Introduction to PK - Integration of Concepts
We are almost at the end of our series of videos. If you are feeling at this time slightly confused, it is quite normal. It will take some time, and practice through different problem sets before you get the hand of things.
This video will take you through the concepts we covered previously and I will try to help you visualize how these come together.
To begin, let’s consider the main processes we commonly recognize – absorption, distribution, metabolism and excretion, or ADME for short. These 4 processes are represented by 4, what we recognize as, primary pharmacokinetic parameters. Rate of absorption as well as Bioavailability describe the Absorption process. Volume of Distribution describes the Distribution process. Clearance covers Metabolism as well as Excretion.
The elimination Half-life is often mistaken to be one of the primary parameters, but actually it isn’t. It is a derived parameter, and related to Volume of Distribution divided by Clearance.
But what do we do with these parameters? To answer that we have to know what to look for in the plasma concentration graphs.
First of all, look at how long it takes for the concentrations to reach steady state. This is the time when concentrations, despite fluctuations, show some dose-to-dose stability. Next look at what the maximum concentrations are. The what the minimum concentrations are at steady-state.
Next the average concentrations at steady-state. You can’t measure this but if you average the maximum and minimum, you will get an approximation of this.
Dividing the maximum by the minimum will give you a measure of the fluctuations. You can’t see the half-life easily, but you can get a quick approximation of this.
It may be a bit tricky to do, but you can measure the area under the curve at steady-state, as well as the area under the first dose. Dividing the former by the latter will give you a measure of the accumulation.
Alternatively, you can just compare the trough or minimum concentrations.
OK, now that we have got the graphs sorted out, we can look at how changing the primary parameters affect the graphs, beginning with Bioavailability. Reducing bioavailability essential just reduces the effective dose. Therefore, all the concentrations reduce proportionately. Half-life is unchanged since there are no changes to either volume of distribution or clearance. Consequently since time to reach steady state takes approximately 5 x half-lives, the time to steady state is unchanged.
Next, we will look at the effect of reducing the volume of distribution. In this single dose plot, which you have seen in an earlier video, you can see that as the volume is decreased, the C0, or concentration at zero time, proportionately rises. The half-life is reduced, but the area under the curve is unchanged.
You can see the same effects in a multiple dose situation. Here, when you reduce the volume of distribution, the area under the curve and steady state concentrations are unchanged. But the maximum is higher, whereas the minimum concentration is lower. Consequently, the fluctuations are increased. Reducing the volume also reduces the half-life and shortens the time to reach steady state.
Reducing clearance increases the area under the curve as well the half-life. It looks like the reverse of reducing bioavailability except that it additionally has an impact on the half-life.
In a multiple dose situation, everything is increased, except that because of the increased half-life, the fluctuations are decreased.
OK, this is probably all you need to get started. Don’t worry if you still have difficulty understanding or remembering. It will come with practice and repeated exposure. To help along with this, I have created several interactive graphs for you to explore. Please go to pharmacologytutorials.com “interactive graphs” and practice making changes to the primary pharmacokinetic parameters. Learn to recognize the effects of parameter changes, and try to visualize the impact these have on therapeutics.
Hope you enjoyed these series of videos. Subscribe to this channel so that you can have access to new videos that I create. Don’t go away as yet, as the coming videos will be covering Pharmacodynamics.
Bye for now!