Katzung & Trevor's Pharmacology Examination and Board Review, 9th Edition

Chapter 23. Alcohols

Alcohols: Introduction

Ethanol, a sedative-hypnotic drug, is the most important alcohol of pharmacologic interest. It has few medical applications, but its abuse causes major medical and socioeconomic problems. Other alcohols of toxicologic importance are methanol and ethylene glycol. Several important drugs discussed in this chapter are used to prevent the potentially life-threatening ethanol withdrawal syndrome, to treat chronic alcoholism, or to treat acute methanol and ethylene glycol poisoning.

High-Yield Terms to Learn

Alcoholism Compulsive use of ethanol Alcohol withdrawal syndrome The characteristic syndrome of insomnia, tremor, agitation, seizures, and autonomic instability engendered by deprivation in an individual who is physically dependent on ethanol Delirium tremens (DTs) Severe form of alcohol withdrawal whose main symptoms are sweating, tremor, confusion, and hallucinations Fetal alcohol syndrome A syndrome of craniofacial dysmorphia, heart defects, and mental retardation caused by the teratogenic effects of ethanol consumption during pregnancy Wernicke-Korsakoff syndrome A syndrome of ataxia, confusion, and paralysis of the extraocular muscles that is associated with chronic alcoholism and thiamine deficiency



After ingestion, ethanol is rapidly and completely absorbed; the drug is then distributed to most body tissues, and its volume of distribution is equivalent to that of total body water (0.5-0.7 L/kg). Two enzyme systems metabolize ethanol to acetaldehyde (Figure 23-1).


Metabolism of ethanol by alcohol dehydrogenase (ADH) and the microsomal ethanol-oxidizing system (MEOS). Alcohol dehydrogenase and aldehyde dehydrogenase are inhibited by fomepizole and disulfiram, respectively.

(Reproduced, with permission, from Katzung BG, Masters SB, Trevor AT, editors: Basic & Clinical Pharmacology, 11th ed. McGraw-Hill, 2009: Fig. 23-1.)

Alcohol Dehydrogenase (ADH)

This cytosolic, NAD+-dependent enzyme, found mainly in the liver and gut, accounts for the metabolism of low to moderate doses of ethanol. Because of the limited supply of the coenzyme NAD+, the reaction has zero-order kinetics, resulting in a fixed capacity for ethanol metabolism of 7-10 g/h. Gastrointestinal metabolism of ethanol is lower in women than in men.

Microsomal Ethanol-Oxidizing System (MEOS)

At blood ethanol levels higher than 100 mg/dL, the liver microsomal mixed function oxidase system that catalyzes most phase I drug-metabolizing reactions (see Chapter 2) contributes significantly to ethanol metabolism (Figure 23-1). Chronic ethanol consumption induces cytochrome P450 enzyme synthesis and MEOS activity; this increase may be partially responsible for the development of tolerance to ethanol. The primary isoform of cytochrome P450 induced by ethanol—2E1 (see Table 4-3)—converts acetaminophen to a hepatotoxic metabolite.

Acetaldehyde formed from the oxidation of ethanol by either ADH or MEOS is rapidly metabolized to acetate by aldehyde dehydrogenase, a mitochondrial enzyme found in the liver and many other tissues. Aldehyde dehydrogenase is inhibited by disulfiram and other drugs, including metronidazole, oral hypoglycemics, and some cephalosporins. Some individuals, primarily of Asian descent, have genetic deficiency of aldehyde dehydrogenase. After consumption of even small quantities of ethanol, these persons experience nausea and a flushing reaction from accumulation of acetaldehyde.

Acute Effects


The major acute effects of ethanol on the CNS are sedation, loss of inhibition, impaired judgment, slurred speech, and ataxia. In nontolerant persons, impairment of driving ability is thought to occur at ethanol blood levels between 60 and 80 mg/dL. Blood levels of 120 to 160 mg/dL are usually associated with gross drunkenness. Levels greater than 300 mg/dL may lead to loss of consciousness, anesthesia, and coma sometimes with fatal respiratory and cardiovascular depression. Blood levels higher than 500 mg/dL are usually lethal. Chronic alcoholics who are tolerant to the effects of ethanol can function almost normally at much higher blood concentrations than occasional drinkers. Additive CNS depression occurs with concomitant ingestion of ethanol and a wide variety of CNS depressants, including sedative-hypnotics, opioid agonists, and many drugs that block muscarinic and H1 histamine receptors. The molecular mechanisms underlying the complex CNS effects of ethanol are not fully understood. Specific receptors for ethanol have not been identified. Rather, ethanol appears to modulate the function of a number of signaling proteins. It facilitates the action of GABA at GABAA receptors, inhibits the ability of glutamate to activate NMDA (N-methyl-D-aspartate) receptors, and modifies the activities of adenylyl cyclase, phospho-lipase C, and ion channels. It has been suggested that alcohol "blackouts" may result from interference with NMDA receptors.

Other Organ Systems

Ethanol, even at relatively low blood concentrations, significantly depresses the heart. Vascular smooth muscle is relaxed, which leads to vasodilation, sometimes with marked hypothermia. Ethanol relaxes uterine smooth muscle.

Chronic Effects

Tolerance and Dependence

Tolerance occurs mainly as a result of CNS adaptation and to a lesser extent by an increased rate of ethanol metabolism. There is cross-tolerance to sedative-hypnotic drugs that facilitate GABA activity (eg, benzodiazepines and barbiturates). Both psychological and physical dependence are marked.


Liver disease is the most common medical complication of chronic alcohol abuse. Reduced gluconeogenesis can lead to hypoglycemia. Progressive loss of liver function occurs with reversible fatty liver progressing to irreversible hepatitis, cirrhosis, and liver failure. Hepatic dysfunction is often more severe in women than in men and in both men and women infected with hepatitis B or C virus.

Gastrointestinal System

Irritation, inflammation, bleeding, and scarring of the gut wall occur after chronic heavy use of ethanol and may cause absorption defects and exacerbate nutritional deficiencies. Chronic alcohol abuse greatly increases the risk of pancreatitis.


Peripheral neuropathy is the most common neurologic abnormality in chronic alcoholics. More rarely, thiamine deficiency, along with ethanol abuse, leads to Wernicke-Korsakoff syndrome, which is characterized by ataxia, confusion, and paralysis of the extraocular muscles. Prompt treatment with parenteral thiamine is essential to prevent a permanent memory disorder known as Korsakoff's psychosis.

Endocrine System

Gynecomastia, testicular atrophy, and salt retention occur, partly because of altered steroid metabolism in the cirrhotic liver.

Cardiovascular System

Excessive chronic ethanol use is associated with an increased incidence of hypertension, anemia, and dilated cardiomyopathy. Acute drinking for several days ("binge" drinking) can cause arrhythmias. However, the ingestion of modest quantities of ethanol (10-15 g/day) raises serum levels of high-density lipoprotein (HDL) cholesterol and may protect against coronary heart disease.

Fetal Alcohol Syndrome

Ethanol use in pregnancy is associated with teratogenic effects that include mental retardation (most common), growth deficiencies, microcephaly, and a characteristic underdevelopment of the midface region. Facial abnormalities are particularly associated with heavy consumption of alcohol during the first trimester of pregnancy.


Ethanol is not a primary carcinogen, but its chronic use is associated with an increased incidence of neoplastic diseases in the gastrointestinal tract and a small increase in the risk of breast cancer.

Immune System

Chronic alcohol abuse has complex effects on immune functions because it enhances inflammation in the liver and pancreas and inhibits immune function in other tissues. Heavy use predisposes to infectious pneumonia.

Treatment of Acute and Chronic Alcoholism

Excessive CNS Depression

Intoxication resulting from acute ingestion of ethanol is managed by maintenance of vital signs and prevention of aspiration after vomiting. Intravenous dextrose is standard. Thiamine administration is used to protect against Wernicke-Korsakoff syndrome, and correction of electrolyte imbalance may also be required.

Alcohol Withdrawal Syndrome

In persons physically dependent on ethanol, discontinuance can lead to a withdrawal syndrome characterized by insomnia, tremor, anxiety, and, in severe cases, life-threatening seizures and delirium tremens (DTs). Peripheral effects include nausea, vomiting, diarrhea, and arrhythmias. The abstinence syndrome is managed by correction of electrolyte imbalance and administration of thiamine and a sedative-hypnotic. A long-acting benzodiazepine (eg, diazepam, chlordiazepoxide) is preferred unless the patient has compromised liver function, in which case a short-acting benzodiazepine with less complex metabolism (eg, lorazepam) is preferred.

Treatment of Alcoholism

Alcoholism is a complex sociomedical problem, characterized by a high relapse rate. Several CNS neurotransmitter systems appear to be targets for drugs that reduce the craving for alcohol. The opioid receptor antagonist naltrexone has proved to be useful in some patients, presumably through its ability to decrease the effects of endogenous opioid peptides in the brain. Acamprosate , an NMDA glutamate receptor antagonist, is also FDA approved for treatment of alcoholism. The aldehyde dehydrogenase inhibitor disulfiram is used adjunctively in some treatment programs. If ethanol is consumed by a patient who has taken disulfiram, acetaldehyde accumulation leads to nausea, headache, flushing, and hypotension (Figure 23-1).

Skill Keeper: Elimination Half-Life

(See Chapter 1)

Search "high and low" through drug information resources and you will not find data on the elimination half-life of ethanol! Can you explain why this is the case? The Skill Keeper Answer appears at the end of the chapter.

Other Alcohols


Methanol (wood alcohol), a constituent of windshield cleaners and "canned heat," is sometimes ingested intentionally. Intoxication causes visual dysfunction, gastrointestinal distress, shortness of breath, loss of consciousness, and coma. Methanol is metabolized to formaldehyde and formic acid, which causes severe acidosis, retinal damage, and blindness. The formation of formaldehyde is retarded by prompt intravenous administration of ethanol, which acts as a preferred substrate for alcohol dehydrogenase and competitively inhibits the oxidation of methanol, and by fomepizole, an inhibitor of alcohol dehydrogenase (Figure 23-2).


The oxidation of ethylene glycol and methanol by alcohol dehydrogenase (ADH) creates metabolites that cause serious toxicity. Ethanol, a substrate preferred by ADH, is used in methanol or ethylene glycol poisoning to slow the rate of formation of toxic metabolites. Fomepizole, an inhibitor of alcohol dehydrogenase, is an alternative to ethanol.

Ethylene Glycol

Industrial exposure to ethylene glycol (by inhalation or skin absorption) or self-administration (eg, by drinking antifreeze products) leads to severe acidosis and renal damage from the metabolism of ethylene glycol to oxalic acid. Prompt treatment with ethanol, which competes for oxidation by alcohol dehydrogenase, or fomepizole may slow or prevent formation of this toxic metabolite (Figure 23-2).

Skill Keeper Answer: Elimination Half-Life

(See Chapter 1)

Drug information resources do not provide data on the elimination half-life of ethanol because, in the case of this drug, it is not constant. The elimination of ethanol follows zero-order kinetics because the drug is metabolized at a constant rate irrespective of its concentration in the blood (see Chapter 3). The pharmacokinetic relationship between elimination half-life, volume of distribution, and clearance, given by

is not applicable to ethanol. Its rate of metabolism is constant, but its clearance decreases with an increase in blood level. The arithmetic plot of ethanol blood level versus time follows a straight line (not exponential decay).


When you complete this chapter, you should be able to:

 Sketch the biochemical pathways for ethanol metabolism and indicate where fomepizole and disulfiram act.

 Summarize characteristic pharmacodynamic and pharmacokinetic properties of ethanol.

 Relate blood alcohol levels in a nontolerant person to CNS depressant effects of acute alcohol ingestion.

 Identify the toxic effects of chronic ethanol ingestion.

 Describe the fetal alcohol syndrome.

 Describe the treatment of ethanol overdosage.

 Outline the pharmacotherapy of (1) the alcohol withdrawal syndrome and (2) alcoholism.

 Describe the toxicity and treatment of acute poisoning with (1) methanol and (2) ethylene glycol.

Drug Summary Table: Alcohols

Subclass Mechanism of Action Clinical Applications Pharmacokinetics Toxicities, Drug Interactions Alcohols Ethanol Multiple effects on neurotransmitter receptors, ion channels, and signaling pathways Antidote in methanol and ethylene glycol poisoning Zero-order metabolism, duration depends on dose Toxicity: Acutely, CNS depression and respiratory failure. Chronically, damage to many systems, including liver, pancreas, gastrointestinal tract, and central and peripheral nervous systems. Interactions: Induction of CYP2E1; increased conversion of acetaminophen to toxic metabolite Methanol: Poisonings result in toxic levels of formate, which causes characteristic visual disturbance plus coma, seizures, acidosis, and death due to respiratory failure Ethylene glycol: Poisoning creates toxic aldehydes and oxylate, which causes kidney damage and severe acidosis Drugs used in acute ethanol withdrawal Benzodiazepines Diazepam BDZ receptor agonist that facilitates GABA-mediated activation of GABAA receptors

Prevention and treatment of acute ethanol withdrawal syndrome; see Chapter 22 See Chapter 22 See Chapter 22 Other long-acting benzodiazepines and barbiturates are also effective (see Chapter 22) Thiamine (vitamin B1 ) Essential vitamin required for synthesis of the coenzyme thiamine pyrophosphate Administered to patients suspected of having alcoholism (those exhibiting acute alcohol intoxication or alcohol withdrawal syndrome) to prevent the Wernicke-Korsakoff syndrome Parenteral administration None Drugs used in chronic alcoholism Opioid receptor antagonist Naltrexone Nonselective competitive antagonist of opioid receptors Reduced risk of relapse in individuals with alcoholism Available as an oral or long-action parenteral formulation. Gastrointestinal effects and liver toxicity. Will precipitate a withdrawal reaction in individuals physically dependent on opioids and will prevent the analgesic effect of opioids Other Acamprosate Poorly understood NMDA receptor antagonist and GABAA agonist effects

Reduced risk of relapse in individuals with alcoholism Oral administration Gastrointestinal effects and rash Enzyme inhibitor Disulfiram Inhibits aldehyde dehydrogenase, it causes aldehyde accumulation during ethanol ingestion Deterrent to relapse in individuals with alcoholism Oral administration Little effect on its own but severe and potentially dangerous flushing, headache, nausea, vomiting, and hypotension when combined with ethanol Drugs used in acute methanol or ethylene glycol toxicity Fomepizole Inhibits alcohol dehydrogenase, it prevents the conversion of methanol and ethylene glycol to toxic metabolites Methanol and ethylene glycol poisoning Parenteral administration Headache, nausea, dizziness, rare allergic reactions Ethanol: Higher affinity for alcohol dehydrogenase; used to reduce metabolism to toxic products

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