Context-sensitive half-time
Context-sensitive half-time refers to the time it takes for drug concentrations to fall by 50% in the plasma following termination of a period of drug administration at a constant rate – usually by infusion – under circumstances where the half-time is impacted by the duration of the infusion.
The terminal half-life for elimination refers to loss of drug from the plasma after an infusion period sufficiently long to allow drug to equilibrate fully between central and peripheral compartments. At that point, the time taken for drug concentration to fall by 50% would be expected to remain fairly constant, regardless of how much longer the infusion was continued before termination.
If the period of infusion is not long enough to allow full equilibration of drug between plasma and tissue compartments, terminating the infusion will result in a fall in the concentration of drug in the plasma with a half-time shorter than the terminal half-life of elimination. The shorter the period of infusion prior to infusion being terminated, the shorter the subsequent half-time for drug loss from the plasma. This phenomenon is what is referred to as context-sensitive half-time. As infusion times become progressively longer, the context-sensitive half-time also increases, until eventually equilibrium is reached between compartments, and the half-time is no longer context-sensitive, but rather is equal to the terminal half-life of elimination.
The reason for the increasing context-sensitive half-time as the duration of infusion increases is that longer infusions result in more (slow) distribution of drug from the central compartment to the tissue compartment(s), and thus larger proportions of the drug present in the body are associated with shallow or deep tissue compartments. As such, as infusion time increases, marginal increases in drug concentrations observed in the central compartment are accompanied by more significant increases in drug concentrations in the tissue compartment(s). In other words, the “pre-steady state” apparent volume of distribution increases with increasing infusion time, until equilibrium is reached. When infusions are then terminated, loss of drug from the central compartment by renal or hepatic clearance is offset to increasing degrees by slow redistribution of drug from the tissue compartment(s) back into the central compartment.
Clinically, this is relevant in situations (a) where the duration of treatment is typically shorter, and possibly much shorter, than the time taken for the drug to equilibrate between all compartments, (b) drug administration usually ends prior to full distribution equilibrium being reached, and (c) the drug target is within a central or shallow tissue compartment such that a patient’s recovery time from the drug’s effects becomes longer with extended administration times because of increasing drug levels in one or more compartments deeper than that in which the target organ exists.
Click here to watch a demonstration of context-sensitive half-time for the general anaesthetic, propofol, where the target organ (brain) is present in the central compartment.
