Pharmacokinetics | Drug Absorption

foreign what's up Ninja nerds in this video today we're going to be talking about pharmacokinetics also to really enhance your learning experience I promise you go through it with me in this particular way you're going to understand it you're going to remember and you're going to do well in those exams go down the description box below we have a link to our website on our website we have all the diagrams that we're going to talk about where it's empty you guys can follow along with me filling in the blanks okay please do that also if you want to you have a completely filled off illustration and also some really comprehensive notes to follow along with me so let's get started talking about pharmacokinetics all right we talk about pharmacokinetics first thing is absorption when we talk about absorption we really need to understand how drugs are administered okay because that obviously plays a role in absorption because absorption is basically the drug being administered and getting into the circulation that's all it is so it's basically a drug that we give to a patient once we give it via a specific route of administration the process by which it actually reaches the bloodstream is absorption pretty straightforward now what are the different routes we're not going to go crazy here but obviously the most common one that you guys should remember is internal right so po you take the medication orally so that'd be one the other one that can go via the GI Rod is the other end right up the sinkhole that would be the rectal Administration so some type of suppository the other thing that you want to remember is we can do this via injections so par intro we can it can actually do injections so we can inject it into the dermis you see how there's different layers so here's the epidermis here and then right underneath it is in this kind of like maroon color here is the dermis so we can do intra dermal injections we can inject it into the subcutaneous tissue Sub-Q injections we can inject it into the muscle intramuscular injections you know not only that but we can also take and squeeze some type of ointment or topical agent onto the skin of the epidermis so it works there locally that would be a topical agent not too hard to figure out right the other thing is we can inject this medication directly into a vein what is that called intravenous administration we can also give these medications by having the patient inhale it getting into their lungs this would be inhaled Administration and then the last two that I want you guys to remember is sometimes you can take a medication and put it between the actual lip all right and the teeth so this is the buccal Administration so buccal some people say buccal I don't really care whichever one you like and then the last one to remember is underneath the tongue so sublingual so sublingual so these are the different routes of administration how we can actually give a drug to a patient the most common ones that I think you guys should definitely remember is going to be po because this is mainly the one that most people do outpatient intravenous via in the hospital and then some of these injections particularly like subcutaneous are intramuscular injections but I'd say the IV and Pia would be the big ones that I want you guys to remember now when a drug is actually taken most commonly po in order for that drug to be able to pass through the gastrointestinal tract and get into the bloodstream it has to be absorbed and so the mechanisms by which a drug is absorbed is very very important so what are those mechanisms by which a drug can get absorbed so for example you take a particular medication runs down the gullet into the stomach gets broken down by particular types of gastric acid and maybe even there are certain types of molecules down here that even break it down a little bit more but what happens is the drug has to be able to pass across the gastrointestinal lining that means it has to pass through particular types of cell membranes so there has to be a very specific transport mechanisms that allow for the drug to be shuttled from the Lumen of the gastrointestinal tract into the Lumen of the vasculature what are those mechanisms well the mechanisms depend upon the actual drug characteristics what am I talking about all right so the first one that I want you guys to know is what's called just your simple or passive diffusion process so passive diffusion is when you take a particular drug like this and it passes through the actual cell membrane of the gastrointestinal tract and through the cell membrane on the basal lateral membrane right into the blood so when it does this the mechanism by which it does this is via moving from areas of high concentration to areas of low concentration that's the concept of simple diffusion now in order for this drug to be able to pass across this lipid bilayer on this apical surface and on the basal lateral surface it has to have a couple particular characteristics one is this drug would have to be very small or it would have to be Hydro phobic these are extremely important if a drug is small and it's hydrophobic it would be able to fit easily between the actual cell membrane or passively and diffuse across the cell membrane so when something is lipid like or it's nonpolar like it's easily able to pass across the lipid bilayer so small hydrophobic molecules would easily diffuse via passive diffusion now let's say that you have another molecule here another drug that you're trying to absorb and move it across here but this drug is a little bit bigger so it's a little bit larger or maybe not just necessarily large but maybe it's Hydro Filak so hydrophilic agents will not be able to easily move across the cell membrane because of that they will require specific types of Transporters special types of proteins that'll facilitate their entry into the cell and these proteins that allow for this drug to be carried that are going to facilitate this entry allows for this to be able to again move from areas of high concentration to areas of low concentration but it just can't do it by passing simply through the cell membrane it needs a particular protein this is called facilitated diffusion so this is called facilitated diffusion so some drugs will do this and again it just depends upon the characteristic of the drug obviously the difference between these two is size and solubility one is hydrophobic one is hydrophilic the other thing that you would need to remember is that sometimes same thing maybe you have a drug that's larger maybe it's charge maybe it's hydrophilic just like we talked about with the facilitated diffusion but the difference here is you're not pumping this drug from areas of high concentration to low concentration you're pumping this drug from areas of low concentration to areas of high concentration this is not a passive process this is an active process and whenever you need to pump something against its concentration gradient this requires energy ATP and so this will be an active transport process that would move this large hydrophilic drug from areas of low concentration to areas of High concentration so this would be active transport so this is another way that we can transport drugs across particular membranes now what I want you to remember is we're talking about this with respect to the gastrointestinal tract and oral route but remember if you take something rectally it has to move across the GI tract there if you take something intradermally it has to pass through different parts of cell layers or tissues before it can actually get into the nearby capillaries same thing with subcutaneous it needs to pass through other layers to get to the actual vasculature intramuscular so remember the only one that will actually move directly into the bloodstream without having to pass through a membrane is intravenous so remember that all right so we have active transport wheelchair pump the drug from low to High large hydrophilic the last one is when you have a gargantuous molecule and I'm talking just a really large molecule so for example you know there's a drug we can give orally B12 it's just too big there's no dang transporter that's going to be big enough to transport this drug across the actual cell membrane so because of that if I have a large drug that there's just no transporter that's big enough that's going to be able to get this thing across what I might need to do is do something called bulk transport and bulk transport is a process where the drug May bind onto little receptors that are present on the actual cell membrane and when it binds onto these receptors let's draw a little pink receptors here it'll bind to it and then trigger this invagination of the drug via a process called endocytosis and then once it's endocytosis taken into the actual cell and then it'll be exocytosed out into the actual vasculature what is this process by where as I take this cell take the large drug into the actual cell via an invagination process it's called endocytosis so the mechanisms by which we transport drugs across cell membranes specifically via a PO route as the best example can move across the cell membrane to get into the bloodstream based upon four mechanisms one passive diffusion from high to low hydrophobic small facilitated hydrophilic large needs a protein carrier to Move It from high to low active transport low to high hydrophilic large molecule but it needs to be pumped via ATP driven process endocytosis too big to be able to be transported needs a receptor mediated endocytosis to be taken in and then exocytosed into the bloodstream an example of this would be B12 but these are the mechanisms by which we absorb particular drugs across the GI tract or across any other thing that has to move across a membrane the only one that doesn't move across a membrane is intravenous most of these other ones have to cross a membrane whenever you cross a membrane to get from wherever it was externally into the bloodstream you have to pass a membrane when you pass a membrane you do it by one of these four mechanisms the best example of this is just po okay now let's talk about things that can actually affect this absorption process because not everything is beautiful and perfect as we make it here sometimes there's certain types of pH changes blood flow changes in surface area the speed at which things move through the GI tract and even little like things called P glycoproteins which can alter and change the absorption of capabilities let's talk about that now all right so we know the absorption mechanisms now what we need to think talk about is what are the ways that we can actually kind of maybe decrease absorption increase absorption is there particular things because when we take a medication we want for the most part most of that medication to get into the bloodstream so when we give the medication whatever route we give it we do want that to have the maximum efficacy which I want most of the medication to reach the bloodstream so is there particular things that I need to take into consideration as a clinician when I prescribe a medication that could affect the absorption of that drug yes the first one is pH now drugs usually exist in two forms okay a weak acid so you guys remember a little bit of chemistry I thought this was never coming back but remember when we have like an acid we can use the the abbreviation h a so that's the weak acid and then what will happen is that weak acid can disassociate to something called a proton and then the conjugate base all right so these are the two molecules that I have here now if I have this weak acid which one of these would be easily absorbed across this actual cell membrane when you think about it this would probably be a little bit more difficult to absorb why because this right here this bad boy is charged in charge molecules are more difficult to be able to absorb okay to cross a cell membrane if something's extremely charged it's going to be moving against something that's again you have those phospholipids structures so on the end the phosphate groups are a little bit more negatively charged that's going to repel this this molecule here so in order for me to be able to make sure that this weak acid this drug gets absorbed I want it to exist in this type of environment the AHA because this one is not charged so we call this one nonpolar if you will right just how we would call this one charge we would call it polar so this one easily absorbed this one not as easily absorbed so if I want most of my drug to be absorbed in this form I need it to be most of the reaction to go in this direction so in order for me to push the reaction in this direction I need more protons to be inside of the actual environment where I put this drug so for example let's say for whatever reason I put this drug in an acidic environment so I put this drug in an acidic environment if I put this drug in an acidic environment what am I going to do to the number of protons I'm going to increase the number of protons in the environment if I increase the number of protons what is your list chatelier's principle say that whenever you have lots of molecules on this side you need to shift this reaction in this direction so that you can have it shift to the other one that there's less of and so in this case this side of the reaction becomes very high I need to shift it to the other side to even it out so I make more of this weak acid that in these in the nonpolar non-charged easily absorbable form so in an acidic environment a weak acid will form this type of component and h a is much more easily absorbed across the actual phospholipid bilayer and into the bloodstream so why is this important whenever I give a drug and that drug exists in a weak acid form weak acid in order for me to enhance the absorption of that drug I need to put that weak acid in an acidic environment for it to be easily absorbed so in acidic environments what would be an acidic environment within the git well obviously the stomach but not much absorption occurs in the stomach if you think about it the stomach does empty some acidic substances right into the proximal duodenum so probably the most you know acidic part of where a drug is absorbed which is the duodenum would be the proximal part of the duodenum this would be an acidic environment where most weak acids are absorbed so what I want you guys to remember is if we think about this here's my purple marker this is going to increase the protons the area where there would be best absorption would be in the proximal duodenum because a drug can exist as a weak acid in two forms the nonpolar form or the non-charge form or the polar charge form the one that's more easily absorbed is the nonpolar non-charge form the only way for me to convert it from The Polar charge form to the nonpolar is to shift this reaction to the left the only way I can shift it to the left is if I increase the number of my protons which means I need to make the environment that it's in very acidic that's why the proximal duodenum is best for absorbing weak acids all right good let's move on to the next thing so if we have weak acids we probably are going to have to have some weak bases that other drugs can exist in because again they can exist in a weak acid or they can exist in a weak base form for example aspirin that would be a weak acid so aspirin would be best absorbed and like potentially the stomach but more the proximal duodenum okay if you think about another drug like amphetamines though amphetamines are a little bit more of a basic drug so they would be more absorbed where and like the distal part of the small intestine like the ilium but let me explain what happens with these so now we're going to take for example a weak base weak bases are usually going to look something like this when we use them in that kind of generic form a BH positive and this disassociates into a b and H Plus okay again when you think about this this guy right here is which one this is the part of the weak base that is going to be polar not easily absorbed this is the one that's going to be nonpolar easily absorbed so if that's the case if I want this to go in this direction I wanted to go to this direction so that this molecule this weak base will be in this form because it's easily going to pass across the cell membrane and get into the blood so what do I need to do to the environment well I need to shift this reaction this way or or the other way I can think about this is decrease the concentration of one of these things in the actual environment here so maybe lowering the amount of protons that'll decrease this side so then I have to shift the reaction this way but the whole goal here is what do I want to do I want to shift the reaction in this direction so if I want to shift the reaction in this direction guess what I'm going to do I'm going to make the the environment more alkaline if I make the environment more alkaline I'm going to decrease the number of protons that are in the environment that this drug is in if I decrease the number of protons that decreases the concentration of the actual molecules on this side of the reaction so we want it to be even if it's down like this we need to shift it to the other side to increase the concentration to bring it to equal according to the chatley's principle so I'm going to shift the reaction this way that means I'm going to make more of this actual weak base in the nonpolar or non-charge form which is the one that's easily absorbed so we say that this would be weak bases would be best absorbed in the parts of the GI tract where it's very alkaline definitely not near the stomach definitely not the proximal duodenum definitely be more distal small intestine like the distal Ilium so it's important to remember that that's where the drugs will actually be best absorbed okay we understand how these can affect the absorption of drugs based upon what PH so weak bases are absorbed best in the proximal I'm sorry the distal ilium weak acids are best absorbed in the proximal duodenum so remember that all right the next thing that affects absorption of particular drugs is blood flow it's very straightforward we need good blood flow to supply particular organs in order for again if you need think about absorption it's the movement of the drug into the bloodstream it's it's the Dr the drug getting into the bloodstream if there's less blood flow to a particular organ where the drug is supposed to be absorbed you're going to get decreased absorption so in situations where there is a market reduction in blood flow what would be a disease by which there is a reduction in blood flow any kind of shock state right so if a patient has any kind of circulatory shock septic shock cardiogenic shock hypovolemic shock in these shock States there's decreased blood flow to these organs if there's decreased blood flow to these organs there's going to be decreased absorption to the GI tract that means less of the drug is going to get absorbed into the bloodstream if there's less blood flow to the skin that means less of the actual drug is going to be absorbed into the bloodstream so just remember that with decreasing blood flow in situations like shock States this will reduce the blood flow to these particular organs such as reduced git perfusion reduced skin perfusion that means that any drug that you're taking orally or any drug that you're taking rectally is going to have less absorption into the bloodstream any drug that you're taking via the skin intramuscular intradermal subcutaneous these are all going to be diminished the only way that you can ensure that you get blood the drug into the bloodstream would be intravenous so that's why and generally in situations when a patient is in shock we don't give medication generally via orally or via some type of injection like the intradermal intramuscular subcutaneous it's usually going to be intravenous because well I guarantee that 100 of the drug is getting into the bloodstream all right so we know how pH effects absorption we know how blood flow affects absorption the next thing is total surface area and contact time it's pretty straightforward if I have a drug that I'm taking orally and I have let's say for example diarrhea right you're peeing out the poop hole if that happens the motility or the movement of the drug is moving through the GI tract so dang fast there isn't even a time frame that's appropriate for you to move this drug across the actual Lumen of the git across the cells and into the blood via passive transport facilitated diffusion active transport endocytosis all of this is going to be inhibited so in diarrhea what happens to the absorption of the drug you're going to decrease the absorption of the drug because you're decreasing the amount of contact that the drug will have with the actual the cells of the git whereas in the opposite situation if a patient is constipated they're having slow Transit time that means that this drug has so so much dang time it can file its taxes and what happens is it's going to have so much time to be able to move across this actual cell because it's going to have tons of contact Time lots of opportunities to passive transport active transport some type of endocytosis process and reach into the bloodstream so in situations like constipation there'll be more contact time and you can increase the absorption of that drug pretty straightforward right so decrease blood flow shock States you're going to have less absorption of the drug weak acids best absorb in an acidic environment like the proximal duodenum and then again weak bases best absorbed in the alkaline environment like the distal Ilium the next thing is with this total surface area so I want you to think about the the surface area of the intestine it's like you know when if you remember back from Anatomy it's like these surface area like a tennis court if you stretched it out that's how much surface area could cover it's massive think about diseases that decrease the surface area by either destroying the microvilli destroying the Villi these things are naturally supposed to increase the surface area of the intestines in situations for example inflammatory bowel disease celiacs some type of gastroenteritis what happens to the microvilli the Villi and therefore the total surface area it decreases we know the relationship total surface area is it increases absorption increases these will do what to your total surface area they're going to decrease your total surface area so what's it going to do to the absorption of the drug it's going to decrease the absorption of the drug my friend so in situations when a patient has some type of diarrhea will decrease the absorption of the drug if they have constipation they'll increase the absorption of the drug based upon contact time if you have diseases that destroy the microvilli the brush borders the Villi in general such as an IBD celiacs gastroenteritis you're going to decrease their surface area and decrease the absorption of the drug the last thing that I want to talk about because this is actually an interesting process here is that some situations people can develop multi-drug resistance because you know the GI tract sometimes if you take a particular drug what happens is there's special Transporters let's say that we take a drug via the you know orally we take the drug gets into the GI tract moves across the cell membrane which much what's the mechanisms passive diffusion active facilitated diffusion or endocytosis once it does it can potentially move into the bloodstream but there's some situations where they have this thing called a p-glycoprotein on their basal on their apical surface and what happens is instead of the drug going to be pushed into the bloodstream then effectively being absorbed what happens this process becomes inhibited because this p-glycoprotein will spit the drug right back out into the git and then you will poop the drug out or you won't be able to absorb the drug so in P glycoprotein what this does is this can decrease the absorption of the drug and this is actually seen in a lot of multi-drug resistant situations so remember that sometimes patients can actually exhibit these p-glycoproteins which will excrete the drug rather than it being absorbed all right so for absorption we've talked about the mechanisms we talked about the factors that affect it via pH blood flow total surface area contact time and P glycoproteins now what I need to do which is actually probably the most important thing for absorption is talking about something called bioavailability all right so when we talk about this next really important component here bioavailability so you can remember this by the Frac well I kind of already gave you the answer but F so it's the fraction of drug that actually does enter into the systemic circulation and we here's what I want you to understand about this when you give a drug via the different routes that we talked about we're the two most important ones that most patients will receive at some point time in their life if they're in the hospital IV and when you give a drug IV does it has to pass through any like type of membrane no it's the only one that does not have to pass through any type of membrane so it goes directly into the blood so when you give 100 milligrams of a particular drug IV 100 milligrams will get into the actual bloodstream so because of that the amount of drug that is administered that gets into the bloodstream and absorbed is 100 so the bioavailability the amount of drug that's there and available for use and to exert it's different types of effects is 100 percent however if you give a drug orally or some other particular route that has to pass through membranes is affected by pH is affected by specific blood flow patterns is affected by total surface area contact time p-glycoproteins the the actual different solubility of the drug if it's lipophilic if it's hydrophilic Etc the size all of those things come into play and maybe likely not all of that drug that you take orally is going to make it into the bloodstream so the bioavailability of that drug is not going to be 100 percent so when we can talk about bioavailability we're really comparing IV to the other route which most commonly is po when you give a drug the concentration of that drug when you give it IV what you'll see is let's say here is at 100 percent 100 percent of the drug you'll see that this drug will reach 100 when you give the drug and over time it'll be you know decrease in its concentration until it's eventually completely eliminated because it'll become metabolized and excreted so this would be the actual concentration of the drug when it's given IV okay and there's a particular area under the curve that will determine that now the other thing here is if I give a drug orally it needs to be given orally and what will happen is when I give it orally you'll see the concentration will rise but it won't make it likely to a hundred percent it may get close 50 60 80 depending upon the drug and a lot of other characteristics but eventually what you'll see is that this drug concentration will fall as it starts to become metabolized and excreted so this would be the oral route the PO route what I want to consider is the area under the curve of these things and what I can do is I can come up with a particular formula for a drug that is actually given po or not IV and determine the bioavailability of the drug remember IV it's always 100 so if I give like I said a hundred milligrams of a drug IV a hundred milligrams of that drug will get into the actual bloodstream so it's bioavailability or this fraction is going to be 1 or 100 percent but if I give a drug orally what has to happen is it has to be absorbed maybe not all the drug gets absorbed because of various different reasons pH blood flow the size of the drug the solubility of the drug the total surface area the contact time the expression of p-glycoproteins all of that stuff and then other things that we didn't talk about like instability that it might be exposed to first pass metabolism by the liver that we didn't get into yet that will actually play a huge role before the actual drug makes it into the systemic circulation so maybe you give a hundred milligrams of this actual drug orally and you know what only 50 milligrams of that drug gets absorbed into the systemic circulation so when you do this you have to take into consideration what would it be if I would actually compare this so now the bioavailability of the drug would be okay if I were to give this IV the bioavailability of this drug would be a hundred milligrams right so what I do is I consider so I use a formula so the formula that we're actually going to talk about here is bioavailability is equal to the AUC the area under the Curve oral Administration over the area under the curve IV Administration what we're going to do is we're just going to say how much of that drug was given IV and then how much of that drug was given orally and what I can actually take into consideration is how much of that drug actually got into the bloodstream so generally what I say is let's say if I were to give this drug IV the amount of that drug that would get into the bloodstream is a hundred milligrams correct because I know if I give a drug IV whatever drug I give the dosage wise all of that's going to get into the bloodstream it doesn't have to pass through any cell membranes there's no first pass effect there's no effect on instability solubility all that stuff but if I give a drug orally it does have factors that are going to influence that and it might not all be absorbed into the actual bloodstream let's say that I gave a drug 100 milligrams only 50 milligrams of it got absorbed so that's the the milligram dosage that's the aucd area under the curve orally so what I'm going to do is I'm going to say 50 milligrams of that drug got absorbed and if it was IV a hundred milligrams of it would actually reach the circulation so the bioavailability is what it's 50 so only 50 percent of the drug actually reached the systemic circulation that's the bioavailability so again it's important to be able to remember this concept because when we give a particular drug if we want 100 of the drug ability to get into the systemic circulation I give it IV if I want to give it and maybe not have all of it reach the systemic circulation you can give it orally but again it depends upon the drug depends upon a lot of factors here so what are some things that do affect the bioavailability of a drug the first thing is solubility okay so if I think about this very simply if I have a drug that is extremely hydrophobic or lipophilic whichever one it's the same kind of concept hydrophobic it's also maybe a small it's not very highly charged so it's a nonpolar molecule these drugs are going to easily pass across the cell membranes across the GI tract whatever membrane that it has to move across and get into the bloodstream so there'll be much much more absorption of the drug and much more bioavailability meaning the amount of drug that gets into the bloodstream is going to be more so I would expect that what would happen to my bioavailability here it would increase now if I take the opposite situation where I have a drug that's extremely hydrophilic okay loves water it's also a large drug what's going to happen to the absorption of this drug it's going to decrease and so the amount of drug that I actually administer and then the amount of drug that actually gets into the actual bloodstream will be very small so my bioavailability will decrease so obviously that's one particular factor that affects how much of that drug reaches the systemic circulation which is solubility the more lipid soluble it is the smaller the molecule is the easier it is for it to pass across membranes and get into the blood more hydrophilic larger it is the more difficult it is for it to move across the cell membrane and then again get into the blood the next thing is instability according to the area that it actually gets administered so for example if I have most commonly oral Administration I give a particular drug like penicillin G penicillin G is not good orally you want to know why because if I give this drug orally guess what ends up happening to this dank thing you have all of these protons that are being excreted by those parietal cells this will destroy the penicillin G and literally almost none of that drug will actually exist by the time it has to be able to get absorbed and moved into the bloodstream so because of that this actual hydrochloric acid as there's increased hydrochloric acid it'll break down the amount of penicillin G and if there's less penicillin G that gets into the bloodstream what happens to the bioavailability of the drug it decreases that's why penicillin G is given I am or IV other concept here is that sometimes drugs can actually be affected by enzymes that are excreted into the Git You know our pancreas makes special types of proteases and there's a particular drug called insulin you ever seen insulin given orally no there's a reason why because guess what proteases do proteases will break down the insulin if you break down the insulin you render this actual insulin molecule ineffective now and also the amount of drug that's supposed to cross the GI tract get into the actual circulatory system is going to decrease so what happens to the bioavailability of this drug it decreases that's why insulin is given what you can give it IV or you can give us by some type of other injection right but that's the whole component here that you have to be able to remember all right the next thing that we also talk about the factors that affect bioavailability besides the solubility besides the actual instability of the environment that it gets absorbed across is also the first the pass effect and I think that this is probably one of the most important Concepts when it comes to bioavailability when you take a drug orally right we know that it's going to be exposed to a lot of different things that we've already talked about but once it actually moves across the actual git and into the bloodstream when it moves into the bloodstream that's actually going to be going particularly to the liver what is this circulation this is not the systemic circulation you see this baby blue here this right here is called the portal system it's called the hepatic portal system now the portal system will actually be the movement of the drug from the actual git into the actual blood that will then move to the liver from the liver right so now take into consideration you gave 100 milligrams of this drug maybe at this point in time based upon solubility of the drug based upon instability of the drug based upon the size of the drug based upon the blood flow based upon the pH based upon the total surface area the contact time the p-glycoproteins maybe if you give 100 milligrams of this drug maybe only like I don't know 90 milligrams made it into the actual portal system let's just say then let's just say that 100 milligrams you give 100 milligrams only 90 milligrams got into the portal system 10 milligrams got lost somewhere in that process then what happens it has to go to the liver whenever blood flow from the portal system goes to the liver the liver will always take a portion of the drug and say hey you know no free lunch here buddy I always get a little bit of this drug so only a certain amount of this drug is actually going to be remaining and going into the systemic circulation after I'm done I have to I own a little bit of this drug so it's going to take some of that drug 90 milligrams of that drug and some of it it'll actually metabolize and what I mean by that is that in most cases it'll render this drug inactive so maybe the amount that you inactivate let's say for some reason it's 60 milligrams that you inactivate I will only be able to push into the bloodstream now in my systemic circulation I have 30 milligrams left that'll then pass to the tissues and be distributed to the tissues so because of that that is a massive drop in the actual concentration of the drug so if you think about that 30 milligrams is what I actually got into the bloodstream and if I were to give 100 milligrams of this drug IV 100 milligrams would get in there so it'd be 30 divided by 100 and that would give me the bioavailability of this drug that's why it's extremely important to understand bioavailability now why I want you to understand this is I want you to give you guys an example of something like this that actually does happen like this you know there's a drug called nitroglycerin nitroglycerin we give to patients who have maybe some type of anginal chest pain normally we give this sublingual because it doesn't have to go through the first pass so you know what things do not go through first pass something that doesn't get administered orally generally okay so if something's given orally it's going to have to be absorbed across the GI tract into the portal system if you give something radically very small portions of it may also get into the portal system but otherwise IV topical intramuscular intradermal subcutaneous all of those other routes they will not have to go again through the portal system and they won't be having this first pass effect by the liver so because of that I would want to change the actual delivery of my drug if it's getting chewed up by the liver so nitroglycerin if you give it po just as an example here you give it po let's say that you gave 100 milligrams of that drug po when you actually get it to the systemic circulation to be delivered to the tissue the heart guess how much is actually remaining 10 milligrams that means that 90 milligrams of drug was chewed up during the process of moving across the git first pass effect and then getting into the bloodstream so guess what because of it the first pass effect it chews up so much of the nitroglycerin so guess what we'd want to do maybe not give nitroglycerin orally have it bypass the first pass effect give it sublingually give it IV give it IM all of those will forego the actual first pass metabolism that's why it's super important to understand this all right so when we talk about bioavailability again it's basically the concept if you were to give a drug IV 100 of that drug will get into the bloodstream if you give it orally it has a lot of factors that can affect its absorption process so if you take the amount of drug that actually gets into the bloodstream when you gave it orally and divided by the amount that would get into it if you give an IV that will give you the percentage or bioavailability of that drug the factors that can affect it is solubility you want the actual bioavailability to give you go up give small hydrophobic or lipophilic drugs you want it to go down give large hydrophilic drugs you want the bioavailability of the drug to go down give a drug that gets completely demolished by the actual gastric pH or it gets broken down by proteases the bioavailability of that drug will decrease significantly and then if a drug gets chewed up by the liver via first pass metabolism guess what you're going to have very little of that drug in the actual bloodstream the systemic circulation so a lot and I mean a lot of the drug gets chewed up by first pass consider giving another route that will bypass the first pass such as IV I am Sub-Q sublingual and use this as an example of nitroglycerin you give the sublingual you get a good chunk of it that gets into the bloodstream because it doesn't get chewed up by the liver if you give it via orally it gets chewed up by the liver so much that very little of it actually gets into the bloodstream to exert its effects and that's why certain drugs are given via certain routes alright guys so we're going to work on some questions here to really test your knowledge of absorption so first thing we have an 18 year old female brought to the emergency department for a drug overdose which route out of all of these would be the best the most desirable for administering the antidote realizing that when we give a drug any particular way we have to think about the amount of drug that actually reached the systemic circulation so the bioavailability of that antidote which one of these has 100 bioavailability it would not be oral it wouldn't be subcutaneous wouldn't be I am IV is the only one that you have 100 bioavailability and I would want that in a drug overdose I wouldn't want only a small percentage of it or not the whole amount of the drug to get in there so IV is definitely going to be the best bet for these because you're going to get 100 by availability all right second question to really test your knowledge so we have drug a it's a weekly basic drug with a pka of 7.8 now again when we think about these ideally we want the pka to get close to the pH or at least equal the pH because then we have somewhat of a kind of equal amount of the charged base and the non-charge base in this situation so if we give this weak basic drug in an oral situation which one of the following sites will absorption occur best that's all that we're kind of looking at so in other words I want that weak base for its pka of this actual weak base to be very close to the actual pH of the solution so which one of these would actually absorb best and now thinking back to this whenever we have a base go back to our diagram here so this is going to be the bottom part here's our weak base it's in this BH positive form it can disassociate into B and H Plus in this nonpolar form this is the form that will actually easily be absorbed across the actual membrane so if we think about that we know that the distal ilium is going to be the best situation so we know in an alkaline environment this weak base will be better absorbed and compared to an acidic environment it will not and the reason why is you think about this equation in What's called the chat lace principle right so if you have a situation here where we have lots of protons in this actual uh this equation here Le chatelis will say that this side of the reaction is way too high and will shift to the left and then we won't get good absorption but if we decrease the concentration of the protons meaning that we have an alkaline environment it'll shift the reaction to the right we have more of this nonpolar molecule which easily absorbs so which one out of all of these do we see that it's actually going to be more basic and it's closest to the pka of this weak base we would say definitely right here the jejunum it's definitely going to be the most basic solution would be best for the weak base and it's about only 0.2 away from this actual PKA so we want the pH to be very close or almost equal to the PK to allow for the best absorption of that drug alright guys so that will cover all that we needed to talk about for the pharmacokinetics component here for absorption I hope this made sense I hope that you guys did enjoy and learned a lot stick around we're going to move into the next part now of our pharmacokinetic series and that's going to be talking a little bit more about what the distribution of a drug so I'll see you guys there foreign [Music]

Channel: Ninja Nerd

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Keywords: Ninja Nerd Lectures, Ninja Nerd, Ninja Nerd Science, education, whiteboard lectures, medicine, science

Id: kkUxUBoM-hM

Length: 42min 52sec (2572 seconds)

Published: Fri Jul 22 2022