WEBVTT
Kind: captions
Language: en
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I've provided two charts that summarize.
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This first one summarizes dose and volume changes.
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Now I don't I don't expect you to memorize
what's in these charts by any means.
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These are meant to illustrate the relationships
between all the variables we've been discussing
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and you should be able to go through this
chart and understand why certain combinations
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result in an increase or a decrease.
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What I'd like to point out is the no change.
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Now we know that C average steady state is not affected by volume
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whether the volume increases or decreases
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there's no impact on C average steady state because that depends on dose over tau divided by clearance.
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Likewise, area under the curve is not affected by changes in volume either increasing or decreasing
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when we consider C Max minus C min
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if the dose and volume both change proportionally that they cancel each other out
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there will be no change on the in the value of C Max minus C min.
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This chart compares the impact of both the dosing interval
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and the clearance through a series of variables
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and we can see that as the dosing interval changes or k
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or also clearance changes we can see increases in decreases
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in e to the minus K tau C maxi C min C average steady state increases in
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tau or k have no impact whatsoever on C max minus C min
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the only two variables that impact see max minus C min are dose and volume
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Area under the curve has not changed in any way by changing the dosing interval
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because it's the area under the curve
between those two doses
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and that depends only on the dose divided by the clearance
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so area of the curve does not change in response to a dosing interval change
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and if the tau and the K both change inversely,
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essentially they they cancel each other out with only one exception
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and that is area under the curve.
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If we change both tau and K inversely only the the K affects a change in area under the curve
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so however the the K changes you would expect a corresponding change in area under the curve
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but again you don't need to memorize this chart that would be self-defeating.
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What's important about this chart is you can read any cell within the chart
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that consider the variables represented within that cell
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and make sure you understand why the variable would increase or decrease or stay the same.
00:03:20.080 --> 00:03:25.360
Now let's consider the impact of protein binding on serum concentrations.
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If we increase the fraction unbound from point one to point two
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what we see is an increase in the unbound concentration
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from point zero two five milligrams per liter to zero point zero five milligrams per liter
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Now what I represented here graphically the blue and the yellow combined in the rectangle
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represents the total serum concentration of two milligrams per liter.
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So instantaneously when the fraction unbound increases from point one to point two
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the total concentration doesn't change
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but because the fraction unbound double the concentration unbound would double
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However because the fraction the increase in fraction unbound increases the clearance of the drug
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then when steady state is reestablished under
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this new higher clearance the total concentration
is only going to be half as much
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the total concentration would drop from two milligrams
per liter down to one milligrams per liter
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and the fact that the fraction unbound is
now twenty percent rather than ten percent
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the unbound concentration is actually going
to be going to be the same as it was initially
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0.025 milligrams per liter.
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We can represent this graphically as shown
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The concentration unbound is the line on the bottom and the total concentration is the line on the top
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Now in the beginning situation we see that the fraction unbound is 10% concentration is 0.025 unbound
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and the total concentration is 2 milligrams per liter
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The point at which the fraction unbound doubles from point one to point two
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We see that the concentration unbound doubled because of the change in fraction unbound
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but initially the total serum concentration did not change at indication number two
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When steady state is reestablished in number three
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we still have the doubling of the fraction
unbound that hasn't changed
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What we see now is because the clearance doubled at point two
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the concentration of both the total concentration and the unbound concentrate from that point
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would be cut in halfă„ˇ
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The difference is that we started at the actual total concentration
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so the doubling of clearance would cause the total concentration to drop down to half of what it was
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from two milligrams per liter to one milligram per liter.
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But since the unbound concentration initially doubled
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then the doubling of the clearance would cause that concentration to fall on half
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which actually takes it back to what it was originally at 0.025 milligrams per liter.
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Now let's consider what happens in terms of the pharmacologic effects during this process
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At 0.1 the the original total concentration and the original unbound concentration
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at point two we have the doubling of the fraction unbound
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and we can see the concentration of the unbound drug doubling
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the concentration of the total drug has not yet begun to change at point two.
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So we have at point two is a temporary increase in the pharmacologic effect of the drug
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because the unbound concentration has doubled.
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However at point 3 when steady state has reestablished
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the unbound concentration because of the increased clearance has now returned to what it was initially.
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So in this situation when we have a highly protein bound drug
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then that demonstrates an increase in the fraction unbound
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what will happen is the therapeutic effect the pharmacologic effect of the drug will initially increase
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but it's only temporary until steady state conditions are re-established
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because at that point the unbound concentration which is what determines the pharmacologic effect of the drug
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will have returned to what it was initially.
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Let's consider another exercise.
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The patient is being treated with a highly protein bound drug
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if the fraction unbound doubles
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then at that instant before steady state is reestablished what has changed?