Alcohol Use Disorder

GENERAL CHARACTERISTICS AND HISTORY

Evidence of alcohol consumption has been noted as far back as 9,000 years ago by Neolithic farmers in Northern China, and recipes for producing alcohol have been discovered worldwide for thousands of years. Dr. Benjamin Rush is believed to have been the first person to characterize excessive alcohol use as a disorder in 1784. By the late 1800s, temperance movements sprung up across the United States, inspired mainly by religious groups who considered drunkenness a national threat. In 1920, Prohibition was enacted in the form of the 18th Amendment, which prohibited the manufacture and sale of alcohol. This was later repealed in 1933 because of its unpopularity. In 1935, Alcoholics Anonymous (AA) was founded by Bill Wilson and Dr. Robert Smith as a peer-based fellowship to provide group support to other recovering alcoholics when no other treatment options were available. Since then, enormous advances have been made in understanding alcohol use disorder (AUD), including the biological effects of alcohol, treatment approaches for alcohol intoxication and withdrawal, development of medications, and establishment of evidence-based therapies for AUD of which will be reviewed in this chapter.

PHARMACOLOGY OF ALCOHOL

Chemical Structure and Metabolism

Fig. 4.1 shows the chemical structure and metabolism of ethanol and several other alcohols that are clinically relevant to know about and which you may be asked about on the board examination.

Here are some key points to remember about alcohol’s pharmacokinetics and pharmacodynamics:

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  Alcohol undergoes first-pass metabolism in the stomach due to alcohol dehydrogenase (ADH) in the gastric mucosa.

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  Alcohol is metabolized by ADH to acetaldehyde, which is toxic and a known carcinogen. Acetaldehyde is then metabolized by aldehyde dehydrogenase (ALDH) to acetate, which is converted to water and carbon dioxide for easy elimination ( Fig. 4.1 ). CYP2E1 also metabolizes alcohol at higher blood concentrations and produces reactive oxygen species as a byproduct.

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  ADH and ALDH are responsible for metabolizing a range of alcohols encountered in the body, including ethanol, methanol, ethylene glycol, and isopropyl alcohol ( Fig. 4.1 ).

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  Alcohol metabolism follows zero-order kinetics because ADH saturates at very low serum levels of ethanol, leading to constant levels of elimination.

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  Alcohol is metabolized at roughly 0.015 g/dL per hour. The rate of alcohol metabolism is dependent on factors including age, sex, body weight, and differences in expression and enzyme isotypes of ADH and ALDH. Women have a higher blood alcohol concentration than men for an equivalent amount of alcohol use because of lower levels of gastric ADH and first-pass metabolism and lower total body water. Lower body weight and increased age are both associated with a slower metabolism. Gastric ADH levels decline with age.

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  The peak effect of ethanol occurs 30 minutes after consumption.

Nonethanol alcohols that you may be asked about are methanol, ethylene glycol, and isopropyl alcohol.

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  Methanol is found in windshield wiper fluid and is a common impurity in home-distilled spirits (a.k.a. “moonshine”). It is metabolized to formaldehyde and formic acid, which is highly toxic and can lead to blindness by damaging the optic nerve.

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  Ethylene glycol is a common odorless antifreeze component and is metabolized to glycolic acid and other byproducts. Its most toxic byproduct is calcium oxalate, which can accumulate in the body and lead to kidney damage.

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  Isopropyl alcohol is a flammable component of hand sanitizers, rubbing alcohol, disinfectants, and detergents and has a strong odor. ADH metabolizes it to acetone, which is nontoxic and nonacidic.

Neurobiology of Alcohol

Unlike other drugs of abuse that have more targeted pharmacologic effects (e.g., cocaine), alcohol affects many neurotransmitter systems. Here we summarize the key neurotransmitter and receptor systems affected by alcohol and are essential to know for the board examination.

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  γ- aminobutyric acid (GABA): GABA-A and GABA-B receptors are the two main GABA receptor types and are the primary inhibitory receptor system in the central nervous system (CNS); GABA-A is ionotropic and GABA-B is metabotropic. Alcohol’s CNS depressant effects are primarily mediated through enhancement of GABA-A receptor function.

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  Glutamate : Glutamate is the primary excitatory neurotransmitter in the CNS. The three main glutamate receptors are N-methyl-D-aspartate receptor (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and kainate. Alcohol inhibits glutamatergic NMDA receptors, and alcohol withdrawal leads to glutamatergic overactivity owning to loss of NMDA receptor inhibition.

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  Dopamine : The rewarding effects of alcohol are indirectly mediated through the same common pathway as other drugs of abuse, that is, via dopamine release in the ventral tegmental area. Alcohol indirectly increases dopamine levels in the mesocorticolimbic system.

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  Serotonin : Alcohol potentiates 5-hydroxytryptamine 3 (5-HT3) receptor activity; lower overall serotonin neurotransmission is believed to be implicated in AUD. In individuals who abuse alcohol, levels of 5-HT and 5-HT metabolites have been found to be lower in the cerebrospinal fluid.

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  Opioids : Alcohol leads to the release of endogenous endorphins in the ventral tegmentum and nucleus accumbens, which leads to increases in dopaminergic neurotransmission. The use of naltrexone reduces alcohol consumption by blocking opioid receptors.

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  Endocannabinoids : The endocannabinoid system is an important modulator of alcohol’s reinforcing properties.

TOXICOLOGY

Testing for alcohol and other substances is covered at length in Chapter 12 (Drug Testing, Forensic Addictions, and Ethics). Biomarkers for alcohol intoxication or very recent ingestion (typically on the order of hours) include:

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  Blood alcohol concentration (BAC): Tests for alcohol concentration in whole blood samples.

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  Breath alcohol testing, a.k.a. breathalyzer : Tests for alcohol in exhaled air; used by law enforcement agencies and the Department of Transportation.

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  Ethyl glucuronide (EtG): A direct biomarker of alcohol use and a metabolite of ethanol. It can be detected in urine from 1 hour after alcohol intake and up to 3 to 5 days, and then in hair for up to 3 months.

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  Ethyl sulfate (EtS): A direct biomarker of alcohol use and a metabolite of ethanol. It can be detected in urine from 1 hour after alcohol intake and up to 3 to 5 days, and then in hair for up to 3 months.

ALCOHOL INTOXICATION

Alcohol intoxication is associated with a number of complications, including accidents, trauma, homicide, and suicide and accounts for over 600,000 (0.6%) emergency department visits in the United States per year. The following symptoms can be observed at these approximate BACs in nontolerant individuals:

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  50 to 100 mg/dL: Euphoria, disinhibition, slower reaction times

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  100 to 200 mg/dL: Ataxia, slurred speech, deficits in psychomotor skills, impaired judgment

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  200 to 300 mg/dL: Nausea, vomiting, confusion, stupor

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  300 to 400 mg/dL: Hypothermia, amnesia, dysarthria

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  >400 mg/dL: Obtundation, coma, respiratory depression, seizures, arrhythmias, death

In general, uncomplicated alcohol intoxication is not life-threatening, except for alcohol poisoning, which can be fatal. Patients presenting with a BAC greater than 300 mg/dL are at risk for coma, respiratory depression, and death. Keep in mind that an elevated BAC may not be accompanied by any notable signs of intoxication among individuals who use large amounts of alcohol chronically.

Other common sequelae of alcohol intoxication include:

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  Anterograde amnesia (a.k.a. “blackouts”): A common consequence of heavy alcohol use and frequently seen in college-age adults. Some risk factors include a rapid rise in BAC, fatigue, drinking on an empty stomach, and drinking quickly (a.k.a. chugging).

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  Hangovers: They are not well understood but are believed to be caused by a build-up of the intermediate metabolite, acetaldehyde, in addition to dehydration, electrolyte imbalance, and poor sleep. Alcohols with congeners (e.g., red wine and other dark liquors such as rum and brandy) are more likely to cause hangovers than clear alcohols.

ALCOHOL WITHDRAWAL

Following an abrupt reduction or cessation of alcohol use, alcohol withdrawal symptoms can emerge within 6 to 8 hours and may last for up to 7 days. Alcohol enhances inhibitory GABA-A receptor function and inhibits excitatory glutamatergic NMDA receptors; therefore cessation of alcohol in an individual who is physiologically dependent results in alcohol withdrawal pathophysiology: loss of GABAergic inhibition, glutamatergic overactivity, and a severe hyperadrenergic state. Predictors of more severe alcohol withdrawal include longer duration of alcohol use, medical comorbidities, history of prior alcohol withdrawal, seizures or delirium tremens (DTs; due to kindling effects), presence of medical illness (notably electrolyte abnormalities and elevated liver function tests), presentation with BAC greater than 300 mg/dL, and elevated blood pressure and heart rate. There is high individual variation in the severity and duration of alcohol withdrawal symptoms. Keep in mind that patients can experience alcohol withdrawal symptoms before the BAC returns to zero.

Symptoms of mild alcohol withdrawal include anxiety, sweating, irritability, tremor, agitation, nausea, and vomiting, with normal mental status. More severe sequelae of alcohol withdrawal include the following:

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  Alcoholic hallucinosis: Hallucinations are predominantly auditory but can include visual and tactile hallucinations as well. Hallucinosis can occur without the presence of other withdrawal symptoms and the patient’s mental status is otherwise clear. Hallucinosis is not synonymous with DTs.

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  Alcohol withdrawal seizures: Typically tonic-clonic seizures; status epilepticus is uncommon.

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  DTs: This is the most serious complication of alcohol withdrawal with high mortality rates if left untreated. Symptoms include fluctuating levels of consciousness, visual and auditory hallucinations, autonomy instability, and hyperpyrexia.

The general timeline of alcohol withdrawal symptoms is presented here.

After resolution of acute alcohol withdrawal and establishment of abstinence, patients can continue to experience protracted withdrawal symptoms that resemble some of the symptoms of acute withdrawal. These include sleep disruption, depression, mood swings, anxiety, and agitation, and they can render the patient vulnerable to relapse during early abstinence.