Handbook of Clinical Neurology, Vol.

125 (3rd series)

Alcohol and the Nervous System
E.V. Sullivan and A. Pfefferbaum, Editors
© 2014 Elsevier B.V. All rights reserved

Chapter 31

Alcohol–medical drug interactions

BANKOLE A. JOHNSON1* AND CHAMINDI SENEVIRATNE2
1
Department of Psychiatry and Brain Science Research Consortium at the University of Maryland School of Medicine,
Baltimore, MD, USA
2
Department of Psychiatry, Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD, USA

INTRODUCTION tissue also becomes sensitive to chemical compounds in

older adults. The greater use of medications in this
Many over-the-counter and prescription medications
age group and the presence of chronic disease condi-
interact with alcohol when drinking is moderate to heavy.
tions that are often worsened by alcohol increase the
As a result, alcohol can reduce the desired effects, or
potential for alcohol-medication adverse events (Moore
enhance the adverse effects, of the interacting medica-
et al., 2007a).
tions. Risk of developing adverse effects is greatest
Alcohol is a small polarized molecule with
when medications are used in combination with alcohol,
both lipophilic and hydrophilic properties (Ferreira and
as often occurs in people with pre-existing alcoholism
Willoughby, 2008). Amphipathic properties facilitate
or multiple illicit drug addictions. The data from
absorption across biologic membranes and a similar vol-
several US national surveys indicate a growing trend
ume of distribution to that of total body water. These
of concomitant use of alcohol and medications, result-
properties allow alcohol to reach the central nervous sys-
ing in potentially serious medical conditions. For exam-
tem (CNS), exerting its physical and behavioral effects in
ple, the 2012 Drug Abuse Warning Network report
a dose-dependent manner. Pathophysiologic effects of
showed a 115% increase in emergency department (ED)
alcohol are determined by the concentration of alcohol
visits related to medical drug misuse between 2004
present in a person’s blood (blood alcohol concentration:
and 2010 ([Link]
BAC) and parameters that influence its interaction at the
[Link]). Among adults, alcohol
effector sites. Likewise, the blood concentration of some
accounted for 21% of benzodiazepine-, tranquilizer-,
medications and their interaction with their effector sites
and opioid-related ED visits (White et al., 2011). Fifty-five
may also be influenced by alcohol. Based on these mech-
percent of all alcohol-related ED visits in underaged
anisms, alcohol-medication interactions are classified
drinkers (12–20 years) involved a medical drug (http://
into two main categories: (1) pharmacokinetic interac-
[Link]/data/2k10/WEBSR025AlcDrugCombo/
tions and (2) pharmacodynamic interactions. This chap-
[Link]). In young adults (aged 18–24 years),
ter focuses on mechanisms underlying pharmacokinetic
ED visits due to combined alcohol and medication over-
and pharmacodynamic interactions and their implica-
dose increased by 76% from 1999 to 2008 (White et al.,
tions. All examples for alcohol-medication interactions
2011). Another demographic group that is particularly
discussed here are limited to the ones that have been ver-
vulnerable to alcohol-medication interactions is the
ified by independent studies.
elderly (aged
65 years). The risk of adverse reactions
arising from alcohol-medication interactions is much
PHARMACOKINETIC INTERACTIONS
greater in elderly individuals due to physiologic and social
reasons. Physiologic processes in aging affect distribution Alcohol-medication pharmacokinetic interactions refer
and metabolism of alcohol and various medications. Brain to the influence of alcohol on the absorption,

*Correspondence to: Bankole A. Johnson, DSc, MD, MBChB, MPhil, FRCPsych, DFAPA, The Dr. Irving J. Taylor Professor and
Chair in the Department of Psychiatry, Professor of Pharmacology and Professor of Anatomy & Neurobiology, Director of the
Brain Science Research Consortium at the University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Tel: +1-410-328-6735, Fax: +1-410-328-3693, E-mail: bjohnson@[Link]
544 B.A. JOHNSON AND C. SENEVIRATNE
Brain
Alcohol

Peroxisome
NADPH

Microsome
H2O2
Systemic Catalase CYP2E1

Circulation H2 O NAD+
Acetaldehyde
Acetate NAD+

Mitochondria
Acetylcholine
Cytoplasm
Citric acid cycle ALDH2

Acetaldehyde NADH + H+

Acetyl-CoA Acetate
Hepatic Alcohol
Vein
Other organs and tissues
Liver
Mitochondria

Acetate Non-oxidative pathways

~1% Ingested alcohol
ALDH2
EtG, EtS, FAEE, PEth

Alcohol
Cytosol ~60% Microsome

Acetate ALDH1 Acetaldehyde

NADPH
NAD+
ADH CYP2E1

NADH + H+ NAD+ Acetaldehyde Excretion

Alcohol ~3-5% Ingested alcohol

Breath, Urine, Sweat

Fig. 31.1. Pharmacokinetic pathways of alcohol.

distribution, metabolism, and excretion of a medication circulation and is distributed throughout the water com-
or vice versa. All of these factors determine the BAC partment of the body unbound to plasma proteins. Under
and, consequently, the concentrations at their effector normal conditions, tissue distribution occurs until an
sites. Pathways involved in pharmacokinetic mecha- equilibrium is reached between plasma BAC and the tis-
nisms are depicted in Figure 31.1, and common factors sue concentrations of alcohol (Ferreira and Willoughby,
affecting BAC are presented in Table 31.1. 2008). Time to reach equilibrium generally ranges from 1
to 2 hours after the ingestion of alcohol but is influenced
by various factors (Table 31.1). In the absorptive phase,
Absorption and distribution BAC rises more slowly than alcohol concentration in tis-
As alcohol passes along the digestive tract, a small sues, and during the elimination phase, BAC falls more
amount is metabolized in the oral and gastric mucosa slowly than alcohol concentrations in tissues. So, BAC
by the class ΙV isoform of the enzyme alcohol dehydro- may not reflect the actual impact of alcohol on tissues
genase (ADH), and about another 10–20% is absorbed such as the brain.
into the gastric veins. The rest of the ingested alcohol
is rapidly absorbed in the small intestines. Because the
Elimination
rate of absorption is much faster in the small intestine
compared with the stomach, any delay in gastric empty- The main method of elimination of alcohol is through
ing (GE) (Table 31.1) will reduce the speed of alcohol oxidation in the liver. The non-oxidative metabolism of
absorption. On the other hand, factors that increase alcohol accounts only for about 1% of total ingested
intestinal transit time will enhance absorption. GE is alcohol, and it is then excreted in the urine. Only about
the most important contributing factor determining 2–5% of absorbed alcohol is excreted unchanged in
the kinetic parameters of time to reach peak concentra- breath, sweat, or urine (Vonghia et al., 2008). The
tion (tmax) as well as the peak concentration of alcohol in amount of ethanol eliminated per unit of time depends
blood (Cmax). Alcohol absorbed in the stomach and small on the initial amount that was ingested. This pattern of
intestines enters the portal vein and is carried to the liver. elimination is called zero-order kinetics, which follows
In the liver, a portion of the alcohol is metabolized, as the Michaelis-Menten model of enzyme kinetics. Thus,
shown in Figure 31.1. Alcohol that escapes first-pass the half-life of ethanol will be lower with small quantities
metabolism (FPM) in the liver enters the systemic of drinking and higher with severe drinking. Studies
 ALCOHOL–MEDICAL DRUG INTERACTIONS 545
Table 31.1
Factors affecting blood alcohol concentration (BAC)

Variable Effect

Factors affecting absorption

Stomach contents Gastrectomy increases GE: " BAC
Fed state, amount of sugar in an alcohol beverage, cigarette smoking prolongs GE: # BAC
Alcohol concentration Absorption rates are greatest at concentrations between 20% and 30%; alcohol concentrations >30%
irritate gastric mucosa, resulting in lower absorption rates
Autonomic nervous SNS – decrease by slowing GE and portal blood flow
activity PNS – increase GE
Age Prolonged GE with aging
Osmolarity Increases absorption (e.g., carbonated drinks)
Medications See Table 31.2
Portal blood flow A good blood flow in the portal system enhances absorption
Factors affecting distribution
BMI Increased body water facilitates bioavailability
Gender Lower volume of distribution in females per unit of body weight due to smaller blood volume and lean
body mass: " BAC
Age Older people tend to have more body fat
Time to drink Affects time to peak BAC
Alterations to Peripheral vasoconstriction (e.g., cold temperatures, peripheral vascular disease, and cardiac disease):
peripheral " BAC
circulation Increased peripheral blood flow (e.g., high temperatures, exercise, and antihypertensive medications):
# BAC
Factors affecting metabolism
Gender Gastric ADH levels are lower in women than in men of similar weight: " BAC
Age Aging reduces gastric ADH levels
Race Variations in enzyme levels (see Table 31.2 for genetic variations)
Gastric morphology Atrophic gastritis and Helicobactor pylori infection reduce gastric ADH activity
Alcoholism Gastric ADH is lower in alcoholics compared with moderate drinkers

GE, gastric emptying; BMI, body mass index; SNS, sympathetic nervous system; PNS, peripheral nervous system; ADH, alcohol dehydrogenase.

comparing different controlled alcohol doses have of the ingested alcohol; at five or more drinks per day,
shown that the average rate of elimination of alcohol is there was a linear increase of the minimum BAC indicat-
generally around 0.01–0.035 g/100 mL/hour (Jones, ing a certain residual amount. According to this model,
2010). Factors that lower or accelerate these rates are listed when a person consumed 11 or more standard drinks/
in Table 31.1. Although the zero-order kinetic model is day, BAC reached a level that never went down to zero
widely used in forensic sciences, it is an over- within 24 hours. Although an earlier study has shown a
simplified model that does not reflect complexities of lack of linear relationship between self-repots of drink-
pathways involved in alcohol metabolism, such as indi- ing and BAC after 7 standard drinks (Bond et al., 2010),
vidual differences. Several models have been introduced the simulated results in the study by Kovatchev et al.
to improve the understanding of alcohol metabolism (2012) need experimental replication for establishing crit-
following both oral and intravenous administration, ical points of transition from stable to unstable dynamics.
including first-order and combined zero-and-first-order The alcohol that is absorbed by gastric and intestinal
kinetic models. Improving on these models, Breton veins enters the liver through the portal system. The
et al. proposed the Minimal Model of Ethanol Dynamics metabolism of alcohol within both the stomach and
that includes metabolic mechanisms occurring in the the liver is known as FPM as it occurs prior to entering
stomach and gut (Breton, 2010; Kovatchev et al., 2012). the systemic circulation (Levitt et al., 1997). With the gas-
Applying this model, Kovatchev et al. (2012) tric FPM accounting for only 2% or less, liver is undisput-
demonstrated the pattern of blood alcohol kinetics based edly the main site of FPM. FPM reduces the availability of
on different levels of intake. As shown in Figure 31.2, alcohol in the blood. Slow GE accelerates gastric FPM by
during daytime, with 4 standard drinks/day or less, prolonging exposure to gastric ADH. Several other main
BAC levels were zero implicating complete metabolism factors that influence alcohol metabolism are listed in
546 B.A. JOHNSON AND C. SENEVIRATNE

Fig. 31.2. Minimum blood alcohol levels during (A) daytime (7 AM–11 PM) as a function of average number of drinks per day
and, (B) night (11 PM–7 AM) as a function of average number of drinks consumed during the day (7 AM–11 PM). (Figure as
originally published in Kovatchev B, Breton M, Johnson B. (2012). In silico Models of Alcohol Dependence and Treatment Front.
Psychiatry 3:4. [Link]

Table 31.1. However, it should be noted that, despite the et al., 2012). Class ΙΙΙ consists of ADH5, which oxidizes
findings of many early studies that demonstrated a long-chain primary alcohols, but no activity has been
correlation of gastric ADH and FPM, the role of gastric reported in ethanol oxidation (Adinolfi et al., 1984).
ADH in oxidizing significant amounts of alcohol is still Medications that inhibit ADH are shown to increase
debatable, mainly because of its relatively low affinity BAC. When ADH is deficient, as seen in Asian popula-
(high Km) for alcohol compared with the hepatic ADH. tions, the effect of ADH inhibitors on alcohol oxidation
Both FPM and the systemic portion of alcohol will be negligent (Gugler, 1994).
metabolism occur through oxidative and non-oxidative
pathways.
CYP 450 SYSTEM
Oxidative pathways of alcohol metabolism The enzymes of the CYP 450 system are also involved in
Oxidative pathways consist of the enzymes ADH, cyto- oxidizing alcohol to acetaldehyde. The main CYP 450
chrome P450 (CYPs), aldehyde dehydrogenase (ALDH), enzyme involved in alcohol oxidation is CYP2E1 (Heit
and catalase. Medications that compete with alcohol for et al., 2013; Osna and Donohue, 2013). Some recent find-
binding to these enzymes are discussed in Table 31.2. ings have indicated the involvement of other CYP
enzymes such as CYP1A2 (Salmela et al., 1998) and
CYP3A4 (Salmela et al., 1998; Lytton et al., 1999;
ADH FAMILY OF ENZYMES
Feierman et al., 2003) that warrant further investigation.
ADH oxidizes alcohol into its primary metabolite, acet- CYP2E1 activity depends on the pattern of drinking.
aldehyde (Fig. 31.1). There are five main classes of ADH When alcohol is consumed occasionally in small
enzyme isoforms (isozymes Ι–V) in humans. The class Ι amounts, only an insignificant amount of alcohol is oxi-
isozyme (ADH1) catalyzes the rate-limiting step of the dized by CYP2E1. With chronic heavy drinking, CYP2E1
oxidative pathway of ethanol metabolism in the liver activity is induced by about 10-fold. This ability to oxi-
(Osier et al., 2002; Edenberg, 2007). ADH1 is formed dize more alcohol accelerates alcohol clearance from
by heteromers of subunits a, ß, and g. Class ΙΙ and ΙΙΙ blood, leading to development of chronic tolerance
ADH isozymes are also expressed in the liver in smaller (Pizon et al., 2007). Hence, the medications metabolized
amounts (Edenberg, 1998). Class ΙΙ ADH4 and, to a by CYP2E1 are oxidized faster in chronic heavy drinkers,
lesser degree, class Ι ADH1C contribute to gastric alco- requiring higher dosages. In contrast, if a medication
hol oxidation (Lee et al., 2006). ADH4 that is present in metabolized by CYP2E1 is administered following a bout
the liver and gastric mucosa may oxidize about 40% of of acute heavy drinking, the therapeutic effects of the
total alcohol at intoxicating levels (Li et al., 1977; Lewis medication may become prolonged as a consequence
Table 31.2
Medications that commonly interact with alcohol

Drug class Substance Mechanism Outcome Comment

Analgesics NSAIDs Low doses of NSAIDs delay GE # BAC intensifies adverse effects of Adverse effects are worse when
(e.g., aspirin, (Kechagias et al., 1997); the drug such as gastric bleeding NSAIDs are taken on an empty
ibuprofen, aspirin inhibits gastric ADH (Kaufman et al., 1999; Neutel and stomach; avoid NSAIDs within
phenylbutazone) (Weathermon and Crabb, 1999); Appel, 2000) 8–10 hours of drinking
competes for binding sites on
CYP2E1
Acetaminophen Binge drinking increases NAPQ1 impairs calcium Increased risk for hepatotoxicity
metabolism of acetaminophen to homeostasis and causes oxidative with regular or high doses
NAPQ1 in chronic alcoholics by stress and cell death, leading to (>4 g/24 hours) of
induction of CYP2E1 and liver failure acetaminophen (Prescott, 2000)
depletion of glutathione that
inactivates NAPQ1 (Zimmerman
and Maddrey, 1995; Hersh et al.,
2007; Gomez-Moreno et al.,
2008) and inhibits gastric ADH
(Weathermon and Crabb, 1999)
Opioids Agonist effects of opioids on m Opioids combined with alcohol can Avoid alcohol when taking opioids
(e.g., meperidine, methadone, opioid receptors are facilitated by cause excessive central nervous
propoxyphene) alcohol through GABA and system (CNS) depression and
NMDA receptors (McCance- impaired psychomotor function,
Katz et al., 2010) leading to respiratory depression;
overdoses of propoxyphene
combined with alcohol have been
linked to fatal reactions
Antibacterial Erythromycin Accelerates GE through agonist " BAC
effects on smooth-muscle motilin
receptors Urbain et al., 1990;
(Larson et al., 2010)
Chloramphenicol Inhibits low-Km ALDH2 in the brain " BAC
and liver (Vasiliou et al., 1986)
Isoniazid Inhibits low-Km ALDH2 in the brain " BAC " Hepatotoxicity in chronic
and liver (Vasiliou et al., 1986) alcoholics; monitor liver
function; limit or avoid alcohol
use
Cephalosporin drugs with an Ceftriaxone shown to reduce Disulfiram-like reaction to alcohol
N-methylthio-tetrazole moiety ethanol drinking in rodent models (McMahon, 1980)
(NMTT) (e.g., cefoperazone and via activation of glutamate
cefotetan, moxalactam, transporter 1 (GLT1) (Sari et al.,
cefamandole) 2011; Qrunfleh et al., 2013)

Continued
Table 31.2
Continued

Drug class Substance Mechanism Outcome Comment

Anticoagulants Warfarin Acute alcohol " warfarin " Risk of life-threatening Monitor international normalized
availability; chronic alcohol use # hemorrhages with heavy alcohol ratios if the patient consumes >3
warfarin metabolism use (Baker et al., 2004) alcoholic drinks/day or if there
has been a significant change in
the amount of recent alcohol
consumption
Anticonvulsants Phenytoin Alcohol induces hepatic metabolism Chronic alcohol consumption
of phenytoin increases phenytoin metabolism
(Tanaka, 2002)
Antidepressants Tricyclics Alcohol interferes with the first- " Amitriptyline levels in blood;
(e.g., amitriptyline and doxepin) pass metabolism of amitriptyline excessive CNS depression and
in the liver impaired psychomotor function
Monoamine oxidase inhibitors MAOIs interact with alcoholic Tyrosine increases blood pressure, Avoid alcohol when taking MOAIs
(MAOIs) (e.g., phenelzine) beverages containing tyrosine causing severe hypertension
Antidiabetic Chlorpropamide Inhibits low-Km ALDH2 in the brain " Acetaldehyde in blood (Jerntorp,
agents and liver (Vasiliou et al., 1986) 1983; Jerntorp et al., 1986)
Glipizide Alcohol delays glipizide absorption Hypoglycemia Limit alcohol to occasional use;
and elimination completely avoid alcohol if signs
of hypoglycemia occur
Metformin Alcohol potentiates metformin’s Alcohol plus metformin may Limit alcohol to occasional use and
effects on lactate metabolism increase risk for lactic acidosis monitor for signs of lactic
(Shenoy, 2006) acidosis
Insulin Alcohol enhances the glucose- Hypoglycemia Should not drink alcohol in excess
lowering action of insulin or on an empty stomach
Antihistamine Ranitidine Accelerates GE by antagonizing H2 Concurrent antihistamine and
receptors (Oneta et al., 1998) alcohol use " BAC (Amir et al.,
1996; Arora et al., 2000)
Cimetidine Inhibition of ADH2 in small Concurrent medication and alcohol
intestines and liver; inhibition of use " BAC (Caballeria et al., 1991;
class 1 ADH and ALDH in the Weinberg et al., 1998; Monroe
liver under therapeutic doses of and Doering, 2001) and can cause
cimetidine and physiologic levels hepatotoxicity (Devuyst et al.,
of ethanol (Lai et al., 2013) 1993)
Antiprotozoal Metronidazole Acts not by inhibiting ALDH Disulfiram-like reaction to alcohol Should not drink ethanol within 2–3
(Karamanakos et al., 2007) but by (McMahon, 1980) days of taking metronidazole
increasing ADH activity in
intestines
Antipsoriatic Acitretin Alcohol converts acitretin to Etretinate is teratogenic
etretinate (Larsen et al., 1993;
Gronhoj Larsen et al., 2000; Vena
and Cassano, 2012)
Antipsychotics Phenothiazines (e.g., Excessive CNS depression and Avoid alcohol
chlorpromazine); atypical impaired psychomotor
antipsychotics (e.g., risperidone) performance
Gastroprokinetic Cisapride Accelerates gastric emptying by " BAC (Dziekan et al., 1997; Oneta
agents stimulation of presynaptic 5-HT4 et al., 1998; Kechagias et al., 1999)
receptors in the myenteric plexus
(Kechagias et al., 1999; Quigley,
2011)
Metoclopramide Accelerates gastric emptying by " BAC
inhibition of pre- and
postsynaptic D2 receptors and
stimulation of presynaptic 5-HT4
receptors in the myenteric plexus
(Lee and Kuo, 2010)
Nitrates Nitroglycerine ALDH2 bioactivates nitroglycerine Acute alcohol enhances the adverse
to produce nitric oxide (Chen effects of nitroglycerin, such as
et al., 2005, 2008) dizziness or syncope
Sedative agents Barbiturates Competes for binding to CYP2E1 " Barbiturate levels in blood, Avoid alcohol use as death has been
causing CNS depression reported with concomitant use
Benzodiazepines, Alcohol can increase absorption of Excessive CNS depression and Avoid moderate to high amounts of
e.g.,diazepam diazepam and reduce hepatic impaired psychomotor alcohol consumption
lorazepam metabolism; can reduce performance
anxiolytic effects of some
benzodiazepines

NSAIDs, non-steroidal anti-inflammatory drugs; GE, gastric emptying; ADH, alcohol dehydrogenase; BAC, blood alcohol concentration; GABA, gamma-aminobutyric acid; NMDA, N-methyl-d-aspartate;
ALDH, aldehyde dehydrogenase.
550 B.A. JOHNSON AND C. SENEVIRATNE
of alcohol and the medication competing for the binding FAEE
sites on CYP2E1 (Jones, 2010).
FAEE is produced by esterification of ethanol with endog-
enous fatty acids or fatty coenzyme A (Soderberg et al.,
ALDH SYSTEM 2003). The esterification reaction is catalyzed by many
enzymes. FAEEs are detectable in the serum, liver, adi-
Acetaldehyde produced in the initial step of alcohol oxi-
pose tissue, hair, and meconium of neonates (Pragst
dation is classified by the International Agency for
and Yegles, 2008) as direct markers for screening of alco-
Research on Cancer as a known carcinogen (Secretan
hol use or abstinence.
et al., 2009). The toxic acetaldehyde is further metabo-
lized by ALDH into the benign secondary metabolite, ace-
tate. The human ALDH superfamily consists of PETH
19 isozymes with differing kinetic parameters (Song PEth comprises a group of phospholipids carrying two
et al., 2011). The two major human liver isozymes – the variable fatty acid chains connected to a common non-
cytosolic ALDH1 and the mitochondrial ALDH2 polar phosphoethanol head (Gunnarsson et al., 1998).
(Impraim et al., 1982) – are differentiated by their subcel- They are formed in cell membranes from phosphatidyl-
lular localization, kinetic parameters, and electrophoretic choline only in the presence of alcohol (Maenhout et al.,
mobility. There are six enzyme subtypes identified in the 2013). The transphosphatidylation reaction is catalyzed
ALDH1 family. Of these, ALDH1A1 contributes to alco- by the enzyme phospholipase D, which, in the absence
hol oxidation, but with a lower catalytic efficacy (Km for of alcohol, hydrolyzes membrane phospholipids. Hence,
oxidizing acetaldehyde¼ 50–100 mM) than the mitochon- PEth is used as a direct biomarker for the screening of
drial ALDH2 (Nuutinen et al, 1983). Medications that recent alcohol consumption. PEth is measurable in blood
block the hepatic ALDH can cause accumulation of for up to 2 weeks after cessation of drinking (Litten
acetaldehyde, which increases the risk of developing et al., 2010). A single bout of alcohol drinking will not
cancer. The most common examples are presented in produce detectable amounts of PEth; this would require
Table 31.2. Among these medications, disulfiram is continuous drinking of approximately 1000 g of alcohol
designed specifically to target the acetaldehyde metabo- over about 2 weeks. The sensitivity of PEth for the
lism pathway. Disulfiram acts by inhibiting low-Km screening of alcohol use is greater than for traditional
ALDH2 in the brain and liver (Vasiliou et al., 1986), result- biomarkers.
ing in about 5-10-fold higher levels of acetaldehyde fol- Whether the medications interfering with alcohol
lowing alcohol use. pharmacokinetics cause a discrepancy between the
actual amounts of alcohol consumed and the amounts
Non-oxidative pathways of alcohol metabolized into non-oxidative products is unclear. Fur-
metabolism thermore, the variability of these markers among indi-
viduals is also not known.
Metabolism via non-oxidative pathways in humans
accounts for about 1% of the total ingested alcohol.
Alcohol metabolism in the CNS
Non-oxidative pathways include:
Alcohol metabolism in the extrahepatic sites is much
● Conjugation of alcohol with activated glucuronic acid
smaller. Early research studies alleged that the oxidation
to form ethyl glucuronide (EtG) and,conjugation with
of alcohol in the brain into its first metabolite, acetalde-
sulfate to produce ethyl sulfate (EtS)
hyde, was non-enzymatic (Deitrich et al., 2006). This
● Formation of fatty acid ethyl esters (FAEE)
assertion was based primarily on the fact that most stud-
● Formation of phosphatidylethanol (PEth).
ies have failed to detect the main alcohol-metabolizing
enzyme found in the liver, the class Ι ADH, in healthy
human brain tissue (Estonius et al., 1996; Galter et al.,
ETG/ETS
2003). In subsequent studies, it was found that the
EtG formation is catalyzed by the endoplasmic reticulum ADH class ΙΙΙ isoform is predominant in the healthy
membrane-bound enzyme UDP-glucuronosyltransferase. human brain (Galter et al., 2003; Laniewska-Dunaj
Both EtG and EtS are being utilized as biomarkers of alco- et al., 2013) but that it possesses low activity due to its
hol abstinence and moderate/heavy drinking. Studies have high affinity to ethanol (Km > 2.5 M). The other two
shown that alcohol concentrations as low as 5 g are detect- known enzymes that oxidize alcohol into acetaldehyde,
able with human EtG and that liver disease does not sig- catalase and CYP2E1, only play a minor role in eliminat-
nificantly modify urine EtG/EtS readings (Stewart ing ethanol in the periphery at moderate doses of alcohol
et al., 2013). (Correa et al., 2012). However, acetaldehyde produced in
 ALCOHOL–MEDICAL DRUG INTERACTIONS 551
the periphery does not enter the brain because of the 0.02% and 0.065%, the metabolic rate is constant as
presence of ALDH in the blood-brain barrier. Hence, ADH becomes saturated. When the BAC is above
the acetaldehyde present in the brain appears to be 0.065%, CYP2E1 with relatively higher Km (60–80 mg/
locally synthesized. Supporting this hypothesis, 100 mL) becomes active (Jones, 2010), resulting in
Aragon et al. (1991) and Gill et al. (1992) demonstrated greater metabolic rates. Functional genetic variations
the oxidation of acetaldehyde in the rat brain by perox- in the genes of FPM pathways may lead to variations
isomal enzyme system catalase-H2O2. At high concen- in the volume of distribution of alcohol (Zuo et al.,
trations or in chronic use of alcohol, CYP2E1 may 2010). Some of the most tested genetic variants with
oxidize alcohol into acetaldehyde. CYP2E1 expression an impact on alcohol-metabolizing enzymes are
in the brain is region-specific and found in peroxisomes discussed below.
and mitochondria. Acetaldehyde is a potent, biologically
active compound responsible for many behavioral Influence of genetic variability in genes
effects of alcohol. Several studies have implied a multi- encoding alcohol-metabolizing enzymes
tude of roles for acetaldehyde in alcohol preference,
ranging from being the sole compound in the brain ADH GENES
responsible for reinforcing effects of alcohol to having Quantitative or qualitative changes in ADH enzymes can
a modulatory effect on alcohol or endogenous dopa- result in altered levels of acetaldehyde in tissues. Such
mine. Contrary to these findings in the brain, in the inherent differences in enzyme activity might have a var-
periphery, acetaldehyde functions as a reinforcer only ied impact on alcohol-medication interactions in differ-
at low concentrations; at normal to high blood acetalde- ent individuals. As mentioned above, ADH1 and ADH4
hyde concentrations, voluntary ethanol consumption is are the main ADH isozymes involved in alcohol oxida-
reduced in animals, indicating an aversive effect. Tar- tion. ADH1 is formed by heteromers of subunits a, ß,
geting the mechanism of elevated blood acetaldehyde and g that are encoded by genes ADH1A, ADH1B, and
via inhibition of hepatic low-Km ALDH2, disulfiram ADH1C, respectively. The three genes are tightly clus-
was first introduced by Hald and Jacobsen in 1948 as tered to an approximately 77-kb region on chromosome
an adjunct for treatment of chronic alcoholism (Hald 4q21-23 in the 50 -ADH1A-ADH1B-ADH1C-30 direction
and Jacobsen, 1948; Hald et al., 1949). The disulfiram- (Osier et al., 2002). Among these genes, ADH1B and
ethanol reaction, commonly known as “disulfiram- ADH1C genetic variations, compared with those in
like-reaction” is characterized by nausea, vomiting, ADH1A, are widely studied in different ethnic popula-
headaches, and a flushed face and neck; rare signs tions for associations with alcoholism-related traits
include vertigo, blurred vision, hypotension, and syn- and carcinogenesis. The A allele compared with the
cope (McMahon, 1980). In addition to inhibition of G allele of single-nucleotide polymorphism (SNP)
hepatic ALDH2, disulfiram reduces norepinephrine rs1229984 in ADH1B and the A allele of rs698 in ADH1C
(NE) synthesis in the brain by blocking dopamine were found to increase the capacity of ADH to oxidize
b-hydroxylase (DBH). As alcohol induces sedation via alcohol into acetaldehyde by severalfold (Wu et al.,
the same NE–DBH pathway, disulfiram given after a 2013). In fact, rs1229984 is particularly important as both
bout of drinking potentiates alcohol’s sedative effects. population-based candidate gene and genomewide asso-
Medications that affect acetaldehyde metabolism in ciation studies have associated rs1229984 with an
the brain and periphery are presented in Table 31.2. increased risk for alcoholism-related traits and gastroin-
Unlike acetaldehyde, acetate, the secondary metabo- testinal tract cancers in Asian and European populations
lite of alcohol, is readily transported across the blood- (McKay et al., 2011; Park et al., 2013).
brain barrier into the brain. Acetate is then converted into
acetyl-CoA, which is utilized in either the citric acid cycle
ALDH-CODING GENES
or the production of the neurotransmitter acetylcholine
(Fig. 31.1). Women may have higher sensitivity to alcohol The most consistently replicated genetic association with
in the CNS (Ammon et al., 1996). alcohol metabolism in the ALDH family of enzymes is
the exonic non-synonymous SNP rs671 in the ALDH2
gene. The ALDH2 gene encodes the mitochondrial
Regulators of alcohol metabolism
ALDH isozyme ALDH2 and is mapped to chromosome
The rate of alcohol metabolism is regulated by factors 12q24.2. The SNP rs671, also referred to as ALDH2*1/2,
that influence BAC (Table 31.1). At a BAC of is now designated as Glu504Lys from the earlier nomen-
<0.02%, the rate of alcohol metabolism is exponential clature of Glu487Lys (Li et al., 2006). The substitution of
and involves ADH because of its low Km for alcohol glutamine residue with a lysine residue arises from a G to
(2–10 mg/100 mL) (Jones, 2010); between BACs of A allele transition. The protein subunit with the Lys504
552 B.A. JOHNSON AND C. SENEVIRATNE
residue encoded by the rs671:A allele, compared with the 2002). Another functional allele in CYP2E1, located in
Glu504 residue encoded by the rs671:G allele (the wild intron 6, rs6413432:A, which is more common in Asians,
type), has a shorter half-life (Xiao et al., 1996), causing was also shown to increase the expression levels of
an ALDH2 enzyme deficiency (Xiao et al., 1995) and CYP2E1 (Vodicka et al., 2001). Population-based genetic
leading to a restrained ability to metabolize acetalde- association analyses, however, have indicated both a
hyde. The rs671:A allele is present in about 20% of greater susceptibility to alcohol dependence associated
Asians and rarely in African and European populations with these functional alleles and the absence of an asso-
([Link] ciation (Iwahashi et al., 1998; Guo et al., 2011; Celorrio
rs¼671). Population-based candidate and genomewide et al., 2012).
association analyses have consistently reported a protec-
tive effect of the rs671:A allele for developing alcohol- CATALASE-CODING GENES
ism in Asians (Kim et al., 2008; Li et al., 2012; Tan
The catalase gene (CAT) is located on chromosome 11p13
et al., 2012) as a result of the slower metabolism of acet-
(Junien et al., 1980). In vitro studies have shown an allele-
aldehyde, which in turn leads to an aversive disulfiram-
based transcription level difference in the promoter
like-reaction (Goedde et al., 1983; Liu et al., 2005).
region SNP rs1001179(C/T) of the CAT gene, leading
Genetic associations of the ALDH1A1 gene, which
to a genotype-dependent dose response in catalase activ-
encodes the cytoplasmic isozyme ALDH1A1, are rela-
ity (Forsberg et al., 2001). In Asian and European popu-
tively less explored. The ALDH1A1 gene is located on
lations, the homozygous minor allele carriers (TT
chromosome 9q21.13. Spence et al. (2003) detected two
genotype) had the lowest levels of catalase in red blood
ALDH1A1 promoter region variants regulating its
cells, causing a hypo/acatalasemic state (Forsberg et al.,
expression levels. They were the 17-bp deletion polymor-
2001). Interestingly, the rs1001179 genotype effects were
phism ALDH1A1*2, found in Asian, European, and
stronger in women than in men, were influenced by die-
African populations at a frequency of <5%, and the
tary and environmental factors, and are not reported in
3-bp insertion polymorphism ALDH1A1*3, found only
African populations (Nadif et al., 2005; Ahn et al., 2006;
in individuals with African ancestry. In a later study,
Bastaki et al., 2006).
Ehlers et al. (2004) showed that Native American individ-
uals carrying the ALDH1A1*2 allele drank less and their
PHARMACODYNAMIC INTERACTIONS
rate of alcoholism was lower. In individuals of African
descent, ALDH1A1*2 was associated with a greater risk There are two main groups of alcohol-medication phar-
of developing alcoholism (Spence et al., 2003; Moore macodynamic interactions:
et al., 2007b). Several other studies reported a lack of
1. Pharmacodynamic effects of alcohol on a medica-
an association with alcoholism in Asian populations
tion: the influence of acute or chronic alcohol use
(Otto et al., 2013). The inconclusive associations indicate
on a medication at its effector site(s), altering the
the need for larger replication studies. Furthermore, to
desired effects of the medication.
establish the link between drinking levels and individual
2. Pharmacodynamic effects of the medication on alco-
variations in alcohol metabolism, the effects of
hol: the effects of a single or multiple doses of a med-
ALDH1A1*2 or ALDH1A1*3 alleles on cytosolic
ication on alcohol at its effector site(s), altering the
ALDH1A1 isozyme levels need to be characterized.
motor and behavioral effects of alcohol (Jones, 2012).
Enzyme reactions are not involved in mechanisms
CYP2E1-CODING GENES
underlying pharmacodynamic interactions. Some of
The CYP2E1 gene, which was first sequenced by Umeno the common pharmacodynamic mechanisms include:
et al. (1988), is mapped to chromosome 10q24.3 (McBride opening or closing of ion channels; binding to drug trans-
et al., 1987; Kolble, 1993). Several functional polymor- port proteins, receptors, or transcription factors, and
phisms in the CYP2E1 gene have been reported in the release of neurotransmitters. Most of the alcohol-
literature, but their effects remain inconclusive. The medication pharmacodynamic interactions, especially
50 - flanking alleles rs3813867:C and rs2031920:T, which those occurring in the CNS, are synergistic; that is, the
are in linkage disequilibrium with each other, were combined effect of alcohol and the interacting medica-
shown to have greater expression levels of CYP2E1 tion is greater than either of their single effects. Some
enzymes in vitro (Hayashi et al., 1991; Wang et al., medications, such as phenobarbital, interact with alcohol
2009). These alleles are collectively referred to as both pharmacodynamically and pharmacokinetically.
the CYP2E1*5B polymorphism. Both rs3813867:C and For such medications, the type of interaction that poten-
rs2031920:T alleles are common in Asian populations tially occurs with alcohol is believed to vary on the sever-
but rare in Caucasians and Africans (Zavras et al., ity of drinking (Weathermon and Crabb, 1999).
 ALCOHOL–MEDICAL DRUG INTERACTIONS 553
INTERACTION OFALCOHOL WITH impairment, the drug of choice would be topiramate.
CURRENTLY TESTED MEDICATIONS FOR Baclofen can be prescribed to an alcoholic patient with
THE TREATMENT OFALCOHOLISM a similar history but without liver impairment. For young
adults with problem drinking, either ondansetron or nal-
A list of medications tested for the treatment of alcohol
trexone can be prescribed if they carry the genetic vari-
addiction and their mechanisms of action are given in
ants mentioned in Table 31.3. Additionally, naltrexone
Table 31.3. The oldest medication for the treatment of
can be prescribed to elderly alcoholic patients with no
alcohol addiction, disulfiram, was discovered in Denmark
major depression.
in 1948. Disulfiram is marketed as Antabuse or Antabus in
Another population requiring specific attention is
various countries and remains one of the most widely pre-
pregnant women who are dependent on alcohol. Alcohol
scribed medications for alcoholism. As discussed earlier
use during pregnancy can cause fetal alcohol syndrome
in this chapter, disulfiram acts through developing an
(FAS), intrauterine growth retardation, spontaneous
aversive reaction to alcohol, with the goal of scaring the
abortions, stillbirths, and preterm births (Heberlein
patient from drinking. Since the discovery of disulfiram,
et al., 2012). As there is no safe limit to drinking during
several medications targeting the corticomesolimbic
pregnancy, the goal of treatment should be to achieve
dopaminergic system have been tested for reducing drink-
total abstinence or to reduce drinking to a minimum if
ing severity and craving for alcohol in alcoholics. Among
achieving abstinence is not realistic. In fact, the Centers
these medications, oral naltrexone, ondansetron, sertra-
for Disease Control advise women who are planning to
line, finasteride and olanzapine may have indirect effects
become pregnant to avoid drinking, given the severity of
on alcohol metabolism as they undergo significant first
consequences during the first trimester. Drinking reduc-
pass metabolism in the liver. Apart from the potential
tions during pregnancy should be gradual; withdrawal is
liver toxicity reported with prolonged and/or high dose
best treated with benzodiazepine, taking into account the
naltrexone, naltrexone is metabolized in the liver by
risk factors during the first and third trimesters. Benzo-
dihydrodiol dehydrogenase (DD4) into 6b-naltrexol
diazepines may cause permanent functional damage on
(Porter et al., 2000), which belongs to a subgroup of the
the developing brain, and therefore, the dose should
short-chain alcohol dehydrogenase/reductase family
be limited to minimally adequate amount to prevent
(Jouanneau and Meyer, 2006). In the liver, CYP450
major complications of withdrawal (McElhatton, 1994;
enzymes that metabolize alcohol are involved in metabo-
Bhuvaneswar et al., 2007; Heberlein et al., 2012). Anti-
lizing ondansetron (CYP1A2 and CYP3A4), sertraline
convulsant use for withdrawal is associated with greater
(CYP3A4), Finasteride (CYP3A4) (Figg et al., 1996;
teratogenicity and thus should be avoided during preg-
Obach et al., 2005; Huskey et al., 1995). Olanzapine is
nancy for treatment of withdrawal (Heberlein et al.,
non-oxidatively metabolized into N-10-glucuronide in
2012; Bromley et al., 2013).
the liver (Murphy et al., 1998). Topiramate and Acampro-
sate are not known to have direct or indirect effects on
CONCLUDING REMARKS
alcohol metabolism, presumably because they are
excreted as unchanged by the kidneys. Knowledge of the metabolic pathways, absorption,
Alcoholism can be conceptualized as several differ- and elimination of a drug is important to predict its
ent diseases based on pathophysiology, course, and interactions with alcohol. The past few decades have
treatment outcome. Therefore, a single treatment inter- provided a wealth of information on the molecular
vention does not work for all subtypes of alcoholism. mechanisms underlying these pathways. However,
Examples of currently tested medications to reduce several gaps still remain to be addressed on certain
drinking severity include ondansetron, baclofen, nal- aspects of alcohol-medication interactions. These
trexone, and topiramate. Selection of optimal therapy include further characterization of the contribution
should be based on the subtype of alcoholism, such as of non-oxidative pathways of metabolism, alcohol-
early- vs late-onset alcoholism - the former characterized medication interactions under various pathologic condi-
by chronic, more severe symptoms with a greater bio- tions such as diabetes, obesity, or liver disease, and
logic predisposition. Other considerations are the age further elucidation of pharmacodynamic interactions,
of the patient, the presence of other psychiatric disorders which requires a deeper understanding of the mecha-
or conditions, and pharmacogenetic effects. A concise nisms of action of medications and alcohol.
overview of currently available subtype-based alcohol- Genetic studies have identified variants that alter the
ism treatment is presented in the format of several clin- activity of enzymes or receptors in alcohol-medication
ical vignettes in a review by Johnson (2010). For example, interaction pathways. These findings can be incorpo-
for a currently drinking, chronic alcoholic patient pre- rated to provide a tool for identifying high-risk groups
senting with medical complications including liver to prevent the occurrence of adverse events arising from
554 B.A. JOHNSON AND C. SENEVIRATNE
Table 31.3
Pharmacogenetics of medications for alcohol treatment

Pharmacogenetic findings

Medication Mechanism Gene Effect

Acamprosate GABAA receptor agonist, mGluR5 receptor GATA4 Efficacious for relapse prevention in
antagonist rs13273672:A allele carriers (Kiefer
et al., 2011)
Naltrexone Active metabolite 6-b-naltrexol is a competitive OPRM1 Greater efficacy in rs1799971:G (Asp40)
antagonist at m- and k-opioid receptors; low- allele subjects (Oslin et al., 2003; Anton
affinity antagonist at d-opioid receptors et al., 2008; Ray et al., 2012); reduces
craving in rs4654327:A allele carriers
(Ashenhurst et al., 2012)
Ondansetron 5-HT3A receptor antagonist SLC6A4 Greater efficacy for reducing drinking
severity in 50 -HTTLPR:LL (Kenna et al.,
2009; Johnson et al., 2011)* and
rs1042173:TT (Johnson et al., 2011)
genotype carriers
HTR3A Greater efficacy for reducing drinking
severity in rs1150226-AG, rs1176713-GG
carriers (Johnson et al., 2013)
HTR3B Greater efficacy for reducing drinking
severity in rs17614942-AC carriers
(Johnson et al., 2013).
Sertraline Primarily binds to the serotonin transporter and SLC6A4 Sertraline showed a significant
selectively inhibits serotonin reuptake (SSRI); “50 -HTTLPR:LL and rs25531:AA
shows lower affinity for dopamine transporter genotype  age of alcoholism onset”
inhibition, sigma-1 receptor (s1R) antagonist, effect on drinking reductions (Kranzler
a1-adrenergic antagonists et al., 2012)
Finasteride Type II 5a-reductase inhibitor GABRA2 Reduced subjective effects of alcohol in
rs279858:AA genotype individuals
(Pierucci-Lagha et al., 2005)
Olanzapine High-affinity antagonist/inverse agonist at 5-HT2 DRD4 VNTR long (L)-allele individuals showed
serotonin receptors; lower affinity for M3 greater reductions of craving
receptor, serotonin 5-HT1, GABAA, beta- (Hutchison et al., 2003)
adrenergic receptors, and benzodiazepine
binding sites, H1 histamine receptors, serotonin
5-HT2C and dopamine D2 receptors
Topiramate Facilitate GABAA receptors and antagonize GRIK1 Preliminary evidence of greater efficacy
AMPA and Kainate glutamate receptors of topiramate in rs2832407:CC
compared to non-carriers
(Kranzler et al., 2013)

OPRM1 ¼ m opioid receptor gene; SLC6A4 ¼ serotonin transporter gene; HTR3A ¼ serotonin receptor subunit A gene; HTR3B ¼ serotonin recep-
tor subunit B gene; GABRA2 ¼ gamma-aminobutyric acid (GABA) A receptor, alpha 2 gene; GATA4 ¼ transcription factor GATA-4 gene;
DRD4 ¼ dopamine receptor subtype 4 gene; GRIK1 ¼ glutamate receptor, ionotropic, kainate 1; VNTR ¼ variable number of tandem repeats;
5-HT ¼ 5-hydroxytryptamine (serotonin); *study participants randomized by genotype; Results replicated in independent trials.

alcohol-medication reactions. For instance, medications expression of the target receptor molecules may enhance
that lower alcohol-metabolizing enzymes such as ADH the efficacy of medications to reduce drinking.
or ALDH (see Table 31.2 for examples of such medica-
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