Irrelevance of the Terminal Half-Life
Although the term half-life has
been popular and often used in pharmacokinetics, it is not a fundamental pharmacokinetic
parameter. Because the value of half-life is dependent on the primary pharmacokinetic
parameters volume of distribution and clearance, half-life is not independently influenced
by changes in patient physiologic states.[295]
Although the terminal half-life from multicompartmental models has traditionally
been the pharmacokinetic parameter relied on for predictions regarding the duration
of opioid effect, it can be grossly misleading. Distribution volumes and clearances
can be similarly confusing to apply clinically.
For drugs described by multicompartmental models, numerous half-lives
must be considered, along with a host of other parameters. Each half-life contributes
variably to the prediction of drug concentration at a given time after drug administration.
[324]
For most opioids, the terminal elimination
half-life has very minimal impact on the overall decline in drug concentration within
the range of clinical significance, because most of the concentration decrease is
accounted for by other components of the model. The primary shortcoming of half-lives
in opioid pharmacology is that they fail to account for the important influence of
distribution processes on drug disposition ( Fig.
11-15
).[325]
For sufentanil, the volume of one of the peripheral compartments
is large, and the rate of transfer into it from the central compartment is slow.
If the two compartments
Figure 11-15
Hydraulic model analogy of three-compartment pharmacokinetic
model. The height, hi
(t), represents the water level in each compartment.
Each bucket is characterized by a cylindrical area, CAi
, and the pipes
connecting the buckets to each other or to the outside world are characterized by
a conductance, Gi
. Water enters bucket 1 at the rate r(t) and leaks irreversibly
through G1
. (From Hughes MA, Glass PS, Jacobs JR: Context-sensitive
half-time in multicompartment pharmacokinetic models for intravenous anesthetic drugs.
Anesthesiology 76:334–341, 1992.)
have reached equilibrium, the peripheral compartment serves as a reservoir of sufentanil
that reenters the central compartment after termination of an infusion, thus impeding
the decrease in sufentanil concentration produced by elimination from the central
compartment.
