Page 465 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 25 General Anesthetics 451

short-duration general anesthesia in locations outside the operating 100
room (eg, interventional radiology suites, emergency department; see Blood
Box: Sedation & Monitored Anesthesia Care, earlier). 80 Lean tissues
Propofol (2,6-diisopropylphenol) is an alkyl phenol with hyp-
notic properties that is chemically distinct from other groups of Brain and
viscera
intravenous anesthetics (Figure 25–6). Because of its poor solubility 60
in water, it is formulated as an emulsion containing 10% soybean Percent of dose
oil, 2.25% glycerol, and 1.2% lecithin, the major component of 40
the egg yolk phosphatide fraction. Hence, susceptible patients may
experience allergic reactions. The solution appears milky white and Fat
slightly viscous, has a pH of approximately 7, and has a propofol 20
concentration of 1% (10 mg/mL). In some countries, a 2% formu-
lation is available. Although retardants of bacterial growth are added 0 0.125 0.5 1 4 16 64 256
to the formulations, solutions should be used as soon as possible
(unused drug must be discarded 12 hours after opening the vial), Time (min)
and proper sterile technique is essential. The addition of metabisul- FIGURE 25–7 Redistribution of thiopental after an intravenous
fite in one of the formulations has raised concern regarding its use in bolus administration. The redistribution curves for bolus adminis-
patients with reactive airway disease (eg, asthma) or sulfite allergies. tration of other intravenous anesthetics are similar, explaining the
The presumed mechanism of action of propofol is through observation that recovery times are the same despite remarkable dif-
potentiation of the chloride current mediated through the GABA ferences in metabolism. Note that the time axis is not linear.
A
receptor complex.

Pharmacokinetics movement are occasionally observed during induction of anes-
thesia. These effects may resemble seizure activity; however,
Propofol is rapidly metabolized in the liver; the resulting water- most studies support an anticonvulsant effect of propofol, and
soluble compounds are presumed to be inactive and are excreted the drug may be safely administered to patients with seizure
through the kidneys. Plasma clearance is high and exceeds hepatic disorders. Propofol decreases cerebral blood flow and the
blood flow, indicating the importance of extrahepatic metabolism, cerebral metabolic rate for oxygen (CMRO 2 ), which decreases
which presumably occurs in the lungs and may account for the intracranial pressure (ICP) and intraocular pressure; the mag-
elimination of up to 30% of a bolus dose of the drug (Table 25–2). nitude of these changes is comparable to that of thiopental.
The recovery from propofol is more complete, with less “hangover” Although propofol can produce a desired decrease in ICP, the
than that observed with thiopental, likely due to the high plasma combination of reduced cerebral blood flow and reduced mean
clearance. However, as with other intravenous drugs, transfer of arterial pressure due to peripheral vasodilation can critically
propofol from the plasma (central) compartment and the associated decrease cerebral perfusion pressure.
termination of drug effect after a single bolus dose are mainly the When administered in large doses, propofol produces burst
result of redistribution from highly perfused (brain) to less-well- suppression in the EEG, an end point that has been used when
perfused (skeletal muscle) compartments (Figure 25–7). As with
other intravenous agents, awakening after an induction dose of
propofol usually occurs within 8–10 minutes. The kinetics of 150
propofol (and other intravenous anesthetics) after a single bolus
dose or continuous infusion are best described by means of a three-
compartment model. Such models have been used as the basis for Thiopental
developing systems of target-controlled infusions. 100
The context-sensitive half-time of a drug describes the elimi-
nation half-time after discontinuation of a continuous infusion Context-sensitive half-time (min) Midazolam
as a function of the duration of the infusion. It is an important 50 Ketamine
parameter in assessing the suitability of a drug for use as main- Propofol
tenance anesthetic. The context-sensitive half-time of propofol Etomidate
is brief, even after a prolonged infusion, and therefore, recovery 0
occurs relatively promptly (Figure 25–8). 0 1 2 3 4 5 6 7 8 9
Infusion duration (h)
Organ System Effects

A. CNS Effects FIGURE 25–8 The context-sensitive half-time of common intra-
venous anesthetics. Even after a prolonged infusion, the half-time
Propofol acts as hypnotic but does not have analgesic proper- of propofol is relatively short, which makes propofol the preferred
ties. Although the drug leads to a general suppression of CNS choice for intravenous anesthesia. Ketamine and etomidate have
activity, excitatory effects such as twitching or spontaneous similar characteristics, but their use is limited by other effects.