Factors of
influence on PK-PD of IV anaesthetics
Tomiei Kazama, MD
Department
of Anesthesiology, National Defense Medical College
3-2
Namiki, Tokorozawa, Saitama, Japan 359-8513
The compartment pharmacokinetic model
provides useful information with respect to targeting blood concentrations for
long-term infusion if we enter the body weight. However, factors affecting
long-term or steady-state drug effects might be qualitatively and quantitatively
different from the determinants of an acute drug effect such as induction of
anesthesia because the pharmacokinetic model is based on several assumptions.
These include: 1) the pharmacokinetics are not stationary (i.e., volumes and
clearances vary over time because of the cardiovascular depression with
propofol), 2) the parameters of pharmacokinetic model vary depends on
covariates of patient characteristics, 3) residual drug volume exists
especially in high-speed drug administration., 4) instantaneous mixing does not
occur actually in the central compartment.
Various factors
of patient characteristics, administration speed, and pharmacokinetic model
assumption were considered to increase the discrepancy between real effect and
predicted effect-site concentration. The discrepancy will be remarkably large
in anesthesia induction because of wide range of propofol administration rates
from 0 to 300 or 600 ml/h using in anesthesia induction with TCI.
If concentration-effect relation of a drug is
stable over time, an effect parameter derived from the processed EEG signal
could be used to control the propofol infusion rate in order to maintain
hypnosis, sedation, or induction. However, the relation between blood propofol
concentration and the effect is not stable in repeated propofol infusions
(non-steady sate condition). ( 1)
The prediction of induction dose from
physiologic characteristics of patients provides reasonable accuracy at both
high and low administration rates of propofol. On the other hand, a previously
reported pharmacokinetic model that incorporated patient characteristics
provides the same accurate induction dose only at a low rate.
In high
administration rate generally using in induction, distribution of drugs beyond
the intravascular space after rapid i.v. administration begins before
intravascular mixing is complete, making traditional pharmacokinetic models
inadequate to describe the distribution of drugs with a rapid onset of effect
during equilibration with their sites of action.
The keO has been
generally estimated from the electroencephalographic (EEG) response to
propofol. However, PK-PD modeling of EEG or BIS value in which the brain is
considered an effect compartment linearly linked to the arterial blood
concentration appears to be an oversimplification of the complex processes.
Moreover, keO will be affected with propofol administration rate.
At last, pulmonary uptake of propofol,
cerebral blood flow will affect the propofol blood concentration and
distribution to the brain.
High administration
dose of propofol decrease cerebral blood flow as well as hemodynamic depression
and it also will decrease the propofol distribution to the brain tissue that
results in low keO.(2) However, these parameters will influence propofol
distribution to brain in a complicated manner.
References
1. Kuizenga K. et al. Anesthesiology 2001;
95:607-15
2. Ludbrook GL. et al. Anesthesiology 2002;
97:1363-70