Alcohol Effect On Liver

hello and welcome toour lecture number five in the series on alcohol,alcoholism, and inhalants. today we're goingto talk, obviously, about alcohol and itspharmacokinetic properties and its pharmacodynamicproperties, spend a little timetalking about alcoholism, a very brief timetalking about inhalants. inhalants are volatileliquids just like alcohol so that's why they get includedin the same group of drugs.

this is our first foray intotalking about classes of drugs. we spent all ofour time thus far talking about pharmacokinetics,pharmacodynamics, brain, and some issues withdrug abuse and addiction. so now we're going tospend some time talking about-- the rest ofthis semester-- talking about specific drugsand issues with those. so we'll start with alcohol. it's obviously the mostcommonly used intoxicating

drug in the unitedstates and worldwide. we'll talk a little bit aboutthe demographics of alcohol use, talk about whatalcohol actually is, talk about itspharmacokinetics, and talk specifically about the effectsof caffeine and alcohol together. so we'll do aspecial note there. talk about thepharmacodynamics of alcohol, it's pharmacologicaleffects, and finish up

talking about toleranceand dependence. then we'll move on to talkabout alcoholism and inhalants. so first in the demographics,14 million americans have problems withalcohol directly, seven million peoplein the united states are alcoholics-- prettywidespread problem-- 10% of the drinkers in theunited states drink 50% of the alcohol. that's a prettystartling statistic.

half the alcohol is drunkby only 10% of drinkers. most people who drink, theother 90%, drink moderately, drink safely, have noproblem functioning. it is this 10%that we really are focused on when we're talkingabout direct alcoholics. so when we talkabout alcohol, we're talking about of courseethylene-- ethanol or ethyl alcohol which is alcoholthat can be drunk. other alcohols, like isopropylalcohol, are quite toxic,

or methyl alcohol or woodalcohol are all quite toxic. these other alcohols aremetabolized to formic acid and formaldehyde. and as a result, you end upwith vomiting, blindness, coma, and potentially even death. so ethyl alcohol is thealcohol we can drink. there is a lot of controversyover the united states government's actionsduring prohibition because some industrialgrade ethyl alcohols

were specifically poisonedwith methyl alcohol to try to keeppeople drinking them. and they drink it anyway. and as a result,quite a few people were killed, blinded, et cetera,by this particular action. so there's something to becareful of and cautious of make sure that you're getting youralcohol, which is obviously easy to get, but don'tgo making it at home. so there are three majortypes of drinking alcohol.

beer, which is generally3% to 6% alcohol, although if you drink microbrewsthey can have up to 9% and some microbrews can evenhave higher percentages. so keep that in mind if that'swhat you prefer to drink. our first recorded brewerywas in egypt around 3700 before the common era. so that puts it fairlyearly in our history. been drinking beera very long time. not quite as long as wine.

wine is generallyaround 12% alcohol. it can be fortified to 20%with distilled spirits. and the oldest recordedhistory of wine goes back to 5400 bc in iran. distilled spirits tend to bearound 40% to 60% alcohol. they're normallygiven a proof rating which is two times thepercentage of alcohol. so something that is 100proof is 50% alcohol. so a liquor likebacardi 151 you want

to be very careful of becauseit has 75 and 1/2% alcohol. so that's something tobe very cautious of. finally, we get the conversionof wine into brandy. and brandy is simplydistilled wine. that starts to occurduring the middle ages. and so we have a fairlylong history with alcohol, but the law the earliestrecord of distillation is then in the middle ages. so alcohol is, of course,produced by fermentation.

sugar and water and airis invaded by yeasts. yeasts then consume the sugarforming ethanol and carbon dioxide which bubblesup and escapes, unless of courseyou're brewing beer. yeast cannot survive inhigh alcohol concentrations so the best you can get is atabout 10% to 15% at the end of fermentation. so on their own, yeasts canonly produce beer or wine. everything else is producedthrough fermentation

followed by distillation. so distillation is aprocess by which we get actual distilled alcohol. so this removes the water andincreases the alcohol content. and those of you who may havedone this in science class, it's fairly straightforward. you slowly heat thefermented product, and then it gets run througha coil for it to cool down and evaporates.

and if you do this at theappropriate temperature, the alcohol willevaporate earliest and so the early products ofthat distillation product will be higher in alcohol percentage. so the slower it's distilled,the higher the alcohol percentage. that's a big part ofhow this process works. to give you an idea of wherethese different liquors we drink come from, brandyis a form of distilled wine,

whiskey is from grains,primarily corn but other grains as well. rum is distilled withmolasses, schnapps is distilled from potatoes,tequila is distilled from-- or is fermented fromblue agave cactus. so that agave nectar you seeat the grocery store, that's where that comes from. and then gin and vodka aremixtures of pure alcohol with water and flavoring.

and so depending onthe kind of vodka you drink-- and everybody vodkais a little bit different-- some vodka like skye vodkaare filtered to a great extent and, as a result, they areformulated, at least in theory, to provide less of ahangover because they have been filtered out more. whereas the cheaperforms of vodka, oftentimes, have a lotof other crap in them and are much more likelyto give you a hangover.

at least that's the idea. so what is the typicalmeasurement of an alcohol serving? so a typical serving ofan alcoholic beverage should contain about thesame amount of alcohol. we all know that that'snot necessarily the case, but we want to bemindful of this as we're out trying to besafe consumers of alcohol and think about how thisrelates to our blood level.

so a five ounce glassof wine and an ounce and a half of mostliquors or a 12 ounce beer are close to the same thing. now, the problem isthat's the first step in understanding how muchdrinking influences your blood alcohol level. so starting by whatyou're putting in is the first place inthis overall equation. so our blood alcoholconcentration

is expressed interms of milligrams of alcohol per 100milliliters, or one deciliter, of whole blood. so it's expressedas a percentage. so 80 milligramsper deciliter is 80%, which you'd belong since dead by then, but just to give you an example. most of the time when wetalk about blood alcohol concentrations, we'retalking about less than 1%--

1/10, sorry. 1/10 of 1% of alcohol. so 0.1 is pretty intoxicated. so to try to understandhow the dosing of alcohol affects your bloodalcohol concentration, the first place we have to stopis looking at the absorption. so it's absorbedrapidly from the stomach and small intestines. alcohol is solublein both fat and water

so it's absorbed quickly. about 20% is absorbedfrom the stomach. that percentage is affected bya variety of factors, including presence of foodwill slow absorption. anybody who's drankat all knows this, that you if you eatbefore you go out drinking you'll have amuch better experience because alcohol will beabsorbed more slowly, you won't getintoxicated as quickly.

drinking on an emptystomach is always something to try to be avoided. again, the volume andconcentration of a dose is going to alsobe affected-- also going to affect the absorption. this is why shots are oftensuch a nefarious process when we go out drinking becausethey are low volume, high concentration. whereas if you'redrinking a 20 ounce beer,

you're going to drinkthat more slowly, it's going to havewater in with it. if you're drinkinga mixed drink, again, it's going to haveother liquids in with it that are going to help waterdown the amount of alcohol we're drinking. so if you are drinkingsomething like shots, you always want to havesomething non alcoholic, or try to have somethingnon alcohol with it.

some water, soda, or at leastdon't be doing shots and liquor drinks. maybe shots and beer. again try be responsibleand not end up with that highvolume of alcohol. so in the stomach, alcoholis actually an irritant. it increases the flow ofhydrochloric acid and pepsin. this is one the reasonswhy chronic alcoholics have such a problem with ulcers.

so 20% of the alcoholthat's absorbed comes from thestomach, the rest of it comes from the small intestine. anything that affects movementto the small intestine might affect absorption. so food, et cetera. the time from your last drink tomaximal absorption in the blood is about 30 to 90 minutes. again, importantto keep in mind.

when you're leavingthe bar, if you've just had drinks before youleave, you're not as drunk as you're going to be. so that's something toalways watch out for. you just want to becautious about that because it is about 30to 90 minutes before you get that maximal absorption. so alcohol is evenlydistributed throughout the body. it freely crosses theblood brain barrier,

it's freelydistributed to a fetus. fetal blood alcoholconcentration is the same as their mother. concentration in exhaledair versus venous blood is one to 2,300. this calculation is usedfor breathalyzer tests, as you see in the photograph. so a couple of importantthings to understand. the fetal bloodalcohol level is going

to become very importantwhen we start talking about fetal alcohol syndrome. the cdc in the unitedstates has a firm policy that pregnant mothersshould not drink at all. and so that's an importantthing to keep in mind. also, understanding thisbasis for breathalyzer tests is also very important. now, the problem withthis kind of testing is it's based onmathematical modeling.

and so most police departments,if you fail a breathalyzer, will then do anactual blood test to get a much more accurateassessment of your blood so no surprise. alcohol is metabolizedentirely by the liver, or almost entirely by theliver, but 95% of what you drink is metabolized by your liver. the other 5% is excretedunchanged from your lungs. so alcohols a volatileliquid, it evaporates in air.

so as it's passing throughyour-- in your blood through your lungs, it comesout through your breathe. alcoholic dehydrogenase is anenzyme that breaks down ethanol to acetaldehyde. the maximum amount that canbe metabolized by your body is about one drink per hour. this is a really importantthing to keep in mind because if you have threedrinks all in a row, it will be three hoursbefore those are metabolized.

if you have 10 in a row,it's another 10 hours. and so understanding thiskind of metabolic rate is really important. if you have anythingthat is slowing down your metabolic ratein your liver-- so if you take otherprescription drugs, if you drank the nightbefore-- all of those have the tendency to affecthow fast you can break down alcohol.

so one drink per hour is asfast as your body can go. there's always a chance thatit's going to be slower. so that acetaldehydeis then broken down into acetyl-- acetic acidand is expressed out that way by-- as carbondioxide and water. important thing to understandabout the pharmacokinetics of alcohol is there isa huge sex difference in alcohol metabolism. women have higher bloodalcohol concentration

for the same numberof drinks, even if you adjust for body weight. the first thing you have tounderstand about blood alcohol concentration is it's apercentage of the amount of blood you have. if you are a bigger person,you have more blood. and so one drink is going toget distributed across that body more freely. and obviously, onaverage, women tend

to be smaller andshorter than men. now, that doesn'taccount for this issue. women actually, if youjust for body weight, still have a higher bloodalcohol concentration and that has to do withrelatively lower levels of alcohol dehydrogenase. so women have 50% lessgastric metabolism of alcohol which leads to a 7% increase inblood alcohol content over men. and so this is why youget that kind of two

to one rule about how manydrinks men should have versus women, because men aremuch more efficient processors of alcohol. again, about at the 50%level is where woman are. men also have a highermuscle to fat ratio in general and more blood flow. so alcohol is oftenmore diluted in men. women have higher fat content. this doesn't meanthat they're fatter,

but they have breast tissue anda different distribution of fat on their hips, and et cetera. so overall and on average,women have higher fat content which stores littlealcohol which means more alcohol in blood plasma. so someone who hashigher muscle ratio will be able to processmore alcohol because they have more blood flow. higher fat content willnot help that at all.

so to get that this three stepmetabolic process involved in the breakdown of alcohol. acetyl alcohol dehydrogenasefunctions to convert alcohol nicotinamideadenine dinucleotide is required for activity rate,limiting step and reaction. so this is one of thereasons why it's slower. alcohol dehydrogenase convertsto acetaldehyde acetic acid. acetic acid is then broken downinto carbon dioxide and water and thus releasingenergy as calories.

so that's one of the reasonswhy alcohol has a high amount of calories in it. it's always somethingto keep in mind. if you look at thisoccurring in the liver. there are twolobes to the liver. ethanol is primarily-- orentirely-- 95%-- sorry-- broken down in the liver. you can see ethanol getsconverted into acetyl aldehyde and then into acetic acid.

there are of course a greatnumber of individual variations in the elimination of alcohol. so keep in mindthat the same number of-- that the same person mighteliminate alcohol more quickly. so if we look at bloodalcohol illumination in gram percentage per hour,it's down from 0.01 of 0.015. so again, that's apretty dramatic increase, it's a 50% increase, inthe ability of someone to process out alcohol.

and then you have downat the end somebody whose very super rapid atprocessing that alcohol. so there are somegenetic differences. so if we look athow many drinks you might be able tohave before driving, the safest thing is none. the only safe legaldriving limit is zero. impairment begins here. if you look at menversus women, you

can see they've startedthe scale a little bit different in body weight. average male is somewhere inthis 160 to 200 pound range. so the lighter you are,the lower your level is. so at one drink, impairmentbegins immediately for someone who'sonly 100 pounds, and they've already reachedthe legal limit of 0.04 at dwai which is drivingwhile ability impaired. at two drinks, unlessyou're over 220 pounds

your driving skills aresignificantly impaired and you are overthe legal limit. anyone who has morethan four drinks, they're certainlyway over the limit. and so one to twodrinks is really where you want tohold your limit. and you can see for women, it'sfar more at one to two drinks-- certainly far moreat one drink-- that they become impaired.

quick note oncaffeine and alcohol. it's important to understandthat caffeine masks some of the effects of alcohol. as a result of consumingsignificant amounts of caffeine with alcohol, thecaffeine can actually mask how intoxicatedyou really are. because caffeine is anstimulant and alcohol is primarily a depressant. it has someparadoxical qualities

we'll talk about here in aminute with both stimulant and depressant qualities,but caffeine's entirely a stimulant. and so the sleepiness orsome of the light-headedness you might get withalcohol can be masked by consumptionof caffeine, especially with largeamounts of caffeine like with the redbull and vodka. so what's moreimportant is not just

that the caffeine ismasking the alcohol and so you end up consuming morealcohol than is probably safe, that the two have very differentpharmacokinetic profiles. and so, while alcoholis metabolized via a steady state, which isshown in the red line here, caffeine is metabolizedvia a half life. that's going to be ournext topic of discussion is caffeine and nicotine. and so what happens,as you can see,

is while the alcoholis slowly tapering off in a linear fashion,the caffeine drops out rather rapidly. and so as a result, someone whohas had caffeine and alcohol will find themselvessuddenly very intoxicated, as you can see atabout our two or three, because that half life hasdropped off so dramatically. and so what happensis, while alcohol is being steadily andslowly eliminated one

at a time or every hour,that half life decay causes this dramatic suddendrop in caffeine levels. and as a result,people oftentimes find themselves suddenlyvery intoxicated. so something to be verycautious of and very mindful of. so moving on to talk aboutpharmacodynamics of alcohol. alcohol's been a bit ofa mystery for some time. for many years weassumed alcohol was a general depressant fornerve membranes and synapses

working on some sortof general level. there is evidence emergingthat alcohol actually disturbs synaptic activity ofneurotransmitters, particularly glutamate and gaba. and gaba becomes veryimportant because, of course, gaba's an inhibitoryneurotransmitter. and as a result, anythingthat influences gaba is probably going tointeract with alcohol on a pretty significant level.

so it's drugs likebenzodiazepines certainly should never be takenalong with alcohol. the final thing thatalcohol seems to affect is various intercellulartransduction processes. so we'll start by looking at howethanol inhibits responsiveness of nmda receptors to glutamate. so, remember, glutamate's animportant neurotransmitter. that's then exacerbatedby the enhancement of the inhibitoryneurotransmitter gaba.

so we get inhibitionof glutamate receptors, enhancement of gabatransmission, and as a result, you get a depressant effect. acamprosate, which is thestructural analog of glutamate, is currently being usedto maintain abstinence in some alcoholdependent patients because it essentially isan antagonist of glutamate. the gaba receptors--ethanol activates gaba mediated increasesin chloride ion flows.

and so, as a result, youget neural inhibition. this results in sedation, musclerelaxation, and importantly, inhibition of cognitiveand motor skills and some anti anxietyeffects of alcohol. it's the reason why people getalcohol related courage which is sometimes excessiveof where it should be. this ultimatelyleads to augmentation of dopaminergic projectionsfrom the ventral tegmental area to the nucleus accumbens rightthere at that reward circuit.

so here's where the rewardingeffects of alcohol is. that's the reason why alcoholsometimes feels very good. unfortunately, ethanol andstress may actually interact. we know that gaba is animportant part of our stress response. so a gaba mediatedinhibition may actually lead to an activationof opioid receptors which then influencesthe behavior rewarding associated with the activationof the dopaminergic neurons.

so by inhibiting thesegaba neurons-- sorry, gaba mediated inhibitiono--the inhibitions being caused by gaba may lead to theactivation of opioid receptors, which are, of course, animportant part of addiction process, which influencesbehavioral rewarding, which is associated withthe activation of dopaminergic neurons. and so this interactionbetween the two seems to resultin people who are

under a great dealof stress being at greater risk for alcoholism. so alcohol also affectsthe opioid receptors. alcohol dependent people mayhave a genetic dysfunction in the brain's opiate system. we certainly know geneticsare an important part of this puzzle. alcoholism certainlycan run in families. we think that ethanol maytrigger an opioid release.

and more so in people withthis genetic dysfunction, which triggers a dopamineresponsible in the reward circuitry. this is the reasonwhy naltrexone, which is an opioidantagonist, may actually help reduce alcohol cravingby reducing activation of the opiate receptors. and then finally, thesignal one receptors appear to modulate the effectsof alcohol and other drugs

of abuse on neurotransmission,gene regulation, and neural plasticity. so there is a greatdeal of information to still be learned about howalcohol affects receptors, specifically and in particular,the opioid receptors. because there seems to bea lot of work being done to try to understand how alcoholaffects neurotransmission, gene regulation,and the plasticity of neural connections.

alcohol also affectsserotonin receptors as well as cannabinoid receptors. so it actually has somepretty wide based effects. chronic alcohol use augmentsserotonergic activity. so serotonin dysfunctionmay play a role in some types of alcoholism. there seems to be an emphasisin the 5-ht2 and 3 receptors which are located inthe dopaminergic neurons right back in thenucleus accumbens.

so this is where we'd getat that rewarding properties of alcohol are in thenucleus accumbens. serotonin re-uptake inhibitingantidepressants like zoloft seem to be more effectivein reducing drinking in lower risk alcohol males. so there is some questionas to whether or not people you at slight risk forexcessive drinking, something like a serotoninre-uptake inhibitor might reduce theprobability that they

become problematic drinkers. now, the question ofwhether or not that's effective for allmales is, of course, something to wonder about. the cannabinoid receptorsare also affected by alcohol. chronic alcohol usestimulates formation of endogenous cannabinoidtransmitter and anandamide. this leads to down regulationof cannabinoid receptors, thereby disinhibitingthe nucleus accumbens.

cessation ofdrinking then causes a hyperactive endocannabinoidreaction which results in alcohol craving. and ethanol andcannabinoid agonists activate the same reward system. so if we're talking aboutmarijuana and alcohol, they activate similarparts of the reward system. so ceasing drinkingcan result in craving. we'll also talk a little bitabout how chronic alcohol

abuse with the withdrawaleffects associated with that can be pretty severe. so the next spot tofocus on in terms of our understandingof alcohol is to think about itspharmacological effects. so what are the ultimate effectsof how alcohol influences us. certainly we get respiratorystimulation at low doses but respiratorydepression at high doses. high doses of alcoholcan be potentially lethal

because of thatdepression in respiration. alcohol is an anticonvulsantand withdrawal can result to seizures-- orresult in seizures, sorry. alcohol affectsblood circulation and it causes dilation ofblood vessels in the skin. so your skin will feelwarm, people will feel hot, but you're actuallycolder because you're putting off so much more heat. in small amounts, lessthan two drinks per day,

you actually can loweryour risk of heart disease and ischemic stroke. more than 14 drinksper week, however, increases the risk of stroke. and binge drinking iscertainly a big part of this. so it's not that you canhave all 14 of your drinks on one day, it'stwo drinks per day or less seems to have an effecton your risk of heart attack. and that's because alcoholdoes thin your blood a bit.

sleep is anotherproblem with alcohol. alcohol can induce sleep butit will suppress rapid eye movement, or rem sleep. rem sleep is veryimportant for us to actually wake up feelingrefreshed and has some very important neural implications. as a result, if you'vebeen drinking alcohol and you've been insuppressed rem sleep, you'll actually experiencewhat's called rem rebound.

and finally, andvery annoyingly, alcohol may causeearly awakening when you probably reallyfeel like sleeping the most. other psychologicaleffects include, of course, intoxication. at low doses, this is largelydetermined by the person, what we call set and setting. can be from relaxed to euphoricto withdrawn and violent. so both the personand their setting

can really influencethe kind of behavior or psychologicaleffects of alcohol. your mentalexpectations are less important as dosage increases. the dosage starts tooverwhelm whatever your mental expectationsare and you become presently incapacitated as bloodalcohol content increases. you start to get blackoutsat around 0.25 blood alcohol content and then youstart getting into stupor,

passing out, sleeping, anddeath up there are around 0.4. those are very, very highblood alcohol concentrations. anything beyond 0.12 isreally, really intoxicated. and so you always really wantto keep in mind-- keep yourself save and, obviously, if you areanywhere over the 0.04 level, catch yourself an uberor a lyft or a cab or some way to get home thatdoesn't involve driving. alcohol's disinhibitioneffects certainly plays a role in avariety of crimes.

alcohol is implicated in over50% of homicides and assaults. over 40% of violentoffenders in prison were drinking at thetime of their offense. you often get what'scalled alcohol myopia which are cognitive and attentionaldeficits which causes focus on the presentwhich reduces fear and anxiety because there'sno worry about the future. and it certainlyimpairs problem solving. people will do very dumbthings when they are drunk,

as i'm sure you all know. you also get increased concernswith power and dominance and seems to be linked to maleviolence an domestic conflict. there seems to be,again, this disinhibition removes some of the controlrods from aggressive tendencies and people fly of the handleand become very aggressive. or can, depending ontheir personality. of course, we know that peoplewho regularly ingest alcohol develop tolerance.

it's a well-known,well-established phenomenon that most of usare familiar with. there are three differenttypes of tolerance. metabolic tolerancewhere the liver increases drug metabolizing enzymes. this accounts for about 25%of our tolerance at most. we get tissue or what wecall functional tolerance. so neurons adaptto drug's presence. so it's simply that yourneurons have gotten use

to there being alcohol aroundand so these neurons that have adapted to drug presence,the blood alcohol concentration can be double that ofnon tolerant drinkers and be at the same levelof behavioral intoxication. this is behavioral only, nottolerant to memory or cognitive effects. so people who have this levelof tolerance probably black out quite a bit. that is, they have nomemory of what happened.

and then finally,associative tolerance. this is related to environment. and so sometimes thesituation we're in can lead us to beingable to drink more. and if you're out and arereally having a good time and dancing and doingall sorts of other things that are positive. so dependence on alcohol occursafter long term chronic use or can happen over a periodof shorter periods of time

if you've had apretty strong bender. so you can end up withalcohol withdrawal if you have significantalcohol intake. this can develop in severalhours and can be very severe. common cause of adult onsetseizures is alcohol withdrawal. this occurs in 10% of adultsduring alcohol withdrawal. this is most likelyto occur in someone who is a chronic alcohol user. detoxification of alcoholicsduring this period

involves blocking orpreventing seizures. usually this is donewith benzodiazepines or anticonvulsants. there is a kindling model thatshows that repeated alcohol withdrawal leads to anincrease in the severity and greater likelihoodof seizures. so the more someone goes throughthis alcohol withdrawal period, the more likely they areto end up with and have more severe forms of seizures.

the worst of thisis what's called delirium tremens, or the dts. this is a withdrawal syndromeinvolving tremulousness, or tremors, hallucinations,psychomotor agitation, confusion, and sleep disorders. so oftentimes people who aregoing through alcohol rehab are sedated for a periodof time to get them through this withdrawal period. side effects andtoxicity of alcohol.

there is reversibledrug induced dementia. that is, aka, drunkenness. we call it druginduced dementia. it's reversed once you sober up. of course you canget liver damage. ethanol produce oxidants--produces oxidants when metabolized by thehepatocites and causes stress on liver cells. and so you can end up withcirrhosis of the liver.

so 75% of allalcoholism attributed deaths are due tocirrhosis of the liver. and this causes a wide varietyof other problems as well. my father actuallyhad a liver transplant because he had severecirrhosis of the liver. and as a result, he hada number of problems. his blood ph would get offand he would suddenly not know where he was or evenwho he was at some point. he would get thisglobal amnesia.

he also had, co currentwith that, some eye trouble, including macular degeneration. and once he got his newliver, his new liver was able to clean up hisblood enough that he actually could see better. and so really severe problems. so this is the sevenththe most common cause of death in america. there is somedigestive system damage

which can include pancreatitis,chronic gastritis. pancreatitis, i can tellyou, is quite painful. i've had some friends whohave gone through that. and of course, you also getsome destruction of nerve cells, particularly what we callalcohol related dimension which is usually calledkorsakoff syndrome. and we're going totalk a little bit more about that when we talk aboutalcoholism and alcohol abuse here in just a moment.

so that's whatwe'll turn to next is to talk about alcoholismand alcohol abuse. obviously this is asignificant societal problem. getting less severeas the years go by. we see less severeforms of alcohol abuse compared to theprevious centuries. fewer-- lower percentages ofadults report drinking at all. and we certainly have much lowerincidence of severe alcoholism than we used.

now, it is still asignificant problem so let's be sure of that. some of the consequencesof alcohol abuse include what i wasjust mentioning which is called korsakoff's syndrome. and korsakoff'ssyndrome is caused by a variety ofbrain issues that are primarily due todamage to the frontal lobe. you can also get apermanent amnesia

due to damage to what arecalled the mammillary bodies in the brain, where you getno new memories or learning but relatively normal iq. you can get some confabulationwhich this may improve or even recover withthiamine replacement. the cause ofkorsakoff's syndrome seems to be due to a thiaminedeficiency because of the liver damage. so it's secondaryto liver damage.

thiamine or vitaminb is something that's important for us all to have. in fact, oftentimes some ofus don't get enough of it. so it's certainly worthconsidering a vitamin b supplement, or certainly aftera heavy night of drinking, a vitamin b supplementwill oftentimes help you with your hangoverrecovery pretty quickly. more seriously is the problemof fetal alcohol syndrome. this occurs in theoffspring's of mothers

who have a high bloodalcohol concentration during critical stagesof fetal development. this occurs at a rateof about 300 to 500 per 1,000 live births, 30%to 50% of alcoholic mothers, about 2.6 million infants in theus are born annually with fas. features of fas include centralnervous system dysfunction, pretty severedevelopmental disabilities, reduced brain size, and somebehavioral abnormalities that are keen-- akin toattention deficit hyperactivity

disorder. so what happens inthese kids is they have a lot of conduct disorder. and so it presents a similar toadhd, inability to sit still, but often also goesa little bit further. outbursts, inability tobond with their caregivers, that sort of thing. so they tend to have a slowerretarded-- a retarded body growth rate and oftentimeshave facial abnormalities.

and this is really one of thehallmarks of fetal alcohol syndrome and we'll show youa picture here in a second about what this looks like. and then the final andmost severe feature of this is possible congenitalheart defects. so fas has some pretty severeissues associated with it. so this is thefacial features you can see with a fetalalcohol syndrome child. they tend to have a flatmidface, very-- somewhat

minor ear abnormalities,a thin upper lip, they just tend to have thiskind of facial feature. the brain of a baby born withsevere fetal alcohol syndrome, as you can see on the right,is pretty severely deformed relative to the brainof a normal baby. so obviously that'sa severe consequence, and in fact, thecurrent recommendation is that mothers--pregnant mothers-- do not drink at all duringpregnancy, certainly

no more than a single glassof wine at any given time is where you wouldwant to draw the line. so alcoholism is aprimary chronic disease with genetic psychosocialand environmental factors influencing itsdevelopment manifestations. disease is oftenprogressive and fatal. it's characterized by impairedcontrol over drinking, preoccupation withthe drug alcohol, use of alcohol despiteadverse consequences,

and distortions in thinking,most notably denial. each of these symptoms maybe continuous or periodic. so when we're talkingabout alcoholism and we're going to turn totalking about alcoholism as a disease model next, we'retalking about a chronic disease that has a variety ofideologies, including some genetic, someenvironmental, and including thingslike high stress, socioeconomic status,all of these things

can contribute to alcoholism. social support orlack of social support certainly is a big part of that. the biggest hallmarksof alcoholism is this impairedcontrol over drinking. there is an inabilityto not drink. that is, they're just simplypreoccupied with the drug alcohol, they'll use alcoholover all other things despite these adverseconsequences and distortions

in thinking. and again, most notably, denial. so obviously alcoholismis something that receives a lot of attention. it's something most of ushave some familiarity with. i want to start by talking alittle bit about the history of alcoholism as a disease. by 1935 alcoholics anonymouswas founded on this moral model of alcoholism.

aa offered a spiritualand behavioral framework for understanding, accepting,and recovering from alcoholism. and this model stillprevails for some. aa has certainly provided helpthat a number of people need. unfortunately, thereis little research trying to compare aa toother potentially more helpful models. and it's one of thebiggest problems with aa. again, it has helpeda number of people

and i would never deny thatsomeone should go if that's what they feel helps them. but there may be bettertreatment modalities out there. and that's one ofthe things we really need to look at isthe best way-- best evidence-basedpractices-- that we can use to try to treat alcoholics. so 1946, we get a proposed ofa modern disease concept where we divine alcoholism asany use of beverage alcohol

that causes damage to theindividual drinker, to society, or both. now this is obviously a ratherbroad definition and probably overly broad becausesomeone can cause damage to themselves after one nightof drinking that just goes awry where they don't getsomebody to drive them home and they drive themselvesand get into an accident. all sorts of things. so i think this is anoverly broad definition.

from a modernperspective, we focus on this idea of it'sdisrupting their lives, they're unable to controlthemselves, et cetera. so 1957, the americanmedical association defined alcoholism as a disease. by the mid 1970s,alcoholism was redefined as a chronic, progressive,and potentially fatal disease. certainly many peopledie from alcoholism. in 1992 thedescription again was

expanded to includegenetic, psychosocial, and environmental factors. and then finally, weget a behavior model that drinking is a learnedbut maladaptive behavior. and i think it'sall of these things. it is certainly achronic, progressive, and potentially fatal disease. it certainly has thesegenetic psychosocial and i think it certainly can bea learned maladaptive behavior.

another importantthing to consider, and we're going to discussthis in a variety of cases when we talk aboutdrug abuse, is this idea of self medication. where drinking is ameans of self medication for psychological distress. and i think this iscertainly a big part of some chronic drinkingbehaviors and even some social drinking behaviors.

sometimes you just have a badday and a couple of drinks just takes the edgeoff, and i think as long as it's on occasionand not a coping mechanism, i don't think there'sreally that much harm in it. but we're going to talkabout self medication with other drugs. for example, someadhd kids might end up abusing methamphetamines becauseit allows them to concentrate and allows them to feelsomewhat more normal.

and so we'll talk aboutthis idea of self-medication in a variety of contexts. but certainly with alcohol,it's certainly entirely possible that people who useand abuse alcohol do so as a way to deal withstress because they don't have another healthier way to do so. so exercise or someother healthier method of coping and so people useit as a coping mechanism. we know that there is apotential genetic contribution

to alcoholism. the disorder occurs inall classes of society and walks of life. but you can breed animalsrespond differently to alcohol. so it's clearly somethingthat may be inherited. we know, for example, thattaste preference for alcohol is inherited. and so some people may justnot like the taste of alcohol and others do.

and so that's kindof where it starts is this genetictaste preference. taste is a really interestingpart of our genetics. so for example, we knowthat many people can't stand the taste of cilantro. i'm one of them. and that's due togenetics because to us cilantro tasteslike soap and that's due to this specificgenetic change.

similarly, there seems tobe a genetic contribution to taste preference for alcohol. so alcoholism runs in families. children of alcoholicshave a much greater risk for alcoholism,particularly males. now, the problem,of course, is people who grow up in analcoholic family have a different environment and sowe have to tease some of that out.

so the normal prevalence of malealcoholics is about 3% to 5%. if they're children ofalcoholics, it's 20% to 50%. 0.1% is the normalprevalence for females versus about 3% to8% if they grow up in a family of alcoholics. so there is certainly somethingto sex-linked characteristics, whether it has to dowith just basic biology, circulating hormones,neurochemistry, or some difference inthe y and x chromosomes.

this is a mysterythat's still unfolding. alcoholism has a greatdeal of comorbidity. which means it's just simplyco occurs with other problems and disorders orother drug abuse. so much alcoholismmay be associated with other psychopathology. about 30% to 50% ofalcoholics meet the criteria for major depression. again, there's achicken and egg problem.

the alcoholism caused thedepression or the depression caused the alcoholism. about 33% may have acoexisting anxiety disorder. this is where ithink we're clearly talking about somesort of self medication when they have anxiety and thealcohol relieves that anxiety sufficiently so that they canfunction better without it-- or with alcohol, sorry. 38% have some sort ofimpulse control problem.

again, no surprise. one of the cornerstonesof alcoholism is they can't controlthe impulse to drink. and so this dual diagnosis,some sort of comorbid illness, really is usually presumeduntil proven otherwise. because if you addall of this up, we're almost guaranteed thatmost alcoholics will have some sort of comorbid illness. so how do we treat alcoholism?

well, this is, again,an area where there's lots of work being done. the ideal goals for some sortof pharmacotherapy for alcohol abuse and dependencewould be reversal of the acute pharmacologicaleffects of alcohol-- so we start there-- treatmentand prevention of which are all symptomsand complications, and then we want to maintainabstinence and prevent relapse. and then finally,treat coexisting

psychiatric disordersand limit neuronal injury during detoxification byblocking withdrawal induced glutaminergic activationand glutamate receptor up regulations. so one of the thingsthat happens during detox is some pretty significantloss of neurons due to that withdrawalglutaminergic activation and glutamate receptorup regulation. so we have all ofthese things we want

to think about as our goals. and so we'll kind oftake a look at how current treatments addresssome of these issues and where we need some work. so we will start bytalking about that, as of yet, no agent can reversethe acute pharmacological effects of alcohol. so it's not like with naloxonewhich completely reverses the acute effects ofheroin or flumazenil

completely reverses the acuteeffects of benzodiazepines. so currently we havepharmacotherapies that are availablefor the following. to treat and preventwithdrawal symptoms, to reduce relapse todrinking behaviors. to treat and preventwithdrawal symptoms we usually give benzodiazepines. to reduce relapse todrinking behaviors, oftentimes antabuseor naltrexone,

which is a differentdrug, can be given. treating complicationsof alcohol dependent people who aredecreasing or discontinuing alcohol use. again, something likenaltrexone would work there. and then to reduce therelease and glutamate receptor up regulation, which is reducingsubsequent neuronal damage. so here's what weuse for management of alcohol withdrawal.

benzodiazepinesincrease gaba activity, ameliorate thewithdrawal symptoms, prevents seizures andthe delirium tremons. these long-actingbenzodiazepines prevent withdrawal symptoms. and then they're eithermaintained or slowly withdrawn allowing theperson to function. drawbacks here are, ofcourse, these are sedatives and so they sedate people,they end up with psychomotor

deficits, they get additiveinteractions with alcohol, and of course, there isthe potential for abuse and dependence on these drugs. and so we don't wantto move somebody from alcohol toklonopin and then have addicted to klonopin instead. and so you have to be verycareful with this kind of drug activity. anticonvulsant mood stabilizerscan be used for withdrawal.

there are fewer limitationsthan benzodiazepines. but they tend to havea lot of side effects, in particular liver orpancreatic problems. so these are thingslike tegretol, depakote. newer anticonvulsantsseem to be less toxic and have somesignificant potential. these include neurontinand trileptal. we're going to talkabout these drugs later on when we talkabout bipolar disorder.

so somepharmacotherapies to help maintain absenceand prevent relapse include alcoholsynthesizing drugs. so antabuse, or disulfiram,produces an adverse reaction if the patient drinks. opioid antagonistslike naltrexone block the reinforcingproperties of alcohol. and so by blockingthe opioid system, you reduce thecraving by reducing

associated positivereinforcement. and the problemhere is compliance. so people lose thatreinforcement, that reward, and as a result they juststop taking the naltrexone and go right back to drinking. acamprosate, or campral, isthe first pharmacological agent designed to maintainabstinence in alcoholics after detoxification. it's both gaba agnosticand an mnda inhibitory.

so it's kind ofsimilar to alcohol. so it's a gaba agonistmuch like a benzodiazepine, but it's alsoinhibitory of the nmda receptor much like alcohol. it's comparablyeffective to naltrexone. the combination of both drugsmay be additively effective. so if you putthose together, you can see that topdotted line shows the best outcome at 80 days.

we're still talking onlyabout half of patients, but compared tothe less than 10% of patients receiving placebo,it's certainly worth a shot. so some pharmacotherapies isto help maintain abstinence and prevent relapse aresome dopaminergic drugs to try to overcomethat loss of reward. so drugs likebuproprion or welbutrin. they have a theoretical usethat both positive reward and withdrawal seem to involvethe dopaminergic system.

other drugs-- or other areasof interest for investigation are serotoninergic drugs,possibly nicotinic mechanisms, cannabinoid mechanisms. all of these areareas in which people are trying to look atdifferent pharmacotherapies. so lots of work to be done here. i think the mostsignificant work to be done in theseareas is going to involve lookingat pharmacokinetics

and designing treatmentsbased on someone's genetic composition. so the final thing totalk about in this section of our discussion ofdrugs and human behavior is to talk a littlebit about inhalants. and they're includedhere because they're volatile gases as well. so what are they? they are thisheterogeneous group

of central nervousdepressants that are volatile at room temperature. so a volatile liquidis anything that is vaporized from a liquidwhen it's exposed to air. so we have thingslike nitroglycerin, amyl nitrate which-- andbutyl nitrate which are often called poppers andwere used quite a bit in the disco scene of the 1970s. anesthetics include ether,halothane, nitrous oxide.

halothane's a centralnervous system anesthetic used as an inhaledanesthetic in surgery. ether is used--used to be used-- it's sort of the olderof the anesthetics-- you might have seen film ofpatients with a paper mask where ether's being pouredon the mask for them to breathe in. and then nitrous oxide, ofcourse, sometimes people get at the dentist.

people also inhale solventslike toluene and butane. these are volatile organicsolvents like glue, gasoline, paint thinner. not things thatare good for you. and then finally otheraerosols which include haloginatedhydrocarbons, hairspray, typewriter correction fluid. all of this reallydemonstrates to me that if somebody wants to gethigh they're going to get high.

so what do inhalants do? they can cause permanentbrain damage and memory loss. oftentimes that's due to thefact that the person is oxygen deprived. they can suffer hearing loss,nose bleeds and loss of smell, slurred speech, they cansuffocate because they don't have oxygen, you can irregularheartbeat and heart attack, nausea and vomiting, liverdamage, kidney damage, abdominal pain.

these are toxinsfor the most part. particularly things liketoluenes and whatnot. they are very toxicto our bodies. and so why do people abuse them? well, most common age ofabuse are kids 12 to 17. and the us prevalenceamong adolescents is exceeded only by alcohol,tobacco, and marijuana. unfortunately,injuries are often associated with very first use.

even death can occurin first time users. 70% of deaths due toinhalants are 22 or younger, primarily male,and 46% fatalities were from gasoline fuels. so if you look at the age here,this spikes at around 12 to 16, and then a little bit of anincrease there at 20, 21. and then just sort ofother spots here and there. the acute effects of inhalantsinclude intoxication, disorientation, impairedjudgment, hallucinations,

and ataxia which is a lossof motor coordination. only lasts a fewminutes which then leads to repeated useover several hours. they can be verydangerous, again, due to loss of oxygen andpotential organ toxicity. hypoxia is a really significantproblem with inhalants because that loss ofoxygen to the brain can result in braindamage very quickly. chronic effects ofinhalants include

peripheral and centralnervous system dysfunction, liver and kidneyfailure, dementia and loss of cognitivefunctions, loss of coordination. they seem to have anaffinity for things like the basal gangliaand the cerebellum. in a study with normalparticipants, cocaine abusers, and inhalant abusers,inhalant abusers scored the lowest in workingmemory, planning, and problem solving.

and so that's certainlysomething we want to avoid. almost 50% of inhalant abusershave brain abnormalities in an mri compared with25% of cocaine abusers. treatment for inhalants. usually acuteinhalation is primarily treated withsupplemental oxygen. chronic users tendto resist treatment. prevention is thebest treatment, keeping people fromstarting inhalants

is the best thing to do. unfortunately, i can't giveyou the pharmacokinetics and pharmacodynamicsof inhalants because there are so manydifferent kinds of them. we do know that nitrousoxide, for example, has specific receptorsin the brain, but the effects ofall the rest of these are so myriad thatit's impossible to try to get one specificdiscussion of this going.

but these reallycan be dangerous and you really haveto watch out for abuse in kids in particular. well, that's going to be the endof our discussion of alcohol, alcoholism, and inhalants. we'll be revisiting next timewith caffeine and nicotine.