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