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The dose-response relationship can be divided into three parts: the relationship between administered dose and plasma concentration
(the pharmacokinetic phase), the relationship between effect organ concentration and clinical effect (the pharmacodynamic phase) and
the coupling between pharmacokinetics and dynamics. The ultimate goal when administering a particular dose of a drug is to obtain the
desired clinical effect, for which a specific therapeutic concentration of the drug at the site of action (the receptor) is necessary.
Fig. 1: Schematic representation of the pharmacokinetic and dynamic processes determining the relationship between administered dose and
resulting effect intensity of a drug. Pharmacokinetic factors such as distribution, metabolism, and/or excretion determine the relationship between
drug dose and drug-concentration in the plasma and bio-phase (effect-site). In the bio-phase the drug interacts with the receptor resulting in the
pharmacological effect.
1
Until recently, when intravenous anaesthetic agents were used for induction or maintenance of anaesthesia, they were administered either
manually (by hand) or by simple infusion pumps (the anaesthetist calculated the infusion according to the body weight of the patient).
Inline measurement of concentrations is not possible, and the polyexponential equations required to predict the concentrations requires
vast computer processing power. Based on the pioneering work of Kruger-Thiemer
2
and Schwilden et al.
3
, the TCI concept was developed
during the 1980’s and early 1990’s, as advances in computer technology made inline predictions of drug concentrations feasible.
The pharmacokinetic behaviour of most anaesthetic drugs can be described mathematically with a 3-compartment model: usually a
central compartment (V1), a vessel-rich compartment (V2) and a vessel-poor compartment (V3) are described. Transfer of drug between
different compartments (distribution) is described by rate constants (k
12
, k
21
, k
31
and k
13
) or clearances. Drug metabolism is described by the
rate constant k
10
(
Fig. 2
). The aim of TCI techniques is to use pharmacokinetic modelling to calculate the infusion rates required to achieve
a desired plasma concentration. Thus, instead of specifying an infusion rate, the user specifies a “target” concentration, based on clinical
judgement. When a concentration in the plasma compartment is targeted, this is called “open-loop plasma targeted TCI”. When a certain
concentration at the effect compartment is targeted, then this is called “open-loop effect-site targeted TCI”.
Fig. 2: Schematic representation of the three compartment model used for target-controlled infusions.
For anaesthetic agents the effect-site (or bio-phase) is not the plasma
4
but the brain, where concentrations cannot be directly measured.
Until the early 1990’s it was considered that blood-brain equilibration was virtually instantaneous. Early TCI systems were thus all plasma-
targeted. For many drugs the relationship between plasma concentration and clinical effect was described, usually in terms of the Cp50 or
Cp95 (the concentrations required to elicit a specified clinical effect in 50 or 95% of patients respectively). For an example see Ausems et
al.
5
During the 1990’s it was increasingly appreciated that after a change in plasma concentration there is a temporal delay in equilibration
between the plasma and effect-site concentrations. The clinical effect changes in parallel with the effect-site concentration, and so for most
drugs the rate of drug transfer into and from the site of action can be characterized by the time-course of drug effect
6,7
. This means that the
effect can be transferred to concentrations, thereby resulting in a quantitative approach. The concentration at the site of action is called
“the effect-site concentration” and the corresponding compartment
8
(see Fig. 3) is called “the effect-site compartment”. Because the actual
amount of drug entering the brain is very small, the effect-site compartment can be regarded as having no volume, the rate constant k
1e
can
be ignored and the rate constant k
eo
can be used to describe the rate of equilibration between the plasma and effect-site compartments.
Knowledge of the k
eo
for various agents has made targeting of the effect-site possible. With effect-site targeting the TCI system first
calculates the necessary plasma concentration profile required to achieve the effect-site target as rapidly as possible, and then calculates
the infusion rates required to achieve that plasma concentration profile (Fig 3). Effect Site vs Plasma Concentration will generate a larger
induction dose followed by a pause in the infusion to allow plasma to equilibrate with effect site concentration.
Fig. 3: Schematic representation of the concentration-effect relationship.
TCI Overview