Description: Ethanol, or ethyl alcohol, is a widely used CNS depressant. Ethanol was once believed to be the "water of life" and was indicated as a remedy for practically all diseases. The many medical and social problems of ethanol have been well described and, until recently, it was believed that ethanol had limited therapeutic value. Clinically, its main use has been in the treatment of methanol or ethylene glycol poisoning. At one time, ethanol was used as a tocolytic agent in premature labor. Other uses include injection next to nerves or sympathetic ganglia to relieve long-lasting pain such as that occurring in trigeminal neuralgia or inoperable carcinoma and injection into renal arteries to ablate renal tissue such as in recipients of a renal allograft whose native kidney(s) may still be secreting renin.
Ethanol is an excellent solvent and is often used as a vehicle for medicinal preparations.
Currently, there is much interest in determining the effects of ethanol on lipoprotein subfractions and cardiovascular disease. A major review of 12 studies encompassing data from > 350,000 subjects followed for > 1.8 million person-years revealed a strong inverse association between consumption of wine and mortality from CHD, but the association was not as strong for spirits or beer. The authors concluded that if any type of alcoholic drink provides cardiovascular benefit apart from its alcohol content, the benefit is likely to be modest or possibly restricted to certain subpopulations of patients. In another study, it was determined that subjects who consumed 1-2 drinks/day on five or six days each week had a substantially reduced risk for MI compared with nondrinkers. In contrast, those who consumed similar weekly amounts but in binges (i.e., 9 drinks over a one or two day period) had a tendency towards increased cardiac risk.
Mechanism of Action: The intoxication produced by ethanol is believed
to be caused by ethanol interacting with GABA receptors. Ethanol produces
this effect by modification of ion flux through chloride channels activated
by GABA, thereby potentiating the inhibitory effects of GABA. The intoxicating
effects correlate well with serum ethanol concentrations in the mild to moderate
drinker. Dubowski categorizes this correlation into seven stages of
alcohol influence, with each stage being associated with certain clinical
signs and symptoms:
The above-described stages may be less obvious after long-term exposure to ethanol due to the development of tolerance, a phenomenon which can also develop during prolonged administration of barbiturates or benzodiazepines after long-term use. In fact, there is cross-tolerance among barbiturates, benzodiazepines, and ethanol.
Alcohol dehydrogenase is the enzyme responsible for metabolizing alcohols in the body. Methanol and ethylene glycol are converted to their toxic metabolites by alcohol dehydrogenase at a slower rate than ethanol. In the treatment of ethylene glycol or methanol poisoning, infused ethanol occupies the available enzyme, thereby interfering with generation of toxic ethylene glycol or methanol metabolites. Greater quantities of methanol and ethylene glycol are thus eliminated unchanged thereby reducing serum concentrations of the toxic metabolites. Blood ethanol levels of at least 100 mg/dl are required to saturate alcohol dehydrogenase and prevent formation of toxic metabolites.
Ethanol is known to inhibit hormone output from the posterior pituitary. By inhibiting ADH (vasopressin) output, ethanol can cause dehydration. By inhibiting the output of oxytocin, also a posterior pituitary hormone, ethanol can delay labor. Since the release of beta2-agonists such as ritodrine, however, ethanol is rarely used as a tocolytic. Acute ethanol ingestion has also been associated with an increase in postganglionic sympathetic-nerve discharge. This action of ethanol is believed to be mediated by an increase in corticotropin-releasing hormone secretion since pretreatment with dexamethasone blocked the acute pressor effects of ethanol. Acute ethanol ingestion has also been shown to increase serum estradiol concentrations in postmenopausal women receiving hormone replacement therapy (RT) but not in women not receiving RT.
Finally, moderate daily amounts of ethanol appear to increase circulating levels of HDL2 and HDL3. A corresponding decrease in the risk of sustaining myocardial infarction has been associated with moderate ethanol consumption. The mechanism for this protective effect from ethanol is unclear however. A 6-year study of men in Copenhagen implied that the inverse association between ethanol consumption and risk for ischemic heart disease occurs only in persons with higher LDL cholesterol levels, not that ethanol lowered LDL cholesterol. It is still unclear how ethanol affords its cardioprotective effects.
Pharmacokinetics: Ethanol is used orally but can also be administered IV in some clinical settings. It is rapidly absorbed from the gastrointestinal tract, and absorption is altered by the presence of food in the stomach. Absorption is most rapid and complete from the small intestine, and food in the intestine does not affect absorption. Following absorption, ethanol is uniformly distributed to all tissues and fluids. Peak concentrations are achieved 30-90 minutes after ingestion.
Ethanol undergoes zero-order kinetics (i.e., the rate of metabolism is relatively constant, regardless of the concentration in the blood). The average adult metabolizes ethanol at a rate of about 10-20 mL/hr or 120 mg/kg/hr. The metabolism of ethanol is affected by such factors as age, history of ethanol abuse, and liver function. Ethanol is 90-98% metabolized in the liver to acetaldehyde, which is converted to acetyl coenzyme A (acetyl CoA), and is then oxidized through the Kreb's cycle to provide energy or undergoes anabolic reactions to yield cholesterol and fats. Thus, infusion of 5% alcohol and 5% dextrose injection USP provides a very rapid source of energy. Starvation reduces the rate of metabolism, and insulin increases it. Elimination of the small amount of unchanged ethanol is mainly in the urine, but some is lost through exhalation and from the skin surface.
The vasodilating effect of ethanol can cause orthostatic hypotension, especially if used by patients receiving antihypertensive agents.
Myopathy, including cardiomyopathy, is a complication of chronic alcoholism. Acute ethanol myopathy is characterized by painful and swollen muscles, high levels of serum creatine phosphokinase (CK), atrophy and muscle weakness of the shoulder and pelvic girdles, skeletal muscle myopathy and, in some cases, myoglobinemia and myoglobinuria. Ethanol-induced cardiomyopathy develops as a result of several effects on the cardiovascular system. In low daily doses, ethanol decreases myocardial contractility and causes peripheral vasodilatation resulting in a mild drop in blood pressure and a compensatory increase in heart rate and cardiac output. In higher doses (i.e., 3 or more drinks per day), there is a dose-dependent increase in blood pressure. While myocardial biopsied indicate that ethanol-induced cardiomyopathy is clinically and histologically related to idiopathic dilated cardiomyopathy and ischemic cardiomyopathy, patients with ethanol-induced cardiomyopathy are more likely to manifest skeletal muscle weakness concomitantly. Also, women tend to be more sensitive than men to the effects of ethanol on cardiac and smooth muscle.
Ethanol is a CNS depressant. In the early phase of intoxication, ethanol
may cause euphoria and excitation. This is explained by ethanol's depressant
effects on inhibitory pathways. Ethanol causes dizziness, sedation or drowsiness,
and impaired judgement, which could be fatal in situations in which alertness
and judgment are required. Dubowski categorizes the correlation of serum
ethanol levels and intoxicating effects into seven stages of alcohol influence,
with each stage being associated with certain clinical signs and symptoms:
The above-described stages may be less obvious after long-term exposure to ethanol due to the development of tolerance, a phenomenon which can also develop during prolonged administration of barbiturates or benzodiazepines after long-term use. In fact, there is cross-tolerance among barbiturates, benzodiazepines, and ethanol. Other CNS effects associated with ethanol use are cerebral degeneration, alcoholic hallucinations or delirium, amnesia ("black-outs"), and polyneuritis.
Ingestion of ethanol is known to contribute to gastrointestinal problems such as gastritis, pancreatitis, malabsorption syndromes, elevated hepatic enzymes, alcoholic hepatitis and hepatic cirrhosis. Secondary complications due to ethanol ingestion include malnutrition, which contributes to the development of Wernicke's encephalopathy and Korsakoff's syndrome, both of which are due to thiamine (vitamin B1) deficiency.
Fetal alcohol syndrome (FAS) is a teratogenic effect of ethanol. Symptoms of fetal alcohol syndrome include craniofacial dysmorphology, CNS dysfunction, prenatal and antenatal growth deficiencies, and other various abnormalities. As little as 2 drinks early in pregnancy has been associated with FAS. FAS is more commonly seen in infants where the mother consumed 4-5 drinks (60-75 ml of absolute ethanol) per day. The incidence of FAS is somewhere between 1/300 and 1/2000 live births.
Long-term use of ethanol produces physiological dependence which usually results in a withdrawal syndrome upon discontinuation. Ethanol withdrawal is itself a clinical problem, especially after long-term use. The syndrome can range from mild to extremely severe and is dependent on dose and duration of ethanol consumption. The alcohol withdrawal syndrome has been grouped into four stages: Stage one occurs 6-8 hours after the last drink and is characterized by tremulousness, anxiety, sinus tachycardia, and hypertension; symptoms usually resolve in about 24 hours; stage two occurs about 24 hours after cessation and consists of hallucinations; stage three overlaps with stages 1 and 2, can occur 7-48 hours after the last ethanol intake, and is characterized by the occurrence of one to several grand mal seizures over a few hours; and stage four or "delirium tremens" begins 3-5 days after withdrawal and is characterized by autonomic hyperactivity (tremor, diaphoresis, fever, hypertension, and tachycardia); delusions; hallucinations; and global confusion that can last from 1-3 days.
Ethanol is contraindicated in patients with a preexisting seizure disorder. Abrupt withdrawal after continuous use of ethanol for more than several days can provoke withdrawal seizures (see Adverse Reactions).
Ethanol should be avoided in patients who once suffered from alcoholism unless it is used in the treatment of alcohol withdrawal.
Because ethanol is metabolized in the liver, and chronic administration is well known to cause cirrhosis, it is contraindicated in patients with hepatic disease.
Ethanol is contraindicated in patients with shock following cranial surgery and in postpartum hemorrhage because of its effects on bleeding time.
Ethanol is contraindicated in patients with severe renal impairment because ethanol and its metabolites are excreted mainly by the kidneys.
Ethanol should be used with caution in patients with diabetes mellitus because ethanol can cause hypoglycemia, resulting in poor diabetic control. In untreated diabetics, the rate of ethanol metabolism is reduced. Ethanol should not be administered to patients in diabetic coma.
Ethanol is contraindicated during pregnancy and breast-feeding because it
is secreted in milk and crosses the placental barrier readily. Alcohol-related
birth defects (ARBD) have been reported and documented in the literature
for many years, with the most extreme cases of birth defects being termed
fetal alcohol syndrome (FAS). Diagnostic criteria for FAS include symptoms
in three categories;
...all of which are associated with high maternal intake of alcohol.
Ethanol causes hyperuricemia and can precipitate an acute gout attack. Regular use should be avoided in patients with gout.
Ethanol should be administered cautiously in patients with CNS depression. There is a potential for synergistic CNS-depressant effects if ethanol is administered concomitantly with other CNS depressants.
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