Ethanol

Before the advent of ether, ethanol was used as an “anesthetic” agent for surgical procedures, and for many years, ethanol and the general anesthetic agents were assumed to share a common mechanism of action to “fluidize” or “disorder” the physical structure of cell membranes, particularly those low in cholesterol. Although ethanol may interfere with the packing of molecules in the phospholipid bilayer of the cell membrane, increasing membrane fluidity, this bulk fluidizing effect is small and not primarily responsible for the depressant effects of ethanol on the CNS. This action, however, may play a role in disrupting membranes surrounding neurotransmitter receptors or ion channels, proteins thought to mediate the actions of ethanol.

Studies suggest that the effects of ethanol may be attributed to its direct binding to lipophilic areas either near or in ion channels and receptors. The ion channels influenced by ethanol are listed in Table 32-1. Ethanol may have either inhibitory or facilitatory effects, depending on the channel, but its resultant action is CNS depression. Because the barbiturates and benzodiazepines exhibit cross-tolerance to ethanol, and their CNS depressant effects are additive with those of ethanol, they may share a common mechanism, perhaps through the γ-aminobutyric acid (GABA) type A receptor (see Chapter 31). Ethanol may also exert some of its effects by actions at glutamate N-methyl-D-aspartate (NMDA) receptors or serotonin (5-HT) receptors.

TABLE 32–1 Ion Channels Affected by Ethanol

* 100 mM ethanol is 460 mg/dL.

The reinforcing actions of ethanol are complex but are mediated in part through its ability to stimulate the dopaminergic reward pathway in the brain (see Fig. 27-8). Evidence has indicated that ethanol increases the synthesis and release of the endogenous opioid β-endorphin in both the ventral tegmental area (VTA) and the nucleus accumbens. Increased β-endorphin release in the VTA dampens the inhibitory influence of GABA on the tonic firing of VTA dopaminergic neurons, whereas increased β-endorphin release in the nucleus accumbens stimulates dopaminergic nerve terminals to release neurotransmitter. Both of these actions to increase dopamine release may be involved in the rewarding effects of ethanol.

Other Alcohols

Methanol, ethylene glycol, and isopropanol are commonly encountered alcohols. Methanol and ethylene glycol have applications in industry and are fairly toxic to humans, whereas isopropyl alcohol, like ethanol, is bacteriocidal and used as a disinfectant.

Drugs for Alcohol Dependence

Aldehyde Dehydrogenase Inhibitor

Disulfiram, used for the treatment of alcoholism since the 1940s, is an inhibitor of the enzyme aldehyde dehydrogenase (ALDH), a major enzyme involved in the metabolism of ethanol (Fig. 32-1). Inhibiting the catabolism of acetaldehyde produced by the oxidation of ethanol, leads to the accumulation of acetaldehyde in the plasma, resulting in aversive effects.

FIGURE 32–1 Metabolism of ethanol by ADH, ALDH, and cytochrome P450. ETS, Electron transport system; LDH, lactate dehydrogenase.

Ethanol

Alcohol taken orally is absorbed throughout the gastrointestinal (GI) tract. Absorption depends on passive diffusion and is governed by the concentration gradient and the mucosal surface area. Food in the stomach will dilute the alcohol and delay gastric emptying time, thereby retarding absorption from the small intestine (where absorption is favored because of the large surface area). High ethanol concentrations in the GI tract cause a greater concentration gradient and therefore hasten absorption. Absorption continues until the alcohol concentration in the blood and GI tract are at equilibrium. Because ethanol is rapidly metabolized and removed from the blood, eventually all the alcohol is absorbed.

Once ethanol reaches the systemic circulation, it is distributed to all body compartments at a rate proportional to blood flow to that area; its distribution approximates that of total body H₂O. Because the brain receives a high blood flow, high concentrations of ethanol occur rapidly in the brain.

Ethanol undergoes significant first-pass metabolism. Most (>90%) of the ethanol ingested is metabolized in the liver, with the remainder excreted through the lungs and in urine. Alcohol dehydrogenase (ADH) catalyzes the oxidation of ethanol to acetaldehyde, which is oxidized further by ALDH to acetate (see Fig. 32-1). Acetate is oxidized primarily in peripheral tissues to CO₂ and H₂O. Both ADH and ALDH require the reduction of nicotinamide adenine dinucleotide (NAD⁺), with 1 mol of ethanol producing 2 mol of reduced NAD⁺ (NADH). The NADH is reoxidized to NAD⁺ by conversion of pyruvate to lactate by lactate dehydrogenase (LDH) and the mitochondrial electron transport system (ETS). During ethanol oxidation the concentration of NADH can rise substantially, and NADH product inhibition can become rate-limiting. Similarly, with large amounts of ethanol, NAD⁺ may become depleted, limiting further oxidation through this pathway. At typical blood alcohol concentrations (BACs), the metabolism of ethanol exhibits zero-order kinetics; that is, it is independent of concentration and occurs at a relatively constant rate (Fig. 32-2). Fasting decreases liver ADH activity, decreasing ethanol metabolism.

FIGURE 32–2 Disappearance of ethanol after oral ingestion follows zero-order kinetics.

Ethanol may also be metabolized to acetaldehyde in the liver by cytochrome P450, a reaction that requires 1 mol of reduced nicotinamide adenine dinucleotide phosphate (NADPH) for every ethanol molecule (see Fig. 32-1). Although P450-mediated oxidation does not normally play a significant role, it is important with high concentrations of ethanol (≥100 mg/dL), which saturate ADH and deplete NAD⁺. Because this enzyme system also metabolizes other compounds, ethanol may alter the metabolism of many other drugs. In addition, this system may be inhibited or induced (Chapter 2), and induction by ethanol may contribute to the oxidative stress of chronic alcohol consumption by releasing reactive O₂ species during metabolism.

A third system capable of metabolizing ethanol is a peroxidative reaction mediated by catalase, a system limited by the amount of hydrogen peroxide available, which is normally low. Small amounts of ethanol are also metabolized by formation of phosphatidylethanol and ethyl esters of fatty acids. The significance of these pathways is unknown.

Significant genetic differences exist for both ADH and ALDH that affect the rate of ethanol metabolism. Several forms of ADH exist in human liver, with differing affinities for ethanol. Whites, Asians, and African-Americans express different relative percentages of the genes and their respective alleles that encode subunits of ADH, contributing to ethnic differences in the rate of ethanol metabolism. Similarly, there are genetic differences in ALDH. Approximately 50% of Asians have an inactive ALDH, caused by a single base change in the gene that renders them incapable of oxidizing acetaldehyde efficiently, especially if they are homozygous. When these individuals consume ethanol, high concentrations of acetaldehyde are achieved, leading to flushing and other unpleasant effects. People with this condition rarely become alcoholic. As discussed, the unpleasant effects of acetaldehyde accumulation form the basis for the aversive treatment of chronic alcoholism with disulfiram. The pharmacokinetics of ethanol are summarized in Table 32-2.

TABLE 32–2 Pharmacokinetic Considerations of Ethanol

Aldehyde Dehydrogenase Inhibitor

Disulfiram has been the most widely used drug for alcoholism for many years. All of the effects of disulfiram are attributed to its adverse effects that are evident upon ethanol ingestion. Although disulfiram does not have any effect on alcohol craving, it may help prevent relapse in compliant individuals. For disulfiram to be effective, individuals must be highly motivated and compliant.

Glutamate Receptor Antagonist

Acamprosate is modestly effective in maintaining abstinence after alcohol withdrawal. The approval of acamprosate for the treatment of alcoholism in the United States was based largely on results from clinical trials conducted in Europe. Acamprosate appears to have a small therapeutic effect but may be of greater benefit in alcoholics who exhibit increased anxiety rather than the entire population of alcohol-dependent individuals.

Opioid Receptor Antagonist

Short-term, double-blind, placebo-controlled trials have shown that naltrexone decreased the craving for alcohol, the number of drinking days, the number of drinks per occasion, and the relapse rate. Naltrexone appears to have the greatest benefits in individuals with a family history of alcohol dependence and high craving, decreasing the rewarding efficacy of ethanol.

The depot forms of naltrexone may be of benefit because they produce greater compliance than the oral formulation.

Gastrointestinal Tract

The oral mucosa, esophagus, stomach, and small intestine are exposed to higher concentrations of ethanol than other tissues of the body and are susceptible to direct toxic effects. Acute gastritis resulting in nausea and vomiting results from ethanol abuse; bleeding ulcers and cancer of the upper GI tract are possible consequences.

Liver

Ethanol metabolism by the liver causes a large increase in the NADH/NAD⁺ ratio, which disrupts liver metabolism. The cell attempts to maintain NAD⁺ concentrations in the cytosol by reducing pyruvate to lactate, leading to increased lactic acid in liver and blood. Lactate is excreted by the kidney and competes with urate for elimination, which can increase blood urate concentrations. Excretion of lactate also apparently leads to a deficiency of zinc and Mg⁺⁺. A more direct effect of increased NADH concentrations in the liver is increased fatty acid synthesis, because NADH is a necessary cofactor. Because NADH participates in the citric acid cycle, the oxidation of lipids is depressed, further contributing to fat accumulation in liver cells.

The increase in NADH/NAD⁺ ratio and the inability to regenerate NAD⁺ may cause hypoglycemia and ketoacidosis. The former occurs in the noneating user of alcohol when hepatic glycogen stores are exhausted (72 hours), and gluconeogenesis is inhibited as a result of the increased NADH/NAD⁺ ratio. The metabolic acidosis observed in nondiabetic alcoholics is an anion gap acidosis, with an increase in the plasma concentration of β-hydroxybutyrate and lactate.

Acetaldehyde may also play a prominent role in liver damage. If there is an initial insult to the liver, the concentration of ALDH decreases, and acetaldehyde is not removed efficiently and can react with many cell constituents. For example, acetaldehyde blocks transcriptional activation by peroxisome proliferator-activated receptor-α (PPAR-α). Normally, fatty acids activate this receptor, and this action of acetaldehyde may contribute to fatty acid accumulation in liver. Acetaldehyde also increases collagen in the liver.

During ethanol ingestion the intestine releases increased amounts of lipopolysaccharide (endotoxin), which are taken up from the portal blood by the Kupffer cells of the liver. In response to this, these cells release tumor necrosis factor-α (TNF-α) and a host of other proinflammatory cytokines. In the face of depleted glutathione and S-adenosylmethionine, liver cells die. This process of secondary liver injury occurs over and above the primary liver injury caused directly by ethanol. In spite of this, there are many heavy drinkers who never develop severe liver damage, indicating a substantial genetic effect in producing alcoholic hepatic damage.

The use of acetaminophen by alcoholics may result in hepatic necrosis. This reaction can occur with acetaminophen doses that are less than the maximum recommended (4 g/24 hours). Ethanol has this effect because it induces the cytochrome P450 responsible for formation of a hepatotoxic acetaminophen metabolite, which cannot be detoxified when glutathione stores are depleted by ethanol or starvation. This condition is characterized by greatly elevated serum aminotransferase concentrations. N-Acetylcysteine is given orally to provide the required glutathione substrate in such patients.

Pancreas

Ethanol use is a known cause of acute pancreatitis, and repeated use can lead to chronic pancreatitis, with decreased enzyme secretion and diabetes mellitus as possible consequences.

Endocrine System

Large amounts of ethanol decrease testosterone concentrations in males and cause a loss of secondary sex characteristics and feminization. Ovarian function may be disrupted in premenopausal females who abuse alcohol, and this may be manifest as oligomenorrhea, hypomenorrhea, or amenorrhea. Ethanol also stimulates release of adrenocortical hormones by increasing secretion of adrenocorticotropic hormone.

Cardiovascular System

Alcoholic cardiomyopathy is a consequence of chronic ethanol consumption. Other cardiovascular effects include mild increases in blood pressure and heart rate and cardiac dysrhythmias. Cardiovascular complications also result from hepatic cirrhosis and accompanying changes in the venous circulation that predispose to upper GI bleeding. Coagulopathy, caused by hepatic dysfunction and bone marrow depression, increases the risk of bleeding.

Epidemiological studies have demonstrated an association between alcohol use and a reduced risk of cardiovascular disease, including nonfatal myocardial infarction and fatal coronary heart disease. Alcohol increases the levels of high-density lipoprotein cholesterol. However, the biological foundations of the observed cardioprotective effects of alcohol have not been established. Ethanol relaxes blood vessels, and in severe intoxication, hypothermia resulting from heat loss as a consequence of vasodilatation may occur.

Kidney

Ethanol has a diuretic effect unrelated to fluid intake that results from inhibition of antidiuretic hormone secretion, which decreases renal reabsorption of H₂O.

Immune System

Alcoholics are frequently immunologically compromised and are subject to infectious diseases. The mortality resulting from cancers of the upper GI tract and liver is also excessively high in alcoholics. Although the mechanism of this latter effect is unknown, alcohol consumption is a known risk factor for cancer, and this may be related to vitamin A metabolism.

Nervous System

There are several well-documented neurological conditions resulting from excessive ethanol intake and concomitant nutritional deficiencies. These include Wernicke-Korsakoff syndrome, cerebellar atrophy, central pontine myelinosis, demyelination of the corpus callosum, and mamillary body destruction.

Fetal Alcohol Syndrome

Although fetal alcohol syndrome has been recognized from early times, it was rediscovered in the 1970s, and the general public is well aware of the deleterious effects of drinking on the health of the fetus. Consequences of maternal ingestion of alcohol can include miscarriage, stillbirth, low birth weight, slow postnatal growth, microcephaly, mental retardation, and many other organic and structural abnormalities. The incidence of fetal alcohol syndrome in some parts of the United States is estimated to be as high as 1 in 300 births. It is the most common cause of birth defects that is entirely preventable.

Tolerance

Both acute tolerance and chronic tolerance occur in response to ethanol use. Acute tolerance can occur in a matter of minutes and rapidly dissipates when ethanol is applied directly to nerve cells. Chronic tolerance occurs in people who ingest alcohol daily for weeks to months, with very high tolerances developing in some individuals. BACs must be approximately double to produce effects in tolerant as opposed to nontolerant people. This is much less, however, than that observed in those who use opiate drugs, in whom a tolerance of 10- to 30-fold can be demonstrated. The development of tolerance to alcohol has greater implications than that to other agents, because organ systems are exposed to much higher concentrations of ethanol, with deleterious consequences, particularly to the liver. Because the liver becomes injured as a function of the dose and duration of ethanol exposure, metabolism of ethanol may be impaired in late-stage alcoholism with serious liver damage.

Dependence

It is often difficult to diagnose alcohol dependence. Success depends on obtaining a reliable history from the patient or from a member of the patient’s family. Even if a diagnosis can be made, it is frequently difficult to manage the problem, because treatment is often initiated when the disorder is already well advanced.

Over the past 10 to 15 years, the role of genetic factors in the development of chronic alcoholism has been identified with the hope that early intervention may be more successful. Results of studies involving family members of alcoholics and twins support a predisposition and an increased risk among close relatives. This conclusion that primary alcoholism is genetically influenced is based on several interesting findings.

Studies indicate a threefold to fourfold higher risk of alcoholism primarily in sons but also in some daughters of alcoholic parents. Comparisons in identical twins versus fraternal twins should reveal whether alcoholism is related to childhood environment. Because both types of twins have similar backgrounds, if alcoholism is related to childhood environment, its incidence should be the same in identical and fraternal twins. Most studies show that there is a twofold higher concordance for alcoholism in identical twins than in fraternal twins. In another study alcoholic risk was assessed in male children of alcoholics raised by adoptive parents who were nonalcoholic. A threefold to fourfold higher risk of alcoholism was found in these males. Being raised by alcoholic adoptive parents did not increase the risk for alcoholism. In some studies, in fact, there was a protective effect.

Other studies have categorized alcoholics into several subgroups. One is the alcoholism most frequently seen in males and is associated with criminality; the second is a subtype observed in both sexes and influenced by the environment. Genetic predisposition, however, is merely one of several factors leading to alcoholism. Studies are attempting to reveal biological markers with which to identify potential alcoholics (e.g., differences in blood proteins, enzymes involved in ethanol degradation, and enzymes concerned with brain neurotransmitters and signaling components, including G proteins) to encourage such people to seek assistance sooner.

Effective management of chronic alcoholism includes social, environmental, and medical approaches and involves the family of the person undergoing treatment. Several types of treatment are available, including group psychotherapy (e.g., Alcoholics Anonymous) that may be rendered in private and public clinics outside of a hospital setting. Hypnotherapy and psychoanalysis have been used. Studies have shown that pharmacological therapy is of benefit when added to psychosocial/behavioral therapy.

Both psychological and physical dependence are characteristic of chronic alcohol use. The clinical manifestations of ethanol withdrawal are divided into early and late stages. Early symptoms occur between a few hours and up to 48 hours after relative or absolute abstinence. Peak effects occur around 24 to 36 hours. Tremor, agitation, anxiety, anorexia, confusion, and signs of autonomic hyperactivity occur individually or in combinations. Seizures occurring in the early phase of withdrawal may reflect decreased neurotransmission at GABA_A receptors and increased neurotransmission at NMDA receptors. Late withdrawal symptoms (delirium tremens) occur 1 to 5 days after abstinence, and while relatively rare, can be life-threatening if untreated. Signs of sympathetic hyperactivity, agitation, and tremulousness characterize the onset of the syndrome. There are sensory disturbances including auditory or visual hallucinations, confusion, and delirium. Death may occur, even in treated patients. Complicating factors in alcohol withdrawal include trauma from falls or accidents, bacterial infections, and concomitant medical problems such as heart and liver failure. The alcohol withdrawal syndrome is more likely to be life-threatening than that associated with opioids.

Management of withdrawal is directed toward protecting and calming the person while identifying and treating underlying medical problems. Clinical data have demonstrated that the longer acting benzodiazepines (chlordiazepoxide, diazepam, or lorazepam) have a favorable effect on clinically important outcomes, including the severity of the withdrawal syndrome, risk of delirium and seizures, and incidence of adverse responses to the drugs used. The benzodiazepines are the treatment of choice. The phenothiazine antipsychotics and haloperidol are less effective in preventing seizures or delirium. Phenobarbital is problematic because its long half-life makes dose adjustment difficult, and in high doses it may cause respiratory depression. Adrenergic β receptor blockers and centrally acting α₂ adrenergic receptor agonists are useful as adjuvants to limit autonomic manifestations. Neither class of drugs reduces the risk of seizures or delirium tremens.

Treatment of Intoxication

Emergency treatment of acute alcohol intoxication includes maintenance of an adequate airway and support of ventilation and blood pressure. In addition to depressant actions on the CNS, other organs, including the heart, may be affected. It is also important to assess the level of consciousness relative to the BAC, because other drugs may influence the apparent degree of intoxication. Acetaminophen concentration should also be determined. A short-acting opioid receptor antagonist is generally administered as a precaution. Glucose may need to be administered in the event of hypoglycemia, ketoacidosis, or dehydration. Loss of body fluids may necessitate intravenous infusion of fluids containing K⁺, Mg⁺⁺, and PO₄⁻³. Thiamine and other vitamins, such as folate and pyridoxine, are usually administered with intravenous glucose to prevent neurological deficits. Extreme caution is needed when one is modifying Na⁺ concentrations in such patients, however, because overcorrection has been associated with central pontine myelinolysis.

Although the only proven cure for advanced liver damage is transplantation, other drugs are being tried. These include prednisolone, vitamin E, S-adenosylmethionine, precursors of glutathione, propylthiouracil, polyunsaturated lecithin, and colchicine. In general, management regimens have had variable success rates, with many being effective over the long term in no more than 10% to 15% of participants.

Aldehyde Dehydrogenase Inhibitor

Disulfiram causes a rise in blood acetaldehyde concentrations, producing flushing, headache, nausea and vomiting, sweating, and hypotension. Disulfiram also inhibits dopamine β-hydroxylase, the enzyme that converts dopamine to norepinephrine (NE) in sympathetic neurons (see

Chapter 9). Thus, in an alcoholic taking disulfiram, there is an altered ability to synthesize NE, possibly contributing to the hypotension when alcohol is taken in conjunction with disulfiram.

Glutamate Receptor Antagonist

Acamprosate is relatively free from adverse events, with diarrhea the most common, dose-related side effect. Other reported effects include nervousness, fatigue, nausea, depression, and anxiety. Acamprosate has been shown to be teratogenic in animals.

Opioid Receptor Antagonist

The most common adverse effects noted by alcohol-dependent individuals taking naltrexone included nausea, headache, dizziness, nervousness, and fatigue. A small percentage of individuals experienced withdrawal-like symptoms consisting of abdominal cramps, bone or joint pain, and myalgia. Depot injections lead to injection site reactions and eosinophilia. At high doses naltrexone can produce hepatic injury, and a black-box warning noting this effect is included in its labeling.