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Indirect Link Model and Clockwise Hysteresis

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Now let me mention counterclockwise hysteresis because this is what happens to the indirect link PK/PD model. This is the concentration. This is the response. The concentration peaks at 4.5 hours as you can tell from this graph. But where the response peaks? It’s at much later. So this is a counterclockwise hysteresis. The effect peak lags behind the plasma concentration peaking, so this is a counterclockwise hysteresis. So what is hysteresis? Hysteresis is the dependence of a system not only on its current status but also on its past environment. So we have talked about the direct link model, the indirect link model and we also mentioned counterclockwise hysteresis. And here is another example of counterclockwise hysteresis.
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This is the measured serum concentration of insulin. And the Y-axis represents the hypoglycemic response, that is the effect. Look at the maximum measured serum concentration. And look at the effect or the peak effect. They are not quite correlated with each other.
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However, if we simulated or predicted an effected compartment concentration for insulin, then there’s a direct correlation between the effective compartment concentration and the hypoglycemic response. So this is also an example of counterclockwise hysteresis. Now since I mentioned counterclockwise hysteresis, let me take this opportunity also to mention clockwise hysteresis because that represents a very special phenomenon called tolerance. Now, this graph, the plasma concentration is actually the concentration of cocaine. And the Y-axis is the response or the intoxication level of cocaine. And as you can tell, when the first time the plasma concentration hit 100 ng/mL, this is where you see the maximum intoxication. Now the concentration continued to decline and by the time it returns to the original 100 ng/mL.
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The effect is at low and this is where or why the addicted patient or people would need another dose of cocaine. And this is called clockwise hysteresis and this is the basis that we use to explain tolerance. So first time, high is at 100 ng/mL but then when the concentration returns to 100 mark again, the effect is no longer there. And this is the basis of drug addiction. So this is clockwise hysteresis as opposed to counterclockwise hysteresis.
The indirect link model stipulates a separate effect site outside the central compartment, and the drug distribution to that compartment causes the delay of effect. On the other hand, the model could imply a drug tolerance, typical for addictive substances. In such case, the effect-conc plot exhibits a counterclockwise hysteresis.
The indirect link model is typically characterized by a delay of effect, as shown in the case of diclofenac The delayed response can also be manifested as a counterclockwise hysteresis, where the peak effect trails the peak plasma concentration. At least in one case, insulin appeared to follow the hysteresis pattern. Noteworthy is the intoxication of cocaine, where the peak effect occurs before the peak plasma concentration. This counterclockwise hysteresis happens as a result of drug tolerance. The intoxicating effect of cocaine peaks early and dwindles as the concentration in the plasma rises.
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Pharmacotherapy: Understanding Biotechnology Products

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