PHARMACODYNAMIC CONSIDERATIONS
The Biophase
Although the plasma concentration after an intravenous bolus peaks
nearly instantaneously, no anesthesiologist would push an intravenous bolus of a
hypnotic drug and immediately intubate the patient's trachea. The reason, of course,
is that although the plasma concentration peaks almost instantly, additional time
is required for the drug concentration in the brain to rise and induce unconsciousness.
This delay between peak plasma concentration and peak concentration in the brain
is called hysteresis. Hysteresis is the clinical
manifestation of the fact that the plasma is not the site of anesthetic action, only
the mechanism of transport. Drugs exert their pharmacologic effect in the "biophase,"
which is also called the "effect site." Physically, the biophase is the immediate
milieu in which the drug acts on the body, including membranes, receptors, and enzymes.
The concentration of drug in the biophase cannot be measured for
two reasons. First, it is usually inaccessible, at least in human subjects. Second,
even if we could take tissue samples, the drug concentration in the microscopic environment
of the receptive molecules would not be the same as the concentration measured in,
for example, homogenated brain. Although it is not possible to actually measure
drug concentrations in the biophase, by the use of rapid measures of drug effect
we can characterize the time course of drug effect. Knowing the time course of drug
effect, we can characterize the rate of drug flow in and out of the biophase (or
"effect site") by the use of mathematical models,[25]
[26]
as well as the apparent drug concentration
in
the biophase, in terms of the steady-state plasma concentration that would produce
the same effect.
Measures of effect used to characterize the time course of drug
between plasma and the biophase will vary with the drug being evaluated. For neuromuscular
blockers, the twitch response is an ideal measure of effect. For opioids and hypnotics,
the measure of effect is more challenging. The desired effect for opioids is analgesia,
which is a subjective measure that is difficult to monitor and quantify moment by
moment. Similarly for hypnotics, until recently there has been no validated monitor
of drug effect. For these reasons investigators have turned to the EEG as an objective
measure of opioid and hypnotic drug effect. If the EEG did not measure the clinically
desired effect of opioids and hypnotics, it was assumed that changes in the EEG would
at least reflect the time course of clinical effects. Thus, the time course for
equilibration between plasma and the biophase for opioids and hypnotics has largely
been defined by using the EEG. The validity of this approach has been confirmed
in several studies. Glass and colleagues measured the blood concentration of remifentanil
and its analgesic response in volunteers.[27]
The
time course for equilibration between plasma and the biophase calculated in this
study was essentially identical to the time course determined by using the spectral
edge of the EEG as the measure of effect.[28]
Ludbrook
and associates measured propofol concentrations in the carotid artery and jugular
bulb to establish propofol movement into and equilibration with the brain.[29]
They measured the bispectral index simultaneously and found close correlation between
concentrations in the brain (calculated by using mass balance) and changes in the
bispectral index.
