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.