The Pharmacology of Alcohol

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 beferage. 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 casesof 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 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.

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EPIDEMIOLGY

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 years-olds to nearly 70% of 21- to 25-years-olds.
Prevalence decreased among older groups, although it was nearly 50% among 60- to 64-years-
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 wellknown classification schemes are the type I and II forms
proposed by Cloninger and colleagues and the types A and B forms proposed by Babor.
Cloningers type I and Babors 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 blood stream 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 woman show less gastric metabolism of alcohol than men, when
body weights are equivalent, woman 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.

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PHARMACODYNAMICS
Central Nervous System

Acutely, alcohol acts as a central nervous system (CNS) depressant. During the initial phase
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 System

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 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
woman. Alcohol causes changes in contractility and function of cardiovascular system, and
chronic alcohol increase 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.

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 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 alcohols 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 tp 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 it self.

Glutamate is the major excitatory neurotransmitter in the brain and activates three major
subtypes of ion channels called AMPA, kainite, and NMDA receptors. These channels cause
depolarization of the neuronal membrane and are implicated in process 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 Chanel Subtypes

5-HT3 receptors are ligand-gated ion chanels activated by serotonin. Alcohol potentiates currents
carried by 5-HT3 receptor, and 5-HT3 receptort 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 niotiic receptors are expressed. It is not clear how these effects on
the nicotinic receptor are manifested at the behavioral level. However, the 42 nicotinic
receptor particial 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.

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 Potassium channels that are regulated by calcium (SK and BK channels) and those gated by
Gprotein (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 dieresis that accompanies alcohol ingestion. Changes in the expressionand
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 System

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 increase 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 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 ethanolpreference in wild-type mice, and animals
genetically lacking CB1 receptors show reduced alcohol preference.

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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 phycologic 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 alcohl 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 system 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 cerellar gray

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 mater, 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
woman, 2 drinks for men) are associated with reduced risk of cardiovascular disease.

ACKNOWLADGEMENTS
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
bilion.
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: Woman 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 woman typically experience higher blood alcohol levels than men of similar weight
when drinking similar amounts.
2. Which of the following factors is NOT shared by Cloningers type I and Babors type A
alcoholics ?
A. Later onset of alcohol-related problems (>25 years old)
B. Fewer childhood behavior problems
C. Relatively mild alcohol-related issues with fewer hospitalizations
D. Lower degree of novelty-seeking coupled with a preference toward harm avoidance.
E. Greater tendency to run in families
3. Which of the following is NOT a major medical complication arising from heavy drinking ?
A. Skeletal fragility

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 B. Increased risk of developing certain types of cancers
C. Increased volume of brain tissue in areas of the frontal cortex, hippocampus, and
cerebellum
D. Lower rates of brain glucose metabolism
E. Fetal abnormalities

ANSWER
1. True. Woman generally have less gastric metabolism of alcohol (when adjusted for
body/liver weight). Since gastric metabolism makes up a significant proportion of the overall
breakdown of alcohol, the blood ethanol concentration in woman is 20% to 25% higher than
men of comparable body weight following ingestion of similar amounts of alcohol.
2. E. There is less tendency to run in families in type I and type A alcoholics. That factor is seen
with Cloninger type II and Babor type B alcoholics.
3. C. Alcohol can cause decreased volume of brain tissue.

SUGGESTED READINGS
Howard RJ, Slesinger PA, Davies DL, et al. alcohol-binding sites in distinct brain proteins: the
quest for atomic level resolution. Alcohol Clin Exp Res 2011;35(9): 1561-1573, doi:
10.1111/j.1530-0277.2011.01502.x. review. pubMed PMID: 21676006; PubMed Central
PMCID; PMC3201783.
Koob GF. Theoretical frameworks and mechanistic aspects of alcohol addiction: alcohol
addiction as a reward deficit disorder. Curr Top Behav Neurosci 2013;13:3-30. Doi:
10.1007/7854_2011_129. Review. PubMed PMID: 21744309; PubMed Central
PMCID:PMC3448980.
Leggio L, Kenna GA, Fenton M, et al. typologies of alcohol dependence. From Jellineck to
genetics and beyond. Neuropsychol Rev 2009;19(1):115-129. doi: 10.1007/s11065-008-
9080-z. Review PubMed PMID: 19184441.
Neuroscience: Pathways to alcohol dependence. Alcohol Alert. 2009. NIAAAwebsite.
http://pubs.niaaa.nih.gov/publications/AA77/AA77.htm
Riley EP, Infante MA, Warren KR. Fetal alcohol spectrum disorders: an overview. Neuropsychol
Rev Review. PubMed PMID: 21499711: PubMed Central PMCID: PMC3779274.