Ethanol is the most widely abused drug in the world. There are more than 10 million alcoholics in the United States alone. Excessive consumption of alcoholic bever-ages has been linked to as many as half of all traffic ac-cidents, two-thirds of homicides, and three-fourths of suicides, and it is a significant factor in other crimes, in family problems, and in personal and industrial acci-dents. The annual cost to the American economy has been estimated to exceed $100 billion in lost productiv-ity, medical care, and property damage.
Alcoholism has been difficult to define because of its complex nature. A person is generally considered an al-coholic, however, when his or her lifestyle is dominated by the procurement and consumption of alcoholic bev-erages and when this behavior interferes with personal, professional, social, or family relations.
A light drinker generally is defined as one who con-sumes an average of one drink or less per day, usually with the evening meal; a moderate drinker is one who has approximately three drinks per day; and a heavy drinker is one who has five or more drinks per day (or in the case of binge drinkers, at least once per week with five or more drinks on each occasion).
Ethanol (ethyl alcohol, alcohol) is a simple organic mol-ecule composed of a single hydroxyl group and a short two-carbon aliphatic chain, CH 3CH 2OH. The hydroxyl and ethyl moieties confer both hydrophilic and lipophilic properties on the molecule. Therefore, ethanol is an amphophile, a property important to its pharmacological activity.
After oral administration, ethanol is almost completely absorbed throughout the gastrointestinal tract. The rate of absorption is largely determined by the quantity con-sumed, the concentration in the beverage, the rate of consumption, and the composition of the gastric con-tents. Eating food before or during drinking retards ab-sorption, especially if the food has a high lipid content.
After absorption, ethanol is distributed throughout body water. In organs with high blood flow, such as the brain, liver, lungs, and kidney, equilibrium occurs rap-idly. Conversely, in organs with low blood flow, such as muscle, equilibrium occurs more slowly. Ethanol readily passes through the blood–placenta barrier into the fetal circulation. Although the concentration of ethanol in the blood can be quite predictable, measurements of blood ethanol, especially when the concentrations are rising, may lead to erroneous conclusions, since the val-ues obtained can underestimate the concentration of ethanol in the brain. This fact can confound legal pro-ceedings in drunk-driving cases where blood ethanol concentrations are considered an accurate and legally acceptable determinant of the amount of ethanol con-sumed.
Ethanol is metabolized primarily in the liver by at least two enzyme systems. The best-studied and most important enzyme is zinc dependent: alcohol dehydro-genase. Salient features of the reaction can be seen in Fig. 35.1. The rate of metabolism catalyzed by alcohol dehydrogenase is generally linear with time except at low ethanol concentrations and is relatively independ-ent of the ethanol concentration (i.e., zero-order kinet-ics). The rate of metabolism after ingestion of different amounts of ethanol is illustrated in Fig. 35.2.
In adults, ethanol is metabolized at about 10 to 15 mL/hour. Since metabolism of ethanol is slow, inges-tion must be controlled to prevent accumulation and in-toxication. There is little evidence that chronic ingestion of ethanol leads to a significant induction of alcohol de-hydrogenase, even in heavy drinkers.
Some populations, most notably East Asians, exhibit an unusual response after drinking ethanol. The symp-toms include facial flushing, vasodilation, and tachycar-dia. These individuals apparently have a genetic defi-ciency of the enzyme aldehyde dehydrogenase, which leads to an accumulation of acetaldehyde even after they drink relatively small amounts of ethanol. If drugs such as metronidazole, griseofulvin, quinacrine, the hypoglycemic sulfonylureas, phenothiazines, and phenylbutazone are coadministered with ethanol, a sim-ilar accumulation of acetaldehyde may occur.
In addition to alcohol dehydrogenase, ethanol can be oxidized to acetaldehyde by the microsomal mixed-function oxidase system (cytochrome P450 2 EI), as il-lustrated in Figure 35.1. Although this microsomal ethanol-oxidizing system probably has minor importance in the metabolism of ethanol in humans, it may be involved in some of the reported interactions between ethanol and other drugs that are also metabolized by this system.
Microsomal mixed-function oxidases may be induced by chronic ethanol ingestion. Because ethanol is metabolized in the liver, it can interfere with the metabolism of other drugs by blocking microsomal hydroxylation and demethylation. Drug classes whose metabolism is most affected include the barbiturates, coumarins, and anticonvulsants, such as phenytoin. Liver damage resulting from chronic abuse of ethanol can impair metabolism of a variety of drugs.
Normally, 90 to 98% of an ingested dose of ethanol is metabolized by the liver. Most of the remaining 2 to 10% is excreted unchanged in the urine and expired air. The ethanol content in the urine is normally about 130% of the blood concentration and is quite constant; the expired air contains about 0.05% of the blood ethanol level, a concentration that also is remarkably consistent.
A great deal of attention has been focused on a class of proteins termed the ligand-gated ion channels as being important to the mechanism of action of alcohol. These integral membrane proteins function as gates or pores that allow the passage of certain ions into and out of neurons upon binding of the appropriate neurotrans-mitter. This flux of ions largely determines the degree of neuronal activity. Two distinct types of ligand-gated ion channels are particularly sensitive to concentrations of alcohol that produce intoxication and sedation. These are the γ-Aminobutyric acid (GABA) chloride ionophore and the N-methyl-D-aspartate (NMDA) sub-type of glutamate receptor. The GABA–chloride ion channel reduces neuronal activity by hyperpolarizing the neurons, while activation of the NMDA receptor causes neuronal depolarization or excitation. Alcohol has been shown to increase chloride flux through the GABAA receptor and reduce calcium flux through the NMDA receptor. These actions result in powerful sup-pression of nerve cell activity, which is consistent with the depressant actions of alcohol in the brain.
Alcohol is primarily a CNS depressant, and the degree of depression is directly proportional to the quantity of ethanol consumed. However, behavioral stimulation can be found after ingestion of small amounts of ethanol.This stimulation is expressed as decreased social and psycho-logical inhibition and is most likely the result of a de-pression of inhibitory pathways in the brain with release of cortical activity. The behavioral and physiological ef-fects are associated with different blood ethanol concen-trations. As the blood ethanol concentration begins to in-crease, behavioral activation, characterized by euphoria, talkativeness, aggressiveness, and loss of behavioral con-trol, generally precedes the overt CNS depression in-duced by ethanol. At progressively higher blood ethanol concentrations, the stage of relaxation is transformed into decreased social inhibitions, slurred speech, ataxia, decreased mental acuity, decreased reflexive responses, coma, and, finally, death resulting from respiratory arrest. In moderation, however, there is no evidence that the ju-dicious use of small amounts of alcoholic beverages (e.g., a glass of wine with meals) is permanently harmful.
In general, ethanol in low to moderate amounts, is rela-tively benign to most body systems. A moderate amount of ethanol causes peripheral vasodilation, especially of cutaneous vessels, and stimulates the secretion of sali-vary and gastric fluids; the latter action may aid diges-tion. On the other hand, ethanol consumption in high concentrations, as found in undiluted spirits, can induce hemorrhagic lesions in the duodenum, inhibit intestinal brush border enzymes, inhibit the uptake of amino acids, and limit the absorption of vitamins and minerals. In addition, ethanol can reduce blood testosterone lev-els, resulting in sexual dysfunction.
Ethanol is a diuretic. This effect may be caused by its ability to inhibit secretion of antidiuretic hormone from the posterior pituitary, which leads to a reduction in re-nal tubular water reabsorption. The large amount of fluid normally consumed with ethanol also contributes to increased urine production.
Ethanol intoxication is probably the best-known form of drug toxicity. Intoxicated individuals are a threat to themselves and others, particularly if they attempt to drive or operate machinery. Although death can result from ethanol overdose, usually the patient lapses into a coma before ingesting lethal quantities. Ethanol intoxi-cation is sometimes mistakenly diagnosed as diabetic coma, schizophrenia, overdosage of other CNS depres-sant drugs, or skull fracture. An additional feature com-monly associated with excessive ethanol consumption is difficulty in regulating body temperature. Hypothermia frequently results, with body temperature falling toward that of the ambient environment. This problem can be particularly severe in the elderly, who normally have difficulty regulating their body temperature.
One of the consequences of ethanol intoxication is the hangover, a condition characterized by headache, nausea, sweating, and tremor. Although unpleasant, a hangover is not dangerous, even though the person hav-ing one may feel otherwise.
Generally, no treatment is required for acute ethanol in-toxication. Allowing the individual to sleep off the ef-fects of ethanol ingestion is the usual procedure. Hangovers are treated similarly; that is, no effective remedy exists for a hangover, except for controlling the amount of ethanol consumed. Sometimes ethanol over-dose is a medical emergency. For example, prompt treat-ment is required if the patient is in danger of dying of respiratory arrest, is comatose, has dilated pupils, is hy-pothermic, or displays tachycardia.
Treatment for severe ethanol overdose is generally supportive. Increased intracranial pressure can be re-lieved by intravenous administration of hypertonic mannitol. Hemodialysis can accelerate the removal of ethanol from the body. Stimulants of ethanol metabo-lism, such as fructose, are not sufficiently effective, and use of analeptics is not recommended because of the pos-sibility of precipitating convulsions.
Alcoholism is among the major health problems in most countries. Dependence on ethanol, as with other addic-tive drugs, is expressed as drug-seeking behavior and is associated with a withdrawal syndrome that occurs after abrupt cessation of drinking. The ethanol withdrawal syndrome is characterized by tremors, seizures, hyper-thermia, hallucinations, and autonomic hyperactivity.
A number of organs are affected adversely by chronic ethanol use, the result of a direct cytotoxic ac-tion.
Hepatic fatty infiltration and cirrhosis are common in alcoholics; cancer may develop in advanced stages of hepatic disease.
Ethanol produces a number of depressant effects on the myocardium. Atrial arrhythmias and ventricular tachycardia may arise from chronic ethanol use. A seri-ous clinical entity, alcoholic cardiomyopathy, has also been described.
A high rate of ethanol consumption can lead to in-hibition of gastric secretion and irritation of the gastric mucosa. Ethanol irritates the entire gastrointestinal tract, which may lead to constipation and diminished absorption of nutrients. Other pathological effects in-clude pancreatitis and peripheral neuropathy. Severe gonadal failure is often found in both men and women, accompanied by low blood levels of sex hormones.
A variety of pathological problems involving the CNS have been described in chronic alcoholics, the main ones being Wernicke’s encephalopathy and Korsakoff’s psychosis. Brain damage from chronic ethanol consumption can be especially severe in the elderly and may accelerate aging.
Ethanol readily passes across the placenta and into the fetal circulation. The fetal alcohol syndrome has three primary features: microcephaly, prenatal growth deficiency, and short palpebral fissures. Other character-istics include postnatal growth deficiency, fine motor dysfunction, cardiac defects, and anomalies of the exter-nal genitalia and inner ear. A definite risk of producing fetal abnormalities occurs when ethanol consumption by the mother exceeds 3 oz daily, the equivalent of about six drinks.
The immediate concern in the treatment of alcoholics is detoxification and management of the ethanol with-drawal syndrome. Once the patient is detoxified, long-term treatment requires complete abstinence, psychiatric treatment, family involvement, and frequently support from lay organizations such as Alcoholics Anonymous.
One pharmacological approach is aversion therapy using drugs such as disulfiram to associate drinking ethanol with unpleasant consequences. If ethanol is taken after disulfiram administration, blood acetalde-hyde concentrations increase 5 to 10 times, resulting in vasodilation, pulsating headache, nausea, vomiting, se-vere thirst, respiratory difficulties, chest pains, orthosta-tic hypotension, syncope, and blurred vision. In certain cases, marked respiratory depression, cardiac arrhyth-mias, cardiovascular collapse, myocardial infarction, acute congestive heart failure, unconsciousness, convul-sions, and sudden death have been reported. Despite these potentially severe consequences, disulfiram is pre-scribed for some alcoholic patients.
Another pharmacological approach is the use of an-ticraving drugs, for example serotonin uptake inhibitors, dopaminergic agonists, and opioid antagonists. The only treatment that has shown considerable promise is one that uses the opioid antagonist naltrexone.
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