanol-oxidizing system can be altered by acute or chronic ethanol wine, and 40% and higher for distilled spirits. The proof of an alcoholic consumption. Competition between ethanol and other drugs (e.g., phe- beverage is twice its percentage of alcohol (e.g., 40% alcohol is 80 proof). nytoin and warfarin) that are metabolized by CYP2E1 is observed after A 12-oz bottle of beer (355 mL), a 5-oz glass of wine (148 mL), and a acute consumption of ethanol. CYP2E1 is also induced by chronic con- 1.5-oz “shot” of 40% liquor (44 mL) each contain about 14 g ethanol (the sumption of ethanol, and this is the primary mechanism for the develop- density of ethanol is 0.79 g/mL at 25°C) and constitute what is defined as ment of pharmacokinetic tolerance to alcohol. This increased CYP2E1 a “standard drink” in the U.S. activity also increases the clearance of other CYP2E1 substrates, lead- Because the ratio of ethanol in end-expiratory alveolar air and blood ing to a requirement for increased dosing. The increased activity also is relatively consistent, BECs in humans are readily estimated by the increases susceptibility to certain toxins (e.g., CCl4, which CYP2E1 measurement of ethanol levels in expired air; the partition coefficient for metabolizes and thereby activates to the highly reactive trichloromethyl ethanol between blood and alveolar air is about 2100:1. In all states except radical). Ethanol metabolism by the CYP2E1 pathway elevates NADP+ Utah (0.05% w/v), the legally allowed BEC for operating a motor vehicle and limits the availability of NADPH for the regeneration of reduced is 80 mg% (80 mg ethanol per 100 mL blood; 0.08% w/v), which is equiv- glutathione, thereby enhancing oxidative stress. alent to a concentration of 17 mM ethanol in the blood. The consump- The mechanisms underlying hepatic disease resulting from heavy tion of one standard drink by a 70-kg person would produce a BEC of ethanol use probably reflect a complex combination of these metabolic about 30 mg%. However, it is important to note that this is an estimation factors, CYP2E1 induction (and enhanced activation of toxins and pro- because the BEC is determined by multiple factors (e.g., rate of drinking, duction of H2O2 and oxygen radicals), and possibly enhanced release of sex, body weight and water percentage, rates of metabolism and stomach endotoxin as a consequence of ethanol’s effect on gram-negative flora emptying). in the gastrointestinal (GI) tract. The often poor nutritional status of  CH3OH H3C CH2OH 521 Methanol Ethanol H2O2 NAD+ NADPH + O2 Fomepizole Alcohol Catalase X dehydrogenase CYP2E1 NADH + NADP+ + H2O 2H2O H+ O H2C O H3C CH Formaldehyde Acetaldehyde NAD+ SECTION II Aldehyde dehydrogenase X Disulfiram NADH + O O H+ HC OH H3C C OH Formic acid Acetic acid NEUROPHARMACOLOGY Folate-dependent pathway CoA + ATP CO2 + Thiokinase H2O AMP + 2P C β-hydroxy-β-methyl CoA S C CH3 Tricarboxylic glutaryl CoA acid cycle Acetyl CoA Fatty acids Ketone Cholesterol bodies Figure 27–1 Metabolism of ethanol and methanol. alcoholics (malabsorption and lack of vitamins A, D, and thiamine), sup- formic acid production, lessening the toxicity associated with methanol pressed of immune function, and a variety of other generalized effects consumption. likely compound the more direct adverse effects of excessive ethanol con- sumption. An overview of ethanol metabolism and how it can lead to N tissue injury is found in the work of Molina et al. (2014). N H FOMEPIZOLE Methanol Fomepizole (4-methylpyrazole), an ADH inhibitor (Figure 27–1) that Methanol (CH3OH), also known as methyl or wood alcohol, is an impor- is administered alone, or in combination with hemodialysis, is also used tant industrial reagent and solvent found in products such as paint to treat methanol or ethylene glycol poisoning. Plasma levels of 0.8 mg/L removers, shellac, and antifreeze. Methanol is added to industrial-use are effective in inhibiting ADH. Fomepizole should not be used with eth- ethanol to make it unsafe for human consumption. Ingestion of as little anol because it prolongs the half-life of ethanol. Treatment of methanol as 8 g (10 mL) of methanol produces toxicity ranging from blindness to poisoning also consists of using sodium bicarbonate to combat acidosis. death. The toxic effects take about 12 or more hours to manifest them- selves and are dependent on methanol metabolism to formaldehyde and formic acid (see Figure 27–1). Methanol poisoning consists of headache, Effects of Ethanol on Physiological Systems GI distress, and pain (partially related to pancreatic necrosis), difficulty breathing, restlessness, and blurred vision. The visual disturbances occur The Wisdom of Shakespeare from injury to ganglion cells of the retina and the optic nerve by formic William Shakespeare described the acute pharmacological effects of imbib- acid, which produces inflammation, atrophy, and potential bilateral ing ethanol in the Porter scene (act 2, scene 3) of Macbeth. The Porter, blindness. Severe metabolic acidosis can develop due to the accumula- awakened from an alcohol-induced sleep by Macduff, explains three effects tion of formic acid, and respiratory depression may be severe, resulting of alcohol and then wrestles with a fourth effect that combines the contra- in coma or death. dictory aspects of soaring overconfidence with physical impairment: Methanol is rapidly absorbed via the eyes, oral administration, inha- lation, and through the skin, with the last two routes most relevant Porter: … and drink, sir, is a great provoker of three things. in industrial settings. Absorption of methanol taken orally typically Macduff: What three things does drink especially provoke? occurs within 30 to 60 min. Methanol is metabolized by ADH to form- aldehyde, which is then metabolized to formic acid by ALDH. Com- Porter: Marry, sir, nose-painting [cutaneous vasodilation], sleep [CNS petition between methanol and ethanol for ADH is the basis for using depression], and urine [inhibition of antidiuretic hormone (vasopressin) https://ebooksmedicine.net/ ethanol to treat methanol poisoning because ethanol slows the rate of secretion, exacerbated by volume loading]. Lechery, sir, it provokes and  522 unprovokes: it provokes the desire, but it takes away the performance; ethanol levels is necessary to confirm the absence or presence of alcohol therefore, much drink may be said to be an equivocator with lechery: intoxication, and diabetes or other underlying conditions should also be it makes him, and it mars him; it sets him on, and it takes him off; it considered in patients with positive BECs. There is no safe pharmacolog- persuades him, and disheartens him; makes him stand to, and not ical treatment to increase the rate of ethanol metabolism. stand to [the imagination desires what the corpus cavernosum cannot deliver]; in conclusion, equivocates him in a sleep, and, giving him the Chronic Effects and Treatment The transient effects of heavy ethanol consumption that produce a lie, leaves him. “hangover”—the next-morning syndrome of headache, thirst, nausea, Research findings have since provided the physiological correlates for hyperexcitability, and cognitive impairment—may reflect ethanol with- Shakespeare’s enumeration (see the bracketed additions to the Porter’s drawal, dehydration, or mild acidosis. Insomnia is a common and per- words in the preceding paragraph). The most noticeable consequences sistent problem in AUD, even after weeks of abstinence (Brower, 2015), of the recreational use of ethanol still are well summarized by the gre- and should be treated because it may contribute to relapse. Ethanol affects garious and garrulous Porter, whose delighted and devilish demeanor respiration and muscle relaxation, and heavy drinking can produce sleep CHAPTER 27 ETHANOL demonstrates a frequently observed influence of modest concentrations apnea, especially in older dependent individuals. Treatment of insomnia of ethanol on the CNS. must take into account possible pharmacodynamic interactions of etha- nol with another CNS depressant. Central Nervous System Ethanol-induced cognitive impairment may be related to changes in synaptic plasticity (e.g., long-term potentiation and long-term depres- Ethanol is primarily a CNS depressant. Ingestion of low to moderate sion), like those reported in preclinical studies of the hippocampus, pre- amounts of ethanol, like that of other sedative/hypnotics such as barbi- frontal cortex, striatum, and nucleus accumbens (Abrahao et al., 2017). turates and benzodiazepines, can have anxiolytic actions and produce AUD causes shrinkage of the brain due to loss of both white and gray behavioral disinhibition. Individual signs of intoxication vary from matter, and chronic heavy drinking increases the risk of developing alco- expansive and vivacious effects to uncontrolled mood swings and emo- holic dementia. The cognitive deficits and brain atrophy observed after a tional outbursts that may have violent components. With more severe heavy drinking period partially reverse over the weeks to months follow- intoxication, CNS function becomes progressively more impaired, ulti- ing abstinence. Chronic alcohol abuse also reduces overall brain metabo- mately to the point of general anesthesia. Due to respiratory depression, lism, which reverses during detoxification. there is little margin between the concentrations yielding the anesthetic Wernicke-Korsakoff syndrome is a degenerative neurological disorder and lethal effects of ethanol. that encompasses Wernicke encephalopathy and Korsakoff syndrome. These two closely related disorders often occur together, with most Acute Intoxication and Treatment individuals developing encephalopathy first. Some researchers believe Many factors influence the BEC, including body weight, body composi- these are different stages of the same disorder. The disorder is caused tion, and the rate of absorption from the GI tract. In women, with a gen- by thiamine deficiency and is most commonly seen in those with AUD. erally lower volume of distribution for ethanol, BECs may be about 30% It may also result independently of AUD, from malnutrition or condi- to 50% higher than in men for the same quantity consumed. tions that cause nutritional deficiencies. The classic triad of symptoms Signs of intoxication typical of CNS depression are observed in most are confusion, ataxia, and eye abnormalities (double vision, nystagmus, people after two or three drinks, with the most prominent effects seen ophthalmoplegia); however, it is underdiagnosed because of a wide at times of peak BEC, about 30 to 60 min following consumption on an range of symptoms that overlap with other conditions (Chandrakumar empty stomach. These symptoms include an initial stimulatory effect et al., 2018). In its early stages, symptoms of Wernicke encephalopa- (perhaps due to inhibition of CNS inhibitory systems), giddiness, muscle thy are usually reversible with high doses of thiamine, but the mental relaxation, and impaired judgment. Higher blood levels (~80 mg/dL or impairments in Korsakoff syndrome respond more slowly and incom- ~17 mM) are associated with slurred speech, incoordination, unsteady pletely. Untreated Wernicke encephalopathy leads to death in up to 20% gait, and impaired attention; levels between 80 and 200 mg/dL are asso- of cases, and about 75% of those who survive the encephalopathy go ciated with more intense mood lability and greater cognitive deficits, on to develop Korsakoff psychosis, characterized by memory impair- potentially accompanied by aggressiveness and anterograde amnesia (an ment, apathy, anterograde and retrograde amnesia, and confabulation “alcoholic blackout,” i.e., loss of memory of events that transpired while (Chandrakumar et al., 2018; Thomson et al., 2012). Wernicke-Korsakoff intoxicated). BECs greater than 200 mg/dL can produce nystagmus and syndrome is a medical emergency, and early treatment with intravenous sedation, while levels of 300 mg/dL and higher produce failing vital signs, thiamine (followed by oral maintenance treatment) is essential to reverse coma, and death. Heavy drinkers, who have developed significant phar- the Wernicke symptoms and prevent progression or reduce the severity macodynamic tolerance, will display markedly less impairment at these of the Korsakoff state. BECs. All of these symptoms are likely to be exacerbated and occur at a lower BEC if ethanol is taken with other CNS depressants (e.g., benzodi- Molecular Targets: Neurotransmitter and azepines or barbiturates) or with any drug or medication that promotes Neuromodulator Systems sedation and incoordination (e.g., antihistamines). Also see the section Ethanol alters the release of neurotransmitters and neuropeptides and on Drug Interactions later in the chapter. modulates pre-, post-, and extrasynaptic activity through diverse molec- The treatment of acute ethanol intoxication is based on the severity of ular targets (reviewed in Abrahao et al., 2017). The dopaminergic system respiratory and CNS depression. If respiratory depression is not severe, and the endogenous opioid system are sensitive to low concentrations of careful observation is the primary treatment. Patients with evidence of ethanol and play key roles in mediating its rewarding effects, although respiratory depression should be intubated to protect the airway and to ethanol is not believed to directly act at either opioid or dopamine recep- provide ventilatory assistance; stomach lavage can also be considered if tors. Ethanol perturbs the balance between excitatory and inhibitory absorption is not yet complete. Because it is freely miscible with water, transmission, for example, by enhancing the function of inhibitory cys- ethanol can be removed from the blood by hemodialysis. The usual pro- loop ligand-gated ion channels (e.g., GABAA and glycine) or inhibiting tocol involves observing the patient in the emergency room for 4 to 6 h the function of excitatory ionotropic glutamate receptors (e.g., N-methyl- while the ingested ethanol is metabolized. The symptoms associated with d-aspartate [NMDA], α-amino-3-hydroxy-5-methyl-4-isoxazolepropi- diabetic coma, drug intoxication, cardiovascular accidents, and skull onic acid [AMPA], kainate) (Table 27–1). GIRK, 5HT3(serotonin) recep- fractures are similar and may be confused with profound alcohol intoxi- tor-gated, and L-type Ca2+ channels are also sensitive to ethanol at low cation. Testing for breath odor in a case of suspected intoxication can be concentrations. Table 27–1 shows the overall effects of acute ethanol misleading because there can be other causes of similar breath odor (e.g., on some of the neurotransmitter and neuromodulator systems that are diabetic ketoacidosis or other metabolic acidosis). Determining blood involved in the neurocircuitry of addiction.  in the long-term heavy drinker. In contrast to acute tolerance, chronic 523 TABLE 27–1 MOLECULAR SITES OF ETHANOL ACTION tolerance has both pharmacodynamic and pharmacokinetic elements, the latter due to induction of alcohol-metabolizing enzymes, primarily LIGAND- AND VOLTAGE-GATED ION EFFECTS OF ACUTE CHANNELS ETHANOL CYP2E1. In general, the maximum pharmacokinetic tolerance attained would be a doubling of the normal metabolic rate. GABAA receptor-operated channels Enhancement Dependence is defined by a withdrawal syndrome observed several Glycine receptor-operated channels Enhancement hours to days after alcohol consumption is terminated. The symptoms and severity are determined by the amount and duration of drinking and Glutamate receptor-operated channels Inhibition include major motivational changes, sleep disruption, autonomic nervous (e.g., NMDA, AMPA, kainate) system (sympathetic) activation, tremors, and, in severe cases, seizures. Nicotinic acetylcholine receptor-operated Subunit-specific In addition, 2 or more days after withdrawal, some individuals experience channels delirium tremens, characterized by hallucinations, delirium, tachycardia, SECTION II 5HT3 receptor-operated channels Enhancement and a potentially fatal fever or cardiac arrhythmia. Individuals with AUD also show evidence of negative emotional states during acute withdrawal G protein–coupled inwardly rectifying K+ Enhancement that persist into protracted abstinence; such states include symptoms (GIRK) channels related to anxiety, dysphoria, and depression. Persistent depression/ Large conductance, Ca2+-activated K+ Enhancement anxiety-like symptoms are important treatment considerations. Delirium channels (BK) tremens require management as a medical emergency in an intensive care L-type Ca2+ channels Inhibition unit or another inpatient setting. Patients should be kept in a quiet and NEUROPHARMACOLOGY The enhancement or inhibition of channel function recorded here represents an comfortable environment, and their vital signs routinely monitored. Elec- overall consensus of acute ethanol effects. Sensitivity and overall effects may depend trolyte, fluid, and nutritional deficiencies must be corrected. Long-acting on ethanol concentration, time of exposure, channel subunit composition, brain benzodiazepines such as diazepam or chlordiazepoxide are the treatments region, cell type, posttranslational modifications, and other factors. of choice, but phenobarbital, dexmedetomidine, or propofol may be used in benzodiazepine-refractory patients. Comorbidities are common in delir- Putative ethanol binding sites in many of the channel proteins ium tremens patients, especially liver dysfunction, and this may affect in Table 27–1 have been identified through molecular modeling of benzodiazepine dosing regimens. Lastly, clinical management of delirium high-resolution crystal structures (reviewed in Cui and Koob, 2017). tremens would be incomplete if it is not done in the context of anticipated Unlike other drugs, ethanol has a relatively weak affinity for its molecular treatment of the patient’s underlying AUD. Two processes are thought to targets; however, the ease with which ethanol is distributed and diffuses form the neurobiological basis for the withdrawal–negative affect stage: through membranes greatly broadens its targets and long-term neurobi- decreased functioning in reward systems in the ventral striatum and ological effects. Considering this, it is not surprising that the molecular recruitment of the stress systems in the extended amygdala. As depen- mechanisms responsible for alcohol intoxication, reward, and depen- dence develops, brain stress systems, involving corticotropin-releasing dence remain poorly understood. factor, norepinephrine, and dynorphin, are recruited (Koob, 2014), pro- Neurocircuitry and Stages of AUD ducing a powerful motivation for drug seeking. AUD is the chronically relapsing and compulsive use of alcohol, com- The preoccupation-anticipation (“craving”) stage involves dysregula- prising three interacting stages that progressively worsen over time: tion of prefrontal cortex circuits, causing loss of executive control. The binge-intoxication, withdrawal-negative affect, and preoccupation- completion of complex tasks in the AUD brain may involve two oppos- anticipation (“craving”). The neurocircuitry of the basal ganglia is thought ing systems. A “go” system (the anterior cingulate cortex and dorsolateral to mediate the neurobiological basis of the binge-intoxication stage, prefrontal cortex) engages habits via the basal ganglia, while the “stop” including the facilitation of incentive salience, a form of motivational system (the ventrolateral prefrontal cortex and orbitofrontal cortex) salience associated with reward. The basal ganglia are associated with key inhibits the basal ganglia incentive salience and the extended amygdala functions, including voluntary motor control and procedural learning stress system (Koob, 2015). Individuals with AUD show impairments in related to routine behaviors or habits. Release of dopamine and opioid decision making, spatial information, and behavioral inhibition, all of peptides in the ventral striatum (nucleus accumbens) is associated with which drive craving. Craving can be divided into “reward” craving (drug the reinforcing actions of alcohol (Volkow et al., 2007). Endocannabinoid seeking induced by drugs or stimuli linked to drugs) and “relief ” craving signaling may also contribute to the motivational and reinforcing prop- (drug seeking induced by an acute stressor or a state of stress) (Heinz erties of ethanol, and ethanol drinking alters endocannabinoid levels and et al., 2003). Thus, deficits in prefrontal cortical control of basal ganglia cannabinoid receptor 1 expression in brain nuclei in addiction pathways and extended amygdala function may explain individual differences in (Pava and Woodward, 2012). Alcohol use facilitates incentive salience by the predisposition to and perpetuation of addiction. Residual dysregula- imparting motivational properties to previously neutral stimuli. Activa- tion of the neurocircuits mediating incentive salience and stress respon- tion of the ventral striatum leads to recruitment of basal ganglia–globus sivity help perpetuate compulsive drug taking and relapse. pallidus–thalamic–cortical loops that engage the dorsal striatum habit formation, hypothesized to be the beginning of compulsive-like respond- ing for drugs. Endocrine System Tolerance rapidly develops to the rewarding effects of alcohol and is The endocrine system comprises glands that produce and secrete hor- defined as a reduced behavioral or physiological response to the same mones into the blood, affecting almost every cell and organ, and regulat- dose of drug, or the requirement of a higher dose to obtain the same effect ing many processes, including metabolism, energy, electrolyte balance, (see Chapter 28); this may be pharmacokinetic and/or pharmacodynamic stress response, growth, development, and reproduction. The endocrine in nature. The major forms of pharmacodynamic (functional) tolerance system also controls communication between the immune and nervous are acute and chronic. Acute functional tolerance, also known as the Mel- systems and is essential for maintaining homeostasis. Acute and chronic lanby effect, occurs within hours of alcohol administration and is due ethanol differentially alters endocrine function via the hypothalamic- to CNS adaptations to its effects. This is demonstrated by comparing pituitary-adrenal axis, the hypothalamic-pituitary-gonadal axis, the behavioral impairment at the same BECs on the ascending limb of the hypothalamic-pituitary-thyroid axis, the hypothalamic-pituitary-growth absorption phase of the BEC–time curve and on the descending limb of hormone/insulin-like growth factor-1 axis, and the hypothalamic- the curve, as metabolism reduces the BEC. Behavioral impairment and posterior pituitary axis (Rachdaoui and Sarkar, 2017). Chronic etha- subjective feelings of intoxication are much greater at a given BEC on the nol intake disrupts hormones from the endocrine portions of the pan- ascending than on the descending limb. Chronic tolerance also develops creas and adipose tissue and the pituitary hormone prolactin, causing https://ebooksmedicine.net/  524 hyperprolactinemia. The hormonal disturbances contribute to many on lipid profiles by increasing high-density lipoprotein cholesterol (see conditions, such as thyroid and cardiovascular disease, immune and Chapter 37), which transports cholesterol to the liver for elimination, and reproductive dysfunction, cancer, diabetes, and psychological disorders. by decreasing total cholesterol, triglycerides, and low-density lipoprotein cholesterol, which causes cholesterol to accumulate in the arteries. The Sexual and Reproductive Function overall decrease in cholesterol accumulation in arterial walls decreases cardiovascular disease. Many drugs of abuse, including ethanol, have disinhibiting effects that may initially increase libido. Despite the notion that ethanol enhances Hypertension and Stroke sexual function, the opposite effect generally prevails, as Shakespeare’s In general, alcohol-risk relationships for hypertension tend to be J-shaped Porter noted. Sexual dysfunction in AUD includes decreased sexual in women, with decreased risk found at low doses (Piano, 2017). However, arousal, increased ejaculatory latency, and decreased orgasmic pleasure. based on a meta-analysis, women drinking more than 20 g ethanol/day Hyperprolactinemia can decrease fertility in men and women with AUD and men drinking more than 30 g/day showed increased risk of hyperten- by leading to hypogonadism, reduced sperm production, impotence, and sion. Even small increases in blood pressure can increase mortality from CHAPTER 27 ETHANOL menstrual cycle irregularities. Ethanol’s adverse effects on the hypotha- coronary artery disease and from stroke. In men and women, approxi- lamic-pituitary-gonadal axis also contribute to decreased libido and fer- mately one to two drinks per day may have no effect on or slightly reduce tility, gonadal atrophy, and menstrual irregularities. stroke events; however, greater daily alcohol consumption increases stroke risk (Piano, 2017). Bone Cardiac Arrhythmias and Cardiomyopathy Maintaining healthy bone requires a balanced bone remodeling process, Arrhythmias like atrial fibrillation are a serious consequence of con- where old bone is removed by osteoclasts and new bone is formed by suming large amounts of alcohol, particularly during binge drinking. osteoblasts. Chronic heavy drinking disrupts this balance by inhibiting Atrial fibrillation is one of the most common arrhythmias and is strongly bone formation and interfering with bone resorption (Maurel et al., associated with cardiovascular events such as stroke. Alcoholic cardio- 2012). Binge or heavy drinking is particularly concerning during ado- myopathy is an acquired form of dilated cardiomyopathy associated with lescence and in young adults when it can dramatically compromise bone long-term, heavy alcohol consumption (Piano, 2017). It is characterized health. As bone mass and bone mineral density decrease, the risk of oste- by a dilated left ventricle and increased mass, normal or reduced left ven- oporosis and fractures increase. In addition to bone loss from the direct tricular wall thickness, and reduced ejection fraction in advanced stages. effects of alcohol on both osteoblasts and osteoclasts, there are indirect Cardiomyopathy may be caused by oxidative stress, cell death, impaired mechanisms, such as poor vitamin D metabolism and Ca2+ absorption. mitochondrial function, altered fatty acid metabolism and transport, and Hormonal deficiencies in men and women with AUD are also contribut- increased protein breakdown. ing factors. Testosterone, an anabolic hormone important for production of osteoblasts, is decreased, and reduced estrogen levels increase bone Lungs fragility. Elevated levels of cortisol and parathyroid hormone in AUD also The lungs are often overlooked as a site of ethanol action. However, decrease bone formation. individuals with AUD are more likely to develop pneumonia, tubercu- losis, respiratory syncytial virus infection, and acute respiratory distress Body Temperature syndrome (ARDS) (Simet and Sisson, 2015). ARDS is quite deadly in a Ingestion of ethanol causes an initial feeling of warmth due to enhanced healthy person, and someone with AUD is at even greater risk. ARDS can cutaneous vasodilatation. Heat is transferred from the body core to the occur in young AUD patients, whereas cirrhosis or other alcohol-related periphery, and the core temperature falls due to ethanol’s effect on the diseases take much longer to develop. The increased susceptibility to central temperature-regulating mechanism in the hypothalamus. Intake pulmonary infections, injury, and inflammation is caused by impaired of high quantities of ethanol may lead to pronounced decreases in body immune responses. For example, alcohol impairs neutrophil production temperature, especially in cold ambient temperatures. Alcohol is a major and release, lymphocyte function (e.g., T-cell function), ciliary function risk factor contributing to deaths from hypothermia. in airways, and the function of alveolar macrophages. Thus, the “alcoholic lung” is immunocompromised and under oxidative stress. The lungs then Kidneys become depleted of the vital antioxidant glutathione. Ethanol inhibits the release of vasopressin (antidiuretic hormone) from Skeletal Muscle the posterior pituitary gland, resulting in enhanced diuresis. This dehy- drating effect can lead to headaches and nausea. Alcohol-dependent Skeletal muscle dysfunction (myopathy) is a very common clinical man- individuals in withdrawal exhibit increased vasopressin release and a ifestation in AUD, but it often goes unrecognized (Simon et al., 2017). consequential retention of water, as well as dilutional hyponatremia. Approximately 50% of chronic drinkers may develop alcoholic myopa- thy, which is five times more common than the incidence of liver cir- rhosis. Cirrhosis may also influence the development of myopathy, and Cardiovascular System myopathy worsens the clinical outcome. The decreased muscle mass in There is a complex relationship between ethanol consumption and alcohol-induced myopathy results from an imbalance in protein synthe- cardiovascular disease, a leading cause of death and disability. Heavy sis and degradation. In particular, there is decreased protein synthesis of alcohol use greatly increases risk for cardiovascular disease. Although myofibrillar and sarcoplasmic proteins. Some of the specific anabolic and observational studies have suggested lower risk in light to modest drink- catabolic mechanisms that are implicated in muscle wasting in AUD may ers, the perceived benefit may be the product of healthier lifestyles in involve decreased mammalian target of rapamycin–mediated protein this group. Drinking recommendations from clinicians should remain synthesis and excessive protein degradation via the ubiquitin proteosome guarded given that risk depends on dose and many other factors (e.g., pathway and the autophagic-lysosomal system (Simon et al., 2017). sex, age, drinking patterns, lifestyle factors, and genetic risk), that there is Functional improvements in muscle strength occur over time following the potential for other ethanol-related problems, and that there is a lack abstinence or reduced drinking. Optimizing nutritional status can also of randomized controlled trials on ethanol’s long-term effects on cardio- improve muscle function. vascular function. Serum Lipoproteins Digestive System A common risk factor for cardiovascular disease is the composition of The body priorities metabolizing alcohol over other functions. As etha- lipids in the blood. Low alcohol consumption may have positive effects nol is absorbed and metabolized, it can damage the organs of the digestive system and increase the risk of several cancers (discussed in a later sec- Patients with alcohol-related liver disease show changes in the com- 525 tion). Heavy drinking damages the mucosa of the esophagus, stomach, position of their gut microbiomes, increased intestinal permeability, and and intestines, disrupts gastric and intestinal barriers, impairs nutrient increased circulating levels of the gut-derived microbial endotoxin LPS and protein absorption, impairs immune responses, and causes gastritis, (lipopolysaccharide). LPS is an important trigger for steatosis, inflamma- pancreatitis, and liver diseases. The gut dysbiosis caused by ethanol has tion, and fibrosis by stimulating the generation of reactive oxygen species widespread inflammatory consequences. and a cascade of events that culminate in the transcription of proinflam- matory cytokines. Esophagus and Stomach Fatty liver disease and acute alcoholic hepatitis are usually reversible Ethanol directly damages the mucosa of the esophagus and stomach. It with abstinence. In severe cases of alcoholic hepatitis or cirrhosis, absti- lowers esophageal sphincter pressure, impairs motility, and alters gas- nence may stop or delay disease progression, but cirrhosis is usually ter- tric acid secretion. AUD patients may develop gastroesophageal reflux minal if the patient does not receive a liver transplant. disease, ulcers, or acute and chronic gastritis. Heavy drinking is also a predisposing factor for Mallory-Weiss syndrome, which is character- Hematological Effects SECTION II ized by mucosal tears at the gastroesophageal junction and upper GI bleeding. Proton pump inhibitors and histamine H2 antagonists are used While nutritional deficiencies can play a role in alcohol-related anemias, to decrease gastric acidity. alcohol also directly interferes with red blood cell production. Heavy drinking is associated with different anemias (e.g., macrocytic and side- Intestines roblastic anemias). Thrombocytopenia is common in heavy drinkers and Ethanol damages the intestinal mucosa directly and indirectly by altering can complicate alcohol withdrawal syndrome (Silczuk and Habrat, 2020). the microbiota and impairing mucosal immune function. Many individ- Leukopenia is also commonly found in AUD and increases susceptibility NEUROPHARMACOLOGY uals with AUD have chronic diarrhea caused by malabsorption in the to infections. small intestine. The rectal fissures and pruritus ani that are associated with heavy drinking are likely related to chronic diarrhea. Diarrhea is Immune System caused by structural and functional changes in the small intestine; for Ethanol disrupts innate and adaptive immune signaling, further increas- example, the intestinal mucosa has flattened villi, and digestive enzyme ing the risk of infection and causing systemic inflammation that can levels often are decreased. These changes are usually reversible after a damage organs and increase cancer risk. Immune responses are central to period of abstinence. the pathogenesis of alcoholic liver disease. In addition to effects on gran- Pancreas ulocytes (leukopenia), ethanol alters lymphocyte composition, decreases Heavy alcohol use is the most common cause of both acute and chronic T-cell mitogenesis, and changes immunoglobulin production. Individu- pancreatitis in the U.S. Acute alcoholic pancreatitis is characterized by als with AUD have weakened resistance to infections (e.g., to Klebsiella the abrupt onset of abdominal pain, nausea, vomiting, and increased lev- pneumonia and tuberculosis). The function of alveolar macrophages and els of serum or urine pancreatic enzymes. Treatment usually consists of neutrophils in the airways is impaired, causing damage that may not be intravenous fluid replacement (often with nasogastric suction) and opi- evident until the patient encounters a secondary respiratory infection. As oid pain medication. Similar to alcoholic cirrhosis, chronic pancreatitis a consequence of ethanol’s harmful effects on the gut microbiome and results from progressive cellular destruction and fibrosis and develops the integrity of the GI tract, gut microbes escape into the bloodstream after recurrent episodes of acute pancreatitis. Ethanol metabolites and where they go on to trigger or exacerbate immune and proinflammatory by-products like reactive oxygen species directly injure pancreatic acinar responses in different tissues and organs. The immune dysfunction is not cells, causing stellate cells to produce extracellular matrix, which leads to confined to peripheral injury or illness. It is not clear whether peripheral the atrophy-fibrosis sequelae characteristic of chronic pancreatitis. Com- responses are required to induce neuroinflammation or if ethanol also pared with the liver, the ability to oxidize ethanol in the pancreas is low. has direct proinflammatory effects in the brain. However, during chronic alcohol abuse, the pancreas has a much greater capacity than the liver for nonoxidative metabolism of ethanol to fatty Neuroimmune System acid ethyl esters (Rasineni et al., 2020). Inhibition of hepatic ADH dur- The impact of immune signaling in the brain on the neurobiological and ing chronic drinking and the resulting increased production of fatty acid behavioral changes in AUD or other CNS diseases has been an area of ethyl esters in the pancreas may be a major mechanism in the pathogene- focus over the past decade (Erickson et al., 2019). Chronic ethanol con- sis of chronic pancreatitis. The clinical symptoms are pain, malnutrition, sumption increases the levels of circulating innate immune signaling and diabetes mellitus. Insulin may be needed to control the hyperglyce- molecules (e.g., proinflammatory cytokines) that are capable of reach- mia (see Chapter 51), and pancreatic enzyme capsules containing lipase, ing the brain, where they elicit long-lasting neuroimmune responses amylase, and proteases can treat malabsorption (see Chapter 54). through the transcription of immune-related genes and the activation Liver of astrocytes and microglia. These cells are the principal immune medi- As the main organ involved in ethanol metabolism, the liver is a well- ators in the brain, responding to and releasing molecules like cytokines known target for the pathological effects of chronic ethanol. According to and chemokines. Neurons also mediate immune responses and express the CDC in 2018, about 43% of deaths due to liver disease among individ- immune-related genes. Although microglia are the resident macro- uals ages 12 and older involved alcohol. Over time, the dose-dependent phages in the brain, there is new appreciation for how they directly com- effects progress from fat accumulation (steatosis) to fatty liver accom- municate with neurons. The transition of microglia to reactive states is a panied by inflammation (steatohepatitis), to collagen deposition (fibro- diverse process with different functional states that may dictate healthy sis), to fibrous scarring and loss of liver cells (cirrhosis). However, heavy CNS function or trigger neuroinflammatory processes in psychiatric and drinkers may develop cirrhosis without first developing hepatitis. neurodegenerative diseases. Drugs that inhibit neuroimmune/proin- Ethanol perturbs most aspects of hepatic lipid metabolism (You and flammatory signaling have opened new avenues for therapeutics and are Arteel, 2019), and the accumulation of fat in the liver is an early event currently being studied for their potential to reduce alcohol drinking. that can develop over a few days. The generation of excess NADH, via metabolism of ethanol and acetaldehyde by ADH and ALDH, inhibits Cancers the tricarboxylic acid cycle and the oxidation of fat, leading to steatosis Ethanol is a procarcinogen and increases the risk of several types of (see Figure 27–1). Fibrosis, resulting from tissue necrosis and chronic cancers (National Cancer Institute, 2020). People who drink 50 g (~3.5 inflammation, is the underlying cause of alcoholic cirrhosis. Fatty liver drinks) or more of alcohol daily are at two to three times greater risk disease is common in those with AUD, while a minority will go on to of cancers of the oral cavity, pharynx, and larynx; tobacco use further escalates these risks. Compared with non- or occasional drinkers, this https://ebooksmedicine.net/ develop cirrhosis.  526 level of drinking is associated with a 1.5 times greater risk of developing colorectal cancer. AUD is a major risk factor for esophageal squamous Clinical Uses of Ethanol cell carcinoma, as is genetic deficiency of ALDH2. AUD is a primary For the treatment of poisoning by methanol or ethylene glycol, fomepizole cause of liver cancer. Epidemiological studies show a higher risk of breast is the first-line treatment, but systemically administered ethanol is also cancer in women who are heavy drinkers. A notable complication in the used; it acts at ADH to competitively slow the metabolism of methanol to treatment of cancer patients with AUD is that ethanol can interfere in the formaldehyde and thence formic acid (see Figure 27–1). Dehydrated alco- metabolism of some chemotherapeutic agents. The effects of acetalde- hol injected in close proximity to nerves or sympathetic ganglia is used to hyde, a demonstrated carcinogen in animal models, and oxidative stress relieve long-lasting pain related to trigeminal neuralgia, inoperable car- are widely cited mechanisms for the increased rate of carcinogenesis cinoma, and other conditions. Epidural, subarachnoid, and lumbar para- among individuals with AUD. Evidence also points to a role for aber- vertebral injections of ethanol are also administered for inoperable pain. rant DNA methylation patterns and other epigenetic modifications that For example, lumbar paravertebral ethanol injections destroy sympathetic control genome activity as mechanisms in alcohol-induced cancer devel- ganglia and thereby cause vasodilation, provide pain relief, and promote opment and progression. Epigenetics refers to processes that affect gene CHAPTER 27 ETHANOL healing of lesions in patients with vascular disease of the lower extremities. expression without changes in DNA sequence. Teratogenic Effects: Fetal Alcohol Drug Interactions Spectrum Disorders There are hundreds of over-the-counter and prescription medications that can interact adversely with ethanol. Ethanol increases the risk of Ethanol is the most common teratogen in humans. Ethanol from a moth- liver damage or internal bleeding associated with aspirin or other non- er’s blood passes freely to her baby through the umbilical cord, and it steroidal anti-inflammatory drug use. Due to synergistic effects in the can be assumed that embryo or fetal BECs will be similar to maternal CNS, caution must be taken when administering sedatives in patients levels. Children born to mothers who are heavy drinkers display mental who have ingested heavy doses of ethanol or other CNS depressants. deficits and a common pattern of distinct dysmorphology known as FAS Acute ethanol intoxication decreases general anesthetic requirements, (fetal alcohol syndrome). The diagnosis of FAS is typically based on the and elective surgery should be postponed in intoxicated patients. In observance of a triad of abnormalities associated with a history of prena- contrast, chronic ethanol drinking increases anesthetic requirements tal ethanol exposure (Dorrie et al., 2014): largely due to pharmacodynamic cross-tolerance. An additional com- A cluster of craniofacial abnormalities plication is the use of neuromuscular blockers and sedative/anesthetic CNS dysfunction (structural or functional) agents in patients with AUD presenting with compromised liver func- Pre- or postnatal growth deficiencies (weight or height) tion. This is particularly true for patients administered succinylcholine and benzodiazepines. Fetal alcohol spectrum disorder is not a diagnostic term used by clini- Pharmacokinetic interactions between ethanol and other drugs must cians but rather an umbrella term that encompasses all of the disabilities also be considered. Acute administration of ethanol inhibits the function caused by prenatal alcohol exposure. For example, children who do not of enzymes responsible for metabolizing a variety of different drugs, meet all the criteria for a diagnosis of FAS may show physical or men- including codeine, morphine, phenytoin, some benzodiazepines, tolbuta- tal deficits consistent with partial phenotypes, including partial FAS, mide, and warfarin, among others. One in five prescription opioid deaths alcohol-related neurodevelopmental disorder (ARND), and alcohol-related involves alcohol, and mixing these drugs increases risk of overdose and birth defect (ARBD) (Dorrie et al., 2014). The DSM-5 characterizes neuro- death. Because ethanol is a substrate for CYP2E1, any drug being metab- behavioral disorder associated with prenatal alcohol exposure as a condition olized by this CYP isozyme will be metabolized at a slower rate in the associated with problems in thinking, behavior, and life skills (Hagan et presence of ethanol. In contrast, the chronic administration of ethanol al., 2016). The incidence of FAS is about 0.5 to 2 per 1000 live births in the acts as an enzyme inducer, particularly of CYP2E1, increasing the rate general U.S. population, while the incidence of FAS, ARND, and ARBD of metabolism of phenytoin, warfarin, propranolol, and benzodiazepines. combined is at least 1%. Early diagnosis and treatment intervention are Activation of CYP2E1 in heavy drinkers can change acetaminophen into a important for these children. Higher rates of FAS occur in children born toxic chemical and exacerbate hepatoxicity (see Figure 9–4). to African and Native American women. Children of binge-drinking mothers show severe mental and behavioral deficits, likely due to the high peak BECs (Dorrie et al., 2014). The FAS craniofacial abnormalities associated with maternal drinking Comorbidity of Alcohol Use Disorder With in the first trimester consist of microcephaly, shortened palpebral fis- Other Psychiatric Disorders sures, thin upper lip, smooth philtrum, and epicanthal folds. Magnetic Patients diagnosed with a mood or anxiety disorder are about twice resonance imaging studies demonstrate decreased volumes in the basal as likely to suffer from a drug abuse disorder and vice versa. AUD is ganglia, corpus callosum, cerebrum, and cerebellum that correlate with comorbid with other SUDs, major depressive and bipolar disorders, the facial abnormalities. CNS dysfunction attributed to in utero ethanol certain phobias, and antisocial and borderline personality disorders. exposure consists of hyperactivity; attention and mental deficits; learn- AUD or other SUDs also co-occur with schizophrenia. Interestingly, ing disabilities; language, memory, and motor disorders; and psychiatric there is a common neuroimmune link among AUD and some comor- conditions. FAS is the number one preventable cause of cognitive and bid psychiatric disorders, suggesting a rationale for the development attention deficits in the Western world, with afflicted children consis- of therapeutics that target the key neuroimmune pathways. Although tently scoring lower than their peers on a variety of IQ tests. Although selective serotonin reuptake inhibitors (SSRIs) have not been shown to the evidence is not conclusive, it has been suggested that even mod- be effective treatments for AUD in those without a mental health disor- erate alcohol consumption (28 g/day) in the second trimester of preg- der, SSRIs and other antidepressants may decrease alcohol intake when nancy is correlated with impaired academic performance of children at AUD and depression co-occur. If alcohol use occurs as a consequence of age 6. Maternal age also may be a factor: Pregnant women over age 30 depression, treating the underlying problem can decrease drinking. who drink alcohol create greater risks to their children than do younger Exposure to traumatic events, and the debilitating, long-term anx- women who consume similar amounts of alcohol. In addition, the intake iogenic symptoms that often result, are a cornerstone of posttraumatic of high amounts of alcohol, particularly during the first trimester, greatly stress disorder (PTSD). Classic symptoms include: increases the chances of spontaneous abortion. Alcohol use is risky throughout pregnancy, and there is no known safe amount. Current rec- Intrusion or reexperiencing the event ommendations are to drink no alcohol during pregnancy. Avoidance of internal and external reminder  Negative changes in mood and cognition 527 Hyperarousal and reactivity TABLE 27–2 FDA-APPROVED MEDICATIONS FOR TREATING ALCOHOL USE DISORDER PTSD increases the risk of developing AUD or other SUDs. There is a high prevalence of comorbid AUD and PTSD in the U.S., and, not MEDICATION USUAL DOSE MECHANISM/EFFECT surprisingly, a dual diagnosis exacerbates the symptoms of each disorder Disulfiram 250 mg/d Inhibits ALDH with resulting ↑ and worsens the prognosis for recovery. AUD and PTSD share consid- (range of acetaldehyde in the presence of erable overlap in neural substrates and neuropathologies (Gilpin and 125–500 mg/d) ethanol. Abstinence is reinforced Weiner, 2017). The SSRIs sertraline and paroxetine are FDA-approved to avoid the adverse reaction. for PTSD, but few studies have examined their efficacy in patients with PTSD and AUD. In one clinical trial, sertraline modestly improved Naltrexone 50 mg/d Opioid receptor antagonist; may PTSD symptoms and drinking measures but only in a subset of patients (oral) ↓ drinking by ↓ the rewarding with early-onset PTSD and less severe AUD (Gilpin and Weiner, 2017). and reinforcing properties of SECTION II Verplaetse et al. (2018) have reviewed different treatment interventions alcohol. for comorbid PTSD and AUD. For example, naltrexone (FDA-approved Naltrexone 380 mg/4 Same mechanism and effect as for AUD and discussed later) has modest effects on alcohol outcomes (IM) weeks oral naltrexone. Long-acting but does not significantly improve PTSD symptoms. Randomized clin- depot formulation may improve ical trials are needed to study potential drug combinations in these bioavailability and patient comorbid diseases. compliance. NEUROPHARMACOLOGY Acamprosate 666 mg three May modulate glutamate and times daily GABA neurotransmission; may Alcohol Use Disorder and Genetics work best in patients who are As with other complex trait disorders, the development and progression abstinent at treatment initiation. of AUD are influenced by multiple genetic and environmental factors, including stressors such as emotional, physical, or sexual abuse and drinking patterns within one’s culture and peer group. The heritability of AUD is estimated to be 50% to 60%, as judged by family and twin Pharmacotherapies for Alcohol Use Disorder studies. In the U.S., the lifetime prevalence rate for AUD is estimated to be Among the genetic variants identified, the most significant are in the 29% (Grant et al., 2015). Despite evidence-based treatment options, ethanol-metabolizing enzymes. Linkage analyses show that genes clus- however, AUD often goes undiagnosed and untreated. There are still tered in the ADH region affect risk for alcohol dependence (Edenberg only a few FDA-approved drugs for AUD: disulfiram, naltrexone (oral et al., 2006). For example, the ADH1B*2 variant is found in high frequen- and long-acting injectable), and acamprosate (Table 27–2). Disulfiram cies in Asian populations and may protect against AUD. It results in faster inhibits ALDH and thereby alters the pharmacokinetics of ethanol; metabolism of ethanol and a transient higher blood level of acetaldehyde, the other agents have neurobiological mechanisms. They have reason- which is associated with a lower risk for heavy drinking, but a higher risk able efficacy, with effect sizes similar to those of antidepressant drugs. for esophageal, head, and neck cancers in those who drink. The ADH1B*3 However, they are prescribed in less than 9% of patients (Kranzler and single nucleotide polymorphism found in individuals of African descent Soyka, 2018). is also associated with lower incidence of AUD. Benzodiazepines are the treatment of choice for management of acute ALDH2 is the most efficient isozyme in humans for the metabolism alcohol withdrawal (see Table 27–2) and to prevent the progression from of ethanol-derived acetaldehyde. Low levels of acetaldehyde are reward- minor withdrawal symptoms to major ones, such as seizures and delirium ing and stimulating, while high blood levels produce toxic reactions such tremens (see Chapter 28). as vomiting, diarrhea, and unstable blood pressure; thus, variation in ALDH2 activity could affect the rewarding or aversive properties of eth- Disulfiram anol. The genetic variant ALDH2*2 encodes for an enzyme that cannot Disulfiram (tetraethylthiuram disulfide) was the first drug approved to fully convert acetaldehyde to acetate; and in those who drink, acetalde- treat alcohol abuse but is not considered a first-line treatment today. It hyde (a group 1 carcinogen) can accumulate to toxic levels, increasing inhibits ALDH and rapidly increases the blood acetaldehyde concentra- risk of esophageal, head, and neck cancers. Approximately 10% of East tion by 5 to 10 times the level measured when ethanol is administered Asians are homozygous for ALDH2*2 and develop severe adverse reac- alone. Disulfiram irreversibly inactivates cytosolic and mitochondrial tions after the consumption of one drink or less. Similar effects occur forms of ALDH to varying degrees. It is unlikely that disulfiram, itself, if ethanol is consumed with the ALDH inhibitor disulfiram (the first is responsible for ALDH inactivation in vivo. Several active metabo- pharmacotherapy for AUD, discussed in the next section of this chapter). lites, especially diethylthiomethylcarbamate, behave as suicide-substrate Almost 40% of East Asians are heterozygous for ALDH2*2 and experience inhibitors of ALDH in vitro; these metabolites reach significant concen- facial flushing and enhanced sensitivity to alcohol but do not necessarily trations in plasma following the administration of disulfiram. report adverse responses. Because ALDH2 deficiency poses increased Alcohol consumption by individuals previously treated with disulfiram risk of carcinogenesis, those individuals who drink should not dismiss gives rise to marked signs and symptoms of acetaldehyde poisoning. At mild responses to alcohol as inconsequential. BECs of 5 to 10 mg%, mild effects are noted, increasing markedly in As gene discovery efforts continue to progress, findings from a large severity as the BEC reaches 50 mg%. If the patient attains a BEC of 125 sample size show the polygenicity of alcohol use phenotypes and enrich- to 150 mg%, loss of consciousness may occur. Within 5 to 10 min, the ment of candidate genes in tissues from cortical and subcortical regions face feels hot and soon becomes flushed and scarlet in appearance. As known to be involved in AUD or SUDs (Liu et al., 2019). Many classical the vasodilation spreads over the whole body, intense throbbing is felt in neurotransmitter and neuromodulator risk genes for AUD have been the head and neck, and a pulsating headache may develop. Respiratory identified in genome-wide association studies, as well as robust changes difficulties, nausea, vomiting, sweating, thirst, chest pain, hypotension, in genes involved in brain stress and immune signaling. A genome-wide orthostatic syncope, weakness, vertigo, blurred vision, and confusion are meta-analysis in individuals of European ancestry identified new risk observed. The facial flush is then replaced by pallor, and blood pressure loci for problematic alcohol use and also found genetic correlations with may fall to levels seen in shock. Thus, the use of disulfiram requires careful other substance use and psychiatric traits, particularly major depressive medical supervision and patient education and should only be attempted disorder (Zhou et al., 2020). https://ebooksmedicine.net/ in motivated patients committed to maintaining abstinence. Patients must  528 learn to avoid disguised forms of alcohol that may be present in sauces, fer- Baclofen, a GABAB receptor agonist, is a skeletal muscle relaxant mented vinegar, cough syrups, and even aftershave lotions. Disulfiram does used to reduce spasticity. It is approved to treat AUD in France and is not reduce craving; its effectiveness is based on the fear of adverse effects in indicated for use in patients not responsive to other treatments. There the presence of ethanol, resulting in poor patient compliance. is increased risk of sedation when combining baclofen with alcohol. Disulfiram should not be administered until the patient has abstained In a meta-analysis of randomized clinical trials, baclofen was asso- from alcohol for at least 12 h. The FDA-approved dosage is 250 to ciated with a delay in return to drinking and a greater likelihood of 500 mg/day. Unless sedation (the most common side effect) is promi- abstinence, especially in those with higher daily alcohol use at baseline nent, the daily dose should be taken in the morning, the time when the (reviewed in Kranzler and Soyka, 2018). Although some results have resolve not to drink may be strongest. Sensitization to alcohol may last as been promising, evidence overall is uncertain regarding its use, par- long as 14 days after the last dose because of the slow rate of restoration of ticularly as a first-line treatment. For a review of baclofen in treating ALDH. It should be used with caution in patients with liver disease and is AUD, see de Beaurepaire et al., 2019. contraindicated in those with cardiovascular disease. Nalmefene (an analogue of naltrexone) is a mu- and delta-opioid recep- Disulfiram or its metabolites can inhibit many enzymes with sulfhy- tor antagonist with partial agonist activity at kappa receptors. Compared CHAPTER 27 ETHANOL dryl groups, producing a wide spectrum of biological effects. Hepatic with naltrexone, nalmefene has a longer half-life, greater bioavailability, CYPs are inhibited, thereby interfering with the metabolism of phenytoin, and decreased risk of liver toxicity. The European Medicines Agency chlordiazepoxide, barbiturates, warfarin, and other drugs. has recommended nalmefene for as-needed use (18 mg) to reduce heavy drinking. Such targeted use may be beneficial in high-risk situations or in Naltrexone problem drinkers who are not medication compliant or may otherwise not Naltrexone, an opioid receptor antagonist, is approved for AUD in both seek treatment. In a meta-analysis of randomized clinical trials, nalmefene oral and extended-release injectable forms. Naltrexone is chemically was associated with a slight reduction in the number of binge-drinking related to naloxone but has higher bioavailability and a longer duration days and in total alcohol consumption at 6 months (reviewed in Kranzler of action when administered orally. It is also approved for treatment of and Soyka, 2018). opioid dependence (see Chapters 23 and 28). Naltrexone reduces endoge- Gabapentin is an anticonvulsant and GABA analogue that inhibits the nous opioid activity in mesolimbic reward pathways and may reduce α2δ-1 subunit of voltage-gated Ca2+ channels. It is primarily used to treat the reinforcing effects of alcohol by blunting opioid-mediated dopa- neuropathic pain, restless leg syndrome, and as an adjunctive treatment mine transmission. Naltrexone is typically prescribed after no opioids for partial-onset seizures. It is prescribed off-label for anxiety and other have been taken for 7 to 10 days at a dose of 50 mg/day (see Table 27–2). psychiatric disorders. APA guidelines suggest using it to treat AUD after The extended-release intramuscular formulation (380 mg) may increase first trying naltrexone or acamprosate. In one clinical trial, gabapentin bioavailability and overcome problems with medication adherence. It is (particularly at 1800 mg/day) increased the rate of abstinence and pre- approved for monthly injection in those who can abstain from alcohol in vented binge drinking (reviewed in Kranzler and Soyka, 2018). Gabap- an outpatient setting before starting naltrexone. Naltrexone is underuti- entin is also associated with decreased alcohol craving and is used to treat lized in clinical practice, although current American Psychiatric Association mild to moderate alcohol withdrawal (Ahmed et al., 2019). For additional (APA) guidelines recommend it as a first-line drug. information on gabapentin, see Chapter 20. A meta-analysis shows that oral naltrexone reduces risk of relapse to Topiramate is an anticonvulsant that modulates voltage-gated sodium any drinking and to binge drinking (reviewed in Kranzler and Soyka, channels and GABA and glutamate activity in the CNS. It is FDA-approved 2018). Both oral (50 mg/day) and injectable (380 mg, single injection) for seizure disorders and migraine prevention and is used off-label as naltrexone increased the likelihood of no binge drinking in a 1-month an adjunct therapy for chronic weight management. As with gabap- pilot study of male veterans (Busch et al., 2017). entin, current APA guidelines suggest using topiramate as a second-line Naltrexone is well tolerated, the most common adverse effect being nau- treatment for AUD, typically after trying naltrexone or acamprosate. A