CHAPTER 43 Aliphatic Alcohols
The aliphatic alcohols of therapeutic value are ethyl alcohol (ethanol) and isopropyl alcohol. Methanol and ethylene glycol, the latter a dihydroxy alcohol, are mainly of toxicologic interest. Propylene glycol, another dihydroxy alcohol, is useful as a food additive and in drug compounding. Isopentanol is one of the longer chain alcohols found in small concentrations in alcoholic beverages. The principal medical use of ethyl and isopropyl alcohol is topical disinfection, as discussed in Chapter 46. Although ethanol has limited clinical application, as the most common intoxicant in Western civilization it is of immense importance because of its potential for abuse and dependence and because it is a major contributing factor to individual and social ills in the United States and other nations.
The alcohols discussed in this chapter are hydroxyl derivatives of aliphatic hydrocarbons (Table 43-1). They are clear, colorless, flammable liquids that are completely miscible with water and most organic solvents. Aliphatic monohydroxy alcohols form a homologous series and, with increasing numbers of carbon atoms, display increasing potency as nonselective central nervous system (CNS) depressants. Dihydroxy alcohols (glycols) have similar CNS properties, whereas trihydroxy derivatives lack depressant effects.
|Methyl alcohol||Methanol, carbinol, wood alcohol, wood spirit||CH3OH|
|Ethyl alcohol||Ethanol, grain alcohol||CH3CH2OH|
|Isopropyl alcohol||Isopropanol, 2-propanol, secondary propyl alcohol|
Ethanol can be obtained as anhydrous alcohol (100% ethanol), as neutral spirits (95% ethanol), and as denatured alcohol. Denatured alcohol, intended primarily for industrial use, is ethanol with a substance added to render it unfit for consumption, such as methanol, benzene, diethyl ether, or kerosene.
The social costs of ethanol abuse are staggering. Ethanol abuse–related costs, including health care costs, criminal damage costs, and workplace costs, are estimated to be several hundreds of billions of U.S. dollars worldwide.3 Approximately 50% of all fatal traffic accidents are related to the use of ethanol. Drinking aggravates criminal behavior. Ethanol is involved in approximately one third of suicides and rapes, half of assaults, and one half to two thirds of homicides.
It has long been believed that the effects of ethanol on the CNS are mediated by an increase in membrane fluidity, leading to disorder of the membrane lipids and resulting in abnormal activity of ion channels and other proteins. Although there is evidence to support this mechanism, the focus more recently has been on the effect of ethanol on excitatory and inhibitory amino acids in the brain. Ethanol potentiates the effect of γ-aminobutyric acid (GABA) at GABAA receptors. Its mechanism in this respect is similar to that of other sedatives, such as benzodiazepines, which also enhance the effect of GABA at GABAA receptors and increase Cl− conductance. In addition, ethanol exerts an inhibitory effect on the CNS by reducing glutamate activation of excitatory ion channels. More specifically, ethanol inhibits the response of the N-methyl-d-aspartate (NMDA) receptor to glutamate.
Long-term ethanol abuse may cause a change in the subunit structure of the NMDA receptor, leading to an excitatory toxic effect when ethanol is withdrawn acutely. It may also be possible to attribute other side effects, such as chronic CNS effects, to actions on the NMDA receptor. Consistent with this notion is the observation that certain NMDA receptor antagonists can reduce the intake of ethanol in an animal model given long-term treatment. This observation has led to the search for NMDA receptor antagonists as potential therapeutic agents in treating alcohol dependence.
Biochemical mechanisms involved in the CNS effects of ethanol also seem to involve, among others, dopaminergic, adrenergic, serotoninergic, and opioid pathways. Reward mechanisms are enhanced by dopaminergic stimulation and by opioid peptides. Naltrexone, an opioid receptor antagonist, inhibits the desire for alcohol intake, as do dopamine receptor antagonists. Agonists at these respective receptors have the opposite effect. Ethanol can deplete the neurotransmitter 5-hydroxytryptamine, which is consistent with aggressive behavior in an alcohol abuser. Although ethanol has a wide range of effects on neurotransmitters and receptors in the CNS, the exact contributions of these systems to the pharmacologic features of ethanol are unknown at this time. The mechanisms by which these receptors and neurotransmitters are affected are not well described.
There is a common but mistaken notion that ethanol is a CNS stimulant. To the contrary, ethanol is a sedative-hypnotic that depresses the CNS in a dose-dependent fashion. Much of the apparent stimulation resulting from ethanol use results from disinhibition of CNS function because of selective depression of inhibitory pathways at lower concentrations of ethanol. Although mental processes, memory, and concentration are reduced, the individual may feel euphoric, confident, and socially uninhibited. Higher doses (intoxication) lead to overall depression of the CNS. As with other CNS depressants, the major acute toxicity of ethanol is respiratory depression from inhibition of the medullary respiratory center.
The concentration of ethanol in alcoholic beverages is often listed as the “proof.” The actual concentration of ethanol, in percent by volume, is half the proof number: 80 proof equals 40% ethanol by volume. Because of the variability of absorption of different alcoholic beverages, the effects of ethanol are most commonly correlated with the blood alcohol concentration (BAC), as illustrated in Table 43-2. The effects of ethanol are dose-related and progress through the typical sequence of anxiolysis, sedation, hypnosis, anesthesia, and death. Ethanol is a soporific, increasing the time spent in sleep and decreasing the time it takes to get to sleep. With low doses of alcohol, an electroencephalogram displays a reduced frequency and increased amplitude of α waves, and with high doses, the electroencephalogram displays an enhanced δ activity similar to a pattern of deep sleep. At a BAC of approximately 150 mg/dL, there is a reduction in the length, although not in the number, of episodes of rapid eye movement sleep throughout the night, together with reduced movement during sleep. Sleep patterns are disturbed with repeated ingestion, however, so that sleep comes in short segments, and the wake time is actually increased.
|BAC (mg/dL)||CLINICAL STATE*|
|150||Drunk and disorderly|
|300||Dazed and dejected|
At a BAC less than 50 mg/dL, binocular fusion is impaired, and blurred vision occurs. Handwriting deteriorates, fine motor coordination is reduced, and complex sensorimotor tasks begin to show impairment. The Romberg “standing steadiness” test reveals marked unsteadiness and increased body sway at a BAC of 30 mg/dL. At a BAC of 50 to 100 mg/dL, a drinker displays reductions in anxiety, critical judgment, and self-criticism, with enhanced sociability and self-esteem in group situations. Disinhibition, with talkativeness and a feeling of elation, occurs at the same time that mild sedation is produced, along with relaxation, drowsiness, and reduced alertness. Speech, movement, and simple reaction times are slowed. Fear is reduced, and impulsive risk-taking behavior becomes evident. Many performance tasks are unaltered at a BAC of 50 mg/dL, but most are impaired at 100 mg/dL. Sexual motivation may be enhanced at a lower BAC through a reduction in anxiety and muscular tension, and maximum penile diameter, in response to visual stimulation, is increased at a BAC of 25 mg/dL but is reduced at concentrations greater than 50 mg/dL.
At a BAC of 100 to 200 mg/dL, nausea, vomiting, and loss of self-control are common in an inexperienced drinker, whereas an experienced drinker speaks and moves with exaggerated care. Subjective time passes more slowly. Speech becomes slurred, and ataxia with staggering gait occurs. A unique positional alcohol nystagmus is produced in which, with the head tilted to the side, the eyes drift slowly upward and then jerk rapidly downward. Ethanol produces deficits in short-term and long-term memory, and amnesia (“blackouts”) may occur. Ethanol increases assertive or aggressive behavior and may precipitate a rage-release reaction, especially if the initial mood of the drinker is unpleasant. Significant analgesia is also produced.
In the range of 300 mg/dL of ethanol, intoxication is severe and is accompanied by a loss of consciousness. There may be mydriasis, sweating, hypotension, and hypothermia. At a BAC of 400 to 500 mg/dL, medullary paralysis, cardiovascular depression, and death are likely to occur.
The legal blood limit for drivers in the United States is 80 mg/dL (0.08%). Drivers younger than 21 years are restricted to a BAC of less than 20 mg/dL—the “zero tolerance policy.” Sobriety tests are used to give an indication of BAC.13 Certain conditions such as sleepiness may make individuals susceptible to the effects of small amounts of ethanol or to the effects of previous exposure to alcohol even when the BAC is undetectable.
Acute alcohol administration results in an elevated catecholamine concentration in blood and urine. Adrenal monoamine release is accompanied by compensatory increases in the activity of medullary tyrosine hydroxylase, dopamine β-hydroxylase, and phenylethanolamine-N-methyltransferase. Vascular smooth muscle exhibits hyperreactivity to norepinephrine at low ethanol concentrations and hyporeactivity at high concentrations. The latter effect may be caused by ethanol-induced facilitation of neuronal monoamine uptake.
The direct actions of ethanol on vasomotor tone, coupled with its complex adrenergic effects and centrally mediated influences, produce variable cardiovascular responses. In general, coronary blood flow is slightly enhanced, but there is no concomitant increase in myocardial oxygen uptake. Myocardial contractility is depressed by ethanol. Direct vasoconstriction has been observed in cerebral and renal vascular beds in vitro, but in vivo the effect of ethanol, occurring only at large doses, is an increase in blood flow to the brain and kidneys. Mesenteric blood flow also seems to be increased.
A consistent cardiovascular effect of alcohol ingestion is cutaneous vasodilation. The increased blood flow to the skin provides a feeling of warmth. In cold environments, heat loss may be greatly accentuated, and alcohol generally should be avoided in treating hypothermic individuals. At low ambient temperatures, individuals under the influence of ethanol have a high risk of hypothermia.
The ethanol metabolite acetaldehyde causes catecholamine release and produces tachycardia, increased cardiac output, and increased arterial blood pressure, effects that are abolished by adrenoceptor blockade. The concentrations of acetaldehyde normally resulting from low amounts of ingested ethanol have little acute effect on the cardiovascular system, however. Long-term effects of ethanol differ from its short-term effects. When ingested in excess on a long-term basis, ethanol increases the risk of hypertension and adverse cardiac effects. Long-term ethanol abuse can cause a cardiomyopathy characterized by a decreased ventricular ejection fraction and heart failure. Fibrosis of the myocardium may also occur.
A number of effects of ethanol on the liver have been documented. Acute ingestion of intoxicating amounts of ethanol leads to a reduced liver-metabolizing activity. This effect is reversed when the ethanol is eliminated. In a long-term alcoholic, induction of liver microsomal enzymes is common; if the individual is not intoxicated, drug metabolism may be enhanced. If cirrhosis of the liver occurs, overall metabolism is reduced because of impaired hepatic blood flow and destruction of liver tissue. The use of ethanol has several implications for drug metabolism.
Ethanol can also influence nutritional status. Ethanol inhibits the activation of vitamins A and D and causes depletion of pyridoxine. Trace metals, such as zinc and selenium, are also depleted. Cirrhosis of the liver leads to further reduction in nutritional status. Nutritional deficiencies are also common because ethanol can marginally meet an alcoholic’s caloric needs without supplying other nutritional requirements. Other long-term effects are discussed later.
Ethanol has a diuretic effect resulting from inhibition of antidiuretic hormone secretion by the posterior pituitary. Urinary Na+, K+, and Cl− concentrations are reduced, whereas Mg++ and norepinephrine are increased.
Ethanol interferes with sexual function in men and women. It can cause temporary impotence even though overall aggressiveness may be enhanced. Long-term alcoholism may lead to more lasting impotence and sterility. Testosterone production may be depressed, and testosterone metabolism may be enhanced, the latter as a result of induction of liver microsomal enzymes. Feminization in men is a possible outcome.
A potential salutary effect of moderate consumption of ethanol relates to cholesterol status. Intake on the order of one to two drinks a day increases the ratio of high-density to low-density lipoproteins in the plasma, an effect inversely correlated with the incidence of coronary heart disease and myocardial infarction. Other effects, such as reduced platelet aggregation, may also provide a cardioprotective effect. In one study, men who were homozygous for the “slow” form of one of the isozymes of alcohol dehydrogenase, ADH3, had an especially enhanced increase in high-density lipoprotein and decreased risk of myocardial infarction.10
Alcohol consumption is associated with an increase in serum triglyceride levels. This association may pose a cardiovascular risk, and if the triglyceride levels are high enough, a risk of pancreatitis exists. The overriding issue for the individual and society as a whole is controlling ethanol intake to avoid its many adverse effects.
Small oral doses of ethanol temporarily enhance salivary and gastric acid secretion—the increased salivation probably by a conditioned reflex. Large doses of alcohol reduce salivation. Ethanol is a gastric irritant, producing inflammation of the stomach wall in concentrations greater than 15%. Ingestion of solutions of more than 20% ethanol results in increased gastric mucus secretion and in petechial hemorrhage and ulceration. Ethanol retards intestinal absorption of glucose, amino acids, folic acid, thiamine, and vitamin B12. Adrenal gland activation results in increased blood concentrations of corticosteroids, epinephrine, and glucose.
The effects of ethanol on the peripheral vasculature, CNS, antidiuretic hormone secretion, and sexual function are summarized in the following exchange between Macduff and the porter in Shakespeare’s Macbeth:
Ethanol is rapidly absorbed from the stomach and small intestine. After oral ingestion, the rate of absorption largely depends on the gastric emptying time because 75% of a dose is rapidly and completely taken up from the small intestine. Patients with gastrectomy often note enhanced effects of ethanol. The rate of gastric absorption is reduced by the presence of food. Concentrations of ethanol greater than 20% retard absorption by inducing gastric mucosal irritation and pylorospasm.
Approximately 60% of inspired ethanol vapor is absorbed through the lungs, and intoxication can be achieved by this route. Percutaneous absorption can also occur and has led to death when infants were wrapped in ethanol-soaked cloth to treat hyperthermia.