welcome back to dirty medicines dirty biochemistry series in this video we're going to be talking about alcohol metabolism now luckily alcohol metabolism is a pretty short biochemical pathway in fact it's really only two steps what's really high-yield about alcohol metabolism is not necessarily the pathway itself but rather the cofactors involved in the pathway because it's those cofactors that generate a ton of the high yield questions that you might be asked on your exams so in today's video after I go through the two-step biochemical pathway we're going to pay special attention to a lot of associated high yield findings that have to do with alcohol metabolism so let's dive right in we start of course with alcohol also known as ethanol for the purposes of your exams whenever you see alcohol or ethanol I want you to use those words interchangeably because they mean the exact same thing ethanol alcohol same term so we start with ethanol an ethanol gets metabolized into acetaldehyde and the enzyme that catalyzes this conversion is alcohol dehydrogenase look at the name of the enzyme alcohol dehydrogenase so you know that your dehydrogenated alcohol and since alcohol and ethanol are the same thing your dehydrogenase Rajah nating ethanol so this enzyme is technically called alcohol dehydrogenase but you could also memorize it as ethanol dehydrogenase now regardless of which name you choose it's the first enzyme and it converts alcohol into acid aldehyde now acetaldehyde needs to be further processed and broken down into acetate and the enzyme that catalyzes this conversion is acetaldehyde dehydrogenase acetaldehyde dehydrogenase dehydrogenase acid aldehyde so obviously the reactant is acetaldehyde acetate is the end product of this pathway so I told you it's pretty easy right only two steps ethanol to acetaldehyde and then acetaldehyde to acetic now there's a couple things we need to go over first that could show up on your exams so let's be complete and include all of the information the first step the conversion of ethanol to acetaldehyde happens in the cytosol okay so it's shown here in this light blue square this step is occurring in the cytosol the second step the conversion of acetaldehyde to acetic happens in the mitochondria okay so this is shown here in light pink you should know which part happens in cytosol and which part happens in the mitochondria so now we're back to our pathway and this is really the nuts and bolts of what you need to know the next very high-yield thing that we need to touch on is the kinetics of alcohol dehydrogenase so perhaps you've already studied the pharmacology section and you know that alcohol is metabolized through zero order kinetics when you're memorizing that fact what you're really memorizing is that the conversion of ethanol to acetaldehyde or the enzymatic activity of alcohol dehydrogenase operates at zero order kinetics so zero order kinetics really just means that a constant amount of a drug or a substance is eliminated from the body at a constant rate and this is the graph that accompanies zero order kinetics so when it comes to alcohol metabolism you should memorize it the conversion of ethanol to acetaldehyde done by the enzyme alcohol dehydrogenase or that is to say the elimination of processing of alcohol this is all zero order kinetics so if you see this graph think alcohol think ethanol think alcohol dehydrogenase think the conversion of alcohol or ethanol to acetaldehyde so a constant amount of alcohol is eliminated over time and that will not change regardless of how much alcohol is put into the system so whether it's one beer 20 beers 20 shots or a thousand wine coolers it doesn't matter it's all zero order kinetics it's a constant amount of alcohol eliminated over time now we're back to our pathway again what's incredibly high yield to know about this alcohol pathway is that there is a very very high yield cofactor involved in the step that converts ethanol to acetaldehyde and that cofactor is nad plus so when alcohol or ethanol gets converted to acetaldehyde by alcohol dehydrogenase we also convert nad plus into NADH okay so this is an incredibly important little tidbit of knowledge to understand and the reason is because you need to consider what happens when someone drinks an excessive excessive amount of alcohol right so we're talking about people with alcohol use disorder commonly referred to it's alcoholism so in those states you have a ton of alcohol in the system so the ethanol level is very high and the body is doing its best to convert that ethanol into acetaldehyde but as it's breaking down that alcohol through zero order kinetics over time using the enzyme alcohol dehydrogenase it has to convert NAD+ into NADH so the associated finding is that the level of NADH goes up and the level of NAD+ goes down okay so when we say that the level of NADH goes up and the level of NAD+ goes down another way to state this is that there is an increased NADH to NAD+ ratio okay so I just took those two findings and put them together in a ratio now this is the really high-yield topic when it comes to alcohol metabolism because it's this ratio that starts to affect other biochemical pathways so let's talk about them now and make sense of the symptoms that arise and relate it back to alcohol metabolism so when you have an increased level of NADH or an a decreased level of nad plus that is to say you have an increased NADH to NAD+ ratio the first finding that you see is that you decrease the ability to undergo gluconeogenesis so if the body cannot undergo gluconeogenesis because there's too much NADH and not enough nad plus then the first symptom that you'll see in alcohol use disorder or patients who drink way too much alcohol is fasting hypoglycemia recall that hepatic gluconeogenesis is responsible for maintaining a basal level of glucose in the body and if it cannot do that then you'll get fasting hypoglycemia that is our first high-yield finding of alcohol metabolism the next high yield association is that you have decreased spinning of the TCA cycle and if can't do the TCA cycle than acetyl co a which normally is an input to the TCA cycle has to be used somewhere else because the body is building up acetyl co a over time because pyruvate is being converted to acetyl co a through the pyruvate metabolism pathway but that acetyl co a cannot go through the TCA cycle because in order to go through the TCA cycle you would you'd have to have a smaller level of NADH but because there's so much NADH the body's saying hold up no TCA for you because of this acetyl co a has to go somewhere else right it cannot go into the TCA cycle so if it can't go into the TCA cycle the body will get into a state of ketosis because it's going to be shunted towards ketone pathways so let's take a step back for one second the first association was decreased gluconeogenesis and this was due to the fact that there was too much NADH and not enough nad plus so we decreased our level of gluconeogenesis and that caused fasting hypoglycemia and people that drink too much alcohol the next high yield finding was that we decrease the ability to do the TCA cycle again this has to do with an increased NADH to NAD+ ratio in this state there's so much acetyl co a that's sitting around hoping to go through the TCA cycle but unable to do so that that acetyl co a gets shunted into ketone pathways and you'll get a state of ketosis so in chronic alcohol users not only will you see fasting hypoglycemia but you could see ketones in the urine the next associated finding is lactic acidosis and in this case you have an increased level of lactate pyruvate is being converted to lactate because when it's converted to lactate it uses up NADH so what the body sees is this increased level of NADH and this decreased level of nad plus and it wants to correct that so it says hmm what pathway can I use to eat up some of this NADH and obviously the body has an abundant availability of pyruvate and what it's going to do is convert that pyruvate into lactate because the cofactor in that pathway is NADH so by converting pyruvate into lactate the body can attempt to use up that excess and ADH so in states where there's too much ethanol you'll see increased lactate because it's hoping to metabolize some of the NADH so as you can see all of these high yield associated findings associated with alcohol metabolism all have to do with an increased NADH to NAD+ ratio so how do you remember that this is where the dirty medicine mnemonic comes into play what you should remember is that the increased NADH to NAD+ ratio all has to do with nad or nad and how I remember this is I say natty light natty light is a very popular cheap beer in America and it's natural light is the actual name but everybody here refers to it refers to it as natty light and natty reminds me of nad nad which reminds me of the NADH to NAD+ ratio and of course this is a beer so I relate the mnemonic back to alcohol or alcohol metabolism so once again in alcohol metabolism you have a ton of associated high yield findings shown here on this slide the reason that this is particularly high yield is because this all has to do with biochemistry so by diverting NAD+ to NADH you decrease gluconeogenesis you decrease the TCA cycle and you increase the conversion of pyruvate to lactate acid very very high yield all having to do with the increased NADH to NAD+ ratio which you will remember by saying natty light which is a beer so it obviously has to do with alcohol metabolism so now let's come back to our pathway this is everything that we've talked about so far what you need to memorize is that both of these enzymes in this pathway can be inhibited by a certain drug the first enzyme alcohol dehydrogenase is inhibited by famiy PES all now of note this is actually the treatment that's given to ethylene glycol overdose or methanol overdose so ethylene glycol is antifreeze and methanol either of those substances people tend to overdose on them when they try to commit suicide so if that's the case a lot of times toxicologists might give fomepizole as the antidote so for Fazal inhibits alcohol dehydrogenase and it therefore inhibits the overdose of methanol and ethylene glycol so the way that you can remember this is that if you look at the name of the drug for mep is all MEP MEP methanol ethylene glycol poisoning so it treats methanol and ethylene glycol poisoning so from Epis although MEP MEP from methanol efore ethylene glycol and P for poisoning so really really high yield antidote to know on your exam now the sulfur M is the next drug and that's going to inhibit acetaldehyde dehydrogenase and I solve for M is going to inhibit outside acetaldehyde dehydrogenase which means that you'll have a decreased level of acetate but an increased level of acetaldehyde so the way that this works is that by increasing the level of acetaldehyde you're actually giving somebody a pretty noxious substance so acetaldehyde is responsible for the symptoms of a hangover so tachycardia flushing etc nausea some vomiting and we tend to offer disulfiram as a possible treatment for those with alcohol use disorder because what it does is it give somebody the very unpleasant side effects that are associated with a hangover and it does this by causing a buildup of acid aldehyde so normally the body would process that acetaldehyde into acetate and they wouldn't have those symptoms of a hangover but it's when that acetaldehyde level builds up really high that you get those terrible symptoms nausea vomiting flushing sweating syncope tachycardia etc so disulfiram inhibits this enzyme builds up noxious levels of acetaldehyde which causes the symptoms of a hangover so disulfiram is actually a treatment that's given to folks who have problems drinking because the hope is that by giving them these very unpleasant side effects will make them not want to drink as much but it's very high yield to understand that these enzymes are inhibited acid alcohol dehydrogenase is inhibited by fomepizole and acetaldehyde dehydrogenase is inhibited by disulfiram okay but that's really everything that you need to know about alcohol metabolism if you're looking for a more thorough discussion of why the NADH to NAD+ ratio affects gluconeogenesis the TCA cycle and dick acidosis see the previous videos in the dirty medicine dirty biochemistry series because I've already discussed it a pretty great length and then see future lessons for more information about alcohol