Skip to 0 minutes and 15 secondsLet's consider the answer to this situation. First of all, we know that if the patient's being treated with a highly protein bound drug and if fu doubles at that instant, the unbound concentration is going to double. We also know that under those circumstances if the unbound concentration doubles the pharmacologic effect of the drug is also going to double and we know that if the fu doubles and it's a highly protein bound drug the clearance of the drug will double initially. Now the total concentration does not drop in half initially that does not occur until steady state is reestablished.

Skip to 0 minutes and 59 secondsAnd the volume does not double initially because it takes time for the volume to re-equilibrate as the drug is transported across membranes. So initially the unbound concentration will double the pharmacologic effect will double and the clearance will double but the total concentration and the volume do not change instantly as the fu or the fraction unbound changes Take-home points are that if the fu or the fraction unbound increases for a highly protein bound drug the actual unbound concentration will increase right away. If the unbound concentration increases then the pharmacologic effect increases instantly. So it will be temporary when the fraction unbound increases clearance will increase.

Skip to 1 minute and 51 secondsIf it's a highly protein bound drug but the volume will increase gradually because it takes time for the drug to redistribute across membranes. Likewise the total concentration will decrease but gradually after the clearance increases. Now here's a similar exercise let's walk through this one together. A patient is being treated with a highly protein bound drug. If the fraction unbound doubles and after steady state is reestablished what has changed from before? Now let's consider these. Four first the percent of unbound drug is doubled That's true. Once the percent whatever it is physiologically that has caused the fraction unbound to change is still going to be in effect.

Skip to 2 minutes and 41 secondsSo if the if the fraction unbound doubles from 10 percent 20 percent that will that will remain in effect.

Skip to 2 minutes and 51 secondsWe know also that the clearance of the drug will double. And it remains doubled simply because the fraction unbound remains double and it's the fraction unbound that impacts the clearance of a highly protein bound drug. And we also know that the volume will be doubled if we're talking about steady state conditions having been re-established. The unbound drug concentration is not doubled after steady state, remember the unbound concentration doubles initially but then it falls to its original level due to the doubling of the clearance. The pharmacologic effect of the drug is not doubled. Pharmacologic effect of the drug doubles immediately but it falls to what it was initially when the steady state conditions are re-established .

Skip to 3 minutes and 42 secondsNow this is a very significant point, because when the total concentration drops there is a tendency for those who are monitoring the patient to want to increase the dose but the dosing of the drug of a highly protein bound drug when the serum concentration has changed as a result of a change in protein binding what the factor that the dosing regimen should be based on is the unbound concentration not the total concentration, So even though total concentration dropped in half the fact that the unbound concentration does not change means the dosing regimen should not change. The total concentration does change it does drop in half. So 5 is also a false statement.

Skip to 4 minutes and 30 secondsSo the take-home points: if the fraction unbound doubles clearance doubles which causes the total concentration to drop in half at steady state volume also doubles gradually until steady state has re-established. When the fraction unbound doubled the concentration of unbound doubles right away but since the clearance doubled that concentration unbound decreases back to what it was originally. It's a very important point in in this type of a situation, and since the concentration unbound does not change at steady state once its reestablished the pharmacologic effect increases temporarily but goes back to what it was at steady state despite the drop in total serum concentration.

Skip to 5 minutes and 19 secondsNow here's a final brain exercise. If the clearance drops in half, answer this question.

Skip to 5 minutes and 30 secondsLet's take a look at what the answer would be.

Skip to 5 minutes and 35 secondsA is a true statement if clearance drops in half, k will drop in half that always holds true. k and clearance are intrinsically linked. Let's consider B. B is also true. The dosing interval will have to be doubled to keep the serum levels from changing if the clearance drops in half. And C is a false statement. If the clearance drops in half V or a volume of distribution is not directly impacted by changing clearance. There might be other factors going on physiologically the patient that effect the volume but it would not be a direct impact of the change in clearance. So the answer to this brain exercise is D. Both a and B are correct but C is not.

Skip to 6 minutes and 28 secondsSo let's summarize the key to predicting serum level changes is simply to remember that volume is proportional to dose and dosing interval or tau is inversely proportional to K. If you remember those two pairs and that one is a direct relationship and the other is an inverse relationship and you respond to changes in volume by considering whether to change the dose and you respond to changes in K by considering inverse changes in dosing interval. You can't go wrong. The only thing you also have to consider is that a change in volume will cause an inverse change in K. So a change in volume will necessitate for the change in dose and a change in dosing interval.

Skip to 7 minutes and 23 seconds Our next lesson is going to focus on evaluating a patient's renal function and hepatic function and how that relates the optimal drug dosing for the patient

What has changed before and after steady-state : Summary

Prof. Brown describes the whole process of the ups and downs in serum concentration (C), from the moment fu increases until steady-state is reestablished.

The final brain exercise is about clearance (CL) changing.

The key to predicting serum level changes is: Volume (V) is proportional to dose, and dosing interval (tau) is inversely proportional to k.

This is the final part of this week. Feel free to share some of the key points you have learned or any question you may have ! In the next chapter, we will focus on evaluating a patient’s renal and hepatic function.


Educator:

Prof. Daniel L. Brown


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This video is from the free online course:

Clinical Pharmacokinetics: Dosing and Monitoring

Taipei Medical University