11Ethanol23What is the active ingredient?EthanolMetabolic productsAcetaldehyde – causes oxidative damage, flushingAcetate – is converted to fat and storedCongeners (other substances in the beverage)Beer – hops, malt, asbestos, yeast, cobaltWine – resveratrol (antioxidant)Hard liquor – contaminants, asbestos4AbsorptionHighly efficientIn stomach and small intestine:Males metabolize ~25% of drink in digestive tract, so it never reaches the bloodstream!Female metabolizes ~5% of drink in digestive tract Women make lower levels of this enzymePer drink, females absorb 20% more than do men!Food slows alcohol absorption“Oil shots” & other gimmicks won’t5Genes Affect Ethanol Disposal RateADH: turns Ethanol into AcetaldehydeFast version more common in African Americans See a lower risk for fetal alcohol syndromeSlow version more common in Native Americans Prolongs ethanol action, increased addiction riskALDH: turns Acetaldehyde into AcetateSlow version more common in Asians Acetaldehyde lingers, is unpleasant, lower alcoholism rates6Gender DifferencesWomen are more sensitive to alcohol because:Absorb more per drink, 5% (vs 20%) of alcohol is metabolized by digestive tractWeigh less, so it takes less alcohol to achieve the same BACAlcohol stays in water & away from fat, women have higher fat %, thus alcohol is more2concentrated.Thus women have a higher risk for cirrhosis & breast cancer. Also - fetal alcohol syndrome7Definition of 1 drink15 g of EtOH12 oz of beer5 oz of wine1 oz of hard liquorLegal limit for intoxication 0.08%0.08% = 80 mg ethanol/100 ml bloodMen: ~4 drinks in 1 hrWomen: ~3 drinks in 1 hr8Liver’s job is to remove alcoholIn repeat drinkers, alcohol induces Cyp2E1, an enzyme that removes alcohol faster.Cyp2E1 is sloppy, makes lots of free-radicals These free radicals can damage liverCyp2E1 metabolizes many other drugs Makes drug metabolism unpredictableCyp2E1 turns procarcinogens into carcinogens Cancer risk increases at all alcohol intakesPer drink, woman’s liver sees more Alc than man’sWomen are more likely to get liver cirrhosis9Metabolic Consequences - 1Alcohol is Liquid FatEthanol has 7 kcal/gEthanol calories are stored as fat, not carbo“Joe Six-Pack” and his “love handles” Ethanol inhibits muscle burning of fatSome acetate is turned into ketonesThis is what the “breathalyzer” detects10Metabolic Consequences – 2Ethanol Metabolism is Costly “Screws up” cellular redox levels1 drink = 0.33 moles etoh = 0.66 moles NADH get rid of NADH by making Lactate Lactate lowers blood pH This is major hangover symptom (no cure but time!)11Metabolic Consequences - 3 Cardiovascular Disease Risk3-9 drinks/wk – lowers CVD risk by ↑ HDLmore than this stops this benefit3≥ 2-5 drink/wk –↑ blood pressure 5-10 points↑ heart rate and stroke risk4-6 drinks per sitting ↓ fat burning by 33%“Holiday heart” – angina from energy-starved heartPolyphenols in grape juice & red wine (dark beer)↓ blood clotting, so ↓ heart attack & stroke risk12Metabolic Consequences – 4Cancer & Cell DamageEthanol is mutagenicAcetaldehyde & free radicals damage the DNA↑ cancer risk at all intakesstomach, pancreas, liver, colorectal, breast, prostateAlcohol calories displace protective nutrientsEspecially antioxidants, increased free radical levelsBeverage content is unregulatedNitrosamines, asbestos, dioxins, hydrocarbons13FAS Brain14Fetal Alcohol SyndromeLargest known cause of mental retardationUS: 1/100 live births are affected by alcoholSouth Africa: 4.5/100 births are FASNo safe time in pregnancy or nursing1 drink per day causes serious mental lossesFetus can’t metabolize etoh, so it lasts longerTargets “executive function” more than IQAttention deficit, impulsive, can’t tell cause-and-effect, hard to refocus on tasksKills neurons, blocks synapse formation15What is Alcoholism?Alcohol is a “dirty” drug – no alcohol “receptor” it binds & activates brain receptors that control pleasure, anxiety, rewards targets opioid, cannabinoid, GABA, dopamineIt rewires the brain to enforce reward, pleasureCraving is stronger than heroin, cocaine, nicotine50:50 Genes : EnvironmentGenetic variance in receptors makes alcohol’s effects last longer & harder → addictionEnvironmental cues stimulate the brain to anticipate its alcohol reward = craving416New Drugs to Treat Alcoholism!Disulfuram – blocks etoh metabolismNaltrexone (oral) – reduces cravingmonthly injection also availableAcamprosate – reduces cravingTreatment varies with the individual17Alcoholism – Definition (DSM-IV)Tolerance = need more to get same effectWithdrawal symptomsUnsuccessful attempt to cut down useLots of time spent drinking/recoveringGiving up important events to drinkDrink more and longer than intendedContinue use despite seeing the negative