Implications of the Effect-Time relationship

The relationship as plotted in the earlier post assumes the concentration move from an initial position when it associated with maximum pharmacological effect.

In the first phase, even when concentrations are declining at an exponential rate, effect hardly changes. Not until the effect reaches about 85% of Emax does the rate of decrease in the effect assumes some linearity with respect to time. Between 85% and 15% of Emax, the rate of change of effect is linear when the concentrations are expected to be falling exponentially. Only when the effect is less than 15% of Emax is the rate of decrease exponential. Only then is the rate of change of effect parallel to the change in concentrations.

Implications:

a] When using plasma concentrations as a surrogate for pharmacological effect, a linear relationship between plasma concentration and effect is only seen at low effect levels (less than 15% Emax)

b] At toxicological levels (>85% Emax) as might occur in poisonings, concentrations may fall exponentially with any improve in patient's condition. Some drugs are actually dosed under Emax or near Emax conditions. In such situations one should expect that fluctuations in concentrations, or small adjustments to doses will not be associated with any significant effect changes.

c] For most drugs, presumably the concentrations operate somewhere between 85-15% of Emax. Under such conditions, the effect falls linearly with time, but it is important to note that the effects fall linearly even though concentrations are falling exponentially.

d] Few drugs operate throughout the entire range of concentration-effect curve, hence the effect time relationship is entirely dependent on the concentrations ranges the drug exhibits under a certain dosing regiment. It is important to know where any drug is operating to appreciate how changes of concentrations over time will determine effect variability.