Pharmacokinetics
The pharmacokinetics of propofol has been evaluated by numerous
investigators after a wide range of doses as well as after continuous infusion,[6]
[13]
[14]
[15]
[16]
[17]
[18]
and it has been described by both two- and three-compartment models (see Table
10-1
). After a single bolus injection, whole blood propofol levels decrease
rapidly as a result of both redistribution and elimination ( Fig.
10-2
). The initial distribution half-life of propofol is 2 to 8 minutes.
[6]
[14]
In studies
using a two-compartment model, the elimination half-life has varied from 1.0 to 3
hours.[6]
[13]
[17]
[18]
Studies in which the disposition of propofol
was better described by a three-compartment model have yielded initial and slow distribution
half-lives of 1 to 8 minutes and 30 to 70 minutes and an elimination half-life of
4 to 23.5 hours.[14]
[15]
[16]
[18]
[43]
This longer elimination half-life is indicative of a deep compartment with limited
perfusion, which results in a slow return of propofol back to the central compartment.
Because of rapid clearance of propofol from the central compartment, the slow return
of propofol from this deep
compartment contributes little to the initial rapid decrease in propofol concentration.
The context-sensitive half-time of propofol ( Fig.
10-3
) for infusions lasting up to 8 hours is less than 40 minutes.[44]
Because the required decrease in concentration for awakening after anesthesia or
sedation with propofol is generally less than 50%, recovery from propofol remains
rapid even after prolonged infusions. The volume of distribution of the central
compartment has been calculated as 20 to 40 L, and the volume of distribution at
steady state has been calculated as 150 to 700 L.[6]
[13]
[14]
[15]
[16]
[17]
[18]
Clearance of propofol is extremely high—1.5 to 2.2 L/min.[6]
[13]
[14]
[15]
[16]
[17]
[18]
As discussed earlier, this clearance exceeds hepatic blood flow, and extrahepatic
metabolism has been demonstrated.[7]
[8]
The equilibrium constant (ke0
) for propofol based on suppression of the
electroencephalogram (EEG) (which is strongly correlated with loss of consciousness)
is about 0.3 min-1
, and the half-life of equilibrium between the plasma
concentration and the EEG effect is 2.5 minutes. The time to
Figure 10-2
Simulated time course of whole blood levels of propofol
after an induction dose of 2.0 mg/kg. Blood levels required for anesthesia during
surgery are 2 to 5 µg/mL, with awakening usually occurring at a blood level
lower than 1.5 µg/mL.
peak effect is 90 to 100 seconds.[45]
These values
are dependent on the actual pharmacokinetic set from which they are derived. The
onset of EEG effect with propofol seems to be independent of age. However, if the
measure of effect is systolic blood pressure, its onset is much slower (double the
time) and increases with age.[46]
For both EEG
and hemodynamic end points, the elderly show a concentration-dependent increasing
sensitivity.[46]
[47]
The pharmacokinetics of propofol may be altered by a variety of
factors (e.g., gender, weight, preexisting disease, age, concomitant medication).
[14]
[15]
[18]
[48]
[49]
Propofol
may impair its own clearance by decreasing hepatic blood flow.[50]
Of clinical significance is that propofol may alter its own intercompartmental clearance
because of its effects on cardiac output. Changes in cardiac output alter
Figure 10-3
The context-sensitive half-times for commonly used intravenous
anesthetic drugs are displayed. The context-sensitive half-time is the time for
the plasma level of the drug to drop 50% after cessation of infusion. The duration
of infusion is plotted on the horizontal axis. Note that the rapidity with which
the drug level drops is directly related to the time of infusion (i.e., the longer
the drug is infused, the longer the half-time). Also note that etomidate, propofol,
and ketamine have significantly shorter half-times than thiopental and diazepam do,
which makes them more suitable for prolonged infusion.
propofol concentrations after a bolus dose and during constant infusion. Increasing
cardiac output leads to a decrease in propofol plasma concentration and vice versa.
[51]
[52]
In a
hemorrhagic
shock model, propofol concentrations increase up to 20% until uncompensated shock
occurs, at which point a rapid and marked increase in propofol concentration occurs.
[53]
Women have a higher volume of distribution
and higher clearance rates, but the elimination half-life is similar for males and
females.[14]
[18]
The elderly have decreased clearance rates but a smaller central compartment volume.
[15]
[18]
In addition,
patients presenting for coronary artery bypass surgery seem to have different pharmacokinetic
parameters than other adult populations do. When a patient is placed on a cardiopulmonary
bypass machine, the resulting increase in central volume and initial clearance necessitates
higher initial infusion rates to maintain the same propofol plasma concentration.
[54]
Children have a larger central compartment
volume (50%) and more rapid clearance (25%).[55]
In children older than 3 years, volumes and clearances should be adjusted by weight.
[56]
Children younger than 3 years also demonstrate
weight-proportional pharmacokinetic parameters, but with greater central compartment
and systemic clearance values than in adults or older children.[56]
This finding explains the higher dosing requirements in this age group.[57]
Hepatic disease appears to result in larger steady-state and central compartment
volumes; clearance is unchanged, but the elimination half-life is slightly prolonged.
[48]
The effect of fentanyl administration on the
pharmacokinetic parameters of propofol is controversial. Some studies suggest that
fentanyl may reduce intercompartmental and total-body clearance rates, as well as
volumes of distribution.[58]
When propofol was
administered with alfentanil at similar infusion rates, the measured propofol concentrations
were 22% greater than when propofol was administered alone.[59]
A separate study found that fentanyl did not alter propofol pharmacokinetics after
a single dose of both drugs.[60]
Some of these
differences in propofol pharmacokinetics when given with an opioid may be explained
by studies in cats in which it was shown that pulmonary uptake of propofol is reduced
by 30% when propofol is administered immediately after fentanyl, but not if administered
3 minutes later.[61]
In addition, in vitro studies
on human hepatocytes have demonstrated that propofol inhibits the enzymatic degradation
of both sufentanil and alfentanil in a dose-dependent manner.[62]
Propofol kinetics is unaltered by renal disease.[49]
