1Thomas M. Guenthner, Ph.D.Department of PharmacologyE-417 MSA, m.c. [email protected] AND TOXICOLOGY OF ETHYL ALCOHOLI. "EPIDEMIOLOGY"- Ethyl alcohol (Ethanol, EtOH) is the single most widely used pharmacological agentin the world- Most costly abused drug in western world; cost to US society is 65,000 lives and$136 billion per year- Used regularly by 2/3 of US adults, 1/3 of US adults average > 2 drinks per day (i.e.are functionally influenced by ethanol on a daily basis). 10% of US adults arephysically or psychologically addicted.- Alcohol-induced liver disease #4 cause of death among US males- Total US consumption is 700 million gallons per yearII. CHEMICAL PROPERTIES OF ETHANOL AND OTHER ALCOHOLS- Hydroxylated alkanes, low molecular weight, simple chemical structure- Low boiling point (high vapor pressure)- Good solvents, mix with both water and organic solvents; as chain length increases,lipophilicity increases- Hypnotic and toxic potency generally increases with chain length, i.e. potency ofhexanol > pentanol > butanol > propanol > ethanol > methanol; beyond C6,miscibility with water decreases, potency decreases.- Special exceptions: methanol is toxic due to formaldehyde and formic acidformation, isopropanol is toxic due to acetone formationIII. AVAILABLE FORMS OF ETHANOL- "grain alcohol" = ethanol ("wood alcohol" = methanol, "rubbing alcohol" =isopropanol)- USP ethanol -- 95% ethanol, 5% water (azeotrope)-denatured alcohol- anhydrous (absolute) ethanol -- 100% ethanol- beer - 3-6% ethanol; wine -- 10-12% ethanol (fortified to 20%); distilled spirits -- 40-75% ethanol (80 to 150 proof)- consumable forms pharmacologically equivalent (except for absorption kinetics)- 12 oz. beer = 4 oz. glass of wine = 1 oz. shot of spirits2Time (hours)0123456Blood Ethanol Conc. (mg/ml)0.00.51.0Empty StomachFull StomachEffect of Food on Ethanol Absorption. Blood alcohol in fingertip bloodafter ingestion of ethanol on an empty stomach (upper curve), or witha meal (lower curve). Data from a single human subject.IV. ABSORPTION- Small, lipophilic molecule, easily crosses membranes- Readily absorbed from stomach, small intestine, colon; also from lungs.- More readily absorbed from small intestine than stomach; delaying gastric emptyingslows absorption (see fig.1)- More concentrated solutions absorbed more rapidly (highest rate with 30% EtOH)V. DISTRIBUTION- Eventually distributed in total body water- Initially distributed into highly perfused organs; rapidly enters CNS (see figure 2)- The same blood level is more intoxicating during the rising phase of distribution than in the clearance phase- Readily crosses placenta and is excreted in mothers' milkVI. EXCRETION3- Over 90% metabolized by oxidation (see below)- 2-8% excreted unchanged via urine- Excretion of unchanged ethanol via lung is basis for "breath test"VII. CORRELATION OF BLOOD LEVELS WITH INTOXICATION- Blood levels correlated to pharmacological effects- Prima facie evidence for intoxication under law- 3 ways of expressing blood levels: concentration of 1 g ethanol per liter blood = a) 100 mg/dl b) 100 mg% c) 0.1%- Table 1 shows symptoms corresponding to given blood level; Blood Alcohol Conc.(BAC)Manifestation of effect< 50 mg/dl (0.05%) Increased sociability; euphoria50-100 mg/dl (0.05-0.1%) Disturbances in gaitLack of concentrationIncreased reaction time100-150 mg/dl (0.1-0.15%) AtaxiaImpaired mental and motor skillsImpaired short-term memorySlurred speech200 mg/dl (0.2%) Lack of response to sensorystimuli250 mg/dl (0.25%) Coma500 mg/dl (0.5%) Respiratory inhibition; Death- Not absolute, some chronic alcoholics tolerate 0.5% quite well.- In Illinois, 0.08% is defined as legal limit for DUI- Loading dose of 70 g ethanol (4 12 oz. beers) produces ~0.1% blood level in a 70kg man; this level maintained by consumption of ~10 g ethanol (8-10 oz.beer) / hrVII. CLEARANCE4CH3CHOEthanolAcetaldehydeCH3CH2OH+ NAD++ NADHCH3COAcetaldehydeAcetic acidCH3CHO+ NAD++ NADHOHCH3CHOEthanolAcetaldehydeCH3CH2OH+ H2O2+ H2OCH3CHOEthanolAcetaldehydeCH3CH2OH+ NADPH + O2+ NADP+Alcohol Dehydrogenase(Slow Step)CatalaseCYP2E1(MEOS)Aldehyde Dehydrogenase(Rapid Step)- Figure 3 (above) shows clearance of ethanol after consumption of various amounts.- Clearance is linear (constant rate), and at the same rate for all amounts -- ZEROORDER (not concentration dependent)- Rate of elimination is the same at high and low ethanol concentrations -- about 10g/hr- Consumption of more than 10 g/hr (8-10 oz. beer) will cause blood levels tocontinue to rise- A 70 kg man with a blood level of 0.1% will require 6-8 hours for completeelimination- Hepatic clearance (metabolism) is the most important factor in elimination- The rate of elimination is essentially the rate of hepatic metabolism- Elimination is zero order because metabolism is zero orderVII. METABOLISM- Occurs almost exclusively in the liver- Three known pathways for ethanol (see figure 4, below)- Pathway 1 (alcohol dehydrogenase, ADH) the only really significant pathway forethanol elimination.- Converts ethanol to acetaldehyde with NAD+ as cofactor- Rate limiting process in ethanol elimination- Usual amount of substrate (ethanol) present greatly exceeds Km. Thereforeenzyme acting almost always at maximal velocity, essentially independent ofincreased or decreased ethanol concentration. Explains zero order kinetics.- Suggested that increasing regeneration of NAD+ from NADH could speedethanol metabolism (Fructose). Not practical.- Pathway 2 (catalase) uses peroxide as oxidative cofactor - of very minor importance5- Pathway 3 (Cytochrome P-450) also called MEOS (microsomal ethanol oxidizingsystem)- Not important in overall elimination of ethanol, but has important therapeuticimplications- Specific P-450 (CYP2E1), which metabolizes a number of drugs andenvironmental compounds, is induced by ethanol, and inhibited by ethanol- "Naive" drinkers will metabolize these compounds (phenytoin andtolbutamide are examples) more slowly, because of the inhibitory effects ofethanol on 2E1- Chronic alcoholics may metabolize these compounds more rapidly becauseof induction of CYP2E1 by chronic ethanol. Metabolic activation ofnitrosamines to reactive mutagens is an example.- 4th reaction (aldehyde dehydrogenase) actually part of alcohol dehydrogenasepathway- Converts acetaldehyde (product of ADH) to acetate, with NAD+ as cofactor- Rapid compared to ADH, therefore not rate limiting- Ensures little or no buildup of
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