Pharmacology And Toxicology Of Ethanol

The two-carbon alcohol ethanol, CH3CH2OH, is a CNS depressant that is widely available to adults; its use is legal and accepted in many societies, and its abuse is a societal problem. The relevant pharmacological properties of ethanol include effects on the gastrointestinal (GI), cardiovascular, and central nervous systems (CNS), effects on disease processes, and effects on prenatal development. Ethanol disturbs the fine balance between excitatory and inhibitory influences in the brain, producing disinhibition, ataxia, and sedation. Tolerance to ethanol develops after chronic use, and physical dependence is demonstrated on alcohol withdrawal (see Chapter 23). Understanding the cellular and molecular mechanisms of these myriad effects of ethanol in vivo requires an integration of knowledge from multiple biomedical sciences (the terms ethanol and alcohol are used interchangeably in this chapter).

Compared with other drugs, surprisingly large amounts of alcohol are required for physiological effects, resulting in its consumption more as a food than a drug. The alcohol content of beverages typically ranges from 4-6% (volume/volume) for beer, 10-15% for wine, and 40% and higher for distilled spirits (the "proof' of an alcoholic beverage is twice its percentage of alcohol; e.g., 40% alcohol is 80 proof). A glass of beer or wine, a mixed drink, or a shot of spirits contains ~14 g alcohol, or -0.3 mol ethanol. Consumption of 1-2 mol over a few hours is not uncommon. Since the ratio of ethanol in end-expiratory alveolar air and ethanol in the blood is relatively consistent, blood alcohol levels (BALs) in human beings can be estimated readily by the measurement of alcohol levels in expired air; the partition coefficient for ethanol between blood and alveolar air is -2000:1. Because of the causal relationship between excessive alcohol consumption and vehicular accidents, there has been a near-universal adoption of laws attempting to limit the operation of vehicles while under the influence of alcohol. Legally allowed BALs typically are set at or below 80 mg% (80 mg ethanol/100 mL blood; 0.08% w/v), which is equivalent to a concentration of 17 mM ethanol in blood. A 12-oz bottle of beer, a 5-oz glass of wine, and a 1.5-oz "shot" of 40% liquor each contains -14 g ethanol, and the consumption of one of these beverages by a 70-kg person would produce a BAL of -30 mg%. Note that this is only an approximation; a number of factors influence the BAL, including the rate of drinking, gender, body weight and water percentage, and the rates of metabolism and stomach emptying (see "Acute Alcohol Intoxication" below).

PHARMACOLOGICAL PROPERTIES Absorption, Distribution, and Metabolism

After oral administration, ethanol is absorbed rapidly into the bloodstream from the stomach and small intestine and distributes into total-body water (0.5-0.7 L/kg). Peak blood levels occur -30 minutes after ingestion of ethanol when the stomach is empty. Because absorption occurs more rapidly from the small intestine than from the stomach, delays in gastric emptying (owing, for example, to the presence of food) slow ethanol absorption. Because of first-pass metabolism by gastric and liver alcohol dehydrogenase (ADH), oral ingestion of ethanol leads to lower BALs than would be obtained if the same quantity were administered intravenously. Gastric metabolism of ethanol is lower in women than in men, which may contribute to the greater susceptibility of women to ethanol. Aspirin increases ethanol bioavailability by inhibiting gastric ADH. Ethanol is metabolized largely by sequential hepatic oxidation, first to acetaldehyde by ADH and then to acetic acid by aldehyde dehydrogenase (ALDH) (Figure 22-1). Each metabolic step requires NAD+; thus, oxidation of 1 mol ethanol (46 g) to 1 mol acetic acid requires 2 mol NAD+ (-1.3 kg). This greatly exceeds the supply of NAD+ in the liver; indeed, NAD+ availability limits ethanol metabolism to -8 g (-170 mmol)/hr in a 70-kg adult, or -120 mg/kg/hr. Thus, hepatic ethanol metabolism functionally saturates at relatively low blood levels compared with the high BALs achieved, and ethanol metabolism is a zero-order process (constant amount per unit time). Small amounts of ethanol are excreted in urine, sweat, and breath, but metabolism to acetate accounts for 90-98% of ingested ethanol, mostly owing to hepatic metabolism by ADH and ADLH. CYP2E1 also can contribute (Figure 22-1), especially at higher ethanol concentrations and when its activity is induced. Catalase also can produce acetaldehyde from ethanol, but hepatic H2O2 availability usually is too low to support significant flux of ethanol through this pathway. Although CYP2E1 usually is not a major factor in ethanol metabolism, it can be an important site of interactions of ethanol with other drugs. CYP2E1 is induced by chronic consumption of ethanol, increasing the clearance of its substrates and activating certain toxins such as CCl4. There can be decreased clearance of the same

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