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  • All right friends. Welcome back!

  • Here, we're going to begin our discussion on drug metabolism as we continue our lecture series on pharmacokinetics.

  • And so, the first thing we're going to talk about is first pass metabolism.

  • Before we do that, let's make sure we have general metabolism down.

  • So, first, metabolism.

  • Where is metabolism occurring?

  • That's the first question we want to make sure we are comfortable with

  • and hopefully, you are saying that metabolism occurs in the liver.

  • Very nice!

  • Now, where in the liver is metabolism occurring?

  • Well, it's in the hepatocytes but specifically, it is in the smooth endoplasmic reticulum. That is a part of the cells.

  • Endoplasmic reticulum. The SER.

  • And we remember that to differentiate from the smooth endoplasmic reticulum and the rough endoplasmic reticulum which is responsible for protein synthesis.

  • The smooth endoplasmic reticulum, one of its jobs is for drug detoxification.

  • So, we know metabolism occurs in the liver and before we jump into first pass metabolism,

  • let's make sure we get this idea down.

  • So we have the liver and I'm just going to draw the liver as a box with the word liver in it

  • and something unique about the liver is that it has 2 blood supplies

  • and the simple fact that it has 2 blood supplies makes it very unique.

  • So, from the liver you know we go around the body.

  • Let's say this is the inferior vena cava. It's the blood supply out of the liver.

  • This is the heart. This is the aorta leaving the heart.

  • And I come around here. So this is the aorta.

  • And what is the branch that leaves the aorta. It's a really short artery before - as the blood travels on its way to the liver.

  • Hopefully, you are saying the celiac.

  • And so, from the celiac, it travels through the common hepatic artery before it gets to the liver.

  • And so, this is the idea of general metabolism.

  • By the way, this is obviously not drawn to scale.

  • And so, the idea with general metabolism is that we can give a drug anywhere.

  • Let's say I gave it intravenously inside of a vein and that drug has a chance to get to the rest of the body, have its effect and get to the liver.

  • If I gave a drug sublingual, right one of these drugs given sublingual is nitroglycerin. Let's switch colors. Let's go to red.

  • So if I gave something sublingual, well anything you give sublingual gets absorbed into a capillary plexus, takes the pathway of the veins then gets dumped into the heart

  • and nitroglycerin we remember. Well, we might not have covered it yet but it helps dilate some of the blood vessels that give the heart a little bit more blood supply.

  • This drug then has a chance to get to the rest of the body before it gets to the liver.

  • So, sublingual is part of general metabolism.

  • In other words, if I adminsiter drug sublingually, it will go to the rest of the body before it gets to the liver.

  • Now, the reason that we did this right here is to differentiate general metabolism from first pass metabolism.

  • So I've somewhat eluded to this but what is first pass metabolism?

  • It is the metabolism of a drug before it reaches the systemic circulation.

  • So how could this occur?

  • Well, like I was saying, the liver has 2 blood supplies.

  • And so, one blood supply we saw here is the common hepatic artery

  • but the other blood supply (now, let's switch to maybe a green) is from the portal circulation.

  • So when I deal with the portal circulation, let's say I swallow a pill - you swallow a pill, it goes to my intestines

  • and from the intestines, it goes to the portal vein and from the portal vein, it goes to the liver.

  • So notice this is the other blood supply to the liver and this right here is the pre-systemic circulation.

  • So drugs given by mouth or PO and the fact that they have to go through the intestines

  • and through the portal vein are not able to get to the rest of the body before they get metabolized.

  • And so, this route of administration would be subject to first pass metabolism.

  • Other than the intestines, what's another place where we can give a drug that has to go through the portal vein to get to the liver?

  • Well, how about if I gave it rectally?

  • Like a suppository.

  • So I gave something via rectal administration.

  • Remember, that the superior rectal veins end up going through I believe the inferior mesenteric as they travel toward the liver.

  • And so, thus rectal administration would be also subject to first pass metabolism.

  • So the way that I think about this is if it goes through the portal vein, it undergoes first pass metabolism.

  • This is a one-way street that goes through the hepatic artery though

  • then it's typically has already gotten to the rest of the body before it gets to the liver.

  • So, what are some examples of drugs that won't or administration pathways that won't undergo first pass metabolism?

  • Well, sublingual is one of them. Intramuscularly (let's go back to red).

  • Right, if I gave a drug IM, remember that it gets into the capillaries, it goes into the veins,

  • it gets to the heart,it can go to the rest of the body and then it gets to the liver.

  • So that's first pass metabolism.

  • And what we can do is actually attach first pass metabolism to a concept that we have covered before

  • and that was bioavailability.

  • So, with bioavailability, we talked about this when we were talking about drug absorption.

  • So bioavailability was the fraction of drug given that reaches the systemic circulation.

  • And so, when I say absorbed here, I really am referring to absorbed into the systemic circulation.

  • So, if I give a certain drug by mouth at a certain dose right, remember drugs are given in mg which is a mass

  • and PO is per os or by mouth.

  • I multiply that by the fraction of the drug absorbed, the bioavailability

  • and this is really the only way that we can get a sense of the first pass metabolism.

  • And so, drugs that have a low bioavailability have undergo a lot of first pass metabolism and thus the amount of drug absorbed would decrease.

  • There's one other point I want to make here before I move on

  • and that is that metabolism is not only occurring in the liver.

  • Actually, we actually have some enzymes in the intestines which help metabolize drugs and would also then reduce the bioavailability.

  • Does that make sense?

  • Super important concept.

  • Now, if we are decreasing the amount of drug absorbed, remember that pharmacokinetics,

  • we are really looking at the plasma drug concentration over time and how different things can affect that.

  • So, if I have a decreased amount of drug absorbed, my plasma drug concentration then would be decreased.

  • So, if you have first pass metabolism, drugs will go through the liver.

  • They will get metabolized before they get to the systemic circulation. That would mean a decreased plasma concentration.

  • 2 methods of that occurring is taking a pill by mouth or rectal administration.

  • I hope that makes sense and this kind of ties it to some of our older concepts.

  • This term down here was volume of distribution and we covered it in a previous video.

  • All right, now that we've got metabolism and first pass metabolism down specifically,

  • let's talk about what would happen if I metabolized this drug.

  • What are the outcomes?

  • Well the first outcome is something you're probably familiar with.

  • We gave a drug. It's pharmacologically active and by getting metabolized, this drug then becomes inactive.

  • And this is the case with most drugs.

  • Now, another thing that could happen is we can give a drug and these are not mutually exclusive examples

  • but that drug could be toxic or our body could view that drug as being toxic

  • and therefore, we want to metabolize it to make a non-toxic metabolite. Non-toxic.

  • And this is also commonly one of the reasons we metabolize drugs.

  • Now, I want to say here that this is while we can go from active to inactive and we can go from toxic to non-toxic,

  • sometimes things actually work the other way.

  • So, let's switch to green.

  • And so, some drugs we actually give in their inactive form and we metabolize them and they become active

  • and if that was the case, we would call this inactive drug.

  • If we were going in that direction, we would call this the pro-drug.

  • And so, one example of going from a pro-drug to an active drug is with something called codeine.

  • You might have heard of codeine before. It's a pain medication.

  • And so we need to use enzymes to metabolize codeine and it actually turns it into something called morphine

  • which is a very potent analgesic or opioid analgesic.

  • And so, some people are rapid metabolizers of codeine or ultra rapid metabolizers and they would create too much morphine

  • and recently, the FDA put out a warning about that so, something to know.

  • So, we can go from a non-toxic to a toxic drug too

  • and one example of that occurring is with acetaminophen.

  • So, I can say non-toxic to toxic

  • and the example here is with acetaminophen.

  • Now, I don't want you to get scared here.

  • Acetaminophen, 95% of it when it's metabolized is non-toxic but 5% of it under certain circumstances can actually be metabolized into a toxic or hepatotoxic metabolite.

  • And so, what we're going to do later on is figure out what those particular circumstances are.

  • And finally, the third outcome of drug metabolism is we start with a lipid drug and our body metabolizes it and it becomes water soluble.

  • So lipid here becomes H2O soluble and this one is really important as well.

  • So, let's use this as our step into the next part.

  • So, now we've looked at the outcomes of what happens when you metabolize drugs.

  • Why and how do we metabolize drugs?

  • What's the big picture here?

  • Well, the first reason is drugs are foreign compounds

  • and in order for these foreign compounds to get into our body, a lot of them end up being lipid soluble to get across our intestines.

  • And so, this is a unique trade that a lot of these foreign compounds have and therefore, our body through evolution has developed mechanisms to excrete drugs

  • and in order to excrete drugs, they really need to be water soluble.

  • So to get us from absorbing the drug to excreting the drug, we need metabolism and metabolism thus makes drugs more water soluble.

  • Very important concept.

  • And so, how does this occur? How do we metabolize substances?

  • Well, we have 2 sets of chemical reactions in pharmacology that we talk about when we talk about metabolism.

  • One of them is called Phase I metabolism or a set of Phase I reactions.

  • The other is called Phase II reactions.

  • And a lot of times, these Phase I reactions prepare us for the Phase II reactions but to be clear, that's not always the case.

  • And so, this is what we're going to talk about on the next slide

  • but before we get there, let's just give you a little preview.

  • So these reactions use their own set of enzymes and that's what we're just going to briefly mention.

  • So, Phase I uses somethng called or predominantly uses something called the CYP 450.

  • The Cytochrome P 450 enzymes.

  • And here, we are often oxidizing and these are like oxidation reduction reactions and that helps unmask in oxygen or whatever.

  • We'll get to that in a second.

  • Phase II reactions typically use there's a bunch of different enzymes but if we wanted to come up with a name with it for them all,

  • we call these conjugation reactions

  • and typically here, we are attaching something on to a drug to make it more water soluble.

  • So this is what we're going to cover on the next slide.

  • Before we get there, we have a couple of stop, think, and repeat questions.

  • So, I would highly advise you to push pause. Try to do these questions before moving on.

  • And so, if you like this video, please give it a thumbs up and share it with your friends.

  • I hope to see you at Phase I and Phase II metabolism which will be our next video.

  • Take care.

All right friends. Welcome back!

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B2 metabolism drug liver toxic pass phase

First Pass Metabolism - Pharmacology Lect 6

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    Yu Syuan Luo posted on 2013/10/28
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