Tip:
Highlight text to annotate it
X
All right, welcome back!
Here we're going to talk about first order and zero order kinetics
and before we do that, I want to ask a question.
And this question will help us understand the constraints under which first order and zero order kinetics occurs.
And so, this question is what are two ways to increase the rate of drug metabolism
and we're focused on the big picture here.
So one way to increase the rate of drug metabolism, the first way is to increase the plasma drug concentration.
And so, we know 2 ways to increase the plasma drug concentration.
We go back to our core equation. The most important equation in pharmacokinetics.
And that is concentration is equal to the mass of the drug absorbed divided by the volume of distribution.
So one way is obvious. We give more drug and as we give more drug, we will increase the rate of drug metabolism.
This occurs up to a certain point and we'll discuss what that certain point is.
The other way though is we can give a drug that has a lower volume of distribution.
So what do I mean when I say give a drug that has a lower volume of distribution?
So I decrease the volume of distribution.
What does that mean?
Hopefully, you're telling me oh drugs that have a lower volume of distribution, they like to stay in the plasma.
Give a drug that likes to stay in the plasma.
And drugs that like to stay in the plasma, we know have a lower volume of distribution.
So, as a result, we will increase our plasma drug concentration and that will increase the rate of drug metabolism up to a certain point.
The other way that we can increase the rate of drug metabolism - that's right here. Number 2,
is we can increase the number of available enzymes.
Increase the number of available enzymes.
So what do I mean when I say the number of available enzymes?
We're going to get back to this point later but just to throw some stuff out there,
what would happen in the case of liver disease?
If a patient has liver disease, this would actually decrease the number of available enzymes.
What's one way we can increase the number of available enzymes?
Well one of them is called enzyme induction. This would increase the number of available enzymes
and the other way is called enzyme inhibition.
And this would decrease the number of available enzymes.
This topic here though, the one that I just drew this unfortunate line on. This topic right here is for the next lecture.
So what we're going to focus on here is changing the plasma drug concentration and as we change the plasma drug concentration,
we undergo things called first order and zero order kinetics and the way we'll understand that is with a graph.
So here's a graph on our right and I've made up some numbers for the X and Y axis
For the Y axis, we have the rate of drug metabolism and for the X axis, we have the plasma drug concentration.
So, what happens as I give more of a drug and the plasma concentration increases?
Well, let's switch over to green.
So, we've said here as I increase the plasma drug concentration, this is going to increase the rate of drug metabolism.
So this increases and let's draw that.
So it goes up kind of like this. This is supposed to be a smooth line.
Now remember, I said as you increase the plasma drug concentration, the rate of drug metabolism increases to a certain point.
And so, this first part of the curve has a name and this name. This range of drug dosages which causes an increased rate of metabolism
we call this first order.
Now some people call this first order kinetics. Other people call this, first order metabolism or elimination.
I'm going to call this first order elimination.
And the reason I call this elimination is that we're very clear here.
This is not the amount of drug that we have.
This is how quickly we are eliminating the drug and turning it into its metabolite.
So this is first order elimination.
Now, at the second part here of this graph (let's switch to purple),
As I increase the plasma drug concentration, I'm no longer really changing the rate of drug metabolism.
If it goes up, it goes up just a touch
and once we're at this part of the graph, we call this zero order kinetics.
Zero order kinetics or zero order elimination as I like to call it.
And the idea here is as we increase the plasma drug concentration, the rate of drug metabolism is not increasing anymore.
Now people often confuse these because they think zero goes before first and it makes sense. It's confusing.
The way I remember this is that the slope here. The slope is approximately equal to zero.
Now I'm going to warn you, zero order elimination, we don't want to get to this point.
As clinicians, we like being in this dosage range of plasma concentration.
We like it when first order elimination is occurring.
We don't like it when zero order elimination is occurring
and the reason is we're increasing the amount of drug we're giving but the rate of metabolism isn't going up.
Therefore, the in is not really equaling the out and that's problematic.
So what we're going to do now is we're going to differentiate first from zero order elimination at the bottom of the screen
So first order kinetics or elimination.
So maybe, I'll write here kinetics as well. Kinetics.
So with first order kinetics, as I increase the plasma concentration, we saw that I have an increase in the rate of metabolism.
Increase rate of metabolism.
Now why is this important?
Well the reason this is important is because it tells us that the rate of drug metabolism is proportional to the drug concentration.
We like this because the body is responding to the drug that we're giving. The in is proportional to the out.
And so, what happens is because the rate of metabolism is proportional to the drug concentration
and the in is equal or proportional to the out so to speak. It's not equal. Proportional I should say.
This allows us to really predict what's going on.
And as a result, we can define something called the half-life.
Now what is the half life?
The half life is the amount of time it takes to get rid of 50% of the drug.
It's a lot of writing.
and it's typically written as T 1/2
And so the fact that the half life is constant means this is predictable.
I can give a drug and I can say with this drug, 50% of it will be gone in 1 hour
And therefore, 75% will be gone in 2 hours and we have a whole lecture dedicated to just half life.
Now where do we see first order kinetics?
Well, first order kinetics happens first and therefore, we see it with most drugs at most dosages given.
So this is first order kinetics and what we'll do is we'll differentiate this from zero order kinetics.
So, with zero order kinetics, we're at this part of the graph. The flat part.
And so what I say is I increase the concentration of drug given and as I increase the plasma drug concentration, there is no change in the rate of metabolism.
This triangle represents change.
Now, this is problematic because before, the rate of drug metabolism was proportional to the drug concentration in first order kinetics.
Here, the rate of metabolism becomes independent of drug concentration.
And so, like I was eluding to before here, the in - the amount of drug we're giving, could be going up
but the out - the rate of metabolism isn't changing
and so, as a result, the drug can build up.
And when a drug builds up, that can lead to drug toxicity.
Very, very important.
So now that we understand the rate is independent, so we can't really predict how long it's going to take to get rid of this drug
and therefore, we say the half life is now very important.
You might be able to figure it out but it varies depending on the plasma drug concentration.
So what are some examples of zero order kinetics?
Well there's 3 big examples and those 3 examples are alcohol, aspirin and phenytoin.
So alcohol I've written here as ETOH (Ethanol). And so, alcohol really at most dosages given
you know you drink a beer, you drink several beers. The rate of metabolism is not going to go up. It's fixed. It's limited.
These enzymes get saturated very quickly.
With aspirin and phenytoin and so, phenytoin. That's right what this is, you might not have heard of this.
Phenytoin is an anti-epileptic medication. Another way that this is is an anti-seizure medication.
Anti-seizure med.
And so with phenytoin, this is important because this drug can build up quickly because the rate is independent of the drug concentration.
Small changes in you know the dosages of the drug if you increase the dose of that drug and you're giving this drug repeatedly.
The point I want to make here is small changes can lead to very high plasma concentrations.
And that's important and that's why this concept of zero order kinetics is clinically important.
And so, later on we'll talk about alcohol and breaking it down and you know some of the side effects that we can get from it
and we know aspirin is a pain relieving medication
but these are the big 3 examples that a lot of people are familiar with.
So hopefully this makes sense and it's important to differentiate first order kinetics from zero order kinetics.
What we're going to do in the next lecture is talk about how changes in the number of available enzymes will affect the rate of drug metabolism.
Subtitles by the Amara.org community