Indirect Link Model and Clockwise 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.